FORTHCOMING ISSUES

November 2008 Emerging Infectious Diseases Mary Wilson, MD, Guest Editor January 2009 Osteoarthritis David Hunter, MD, Guest Editor March 2009 Common Neurological Conditions Randolph W. Evans, MD, Guest Editor

RECENT ISSUES
July 2008 Common Hepatic Emergencies Mitchell S. Cappell, MD, PhD, Guest Editor May 2008 Common Gastrointestinal Emergencies Mitchell S. Cappell, MD, PhD, Guest Editor March 2008 Hospital Medicine Scott A. Flanders, MD, Vikas I. Parekh, MD, and Lakshmi Halasyamani, MD, Guest Editors January 2008 Atrial Fibrillation Ranjan K. Thakur, MD, and Andrea Natale, MD, FACC, FHRS, Guest Editors

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WOMENS HEALTH

CONTENTS

Preface Tony Ogburn and Carolyn Voss Barriers to Womens Health: Why Is It So Hard for Women to Stay Healthy? Tony Ogburn, Carolyn Voss, and Eve Espey
Womens health care has made great strides in the past two decades. The recognition that women have different health care needs than men has enabled changes to take place in clinical care, research, and education. However, much remains to be done. Providing health care coverage to all women must be a high priority. Research must address the differences between men and women and how they respond to disease and treatment. The physician workforce needs to be expanded; physicians should be well trained to provide comprehensive health care to women. Strategies, such as used in Comprehensive Centers of Womens Health and womens health residencies, can improve education and increase the number of women in academia.

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Preventive Health for Women: Screening and Immunizations Jennifer R. Zebrack and Keith W. Brown
Womens preventive health issues are frequently encountered in the outpatient setting. Many general internists feel uncomfortable meeting the needs of women due to a general lack of knowledge of womens health and inadequate training in the evaluation of femalespecic care. In this article, the authors summarize evidence-based guidelines for preventive health and immunizations for women.

1011

Contraception: What Every Internist Should Know Eve Espey, Tony Ogburn, and Dana Fotieo
The human costs of unintended pregnancyabortion and parenting under difcult circumstancesare high. For this reason, all physicians who treat female patients should be knowledgeable

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about the basics of contraceptionboth its practical uses and its public health impact. This knowledge will make physicians, including internists, better able to counsel and provide contraceptives for individual patients and to advocate for availability and access. This article discusses the problem and determinants of unintended pregnancy and reviews contraceptive methods.

Preventing Cervical Cancer: The Pap Test and the HPV Vaccine Alan G. Waxman and Meggan M. Zsemlye
Women look to their internists and other primary care physicians to provide preventive health care. Periodic Pap tests are as much a part of a womans ongoing health care as periodic lipid assessments, mammograms, screening for colon cancer, or any of the other recommended screening assessments. This article provides primary care physicians with the information needed to perform Pap tests at the appropriate intervals, or if not set up to do Pap tests themselves, to make the appropriate referrals. Also provided is the necessary information to counsel women with abnormal Pap tests who may need colposcopy or other follow-up evaluation. Finally, the role of the HPV vaccine in the prevention of cervical cancer is summarized.

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Sexually Transmitted Infections and Pelvic Inammatory Disease in Women Bruce G. Trigg, Peter R. Kerndt, and Getahun Aynalem
Sexually transmitted infections (STIs) are an important public health challenge in the United States. Primary care clinicians can contribute to decreasing these largely preventable causes of morbidity and mortality by integrating routine screening, testing, counseling, treatment, and partner management of STIs into their practice. Newer tests for chlamydia and gonorrhea that can be performed on urine specimens allow screening without a pelvic examination. The most recent edition of the Centers for Disease Control and Prevention sexually transmitted disease treatment guidelines provides an evidence-based, reliable, and convenient set of recommendations for treating and caring for patients who have STIs.

1083

Breast Disease: Benign and Malignant Angela L.W. Meisner, M. Houman Fekrazad, and Melanie E. Royce
Breast diseases, both benign and malignant, are common. Typically, young women present with more benign pathologies; however, breast malignancies can occur in young women, especially in those harboring mutations in the BRCA genes, other inherited genetic syndromes associated with increased risk of breast cancer, or familial predisposition for breast cancer. In all women aged 40 and over presenting with abnormalities of the breast, a primary breast cancer should be ruled out because it is the leading cancer among women in developed countries.
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Pelvic Masses Spencer P. Barney, Carolyn Y. Muller, and Karen D. Bradshaw

Pelvic masses develop commonly in women of all ages and states of health. Despite the variety of masses that exist, general guidelines for diagnosis and management allow most masses to be treated in a generalist setting. This article is intended to guide non-obstetric and non-gynecologic physicians through diagnosis and treatment of nonmalignant pelvic masses. It includes information on physical examination, appropriate imaging techniques, laboratory tests, and variations in treatment for adolescents and pre- and postmenopausal women. It also addresses referral guidelines for suspected malignant masses.

1143

Basic Infertility Including Polycystic Ovary Syndrome Maryse Brassard, Youssef AinMelk, and Jean-Patrice Baillargeon
Infertility in women has many possible causes and must be approached systematically. The most common cause of medically treatable infertility is the polycystic ovary syndrome (PCOS). This syndrome is common in young women and is the cause of anovulatory infertility in 70% of cases. It is therefore an important condition to screen and manage in primary care medical settings. In the past 10 years, insulin sensitization with weight loss or metformin has been shown to be a safe and effective treatment for PCOS infertility that eliminates the risk of multiple pregnancy and may reduce the risk of early pregnancy loss as compared with ovulation-inductor drugs. The authors believe metformin should be considered as rst-line therapy because it has the advantage to allow for normal single ovulation, for reduced early pregnancy loss, and, most importantly, lifestyle modications and weight loss before pregnancy. Losing weight not only improves fertility but also reduces adverse pregnancy outcomes associated with obesity.

1163

Medical Issues from Preconception Through Delivery: A Roadmap for the Internist Michael P. Carson and Deborah Ehrenthal
The age of the pregnant population and the number of pregnant women with medical issues are increasing. It is widely recognized that internists have the unique opportunity to identify potential pregnancy issues and address them before a problem arises. Therefore, its important that we become aware of how to approach these issues. In addition to addressing medical issues in a currently pregnant woman, doctors also have the opportunity to identify issues that occurred during a prior pregnancy, such as gestational diabetes, preeclampsia, or pregnancy loss, and to decrease the risk of complications in future pregnancies. The goal of this article is to provide a roadmap to practicing internists so they will incorporate pregnancy planning into their everyday care plans. The approach is similar to that used when performing a preoperative risk assessment: We want to optimize our patients medically for pregnancy.

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Prescribing Medications Safely During Pregnancy William F. Rayburn and Adanna C. Amanze
A large body of information about medications prescribed during pregnancy is readily available to internists and patients either online or through books and medical journals. Much of the evidence about many prescribed drugs is either anecdotal or presented with sufcient warnings about its use during pregnancy. This article discusses specic medications to set the risks and benets into a more proper perspective, thereby alleviating certain fears and, when necessary, improving compliance.

1227

Domestic Violence and Rape Julianne S. Toohey

No compilation of womens health care is complete without confronting domestic violence and sexual assault. Long recognized as a health care and physician issue, intimate partner violence continues to be one of the most frequent causes for injury and death to women in the United States and worldwide. According to the Commonwealth Fund survey in 1998, 31% of women reported either physical or sexual abuse from a husband or boyfriend. One in ve American women also reported being raped during their lifetime. Careful assessment and universal screening are important tools for the primary care physician.

1239

Menopause and the Menopausal Transition Kirsten J. Lund

Menopause and the menopausal transition present unique preventive health and quality-of-life challenges for women. The number of patients in the menopausal age group is increasing and represents a signicant portion of the population. Care of the menopausal patient can be challenging for the caregiver. This chapter reviews the major health care challenges as well as evaluation and treatment of common quality-of-life issues for menopausal patients.

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Urinary Incontinence and Pelvic Organ Prolapse: Diagnosis and Treatment for the Primary Care Physician Husam Abed and Rebecca G. Rogers
This article outlines a simplied approach to diagnosis and treatment of women with urinary incontinence or pelvic organ prolapse that can be used by primary care physicians to identify patients with these conditions and initiate treatment for basic problems.

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CONTENTS

Med Clin N Am 92 (2008) xiiixv

Preface

Tony Ogburn, MD Carolyn Voss, MD Guest Editors

The traditional concept of womens health encompassed only those issues unique to womendpregnancy and childbirth, menstrual disorders, gynecologic cancers, and the menopause, to name a few. Indeed, the specialty of Obstetrics and Gynecology evolved to improve the care of women with such complaints, resulting in major advances in longevity and quality of life for women. Pregnancy and childbirth are safer than imaginable a hundred years ago. Cervical cancer is largely preventable in the United States. Women are able to control their fertility and plan their pregnancies. Despite dramatic improvements, the care of women has suered from the misconception that all traditional womens health issues should be treated by a specialist in womens health, along with the assumption that other medical issues will be handled by other providers. As a result, womens health care is often fragmented. An internist may care for a womans hypertension, while the obstetrician gynecologist performs the Pap smear, discusses family planning, and schedules the mammogram. Such fragmentation has had a second unintended consequence: treatment decisions for medical conditions unrelated to gender have long been based on information gathered from the study of men. Research, medical education, and the clinical practice of womens health traditionally focused on the limited areas noted above with little regard for the uniqueness of women in all aspects of health.

0025-7125/08/$ - see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2008.07.006 medical.theclinics.com

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Fortunately, the past two decades have witnessed a change in the care of women. In addition to great strides in traditional areas of womens health, the broader needs of women have been increasingly recognized. Women are more often included as subjects of clinical trials, womens health research has received increased funding, and training programs in all specialties have focused on improving the education of physicians in the special needs of women. Though gains have been great, opportunities to elevate the health of women remain plentiful. A major area for improvement is the integration of health care services for women. The general internist, serving as a womans primary care provider, is in the position to coordinate and facilitate all of her health care needs. A good understanding of internal medicine, as well as primary care womens issues, allows the internist to provide the highest quality of care to his or her female patients. An understanding of womens health care needs enables the internist to provide preventive services, such as contraception, cervical cytology, and STI screening. These services are often not consistently provided by general internists but can have a dramatic impact on a womans health and well-being. This issue of Medical Clinics of North America brings together an outstanding group of authors to review advances in womens health. Information is presented in a practical fashion with the intent that internists may easily incorporate the material into their routine clinical practice. Drs. Ogburn, Voss, Espey review current barriers to optimal womens health and discuss strategies for improvement. Drs. Zebrack and Brown review the most recent recommendations for preventive health services and immunizationsdservices that all specialties should provide more consistently. Drs. Espey, Ogburn, and Fotieo provide an overview of available contraceptive methods with emphasis on Long Acting Reversible Contraceptives, such as IUDs and the new implant Implanon (Schering-Plough, Kenilworth, New Jersey). Drs. Waxman and Zsemlye discuss the latest guidelines for cervical cancer prevention, including the exciting breakthrough of the HPV vaccine and how it should be utilized. Drs. Trigg, Kerndt, and Aynalem review the latest information on screening and treatment of sexually transmitted infections and pelvic inammatory disease in women, which are a major cause of infertility in the United States. Drs. Meisner, Fekrazad, and Royce provide practical guidelines for evaluation and treatment of benign breast disease, as well as an overview of the current understanding of breast malignancies. Drs. Barney, Muller, and Bradshaw provide guidelines for the evaluation of pelvic masses with emphasis on age-specic evaluation. Infertility and polycystic ovarian syndrome are common entities among reproductive-aged womendDrs. Brassard, Baillargeon, and AinMelk review the current understanding of these issues and provide simple guidelines for their initial management and treatment. The internist is often called upon to provide consultative care for medical conditions during pregnancy. Drs. Carson and Ehrenthal

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provide a comprehensive overview of medical conditions in the preconception period and during pregnancy, while Drs. Rayburn and Amanze provide guidance on drug prescribing during pregnancydan area many physicians nd especially challenging. Domestic violence is an issue often under reported and undertreated by all specialties. Dr. Toohey provides practical strategies to improve identication and care of this dicult problem. Finally, issues of menopause and urinary incontinence (problems seen with increasing frequency as our population ages) are addressed in the articles by Dr. Lund and Drs. Abed and Rogers. In addition to the outstanding contributions of the authors, the guest editors would like to thank Rachel Glover and the sta at Elsevier for their support, assistance, and patience. We hope internists will nd this a valuable resource, enabling them to understand current issues in womens health and integrate new strategies into their practice. Tony Ogburn, MD Department of Obstetrics and Gynecology University of New Mexico School of Medicine MSC 10 5580 1 University of New Mexico Albuquerque, NM 87131 E-mail address: jogburn@salud.unm.edu Carolyn Voss, MD Department of Internal Medicine Ambulatory Care University of New Mexico MSC10 5550 1 University of New Mexico Albuquerque, NM 87131 E-mail address: cvoss@salud.unm.edu

Med Clin N Am 92 (2008) 9931009

Barriers to Womens Health: Why Is It So Hard for Women to Stay Healthy?

Tony Ogburn, MDa,*, Carolyn Voss, MDb, Eve Espey, MD, MPHc
a

Department of Obstetrics and Gynecology, University of New Mexico School of Medicine, MSC 10 5580, 1 University of New Mexico, Albuquerque, NM 87131-0001, USA b Department of Internal Medicine, Ambulatory Care, University of New Mexico, MSC10 5550, 1 University of New Mexico, Albuquerque, NM 87131-0001, USA c Department of Obstetrics and Gynecology, University of New Mexico School of Medicine, MSC 08 4700, 1 University of New Mexico, Albuquerque, NM 87131, USA

Of all the forms of inequality, injustice in health care is the most shocking and inhumane. Dr. Martin Luther King, Jr

Health care in the United States is often touted as the best in the world. It certainly is the most expensive. Expenditures on health care exceeded 2.1 trillion dollars, or $7025 per capita, in 2006. Health care spending accounted for w16% of the gross domestic product (GDP) in the United States, ranking rst in the world [1]. Despite greater spending on health care, the United States ranks 37th out of 191 countries in overall health, according to the World Health Organization [2]. France is number one in health rankings, yet spends less than 10% of its GDP on health care. Other countries that spend less than the United States but have higher health rankings include the United Kingdom, Italy, and Germany [2]. By 2017, health care spending in the United States is projected to exceed 4.3 trillion dollars and to account for 19.5% of the countrys GDP [1]. Many people think that the United States health care system is in crisis and the topic is a source of frequent public debate. A majority of Americans are dissatised with the current health care system: 73% state that the system is in crisis or has major problems [3]. Leading up to the presidential election, all the major candidates have indicated that health care reform is a priority for the country. Opinions about the reasons for the crisis are

* Corresponding author. E-mail address: jogburn@salud.unm.edu (T. Ogburn). 0025-7125/08/$ - see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2008.05.002 medical.theclinics.com

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varied and there is little consensus on solutions. Unfortunately, the crisis in health disproportionately aects women. This articles discusses several of the main issues in health care including: lack of health care coverage and access to care; underfunded research in womens health; and the fragmentation of womens health care among medical specialties. Potential solutions to improve the health of women in the United States are explored.

Access to care Millions of Americans lack adequate access to health care. The uninsured have minimal access except for emergency services and the underinsured face barriers that impede optimal health. The uninsured The United States is the only developed country in the world that does not provide universal health coverage for its population. Instead, a mix of employer-based health insurance and government programs, including Medicare and Medicaid, cover only 85% of the population. It is estimated that over 46 million people are uninsured in the United States [4]. The majority of the uninsured are in working families (82%) [4]. They typically work in small businesses, the service industry, or in blue collar positions that do not oer employer sponsored insurance. Medicaid and the State Childrens Health Insurance Program (SCHIP) provide coverage for some many, but the programs eligibility requirements exclude many of the working poor. Over 80% of the uninsured are citizens [5]. The number of uninsured people is rising steadily in the United States. Between 2004 and 2006, three million more people became uninsured [5]. Between 2000 and 2006, the number increased by almost nine million [6]. Several factors explain the steady rise. Despite an employer-based health care system, one third of businesses in the United States do not oer health care coverage to their employees [7]. This lack of coverage disproportionately aects employees in small businesses: in the time period 20002005, over 250,000 small businesses stopped providing coverage [8]. Increased costs were the primary reason for discontinuing health care benets. Costs to employers rose at three to four times the rate of ination over the past decade [7]. Even if insurance is oered, employee contributions to premiums have increased dramatically, which makes health insurance unaordable for many. The annual cost of coverage for a family of four exceeded $12,000 in 2006 and the employee contribution rose to $3300 [7]. Considering a minimum wage worker earns approximately $11,000 per year, it is clear why many workers choose not to participate in employer-sponsored programs. Government programs cover many Americans. Additionally, about 25% of the uninsured are eligible for coverage by Medicaid or SCHIP but are not enrolled [5]. A lack of awareness of eligibility and cumbersome enrollment

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procedures play a role in preventing more eligible individuals from participating. In addition, policies requiring re-enrollment every 612 months result in loss of coverage. Individuals who remain eligible are disenrolled due to these procedural barriers. Of the remaining uninsured people, w56% are not eligible for public programs, usually because their incomes exceed eligibility requirements. Eligibility is based on percentage of the Federal Poverty Level (FPL). In 2006, the FPL was dened as an income of $20,614 for a family of four. Typically, programs for children and pregnant womendand in some states for Family Planning servicesdhave income requirements of w200% of the FPL [4]. Experts estimate that a family would need an income of O300% of FPL to afford health care coverage if they were purchasing it directly in the marketplace. The health impact of being uninsured is signicant and aects women in many ways. Women with health coverage are more likely to obtain appropriate preventive, primary, and specialty care [9]. Approximately 38% of women have employer-based insurance in their own name, while 25% of women have dependent coverage. Dependent insurance in the spouses name makes a woman vulnerable to a loss of coverage when divorced or widowed. Eighteen percent of women are uninsured. Uninsured women are less likely to have had a visit with a provider in the past year (67%), compared with women with either private insurance (90%) or public insuranceMedicaid (88%) and Medicare (93%) [10]. In addition, they are more likely than women with insurance to report not having a current Pap smear, not lling a prescription due to cost, and having no regular physician [9]. Uninsured women with serious or chronic conditions are less likely to receive the care they need [11]. The Institute of Medicine (IOM) estimates that 18,000 excess deaths occur among individuals under age 65 attributable to lack of health coverage [11]. The underinsured Even women with insurance face barriers to health care. One in six women with private health insurance and one in three women with Medicaid report that they postponed or went without needed health care services in the previous year because they could not aord it [10]. Access to medications, specialty care, and needed procedures may be limited in several ways including copays, capping the scope of drug coverage, and limiting the number of prescriptions for which a patient is eligible. These restrictions disproportionately impact lower income women. Prescription contraceptive coverage provides an example of limitations placed on womens access to needed health care. Most insurance companies allow only a one months supply of medications, requiring a co-pay each month. One study found that overall women pay a greater proportion of the costs of contraceptives compared with other prescription medications. Women with private insurance paid approximately 60% of the total cost

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of oral contraceptives, compared with typical out-of-pocket costs for noncontraceptive medications of only 33% [12]. In addition to increased costs, receiving only one month of pills at a time is a barrier to pill continuation. Dispensing 6 months or one years supply of pills allows women to comply better with the pill regimen. Many insurance companies dont cover all available methods of contraception. A 2001 survey found that while 98% of insured employees had general prescription coverage, only 41% had coverage of all available reversible contraceptive methods [13]. Womens access to the most eective methods, such as use of intrauterine devices and implants, are often excluded due to high up front costs. Such an approach is short-sighted because these methods are the most cost eective after approximately one year of use. The practice of limiting coverage of contraceptives is discriminatory because contraceptives are one of the most commonly used prescription drugs among younger Americans and they are used only by women. There is an increasing trend to legislate contraceptive coverage or contraceptive equity. Twenty-seven states have enacted laws that require insurers that provide prescription drug coverage to cover contraceptives. Federal law requires that insurers of federal employees provide comprehensive contraceptive coverage [14]. Federal legislation entitled Putting Prevention First has been introduced that would mandate contraceptive coverage for all insured women nationally, but the proposal has made little headway to date. Many insurance plans have high deductibles for or completely exclude specic services. The Hyde amendment, enacted in its initial version in 1976, forbids the use of federal funds for abortion except in the case of rape, incest, or physical endangerment of the mothers life [15]. This proscription includes individuals covered by Medicaid, Medicare, the military, and the Indian Health Service. More than seven million women who rely on Medicaid do not have access to federal support for abortion care though they are typically poor and the least likely to aord services out of pocket. Similarly, some insurance plans exclude abortion except in certain circumstances such as rape endangerment of the mothers life. Abortion is one of the most common medical procedures for women. There is no common procedure that is excluded for males. In spite of the federal ban on abortion funding, seventeen states allow the use of state funds to pay for all or most abortions for Medicaid enrollees [16]. Solutions to access issues Several strategies may improve access to care. Most agree that universal health care coverage is desirable although the specics of implementation are hotly debated. A single payer system has the signicant advantage of decreasing total administrative costs. In 2004, these costs accounted for 31% of health care expenditures in the United States compared with only

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16.7% in Canada, a country with a single payer, national health insurance program [17]. Physicians for a National Health Plan, an organization representing more than 15,000 physicians, medical students and other health care professionals in the United States, estimates that the savings from decreased administrative costs of a single payer system could cover all Americans without increasing overall costs [18]. Others advocate for universal care through employee/individual or employer mandates. Massachusetts enacted a law in 2006 that required all individuals to purchase health care or be subjected to nes. State subsidies would be available to ensure aordability [19]. It is too soon to determine the success of the program. The confusion regarding the best approach to health care reform can be illustrated by the proposals of the two major candidates in the 2008 presidential campaign. John McCain proposes a free market approach with access to aordable health care for all by paying only for quality health care, maintaining insurance choices that are diverse and responsive to individual needs, and encouraging personal responsibility. His proposal does not include provisions to ensure coverage for all [20]. Barack Obama supports aordable and high-quality universal coverage through a mix of private and public insurance; his proposal only requires children to have coverage. The American College of Obstetricians and Gynecologists (ACOG) [21] recently proposed a health care reform plan that calls for universal health coverage that promotes prevention, especially prenatal care and contraception, continuity of care, and a medical home and core services for women. ACOG further states that health coverage should be accessible and aordable to everyone in the United States, regardless of citizenship or residency status. Given the widespread attention that health care issues are receiving from politicians at all levels, professional organizations, and the public, it is apparent that health care reform is needed in the United States. There is general agreement that such reform should provide coverage for all Americans while maintaining quality of care. However, given the lack of consensus on how to achieve these goals, signicant reform may not occur in the next few years. Other strategies should be used in the short term. Continuation and expansion of programs such as the Medicaid waiver program would provide coverage for some services. This program allows states to extend family planning services to certain groups as long as the program is budget neutral or results in overall cost savings [22]. These programs typically extend services to women; services oered are based on income requirements at or near 200% of poverty level. Such programs increase the number of family planning providers, increase accessibility, decrease unintended pregnancy, and provide overall costs savings [23]. Targeted eorts, such as provider and patient education about the availability of Medicaid coverage, could increase the participation of women who are eligible but have not enrolled.

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Research in womens health Research in womens health is critical to improving the health status of women, to reducing the incidence of disease, to providing optimal treatments, and to improving quality of life. Women have traditionally been excluded or marginalized from most medical research. Womens health research historically encompasses disease involving the reproductive tract including pregnancy-related issues and reproductive health. Other conditions, such as cardiovascular disease and infectious diseases were studied in men, and results were applied to women with the incorrect assumption that women were the same as men except for the reproductive tract. Researchers have found that wide variations exist between women and men in their responses to disease and treatments, including HIV infection, urinary incontinence, cardiovascular disease, pain response, and mental illness [24]. Although the past two decades have seen improvements in womens health research, much remains to be accomplished. History of women in clinical research Policies that were formed as recently as the 1980s excluded or limited the involvement of women in clinical trials. These policies derived from concerns about female vulnerability, ethical and legal concerns, and a presumption that research risk outweighed the benets [25]. Such policies seem misguided in retrospect, but they were intended to protect women, especially during pregnancy. In the 1960s and 1970s, the disastrous experiences with thalidomide, the Dalkon Shield, and diethylstilbesterol (DES) created a protectionist atmosphere that went too far in its reach. Pregnant women, and by extension reproductive-aged women who might unknowingly be pregnant, were included as a category of vulnerable populations for purposes of research along with prisoners and mentally disabled persons. In 1985, the Public Health Service issued a report from its Task Force on Womens Health that identied areas for improvement including womens health research [26]. In response to the report, the National Institutes of Health (NIH) established guidelines in 1986 that encouraged inclusion of women in clinical research. Minorities were included in 1987 [27]. Despite these guidelines, concerns persisted that women and minorities remained underrepresented in research. In 1990, the Government Accountability Oce (GAO) published the results of an investigation reporting that the NIH had made little progress in achieving its goals of increased inclusion of women and minorities in research. In response to the GAO report and other publicity, changes occurred in the 1990s. In 1991, the Oce of Womens Health (OWH) was established in the Department of Health and Human Services with a mission to provide leadership to promote health equity for women and girls through sex/gender-specic approaches [28]. In addition the Oce of Research on

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Womens Health (ORWH) was established at the NIH in 1990 [29]. One of the main functions of the ORWH is to coordinate and serve as a focal point for womens health research funded by the NIH. Most important was the passage of the NIH Revitalization Act of 1993, which was signed into law by President Clinton in 1994. This act put into law existing NIH policies and guidelines with several key dierences. It required that: 1) the NIH ensures that all women and minorities are included in all research; 2) women and minorities are included in all Phase III trials in adequate numbers to allow for valid analyses of dierences in intervention eect; 3) cost is not allowed as an acceptable reason for excluding these groups; and 4) the NIH initiates programs and support for outreach eorts to recruit and retain women and minorities and their subpopulations as volunteers in clinical trials [27]. These requirements were a signicant step forward in womens health research. The Food and Drug Administration In 1977 the Food and Drug Administration (FDA) issued guidelines limiting the participation of broadly dened women of childbearing potential in drug research. This was in part due to concerns arising from the DES and thalidamide experiences. Womens participation was limited to Phase III trials, and then only after animal reproductive studies and Phase I and II trials were completed. Because manufacturers were not required to perform animal reproductive studies, women continued to be excluded from the latter stage trials [25]. Responding to changes at the NIH, the FDA issued revised guidelines in 1993. The new policy strongly encouraged the inclusion of representatives of both genders in drug trials in numbers adequate to allow the detection of clinically signicant gender dierences in drug response. It also encouraged the analysis of sex dierences as a part of new drug applications (NDAs). The regulations stopped short of requiring womens participation [30]. In 1998, a new regulation required the separate presentation of safety and ecacy data for men and women in NDAs, but it did not require discussion or analysis of these data. The 1998 regulation also required the tabulation of study participants by sex in NDA annual reports. Overall, the regulations have had a positive impact. A GAO report issued in 2001 found that adequate numbers of women were included in pivotal trials on drug ecacy. However, concern was expressed that early, small-scale studies to determine toxicity and dosing levels had a low proportion of women; concern was also expressed that the data available from studies was not optimally analyzed to explore potential sex dierences in dosing and that the FDA lacked appropriate oversight capability to ensure compliance with the regulations regarding women in research [31].

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Future directions The establishment of regulations at the NIH and FDA as well as the formation of the ORWH and the OWH has led to signicant improvements in womens health research. In addition to the FDA and NIH, other government agencies have oces or divisions of womens health including the Centers for Disease Control, Health Resources and Administration (HRSA), and the Agency for Health care Research and Quality (ARHQ). Eorts must be made to maintain the gains of the last two decades and to ensure that the existing gaps are lled in. The work of the OWH and others has been successful in increasing the number of studies on womens health. For example, the number of applications for NIH Research Project Grants (RO1) funding and other types of project grants for womens health research increased by 48% from 19891990 to 19992000, nearly double the 25% increase for all applications [32]. Funding for womens research agencies must continue and expand. Unfortunately, from 2006 to 2008, funding for womens health oces at federal agencies remained at or grew only modestly. The OWH budget increased from 28 to 30 million dollars while the OWHR at the NIH remained the same at 40.9 million dollars. Overall, this level of funding amounted to a decrease when taking ination into account [33]. Furthermore, only oces at the NIH and the Substance Abuse and Mental Health Administration (SAMHSA) are authorized by statute. Oces in agencies such as the CDC and FDA are at risk each budget cycle. The Womens Health Oce Act was introduced in the House and Senate in 2007 and would provide for statutory authorization of womens health oces in the other federal health agencies including the FDA, HHS and ARHQ. In addition to adequate funding, research must be designed to ensure not only participation by adequate numbers of women but also to account for inherent gender dierences and the impact that these dierences may have on study results. Studies should be designed and implemented so that results can be analyzed by gender to determine if dierences do exist for women [34,35]. These tenets are critical for studies on conditions such as cardiovascular disease that aect both genders. For example, the Multiple Risk Factor Intervention Trial (MR. FIT), a study of the relationship between heart disease, cholesterol, and behavioral factors included women only in the observational arm. The experimental arm was comprised of 13,000 men, making it impossible to draw conclusions about women from the results of this study [36]. Women in academics Limitations in womens health research and policy may derive from the lack of women in positions of inuence. Eorts should be made to increase the number of women in the biomedical sciences. Womens health research

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may languish in the absence of women on university faculties. Female researchers are more likely to investigate diseases in women and tend to ask scientic questions dierently [37]. One of the main activities of the ORWH is the promotion of women in the biomedical sciences to achieve a critical mass of female researchers. One example of an initiative that works is the reentry program. This program enables fully trained researchers to participate on a grant after taking time o for family or personal needs. Other approaches include the recruitment of more women into NIH postdoctoral fellowships as well as career development workshops and seminars designed to encourage and assist women in applying for research funding [32]. These eorts have achieved a degree of success measured by an increase of 84% in the number of research awards to women compared with a 49% increase for men in the decade since implementation. Despite these gains, there is room for improvement. Although roughly equal numbers of women and men enter medical school, women who choose to enter academic medicine are less likely to be promoted or serve in leadership positions [38]. Women are less likely to achieve the rank of full professor, have their own laboratory space and grant support early in their careers, and have lower salaries than men with similar experience and academic rank [39]. A multi-faceted approach is necessary to decrease these nequities. Continued monitoring of womens progress is essential to ensure that persistent inequities are identied. Women must be eectively mentored in the early and middle portions of their careers by senior faculty. Men in senior leadership roles must be trained and encouraged to provide eective leadership to women, as insucient numbers of senior female faculty are available to fulll the need. Additionally, career paths should be more exible. Stringent timelines for promotion and tenure may be a barrier to women who are more likely than men to work fewer hours and take extended periods of leave. This variation should be accommodated and pathways devised that allow women to progress in academia while fullling other personal obligations.

Who are womens health physicians? Womens health is a broad term that lacks clear denition. Historically, womens health focused on reproductive tract conditions such as pregnancy, contraception, disorders of the menstrual cycle, and menopause. Broader denitions have emerged in recent years as womens health is dened as encompassing a broad range of issues. There are major dierences in how men and women develop and handle disease that must be considered. In addition, there are dierent challenges faced by men and women, such as social and economic factors that aect health. As womens health has become more complex, so has the role of the womens health care provider. Unfortunately, no consensus exists about

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who the primary provider of health care to women should be. As a result, care is typically fragmented, which results in gaps in the provision of preventive services as well as acute and chronic care. What health care services do women need? Ideally, women need a physician who can provide gender specic needs such as obstetric care, cervical and breast cancer screening, contraception, and menopausal care. In addition, they need the broader range of preventive services including colon cancer screening, lipid screening, and immunizations. Ideally, their provider would be able to provide general acute care for common conditions such as urinary tract infections, upper respiratory infections, and sexual transmitted diseases as well as common chronic conditions such as hypertension, diabetes and asthma. Finally, women need a provider who is able to address behavioral and psychosocial issues such as smoking cessation and domestic violence. Who provides care? Three specialties typically provide primary care to women: internists, obstetrician- gynecologists, and family medicine physicians, as well as nurse practitioners and physician assistants trained in these disciplines (a group whose role will become ever more important as the primary care physician workforce continues its rapid decline in number). All three specialties have advocated for being the primary care providers for women. Susan Fryhofer, then president of the American College of Physicians (ACP), in a column in the ACP-ASIM Observer entitled Why doctors of internal medicine are the best choice for womens health stated that internists were most suited to provide care for women because they could provide not only gender specic needs such as breast and cervical cancer screening but also care for other complex disorders such as colon cancer, heart disease, and diabetes [40]. Hal Lawrence, Vice President for Practice Activities at the American College of Obstetrician-Gynecologists, writes that Ob/Gyns are best suited to be a womens ongoing physician since they can provide care across her life time including caring for menstrual disorders in the adolescent, pregnancy related care and contraception in the reproductive years, and deal with issues such as heart disease prevention and bone health during the menopausal years. Throughout the lifespan Ob/Gyns can provide wellness promotion, education, preventive services, and initiate the detection of gynecologic and nongynecologic health issues [41]. The Future of Family Medicine project, an organization commissioned by seven national family medicine organizations, advocates that family medicine physicians are positioned to provide a medical home to patients and provide a basket of services that includes acute and chronic care, preventive services, and maternity care [42].

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In reality, the evidence indicates that none of the specialties provides optimal comprehensive care for women. Reports consistently indicate that Ob/Gyns provide gender specic services at higher rates than other primary care physicians but that all specialties do poorly providing gender neutral preventive services. A recent study using data from the 2000 National Health Interview Survey (NHIS) found that women who saw a gynecologist were more likely to have gender specic preventive services, such as Pap smear, mammography, and clinical breast examination, than if they saw a general medical physician only [43]. Seeing both types of providers did not increase the chances of obtaining these services. For gender-neutral services including colorectal cancer screening, diet counseling, and exercise counseling, rates of screening did not dier between patients who saw a gynecologist or general medicine physician. However, higher rates of each service were seen if a patient saw both types of provider. Unfortunately, overall rates of screening for these services were low no matter what type or types of provider was seen. For example colorectal cancer screening rates were 39% for general medical physicians, 44% for gynecologists, and 46% for patients that used both. A study using data from the National Ambulatory Care Survey (NAMCS) found that internists and family medicine physicians were more likely to provide gender-neutral services such as cholesterol screening while Ob/Gyns were more likely to provide gender specic services. Again, provision of gender-neutral services was low among all specialties [44]. In another study using the NAMCS database, patients seeing an Ob/Gyn for a preventive care visit had a clinical breast examination performed 87% of the time. Rates were much lower for Internists (33%) and family medicine physicians (45%) [45]. A phone survey of women in the Baltimore area found that women using both an Ob/Gyn and a generalist physician received more appropriate preventive services than those seeing a generalist alone [46]. A study based on claims made to a large Midwestern health plan found that women were much more likely to have a Pap smear or mammogram if seen by an Ob/Gyn compared with an internal medicine physician. They did not look at gender neutral services [47]. Even if one of the three specialties was able to provide the comprehensive care that women need, none is positioned to be the sole provider of womens health care. There are not enough Ob/Gyns, family medicine physicians or internists to provide all the primary care that women need currently now or in the future. Of the physicians completing residency training in internal medicine each year, about 80% subspecialize and approximately 10% become hospitalists, leaving only about 10% to provide general internal medicine or primary care. Family medicine residency positions have decreased from 2920 positions oered in 2003 to 2603 in 2007 [48]. Of these positions, only 88% were lled through the Match; and only 42% were lled by United States graduates. The number of positions in obstetrics/gynecology has

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remained stable for many years at w1,150. Approximately 10% of obstetrics/ gynecology graduates subspecialize. Strategies for improvement Multiple approaches must be used to ensure optimal care for women. With our current workforce, no single specialty will be able to provide the services needed. A collaborative approach is needed where providers in all three specialties can provide the basics of care and coordinate needed care that is beyond their expertise. Undergraduate medical education A recent survey of United States medical schools using the Association of American Medical Colleges Curriculum Management and Information Tool (CurrMIT) found that few schools oer interdisciplinary womens health courses/clerkships or include gender-specic information in their curricula [49]. They found that having a formal womens health program at the institution or having a female dean increased were positively correlated with inclusion of womens health in the curriculum. Another survey in 2001 found that only 44% of schools had a womens health curriculum, although an additional 18% were in the process of developing one [50]. The authors suggested that ensuring that womens health has an academic home with resources provided for faculty training in womens health was a key to success. Undergraduate medical education must integrate comprehensive womens health into the curricula so that all graduates have the knowledge and skill set to provide the basics of care. All medical students should graduate with an understanding of the specic health needs of women, a knowledge base that includes the gender dierences, and have the technical skills to provide care including performing a pelvic examination. In addition to improving education in womens health care, the number graduates must be increased. The American Association of Medical Colleges (AAMC) recommends increasing the number of graduates by 30% over 2002 levels by 2012 [51]. The AAMC also recommends increasing residency positions to accommodate the proposed increase in medical school graduates. The Council on Graduate Medical Education (COGME), authorized by Congress in 1986 to provide an ongoing assessment of physician workforce trends, training issues and nancing policies, and to recommend appropriate federal and private sector eorts to address identied needs, reported in 2005 that the United States faces a shortage of 85,000 physicians by 2020 and that the number of physicians entering residency training should be increased by 3,000 per year by 2015 [52].

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Graduate medical education Current program requirements for internal medicine residents regarding womens health are general. They require that residents receive instruction and clinical experience in the prevention, counseling, detection, and diagnosis and treatment of gender-specic diseases of men and women. In addition residents must have sucient instruction and clinical experience in oce gynecology and be instructed in the indications, contraindications, complications, limitations, and interpretations of ndings and develop technical prociency in. pap smear and endocervical culture [53]. There are no specied criteria for what diseases must be covered or a minimum number of exams to achieve prociency. These requirements provide great latitude for programs in how they provide instruction in womens health and assess competency. A survey of internal medicine program directors in 2004 found that more than one third thought the majority of their residents did not achieve competency in evaluating and treating common conditions such as vaginitis, domestic violence, and contraception [54]. The American Board of Internal Medicine requires competency in performing a Pap smear for board certication and species that a resident must be an active participant in at least ve procedures [55]. A study of internal medicine residents found that those performing more than 10 pap smears were far more likely to feel condent to perform the procedure [56]. Family medicine program requirements specify that residents must receive instruction and clinical experience in womens health but do not specify how this is to be accomplished or set specic criteria for competency [57]. As with internal medicine, these requirements may by interpreted and implemented in many ways by individual training programs. The concern for Ob/Gyns is not lack of competency in gender specic care such as cervical and breast cancer screening, but instead it is their competency in gender neutral conditions that may be decient. Program requirements in Ob/Gyn specify that residents must have at least six months of instruction and experience in primary and preventive care and that this training can occur in Ob/Gyn continuity and high risk obstetrics clinics as well as in internal medicine clinics or rotations in the emergency department [58]. Again, a fair amount of latitude exists in how extensive or comprehensive training may be. It is also questionable how applicable primary and preventive care experience in a high risk obstetrics clinic is to the general, nonpregnant population. A recent Presidential task force at the American College of Obstetricians and Gynecologist addressed the role of Ob/Gyns. It recommended that, at a minimum, Ob/Gyns should be able to provide screening, prevention, diagnosis, and management of common health issues that aect all women. Management may include appropriate referral, initiation of treatment accompanied by referral, or full continual management, depending on the expertise of the provider.

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All three specialties must ensure that graduates have the core skills needed to provide basic primary care for women. Internists and family medicine physicians should be able to provide gender specic care including Pap smears and breast exams to their female patients. Ob/Gyns should be able to appropriately screen patients for the full range of preventive services. All Ob/Gyns likely will not have the interest, expertise, or time to provide ongoing care for chronic illness, but they should be able to screen for such conditions and refer appropriately. They may also be in the position of providing a medical home for many women, providing care within their scope of practice, and coordinating the remainder of a patients care. Womens health residencies and fellowships are an interdisciplinary approach to train physicians that are specialist in comprehensive womens health excluding obstetrics. Programs usually are based an internal medicine department and trainees typically completing rotations in Ob/Gyn and other pertinent clinical rotations such as sports medicine, behavioral health, and breast clinics. Currently, there are 10 residencies and 22 fellowship programs in the United States. While such programs do not yet train large number of providers, they may in the future as the need for comprehensive womens health providers increases and interest in this type of practice grows. In addition such programs may be a source for leaders in the eld of womens health. Comprehensive womens health centers In 1996 the US Department of Health and Human Services Oce on Womens Health established the National Centers of Excellence in Womens Health (CoEs). Located in academic medical centers around the country, the CoEs program works to establish and evaluate a new model health care system that unites state-of-the-art health care services addressing all of a womans needs, gender-based research, public and professional education and training, community linkages for health services and programs, and leadership positions for women in academic medicine [59]. The potential success of such centers is well documented. At the University of Michigan, where a program was established in the early 1990s and received designation as a CoE in 1997, there have been notable improvements in patient care and research, increased recruitment and promotion of women faculty, and increased inclusion of womens health issues in the curriculum. Since the programs inception, the ranks of senior women faculty have increased by 182% compared with 26% for men and tenured women faculty grew by 108% compared with an increase of 9% for men [60]. Summary Womens health care has made great strides in the past two decades. The recognition that women have dierent health care needs than men has

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enabled changes to take place in clinical care, research, and education. However, much remains to be done. Providing health care coverage to all women must be a high priority. Research must be adequately funded and continue to address the dierences that exist between men and women and how they respond to disease and treatment. The physician workforce needs to be expanded and physicians should be well trained to provide comprehensive health care to women. Strategies, such as used in Comprehensive Centers of Womens Health and womens health residencies, should be used to ensure improved education and increases in the numbers of women in the ranks of academia. References
[1] Centers for Medicare and Medicaid. National health expenditure Data Fact Sheet. Available at: http://www.cms.hhs.gov/NationalHealthExpendData/25_NHE_Fact_Sheet.asp#TopOf Page. Accessed July 14, 2008. [2] World Health Organization. The world health report 2000 Health systems: improving performance. Available at: http://www.who.int/whr/2000/en/whr00_en.pdf. Accessed July 14, 2008. [3] Gallup Poll. Annual health and healthcare survey. Available at: http://www.gallup.com/ video/102922/Americans-Assess-Health-Care-System.aspx. Accessed July 14, 2008. [4] KaiserFamily Foundation. The uninsured and their access to health care. Available at: http://www.k.org/uninsured/upload/1420_09.pdf. Accessed July 14, 2008. [5] Kaiser Family Foundation Commission on the Uninsured. Characteristics of the uninsured: who is eligible for public coverage and who needs help aording coverage? Available at: http://www.k.org/uninsured/upload/7613.pdf. Accessed July 14, 2008. [6] DeNavas-Walt CB, Proctor B, Smith J. Income, poverty, and health insurance coverage in the United States: 2006. U.S. Census Bureau August 2007. Available at: http://www.census. gov/prod/2007pubs/p60233.pdf. Accessed July 14, 2008. [7] The Henry J.Kaiser Family Foundation. Employee health benets: 2007 annual survey. Available at: http://www.k.org/insurance/7672/index.cfm. Accessed July 14, 2008. [8] The Henry J. Kaiser Family Foundation. The uninsured: a primer, key facts about Americans without health insurance. Available at: http://www.k.org/uninsured/. Accessed July 14, 2008. [9] The Henry J. Kaiser Family Foundation. Womens health insurance coverage. December 2007. Available at: http://www.k.org/womenshealth/upload/6000_06.pdf. Accessed July 14, 2008. [10] The Henry J. Kaiser Family Foundation. Women and health care, a national prole. Available at: http://www.k.org/womenshealth/whp070705pkg.cfm. Accessed July 14, 2008. [11] Institute of Medicine of the National Academes. Uninsurance facts and gures: the uninsured are sicker and die sooner. Available at: www.iom.edu/uninsured. Accessed July 14, 2008. [12] Phillips K, Stotland N, Liang S, et al. Out of pocket expenses for oral contraceptives and number of packs per purchase. J Am Med Womens Assoc 2004;59:3642. [13] The Guttmacher Institute. Report on Public Policy Special Analysis: the cost of contraceptive insurance coverage. 2003;vol. 6:Number 1. [14] The Guttmacher Institute. State policies in brief. Insurance coverage of contraceptives. Available at: http://www.guttmacher.org/statecenter/spibs/spib_ICC.pdf. Accessed July 14, 2008. [15] The Guttmacher Institute. Policy review: the heart of the matter: public funding of abortion for poor women in the United States. Available at: http://www.guttmacher.org/pubs/gpr/10/ 1/gpr100112.html. Accessed July 14, 2008.

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[16] Guttmacher Institute. Guttmacher state policies in brief: state abortion policies. Available at: http://www.guttmacher.org/statecenter/spibs/spib_OAL.pdf. Accessed July 14, 2008. [17] Woolhandler S, Campbell T, Himmelstein D. Costs of health care administration in the United States and Canada. N Engl J Med 2003;349:76875. [18] Physicians for a National Health Plan. Single-payer national health insurance. Available at: http://www.pnhp.org/facts/single_payer_resources.php. Accessed July 14, 2008. [19] Kaiser Family Foundation. Massachusetts health care reform plan: an update. Available at: http://www.k.org/uninsured/upload/749402.pdf. Accessed July 14, 2008. [20] The HenryKaiser Family Foundation J. Presidential candidate health care reform proposals: a side by side comparison. Available at: http://www.health08.org/sidebyside_results. cfm?c5&;c11&c16. Accessed July 14, 2008. [21] American College of Obstetricians and Gynecologists. Health care for women, health care for all. A reform agenda. Available at: http://www.acog.org/departments/govtrel/HCFWHCFAReformPrinciples.pdf. Accessed July 14, 2008. [22] Espey E, Cosgrove E, Ogburn T. Family planning American style: why its so hard to control birth in the US. Obstet Gynecol Clin North Am 2007;34:117. [23] Gold R. Doing more for less:study says state medicaid family planning expansions are costeective. Guttmacher Rep Public Policy 2004;7(1). Available at: http://www.guttmacher. org/pubs/journals/gr070101.html. Accessed July 14, 2008. [24] Pinn V. Sex and gender factors in medical studies: implications for health and clinical practice. JAMA 2003;289:397400. [25] Johnson T, Fee E. Womens health research: a historical perspective. In: Haseltine F, editor. Womens health research: a medical and policy primer. Washington, DC: American Pyschiatric Press; 1997. p. 2746. [26] United States Public Health Service. Womens health. Report of the Public Health Service Task Force on womens health issues. Public Health Rep 1985;100(1):73106. [27] Oce of Research on Womens Health. Inclusion of women in research. Available at: http:// orwh.od.nih.gov/inclusion.html. Accessed July 14, 2008. [28] Oce of Womens Health. About us. Available at: http://www.4woman.gov/owh/index.cfm. [29] Oce of Research on Womens Health. About ORWH. Available at: http://orwh.od.nih. gov/about.html. Accessed July 14, 2008. [30] Food and Drug Administration. Guideline for the study and evaluation of gender dierences in the clinical evaluation of drugs. Fed Regist 1993;58(139):3940616. [31] Government accountability oce. Womens health: women suciently represented in new drug testing but FDA oversight needs improvement. GAO Report # 01754, July 6, 2001. Available at: http://www.gao.gov/new.items/d01754.pdf. Accessed July 14, 2008. [32] Stone J, Pinn V, Rudick J, et al. Report from the NIH Oce of Research on Womens Health: Evaluation of the rst 10 years of the Oce of Research on Womens Health at the National Institutes of Health: selected ndings. J Womens Health 2006;15(3)):23447. [33] Society of Womens Health Research. Issue: federal funding of womens health research. Available at: http://www.womenshealthresearch.org/site/PageServer?pagenamepolicy_ issues_funding. Accessed July 14, 2008. [34] Pinn V. Research on womens health: progress and opportunities. JAMA 2005;294:140710. [35] Institute of Medicine. Exploring the biological contributions to human health: does sex matter? 2001. Available at: http://www.nap.edu/catalog/10028.html. Accessed July 14, 2008. [36] Moncher K, Douglas P. Importance of and barriers to including women in clinical trials. In: Legato M, editor. Principles of gender specic medicine. New York: Elsevier Academic Press; 2004. p. 27582. [37] Haseltine F. Formula for change: examining the glass ceiling. In: Haseltine F, editor. Womens health research: a medical and policy primer. Washington, DC: American Pyschiatric Press; 1997. p. 22530. [38] Nonnemaker L. Women physicians in academic medicine new insights from cohort studies. N Engl J Med 2000;342:399405.

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[39] Hamel M, Ingelnger J, Phimster E, et al. Women in academic medicinedprogress and challenges. N Engl J Med. 2006;355(3):3102. [40] Fryhofer SA. Why doctors of internal medicine are the best choice for womens health. America College of Physicians/American Society fo Internal Medicine Observer 2000; 20(5):8. [41] Lawrence HA. Womens ongoing physician? Her Ob/Gyn. Ob Gyn News 2008;43(2):11. [42] Future of Family Medicine Leadership Committee. The future of family medicine: a collaborative project of the family medicine community. Ann Fam Med 2004;2(Supp 1):S332. [43] Lewis B, Halm E, Marcus S, et al. Preventive services use among women seen by gynecologists, general medical physicians, or both. Obstet Gynecol 2008;111:94552. [44] Scholle S, Chang J, Harman J, et al. Trends in womens helath services by type of provider seen: data from the 1985 and 199798 NAMCS. Womens Health Issues 2002;12(4):16577. [45] Wallace A, MacKenzie T, Weeks W. Womens primary care providers and breast cancer screening: whos following the guidelines? Am J Obstet Gynecol 2006;194:7448. [46] Henderson J, Weisman C, Grason H. Are two doctors better than one? Womens physician use and appropriate care. Womens Health Issues 2002;12:13849. [47] Lurie N, Slater J, McGovern P, et al. Preventive care for women does the sex of the physician matter? N Engl J Med 1992;329:47882. [48] National Residency Matching Program. Selected data tables: Positions oered and percent lled by U.S. seniors and all applicants 20032007. Available at: http://www.nrmp.org/ res_match/tables/table6_2007.pdf. Accessed July 14, 2008. [49] Henrich J, Viscoli C. What do medical schools teach about womens health and gender differences? Acad Med 2006;81:47682. [50] Keitt S, Wagner C, Tong C, et al. Positioning womens health curricula in US medical schools. MedGenMed 2003;5(2):40. [51] American Association of Medical Colleges. AAMC statement on the physician workforce. Available at: http://www.aamc.org/workforce/workforceposition.pdf. Accessed July 14, 2008. [52] Council on Graduate Medical Education. Physician workforce policy guidelines for the United States, 20002020. Sixteenth Report. January, 2005. [53] Accreditation Council for Graduate Medical Education. Internal medicine program requirements. Available at: http://www.acgme.org/acWebsite/downloads/RRC_progReq/140_im_ 07012007.pdf. Accessed July 14, 2008. [54] Spencer A, Kern L. Primary care program directors perceptions of womens health education: a gap in graduate medical education persists. J Womens Health 2008;17:54956. [55] American Board of Internal Medicine. General requirements. Available at: https://www. abim.org/certication/policies/imss/im.aspx#procedures. Accessed July 14, 2008. [56] Chew R, Chew L, Bradley K. The association between numbers of pap smears performed and self-reported condence in an internal medicine residency. J Womens Health 2006;15:92833. [57] Accreditation Council for Graduate Medical Education. Family medicine program requirements. Available at: https://www.acgme.org/acWebsite/downloads/RRC_progReq/ 120pr07012007.pdf. Accessed July 14, 2008. [58] Accreditation Council for Graduate Medical Education. Obstetrics and gynecology program requirements. Available at: https://www.acgme.org/acWebsite/downloads/RRC_ progReq/220obstetricsandgynecology01012008.pdf. Accessed July 14, 2008. [59] Oce of Womens Health. National Centers of Excellence in Womens Health. Available at: http://www.4woman.gov/coe/. Accessed July 14, 2008. [60] Rogers J, Johnson T, Warner P, et al. Building a sustainable womens health program: the Michigan model. J Womens Health 2007;16(6):91925.

Med Clin N Am 92 (2008) 10111035

Preventive Health for Women: Screening and Immunizations

Jennifer R. Zebrack, MD, FACP, CCDa,*, Keith W. Brown, DO, FACOOG, CCDb,c
a

Division of General Internal Medicine, University of Nevada School of Medicine, 2345 E. Prater Way, Suite 211, Sparks, NV 89434, USA b Division of Gynecology, University of Nevada School of Medicine, 2345 E. Prater Way, Suite 211, Sparks, NV 89434, USA c Center for Bone Health, University of Nevada School of Medicine, Reno, 1500 E. Second Street, Suite 302, Reno, NV 89502, USA

Womens preventive health issues are frequently encountered in the outpatient setting. Many general internists feel uncomfortable in meeting the needs of women because of a general lack of knowledge of womens health and inadequate training in the evaluation of female-specic care. In this article, the authors summarize preventive health guidelines (ie, screening tests) and immunization recommendations for women. A test is considered a good screening tool if the disease is fairly common and has an eective treatment, and the screening test is low-cost, accurate, and generally acceptable to patients. Once a screening test is positive, the patient must be treated or referred appropriately. Evidence-based clinical guidelines for preventive health for women are developed by national organizations (eg, American Cancer Society, American College of Obstetrics and Gynecology, American Heart Association, National Osteoporosis Foundation, United States Preventive Services Task Force), and their publications and Web sites are excellent resources for internists who care for women. Screening for hypertension and cardiovascular diseases Worldwide, heart disease is the number one cause of death of women [1]. Almost 40% of all female deaths in America occur from cardiovascular
Dr. Brown is a paid consultant for Novartis Pharmaceuticals Corporation and Proctor & Gamble Pharmaceuticals. * Corresponding author. E-mail address: jjzebrack@yahoo.com (J.R. Zebrack). 0025-7125/08/$ - see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2008.04.002 medical.theclinics.com

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disease, which includes coronary heart disease (CHD), stroke, and other cardiovascular diseases [2]. Hypertension, a major risk factor for CHD and stroke, is very common in older women; approximately 50% of women aged 60 to 69 years old and 75% of women aged 70 years and older have hypertension [3]. According to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) [4], hypertension is dened as a systolic blood pressure (SBP) 140 mmHg or greater and a diastolic blood pressure (DBP) 90 mmHg or greater. Prehypertension is dened as a SBP from 120 to 139 mmHg and a DBP from 80 to 89 mmHg. Prehypertensive women should be encouraged to make lifestyle modications to prevent the progressive rise in blood pressure. The United States Preventive Services Task Force (USPSTF) recommends that all women 18 and older be screened for hypertension to identity those at increased risk for cardiovascular disease (CVD) [5]. The JNC 7 recommends screening for hypertension every 2 years for women who have normal blood pressure and at least annually for those who have prehypertension. Stage 1 hypertension (140159 SBP and 9099 DBP) should be conrmed within 2 months. Stage 2 hypertension (R160 SBP and R100 DBP) should be evaluated within 1 month, unless signicantly elevated, greater than 180/110 mmHg (requiring immediate or within 1 week evaluation, depending on the clinical scenario) [4]. The auscultatory method with a trained observer and sphygmomanometer is the preferred method for blood pressure measurement in the oce [3,4]. Exercise, caeine, and smoking should be avoided 30 minutes before blood pressure measurement. Correct positioning of the patient and selection of cu size (especially in obese patients) are essential to accurate measurement. Blood pressure should be taken after the patient is seated quietly for 5 minutes. Two readings should be taken 5 minutes apart with the patient seated in a chair with feet on the oor. The average of the two should be used. The arm should be at the level of the heart with the bladder cu encircling at least 80% of the arm. Elevated readings should be conrmed in the contralateral arm. Because of variability in individual measurements, it is recommended that hypertension be diagnosed only after two or more elevated readings are obtained on at least two visits. Twenty-four-hour ambulatory blood pressure monitoring is indicated for the evaluation of possible white-coat hypertension [3,4]. Because the lifetime risk of CVD is high, aecting almost 1 out of every 2 women, all women should be evaluated for their individual risk for CVD (ie, classication into high risk, at risk, or optimal risk) and need for risk reduction strategies (eg, aspirin therapy, lipid therapy, blood pressure control, weight reduction, physical activity, smoking cessation) [1]. Lowdose aspirin therapy (81100 mg per day) should be considered in all women 65 years or older to prevent CVD if blood pressure is well-controlled and the benets are felt to outweigh the risks (eg, bleeding) [1]. Women younger than 65 should be considered for aspirin therapy if they are at increased

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risk for stroke; however, aspirin has not been shown to prevent myocardial infarction in women under the age of 65 [1]. The USPSTF recommends against routine screening for coronary artery disease with diagnostic testing such as resting EKG, exercise treadmill test, or coronary CT scan in low-risk women [5]. USPSTF also states that there is insucient evidence to recommend routine diagnostic screening in asymptomatic women who are at increased risk for coronary artery disease; however, given that women are more likely than men to present with atypical symptoms when suering from heart disease, physicians should have a low threshold for stress testing when symptoms are in any way suggestive [1]. Furthermore, routine screening for abdominal aortic aneurysm and peripheral vascular disease (eg, carotid ultrasound, arterial brachial index) in asymptomatic women is not recommended [5]. Screening for lipid disorders The American Association of Clinical Endocrinologists (AACE) recommends that all women ages 20 to 75 be screened for lipid disorders. Those over age 75 should be screened if multiple risk factors for CVD are present and no other major life-limiting disease is present [6]. Women who are low risk should be screened every 5 years [6,7]; testing should occur more often if there is a family history of premature heart disease in a male rst-degree relative (!age 55) or a female rst-degree relative (!age 65) [6]. The USPSTF recommends that all women 45 and older be screened for lipid disorders, and those women aged 20 to 44 be screened if other risk factors for heart disease are present [5]. USPSTF states that an optimal screening interval is uncertain, but every 5 years is reasonable for low-risk women, with more frequent intervals for those who have borderline values or CVD risk factors. USPSTF also does not establish an age to stop screening, but notes that lipid levels are less likely to change after the age of 65. A complete lipoprotein paneldtotal cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglyceridesdis the preferred screening test, and should be collected after a 12-hour fast [7]. High LDL cholesterol is a signicant risk factor for CVD and the primary target for therapy. The goal LDL depends on a womans risk factors for CVD, as outlined in the National Cholesterol Education Program (NCEP) (Table 1) [7,8]. Women who have low HDL or elevated triglycerides may also require therapy if lifestyle modications are unsuccessful. Screening for obesity and the metabolic syndrome Obesity is more common in women than men. With the incidence of obesity increasing in epidemic proportions, it is estimated that more than 65% of US women are overweight or obese [5]. Obesity can lead to multiple health problems in women, including heart disease, diabetes, hypertension,

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Table 1 National cholesterol education program (NCEP) LDL goal based on risk factors LDL goal (mg/dl) !70 !100 LDL threshold to initiate lifestyle changes (mg/dl) R100 R100 LDL threshold to initiate drug therapy (mg/dl) O100 (O70 could also be considered) R100 (100129 drug optional) 10-year risk 10%20% O130 10-year risk !10%: R160 R190 (160189 drug optional)

Risk category CHD & multiple other risk factors CHD or CHD risk equivalentsa (10-year risk O20%) 2 risk factorsb (10-year risk %20%) 01 risk factor
a

!130

R130

!160

R160

Peripheral vascular disease, diabetes, Framingham risk O20%/10 years. Risk factors: age (male R45; female R55); CHD in male rst-degree relative !55 or female rst-degree relative !65; diabetes; current cigarette smoking; hypertension; low HDL (men !40 mg/dL; women !50 mg/dL). If HDL is R60 mg/dL, then subtract one from the risk factor total. Data from Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) nal report. Circulation 2002;106(25):322731, 32437; and Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110(2):236.
b

dyslipidemia, musculoskeletal problems, depression, infertility, pregnancy complications, and an increased risk for breast, uterine, and colorectal cancer [9]. Up to 30% of women who have weight problems also have an eating disorder (eg, binging, purging). The USPSTF recommends that all women be screened for obesity using the body mass index (BMI)dbody weight in kilograms divided by the height in meters squared [kg/m2]dat least every 2 years [5]. Obesity is dened as a BMI greater than or equal to 30 kg/m2. Morbid obesity (class 3) is a BMI greater than or equal to 40 kg/m2 [9]. BMI correlates well with total body fat, but does not account for body fat distribution. Therefore, measurement of the waist circumference (WCf) can determine if the patient has abdominal obesity (ie, central or male-type fat distribution). This is done in the horizontal plane at the level of the iliac crest. A high WCf in women is greater than 35 in (88 cm) [9]. A central fat distribution results in greater cardiovascular risks than gluteofemoral fat distribution. According to the NCEP, women who have three or more of the characteristics in Box 1 meet criteria for metabolic syndrome, indicating that they are at very high risk for CVD [7]. Screening for diabetes The prevalence of type II diabetes mellitus is increasing dramatically worldwide. Approximately 20 million Americans have diabetes (7% of the

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Box 1. National cholesterol education program criteria for metabolic syndrome Fasting glucose 100 mg/dL Blood pressure >130/85 mmHg Serum triglycerides 150 mg/dL, Serum HDL <50 mg/dL Waist circumference >35 inches
Data from Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) nal report. Circulation 2002;106(25): 3189.

US population) and 40 million have prediabetes (eg, impaired fasting glucose) [10]. Those at greater risk of developing diabetes are those who have a family history, those who are overweight or obese, and certain ethnic populations (ie, Hispanic, African, Native American, South or East Asian, or Pacic Island ancestry). According to the American Diabetic Association (ADA), screening for type II diabetes should begin at age 45 (younger for women at higher risk), and if normal, should be repeated every 3 years [11]. The AACE recommends that women age 30 or older who are at risk be screened annually [10]. The USPSTF recommends screening for diabetes in all women who have hypertension or dyslipidemia, but found insucient evidence for routine screening in asymptomatic women [5]. The fasting plasma glucose level is the recommended screening test. The criteria for diagnosing diabetes are listed in Box 2. Oral glucose tolerance testing (OGTT) is reserved for individuals who have potential symptoms of diabetes or its complications, as well as fasting plasma glucose below 126 mg/dL [11]. Impaired fasting glucose (IFG) is dened as fasting plasma glucose from 100 to 125 mg/dL, and impaired glucose tolerance (IGT) is dened as plasma glucose from 140 to 199 mg/dL after an OGTT [11]. Box 2. Criteria for diagnosing diabetes mellitus Two fasting plasma glucoses >125 mg/dL Random plasma glucose >200 mg/dL and symptoms of diabetes are present 75-g 2-hour OGTT 200 mg/dL
Data from American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract 2007;13(S1):S11.

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The ADA and American College of Obstetrics and Gynecology (ACOG) recommend that pregnant women be screened for gestational diabetes mellitus (GDM) at 24 to 28 weeks with an OGTT [11,12]; however, ADA and ACOG state that those at low risk, with all of the following characteristics, are not likely to benet from screening: younger than 25 years old, body mass index 25 or less, no history of abnormal glucose tolerance, no history of previous adverse pregnancy outcome associated with gestational diabetes, no rst-degree relative with diabetes, and not of Hispanic, African, Native American, South or East Asian, or Pacic Island ancestry [11,12]. The ADA recommends that women who have GDM be screened for diabetes at 6 to 12 weeks postpartum, with subsequent periodic screening for the development of diabetes [11]. The AACE recommends screening all pregnant women for gestational diabetes: those at lower risk at 24 to 28 weeks and those at higher risk at 20 weeks [10].

Screening for thyroid disorders Over 20 million people in the United States are under treatment for a thyroid disorder, and thyroid disorders are eight times more common in women than in men [13]. An estimated 1 million Americans suer from Graves disease, the most common form of hyperthyroidism [13]. Hashimotos thyroiditis, the most common cause of hypothyroidism, aects approximately 10% to 17% of women in the United States [13]. The USPSTF found insucient evidence to recommend for or against the routine screening for thyroid disorders in asymptomatic women [5]. Because thyroid disorders are common in women, thyroid testing is recommended in any woman who has subtle signs or symptoms of thyroid disease (eg, weight changes, menstrual changes, fatigue, depression, sleep disturbance). The ACOG does not recommend routine screening for thyroid disorders in pregnant women, stating that there is a lack of evidence that identifying and treating pregnant women who have subclinical thyroid disorders improves outcomes [14]. The ACOG recommends testing if a pregnant woman has signs or symptoms, a history of thyroid problems, or a medical condition associated with thyroid disease (eg, diabetes). The AACE states that thyroid screening should be performed in women of childbearing age before pregnancy or during the rst trimester [15]. The thyroid-stimulating hormone (TSH) is the preferred screening test, because it is the most sensitive test for detecting mild thyroid excess or deciency [15].

Breast cancer screening Breast cancer is the second most common cancer among American women, after skin cancer. The chance of developing invasive breast cancer at some time in a womans life is about 1 in 8 (12%), and about 1 in

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35 women will die of breast cancer (about 3%) [16]. Death rates from breast cancer have been declining since about 1990, likely because of earlier detection with routine screening as well as improved treatment [16]. Risk factors for breast cancer include increasing age, personal or rst-degree family history, menarche before age 12, nulliparity, history of breast biopsy, history of atypical hyperplasia, and increased breast density [5,17]. There are several methods of screening for breast cancer. Mammogram The American Cancer Society (ACS) recommends that women who are 40 years of age and older have an annual screening mammogram and continue to do so for as long as they are in good health [18]. The USPSTF recommends screening mammography every 1 to 2 years beginning at age 40 [5]. The ACOG recommends screening mammography every 1 to 2 years for women aged 40 to 49 and annually for women aged 50 and older [19]. Although there is no precise age when to discontinue mammograms, women who have chronic diseases in poor health are unlikely to benet from screening [5]. Clinical breast examination According to the ACS, women in their 20s and 30s should have a clinical breast examination (CBE) by a health care professional at least every 3 years. After age 40, women should have a CBE every year [18]. Breast self-examination According to the ACS, beginning in their 20s, women should be counseled about the benets and limitations of breast self-examination (BSE) [18]. Research suggests that BSE does not improve outcomes and may lead to unnecessary anxiety and diagnostic tests; however, women should report any changes in how their breasts look or feel to their health professional immediately. Magnetic resonance imaging According to the ACS, women at high risk (greater than 20% lifetime risk) should get an MRI and a mammogram every year [18]. Women at moderately increased risk (15%20% lifetime risk) should talk with their doctors about the benets and limitations (eg, false positives) of adding MRI screening to their yearly mammogram. MRI screening is not recommended for women whose lifetime risk of breast cancer is less than 15% [18]. A womans risk for breast cancer can be calculated using the National Cancer Institutes Breast Cancer Risk Assessment Tool (Gail model) at www.cancer.gov/bcrisktool/.

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Women who have a higher calculated risk for breast cancer may consider chemoprevention with a selective estrogen-receptor modulator (ie, raloxene or tamoxifen) after taking into consideration the benets and risks of these drugs [5,20,21]. For further information on breast cancer screening and the evaluation and treatment of breast conditions, see the article by Dr. Royce and colleagues elsewhere in this issue. Colorectal cancer screening In the United States colorectal cancer (CRC) is the third most common cause of cancer mortality in women, with a lifetime risk for CRC of approximately 6%. The majority of colorectal cancers (90%) are diagnosed after the age of 50 [5]. Screening for CRC should begin at age 50 for women of average risk [5,22]. The ACOG recommends colonoscopy as the preferred screening test in both average-risk and high-risk women, because studies have shown that women are more prone to right-sided colon lesions when compared with men [22]. The ACS recommends one of ve screening options: [18]. 1. Yearly patient-collected fecal occult blood testing, 2. Flexible sigmoidoscopy every 5 years, 3. Yearly patient-collected fecal occult blood testing plus exible sigmoidoscopy every 5 years, 4. Double-contrast barium enema every 5 years, 5. Colonoscopy every 10 years. Digital rectal examination should not be used as a screening method for colon cancer. Women who have one of the following risk factors should discuss with their physician the need for sooner or more frequent screening [18,22]: Personal history of CRC or polyps First-degree relative who has a history of CRC or polyps before the age of 60 Two rst-degree relatives who have CRC at any age Inammatory bowel disease Family history of a hereditary colorectal cancer syndrome Cervical cancer screening Cervical cancer was the leading cause of cancer death in American women in the 1930s. The incidence and mortality from cervical cancer have decreased signicantly since the 1970s because of widespread screening with the Pap test [23]; however, in 2007, it is estimated that over 11,000 US women will be diagnosed with cervical cancer, and almost 4000 US women

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will die of cervical cancer [24]. Infection with human papillomavirus (HPV) is the most important risk factor for cervical dysplasia and cancer. Cervical cancer screening should begin within 3 years after the initiation of vaginal intercourse or by age 21, whichever comes rst [5,18,23]. The ACS and ACOG recommend annual screening for women until age 30 [18,23]. Women over age 30 may extend their Pap test interval to every 2 to 3 years if the last three Pap tests have been normal and the patient is not at higher risk, with a history of cervical intraepithelial neoplasia grade 2/3 (CIN 2/3) or cervical cancer, immunocompromised, known HPV infection, or in utero diethylstilbestrol (DES) [18,23]. The ACS and ACOG also support an alternative screening method with simultaneous Pap and HPV testing for women over 30; if both are negative, the patient can be screened every 3 years (if low-risk) [18,23]. The USPSTF states that Pap testing should be done at least every 3 years [5]. Recommendations dier with regard to the discontinuation of screening in older women. The ACS states that Pap tests may be stopped in low-risk women who are age 70 and older, have had routine screening with three consecutive normal Pap tests, and no abnormal Pap tests in the past 10 years [18]. The ACS recommends continuing cervical cancer screening in women who are immunocompromised (eg, chemotherapy or other medications that reduce immunity, HIV-positive), are positive for HPV, or have a history of in utero DES exposure or cervical cancer [18]. The USPSTF recommends discontinuing Pap tests in women age 65 and older who have had adequate recent screening and are not high risk [5]. The ACOG states that the evidence is inconclusive to establish an upper age limit, and that a decision to discontinue Pap tests should be individualized [23]. Women who have had a total hysterectomy for benign disease (with conrmed absence of the cervix) no longer require Pap testing [5,18,23]. Women with an uncertain reason for the hysterectomy or history of CIN 2/3 should have three consecutive vaginal cu smears and no abnormal Pap tests within the last 10 years before discontinuation of screening [18,23]. Cervical cancer screening should be continued in hysterectomized women who have a history of cervical cancer or in utero DES exposure [18,23]. HPV types 16 and 18 are responsible for 70% of cervical cancers, and types 6 and 11 are responsible for 90% of genital warts [24]. Two HPV vaccines have been developed to prevent cervical cancer and genital warts. There is an available quadrivalent vaccine to prevent HPV types 6, 11, 16, and 18, and a bivalent vaccine to prevent HPV types 16 and 18 currently pending Food and Drug Administration (FDA) approval. The former vaccine has been shown to be 100% eective in preventing precancerous lesions and genital warts caused by HPV 6, 11, 16, and 18 [24]. Specic recommendations for the HPV vaccination are listed in Table 2. Ideally, the HPV vaccine should be administered before vaginal intercourse, because the benets are likely to decrease with an increasing number of lifetime sexual partners [24]. Currently, the HPV vaccine is not recommended

1020

Table 2 Immunization guidelines for women [46,47] Immunization Hepatitis A CDC recommendation Any female who desires immunity. Travel to countries other than the USA, Western Europe, New Zealand, Australia, Canada, Japan. Chronic liver disease, drug users, clotting-factor disorders, food handlers, and those working with hepatitis A in experimental labs. All females up to age 18 and women O18 who desire immunity. Health care workers and public safety workers who may be exposed to blood, sexually active and not in long-term monogamous relationship, HIV or recent STD, household contacts and sex partners of HBsAg positive persons, chronic liver disease, injecting drug users, hemodialysis or renal disease that may result in dialysis, sta and individuals in institutions for developmentally disabled, inmates of correctional facilities, international travel to endemic areas (see CDC Web site: www.cdc.gov). Same indications as above for hepatitis A and B, except only approved for those R18 years old. Schedule Two doses at 0 and 6 months Safe for use in pregnancy? Safety not established but theoretic risk considered low; weigh risks and benets.

ZEBRACK & BROWN

Hepatitis B

Three doses at 0, 1, and 6 months. Alternate dosing: 0, 2, and 4 months and 0, 1, 4 months

Yes. Serologic testing recommended early in pregnancy. Pregnant women at risk should be vaccinated.

Hepatitis A and B combination vaccine

Three doses at 0, 1, 6 months. Alternate dosing: 0, 7, 2130 days, and booster at 12 months

As above for hepatitis A and B.

Human papillomavirus (HPV)

Trivalent inactivated inuenza vaccine (TIV)

Live attenuated inuenza vaccine (LAIV)

All unvaccinated women through age 26 (even if prior HPV infection). FDA-approved for females ages 926, and recommended as routine immunization for females at age 1112. Quadrivalent vaccine is 100% eective against HPV 6, 11, 16, and 18. HPV 16 and 18 cause about 70% of all cervical cancers. HPV 6 and 11 cause genital warts. All women who want to reduce their risk for inuenza. Higher risk: Rage 50, heart disease, lung disease, kidney disease, diabetes, immunosuppression, hemoglobinopathy, cognitive dysfunction, spinal cord injury, seizure disorder, other neuromuscular disorders, health care workers, chronic care facilities, dormitory residents, pregnant women, household contacts and caregivers of children age 059 months, working or living with others at risk, travel to areas or among people from areas of the world where there is inuenza activity. Healthy nonpregnant women !age 50 who work or live with those at risk, health care workers (except if close contact with immunosuppressed people), dormitory residents, household contacts and caregivers of children age 059 months, travel to areas or among people from areas of the world where there is inuenza activity.

Three doses at 0, 2, and 6 months

Safety not established; delay until after pregnancy.

One dose yearly in fall or winter

Yes. Strongly recommended for women pregnant during DecemberMarch.

PREVENTIVE HEALTH FOR WOMEN

One dose yearly in fall or winter

Contraindicated. Pregnancy should be avoided for 4 weeks after immunization.

(continued on next page)

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Table 2 (continued ) Immunization MMR (measlesmumps-rubella) CDC recommendation Women born 1957 or later should receive at least one dose (especially if born outside the United States) if no serologic proof of immunity or no dose given on or after rst birthday. Health care workers, college students, international travelers should have two doses. Contraindicated in immunocompromised state. In HIV, may consider if CD4 count R200 cells/mcL. Schedule One or two doses Safe for use in pregnancy? Contraindicated. Pregnancy should be avoided for 4 weeks after immunization. Rubella serology recommended early in pregnancy and preconception if immunity status unknown. Vaccinate women without proof of immunity after completion of pregnancy. MCV4: safety not established; delay until after pregnancy. MPSV4: safe in pregnancy.

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Meningococcal conjugate (MCV4) and polysaccharide (MPSV4)

All females age 1118, college freshman in dorms, anatomic or functional aspenia, terminal complement deciency, travel to or living in endemic areas (eg, meningitis belt of sub-Saharan Africa), microbiologists exposed to Neisseria meningitides. All women 65 years and older, chronic heart or lung disease (excluding asthma), chronic liver disease, alcoholism, diabetes, cerebral spinal uid leak, candidate for or recipient of cochlear implant, Alaskan Natives and certain American Indian populations. Highest risk groups: anatomic or functional asplenia, sickle cell disease, chronic renal failure or nephritic syndrome, organ or bone marrow transplant, immunocompromised (eg, HIV, cancer) or on chronic immunosuppressive therapy (eg, steroids).

Pneumococcal polysaccharide (PPV)

MCV4 is preferred over MPSV4 for those 55 and younger. Only one dose if MCV4 was given. Revaccinate after 5 years (if still at risk) if MPSV4 was given. One dose; one-time second dose 5 years later for highest risk groups or if rst dose given before age 65.

Safety during rst trimester not established, but no adverse eects reported. Weigh risks and benets.

Td, Tdap (tetanusdiphtheria; tetanusdiphtheria-acellular pertussis)

All adults who did not receive the three-part series should be vaccinated. All adults booster every 10 years. If wound, booster may be needed as early as 5 years after previous dose (see www.cdc.gov for details). Tdap: all women !65 years old who have not received a previous Tdap; strongly recommended for women !65 yrs who are health care workers or in contact with infants younger than 12 months.

Unvaccinated: Td series at 0, 12, and 612 months. Td booster every 10 years. Tdap one-time dose for ages 1864 to replace one Td booster.

Varicella (chicken pox)

Zoster (shingles)

All adult women without evidence of immunity (eg, previous chicken pox or serologic proof of immunity). Contraindicated in immunocompromised state. In HIV, may consider if CD4 count R200 cells/mcL. All women Rage 60 (even if prior shingles infection). Contraindicated in immunocompromised state.

Two doses at 0 and 1 or 2 months. If second dose is delayed do not repeat dose 1. One dose

Yes, and administering during second or third trimester is preferred. Recommended pregnancy schedule is Td at 0 and 1 month and Tdap at 6 months (post-partum). Tdap is not contraindicated in pregnancy, but data on safety are lacking. Tdap during pregnancy may be considered in certain groups (eg, adolescents, health care workers, child care providers). Contraindicated. Pregnancy should be avoided for 4 weeks after each dose.

PREVENTIVE HEALTH FOR WOMEN

Contraindicated. Pregnancy should be avoided for 3 months after immunization.

Data from Guidelines for vaccinating pregnant women from recommendations of the Advisory Committee on Immunization Practices (ACIP): Updated May 2007; with permission. Available at: http://www.cdc.gov/vaccines/pubs/downloads/b_preg_guide.pdf. Accessed November 30, 2007; and Department of Health and Human Services. Centers for Disease Control and Prevention. Advisory Committee on Immunization Practices (ACIP) Recommended adult immunization scheduled United States, October 2007 to September 2008. Vaccines and immunizations. MMWR Recomm Rep 2007;56(41):Q14. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5641a7.htm?s_cid=mm5641a7_e. Accessed November 30, 2007. 1023

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for women older than age 26 years or for males. Screening for cervical dysplasia and cancer should continue in vaccinated females according to current guidelines. See the article by Drs. Waxman and Zsemlye elsewhere in this issue for more information on cervical cancer screening and management of abnormal Pap tests. Ovarian cancer screening The ACS estimates that in 2007 there will be 22,430 new cases of ovarian cancer in the United States, and that 15,280 women will die of this disease [25]. The lifetime risk of ovarian cancer is very low, but the mortality rate is high, with a 5-year survival rate of less than 50% [26]. Long-term survival with ovarian cancer has been slow to improve because the prognosis depends on early diagnosis, and there is currently no reliable method to diagnose ovarian cancer at an early stage. Physicians and patients should be aware of the early signs and symptoms of ovarian cancer, such as abdominal or pelvic pain, urinary or bowel changes, bloating, and weight loss. The greatest indicator of risk is a family history of ovarian cancer in either the maternal or paternal line. Families that have a history of early-onset breast cancer caused by mutations in breast cancer genes (ie, BRCA1 and BRCA2) are also at risk for ovarian cancer [27]. Additional risk factors include increasing age (the disease is very rare in women under 30 years) and nulliparity. The risk for ovarian cancer is reduced with oral contraceptive (OC) use (50% decreased risk with 5 years of OC use) and history of pregnancy of any duration. Routine screening for ovarian cancer is not recommended by any medical organization. The ACS states that women at high risk for ovarian cancer (eg, strong family history, BRCA1 and BRCA2) may consider screening [18]. Combining the transvaginal ultrasonography (TVU) and measurement of cancer antigen 125 (CA-125) is the most common type of screening offered to women at high risk [27]. Physicians should discuss the limitations of these tests with women considering screening. More than 50% of early-stage tumors fail to produce elevated CA-125 levels, and many benign conditions can lead to elevated CA-125 levels, including pregnancy, pelvic inammatory disease, tuberculosis, and cirrhosis of the liver [27]. Although the TVU provides a more accurate assessment of the ovaries than either manual examination or conventional abdominal ultrasound, it is not 100% accurate, and may lead to false-positive ndings resulting in signicant anxiety and unnecessary surgeries, as well as false-negative results. Uterine cancer screening Uterine or endometrial cancer is the most common invasive gynecologic cancer in women, with approximately 36,100 new cases each year [25]. The lifetime risk of developing uterine cancer for an American woman is 2%,

PREVENTIVE HEALTH FOR WOMEN

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and it is estimated that approximately 6500 women will die of uterine cancer in the United States each year [25]. Risk factors for endometrial cancer include early menarche, late menopause, few pregnancies, infertility, family history, obesity, diabetes, polycystic ovarian syndrome, prior pelvic radiation, taking the medication tamoxifen, and having (or being at risk for) hereditary non-polyposis colon cancer (HNPCC). Routine screening for uterine cancer is not recommended by any medical organization; however, for women who have or are at high risk for HNPCC, yearly screening should be oered with endometrial biopsy beginning at age 35 [18]. Patients on tamoxifen may consider periodic screening after a discussion with their physician. The ACS recommends that at the time of menopause women be counseled about the symptoms of endometrial cancer and encouraged to report any unexpected bleeding to their health care provider [18]. Abnormal bleeding or undiagnosed postmenopausal bleeding warrants immediate evaluation with endometrial biopsy or dilatation and curettage of the uterus. TVU for the evaluation of the thickness of the endometrium can be used in some patients instead of immediate biopsy [28]. Skin cancer screening Skin cancers, which include basal cell carcinoma, squamous cell carcinoma, and melanoma, occur more commonly than any other type of cancer. Basal and squamous cell carcinomas are usually cured by surgical removal [29]. Melanoma is a potentially fatal type of skin cancer that begins in the melanocytes. The incidence rate of melanoma has been climbing steadily since the early 1970s. The ACS estimates that almost 60,000 cases of melanoma will be diagnosed and that 8000 deaths will occur from the disease in 2007 [25]. The primary risk factors for melanoma are family history, presence of atypical mole syndrome, history of previous melanoma, fair skin/ blue eyes/red hair, history of blistering sunburn, and numerous moles [30]. When detected early, most melanomas can be cured with surgery alone. The ACS recommends that women check their own skin about once a month and have a skin examination every 3 years if between the ages of 20 and 40, and annually if over age 40 [30]. Women should use a full-length mirror to familiarize themselves with the pattern of moles on their skin. It is important to notice any new moles or changes in the size, shape, or color of existing moles. The ABCD rule can also help in the evaluation of moles. The presence of any of these signs would be more concerning for melanoma: (1) asymmetry, (2) irregular border, (3) color irregularity, and (4) diameter wider than 6 mm [30]. Within the rst 5 years of a diagnosis of non-melanoma skin cancer, an estimated 30% to 50% of patients will develop another non-melanoma skin cancer [31]. Patients who have had non-melanoma skin cancer are also at increased risk of developing melanoma. Patients who have been diagnosed

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with melanoma have a 10 to 25 times greater risk of developing a second melanoma than the general population. As a result of this increased risk, these patients should be evaluated every 6 months for 5 years, then annually [32].

Screening for sexually transmitted diseases Sexually transmitted diseases (STDs) remain a major public health challenge in the United States. The Centers for Disease Control and Prevention (CDC) estimates that 19 million new infections occur each year, almost half of them among young people ages 15 to 24 [33]. In addition to the physical and psychologic consequences of STDs, direct medical costs associated with STDs in the United States are estimated to be as high as $14 billion annually [34]. Because Chlamydia trachomatis is common among young women, the CDC recommends annual Chlamydia screening for all sexually active females under the age of 26, as well as for older women who have risk factors such as new or multiple sex partners [35]. Screening pregnant women who are at increased risk for Chlamydia is recommended at the rst prenatal visit [35]. Pregnant women who remain at increased risk or who acquire a new risk factor, such as a new sexual partner, should be screened during the third trimester [35]. Chlamydia nucleic acid amplication tests have high specicity and sensitivity, and can also be used with urine and vaginal swabs, enabling screening without a pelvic examination [35]. Women should be screened for gonorrhea if they are at increased risk for infection, but routine screening is not recommended in low-risk women [5]. The CDC recommends that all sexually active persons between the ages of 13 to 64 years of age be tested for HIV after the patient has been notied that testing will be performed (unless the patient declines) [36]. Those individuals at high risk should be screened annually (eg, IV drug users, multiple sex partners, women who exchange sex for money) [36]. Pregnant women should be screened early in pregnancy and repeat testing should be performed during the third trimester in high-risk patients and in areas with high HIV infection rates [36]. Rapid HIV testing is recommended for women in labor with no documented HIV test during pregnancy [36]. In addition to HIV, pregnant women should be screened for hepatitis B and syphilis early in pregnancy [5]. For further information on STDs, see the article by Dr. Trigg and colleagues elsewhere in this issue.

Osteoporosis screening Osteoporosis causes more than 1.5 million fractures annually (300,000 hip fractures, 700,000 vertebral fractures, 250,000 wrist fractures, and more than 300,000 fractures in other bones) [37]. The estimated cost for

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osteoporosis and related injuries is over $18 billion each year in the United States [37]. Approximately 80% of individuals who have osteoporosis are women. The prevention of osteoporosis involves several aspects, including nutrition, exercise, and screening. Women should be counseled about daily calcium and vitamin D requirements. Not getting enough calcium during a lifetime signicantly increases the risk of developing osteoporosis. According to the National Osteoporosis Foundation (NOF), adults under age 50 need 1000 mg of calcium daily, and adults age 50 and over need 1200 mg of calcium daily [38]. Good sources of calcium include low-fat dairy products (eg, milk, yogurt, cheese, and ice cream), dark green leafy vegetables (eg, broccoli, collard greens, and spinach), sardines and salmon with bones, tofu, almonds, and foods with added calcium such as orange juice, cereals, soy products, and breads. Calcium supplements are also available. Vitamin D is important for calcium absorption. If one is vitamin D decient, the body uses bone calcium to maintain serum calcium levels within tight limits, thereby contributing to bone loss. Vitamin D comes primarily from two sources: it is made in the skin through direct exposure to sunlight, and it comes from vitamin D-rich foods. Vitamin D is found in fortied dairy products, egg yolks, saltwater sh, and liver. Vitamin D production decreases with age, in those using sunscreens, those living at higher latitudes, and during the winter when sun exposure is decreased. In many cases, women may need vitamin D supplements to ensure a daily intake of 400 to 800 IU if under the age of 50, and 800 to 1000 IU if over the age of 50 [38]. Women at risk for osteoporosis should be screened for vitamin D deciency with a 25 hydroxy vitamin D level (normal range approximately 30 to 100 ng/mL). The best exercises to prevent osteoporosis are weight-bearing exercises that work against gravity. These exercises include walking, hiking, jogging, climbing stairs, playing tennis, jumping rope, and dancing. Furthermore, resistance exercises such as weight lifting help to build muscle mass and strengthen bone. Additional benets of exercise include improved coordination and balance, which may lead to reduced fall risk [37]. The NOF and USPSTF recommend that all women age 65 and older be screened for osteoporosis with a bone density test [5,39]. The NOF recommends that postmenopausal women under the age of 65 be screened if they have suered a low-trauma fracture or have one or more risk factors for osteoporosis: weight under 127 lbs, smoking, family history of osteoporotic fracture, alcohol abuse, low calcium intake, premature menopause, medications associated with bone loss (eg, steroids, anticonvulsants, methotrexate, medroxyprogesterone acetate, aromatase inhibitors, too much thyroid replacement, gonadotropin-releasing hormones), and certain medical conditions (eg, hyperparathyroidism, Cushings disease, acromegaly, hyperthyroidism, hyperprolactinemia, eating disorders, Crohns disease, celiac disease) [39]. The USPSTF recommends that women at increased risk begin

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screening at age 60, rather than age 65 [5]. Dual-energy radiograph absorptiometry (DXA) is currently the best method for measuring bone density [5]. The optimal interval for repeated screening is currently unknown; at least 2 years may be needed to reliably measure a change in bone mineral density [5]. For more information on osteoporosis, see the article by Dr. Lund elsewhere in this issue. Vision screening Several common eye conditions, such as glaucoma, cataracts, diabetic retinopathy, and macular degeneration, may occur with no or only mild symptoms [40]. With appropriate intervention, potentially blinding diseases often have a favorable outcome. For adults who have no risk factors for eye disease, the American Academy of Ophthalmology recommends a comprehensive eye evaluation every 5 to 10 years for those under 40, every 2 to 4 years for those 40 to 54, every 1 to 3 years for those age 55 to 64, and every 1 or 2 years for those 65 years and older [40]. Patients who have risk factors or symptoms of eye disease may require additional evaluations during these periods. Screening for hearing loss Hearing loss is a prevalent chronic condition among adults of all ages, and aects approximately 30 million Americans. The number of Americans who have hearing loss has doubled in the past 30 years [41]; however, adults tend to ignore its eects and delay seeking care. The most common risk factors for hearing loss include age, noise exposure, and family history. The American Speech-Language-Hearing Association recommends that adults be screened with a formal hearing test preformed by a certied audiologist at least every decade through age 50, and at 3-year intervals thereafter [41]. Screening for domestic violence Approximately one out of every four women will experience domestic violence sometime during their lives [42]. Clinicians should be alert to the subtle signs of domestic violence. In addition to physical abuse, victims may experience intimidation, isolation from family and friends, loss of control over nances, using children to manipulate, and possessiveness. Risk factors for abuse include pregnancy, lower socioeconomic status, mental health problems, substance abuse, and history of childhood abuse. Brief screening instruments are available, such as the four-item HITS (Hurt-Insult-ThreatenScream) and three-item Partner Violence Screen (PVS) (Box 3) [43]. The National Domestic Violence Hotline (1-800-799-SAFE) and National Coalition Against Domestic Violence Web site (http://www.ncadv.org/) are

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Box 3. Partner violence screen for domestic violence [43] Have you been hit, kicked, punched, or otherwise hurt by someone within the past year? If so, by whom? Do you feel safe in your current relationship? Is there a partner from a previous relationship who is making you feel unsafe now?
From USPSTF. Screening women and elderly adults for family and intimate partner violence. Available at: http://www.ahrq.gov/clinic/3rduspstf/famviolence/ fvrevapp3.htm. Accessed December 10, 2007.

resources available to victims of abuse. More detailed information on domestic violence can be found in the article by Dr. Toohey elsewhere in this issue.

Screening for depression The USPSTF recommends that health professionals screen women for depression [5]. Risk factors for depression include female gender, family history, unemployment, chronic illnesses, substance abuse, and other psychiatric illnesses (eg, anxiety). Multiple screening instruments are available, such as the Zung Self-assessment Depression Scale and the Beck Depression Inventory. A brief screening intervention asking only two questions is also eective: (1) Over the past 2 weeks, have you felt down, depressed or hopeless?, and (2) Over the last 2 weeks, have you had little interest or pleasure in doing things? [5].

Screening for alcohol misuse The USPSTF recommends that women be screened for alcohol misuse [5]. Hazardous (or risky) drinking is dened as more than 7 drinks per week or more than 3 per occasion for women, compared with more than 14 per week or more than 4 per occasion for men [5]. Harmful drinking is dened as alcohol use that results in physical, social, or psychologic harm but does not meet the criteria for dependence. Alcohol abuse and dependence should be suspected when alcohol use has resulted in repeated negative physical, social, or psychologic harm [5]. Pregnant women and women contemplating pregnancy should be advised to abstain from alcohol during pregnancy and counseled about the harmful eects of alcohol on the fetus [5]. Brief screening tools include the CAGE and TWEAK tests (Boxes 4 and 5) [44]. The TWEAK tool is often preferred in women, especially during pregnancy, because it detects lower levels of alcohol consumption [5]. These and

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Box 4. Screening for alcohol problems using the CAGE testa 1. 2. 3. 4. Have you ever felt you should cut down on your drinking? Have people annoyed you by criticizing your drinking? Have you ever felt bad or guilty about your drinking? Have you ever had a drink rst thing in the morning (eye opener) to steady your nerves or to get rid of a hangover?
a

Two Yes answers identify a problem with alcohol.

other screening instruments are available on the National Institute on Alcohol Abuse and Alcoholism Web site (www.niaaa.nih.gov/Publications/ AlcoholResearch/). Screening for tobacco abuse Smoking is the leading preventable cause of death in the United States, and lung cancer is the leading cause of cancer death among American women [25]. About 90% of all lung cancer deaths among smoking women are attributable to smoking. Women who smoke also signicantly increase their risk for menstrual problems, infertility, pregnancy complications, early menopause, more severe menopausal symptoms, osteoporosis, lung disease, heart disease, and stroke [5]. Women smokers who take oral contraceptives that contain estrogen increase their risk for venous thromboembolism and

Box 5. Screening for alcohol problems using the TWEAK testa 1. How many drinks does it take to make you feel high? 2. Have friends or relatives worried about your drinking in the past year? 3. Do you sometimes take a drink (eye opener) in the morning when you rst get up? 4. Has someone ever told you about things you said or did while you were drinking that you could not remember? 5. Do you sometimes feel you should cut down on your drinking?
a The maximum score on the test is seven points; the rst two questions count for two points each and the last three count for one point each. For question number one, if a woman responds that it takes three or more drinks to feel high, she scores two points. If she responds less than three, she scores zero on the question. A total score of two or more on the test is an indication of harmful drinking and further evaluation is indicated.

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cardiovascular events (eg, stroke and heart attack), especially if they are 35 years of age and older. The USPSTF strongly recommends that clinicians screen for tobacco use and provide smoking cessation interventions [5]. Brief screening and counseling interventions (3 minutes or less) have proven to increase quit rates [5]. The 5-A counseling strategy can help to provide a framework for these brief interventions (Box 6); however, brief interventions are less eective in pregnant smokers, and more detailed pregnancy-tailored counseling with self-help materials are recommended in these women [5].

Immunizations for women A 2007 nationwide survey of adults reveals that adult immunization rates are low in the United States [45]. Only 69% and 66% of adults aged 65 and older had been immunized against inuenza and pneumococcal disease, respectively. Furthermore, only 44% of these adults aged 65 and older had received a tetanus-diphtheria (Td) booster within the last 10 years, and only 2% of the adults aged 18 to 64 had received a tetanus-diphtheria-acellular pertussis (Tdap) booster. With regard to the newer vaccines, only 2% of eligible adults aged 60 and older had received the shingles vaccine, and only 10% of women aged 18 to 26 had received at least one dose of the HPV vaccine. Primary care physicians should develop strategies in their clinics to ensure that their patients receive these necessary vaccinations. Box 7 lists several approaches for increasing immunization rates in the outpatient setting. The pneumococcal vaccine is recommended for all women 65 years and older (or sooner if at risk), and the inuenza vaccine is recommended for all women 50 and older (or sooner if at risk). The HPV vaccine is recommended as a routine immunization for females at age 11 or 12 and as a catch-up vaccine for all women up to age 26. Women should have a Td booster every 10 years, with a one-time Tdap sometime between the ages of 18 and 64. The shingles vaccine is recommended for women 60 years of age and older. More detailed vaccination information is listed in Table 2 (eg, dosing schedule, use in pregnancy, contraindications).

Box 6. The 5-A counseling strategy for smoking cessation Ask about tobacco use. Advise to quit and personalized risks. Assess readiness to quit. Assist to quit. Arrange follow-up and support.

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Box 7. Strategies for increasing immunizations rates Support staff to routinely screen patients for needed vaccines on check-in Standing orders for immunizations Electronic medical record or computerized prompts Immunization record in all patient charts Patient education materials easily available in clinic Drop-in immunization clinics Physician feedback on patient panel immunization rates Mail or phone reminders to patients There is no evidence that inactivated vaccines or toxoids are harmful in pregnancy, but the risks and benets should be weighed [46]. The benets of vaccinating a pregnant woman may outweigh the potential risks when: (1) the likelihood of disease exposure is high, (2) infection would pose a risk to the mother or fetus, and (3) the vaccine is unlikely to cause harm. Live vaccines pose a theoretic risk to the fetus and are contraindicated in pregnancy [46]. Breast-feeding is not a contraindication to any inactivated or live vaccine except smallpox [46]. Refer to the CDC Web site (www.cdc. gov) for the most updated recommendations for vaccine use in pregnancy and lactation. References
[1] Mosca L, Banka CL, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation 2007;115:1481501. [2] Department of Health and Human Services, Centers for Disease Control and Prevention. Leading causes of death in females, United States, 2004. Available at: http://www.cdc. gov/women/lcod.htm. Accessed November 3, 2007. [3] Pickering TG, Hall JE, Appel LJ, et al. American Heart Association scientic statement: recommendations for blood pressure measurement in humans and experimental animals. Part 1: blood pressure measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Hypertension 2005;45:14261. [4] Chobanian AV, Bakris GL, Black HR, et al. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 complete report. Hypertension 2003;42:120652. [5] Department of Health and Human Services, Agency for Healthcare Research and Quality, U.S. Preventive Services Task Force. Available at: http://www.ahcpr.gov/clinic/uspstx. htm. Accessed November 5, 2007. [6] American Association of Clinical Endocrinologists. Medical guidelines for clinical practice for the diagnosis and treatment of dyslipidemia and prevention of atherogenesis. Endocr Pract 2000;6:162213.

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[7] National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) nal report. Circulation 2002;106(25):3143421. [8] Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110(2):236. [9] NHLBI Obesity Education Initiative. Clinical guidelines on the identication, evaluation, and treatment of overweight and obesity in adults: the evidence report. Bethesda (MD): U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute; 1998. NIH publication no. 98-4083. Available at: http://www.nhlbi.nih.gov/guidelines/obesity/ob_home.htm. Accessed November 5, 2007. [10] American Diabetic Association. Standards of medical care in diabetesd2007. Diabetes Care 2007;30(S1):S141. [11] American Association of Clinical Endocrinologists. Medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract 2007;13(S1):S166. [12] American College of Obstetricians and Gynecologists (ACOG). Gestational diabetes. Washington, DC: American College of Obstetricians and Gynecologists (ACOG); 2001. p. (ACOG practice bulletin; no. 30). [13] Columbia University Medical Center. Department of surgery. Available at: http://www. columbiasurgery.org/cli/endo/thyroid.html. Accessed December 7, 2007. [14] American College of Obstetricians and Gynecologists. Practice bulletin no. 37: thyroid disease in pregnancy. Washington, DC: American College of Obstetricians and Gynecologists; 2002. [15] AACE Thyroid Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract 2002;8:45769. [16] American Cancer Society. Cancer reference information. Available at: http://www.cancer.org/ docroot/CRI/content/CRI_2_2_1X_How_many_people_get_breast_cancer_5.asp?rnavcri. Accessed October 15, 2007. [17] Boyd NF, Guo H, Martin LJ, et al. Mammographic density and the risk and detection of breast cancer. N Engl J Med 2007;356:22736. [18] Smith RA, Cokkinides V, Eyre HJ. American Cancer Society guidelines for the early detection of cancer, 2006. CA Cancer J Clin 2006;56:1125. Available at: http://www.cancer.org/ docroot/PED/content/PED_2_3X_ACS_Cancer_Detection_Guidelines_36.asp?sitearea PED. Accessed November 30, 2007. [19] American College of Obstetricians and Gynecologists. Primary and preventive care: periodic assessments. ACOG Committee opinion 246. Washington, DC: ACOG; 2000. [20] Vogel VG, Costantino JP, Wickerham DL, et al. Eects of tamoxifen vs. raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP study of tamoxifen and raloxifene (STAR) P-2 trial. JAMA 2006;295:272741. [21] Land SR, Wickerham DL, Costantino JP, et al. Patient-reported symptoms and quality of life during treatment with tamoxifen or raloxifene for breast cancer prevention: the NSABP study of tamoxifen and raloxifene (STAR) P-2 trial. JAMA 2006;295:274251. [22] American College of Obstetricians and Gynecologists. ACOG Committee Opinion No. 384: colonoscopy and colorectal cancer screening and prevention. Obstet Gynecol 2007;110: 1199202. [23] American College of Obstetricians and Gynecologists Committee on Practice Bulletins. ACOG practice bulletin: cervical cytologic screening. Obstet Gynecol 2003;102(2):41727. [24] Centers for Disease Control and Prevention. Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2007;56:124.

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[25] American Cancer Society. Cancer facts and gures 2007. Available at: http://www.cancer.org/ docroot/MED/content/downloads/MED_1_1x_CFF2007_Estimated_New_Cases_Deaths_ by_Sex_US.asp. Accessed December 7, 2007. [26] Ries LAG, Eisner MP, Kosary CL, et al, editors. SEER Cancer Statistics Review, 1975 2002. Available at: http://seer.cancer.gov/csr/1975_2002/. Accessed May 16, 2008. [27] Stirling D, Evans DG, Pichert G, et al. Screening for familial ovarian cancer: failure of current protocols to detect ovarian cancer at an early stage according to the international federation of gynecology and obstetrics system. J Clin Oncol 2005;23:558896. [28] Oncology Information Center. Available at: http://patient.cancerconsultants.com/ CancerTreatment_Uterine_Cancer.aspx?LinkId54047. Accessed December 7, 2007. [29] Skin Cancer Foundation. Available at: http://www.skincancer.org/. Accessed December 7, 2007. [30] American Cancer Society. Monitor your skin for changes. Available at: http://www.cancer. org/docroot/NWS/content/NWS_1_1x_Monitor_Your_Skin_for_Signs_of_Skin_Cancer. asp. Accessed December 7, 2007. [31] Rosenberg CA, Khandekar J, Greenland P, et al. Cutaneous melanoma in postmenopausal women after nonmelanoma skin carcinoma: the Womens Health Iinitiative Observational Study. Cancer 2006;106:65463. [32] Oncology Information Center. Available at: http://patient.cancerconsultants.com/ CancerTreatment_Skin_Cancer.aspx?LinkId54623. Accessed October 23, 2007. [33] Weinstock H, Berman S, Cates W Jr. Sexually transmitted diseases among American youth: incidence and prevalence estimates, 2000. Perspect Sex Reprod Health 2004; 36(1):610. [34] Chesson HW, Blandford JM, Gift TL, et al. The estimated direct medical cost of STDs among American youth, 2000. 2004 National STD Prevention Conference. Philadelphia, PA. March 811, 2004. Abstract P075. [35] Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2006. MMWR Recomm Rep 2006;55:194. [36] Centers for Disease Control and Prevention. Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. MMWR Recomm Rep 2006;55(RR-14):117. [37] National Osteoporosis Foundation. Disease facts. Available at: http://www.nof.org/ osteoporosis/diseasefacts.htm. Accessed November 7, 2007. [38] National Osteoporosis Foundation. Calcium and vitamin D. Available at. http://www.nof. org/prevention/calcium_and_VitaminD.htm. Accessed December 10, 2007. [39] National Osteoporosis Foundation. Physicians guide to prevention and treatment of osteoporosis. Washington, DC: NOF; 1999. Available at: www.nof.org/physguide. Accessed December 10, 2007. [40] American Academy of Ophthalmology. Available at: http://one.aao.org/CE/PracticeGuidelines/ PPP_Content.aspx?cid153cbf54-fb49-4771-ad13-644da74d8348. Accessed November 7, 2007. [41] American Speech-Language-Hearing Association. Available at: http://www.asha.org/ public/hearing/testing#Top. Accessed November 7, 2007. [42] National Coalition Against Domestic Violence. Domestic violence facts. Available at: http:// www.ncadv.org/les/domesticviolencefacts.pdf. Accessed December 10, 2007. [43] USPSTF. Screening women and elderly adults for family and intimate partner violence. Available at: http://www.ahrq.gov/clinic/3rduspstf/famviolence/fvrevapp3.htm. Accessed December 10, 2007. [44] National Institute on Alcohol Abuse and Alcoholism. Available at: http://www.niaaa.nih. gov/Publications/AlcoholResearch/. Accessed December 10, 2007. [45] Centers for Disease Control and Prevention. CDC and National Foundation for Infectious Diseases news conference, January 23, 2008. Available at: http://www.medicinenet.com/ script/main/art.asp?articlekey86608. Accessed March 7, 2008.

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[46] Centers for Disease Control and Prevention. Guidelines for vaccinating pregnant women from recommendations of the Advisory Committee on Immunization Practices (ACIP): updated May 2007. Available at: http://www.cdc.gov/vaccines/pubs/downloads/b_preg_ guide.pdf. Accessed November 30, 2007. [47] Department of Health and Human Services. Centers for Disease Control and Prevention. Advisory Committee on Immunization Practices (ACIP) Recommended adult immunization scheduledUnited States, October 2007 to September 2008. Vaccines and immunizations. MMWR Recomm Rep 2007;56(41):Q14. Available at: http://www.cdc.gov/mmwr/ preview/mmwrhtml/mm5641a7.htm?s_cidmm5641a7_e. Accessed November 30, 2007.

Med Clin N Am 92 (2008) 10371058

Contraception: What Every Internist Should Know

Eve Espey, MD, MPHa,*, Tony Ogburn, MDb, Dana Fotieo, MDc
Department of Obstetrics and Gynecology, University of New Mexico School of Medicine, MSC 08 4700, 1 University of New Mexico, Albuquerque, NM 87131, USA b Department of Obstetrics and Gynecology, University of New Mexico School of Medicine, MSC 10 5580, 1 University of New Mexico, Albuquerque, NM 87131-0001, USA c Department of Internal Medicine, University of New Mexico, 1 University of New Mexico, Albuquerque, NM 87131, USA
a

The longstanding epidemic of unintended pregnancy in the United States continues unabated. Although the rate of unplanned pregnancy has declined somewhat over the last two decades, it continues to hover around 50% [1]. No other developed country has a rate this high. The human costs of unintended pregnancydabortion and parenting under dicult circumstancesd are high. For this reason, all physicians who treat female patients should be knowledgeable about the basics of contraceptiondboth its practical uses and its public health impact. This knowledge will make physicians, including internists, better able to counsel and provide contraceptives for individual patients and to advocate for availability and access. This article discusses the problem and determinants of unintended pregnancy. Contraceptive methods, particularly the long-acting reversible contraceptives, are reviewed and their potential impact on unintended pregnancy is examined.

Barriers to reducing unintended pregnancy Of the approximately 6 million pregnancies each year in the United States, about half are unintended [2]. Of these, approximately one million, or 42%, are aborted. Not only is the United States unintended pregnancy rate the highest of developed countries, but the abortion rate and teen
* Corresponding author. E-mail address: eespey@salud.unm.edu (E. Espey). 0025-7125/08/$ - see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2008.05.001 medical.theclinics.com

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pregnancy rate are similarly high [3]. European countries have far lower unintended pregnancy, teen pregnancy, and abortion rates. Why is one of the richest nations in the world plagued by such poor reproductive health statistics? The answer lies in the unique social, political, and medical landscape in the United States. Socially, we have made the decision to tie health care to an employer-based insurance system that does not cover all Americans, often does not cover all contraceptives, and does not adequately cover costs even when contraceptives are included. Additionally, we remain an odd blend of commercialism and prudishness [4]. Capitalism drives unbridled sexuality in the media but Puritan roots drive a strong reluctance to discuss sexuality as a normal component of human behavior, leading to the illogical but widely adopted implementation of abstinence-only sex education. Bipartisan politics hold womens reproductive health hostage: increasingly, contraception and abortion come under the purview of politics, not of the health care system. Far reaching reproductive health decisions are made by courts instead of by patients and their physicians. Medically, the birth control pill continues to dominate the reversible contraceptive market in the United States, despite our knowledge that other methods work much better in typical use. Intrauterine contraception and implantsdsimilar in the lack of patient compliance required for usedare the gold standard of reversible contraception, yet are used by a fraction of women because of attitude, training, and cost barriers [5]. Abstinence-only sexuality education Over the last decade, the federal government has allocated over a billion dollars to abstinence-only sexuality education for teenagers. Abstinenceonly education specically prohibits education about contraceptives and has been adopted throughout the country. From 1995 to 2002 formal instruction about birth control methods declined from 81% to 66% for adolescent males and from 87% to 70% for females [6]. No federal money has been allocated to comprehensive sexuality education, in which abstinence is stressed but contraceptives are discussed. Not only do most Americans believe that contraception and sexually transmitted infection (STI) prevention should be included in sexuality education [7], but professional organizations, including the American College of Obstetrician Gynecologists, also support a more comprehensive approach [8]. European countries, such as Sweden and the Netherlands, both with much lower rates of unintended pregnancy and abortion, are known for early and accurate sexuality education coupled with easy access to contraceptives [9]. Lack of access to contraceptives: no insurance, underinsurance and insurance regulations Lack of adequate insurance is a barrier to contraceptive use. It is estimated that one in ve reproductive-aged women was uninsured in

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2003 [10]. About 17 million women depend on publicly funded family planning services. Despite the rapidly growing population segment that requires assistance to access family planning, funding for family planning has been reduced or remained at over the last decade. Federal Healthy People 2010 goals include Increasing the proportion of health insurance policies that cover contraceptive supplies and services [11], yet no federal law requires contraceptive coverage and only 26 states have enacted contraceptive equity laws [12]. Such laws improve access to contraceptives, with the full range of contraceptives oered by 90% of insurance companies in states with equity laws compared with only 56% in states without such a law [13]. Additional barriers to contraceptive use even in women with insurance include:  Co-pays and deductibles. These are often high enough to discourage consistent contraceptive use: women pay substantial out-of-pocket costs for contraceptives, higher than those for other medications [14]. In European countries, all women have insurance coverage and contraceptives are universally covered.  One month at a time. The majority of insurers dispense only 1 month of contraceptives at a time with a co-pay required each month. Women may only access the next month of contraceptives within a narrow window of time with the net eect of obstructing consistent contraceptive use. This may be cost-saving in the short run but impedes consistent contraceptive use, resulting in increased overall costs. Societal supports for unintended pregnancy and early motherhood In contrast to school based abstinence-only messages, the content of media is sexually explicit. Over 70% of shows geared to teens include sexual content, though little of that content promotes responsible sexuality [15]. Ironically, networks have highly restrictive policies about advertising for birth control but advertisements for male erectile dysfunction are widespread. The combination of sexually charged media and reduced access to contraceptive information and supplies may be a major determinant of unintended pregnancy. Teenagers in the United States are more likely than teens in other countries to become pregnant and to continue their pregnancies. United States teens still have more abortions than teens in other developed countries because of the high rate of unplanned pregnancy in United States adolescents [9]. Surveys reveal that United States teens are more likely to desire motherhood than teens in other countries [16]. Poverty and social disadvantage increase the risk of early childbearing and unplanned pregnancy, but teens across the socioeconomic spectrum in the United States are more likely to experience unplanned pregnancy than their counterparts in other countries. Investigators have speculated that one factor explaining decreased teen childbearing in other countries is the strong social support for the concept of reserving parenting for

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adulthood. Similarly, the acceptance of sexual activity in young people and the pragmatic approach of making sexuality education and contraceptives readily available are features of European countries that have low unplanned pregnancy and abortion rates [16]. In the United States, well-intentioned social supports are designed to assist teen mothers. Special schools allow young mothers to return to school and nancial aid assists with health care and food purchases. These supports may paradoxically serve an enabling role and send a message that teen pregnancy is acceptable. Choice of method A major reason for high-unintended pregnancy may be the top methods chosen by American women. In the 2002 National Survey of Family Growth, a periodic survey conducted by National Center for Health Statistics, the most common three methods in order were oral contraceptives (used by 31% of reproductive-aged women using contraception), followed by female sterilization (27%) and condoms (18%) [5]. Other methods are used much less commonly. Although sterilization is an extremely reliable form of contraception, the two most commonly used reversible methods, condoms and oral contraceptive pills, are prone to inconsistent use and human error. Both methods are plagued by typical use pregnancy rates that deviate greatly from perfect use rates (Table 1). Additionally, to determine the true eectiveness of a contraceptive method, the likelihood of continuing that method must factor into the equation. Although oral contraceptive continuation is relatively high, use of condoms has a very low continuation. The World Health Organization has dened the hierarchy of contraceptive methods, from most eective (top tier) to least eective. The top tier contraceptivesdintrauterine devices (IUDs), implants, and sterilizationd all have in common that no ongoing compliance is required for long-term use (Fig. 1). Of the three, only sterilization is widely used in the United States. Contraceptive implants have just reappeared on the American market after a hiatus of 6 years. A six-rod contraceptive implant, removed from the market in 2000, was used by fewer than 5% of contraceptive users. The extent of use of a new one-rod implant available in the United States since 2006, is unknown at this time. The IUD, the most common method of reversible contraception worldwide, is used by only 1.3% of American women contraceptive users. Unfortunately, the IUD is still plagued by an unearned negative reputation, perpetuated by both the public and by physicians. Physicians can play a major role in improving womens ability to contracept by becoming knowledgeable about current safety and acceptability data for long-term forgettable contraceptives and advocating for these safe, long-term methods. Increased use of IUDs, implants, and sterilization could have a signicant impact in reducing the rate of unintended pregnancy in the United States.

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Table 1 Contraceptive failure rates- perfect versus typical use First-year contraceptive failure rates Method Pill (combined) Tubal sterilization Male condom Vasectomy 3-month injectable Withdrawal IUD Copper-T IUD Periodic abstinence Calendar Ovulation method Sympto-thermal Post-ovulation 1-month injectable Implant Patch Diaphragm Sponge Women who have had a child Women who have never had a child Cervical cap Women who have had a child Women who have never had a child Female condom Spermicides No method Perfect usea 0.3 0.5 2.0 0.1 0.3 4.0 0.6 0.1 9.0 3.0 2.0 1.0 0.05 0.05 0.3 6.0 20.0 9.0 26.0 9.0 5.0 18.0 85.0 Typical use 8.0 0.5 15.0 0.15 3.0 27.0 0.8 0.1 25.0 25.0 25.0 25.0 3.0 0.05 8.0 16.0 32.0 16.0 32.0 16.0 21.0 29.0 85.0

a Most perfect-use rates have been clinically evaluated, but some are based on clinical expertise or best guesses (such as some forms of periodic abstinence, withdrawal and no method use). Data from Guttmacher Institute. Facts on contraceptive use. Available at: http://www. guttmacher.org/pubs/fb_contr_use.html. Accessed June 30, 2008.

Contraceptive methods Intrauterine contraception IUDs are small, T-shaped, plastic devices inserted in the uterus (Figs. 2 and 3). The hormonal IUD, the levonorgestrel (LNG) intrauterine system, and the copper IUD (Copper T380A) are the two IUDs available in the United States. Both are highly eective, with low failure rates and work primarily by preventing fertilization because of an intrauterine sterile inammation that is spermicidal. Costs of IUDs are front-loaded: they are relatively expensive and insertion fees are high. However, over time IUDs are the most cost-eective of available birth control methods.

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Fig. 1. Comparative eectiveness of contraceptive methods. (Courtesy of Family Health International, Durham, NC. http://www.fhi.org/nr/shared/enFHI/Resources/EectivenessChart.pdf; with permission.)

Fig. 2. Copper T380A intrauterine device. (Courtesy of Barr Pharmaceuticals, Inc., Pomona, NY; with permission. Copyright 2008 Duramed Pharmaceuticals, Inc. All rights reserved.)

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Fig. 3. LNG-IUS intrauterine device. (From Gupta S. Non-oral hormonal contraception. Curr Obstet Gynaecol 2006;16:34; with permission.)

Levonorgestrel intrauterine system and copper (T380A) IUD The LNG intrauterine system (IUS) is eective for 5 years and has a failure rate of less than 1%. It releases a small amount of progestin into the uterus that thins the endometrium. During the rst 1 to 3 months of use, the LNG-IUS may cause irregular spotting and bleeding, but thereafter typically causes a substantial reduction in menstrual blood loss. Approximately 20% of users become amenorrheic. The copper IUD is eective for 10 years and also has a failure rate of about 1%. The copper IUD may initially cause heavier menses and dysmenorrhea, although these usually decrease with time. Most women are good candidates for IUDs, even young nulliparous women. Despite its reputation, the IUD does not cause pelvic inammatory diseasedexcept for a brief period of slightly increased risk at the time of insertiondor infertility [17,18]. It is not an abortifacient, as it prevents fertilization or implantation but does not disrupt an established pregnancy [19]. The IUD is an acceptable option for women with a history of ectopic pregnancy [20]. Intrauterine contraception may be particularly suitable for women who have medical problems, such as history of thromboembolism, hypercoagulable disorders, or migraines with aura, in whom estrogen is contraindicated [19]. Advantages and disadvantages Intrauterine contraception is highly eective and requires no action after placement of the device. User satisfaction with the IUD is excellent and return to fertility occurs as soon as the IUD is removed. Disadvantages include the small risk of uterine perforation (about 1 in 1,000 insertions), expulsion (about 3%), and infection (the risk of pelvic infection is slightly increased for the rst 20 days after insertion). The copper IUD has no hormonal content, so it is a good choice for women who wish to avoid

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hormones as well as women who are breastfeeding. The LNG-IUS may cause irregular unpredictable bleeding, typically limited to the rst 1 to 3 months of use. IUDs do not protect against STIs. In general, for most women advantages of the IUD far outweigh the disadvantages. Etonogestrel implant A new contraceptive implant on the market is a single rod inserted under the skin of the upper arm (Fig. 4). It releases a synthetic progestin, etonogestrel, and protects against pregnancy by preventing ovulation. The method is highly eective for up to 3 years, with a failure rate of less than 1% [21]. The implant may be placed by trained physicians and advanced practice clinicians. The simple procedure only takes approximately 5 to 10 minutes. The implant is placed in the medial aspect of the upper arm, using a small amount of local anesthetic. It is placed directly into the skin through a large bore needle inserter. Signicant pain or other complications are rare with the procedure. Removal of the implant is also typically straightforward, with rapid return to fertility. As with the IUD, up-front costs are relatively high, but this device is highly cost eective over time. Advantages and disadvantages The major advantages of the implant are its outstanding eectiveness and its convenience: no action is required on the patients part after placement of the device. The major disadvantage of the implant is irregular bleeding, which may last for the entire 3 years of the implant [22]. The bleeding is typically light or spotting, but is unpredictable. Despite the irregular bleeding, continuation is excellent. Over 90% of women continue the method at 1 year and 72% at 3 years [23].

Fig. 4. Etonogestrel-releasing contraceptive implant disposable applicator. (From Funk S, Miller MM, Mishell DR, et al. Safety and ecacy of Implanon, a single-rod implantable contraceptive containing etonogestrel. Contraception 2005;71:320; with permission.)

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Sterilization Female and male sterilization together constitute the leading method of contraception in the United States. Tubal sterilization may be performed laparoscopically, through a mini-laparotomy, or hysteroscopically. Tubal sterilization is a permanent and highly eective method, with a lifetime failure rate of 1% or less [24]. Laparoscopic or postpartum tubal sterilization In interval laparoscopic procedures, the fallopian tubes are closed by tying, banding, clipping, cutting, or sealing them with electric current. These procedures are routinely done under general anesthesia in an operating room, usually as an outpatient surgery. The abdomen is typically insuated with CO2 gas and instruments are placed through one or two small incisions in the abdomen. Postpartum tubal sterilization is accomplished through a mini-laparotomy, usually within 1 to 2 days of a vaginal delivery. A small incision is made just below the umbilicus and the tubes are grasped, tied, and cut. The same procedure may be used for women undergoing sterilization at cesarean section. Hysteroscopic sterilization Transcervical sterilization is a recent option for permanent sterilization (Figs. 5 and 6). There is only one currently available micro-insert method in the United States, though an additional method is currently undergoing clinical trials and is anticipated to be available in the near future. Both are performed via hysteroscopy. The currently available method is highly effective, with a failure rate of less than 1%, does not involve any incisions, can be done in a doctors oce, and does not require anesthesia [25]. The procedure is performed via hysteroscopy, where a small scope is placed through the cervix into the uterus. Under direct visualization, a small spring-like coil is inserted into each fallopian tube. The device causes

Fig. 5. Transcervical sterilization. (Courtesy of Conceptus, Inc., Mountain View, CA; with permission.)

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Fig. 6. Transcervical sterilization microinsert component. (Courtesy of Conceptus, Inc., Mountain View, CA; with permission.)

inammation and scarring, with resulting brous ingrowth, occluding the fallopian tube. It takes up to 3 months for tubal occlusion and a hysterosalpingogram (HSG) must be performed to verify that the tubes are blocked. The HSG is a uoroscopic examination in which dye is injected into the uterus, verifying lack of tubal patency. Advantages and disadvantages The major advantages of tubal sterilization are its permanence and that no action is required on the patients part after the procedure is performed. Advantages of the transcervical approach are the ability to perform the procedure in the oce without anesthesia and minimal risk of complications. The major disadvantages to laparoscopic and postpartum tubal sterilization are the requirement for regional or general anesthesia, initial costs, and rare but potentially life threatening complications (vessel laceration, bowel perforation). The major disadvantages of hysteroscopic sterilization are the 3-month delay before it works and the requirement for an HSG. The major disadvantage of all forms of sterilizations is the diculty or impossibility of reversal if a woman changes her mind. Sterilization for men A vasectomy works by blocking the tubes that carry sperm from the testes to the penis, preventing the release of sperm. The vasa are tied, cut, clipped, or sealed through one or two small cuts in the skin of the scrotum. Some doctors use a no-scalpel technique. There is minimal data to determine which method is best, though fascial interposition may improve ecacy while the no-scalpel technique is associated with fewer complications [26,27]. These procedures may be done in a doctors oce, clinic, or hospital. Typically 3 months are required for the sperm count to decline to the point that the couple may rely on the method. A nal sperm count is required to ensure sterility. Reported failure rates are typically 1% or

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less, similar to that of female sterilization [28]. Advantages of male sterilization include its lower expense and fewer signicant complications compared with female sterilization. Obviously, if a woman has a new partner she will not be protected. Depo-medroxyprogesterone acetate Depo-medroxyprogesterone acetate (DMPA) is an injection that provides protection from pregnancy for 3 months. It is a highly eective form of contraception with a very low failure rate of approximately 0.1% when used correctly. Typical use failure rates are approximately 3% [29]. The method consists of a large dose of medroxyprogesterone that prevents ovulation and thickens cervical mucus [30]. DMPA is an alternative for women who have diculty using daily or weekly birth control methods, like the pill or patch. Injections are also an alternative for women with contraindications to estrogen containing hormonal methods, such as those at high risk for thromboembolism and smokers over age 35. Advantages and disadvantages Advantages of DMPA include its four-times-a-year dosing and the eventual side eect of amenorrhea in most women. Disadvantages include irregular bleeding and possible weight gain. Although most women become amenorrheic when on DMPA long-term, women can experience up to a year of irregular bleeding before becoming amenorrheic. Current use of DMPA is associated with a decrease in bone mineral density, particularly with long-term use (ie, over 2 years) [31]. Women on DMPA should engage in weight bearing exercise and have adequate calcium and Vitamin D intake. Bone loss reverses after injections are stopped, though it is unclear whether the reversal is complete [32]. Though there is at least a transient loss of bone density with DMPA use, data are reassuring that women who used DMPA in the past do not have more fractures than women who did not use DMPA. It is not recommended to limit the duration of DMPA use in a young, healthy woman if it is deemed to be the best form of contraception for her. Bone density measurements are not recommended. Another disadvantage of DMPA is the potential delay in return to fertility after stopping use. It may take 9 to 18 months to ovulate again after cessation of DMPA, which should be considered for patients considering a pregnancy in the near future [33]. Combined hormonal contraceptives: birth control pills, patch, and vaginal ring These prescription methods use a combination of two hormonesestrogen and progesterone. All combination methods work primarily by preventing ovulation [34]. Combination methods are highly eective and have several noncontraceptive benets, the most recognized of which is cycle controldmaking menses regular, light and less painfuldand are often used for

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this purpose even in women who do not require contraception. Additional noncontraceptive benets are reduction in acne and reduction in risk of uterine and ovarian cancer that may be as great as 40% to 50%, depending on length of use [35,36]. Signicant risks of combination methods are few. Combination methods increase the risk of deep venous thrombosis, but much less than the risk conveyed by pregnancy. Certain medical conditions constitute a contraindication for combination methods, including a history of thromboembolic disease, uncontrolled hypertension, migraine headache with aura, cardiovascular disease, and active liver disease [37]. An IUD or a progestin-only method, such as an etonogestrel implant, may be a better choice for such patients. Birth control pills Combination pills contain the hormones estrogen and progestin. They are highly eective when taken every day, with perfect use failure rates of less than 1%. However, the typical failure rate of combination birth control pills is 3% to 8% and much higher in some populations [38]. The range is wide because so much depends on whether women can be adherent to a daily pill regimen. Side eects of the pill, including breast tenderness, nausea, headaches, and bloating, are usually limited to the rst 1 to 2 months of use, but may discourage continuation. A backup method of birth control, such as condoms, should be used for the rst week after pills are started. Few clinical dierences have been noted among the myriad dierent pill formulations (monophasic, biphasic, triphasic, dierent generation progestins, and other formulations) so it is reasonable to prescribe a generic monophasic pill containing 30 to 35 micrograms of estrogen for most patients [39]. A recent development in combination pills are the extended dosing regimens. Three dedicated products package the pills in extended dose regimensd two in packs of 84 active pills followed by 7 placebo or low dose days, and one in packs of 28 active pills. These regimens may have the advantage of reducing scheduled bleeding. In the case of the 9-day packs, they have the additional advantage of ensuring that women have more pills on hand than the traditional one-pill pack at a time. Though studies have conrmed the safety and ecacy of these regimens, further studies are needed to determine the best formulations [40]. Progestin-only birth control pills contain only the hormone progestin and are often called the progestin-only pill or the minipill. They are not as widely used as combination pills because of their inferior ecacy and increased side eect prole. They are a better choice for women with problems, such as high blood pressure or smoking over age 35, which may be negatively impacted by estrogen containing pills. The progestin-only pill is often recommended for breastfeeding women.

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Advantages and disadvantages Birth control pills are very eective when taken daily. They make periods lighter, regular, and less painful, protect against endometrial and ovarian cancer, and can improve acne. Side eects are typically few and improve over time. Disadvantages include the need to take a pill daily and to get a prescription relled monthly. In addition, pills are contraindicated in women with certain medical conditions. Skin patch The contraceptive skin patch is a small (1.75 inch) adhesive patch that is worn on the skin (Fig. 7). The patch contains estrogen and progestin that are absorbed through the skin. The patch is worn for a week at a time for a total of 3 weeks in a row. During the fourth week, a patch is not worn, and a menstrual period occurs. After week 4, a new patch is applied and the cycle is repeated. Some patients have success using the patch in a continuous fashion: that is, using a new patch each week without having a patch free interval. Many patients will become amenorrheic with this approach but may experience irregular bleeding. A backup method of birth control, such as a condom, should be used for the rst week of the rst patch. The patch can be placed on the buttocks, chest (excluding the breasts), upper back, arm, or abdomen. It should be applied to a new place each week to avoid irritation. The failure rate of the patch is similar to that of the combination pill [41]. Concern has been raised that the ecacy of the patch may be decreased in obese patients; however, it is still highly eective

Fig. 7. Contraceptive patch. (From Swica Y. The Transdermal Patch and the Vaginal Ring: Two Novel Methods of Combined Hormonal Contraception. Obstet Gynecol Clin North Am 2007;34(1):3142; with permission.)

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if used correctly and is a reasonable choice if it is the best method for an individual patient, regardless of her weight [42]. Another concern with the patch is a possible increased risk of thromboembolic disease compared with pills. The risk is primarily theoretic because of higher total estrogen dosages, but is still much less than pregnancy [43]. Advantages and disadvantages Evidence suggests that it may be easier to remember the patch, but no major dierences in eectiveness between pill and patch have been shown. Side eects and noncontraceptive benets are similar to those of the pill. It may be a good option for patients who are not able to take oral medications. Vaginal ring Another combination estrogen and progestin hormone method is the vaginal ring (Fig. 8). It is made of exible plastic and is placed by the woman in the vagina for three weeks in a row. It also works primarily by preventing ovulation. After removal of the ring, menses period usually will start within 2 to 3 days. A new ring is inserted a week after the last one was removed. The ring may also be used in a continuous fashion with a new ring inserted once a month, with no ring free interval. Many women will become amenorrheic using this approach, though some will experience irregular bleeding. When a woman begins using the vaginal ring, she should use a backup

Fig. 8. Vaginal ring. (From Barnhart et al. In vivo assessment of NuvaRing placement. Contraception 2005;72:197; with permission.)

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method of birth control, such as condoms, for the rst 7 days of use. Rarely, the vaginal ring slips out of the vagina. If the ring is out of the vagina for more than 3 hours, a backup method of birth control should be used for 7 days. If the vaginal ring slips out often, is uncomfortable for the woman or her partner, or causes a discharge, a dierent method of birth control may be needed. The failure rate is similar to that of the combination pill. Advantages and disadvantages The ring, like the patch, has similar benets and risks as the birth control pill. The ring may be easier to remember than the pill because it only needs to be replaced once a month. A disadvantage is that some patients or their partners may feel the ring during intercourse, though this is typically not a reason for discontinuation. Barrier methods Condom The male condom is a thin sheath of latex (rubber), polyurethane (plastic), or animal membrane that is worn over the erect penis. Latex condoms not only protect against pregnancy, but are the only method to reliably protect against STIs, including HIV [44]. Condoms work better to prevent pregnancy when used with a spermicide. To be eective, a condom must be used with every act of intercourse. The failure rate with typical use is approximately 20%. Spermicides, used in conjunction with condoms, are put in suppositories, foam, cream, jelly, or lm (thin sheets) and kill or inactivate sperm. Advantages and disadvantages The major advantage of condoms is the strong protection they aord against STIs. Additionally, they are accessible and inexpensive. Disadvantages are that they are less eective than other methods, must be used with every act of intercourse, interrupt sex, and are perceived as messy, especially when used with spermicides. Sponge The sponge is a doughnut-shaped device made of foam instilled with spermicide. The sponge is wetted with water before intercourse and is inserted into the vagina, where it covers the cervix and blocks sperm from entering the uterus. The sponge may be put in the vagina up to 24 hours before sex and should be kept in place for at least 6 hours after sex. It should not be left in for more than 24 hours after sex. The sponge is relatively inexpensive and is available over the counter. The typical failure rate is high, at approximately 24% [45].

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Advantages and disadvantages Advantages include accessibility and relatively low expense. Disadvantages are its lower eectiveness than other methods and the need to use a sponge with every act of intercourse. Diaphragm The diaphragm is a small, latex dome-shaped device that ts inside the womans vagina and covers the cervix. It is relatively inexpensive and typically lasts for about two years. It works better when used with spermicide. The diaphragm can be inserted up to 6 hours before sex. After sex, the diaphragm must be left in place for 6 hours, but not more than 24 hours. A diaphragm requires a prescription and should be tted by a provider. The failure rate for the diaphragm with spermicide is about 13%. Advantages and disadvantages Using the diaphragm may reduce the risk of some STIs and if used with the male condom, provides added protection from pregnancy and STIs. The diaphragm is inexpensive. Disadvantages are that it is less eective than other methods, must be used with every act of intercourse, and is perceived as messy.

Emergency contraception Two forms of emergency contraception (or morning-after contraception) are available. There is only one dedicated product available in the United States, a high-dose progestin that may be used to prevent pregnancy for up to 5 days after an act of unprotected intercourse [46]. This high-dose progestin is most eective the earlier it is used and may prevent 87% of pregnancies. It is packaged as two pillsdthe rst taken as soon after unprotected intercourse as possible, the second taken 12 hours later. There is evidence that both tablets of this high-dose progestin may be administered as one dose with no decrease in ecacy [46]. Nausea and vomiting is unusual with progestin-only methods. This form of emergency contraception is thought to work primarily by preventing ovulation and will not disrupt an established pregnancy. It is over-the-counter for women over age 17 and requires a prescription for women aged 17 and younger. Discussing this form of emergency contraception should be routine for sexually active women using a method other than sterilization, implants, or an intrauterine device. Although this high-dose progestin is over-the-counter for most women, many are unaware of the medication. Education media campaigns, as well as individual physician-patient counseling, are needed to improve use of this form of emergency contraception. The older method of emergency contraception using combined oral contraceptive pills, known as the Yuzpe method, is not typically

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recommended because of its lower ecacy rate, lack of a dedicated product, and greater incidence of nausea and vomiting. Placement of a copper IUD is an even more eective postcoital contraceptive method that, when placed up to 7 days after unprotected intercourse, may prevent up to 99% of pregnancies. It also has the advantage that it may be maintained for long-term use and is ideal for the patient needing ongoing contraception [47]. Initiating contraception Internists may be in the position of deciding whether to initiate contraception or to refer to another physician. Ask about contraception: its an emergency! The rst step is simply to take a contraceptive history for every woman in the reproductive age range at every visit. Although women mostly visit internists for reasons unrelated to contraception, every visit constitutes a potential opportunity to make an impact on unintended pregnancy. Many women discontinue previously prescribed contraception without discussing the decision with a physician. If all reproductive aged women are considered at risk of pregnancy, the internist will identify at-risk women and initiate contraceptive counseling or make a referral. For the patient who desires intrauterine contraception, an etonogestrel implant, or permanent sterilization, specialized training is needed and unless the physician has such skills the patient should be referred in a timely fashion. However, for prescription hormonal methods, including the birth control pill, patch, and ring, the internist should consider initiating the method the same day. The clinician should also be prepared to provide information about barrier methods, such as condoms and sponges, as well as emergency contraception. Internists may even consider bridging women who desire a more permanent method with hormonal methods, if a delay to obtaining a more permanent method is anticipated. Given the epidemic of unintended pregnancy in this country, we should consider the woman sexually active with a man and not using contraception (or out of contraceptives) as a contraceptive emergency, and every eort should be made to provide an appropriate method immediately. Discuss methods or prescribe one: pills, patch, or ring In young healthy women without medical problems and who do not smoke, consider writing a prescription for pills, patch, or ring. A low dose (%35 micrograms of estrogen) generic, monophasic pill is an excellent standard pill to prescribe for contraception. Quick start is a method that may be adapted to expedite initiation [48]. In the true quick start method, the woman takes the rst pill under observation in the clinic. The pill may be

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prescribed, however, and the patient instructed to take the pill the same day. The pill may be initiated at anytime during the womans cycle. Seven days of a backup method are recommended before relying on the pills. Discussing condoms for STI prevention may also be helpful. Providers may be concerned that initiating a method can be harmful if a patient is already early in pregnancy. Sensitive pregnancy tests make this less likely, as they typically detect pregnancy 7 to 10 days after conception. Even if the patient is pregnant, hormonal methods including pills, patches, rings, DMPA, and single-rod implant, will not adversely aect the pregnancy. A Pap and pelvic examination are not required The tradition of bundling pill prescriptions with a Pap smear and a pelvic examination may lead to unintended pregnancy. The need for an oce visit may create a nancial barrier to contraceptive services. Additionally, adolescents may be intimidated by the need for a pelvic exam and forego contraception to avoid an exam. An internist may initiate pills without performing a pelvic examination or Pap smear that day. If the patient needs a Pap, it can be done that day, rescheduled to another day, or referral initiated if the physician does not perform Pap smears. Pregnancy prevention should not be made conditional on, for example, cervical cancer screening, an entirely unrelated service. In general, little is needed other than a medical history to initiate most methods. For hormonal contraceptives, major morbidity (which is quite rare) relates to patients risk for deep venous thrombosis, heart attack, and stroke. Risk factors are determined from history and rarely from physical examination. In addition to a history, a blood pressure determination and perhaps a pregnancy test are usually all that are required to initiate hormonal contraceptives. Other myths Oral contraceptives and other methods are plagued by myths that deter physicians from prescribing them and patients from using them. One such myth is that pills are generally unsafe and have many contraindications. In general, pills are quite safe with few contraindications and few true medical consequences (Box 1). Another common myth is that pills reduce the eectiveness of antibiotics, or vice versa. In fact, the only antibiotic that may reduce pill eectiveness is rifampin, an antibiotic reserved for specic circumstances and not commonly used. Similarly, many believe that anticonvulsants reduce the ecacy of hormonal contraceptives, an unlikely association. Although anticonvulsants may reduce the level of serum hormones, they have not been observed to be associated with increased incidence of ovulation or accidental pregnancy [37]. Women of reproductive age are often prescribed medications, such as angiotensin-converting enzyme inhibitors that are contraindicated in

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Box 1. Contraindications to oral contraceptive pill use Migraine headaches with focal neurologic signs Cigarette smoking in women older than 35 years History of thromboembolic disease Hypertension in women with vascular disease or older than 35 years Systemic lupus erythematosus with vascular disease, nephritis, or antiphospholipid antibodies Coronary artery disease Congestive heart failure Cerebrovascular disease including history of stroke
Data from Cook LA, Van Vliet H, Lopez LM, et al. Vasectomy occlusion techniques for male sterilization. Cochrane Database Syst Rev 2007;(2):CD003991.

pregnancy. It is important that all women of reproductive age be queried about their reproductive plans and oered contraception. Women who are planning pregnancy should be receiving focused counseling about medications that might adversely aect pregnancy. Women who are on potentially teratogenic medications should be given strong guidance about eective contraceptives, with encouragement to use a top tier method, such as an IUD or implant. Combination hormonal contraception may be safely continued until menopause in women without signicant cardiovascular risk factors, such as smoking or diabetes. The optimal way to transition women o combination hormonal contraceptives has not been studied. Women may transition either to no method or to hormone replacement therapy. A practical approach is to discontinue hormonal contraceptives at age 50 to 51, when the risk of spontaneous pregnancy is remote. If the patient continues to menstruate after discontinuing the contraceptives, she may restart the method for an additional year. If menses do not resume, no therapy is needed unless the patient has menopausal symptoms requiring treatment. Monitoring follicle-stimulating hormone levels is typically unhelpful, as decision making about perimenopausal hormone therapy is best based on clinical symptoms [37]. Summary The epidemic of unintended pregnancy in the United States is largely preventable with a combination of public health and medical measures. Although unintended pregnancy has declined over the last two decades, most would agree that a rate of almost 50% is unacceptably high. Unlike

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the cure for such complex diseases as cancer, the cure for unintended pregnancy is well known and could be implemented. Comprehensive sex education, accessibility to aordable long-term contraceptives, facilitation of procurement of ongoing prescribed contraceptives, and use of longterm forgettable methods are all strategies that could reduce unintended pregnancy and abortion in the United States. Internists are in a position to decrease the risk of unintended pregnancy for their patients. Asking all reproductive age women about their need for contraception and then providing a method or a timely referral could go a long way to decreasing the epidemic of unintended pregnancy in the United States. References
[1] Finer LB, Henshaw SK. Abortion incidence and services in the United States in 2000. Perspect Sex Reprod Health 2003;35(1):615. [2] Finer LB, Henshaw SK. Disparities in rates of unintended pregnancy in the United States. Perspect Sex Reprod Health 2006;38(2):906. [3] Darroch JE, Singh S, Frost JJ. Dierences in teenage pregnancy rates among ve developed countries: the roles of sexual activity and contraceptive use. Fam Plann Perspect 2001;33(6): 24450, 281. [4] Espey E, Cosgrove E, Ogburn T. Family planning American style: why its so hard to control birth in the US. Obstet Gynecol Clin North Am 2007;34(1):117, vii [review]. [5] Mosher WD, Martinez GM, Chandra A, et al. Use of contraception and use of family planning services in the United States: 19822002. Adv Data 2004;350:135. [6] Duberstein LL, Santelli JS, Singh S. Changes in formal sex education: 19952002. Perspect Sex Reprod Health 2006;38(4):1829. [7] SIECUS. Public support for sexuality education. Available at: www.siecus.org/school/ sex_ed/sex_ed0002. Accessed January 1, 2008. [8] American College of Obstetricians and Gynecologists, Committee on Adolescent Healthcare. Strategies for adolescent pregnancy prevention. Monograph. Washington, DC 2007. Available at: http://www.acog.org/departments/dept_notice.cfm?recno7&;bulletin3271. Accessed January 15, 2008. [9] Singh S, Darroch JE. Adolescent pregnancy and childbearing: levels and trends in developed countries. Fam Plann Perspect 2000;32(1):1423. [10] Guttmacher Institute. Gap widening between U.S. womens birth control needs and government response. News release 3/1/2005. Available at: http://www.guttmacher.org/media/nr/ 2005/02/22/index.html. Accessed January 1, 2008. [11] Centers for Disease Control and Prevention. Healthy people 2010 goals. Available at: http:// www.healthypeople.gov/document/HTML/tracking/OD09.html. Accessed January 1, 2008. [12] Guttmacher Institute. State policies in brief. Insurance coverage of contraceptives as of December 2007. Available at: http://www.guttmacher.org/statecenter/spibs/spib_ICC.pdf. Accessed January 1, 2008. [13] Soneld A, Benson R, Gold J, et al. U.S. Insurance coverage of contraceptives and the impact of contraceptive coverage mandates, 2002. Perspect Sex Reprod Health 2004;36(2):729. [14] Phillips KA, Stotland NE, Liang SY, et al. Out-of-pocket expenditures for oral contraceptives and number of packs per purchase. J Am Med Womens Assoc 2004;59:3642. [15] Kunkel D, Eyal K. Sex on TV 4. Menlo Park (CA): Kaiser Family Foundation, 2005. [16] Darroch JE, Frost J, Singh S, et al. Teenage sexual and reproductive behavior in developed countries: can more progress be made? Guttmacher occasional report No. 3, 2001. Available at: http://www.guttmacher.org/pubs/eurosynth_rpt.pdf. Accessed January 1, 2008.

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[17] Grimes DA, Schulz FK. Antibiotic prophylaxis for intrauterine contraceptive device insertion. Cochrane Database Syst Rev 1999;(3):CD001327. 10.1002/14651858.CD001327. [18] Walsh T, Grimes D, Frezieres R, et al. Randomised controlled trial of prophylactic antibiotics before insertion of intrauterine devices. IUD study group. Lancet 1998;351(9108): 10058. [19] American College of Obstetricians and Gynecologists. Intrauterine device. Practice Bulletin No. 59, January 2005. Available at: http://www.acog.org/publications/educational_bulletins/ pb059.cfm. Accessed June 30, 2008. [20] World Health Organization. Medical eligibility criteria for contraceptive use. 3rd edition Geneva (Switzerland): WHO; 2004. [21] Darney P, Patel A, Rosen K, et al. Safety and ecacy of a single-rod etonogestrel implant (Implanon): results from 11 international clinical trials. Fertil Steril 2008, in press. [22] Hohman H, Creinin M. The contraceptive implant. Clin Obstet Gynecol 2007;50(4):90717. [23] Power J, French R, Cowan F. Subdermal implantable contraceptives versus other forms of reversible contraceptives or other implants as eective methods of preventing pregnancy. Cochrane Database Syst Rev 2007;(3):CD001326. [24] Peterson HB, Xia Z, Hughes JM, et al. The risk of pregnancy after tubal sterilization: ndings from the U.S. Collaborative Review of Sterilization. Am J Obstet Gynecol 1996;174:116170. [25] Ogburn T, Espey E. Transcervical sterilization: past, present, and future. Obstet Gynecol Clin North Am 2007;34(1):5772. [26] Cook LA, Pun A, van Vliet H, et al. Scalpel versus no-scalpel incision for vasectomy. Cochrane Database Syst Rev 2007;(2):CD004112. [27] Cook LA, Van Vliet H, Lopez LM, et al. Vasectomy occlusion techniques for male sterilization. Cochrane Database Syst Rev 2007;(2):CD003991. [28] Royal College of Obstetricians and Gynaecologists. Male and female sterilisation. EvidenceBased guideline No. 4. London: RCOG Press; 1999. [29] Trussell J. Contraceptive failure in the United States. Contraception 2004;70:8996. [30] Mishell DR Jr. Pharmacokinetics of depot medroxyprogesterone acetate contraception. J Reprod Med 1996;41:38190. [31] Curtis KM, Martins SL. Progestogen-only contraception and bone mineral density: a systematic review. Contraception 2006;73:47087. [32] Kaunitz A, Arias R, McClung M. Bone density recovery after depot medroxyprogesterone acetate injectable contraception use. Contraception 2008;77(2):6776. [33] Schwallie PC, Assenzo JR. The eect of depot medroxyprogesterone acetate on pituitary and ovarian function, and the return of fertility following its discontinuation: a review. Contraception 1974;10:181202. [34] Spero L, Darney P. A clinical guide for contraception. 4th edition. Philadelphia: Lippincott Williams & Wilkins; 2005: 21138. [35] Harper JC. Tailoring individualized treatment plans for acne. Cutis. 2008;81(1 Suppl):235. [36] Collaborative Group on Epidemiological Studies of Ovarian Cancer. Brea V, Doll R, Hermon C, et al. Ovarian cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls. Lancet. 2008;371(9609):30314. [37] American College of Obstetricians and Gynecologists. Use of hormonal contraception in women with coexisting medical conditions. Practice Bulletin No. 73, 2006. Available at: http://www.acog.org/publications/educational_bulletins/pb073.cfm. Accessed June 30, 2008. [38] Curtis KM, Chrisman CE, Mohllajee AP, et al. Eective use of hormonal contraceptives: Part I: combined oral contraceptive pills. Contraception 2006;73:11524. [39] Kiley J, Hammond C. Combined oral contraceptives: a comprehensive review. Clin Obstet Gyn 2007;50(4):86877. [40] Edelman AB, Gallo MF, Jensen JT, et al. Continuous or extended cycle versus cyclic use of combined oral contraceptives for contraception. Cochrane Database Syst Rev 2005;3:CD004695.

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[41] Urdl W, Apter D, Alperstein A. Contraceptive ecacy, compliance and beyond: factors related to satisfaction with once-weekly transdermal compared with oral contraception. Eur J Obstet Gynecol Reprod Biol 2005;121:20210. [42] Zieman M, Guillebaud J, Weisberg E, et al. Contraceptive ecacy and cycle control with the Ortho Evra/Evra transdermal system: the analysis of pooled data. Fertil Steril 2002; 77(Suppl 2):S138. [43] Burkman R. Transdermal hormonal contraception: benets and risks. Am J Obstet Gynecol 2007;197(2):134.e16. [44] Center for Disease Control. How eective are latex condoms in preventing HIV. Available at: http://www.cdc.gov/hiv/resources/qa/condom.htm. Accessed April 24, 2008. [45] Kuyoh MA, Toroitich-Ruto C, Grimes DA, et al. Sponge versus diaphragm for contraception: a Cochrane review. Contraception 2003;67(1):):158. [46] von Hertzen H. Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO multicentre randomized trial. Lancet 2002;360:18039. [47] American College of Obstetricians and Gynecologists. Emergency Contraception. Practice Bulletin No. 69, December 2005. Available at: http://www.acog.org/publications/educational_ bulletins/pb069.cfm. Accessed June 30, 2008. [48] Zurawin RK, Ayensu-Coker L. Innovations in contraception: a review. Clin Obstet Gynecol 2007;50(2):42539 [Review].

Med Clin N Am 92 (2008) 10591082

Preventing Cervical Cancer: The Pap Test and the HPV Vaccine
Alan G. Waxman, MD, MPH*, Meggan M. Zsemlye, MD
Department of Obstetrics and Gynecology, University of New Mexico Health Sciences Center, MSC 10 5580, 1 University of New Mexico, Albuquerque, NM 871310001, USA

Care of women with renal failure and other sequelae of advanced cervical cancer was once a common part of internal medicine practice. Before the widespread implementation of screening with the Pap test in the mid1950s the incidence of cervical cancer was over 25 per 100,000 women in parts of the United States [1]. Since the 1950s, however, cervical cancer incidence and mortality rates have declined dramatically. The standardized age-adjusted incidence of cervical cancer has declined in the United States by more than half in the last 30 years, from 14.8 per 100,000 women in 1975 to 7 per 100,000 women in 2004 [2]. In African American women the decrease has been threefold, from 33.1 to 10.3 [2]. This reduction can be attributed largely to the widespread acceptance of periodic cervical cytology screening using the Pap test, by both American women and their health care providers. Women look to their internists and other primary care physicians to provide preventive health care. Although many during their childbearing years depend on their obstetricians and gynecologists for Pap tests, the internist frequently continues to care for women after they no longer feel the need to see an obstetrician or gynecologist. It is important to remember that periodic Pap tests are as much a part of a womans ongoing health care as periodic lipid assessments, mammograms, screening for colon cancer, or any of the other recommended screening assessments. This article provides primary care physicians with the information needed to perform Pap tests at the appropriate intervals, or if not set up to do Pap tests themselves, to make the appropriate referrals. Also provided is the necessary

* Corresponding author. E-mail address: awaxman@salud.unm.edu (A.G. Waxman). 0025-7125/08/$ - see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2008.04.012 medical.theclinics.com

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information to counsel women with abnormal Pap tests who may need colposcopy or other follow-up evaluation. Finally, a summary of the role of the human papillomavirus (HPV) vaccine in the prevention of cervical cancer is oered. Eectiveness and limitations of cervical cancer screening As eective as the Pap test has been in the detection of early cancers and premalignant lesions, it is not without its limitations. Cervical cytology screening is a form of secondary prevention. Abnormalities arise only after infection with one or more of 15 high-risk types of HPV and after the virus has either replicated within the host epithelial cells or has incited neoplastic transformation. Epithelial changes are usually manifested years to decades after initial infection. A single Pap test is not a very sensitive screening test. Sensitivity of a single Pap test ranges between 51% and 90% [3,4]. Moreover, a single Pap result is not highly reliable. In a multicenter study by the National Cancer Institute (NCI), nearly 5000 Pap tests initially diagnosed by pathologists at four academic institutions were independently reviewed by members of a quality control panel with only moderate reproducibility of the results (k 0.46 [95% condence interval, 0.440.48]). There was 78% concordance of diagnoses for negative for intraepithelial lesion or malignancy, and 68% for low-grade intraepithelial lesion (LSIL). There was agreement less than half of the time when the initial diagnosis was atypical squamous cells of undetermined signicance (ASC-US) (43%), or high-grade intraepithelial lesion (HSIL), or cancer (47%) [5]. Despite its poor sensitivity and reliability, the Pap test works well to prevent cervical cancer. Its eectiveness takes advantage of the long latency period between infection with HPV and the development of the cancer precursor, cervical intraepithelial neoplasia grade 3 (CIN 3). Development of CIN 3 typically takes an average of 7 to 15 years from the time of initial infection. In addition, women with invasive cancer are on average 10 years older than those with high-grade CIN [6]. Furthermore, most women with HPV infections do not develop precancerous changes, and many untreated cases of CIN 3 do not progress to cancer. Natural history studies suggest that at least 12% of cases of untreated CIN 3 progress to invasive cancer. Although most of such studies are small and for ethical reasons do not let high-grade dysplasia continue untreated, progression rates as high as 50% and 75% have been reported [7]. This, plus the practice of repeating the Pap test at intervals over a womans adult life, permits ample opportunity for detection, intervention, and the prevention of invasive cancer. Despite the success of cytology screening with the Pap test, the American Cancer Society (ACS) estimates there will be 11,070 new cases of cervical cancer and 3870 deaths from the disease in 2008 [8]. Seventy percent of new cases have been attributed to lack of screening or follow-up according

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to recommended guidelines: 50% of new cancers occur in women who have never had a Pap test; 10% in those who have not been screened within the prior 5 years; and 10% in women who, despite appropriate screening, did not receive proper follow-up of abnormal ndings [9]. The remaining 30% of cancers diagnosed each year have been attributed to limitations in performing or interpreting the test including failure to transfer dysplastic cells from the cervix to the microscope slide or misinterpretation of the slide by the cytotechnologist or pathologist. Although new technologies for collecting, preparing, and reading Pap tests are being implemented in most clinical laboratories, these new techniques will not have nearly as great an impact on reducing the incidence of cervical cancer as increasing the number of women who are adequately screened and treated. Liquid-based cytology versus the conventional Pap test Over the past decade, an increasing percentage of Pap tests have used liquid-based, thin-layer technology as opposed to the conventional Pap technique. The conventional Pap slide is made by collecting cervical cells from the ectocervix and endocervix, transferring them directly to a glass slide, and xing them using ethyl alcohol or spray xative. Issues that may make it dicult accurately to interpret the Pap test include clumping of epithelial cells and presence of inammatory cells and noncellular debris. Liquid-based cytology minimizes or eliminates these problems. Cellular material taken from the cervix is suspended in a liquid transport medium. In the laboratory, epithelial cells are separated from inammatory cells and noncellular material by ltration or diusion gradient technology and are placed in a uniform monolayer on a glass slide. The uniform layer of cells is easier to interpret, although cytotechnologists and pathologists, once trained to consider inammatory cells and background debris in their diagnoses, can no longer use these clues to render diagnoses with liquidbased cytology [4]. The question of whether liquid-based cytology is more sensitive than conventional cytology has not been fully resolved. Early studies seemed to show that the liquid technology diagnosed more dysplasia than the conventional Pap test [1012]. This is refuted by more recent research [1315]. Davey and colleagues [16] reviewed 56 studies and found that all had aws in study design. None of the studies both randomly assigned women to one or the other type of cytology and also used a masked reference standard to conrm the ndings of at least all positive slides. Five paired sample studies (ie, each cervix was sampled using both Pap types), although not ideal, were considered to be of high quality. In these studies, slides made with each type of cytology were read without knowledge of the results of the other. In addition, a reference standard was used without knowledge of the Pap test result, and at least all discordant slides were veried. Among these high-quality studies, whereas the liquid-based Pap tests classied more slides as ASC-US or

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LSIL, the conventional cytology technology classied more as HSIL. The authors found only four studies that provided sucient data to estimate sensitivity and specicity with any validity. They concluded that given the limitations of the current literature the available data do not support the thesis that liquid-based cytology is more accurate than conventional, nor did they nd a lower rate of unsatisfactory specimens with the liquid-based preparations [16]. Arbyn and colleagues [4] performed a meta-analysis of eight studies comparing liquid-based and conventional cytology that subjected all participants to colposcopy, considered the gold standard for diagnosis of dysplasia. They also included a large randomized controlled trial in which colposcopy was performed on all women with abnormal results. The inclusion of a gold standard in these nine studies allowed computation of sensitivity and specicity. They found no signicant dierence in sensitivity or specicity for diagnosing CIN 2 or worse between the two technologies when the cuto was set at LSIL or HSIL. When the cuto was set at ASC-US or worse, the specicity was lower for the liquid-based method. Despite the lack of clear data showing that liquid-based cytology is more sensitive than the conventional Pap smear, most Pap tests performed in the United States use one of the several Food and Drug Administration (FDA)approved liquid-based techniques. This is somewhat surprising in light of the higher cost of the liquid-based products. The use of liquidbased cytology in part reects marketing to laboratories of computer-assisted technologies for reading cytology and automated work stations, which require use of one of the proprietary liquid-based cytology products. An advantage of the liquid-based Pap test for the clinician is the ability to use the uid that remains after the cytology preparation for testing for gonorrhea, Chlamydia, and HPV DNA. The ability to test for HPV DNA is especially useful because it allows for reex HPV testing. This is a sensitive and cost-eective approach to determining which patients with ASC-US should be followed with colposcopy, and which can be safely managed with a repeat cytology examination in 12 months (see later) [17,18]. The ability to test for HPV also permits HPV DNA testing to be incorporated into primary screening as an adjunct to cytology (see later). Despite these advantages of liquid-based screening, it is appropriate to continue to use traditional slide Pap smears depending on the resources available to the provider. How to perform a Pap test Patients should refrain from sexual intercourse, douching, tampon use, or placing medications into the vagina for 2 days before the Pap test. The test may be performed if a patient is having a small amount of menstrual bleeding; however, it should be deferred during heavy menstrual bleeding. A speculum is placed in the vagina (a small amount of water or water-soluble gel may be placed on the speculum), and the cervix is viewed completely. The

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cell collection device (broom or brush plus spatula) is used to collect endocervical and ectocervical cells, which are then spread on a glass slide or placed in the liquid collection medium. If the spatula is used, the more prominent end should be placed in the cervical os and the spatula rotated 360 degrees such that the entire ectocervix is sampled. The nylon cytobrush is then placed into the endocervical canal up to the base of the brush and gently rotated 180 degrees. If the broom device is used, it should be placed with the tip in the cervical os deeply enough that the outermost (shorter) bristles contact the ectocervix. The broom should be rotated 360 degrees ve times. Generally, practitioners use the spatula and cytobrush or the broom. To perform a conventional Pap smear, the contents of spatula and cytobrush or broom are spread thinly and evenly across a microscope slide, and the slide is immediately sprayed with xative or immersed in alcohol xative. If the specimen is spread too thick, is allowed to air-dry, or represents an incomplete sample, the sensitivity of the test is reduced and may be reported as unsatisfactory. The liquid-based Pap test relies on a liquid transport medium from which cells are transferred to glass slides in the laboratory. The dierent proprietary liquid-based systems each have their own recommended technique for transferring cells to the transport medium. Providers should follow the manufacturers instructions for the system used. All specimens, both conventional slide and liquid-based vial, should be clearly labeled with the patients name and the date of collection. Clinical information, such as the patients parity and last menstrual period, should be recorded on the requisition. Equally important to document on the requisition is any history of prior cytologic abnormalities or treatment to the cervix because pathologists take a history of a previous abnormality into consideration when interpreting the Pap test. Care should be taken to review the requisition for additional testing. HPV testing should not be the default order and should only be ordered if reex HPV testing or combined Pap plus HPV testing is specically desired.

Whom to screen, when to screen When should a young woman have her rst Pap test? The rst Pap test should be performed about 3 years after the onset of vaginal intercourse or at age 21, whichever comes rst. There is consensus on this among the American Cancer Society (ACS), American College of Obstetricians and Gynecologists (ACOG), and the US Preventive Services Task Force (Table 1) [1921]. The recommendation to delay an adolescents rst Pap test until about 3 years after the start of vaginal intercourse (coitarche) ts well with recent studies of the natural history of dysplasia in adolescents. HPV is very

1064 Table 1 Cervical screening recommendations: a comparison of recommendations by American Cancer Society, American College of Obstetricians and Gynecologists, United States Preventive Services Task Force ACS Guidelines [19] When to start screening Screening interval Age 21 or about 3 years after onset of vaginal intercoursed Annually until age 30. Biennially if liquid-based cytology used Age 30 or older: after three consecutive, satisfactory, negatives may screen every 23 yearsa ACOG Guidelinese [20] Age 21 or about 3 years after onset of vaginal intercourse Annually until age 30 using either conventional or liquid-based cytology Age 30 or older: after three consecutive, satisfactory, negatives and no history of CIN 2 or 3, may screen every 23 yearsa Evidence inconclusive to set upper age USPSTF Guidelines [21] Age 21 or about 3 years after onset of vaginal intercourse Every 3 years
WAXMAN & ZSEMLYE

When to stop screening Posthysterectomy

Additional technologies

Age 70 in well-screened low-risk Age 65 in well-screened low-risk women womena,b Screening not recommended Screening may be discontinued after Discontinue screening after hysterectomy after hysterectomy for benign hysterectomy for benign indications if no evidence of cervical neoplasia indications if cervix removed if cervix removed if no prior CIN 2 or 3c or cancer if no prior CIN 2 or 3a,c Insucient evidence to recommend Screening with cytology plus high-risk Screening with cytology plus high-risk for or against liquid-based cervical HPV DNA may be reasonable in HPV DNA is appropriate in women cytology or computer-based screening women aged 30 and older. If aged 30 and older. If both negative both negative the next screening the next screening should be no or rescreening should be no sooner than 3 years. sooner than every 3 years.

Screening after treatment No recommendation for CIN 2 or 3

Annual gynecologic examinations

No recommendation

Women treated for CIN 2 or 3 who have completed follow-up should continue to be monitored annually until at least three consecutive negative cytology examinations Annual examinations including pelvic examinations recommendede

No recommendation

No recommendation

Abbreviations: ACOG, American College of Obstetricians and Gynecologists; ACS, American Cancer Society; CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; USPSTF, United States Preventive Services Task Force. a Continue annual screening in women with these risk factors: in utero diethylstilbestrol exposure, history of cervical cancer, or immunosuppression including HIV. b Screening may be stopped at age 70 after three consecutive, satisfactory, negative cytology examinations in the prior 10 years with no intervening abnormal Pap test. Women who have not been previously screened, in whom prior screening is unlikely, or in whom the screening history is unknown should continue to be screened. Women in this age group who are in poor health or have life-threatening illnesses may forgo screening. Current data are not sucient to recommend discontinuing screening in women who have tested positive for HPV DNA. c Women with a history of CIN 2 or 3 or for whom the history is unknown should continue screening until they have three consecutive, satisfactory, negative cytology examinations in the prior 10 years with no intervening abnormal Pap test (ACOG does not specify that the three examinations be in the previous 10 years). d Although adolescents may not need cervical cytology in the rst 3 years after initiating intercourse, they should receive appropriate preventive care including education and care related to health risks, contraception, and sexually transmitted infections. e Citing level C evidence (ie, based primarily on consensus and expert opinion), ACOG acknowledges that there is room for individualization regarding when to start screening, how often to screen, and when screening is no longer needed. They include yearly Pap testing as an acceptable option. Data from Waxman AG. Guidelines for cervical cancer screening: history and scientic rationale. Clin Obstet Gynecol 2005;48:923.

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eciently acquired in adolescents. Prospective studies of adolescents and young women in New Jersey, Indiana, and Washington found 20% to 28% to be HPV positive at registration. After following them prospectively for 2 to 5 years, the incidence of at least one HPV type increased to 60% to 82% [2224]. Most HPV infections, however, cleared spontaneously within 2 years. The median duration of a positive HPV test was 8 months in the New Jersey study and 5.6 months in the Indiana study [22,23]. Eighty-one percent of the new infections in the New Jersey study were not detectable after 2 years. Of the small proportion of HPV infections that result in squamous intraepithelial lesions in adolescents, most are low grade, and most of those revert to normal without treatment. Wright and colleagues [25] reviewed 10,090 Pap tests from women aged 12 to 18 in one laboratory from 1997 to 2003. A total of 422 (5.7%) were LSIL, and only 55 (0.7%) were HSIL. A prospective study of 187 women aged 18 to 22 with LSIL followed without treatment for 3 years found that only 3% progressed to HSIL, whereas 91% regressed to normal [26]. About two thirds of adolescents diagnosed with HSIL have CIN 2, which typically regresses spontaneously. Another study reviewed the ndings on 495 women under age 22 referred for colposcopy. One hundred seventyone (24%) were diagnosed with CIN 2 or 3, with approximately two thirds of these being CIN 2. Twenty-three of the patients with CIN 2 were followed without treatment. After a median follow-up of 18 months, 15 (65%) had reverted to negative, 4 (17%) persisted as CIN 2, and 3 (13%) progressed to CIN 3. None had progressed to cancer [27]. Invasive cancer is exceedingly rare before age 20. The NCIs SEER data of cancer surveillance estimates the incidence of cervical cancer before age 20 at 0.1 per 100,000 [2]. The recommendation to delay screening until about 3 years after the onset of vaginal intercourse acknowledges that HPV is very prevalent in the adolescent age group, but it usually clears spontaneously. Although dysplasia may develop in this age group, most resolve without treatment, are rarely severe (CIN 3), and almost never progress to cancer within 3 years. Development of cancer takes years to decades after rst exposure to HPV. Delaying the rst Pap test until about 3 years after onset of intercourse also prevents overtesting and treatment in this age group. Although Pap screening is not recommended during the rst 3 years after coitarche, counseling about safe sex, testing for sexually transmitted infections, and initiating a contraceptive method remain very important. These services can usually be provided without a pelvic examination. How often should women have Pap tests? After age 20, the incidence of cervical cancer increases in a linear fashion for the next 20 to 25 years [2]. The ACS and ACOG recognize the decade of

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the 20s as an ideal time to do aggressive screening for cancer and its precursors [19,20]. Screening every 1 to 2 years from the rst Pap test until age 30 optimizes the opportunity to identify precancerous lesions that have developed from persistent high-risk HPV infections. Multiple cytologic screenings at relatively short intervals maximizes sensitivity far beyond the limitations of a single Pap test. The ACOG guidelines put an emphasis on sensitivity and recommend annual Pap tests from the onset of screening until age 30 [20]. The ACS, although also recommending aggressive screening for women of the same ages, suggests that if liquid cytology is used screening should be every other year for these women [19]. This recommendation was based on early studies that suggested an increased sensitivity but also a slightly higher false-positive rate with the liquid-based Pap test products. The US Preventive Services Task Force makes no age distinction and recommends an interval of every 3 years after screening has begun [21]. Recognizing the protection aorded by multiple negative examinations all three organizations recommend prolonging the interval for screening in women over 30 who have had three or more consecutive negative Pap tests. ACS and ACOG recommend extending the interval to every 2 to 3 years, and the US Preventive Services Task Force recommends every 3 years. Women who are immunocompromised or were exposed in utero to diethylstilbestrol should continue annual screening [1921]. Is it safe to screen women at intervals greater than once a year? It has long been recognized that to maximize the sensitivity of cervical screening, the Pap test must be repeated periodically throughout a womans adult life. In 1957, the ACS in its Uterine Cancer Year campaign promoted the annual Pap smear. Other professional organizations soon followed suit [28]. One year between tests was an interval of convenience. Studies have long shown that acceptable sensitivity can be obtained with testing less frequently than every year. In 1976, the Walton Report [29], developed by a task force commissioned by the Conference of Deputy Ministers of Health of Canada, recommended that after two negative annual examinations, low-risk women could be eectively screened with Pap tests at 3-year intervals until age 35, then every 5 years until age 60. The ACS echoed this recommendation in 1980 calling for every 3 year Pap tests in women after two negative annual examinations [30]. A multicenter trial conducted in Europe and North America and published in 1986 used a mathematical model to estimate the cumulative decrease in invasive cancer on a cohort of women with an initially negative cytology who were tested from age 35 to 64. Compared with no testing, yearly Pap testing (approximately 30 lifetime tests) decreases the incidence of invasive cervical cancer by 93.5%. Biennial Pap testing was similarly eective, decreasing the cumulative incidence of cancer by 92.5%. The protection oered by testing at 3-year intervals was still excellent at 90.8% and required only 10 tests.

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Ecacy decreased dramatically if the interval was prolonged to 5 or more years [31]. A more recent study evaluated 128,805 women after an initial negative Pap test. The rates of HSIL on their next Pap test were not signicantly dierent whether the interval was 9 to 12 months (25 per 100,000 women); 13 to 24 months (29 per 100,000 women); or 25 to 36 months (33 per 100,000 women) [32]. Three or more consecutive negative Pap tests confer a high degree of condence that cervical cancer will not develop within 3 years, and the risk of missing an existing high-grade lesion is quite low. Sawaya and coworkers [33] assessed 32,230 women with three consecutive negative annual examinations. In their next Pap test 1 to 2 years later, nine had CIN 2 (0.028%), whereas only seven had developed CIN 3 (0.022%). There were no cancers detected. A report from the NCI that followed 20,810 women over a 10-year period found the negative predictive value of a Pap test at baseline was 99.47 [34]. The recommendation to increase the screening interval seems prudent in most women over age 30 who have had three or more consecutive negative Pap tests. Overscreening is not cost eective. Data from the BCCEDP study noted previously were used to calculate the risk imposed by extending the screening interval in women with three or more prior negative Pap tests. Using a computer model, it was estimated 3 cancers per 100,000 women aged 30 to 44 would have been prevented had Pap tests been performed annually rather than every 3 years. A total of 69,665 additional Pap tests and 3861 additional colposcopies would have been necessary, however, to prevent each case. In the 45 to 59 age group, annual Pap testing prevents 1 cancer per 100,000 women at a cost of 209,324 additional Pap tests and 11,502 additional colposcopies [33]. When counseling patients, it is important to distinguish the Pap test from the overall gynecologic examination. Although annual cervical cytology is no longer recommended for well-screened women after age 30, more frequent reproductive health visits may still be appropriate for other preventive health measures. Pap testing after menopause or hysterectomy Postmenopausal women who have had multiple, negative Pap tests across the span of their adult lives are at extremely low risk for acquiring cervical cancer [35]. The prevalence of high-risk HPV infections declines with age from over 20% of women 20 to 24 years of age to well under 10% in women over 50 [36,37]. The active transformation zone of the cervix, where squamous metaplasia and neoplasia are most likely to develop, is generally protected by an endocervical position in older women reducing the risk of developing new dysplasia. It is important to note, however, that in some ethnic groups, particularly

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African Americans, Hispanics, and Native Americans, the incidence of cervical cancer continues to rise with increasing age [38]. This may be related to less regular screening earlier in life, and underscores the need to ensure at least three negative Pap tests in the previous 10 years before discontinuing screening. There is no agreement among professional organizations as to the best age to discontinue screening in low-risk, well-screened women. The US Preventive Services Task Force sets a lower age of 65 [21], whereas the ACS says age 70 [19]. The ACS adds the additional caveats that immunocompromised and diethylstilbestrol-exposed women should continue periodic screening [19]. Because women with a history of cervical cancer or previously treated CIN 2 or 3 are at risk for long-term delayed recurrence, it seems prudent to continue testing this group. In older women for whom continued screening is indicated but who may have medical conditions expected to shorten their lives, however, a Pap test is unnecessary [19]. Women who have had a hysterectomy with removal of the cervix and who have not had cervical cancer or high-grade dysplasia do not need cytology testing. Screening should be continued in those with previous highgrade dysplasia, because there is a risk of recurrence at the vaginal cu. Women who have had supracervical hysterectomies should also continue to be screened because these procedures retain the cervix. Pap tests after removal of the cervix do screen for vaginal cancer. The incidence of vaginal cancer is extremely low, however, estimated at 0.7 per 100,000 women, making screening not cost eective [39]. Interestingly, although it has been recommended since 1996 that Pap screening is no longer needed for women who have undergone hysterectomy for benign indications, a recent survey found that 69% of such women still get Pap tests [40]. Human papillomavirus and cervical cancer It is now well established that HPV is the etiologic agent of almost all cervical cancers. This includes virtually all squamous and adenocarcinomas. In a study by the International Agency for Research on Cancer, HPV was detected in 99.7% of invasive cervical cancers from 22 countries [41]. Although 15 high-risk HPV types have been shown to be associated with cancer [41], eight of these have been associated with 90% of invasive cancers: in descending order of frequency these are HPV 16, 18, 45, 31, 33, 52, 58, and 35. Types 16 and 18 are responsible for two thirds to three quarters of cervical cancers worldwide [42,43]. In addition to cervical cancer, HPV is responsible for 40% of penile, vulvar, and vaginal cancers; 90% of anal cancers; up to 12% of oropharyngeal; and 3% of mouth cancers. As with cervical cancer, most of these are caused by HPV types 16 and 18 [39,44]. Although infection with high-risk HPV is a necessary factor in the development of cervical cancer, it alone is typically not sucient for cancer to

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develop. Persistence of the HPV infection over time is a signicant risk factor in the progression from HPV positivity to CIN 3 [6,45,46]. Among HPV-positive women, smoking is a consistent cofactor in the development of CIN 3 and cancer. Infection with Chlamydia trachomatis and failure to use condoms has also been associated with the development of CIN 3 in HPV-positive women. Other potential risk factors have been inconsistent in their association with progression to high-grade dysplasia. These include oral contraception use, nutritional factors, and infections with Trichomonas vaginalis and herpes simplex [6]. Pap plus human papillomavirus DNA testing Cervical cytology alone has been an extremely valuable tool in decreasing the incidence of and mortality from cervical cancer. Pap testing is widely used and is familiar to patients. Because a single Pap test performs poorly with regard to sensitivity, however, it must be repeated at frequent, regular intervals. Because infection with HPV is the necessary etiologic factor for cervical cancer it raises the question of whether screening for the presence of the virus is a more eective method to prevent cervical cancer? Numerous studies have compared the screening validity of cervical cytology with HPV DNA testing. Consistently, HPV testing has been found to be more sensitive with a higher negative predictive value, although less specic. When the tests are combined, these dierences are accentuated, with sensitivity and negative predictive value highest for the combination of cytology plus HPV DNA testing. The specicity, as might be expected, is lowest with the combined test [4749]. Using HPV screening might be appropriate for some age groups and not others. Studies of adolescents and young women show that up to a quarter are infected with HPV at any one time and that their risk of infection is high (50%) within 2 years of the onset of sexual activity [22,24,50]. Most of these infections are transient, however, and screening for high-risk HPV DNA in this age group would result in a large number of positive tests in patients not at high risk for developing or having cancer. To subject all young women who are HPV-positive to follow-up testing including colposcopy is unacceptable given the relatively low risk of high-grade disease and extremely low risk of invasive cancer in this group. For these reasons HPV testing should not be included in the cervical cancer screening of women under 30. After the age of 30 the prevalence of high-risk HPV infections declines steadily except for a small increase in the early forties [51]. Cervical cancer incidence, however, increases with age from 1.5 per 100,000 women aged 20 to 24 to 11.5 per 100,000 women in the 30- to 34-year age group [2]. On March 31, 2003, the FDA approved HPV DNA testing with a hybrid test, to be used in addition to cytology for primary screening of women aged 30 and older. HPV DNA testing is not approved to be used alone for screening. The test remains the only one to be FDA approved and with clinically

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validated thresholds for clinical use. Clinicians using this test should only order the test for high-risk HPV types. Identifying low-risk types has no clinical use. A valuable aspect of the combination of cytology with HPV testing is its negative predictive value for the development of dysplasia. An NCI study of women in Oregon showed that the incidence of CIN 3 or worse over a 45-month period following an initially negative Pap test plus a negative HPV test was 0.16% [34]. The high sensitivity and high negative predictive value of testing with cytology combined with HPV testing allows for safely increasing the intervals between screening tests. The ACS and ACOG both recommend that if HPV DNA testing is used in combination with cytology for screening and both are negative, screening should not be repeated within 3 years [19,20]. Management of abnormal Pap tests New guidelines Guidelines for the management of women with abnormal cervical screening tests have recently been issued based on recommendations of a consensus conference held in September 2006 sponsored by the American Society for Colposcopy and Cervical Pathology with participation from 146 experts representing 29 professional organizations [52]. The following summarizes these guidelines as published in October 2007 [52,53]. General guidelines More conservative management is recommended in adolescents with abnormal Pap tests than in women aged 21 and older (Fig. 1) (see discussion later). This departure from previous recommendations recognizes the high frequency of HPV infection, the high rate of spontaneous remission of dysplasia, and the low risk of cancer in women under 21 years of age. In addition, treatment of dysplasia with excision or ablation of the cervical transformation zone has recently been shown to be associated with an increased risk of premature birth in subsequent pregnancies [54,55]. The consensus conferees provided the caveat that the guidelines are general recommendations and may not cover every situation. The practitioners best clinical judgment should be used in unique situations. Atypical squamous cells of undetermined signicance A cytologic diagnosis of ASC-US is reported in approximately 5% of Pap smears, although the chance of a woman with an ASC-US having cancer is only 0.1% to 0.2% [56]. There are three appropriate methods for triaging women with ASC-US on cytology [52]: (1) repeating cytology in 6 and 12 months, (2) immediate colposcopy, or (3) reex HPV testing. Of the

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Routine screening depending on age Positive for high-risk types Negative Colposcopy Repeat Pap one year Routine screening Colposcopy

HPV DNA Testing Reflexif available Repeat Pap test in 6 months and 12 months Colposcopy

ASC-US (over age 20)

Both negative If either is ASC-US

ASC-H (any age) LSIL (between age 21 and menopause) ASC-US/LSIL (under age 21) LSIL after menopause HSIL (any age) AGC or atypical endocervical cells or AIS Atypical endometrial cells AGC or Atypical Endocervical cells Age 35, anovulatory or Abnormal bleeding Suspicious for Cancer

Colposcopy

Colposcopy

1 annual Pap HSIL

nd

st

Colposcopy

Follow with annual Pap X2 Manage same as ASC-US over age 20 Colposcopy Colposcopy with endocervical sampling & HPV testing Endocervical & endometrial Sampling Colposcopy with endocervical and endometrial sampling & HPV testing Consult gynocologist or gyneologic oncologist If no endometrial pathology Colposcopy 2 annual Pap ASC-US Colposcopy

Fig. 1. Algorithm for management of Pap test.

three, reex HPV testing is preferred if liquid-based cytology is used. The term reex HPV testing implies that a test for high-risk HPV DNA is run if the Pap test is read as ASC-US. If reex HPV testing is positive for high-risk HPV types, colposcopy is indicated. If the test is negative, the patient may return to routine screening. If repeat cytology is used and the follow-up Pap test in 6 months is greater than or equal to ASC-US, the patient should be referred for colposcopy. If it is negative, a Pap test in 6 more months is obtained with the same threshold for colposcopy. If both are negative, the patient may return to routine screening. Guidelines for the management of adolescents with ASC-US are the same as for adolescents with LSIL, and are discussed later under LSIL. Atypical squamous cells cannot rule out high-grade squamous intraepithelial lesion The subcategory of atypical squamous cells carries a risk of CIN 2 or 3 similar to that found with a reading of HSIL on Pap test [57]. Women with this diagnosis on cytology should be immediately referred for colposcopy [52]. If biopsies are negative for dysplasia, the recommended followup is to perform HPV testing in 1 year or follow-up cytology at 6 and 12 months. If the follow-up HPV result is positive for high-risk types or

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repeat cytologic testing is greater than or equal to ASC-US, the patient should be referred for colposcopy. Low-grade squamous intraepithelial lesion Colposcopy is recommended for the LSIL Pap test, except in adolescent and postmenopausal women. HPV testing is not recommended for LSIL except after menopause because the rate of positive testing for high-risk HPV in premenopausal women with LSIL is too high (approximately 85%) for it to be practical as a triage test [17]. If colposcopically directed biopsies with LSIL do not show CIN 2 or 3 or cancer, close follow-up is important. It is acceptable to follow with an HPV test in 1 year or repeat cytology in 6 and 12 months. Repeat colposcopy should be performed if the follow-up HPV is positive or if either follow-up cytology is greater than or equal to ASC-US. These two options are sensitive for the presence of CIN 2 or worse as follows: cytology, 88%; and HPV testing, 92% [58,59]. If HPV is negative for high-risk types or both follow-up Pap tests are negative, the patient may return to routing screening. Adolescents Adolescents, dened as under age 21, with ASC-US or LSIL should be followed closely with annual repeat cytology examinations for 2 years [52]. Referral for colposcopy is not necessary because the incidence of CIN 2 or 3 is low (!10%) and the regression rate is high (R90%) [26]. If the rst annual follow-up cytology remains less than or equal to LSIL, a Pap test is scheduled in 1 year. If the rst follow-up examination progresses to HSIL, however, colposcopy is indicated. If the second follow-up Pap test continues to show ASC-US or worse, the patient should have colposcopy [52]. Because of the high prevalence of highrisk HPV in adolescents, HPV DNA testing should not be performed in this age group, and if inadvertently ordered, the results should not inuence management. Postmenopausal women The rate of HPV-negative LSIL Pap tests increases with age, with postmenopausal women having a higher rate than reproductive-aged women [60]. Management options for postmenopausal patients with LSIL on cytology includes reex HPV DNA testing, repeat cytology at 6 months and 1 year, or immediate referral to colposcopy. If HPV testing or repeat cytology results are positive or abnormal, the patient should have a colposcopy [52]. Pregnant women Pregnant women over the age of 20 with ASC-US or LSIL Pap tests should be referred to colposcopy. It is acceptable, however, to defer the colposcopy to 6 or more weeks postpartum [52].

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High-grade squamous intraepithelial lesion HSIL on cytology is an indicator that dysplasia, especially high grade, is probably present. On colposcopy, over half of women have CIN 2 or worse and if a loop excision is performed, up to 97% have CIN 2 or worse [61]. Women with HSIL should be referred immediately to colposcopy [52]. Conrmation of HSIL (CIN 2 or 3) on biopsy is indication for treatment with excision or ablation of the cervical transformation in all but adolescents and young women, who may be observed with semiannual cytology and colposcopy [53]. If HSIL is not found on colposcopy, excision by loop excision procedure or conization is needed to rule out occult HSIL. The see and treat method, or immediate loop excision after a Pap test showing HSIL, is also an acceptable option except in pregnant or adolescent women [53]. Adolescents Adolescents with HSIL Pap tests should be referred for colposcopy. If CIN 2 or 3 is not identied on colposcopically directed biopsies, preferred management is follow-up with cytology and colposcopy at 6-month intervals [52]. Atypical glandular cells Atypical glandular cells on cytology includes atypical endocervical cells, atypical endometrial cells, and atypical glandular cells not otherwise specied. This cytologic diagnosis is associated with a high rate of squamous and glandular neoplasia. The rate of signicant disease in women with atypical glandular cells is 9% to 38% and the location of disease may include the cervix, endometrium, ovary, fallopian tube, breast, and gastrointestinal tract [62,63]. HPV-mediated disease of the cervix is most common and includes squamous dysplasia and cancer and adenocarcinoma and adenocarcinoma in situ of the cervix [63]. Reex HPV testing has a low sensitivity to detect noncervical lesions and should not be used as an initial triage in patients with atypical glandular cells on Pap test. Initial evaluation requires colposcopy and endocervical sampling [52]. Endometrial sampling should be performed on women over 35 years of age or those under 35 at risk for endometrial disease (eg, chronic anovulation or abnormal bleeding). If no disease is uncovered after initial careful evaluation of the ectocervix, endocervix, and endometrium, follow-up may use cytology at 6-month intervals for 2 years. Alternatively, if HPV status is known, follow-up may be performed with HPV DNA testing in 6 months if initially positive for high-risk types or 12 months if initially negative [52]. Management of cytology plus human papillomavirus DNA testing Screening with cytology plus HPV DNA testing is appropriate for women aged 30 and older at 3-year intervals as long as both tests are negative [52].

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Patients with cytology results of ASC-US with positive high-risk HPV testing or whose cytology is greater than ASC-US regardless of HPV result should have a colposcopy. A cytology result of ASC-US and a negative HPV test indicates a repeat cytology at 12 months. About 5% of patients have normal cytology but test positive for HPV. At any time, 5% to 15% of women age 30 or over are positive for HPV [48]. The incidence of these patients (O30 with HPV) having CIN 3 or cancer on biopsy in the next 45 months is only 4.4% (95% condence interval, 3.45.4) [34]. These women do not need immediate colposcopy but should have both tests (HPV and cytology) repeated in 12 months. If at the time of the repeat testing the HPV test remains positive or if the cytology shows anything worse than ASC-US, colposcopy is indicated. If cytology shows ASC-US but HPV is now negative, both tests should be repeated in a year. If both tests return negative, the patient should return to routine screening at 3 years [52].

The human papillomavirus vaccine The recent development of two HPV vaccines has allowed the ght against cervical cancer to move from secondary prevention eorts with eective screening with cytology and HPV DNA testing and with sensitive follow-up regimens, to primary prevention. The rst, approved by the FDA in 2006, is a quadravalent vaccine that targets the oncogenic HPV types 16 and 18, and also types 6 and 11, which are responsible for 90% of genital warts. A second vaccine is awaiting FDA approval at the time of this writing. This is a bivalent vaccine targeting HPV types 16 and 18. It was approved for use in Australia and the Philippines in August 2007. Ecacy The HPV vaccines take advantage of the antigenic properties of the viral capsid. Both HPV vaccines consist of a virus-like particle, which is a typespecic capsid devoid of viral DNA, plus an aluminum-containing adjuvant. The vaccines stimulate a high antibody response that has been shown to persist for at least 5 years [6466]. They are highly eective in women who have not been exposed to the targeted virus [6770]. Two studies of the quadravalent vaccine published under the acronyms FUTURE I and FUTURE II used the development of CIN or adenocarcinoma in situ related to the vaccine-targeted HPV types as study end points [69,70]. The authors evaluated vaccine ecacy by both per-protocol and intention-to-treat analyses. Women in the per-protocol group were naive to HPV 6, 11, 16, and 18 at the start of study as determined by both HPV DNA testing and antibody testing; they received all three doses of vaccine. The intention-to-treat group included all subjects regardless of baseline HPV status. The women in the intention-to-treat analysis were not excluded if they had an existing infection or lesions with vaccine-type HPV at the start

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of the study. Over 95% of women in the intention-to-treat analysis in these two studies had received at least one vaccine dose and at least one follow-up visit. An additional analysis of women in the intention-to-treat population included as an end point not only lesions related to the four vaccine targeted HPV types, but lesions related to any type of HPV [69,70]. In the per-protocol analysis, only 1 of the 7546 vaccinated women developed an end point lesion related to a targeted HPV type. In the control group, 107 such lesions were diagnosed. Vaccine ecacies were 100% and 98%, respectively in FUTURE I and II. The intention-to-treat analyses had lower ecacy results; 55% in the FUTURE I study [69] and 44% in FUTURE II [70]. Most of the cases of cervical disease in vaccinated subjects of the intention-to-treat group were attributed to HPV 16 or 18 infections present before the rst injection. The vaccine did not seem to alter the course of HPV 16 or 18 infections present at the start of the study, nor of related CIN or adenocarcinoma in situ. Analyzing the data for cervical lesions related to any HPV type, the vaccine ecacy in FUTURE I and FUTURE II declined to 20% and 17%, respectively. This underscores the importance of vaccinating women before they become infected, which, in most cases, means before the onset of sexual activity. The ecacy for preventing vulvar and vaginal lesions was evaluated in the FUTURE I study [69]. The quadravalent vaccine was 100% protective against HPV 6, 11, 16, and 18 associated condylomata and vulvar and vaginal intraepithelial neoplasia in the per-protocol analysis, and 62% to 78% ecacy in the intention-to treat analysis [69]. Adverse events Adverse events associated with the HPV vaccine seem to be mostly related to the aluminum adjuvant used for injection. In studies presented to the FDA, reactions were most common at the injection site with pain, swelling, and erythema present in 83.9%, 25.4%, and 24.7%, respectively in women receiving the vaccine and 75.4%, 15.8%, and 18.4% in the placebo group receiving only the adjuvant [39]. Pain was rated as severe in 2.8% of patients receiving vaccine and 1.3% receiving placebo. Fever was reported in 4% to 5% after each dose, less than 1% rising to 102 F, with frequencies similar for vaccine and placebo. Nausea and nasopharyngitis were reported in less than 7% in each group. Dizziness, diarrhea, vomiting, myalgia, and malaise were also similarly distributed between vaccine and placebo and reported in 4% or fewer cases. The vaccine is rated class B for use in pregnancy [39]. Administration The vaccine is given as a 0.5-mL intramuscular injection, preferably given in the deltoid muscle. Ideally, the three-dose regimen is given on day 1 and at 2 and 6 months. The rst and second doses may be given as close as

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4 weeks apart, whereas the second and third should be separated by at least 12 weeks. If the second dose is delayed beyond 2 months, it should be given as soon as possible with the third dose following in no sooner than 12 weeks. If only the third dose is delayed, it should be given as soon as possible [39]. The FDA has approved the quadravalent vaccine for females aged 9 to 26. The Advisory Committee on Immunization Practice recommends vaccination of girls aged 11 to 12, an age before infection through sexual transmission is likely. They recommend a catch-up vaccination for women 13 to 26 who were not vaccinated as preadolescents. It is currently not clinically possible to determine if an individual woman has been previously infected with one or more of the four vaccine covered HPV types, and HPV testing before vaccination is discouraged. Women who have been infected should benet from protection against types to which they have not been exposed [39]. Although the vaccine is not licensed for use in women over age 26, studies are ongoing and preliminary data look promising. Studies on ecacy in males are also currently in progress [39].

Summary Secondary prevention of cervical cancer with periodic cervical cytology has been extremely successful in reducing the incidence of this disease in the United States and other industrialized nations. Clearly, Pap testing works. Its success, however, is not without cost. Precancer is often identied only after multiple periodic Pap tests. For many women, diagnosis of a precancerous lesion involves colposcopy, biopsy, and often diagnostic excision with cone biopsy or electrosurgical excision. Once identied, CIN 2 or 3 is treated with excision or ablation procedures. Cytopathology laboratories report an average of 6.7% of Pap tests have results of ASC-US or worse [71]. Of the estimated 50 million Pap tests performed per year, this translates to over 3 million women requiring additional testing, over two thirds of whom need colposcopy. New follow-up guidelines were designed to reduce that number especially in the adolescent age group, but colposcopy with biopsy remains the gold standard for cervical diagnosis. Primary prevention with the HPV vaccine promises to cut further the already low incidence of invasive cervical cancer in United States women. Its greatest potential in the United States and other countries with widespread Pap testing, however, may be to decrease the incidence of high-grade dysplasia and thereby reduce the morbidity, cost, discomfort, and inconvenience from the evaluation and treatment of cancer precursors. In the developing world, however, where widespread cytology screening and follow-up testing are not available, the impact of the vaccine will be on prevention of cervical cancer itself. Widespread implementation of the HPV vaccine could potentially prevent two thirds to three quarters of the over 400,000 new cases each year [44].

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The vaccine will have its greatest impact if given to young women before the onset of sexual activity. Given the long latent phase of the disease, it has been estimated that once there is widespread vaccination of 9- to 14-year-old girls it will take 20 years before a signicant decrease in cervical cancer incidence attributable to the vaccine is noticed. A decrease in the rate of high-grade dysplasia, however, is expected a decade sooner [72]. Because the current vaccines only cover 2 of the 15 oncogenic HPV types, and because many postadolescent women who receive the vaccine can be expected to have prior exposure to HPV 16 or 18, even vaccinated women should undergo periodic Pap screening by the recommended guidelines. Combination of primary and secondary prevention, the HPV vaccine and continued cervical screening, has the potential to eradicate cervical cancer. There is a long way to go before this happens. In countries, such as the United States, with access to cytology and HPV screening, too many women still fail to take advantage of periodic Pap tests. All primary care physicians who care for women should provide appropriate cervical cancer screening to their patients or ensure that they are referred to someone who can. There has been controversy over mandatory vaccination of preadolescents against a sexually transmitted virus. It remains to be seen whether enough of the susceptible population will be vaccinated to have a signicant eect on cancer incidence. The vaccine has been licensed in several developing countries. If it can be made aordable and distributed eciently, it is in these countries that the biggest impact will be felt.

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[52] Wright TC, Massad LS, Dunton CJ, et al. 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol 2007;197: 34655. [53] Wright TC, Massad LS, Dunton CJ, et al. 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ. Am J Obstet Gynecol 2007;197:3406. [54] Samson SA, Bentley JR, Fahey TJ, et al. The eect of loop electrosurgical excision procedure on future pregnancy outcome. Obstet Gynecol 2005;105(2):32532. [55] Jakobsson M, Gissler M, Saino S, et al. Preterm delivery after surgical treatment for cervical intraepithelial neoplasia. Obstet Gynecol 2007;109:30913. [56] Jones BA, Novis DA. Follow-up of abnormal gynecologic cytology: a College of American Pathologists Q-probes study of 16132 cases from 306 laboratories. Arch Pathol Lab Med 2000;124:66571. [57] Sherman ME, Solomon D, Schiman M, et al. Qualication of ASCUS. A comparison of equivocal LSIL and equivocal HSIL cervical cytology in the ASCUS/LSIL Triage Study. Am J Clin Pathol 2001;116:38694. [58] Cox JT, Schiman M, Solomon D. Prospective follow-up suggests similar risk of subsequent cervical intraepithelial neoplasia grade 2 or 3 among women with cervical intraepithelial neoplasia grade 1 or negative colposcopy and directed biopsy. Am J Obstet Gynecol 2003;188: 140612. [59] Guido R, Schiman M, Solomon D, et al. Post colposcopy management strategies for women referred with low-grade squamous intraepithelial lesions or human papillomavirus DNA-positive atypical squamous cells of undetermined signicance: a two-year prospective study. Am J Obstet Gynecol 2003;188:14015. [60] Sherman ME, Schiman M, Cox JT, et al. Eects of age and human papilloma viral load on colposcopy triage: data from the randomized Atypical Squamous Cells of Undetermined Signicance/Los-Grade Squamous Intraepithelial Lesion Triage Study (ALTS). J Natl Cancer Inst 2002;94:1027. [61] Massad LS, Collins YC, Meyer PM. Biopsy correlates of abnormal cervical cytology classied using the Bethesda system. Gynecol Oncol 2001;82:51622. [62] Sharpless KE, Schnatz PF, Mandavilli S, et al. Dysplasia associated with atypical glandular cells on cervical cytology. Obstet Gynecol 2005;105:494500. [63] Krane JF, Lee KR, Sun D, et al. Atypical glandular cells of undetermined signicance: outcome predictions based on human papillomavirus testing. Am J Clin Pathol 2004;121: 8792. [64] Inglis S, Shaw A, Koenig S. Chapter 11: HPV vaccines: commercial research and development. Vaccine 2006;3(Suppl 24):S99105. [65] Koutsky LA, Ault KA, Wheeler CM, et al. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 2002;347:164551. [66] Ault KA. Long-term ecacy of human papillomavirus vaccination. Gynecol Oncol 2007; 107(Suppl 2):S2730. [67] Harper DM, Franco EL, Wheeler C, et al. Ecacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet 2004;364:175765. [68] Harper DM, Franco EL, Wheeler CM, et al. Sustained ecacy up to 4.5 years of bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomized control trial. Lancet 2006;367:124755. [69] Garland SM, Hernandez-Avila M, Wheeler CM, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 2007;356(19): 192843. [70] FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007;356(19):191527.

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[71] Davey DD, Neal MH, Wilbur DC, et al. Bethesda 2001 implementation and reporting rates: 2003 practices of participants in the College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology. Arch Pathol Lab Med 2004;128:12249. [72] Wright TC, Van Damme P, Schmitt HJ, et al. Chapter 14: HPV vaccine introduction in industrialized countries. Vaccine 2006;3(Suppl 24):S12231.

Med Clin N Am 92 (2008) 10831113

Sexually Transmitted Infections and Pelvic Inammatory Disease in Women

Bruce G. Trigg, MDa,b,*, Peter R. Kerndt, MD, MPHc,d, Getahun Aynalem, MD, MPHc
Sexually Transmitted Disease Program, Regions 1 and 3, New Mexico Department of Health, 1111 Stanford Drive NE, Albuquerque, NM 87106, USA b Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA c Sexually Transmitted Disease Program, Los Angeles County Department of Public Health, 2615 South Grand Avenue, Room 500, Los Angeles, CA 90007, USA d Department of Medicine, Division of Infectious Diseases, Los Angeles County and University of Southern California Medical Center, 1200 N. State Street, Room 6442, Los Angeles, CA 90033, USA
a

Most sexually transmitted infections (STIs) in the United States are diagnosed and treated in primary care settings rather than in specialized public health department STI clinics or infectious disease clinics. Clinicians who provide care to women need to be cognizant of the fact that women have higher rates of STIs than men because of their greater biologic susceptibility and the ease of transmission from men to women. In addition, 85% of women with an STI delay seeking medical care because they have no symptoms or minimal symptoms and do not believe that anything is wrong [1]. Approximately 70% of chlamydial infections and 50% of gonococcal infections in women are asymptomatic [24], and therefore go undiagnosed and untreated. Because of the high incidence and prevalence of STIs in the general population and the potential for serious sequelae, clinicians who provide primary care health services to women need to be familiar with nationally recognized clinical screening, treatment, and prevention recommendations concerning STIs. Two evidence-based guidelines for diagnosis, treatment, and screening recommendations for STIs are readily available to practitioners: the Centers for Disease Control and Preventions (CDC) sexually transmitted disease
* Corresponding author. New Mexico Department of Health, 1111 Stanford Drive NE, Albuquerque, NM 87106. E-mail address: bruce.trigg@state.nm.us (B.G. Trigg). 0025-7125/08/$ - see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2008.04.011 medical.theclinics.com

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(STD) treatment guidelines [5] and the Agency for Healthcare Research and Qualitys (AHRQ) guide to clinical prevention services [6]. The 2006 CDC STD treatment guidelines provide evidence-based recommendations for counseling, testing, and treatment of STIs [7]. The AHRQ guide to clinical prevention services covers a wide range of clinical prevention topics, including infectious diseases and STIs. The full task force recommendations are available online [8]. Screening of asymptomatic women for STIs is a key clinical prevention strategy for addressing the high rates of STIs. Screening for chlamydia, gonorrhea, HIV, and other STIs is recommended by the CDC, AHRQ, and national medical specialty associations [5,6,9,10] but, unfortunately, has not been widely implemented in clinical practice. The National Committee for Quality Assurance promulgates performance measures called HEDIS (Healthcare Eectiveness Data and Information Set). The HEDIS measure for chlamydia is the annual rate of screening of all sexually active women in the managed care plan. Although there has been modest and steady improvement in the rates of screening women for chlamydial infection, in 2004, the screening rate for chlamydia was still only 32.6% among women aged 16 to 20 years in commercial health plans and 45.9% among women enrolled in Medicaid-managed care plans [11]. For women aged 21 to 25 years, the rates were 31.7% in commercial plans and 49% in Medicaid plans [11]. Even when symptomatic women seek medical care, they may not receive appropriate treatment. A 1996 survey of primary care physicians who had treated at least one case of pelvic inammatory disease (PID) within the past 12 months found that 52% were unsure of or did not follow the CDC guidelines for the treatment of PID [12]. Furthermore, only 3% of the physicians surveyed were able to answer all the PID management questions correctly. Given the high prevalence and incidence of STIs in the United States, primary care providers, including clinicians who care for patients in emergency room and urgent care settings, need to be familiar with current screening recommendations for STIs and to test and treat presumptively when caring for symptomatic patients who are at risk for STIs according to CDC treatment guidelines [5]. Epidemiology STIs continue to be a signicant public health problem. The economic burden of STIs in the United States is estimated at $14.1 billion in direct medical costs to the health care system [13,14]. Including viral STIs, such as human papillomavirus (HPV), herpes simplex virus (HSV) and HIV, it is estimated that more than 19 million new cases of STIs occur annually in the United States [15,16]. A recently released CDC study found that one in four 15- to 19-year-old adolescent girls in the United States was infected with trichomoniasis,

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chlamydia, HPV, or HSV. The rate was 50% in African-American teenagers and 20% in white and Hispanic girls. In 2006, among US women, 780,515 cases of chlamydial infections, 187,257 cases of gonococcal infections, and 1505 cases of primary and secondary (P&S) syphilis cases were reported to the CDC [15]. Between 2005 and 2006, the rate of chlamydial infections in women increased from 492.2 to 515.8 per 100,000 women. The gonococcal infection rate for women in 2006 was 124.3 per 100,000 women [15]. Other common STIs are HSV and HPV. Studies have shown that 22% of adults in the United States are infected with HSV-2; of those, almost 90% are unaware of their infection [16,17]. The annual prevalence of genital HPV is estimated to be 6.2 million cases among 15- to 44-year olds [18]. Modeling estimates suggest that up to 50% to 80% of sexually active women have acquired genital HPV by the age of 50 years [19]. Reducing STIs is a major strategy for controlling the HIV epidemic domestically and internationally. Studies have demonstrated that a person who is infected with an STI is at least two to ve times more likely than an uninfected individual to acquire HIV if he or she is exposed to the virus through sexual contact [20]. In addition, an HIV-infected person who is also infected with another STI is more likely to transmit HIV through sexual contact than is an HIV-infected person without an STI infection. Barriers to diagnosis and treatment Signicant barriers to appropriate diagnosis and care for patients who have STIs include not having medical insurance and lack of access to clinical services. In addition, the perceived stigma of having an STI; condentiality concerns; and discomfort on the part of the patient, clinician, or both in discussing sexuality issues, such as indelity, having multiple sex partners, and sexual orientation, are barriers to diagnosis and timely treatment. Among the 47 million uninsured Americans, the highest STI rates are found in the same age groups (18- to 24-year-olds) and racial and ethnic groups (Hispanics and African Americans) that are most likely to be uninsured. Public health programs that have historically served as a safety net for the uninsured and other disadvantaged populations have experienced signicant budgetary cutbacks that have aected their ability to fulll their traditional role in providing clinical care and partner notication services. Clinicians are often not aware that minors at the age of 12 years (age of 14 years in some states) can legally consent for their own health services for the diagnosis and treatment of STIs. Updated information for each state is available on-line from the Guttmacher Institute [21]. A medical practice can prevent misunderstandings by having an explicit policy that explains the legal rights of adolescents and the importance of providing condential medical care for STIs.

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Because of the stigma associated with STIs, patients are often reluctant to talk about their concerns. A sexual history should routinely be obtained from all patients in a straightforward, respectful, and nonjudgmental manner. A sexual history can provide useful information for guiding decisions about STI management or additional examinations or tests that might benet the patient. All patients should be asked about the following:  Any symptoms of an STI  Social history, including use of alcohol and other substance use that may increase STI risk  Previous pregnancies, last menstrual period, menstrual pattern, and contraception  Sexual history, including number and gender of sexual partners, concurrent or anonymous sex partners, drug or alcohol use before or during sex, use of the Internet to meet new sex partners, and specic sexual practices (oral or anal) with or without barrier methods (male or female condoms) Asking all patients whether they have sex with men, women, or both generally elicits the necessary information to guide further inquires about risk factors. The CDC STD treatment guidelines [5] provide specic screening recommendations for women who have sex with women. Asking openended questions when taking a sexual history, using understandable language, and not assuming that married patients or patients in long-term relationships or their partners are necessarily monogamous also helps to obtain relevant information. Clinicians who wish to receive additional training on taking a sexual history or behavioral interventions, such as clientcentered prevention counseling or STI clinical training, can contact their local health department or one of the regional CDC-funded STD/HIV prevention training centers [22] to nd out about their course oerings. Prevention of sexually transmitted infections: the role of condoms The World Health Organization (WHO) and the Joint United Nations Program on HIV/AIDS (UNAIDS) describe the male latex condom as the single most ecient available technology to reduce the sexual transmission of HIV and other STIs. Consistent and correct condom use reduces the risk for infection with chlamydia, gonorrhea, trichomoniasis, and PID. Studies have shown that condoms even oer more protection against viral STIs spread by skin-to-skin contact than had been anticipated. One recent study showed that women whose male partners used condoms consistently were 70% less likely to become infected with HPV than were those whose partners used condoms less than 5% of the time [23]. Other studies have shown that condoms reduce the sequelae of HPV infection (ie, genital warts, cervical cancer) and protect against the risk for recurrent PID [24]. The female condom, a polyurethane pouch that is inserted into the vagina using

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a exible ring, has also been shown to prevent STIs, including HIV. Although more expensive than male condoms, they are especially useful for women whose male partners may be unwilling to use a condom. Clinicians should inquire about their patients condom use and encourage use. In some practices, a nurse or other sta member oers a brief counseling session to young male and female patients to discuss condom use and to demonstrate correct technique using a penis model. Ideally, the patients are provided with condoms at the completion of the session. Making condoms available at the reception desk, in the examination room, or in the restrooms is a good way to assure patients that the practice is open to discussing sexual issues. Clinical sequelae of sexually transmitted infections in women STIs have a serious impact on the reproductive health of women. Although most women with an STI recover, delayed or untreated gonococcal or chlamydial infections may damage the upper reproductive tract and lead to long-term sequelae. Between 20% and 40% of women who have chlamydial infection [25] and 10% to 20% of women who have gonococcal infection [26] develop PID. This upper genital tract infection increases womens risk for subsequent ectopic pregnancy, tubal infertility, and chronic pelvic pain [27,28]. STIs in pregnancy, such as syphilis, gonorrhea, chlamydia, HSV, hepatitis B, and HIV, pose signicant health risks to the fetus, neonate, or infant. Poor pregnancy outcomes associated with STIs include preterm labor, miscarriage, stillbirth, and congenital infection. Most serious health problems and the poor pregnancy outcomes associated with STIs in women can be avoided or minimized with routine screening of all pregnant women for gonorrhea, chlamydia, syphilis, and HIV in addition to eective case management practice. In addition to symptom recognition and early treatment, an important way of reducing the clinical sequelae of STIs in women is early detection of asymptomatic infection when patients seek care for family planning, student health services, or visits for other reasons. Partner management and expedited partner therapy The medical care of a woman with an STI is incomplete until specic arrangements are made for treatment of her sexual partners. Providers ideally help to make arrangements to examine, test, and treat sexual partners themselves. Managed care restrictions, lack of insurance, or unwillingness of the patient to inform her partner or of the partner to seek medical care may hinder such plans, however. Public health programs may be available to contact and arrange for treatment of sexual partners. Several studies have shown that reinfection rates of patients treated for gonorrhea and chlamydia are

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quite high. Recent studies of patients treated for chlamydia infection showed a reinfection rate of 11% to 13% within 4 months of treatment [2931]. Expedited partner therapy (EPT) is a way for providers to treat patients with whom they have not established a therapeutic relationship so as to prevent reinfection of an index patient. Patients may deliver medication or a prescription to their sex partners. Three recent multicenter randomized controlled trials have demonstrated that heterosexual patients who have gonorrhea or chlamydia were less likely to become reinfected with gonorrhea or chlamydia if they used EPT rather than unassisted patient referral for their partners [3032]. Adverse reactions to the antibiotics commonly used for EPT (azithromycin for chlamydia and oral third-generation cephalosporins for gonorrhea) are quite rare. No serious adverse reactions were documented in the study populations, and none have been reported in those states that allow for EPT. The CDC has issued a review of the evidence for EPT and has concluded that it is a useful option to facilitate partner management, particularly for treatment of male partners of women with chlamydial or gonorrheal infection [33]. Therefore, the CDC encourages the medical and public health systems to work toward removing legal and administrative barriers that prevent use of EPT. EPT is currently allowed in 11 states, is potentially legal in 28 states or territories, and is prohibited in 13 states. The CDC has a Web site that tracks the legal obstacles and progress of each state in making this option available for clinicians [34]. Although a full medical evaluation of any person exposed to an STI continues to be the best approach, EPT should be considered as an option for providing medication to partners of patients who have gonorrhea or chlamydia when sex partners are not able or not willing to obtain a medical evaluation. Reporting requirements Syphilis, gonorrhea, chlamydia, chancroid, HIV, and AIDS are reportable in every state in the United States. Clinicians should be familiar with local and state reporting rules and ensure complete and timely reporting to local health departments. Frequently, reporting is completed by the laboratory. Public health workers who follow up on positive STI tests may contact health care providers to verify diagnosis and conrm appropriate treatment [5].

Common sexually transmitted infections in women Chlamydia Clinical manifestations Most women with Chlamydia trachomatis infection have no symptoms. Others may present with signs or symptoms of mucopurulent cervicitis (MPC) (Fig. 1), acute urethral syndrome, or PID.

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Fig. 1. Chlamydial cervicitis. (Courtesy of C. Celum, MD, MHP, and W. Stamm, MD, Seattle, WA.)

Screening recommendations The U.S. Preventive Services Task Force screening recommendations for chlamydia can be found in Box 1. Diagnosis. The selection of a diagnostic test for chlamydia is aected by several factors, such as sensitivity, specicity, ease of specimen collection, processing, and cost. Available technologies for diagnosing chlamydia are divided into those that are designed for clinical laboratory testing or point-of-care testing. Laboratory-based tests include culture, nucleic acid amplication tests (NAATs), nucleic acid hybridization (DNA probe), enzyme immunoassays (EIAs), and direct uorescent antibody (DFA) tests. Point-of-care tests are available that use EIAs. Tissue culture is highly specic and is the standard test for medicolegal cases, such as sexual assault and child abuse cases. Because of the higher cost and technical complexities, however, it is rarely used for other purposes. NAATs are the tests of choice for urethral, cervical, vaginal, and urine specimens because of their superior sensitivity and excellent specicity [35,36]. NAATs include the polymerase chain reaction test (PCR), the transcription mediated amplication test (TMA), and the strand displacement amplication (SDA). These tests are more convenient than older testing technologies because they can be performed on urine specimens or on urethral or cervical swabs. In addition, some have been approved for patient self-obtained vaginal swabs. Some laboratories have validated NAAT tests so that they can be used to detect chlamydia in the rectum. NAATs are particularly well suited for rapid screening of asymptomatic patients, avoiding the time and discomfort associated with pelvic examinations and urethral swabs. Symptomatic female patients are best served with a complete pelvic examination, however. There are several commercially available EIA point-of-care tests on the market that have a lower sensitivity than NAATs [37] and are approved for use only on endocervical and urethral specimens. Their advantages include ease of specimen processing, transport, and relatively low cost. In view of their low sensitivity compared with NAATs, they should generally

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Box 1. US Preventive Services Task Force recommendations Chlamydia The US Preventive Services Task Force (USPSTF) strongly recommends that clinicians routinely screen all sexually active women aged 25 years and younger, in addition to other asymptomatic women at increased risk for infection, for chlamydial infection. Those at increased risk include women with a new or multiple sex partners, those with a diagnosis of gonorrhea or chlamydia within the previous year, and those who do not consistently use barrier methods. Gonorrhea The USPSTF recommends that clinicians screen all sexually active women, including those who are pregnant, for gonorrhea infection if they are at increased risk for infection (ie, if they are young or have other individual or population risk factors). Individual risk depends on local epidemiology of disease. Local public health authorities provide guidance to clinicians to help identify populations that are at increased risk in their communities. Herpes simplex virus The USPSTF recommends against routine serologic screening for HSV in asymptomatic pregnant women at any time during pregnancy to prevent neonatal HSV infection. The USPSTF recommends against routine screening for HSV in asymptomatic adolescent and adults. Syphilis The USPSTF strongly recommends that clinicians screen persons at increased risk for syphilis infection and all pregnant women for syphilis infection. The USPTF strongly recommends against routine screening of asymptomatic persons who are not at increased risk for syphilis infection. Populations at risk based on incidence rates include men who have sex with men and engage in high-risk sexual behavior, commercial sex workers, persons who exchange sex for drugs, and those in adult correctional facilities. Clinicians should consult local health departments to nd out local prevalence rates and populations at increased risk.
From US Department of Health and Human Services Agency for Healthcare Research and Quality. AHRQ Publication No. 06-0588, June 2006. Available at: http://www.ahrq.gov/clinic/pocketgd.pdf. Accessed June 11, 2008.

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be used only in clinical settings in which the patient is unlikely to return for treatment, such as street outreach or correctional settings. Treatment. Azithromycin and doxycycline are the rst-line therapies for C trachomatis infection (Table 1) [5]. Microbial cure rates of 97% and 98% have been shown for azithromycin and doxycycline, respectively [38]. Azithromycin is considered the drug of choice for pregnant women, whereas doxycycline, ooxacin, and levooxacin are contraindicated in pregnancy. HIV-positive women should be treated with the same medications. Treatment of cervicitis in HIV-infected women reduces HIV shedding from the cervix and may reduce HIV transmission to susceptible sex partners [39]. Follow-up and management of sex partners. A test-of-cure is recommended only if the patient is pregnant, if symptoms persist, or if there is concern about reinfection [5,25]. A repeat test should not be done before 3 weeks after completion of therapy, because a false-positive test result may occur, especially with the highly sensitive NAAT tests [40]. All sexual partners within 60 days of onset of symptoms or diagnosis of chlamydia infection [25] should be contacted and encouraged to be evaluated, tested, and treated. EPT should be considered an option if the patients

Table 1 Antimicrobial treatment of chlamydial infections Antimicrobial Most adult women Recommended regimens Azithromycin Doxycycline Alternative regimens Erythromycin base Erythromycin ethylsuccinate Ooxacin Levooxacin Pregnant women Recommended regimens Azithromycin Amoxicillin Alternative regimens Erythromycin base Erythromycin base Erythromycin ethylsuccinate Erythromycin ethylsuccinate Dosage and route of administration

1 g orally in a single dose 100 mg orally twice a day for 7 days 500 800 300 500 mg mg mg mg orally orally orally orally four times a day for 7 days four times a day for 7 days twice a day for 7 days once daily for 7 days

1 g orally in a single dose 500 mg orally three times a day for 7 days 500 250 800 400 mg mg mg mg orally orally orally orally four four four four times times times times a a a a day day day day for for for for 7 days 14 days 7 days 14 days

Data from Centers for Disease Control and Prevention. 2006. Sexually transmitted diseases treatment guidelines. MMWR 2006;55(RR11):3640.

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sexual partners are unlikely to present for medical evaluation. All patients and partners should be advised to abstain from sexual contact until 7 days after treatment. Gonorrhea Clinical manifestations More than 50% of women with gonococcal infection have no symptoms. Although the urethra and rectum may be involved, the locus of infection in women is typically the endocervix. When present, symptoms of gonorrhea in women may include burning or frequent urination, a yellowish vaginal discharge, redness and swelling of the genitals, and a burning or itching of the vaginal area. The classic nding of MPC is not always present in women. Even when present, the cervicitis is clinically indistinguishable from that caused by other genitourinary pathogens, including C trachomatis [28]. Gonorrhea infections of the rectum may be spread from infected vaginal secretions or from anal intercourse. Rectal gonorrhea is usually asymptomatic or may manifest as itching, bloody or mucoid discharge, or tenesmus. Pharyngeal infections are usually asymptomatic but may cause pain with swallowing. Screening recommendations The U.S. Preventive Services Task Force screening recommendations for gonorrhea can be found in Box 1. Diagnosis. Culture, Gram stain, nucleic acid hybridization tests, and NAATs are available for the diagnosis of gonococcal infection. Culture has been the gold standard method for diagnosis and antimicrobial sensitivity analysis of gonococcal infections. Culture from endocervical infection has been reported to have a sensitivity of 85% to 95% [41,42]. For an optimal result, the specimen should be collected using a swab that has a wire shaft and a calcium alginate or synthetic ber tip [43] Gonorrhea cultures require special handling; they must be incubated at 35 C to 36.5 C and be kept in a 5% carbon dioxideenriched environment [35]. An endocervical Gram stain, rarely available today in oce-based settings, is of limited utility because of its low sensitivity (30%50%), although the specicity is high (up to 99%) [44]. Nucleic acid hybridization (DNA probes) or nucleic acid amplication tests. NAATs have the ability to detect small amounts of nucleic acid and may, at times, detect nonviable organisms. NAATs can be performed on urine samples, endocervical and urethral swabs, or self-collected vaginal swabs. The ease of collection of specimens for these tests has made them the preferred method over culture in most settings. Some laboratories have validated NAATs for throat and rectal testing as well. They oer the additional advantage of allowing concurrent testing for C trachomatis. DNA probes are sensitive (92.1%) but can only be performed on

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endocervical specimens [45]. These tests cannot be used to monitor antibiotic resistance. Culture is the only technique that can isolate the organism for antimicrobial sensitivity testing and is required for medicolegal cases [45]. Treatment. Treatment of gonorrhea is complicated by the ability of the organism to develop resistance. Surveillance for antimicrobial resistance in the United States in 2004 found that 15.9% of isolates were resistant to penicillin or tetracycline [46]. Increased quinolone-resistant Neisseria gonorrhoeae (QRNG) has led to the revision of the national guidelines that now limit the recommended treatment of gonorrhea to a single class of drug: the cephalosporins [47]. Treatment recommendations are summarized in Table 2. All recommended therapies are given as a single dose. Tests of cure are not recommended for uncomplicated gonococcal infections that are treated with one of the recommended regimens [48]. Failure to improve after proper treatment requires culture for antimicrobial susceptibility. Infections identied after completion of treatment are usually attributable to reinfection rather than to treatment failure, especially if the patient initially improved. Dual therapy for gonococcal and chlamydial infections Patients infected with N gonorrhoeae frequently are coinfected with C trachomatis. Therefore, dual therapy for gonococcal and chlamydial infection is recommended unless the patient has a negative chlamydia test result using NAAT technology, because these tests are highly sensitive [5].

Table 2 Antimicrobial treatment of uncomplicated gonococcal infections Antimicrobial Recommended regimens Ceftriaxone Cexime Alternative regimensa Spectinomycinb Ceftizoxime sodium Cefotaxime sodium Cefoxitin sodium Cefpodoximec Cefuroxime axetilc
a

Dose and route of administration 125 mg IM in a single dose 400 mg PO in a single dose 2 g in a single IM dose 500 mg IM in a single dose 500 mg IM in a single dose 2 g IM with probenecid, 1 g PO 400 mg PO in a single dose 1 g PO in a single dose

Abbreviations: IM, intramuscular; PO, per os. a Plus treatment for chlamydia if infection is not ruled out with NAAT. b Not currently available in United States. c Not adequate for treatment of pharyngeal gonorrhea. Data from Centers for Disease Control and Prevention. 2006. Sexually transmitted diseases treatment guidelines. MMWR 2006;55(RR11):434.

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Follow-up and management of sex partners A test-of-cure is recommended only if the patient is pregnant, if symptoms persist, or if there is concern about reinfection [5]. A repeat test should not be done before 3 weeks after completion of therapy, because a falsepositive test result may occur because the NAAT may detect the presence of nonviable organisms. Patients should be instructed to refer all their sex partners within the previous 60 days for evaluation and treatment. Patients should also abstain from sexual intercourse for 7 days after treatment and until their sex partners have been treated. Consider providing EPT for those patients whose partners are unlikely to seek treatment. Herpes simplex virus Clinical manifestations Most people infected with HSV-2 experience no symptoms, whereas some have mild symptoms and remain unaware that they have genital herpes. Classic outbreaks of primary genital HSV infection begin with a prodrome lasting 2 to 24 hours that is characterized by localized or regional pain, tingling, and burning. Patients also may have constitutional symptoms, such as fever, headache, abdominal pain, myalgias, inguinal lymphadenopathy, anorexia, and malaise [49,50]. In women, painful vesicles on an erythematous base usually appear initially on the cervix, introitus, labia, vagina, vulva, urethral meatus, perineum, and surrounding skin. The vesicles typically rupture, leading to ulceration and crusting by 14 to 21 days after their initial appearance and heal without scarring. Recurrent HSV outbreaks usually are milder than the initial episode with typically fewer lesions and viral shedding at a lower concentration and for a shorter duration (ie, approximately 3 days). The prodromal symptoms are similar in recurrent outbreaks, however. For unknown reasons, women have more severe disease, constitutional symptoms, and complications than men [51,52]. This may be a result of the larger aected surface area in women and the ability of the virus to spread more easily over moist surfaces. Cervical ulcerative lesions are common and are almost always associated with rst-episode disease. This type of lesion can present with intermittent bleeding and vaginal discharge. Dysuria and urinary retention may occur from urethral lesions and urine contact with vulvar lesions. Screening recommendations Diagnosis. The diagnosis of HSV infection is made clinically by recognition of the characteristic multiple, shallow, and tender ulceratiosn or vesicles on or around the genitalia (Fig. 2). Clinical diagnosis of genital herpes is insensitive and nonspecic, however. Therefore, a clinical diagnosis should be conrmed by laboratory testing. In addition, all patients who have genital ulcers should have a serologic test for syphilis and testing for HIV.

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Fig. 2. Herpes genitalis: periurethral lesions on the vestibule. (Courtesy of Cincinnati STD/HIV Prevention Training Center, Cincinnati, OH; with permission.)

Viral culture Viral isolation by tissue culture is the preferred method for identifying HSV infection and is also highly sensitive for dierentiating between HSV-1 and HSV-2. Despite its limitations (it may take up to 5 days for a positive test result, and sensitivity is only 70%80%), culture is the diagnostic test of choice for HSV infections. Cultures are more likely to be positive during the vesicular or early ulcerative stages and generally are not productive more than 5 days after the appearance of lesions. The vesicle, if present, should be punctured and the uid absorbed onto a swab using a prepackaged viral collection system rather than a cotton swab. The swab is then placed into the viral collection vial for transport. At the laboratory, specimens are inoculated into cell cultures and monitored microscopically for 5 to 7 days to obtain maximum sensitivity. Polymerase chain reaction PCR testing for HSV DNA has greater sensitivity than viral culture at 95% compared with 75% for culture [53,54] Because of its higher cost and limited availability, however, it is chiey used today for the diagnosis of HSV encephalitis or for neonatal infections, because the results are more rapid than viral culture [55]. Type-specic serologic tests Type-specic HSV serologic assays are based on the HSV-specic glycoprotein G2 (HSV-2) and glycoprotein G1 (HSV-1). These assays are used to conrm HSV infection in persons with a questionable history or in those

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who have unrecognized or subclinical infections in the presence of a falsenegative culture [56] and to test a partner of a person with genital herpes. Their routine use in asymptomatic patients is controversial. Treatment Counseling regarding the natural history of genital herpes, sexual and perinatal transmission, and methods to reduce transmission is integral to clinical management. Oral antiviral medications are available for the treatment of genital herpes. These agents do not cure the disease but can partially control the signs and symptoms. They decrease the time until lesions are crusted and healed by several days in addition to decreasing localized pain, constitutional symptoms, and viral shedding [57]. Commonly used agents include acyclovir, now available as a generic drug, valacyclovir, and famciclovir. All have rare but similar side eects, which include nausea, vomiting, headache, and diarrhea. All are equally eective, but acyclovir requires more frequent dosing. The treatment of HSV can be for a rst clinical episode, suppression treatment, or episodic therapy for recurrences (Table 3). The goal of treatment for a rst clinical episode is to improve symptoms and speed recovery. The treatment goal of suppressive therapy is to reduce the frequency of recurrences. It has been shown to reduce recurrence by 70% to 80% in patients who have frequent outbreaks (ie, more than six per year), and it probably is also eective in patients who have fewer recurrences [58]. The treatment goal of episodic therapy for recurrences is to diminish symptoms and infectivity
Table 3 Antiviral treatment of genital herpes infections Antimicrobial First clinical episode Acyclovir Acyclovir Famciclovir Valacyclovir Suppressive therapy Acyclovir Famciclovir Valacyclovir Episodic therapy for recurrent Acyclovir Acyclovir Acyclovir Famciclovir Famciclovir Valacyclovir Valacyclovir
a a

Dosage and route of administration 400 mg orally three times a day for 710 days 200 mg orally ve times a day for 710 days 250 mg orally three times a day for 710 days 1 g orally twice a day for 710 days 400 mg orally twice a day 250 mg orally twice a day 5001000 mg orally once a day 400 mg orally three times a day for 5 days 800 mg orally twice a day for 5 days 800 mg orally three times a day for 2 days 125 mg orally twice daily for 5 days 1000 mg orally twice daily for 1 day 500 mg orally twice a day for 3 days 1.0 g orally once a day for 5 days

Treatment might be extended if healing is incomplete after 10 days of therapy. Data from Centers for Disease Control and Prevention. 2006. Sexually transmitted diseases treatment guidelines. MMWR 2006;55(RR11):178.

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during recurrences rather than to reduce the frequency of recurrences. Treatment for recurrences must be started within 24 hours of the onset of symptoms and generally shortens the duration of the outbreak by 1 to 2 days. Follow-up and management of sex partners. Patients should be instructed to abstain from sexual activity when ulcers or symptoms are present. They should also be told that even when they have no symptoms, it is still possible to transmit infection. Symptomatic sex partners should be evaluated and treated if they have genital lesions. Asymptomatic sex partners of patients who have genital herpes should be questioned concerning past history of ulcerative genital lesions. Partners may be oered type-specic serologic testing to determine if they are already infected with HSV or if they are at risk for becoming infected. Female patients who have genital herpes should be advised that HSV can cause infections in newborns and that if they become pregnant, they need to inform their doctor about their history of HSV. The risk for perinatal infection is far greater if a primary HSV infection occurs just before delivery than if a pregnant woman is infected before or early in the pregnancy. In the future, vaccines based on mucosal immunity may become feasible [59]. Syphilis Screening recommendations The U.S. Preventive Services Task Force screening recommendations for syphilis can be found in Box 1. Clinical manifestations. Typically, primary syphilis manifests as a chancre: a single, painless, clean-based ulcer that appears 9 to 90 days after exposure (Fig. 3) [60]. In women, the labia and vaginal wall are most often aected.

Fig. 3. Syphilis: multiple chancres. (From Morse SA. Atlas of sexually transmitted diseases and AIDS. Mosby, 1996; with permission.)

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Because many women with primary syphilis are asymptomatic or are not aware of a vaginal or cervical lesion, the primary stage often goes undetected. If the patient remains untreated over the next several weeks to months, most progress to secondary syphilis. Women with secondary syphilis often present with a generalized maculopapular rash, including characteristic lesions on the palms and soles, and systemic symptoms that may include fever, arthralgias, pharyngitis, and lymphadenopathy. Condylomata lata, another manifestation of secondary syphilis, are at, raised, painless, moist lesions found on mucosal areas that may be mistaken for genital warts (condylomata acuminata). These lesions are teeming with spirochetes and are contagious to sexual partners (Figs. 4 and 5). Left untreated, the chancre of primary syphilis and the signs and symptoms of secondary syphilis ultimately resolve [60,61] and the disease becomes latent. During the latent stage, patients are asymptomatic and diagnosis requires serologic testing. Years after the initial symptoms, tertiary or late syphilis develops and may produce a variety of neurologic, cardiovascular, and other systemic manifestations. Because of eective therapy in diagnosed patients and, presumably, because of frequent use of antibiotics in undiagnosed patients, tertiary syphilis is uncommon in the United States. Infection during pregnancy is a medical emergency. Maternal-fetal transmission may result in fetal death, premature delivery, or congenital syphilis. The risk for transmission is much higher in the early stage of maternal disease; however, even in late latent stage, newborns can develop congenital syphilis. Most cases of congenital syphilis are easily preventable if women are screened for syphilis and treated early during prenatal care. The CDC recommends that no newborn should be discharged from the hospital until verication that there was at least one negative prenatal maternal serologic test result for syphilis or until the result of an intrapartum or postpartum test is determined [5,62].

Fig. 4. Condylomata lata lesions of secondary syphilis. (Courtesy of B.G. Trigg, MD, Albuquerque, NM.)

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Fig. 5. Condylomata lata lesions of secondary syphilis. (Courtesy of B.G. Trigg, MD, Albuquerque, NM.)

Diagnosis. A presumptive diagnosis of primary or secondary syphilis can be made on the basis of the physical ndings but requires conrmation with laboratory tests. The most specic technique for diagnosing primary syphilis is dark-eld microscopy, which is no longer generally available outside of specialized STI clinics. Latent syphilis has no signs or symptoms, and therefore must be diagnosed with serologic testing. Women suspected of having syphilis and women being screened for syphilis are initially tested using nontreponemal screening tests; the rapid plasma reagin (RPR) or venereal disease research laboratory (VDRL) test. Both tests are reported quantitatively as serologic dilutions (eg, 1:2, 1:4, 1:8). The level of the titer generally reects the degree of disease activity and is also useful for monitoring a patients response to therapy. If a nontreponemal test result is positive, conrmation using a treponemal-specic test, such as a Treponema pallidum hemagglutination (TPPA) or a uorescent treponemal antibody absorption (FTA-Abs) test, is necessary [63], because falsepositive nontreponemal test results may occur with collagen-vascular disease, intravenous drug use, tuberculosis, vaccinations, pregnancy, infectious mononucleosis, HIV, rickettsial infections, malaria, leprosy, and bacterial endocarditis [64]. Unlike nontreponemal tests, which show a decline in titers or become nonreactive with eective treatment, treponemal-specic tests usually remain reactive for life. Treatment and follow-up. Every state requires that syphilis cases be reported to the state department of health. Patients who have suspected or conrmed syphilis should be referred as quickly as possible to local public health departments, which have the legal responsibility, and generally have special expertise, for interviewing and providing testing, treatment, follow-up, and partner management services to control the spread of syphilis. They also have access to historical information about previous syphilis infections,

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past serologic titers, and treatment that may be helpful in making a diagnosis and determining if a positive test result represents new or old infection. Treatment recommendations are summarized in Table 4. Patients who have syphilis should be oered an HIV test because they frequently engage in behaviors that place them at risk (ie, drug and alcohol abuse, injecting drug use, prostitution). Genital human papillomavirus infection Clinical manifestations HPV is the most common STI in the United States. More than 100 types of HPV exist, of which more than 30 types are sexually transmitted, infecting the vulva and the linings of the vagina and cervix in women. Most HPV infections are asymptomatic, unrecognized, or subclinical. External genital warts may present as esh-colored, at, verrucous, or papillary lesions (Fig. 6). Women with internal warts may have discomfort, pain, bleeding, or diculty with intercourse. These symptoms are more common in patients who have larger cauliower-like lesions. Most HPV infections are asymptomatic and transient and resolve without treatment. Persistent infection with high-risk types, such as 16, 18, 31, and 33, are strongly associated with Papanicolaou test abnormalities, high-grade cervical dysplasia, and

Table 4 Antimicrobial treatment of syphilis Stage Primary, secondary, or early latent disease Antimicrobial Penicillin G benzathine, doxycycline Erythromycin Ceftriaxone sodium Penicillin G benzathine Penicillin G (aqueous) Dosage and route of administration 2.4 million units IM as a single divided dose 100 mg PO bid for 14 days 500 mg qid for 14 days 1 g IM for 810 days 2.4 million units IM weekly for 3 weeks 1824 million units in divided doses every 4 hours for 1014 days 2.4 million units IM daily plus probenecid, 500 mg PO qid for 1014 days 2.4 million units IM in a single divided dose

Late latent disease Neurosyphilis

Penicillin G procaine plus probenecid Pregnancy (primary, secondary, or early latent disease)a Penicillin G benzathine

Abbreviations: bid, twice daily; IM, intramuscular; PO, per os; qid, for times daily. a Some authorities suggest a second dose of IM penicillin administered 1 week after the rst dose in pregnant women. Data from Centers for Disease Control and Prevention. 2006. Sexually transmitted diseases treatment guidelines. MMWR 2006;55(RR11):249.

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Fig. 6. Vulvar warts. (Courtesy of G.D. Davis, MD, Phoenix, AZ.)

cervical cancer, however. HPV types 16 and 18 account for approximately 70% of cervical cancers in the United States. The HPV types that cause genital warts are not associated with cervical dysplasia and cancer. The evaluation and treatment of cervical dysplasia are covered in the article by Waxman and Zsemlye elsewhere in this issue. Diagnosis External genital warts typically are diagnosed clinically, based on their characteristic appearancedat, papular, or pedunculated growths on the genital mucosa. A biopsy is needed if the diagnosis is uncertain; the lesions do not respond to standard therapy; the disease worsens with therapy; the patient is immunocompromised; or the warts are pigmented, indurated, xed, friable, or ulcerated. A biopsy is not typically recommended, and no data support the use of HPV nucleic acid tests in the routine diagnosis or management of visible genital warts. Treatment In the absence of genital warts or cervical Squamous Intraepithelial Lesion (SIL), treatment is not recommended for subclinical genital HPV infection, whether it is diagnosed by colposcopy, biopsy, or through the detection of HPV by laboratory tests [5]. Visible genital warts are removed primarily for cosmetic reasons. This can be achieved by patient-applied topical therapies,

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including 0.5% podolox solution or gel or 5% imiquimod cream; by provider-applied topical therapies, including 10% to 25% podophyllin resin, trichloroacetic acid, or 80% to 90% bichloracetic acid; and by other modalities, such as surgical removal, laser surgery, or cryotherapy. All therapies have similar response rates of 60% to 80% and the choice of therapy typically depends on the training of the provider and availability of the method. Patients should be informed that recurrences occur in approximately 30% of cases. A convenient and cost-eective approach for the oce-based practitioner is to treat genital warts with a cryotherapy product that has a long shelf life and can be used for multiple treatments from a single canister using disposable applicators. Unlike liquid nitrogen, the temperature of the probe is not low enough to cause deep tissue damage. Depending on the specic product used, the lesions are frozen for 10 to 20 seconds and subsequent applications, if needed, are repeated in 1 to 2 weeks. Some warts may require two or more applications. Women with genital warts or those who were diagnosed through use of viral nucleic acid detection should be counseled that HPV infection is common and generally benign. Patients should be counseled that transmission between partners can be signicantly decreased with consistent condom use and that infection usually resolves on its own. Trichomonas vaginalis Trichomoniasis is caused by the protozoan Trichomonas vaginalis and is the most common nonviral STI in the United States, with an estimated annual incidence of 7.4 million cases [18,65]. Trichomoniasis is not a reportable condition. Available studies, although limited, indicate that the prevalence of Trichomonas is high, especially in African-American women, ranging from 22% to 51% [66]. Although clinical manifestations tend to be relatively benign, signs of infection include a malodorous yellow green, sometimes foamy, vaginal discharge. Many small distinctive erythematous lesions (strawberry cervix) are sometimes noted on the exocervix when the infestation has been chronic. There is evidence to suggest that T vaginalis may play an important role in amplifying HIV transmission [66,67]. In addition, Trichomonas has been linked to adverse birth outcomes, including low birth weight and preterm delivery [68]. Culture is the most sensitive and specic method for diagnosis. Because of its simplicity and low cost, however, wet mount is the most commonly used method, with an estimated sensitivity of 58% when compared with culture [69]. To prepare a wet mount, the examiner collects vaginal secretions on a swab that is rubbed against the vaginal walls and placed on a microscope slide. A drop of saline is added to the secretions on the slide. This must be done quickly before the secretions dry if live trichomonads are going to be seen. A coverslip is placed on the slide, and it is immediately examined under 10 and 40 objectives. When the test result is positive, the erratic

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movement of the trichomonads is generally noted at the lower power and waving agella visible on both poles of the trichomonad are noted on higher magnication (Fig. 7). It is recommended that culture be performed in women in whom Trichomonas is suspected but cannot be conrmed on wet mount. There are other US Food and Drug Administration (FDA)approved tests for Trichomonas in women. These tests are performed on vaginal secretions and have a sensitivity greater than 83% and a specicity greater than 97% and tend to be more sensitive than vaginal wet preparations although false-positive results do occur, especially in low-prevalence populations [5]. Recommended treatment is metronidazole or tinidazole in a single 2-g oral dose. The alternative regimen is metronidazole administered at a dosage of 500 mg orally twice a day for 7 days. Sex partners should be treated even if asymptomatic to prevent reinfection. Patients should be advised that alcohol should not be consumed for 24 hours after completion of metronidazole treatment or for 48 hours after completion of tinidazole treatment [5].

Common sexually transmitted syndromes in women Mucopurulent cervicitis MPC is diagnosed by the presence of a purulent or mucopurulent (cloudy) cervical discharge that is visible in the cervical os, when a yellow color is noted on an endocervical swab inserted into the cervical os to obtain a specimen (the so-called positive swab test), or by endocervical bleeding induced by placing a swab in the os. Any of these signs may indicate the presence of MPC. Erythema and edema may also be noted on the exocervix, but this may be dicult to dierentiate from the presence of a normal ectropion found in female adolescents, pregnant women, and in women taking

Fig. 7. Trichomonas vaginalis. (Courtesy of Seattle STD/HIV Prevention Training Center, Seattle, WA; with permission.)

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oral contraceptives. Although the presence of MPC is often asymptomatic, a woman may note the presence of an abnormal vaginal discharge or bleeding between menses or after sexual intercourse. Causes of MPC include infections with gonorrhea, chlamydia, trichomoniasis, genital herpes infection, bacterial vaginosis, and other genital organisms, such as Mycoplasma genitalium. The evaluation of MPC requires testing for gonorrheal and chlamydial infection and obtaining a wet preparation specimen to diagnose trichomoniasis or bacterial vaginosis. Acute urethral syndrome in women Acute urethral syndrome is dened as symptoms suggestive of a lower urinary tract infection in the absence of signicant bacteriuria. Symptoms include dysuria, increased frequency, or urgency. In one study, more than 20% of women between the ages of 20 and 64 years had experienced burning or pain on urination in the past year; in nearly 10%, the dysuria had lasted for more than 2 weeks; only 1 in 10 of the women with dysuria had consulted her general practitioner [70,71]. Because the signs and symptoms of a urinary tract infection are often indistinguishable from those of an acute urethral syndrome caused by gonorrhea or chlamydia, every sexually active woman with urinary symptoms should be asked about recent sexual contacts. If the patient has risk factors (younger than 26 years of age or has a new or multiple sex partners), she should be tested for gonorrhea and chlamydia, in addition to having urine culture and sensitivity testing performed. Pelvic inammatory disease PID, also called salpingitis, is an acute clinical syndrome dened as an ascending infection that spreads from the vagina or cervix to the fallopian tubes, endometrium, ovaries, and peritoneum, leading to any combination of endometritis, salpingitis, tubo-ovarian abscess, and pelvic peritonitis. Although accurate estimates of PID resulting from gonococcal and chlamydial infections are dicult to obtain, in 2004, an estimated 170,076 cases of PID were diagnosed in emergency departments among women 15 to 44 years of age in the United States. This estimate decreased to 147,642 in 2005 in a National Hospital Ambulatory Medical Care survey in 2005 [15]. Approximately one in four women with a single episode of PID experiences tubal infertility, chronic pelvic pain, or an ectopic pregnancy. Tubal infertility occurs in 50% of women after their third episode of PID [72]. Because most cases of gonorrhea and chlamydial infections in the United States today are treated outside of traditional public health and STD clinic settings, it is imperative that screening for gonorrhea and chlamydia becomes a routine part of medical practice in the United States.

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C trachomatis and N gonorrhoeae are the two sexually transmitted organisms most commonly implicated in PID. Gonorrhea is recovered from the cervix in 30% to 80% of women with PID, and chlamydia is found in 20% to 40% of cases. Laparoscopically obtained cultures show that most PID is polymicrobial. The prevailing theory is that PID is generally initiated by endocervical gonorrhea or chlamydial infections and that additional organisms become involved after infection spreads and protective immunologic barriers are disrupted. Other organisms found in PID are abnormal vaginal ora, including anaerobes that are often associated with bacterial vaginosis; enteric organisms, such as E coli, Mycoplasma genitalium, Ureaplasma species, and gram-positive Streptococcus species. Although PID is strongly associated with bacterial vaginosis, its role in the pathogenesis of PID is not clear [38]. Clinical manifestations Clinical manifestations of PID include lower abdominal or pelvic pain, cramping, dyspareunia, dysuria, postcoital or irregular bleeding, vaginal discharge, and fever. Atypical presentations (eg, right upper quadrant pain from perihepatitis, Fitz-Hugh-Curtis syndrome) and asymptomatic infections (so-called silent PID) also occur, however. Risk factors for pelvic inammatory disease Adolescence Previous history of PID Gonorrhea or chlamydial infection or a history of gonorrhea or chlamydial infection Male sexual partner with gonorrhea or chlamydial infection Multiple sex partners Current douching Recent (within 3 weeks) insertion of an intrauterine device (IUD) Bacterial vaginosis Demographics (lower socioeconomic status) Diagnosis The clinical diagnosis of PID is often imprecise because of variable or inconsistent presenting signs and symptoms. In a symptomatic woman, the positive predictive value (PPV) of a clinical diagnosis of PID compared with laparoscopy ranges from 65% to 90%. Even laparoscopy, when available, has diagnostic limitations; it does not detect endometritis and may miss subtle inammation of the fallopian tubes. Over the years, the recommendations for making a clinical diagnosis of PID have been broadened. Empiric antibiotic treatment is now recommended for any sexually active woman who is experiencing acute pelvic or lower abdominal pain and is found to have tenderness on bimanual examination unless there is another plausible explanation for these ndings. The presence

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of uterine or adnexal tenderness or cervical motion tenderness fullls the minimal requirements for diagnosis of PID. On examination, MPC or a large number of white blood cells on a vaginal saline preparation may be present [5]. A normal-appearing cervix and the lack of white blood cells on a saline preparation make the diagnosis of PID less likely, and other causes of pelvic pain should be considered. All women presumed to have PID should be tested for gonorrhea and chlamydial infection and oered testing for HIV. The following additional criteria may increase the specicity of a PID diagnosis, but their absence does not necessarily exclude the diagnosis: Temperature of 38.3 C or greater (O101 F) Presence of an abnormal cervical or vaginal discharge Elevated erythrocyte sedimentation rate (ESR) Elevated C-reactive protein (CRP) Positive laboratory test result for gonorrhea or chlamydia Leukocytosis Other testing modalities, including endometrial biopsy, Doppler studies, and laparoscopy, may be helpful in some situations [5]: Inpatient and outpatient treatment Empiric treatment of PID should be started as soon as possible without awaiting test results or completion of diagnostic studies, because delay in treatment may contribute to reproductive tract sequelae. The question of whether to hospitalize a woman with PID has been a source of some controversy. Although some specialists advise that all patients who have PID should be hospitalized for bed rest and parenteral antibiotics, studies have shown that for mild or moderate PID, outpatient therapy provides similar short- and long-term clinical results. More limited data support outpatient treatment for women with more severe presentations. The CDC recommends the following criteria for hospitalization: To exclude surgical emergencies, such as appendicitis Pregnancy, because of risks for maternal morbidity and preterm delivery Inadequate or nonresponse to oral antibiotics Inability to tolerate oral outpatient therapy Serious illness with severe pain, nausea, vomiting, or high fever Presence of a tubo-ovarian abscess Adolescents Recommended inpatient PID treatments from the 2006 CDC treatment guidelines are summarized in Table 5. For hospitalized patients who receive the recommended treatment regimen (with parenteral cefoxitin or cefotetan), continue parenteral treatment until there is clinical improvement for 24 hours and then continue oral therapy with doxycycline at a dosage of 100 mg twice a day to complete a total of 14 days of therapy. If the alternative treatment regimen is used (clindamycin plus gentamicin), then continue

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Table 5 Centers for Disease Control and Prevention recommended treatment of pelvic inammatory disease Stage Outpatient Antimicrobial Recommended Ceftriaxone Plus Doxycycline With or without Metronidazolea Alternative Cefoxitin with Probenecid Plus Doxycycline With or without Metronidazolea Recommended Cefotetan or Cefoxitin Plus Doxycyclineb Alternative regimens Clindamycin Plus Gentamicin Dosage and route of administration 250 mg IM in a single dose 100 mg twice daily for 14 days. 500 mg orally twice daily for 14 days 2 g IM in a single dose 1 g orally administered concurrently in a single dose 100 mg orally twice a day for 14 days 500 mg orally twice a day for 14 days 2 g IV every 12 hours 2 g IV every 6 hours 100 mg orally or IV every 12 hours. 900 mg IV every 8 hours IV or IM loading dose of 2 mg/kg of body weight, followed by a maintenance dose of (1.5 mg/kg) every 8 hours

Parenteral

a The reason for the addition of metronidazole is the frequent presence of anaerobic organisms. b Doxycycline infusions are painful; therefore, oral doxycycline is suggested when possible, because bioavailability is similar. Data from Centers for Disease Control and Prevention. 2006. Sexually transmitted diseases treatment guidelines. MMWR 2006;55(RR11):579.

with doxycycline (100 mg twice a day) or clindamycin (450 mg orally four times a day) to complete 14 days of therapy. When the patient has a tubo-ovarian abscess, it is recommended to continue oral therapy with doxycycline and metronidazole or clindamycin to improve anaerobic coverage. Outpatient treatment of pelvic inammatory disease Antibiotic therapy should provide broad-spectrum coverage but should always include agents with proved eectiveness against gonorrhea and chlamydial infection. Negative test results for gonorrhea or chlamydia from vaginal, urine, or endocervical specimens do not completely eliminate the possibility that these organisms are present in upper tract sites. Although uoroquinolone antibiotics were previously recommended for treatment

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of PID, in the current era of gonorrhea uoroquinolone resistance, these antibiotics should no longer be used. The current outpatient treatment of PID recommended by the CDC is summarized in Table 5. Although ceftriaxone oers better coverage against gonorrhea, cefoxitin has better anaerobic coverage. No published data support the eectiveness of oral cephalosporins as an alternative therapy. One randomized controlled trial has demonstrated the eectiveness of azithromycin (1 g administered orally for 7 days) in treatment of PID [73,74]. The risk for PID is higher in women within the rst 3 weeks of IUD insertion but subsequently returns to baseline. There is no evidence to support removal of an IUD in a woman diagnosed with PID or chlamydial or gonococcal cervicitis. Follow-up Patients who have PID should be re-evaluated within 72 hours of initiation of therapy. A lack of clinical improvement or worsening of the patients condition should lead to reconsideration of the diagnosis of PID. Hospitalization, parenteral antibiotics, and diagnostic evaluation using laparoscopy or ultrasonography are recommended. Although medical management is usually adequate, surgical intervention might be necessary to drain an abscess or to resect chronically infected pelvic tissue. Male sexual partners of women with PID may have symptomatic or asymptomatic infections with gonorrhea or chlamydia. Male partners should be tested for these and other STIs and treated for uncomplicated gonorrhea and chlamydia regardless of test results in the partner with PID. Prevention New technologies and screening strategies oer the potential to prevent much of the suering and societal costs of PID. A seminal study by Scholes and colleagues [75] showed that a population-based approach of testing women who were at risk for chlamydial infection would result in a decreased incidence of PID. The chief strategy for preventing PID in the United States is to follow the screening recommendations of public health and medical organizations, such as the US Preventive Services Task Force (see Box 1) and the CDC [5], to screen all sexually active women younger than 26 years of age, and older women with specic risk factors, for chlamydia and gonorrhea. Urine tests using NAATs are now widely available and enable clinicians to test asymptomatic women without the necessity of performing a pelvic examination. Summary STIs are an important public health challenge in the United States. The high rates of STIs in women in the United States result in adverse sequelae

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that include tubal infertility, ectopic pregnancies, chronic pelvic pain, perinatal infections, painful ulcerative disease, increased risk for cancer, and acquisition or transmission of HIV. Primary care clinicians can contribute to decreasing these largely preventable causes of morbidity and mortality by integrating routine screening, testing, counseling, treatment, and partner management of STIs into their practice. Newer tests for chlamydia and gonorrhea that can be performed on urine specimens allow screening without a pelvic examination. It is also important that clinicians recognize that most women who have STIs delay seeking medical care because they have no symptoms or minimal symptoms. Clinicians should routinely ask all patients about their sex lives, specically inquiring about any new sexual relationships, without making assumptions about the patients sexual orientation, practices, or marital status. All young women, and any woman with risk factors, should be screened annually for gonorrhea and chlamydia according to current prevention guidelines. Women with signs or symptoms of PID, cervicitis, or acute urethral syndrome should be tested for gonorrhea and chlamydia. It is important to have a high index of suspicion for diagnosing PID in any sexually active woman with pelvic tenderness and to treat presumptively and follow up closely. Clinicians are encouraged, whenever possible, to use NAATs, the most reliable and convenient laboratory technology, to test urine, self-collected vaginal swabs, or endocervical specimens for gonorrhea and chlamydia. The most recent edition of the CDC STD treatment guidelines provides an evidence-based, reliable, and convenient set of recommendations for treating and caring for patients who have STIs. It is important for clinicians to counsel and assist every patient who has an STI to make a specic plan, using public health resources when available, to arrange for treatment of their sex partners. This can be facilitated in those areas in which it is legally permissible by providing medication or a prescription for treatment of gonorrhea and chlamydia through EPT. In addition, clinicians should encourage the consistent and correct use of condoms for all sexually active patients who may be at risk for STIs or for unintended pregnancy.

References
[1] Hillis SD, Joesoef R, Marchbanks PA, et al. Delayed care of pelvic inammatory disease as a risk factor for impaired fertility. Am J Obstet Gynecol 1993;168:15039. [2] Hook EW III, Handseld HH. Gonococcal infections in the adult. In: Holmes KK, Mardh PA, Sparling PF, editors. Sexually transmitted diseases. 2nd edition. New York: McGraw-Hill, Inc.; 1990. p. 14965. [3] Stamm WE, Holmes KK. Chlamydia trachomatis infections in the adult. In: Holmes KK, Mardh PA, Sparling PF, editors. Sexually transmitted diseases. 2nd edition. New York: McGraw-Hill, Inc.; 1990. p. 18193.

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[4] Zimmerman HL, Potterat JJ, Dukes RL, et al. Epidemiologic dierences between chlamydia and gonorrhea. Am J Public Health 1990;80:133842. [5] Centers for Disease Control and Prevention (CDC). 2006. Sexually transmitted diseases treatment guidelines. MMWR 2006;55(RR11):195. [6] US Department of Health and Human Services Agency for Healthcare Research and Quality. The guide to clinical preventive services: recommendations of the U.S. Preventive Services Task Force. AHRQ Publication No. 06-0588. June 2006. [7] Available at: http://cdc.gov/std/treatment. Accessed June 11, 2008. [8] Available at: http://ahrq.gov/clinic/uspstf/us/stopics.htm. Accessed June 11, 2008. [9] Hollblad-Fadiman K, Goldman SM. American College of Preventive Medicine practice policy statement: screening for Chlamydia trachomatis. Am J Prev Med 2003;24:28792. [10] American Academy of Family Physicians. Recommendations for periodic health examinations. Available at: http://www.aafp.org/PreBuilt/PHErev54.pdf. 2003. Accessed October 25, 2003. [11] National Committee for Quality Assurance. The state of health care quality 2005. Industry trends and analysis. Washington, DC: National Committee for Quality Assurance; 2005. Available at: http://www.ncqa.org/Doc/SOHCQ_2005.pdf. Accessed June 11, 2008. [12] Hessol NA, Priddy FH, Bolan G, et al. Management of pelvic inammatory disease by primary care physicians: a comparison with Centers for Disease Control and Prevention guidelines. Sex Transm Dis 1996;23:15763. [13] Institute of Medicine Committee on Prevention and Control of Sexually Transmitted Diseases. The hidden epidemic: confronting sexually transmitted diseases. Washington, DC: National Academy Press; 1996. [14] Chesson HW, Blandford JM, Gift TL, et al. The estimated direct medical cost of STDs among American youth, 2000 [abstract P075]. National STD Prevention Conference. Philadelphia, March 811, 2004. [15] Centers for Disease Control and Prevention. Sexually transmitted disease surveillance, 2006. Atlanta (GA): U.S. Department of Health and Human Services; 2007. [16] Fleming DT, McQuillan GM, Johnson RE, et al. Herpes simplex virus type-2 in the United States, 1976 to 1994. N Engl J Med 1997;337(16):110511. [17] Leone P, Fleming DT, Gilsenan AW, et al. Seroprevalence of herpes simplex virus-2 in suburban primary care oces in the United States. Sex Transm Dis 2004;31(5): 3116. [18] Weinstock H, Berman S, Cates W Jr. Sexually transmitted diseases among American youth: incidence and prevalence estimates, 2000. Perspect Sex Reprod Health 2004; 36(1):610. [19] Myers ER, McCrory DC, Nanda K, et al. Mathematical model for the natural history of human papillomavirus infection and cervical carcinogenesis. Am J Epidemiol 2000;151: 115871. [20] Fleming DT, Wasserheit JN. From epidemiological synergy to public health policy and practice: the contribution of other sexually transmitted diseases to sexual transmission of HIV infection. Sex Transm Infect 1999;75(1):317. [21] Available at: http://guttmacher.org/statecenter/spibs/spib_MASS.pdf. Accessed June 11, 2008. [22] Available at: http://depts.washington.edu/nnptc/. Accessed June 11, 2008. [23] Winer RL, Hughes JP, Feng Q, et al. Condom use and the risk of genital human papillomavirus infection in young women. N Engl J Med 2006;354:264554. [24] Ness RB, Randal H, Richter HE, et al. Condom use and the risk of recurrent pelvic inammatory disease, chronic pelvic pain, or infertility following an episode of pelvic inammatory disease. Am J Public Health 2004;94:13279. [25] Paavonen J, Eggert-Kruse W. Chlamydia trachomatis: impact on human reproduction. Hum Reprod Update 1999;5:43347.

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[26] Handseld HH, Sparling PF. Neisseria gonorrhoeae. In: Mandell GL, Douglas RG, Bennett JE, editors. Mandell, Douglas, and Bennetts principles and practice of infectious diseases. 4th edition. New York: Churchill Livingstone; 1995. p. 190926. [27] Simms I, Stephenson JM. Pelvic inammatory disease epidemiology: what do we know and what do we need to know? Sex Transm Infect 2000;76:807. [28] Westrom L, Joesoef R, Reynolds G, et al. Pelvic inammatory diseases and fertility. A cohort study of 1844 women with laparoscopically veried disease and 657 control women with normal laparoscopic results. Sex Transm Dis 1992;19:18592. [29] Peterman TA, Tian LH, Metcalf CA, et al. High incidence of new sexually transmitted infections in the year following a sexually transmitted infection: a case for rescreening. Ann Intern Med 2006;145:56472. [30] Schillinger JA, Kissinger P, Calvet H, et al. Patient-delivered partner treatment with azithromycin to prevent repeated Chlamydia trachomatis infection among women: a randomized, controlled trial. Sex Transm Dis 2003;30:4956. [31] Golden MR, Whittington WLH, Handseld HH, et al. Eect of expedited treatment of sex partners on recurrent or persistent gonorrhea or chlamydial infection. N Engl J Med 2005; 352:67685. [32] Kissinger P, et al. Patient-delivered partner treatment for male urethritis: a randomized, controlled trial. Clin Infect Dis 2005;41:6239. [33] Centers for Disease Control and Prevention. Expedited partner therapy in the management of sexually transmitted diseases. Atlanta (GA): US Department of Health and Human Services; 2006. Avaiable at: http://www.cdc.gov/std/treatment/EPTFinalReport2006.pdf. Accessed June 11, 2008. [34] Available at: http://cdc.gov/std/ept/legal/default.htm. Accessed June 11, 2008. [35] Centers for Disease Control and Prevention. Screening tests to detect Chlamydia trachomatis and Neisseria gonorrhoeae infections. MMWR 2002;51(RR15):138. [36] Marrazzo JM, Handseld HH, Whittington WL. Predicting chlamydial and gonococcal cervical infection: implications for management of cervicitis. Obstet Gynecol 2002;100(3):57984. [37] Robinson AJ, Ridgway GL. Modern diagnosis and management of genital Chlamydia trachomatis infection. Br J Hosp Med 1996;55:38893. [38] Lau C-Y, Qureshi AK. Azithromycin versus doxycycline for genital chlamydial infections: a meta-analysis of randomized clinical trials. Sex Transm Dis 2002;29:497502. [39] McClelland RS, Wang CC, Mandaliya K, et al. Treatment of cervicitis is associated with decreased cervical shedding of HIV-1. AIDS 2001;15:10510. [40] Gaydos CA, Crotchfelt KA, Howell MR, et al. Molecular amplication assays to detect chlamydial infections in urine specimens from high school female students and to monitor the persistence of chlamydial DNA after therapy. J Infect Dis 1998;177:41724. [41] Ghanem M, Radclif K, Allan P. The role of urethral sample in the diagnosis of gonorrhea in women. Int J STD AIDS 2004;15:457. [42] Barlow D, Phillips I. Gonorrhea in women. Lancet 1978;1:7614. [43] Goodhart ME, Ogden J, Zaidi AA, et al. Factors aecting the performance of smear and culture tests for the detection of Neisseria gonorrhoeae. Sex Transm Dis 1982;9(2):639. [44] Jephcott AE. Microbiological diagnosis of gonorrhea. Genitourin Med 1997;73:24552. [45] Koumans EH, Johnson RE, Knopp JS, et al. Laboratory testing for Neisseria gonorrhea by recently introduced nonculture tests: a performance review with clinical and public health considerations. Clin Infect Dis 1998;27:117180. [46] CDC. Sexually transmitted disease surveillance 2004 supplement: gonococcal isolate surveillance project (GISP) Annual Reportd2004. Atlanta (GA): U.S. Department of Health and Human Services; 2005. [47] Centers for Disease Control and Prevention. Update to CDCs 2006 sexually transmitted diseases treatment guidelines, 2006: uoroquinolones no longer recommended for treatment of gonococcal infections. MMWR 2007;56:3326.

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[48] Carne CA. Epidemiological treatment and tests of cure in gonococcal infection: evidence for value. Genitourin Med 1997;73(1):125. [49] Oxman MN. Genital herpes. In: Gorbach SL, Bartlett JG, Blacklow NR, editors. Infectious diseases. 2nd edition. Philadelphia: Saunders; 1998. p. 9861007. [50] Lautenschlager S, Eichmann A. The heterogeneous clinical spectrum of genital herpes. Dermatology 2001;202:2119. [51] Corey L, Adams HG, Brown ZA, et al. Genital herpes simplex virus infections: clinical manifestations, course, and complications. Ann Intern Med 1983;98:95872. [52] Scoular A. Using the evidence base on genital herpes: optimizing the use of diagnostic tests and information provision. Sex Transm Infect 2002;78:1605. [53] Ashley RL. Genital herpes. Type-specic antibodies for diagnosis and management. Dermatol Clin 1998;16:78993. [54] Koutsky LA, Stevens CE, Holmes KK, et al. Under diagnosis of genital herpes by current clinical and viral-isolation procedures. N Engl J Med 1992;326:15339. [55] Whitley RJ, Kimberlin DW, Roizman B. Herpes simplex virus. Clin Infect Dis 1998;26: 54155. [56] Ashley RL, Wald A. Genital herpes: review of the epidemic and potential use of type-specic serology. Clin Microbiol Rev 1999;12:18. [57] Brown TJ, McCrary M, Tyring SK. Antiviral agents: non-antiretroviral [correction of nonantiviral] drugs [published correction appears in J Am Acad Dermatol 2002;47:972]. J Am Acad Dermatol 2002;47:58199. [58] Whitley RJ, Gnann JW Jr. Acyclovir: a decade later [published corrections appear in N Engl J Med 1993; 328:671 and 1997; 337:1703]. N Engl J Med 1992;327:7829. [59] Langenberg AG, Burke RL, Adair SF, et al. A recombinant glycoprotein vaccine for herpes simplex virus type 2: safety and immunogenicity. Ann Intern Med 1995;122(12):88998 [Erratum: Ann Intern Med 1995;123(5):395]. [60] Hook EW 3rd. Acquired syphilis in adults. N Engl J Med 1992;326(16):10609. [61] Adimora AA. Syphilis and other treponematoses. In: Kassirer JP, Greene HL, editors. Current therapy in adult medicine. 4th edition. St Louis (MO): Mosby; 1997. p. 28992. [62] Centers for Disease Control and Prevention (CDC). Guidelines for prevention and control of congenital syphilis. MMWR 1988;37(S1):113. [63] Hart G. Syphilis tests in diagnostic and therapeutic decision making. Ann Intern Med 1986; 104:36876. [64] Golden MR, Marra CM, Holmes KK. Update on syphilis: resurgence of an old problem. JAMA 2003;290:15104. [65] Romanowski B, Sutherland R, Fick GH, et al. Serologic response to treatment of infectious syphilis. Ann Intern Med 1991;114:10059. [66] Sorvillo F, Smith L, Kerndt P, et al. Trichomonas vaginalis, HIV and African-Americans. Emerg Infect Dis 2001;7:92732. [67] Laga M, Manoka A, Kivuvu M, et al. Non-ulcerative sexually transmitted diseases as risk factors for HIV-1 transmission in women: results from a cohort study. AIDS 1993;7: 95102. [68] Cotch MF, Pastorek JG II, Nugent RP, et al. Trichomonas vaginalis associated with low birth weight and preterm delivery. The Vaginal Infections and Prematurity Study Group. Sex Transm Dis 1997;24:35360. [69] Wiese W, Patel SR, Patel SC, et al. A meta-analysis of the Papanicolaou smear and wet mount for the diagnosis of vaginal trichomoniasis. Am J Med 2000;108:3018. [70] Waters WE. Prevalence of symptoms of urinary tract infection in women. Br J Prev Soc Med 1969;23:2636. [71] Hamilton-Miller JM. The urethral syndrome and its management. J Antimicrob Chemother 1994;33(Suppl A):6373.

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[72] James Drife, Magowan Brian A. Clinical obstetrics and gynecology. United Kingdom: Elsevier Health Sciences; 2004. p. 119. [73] Ness RB, Hillier SL, Kip KE, et al. Bacterial vaginosis and risk of pelvic inammatory disease. Obstet Gynecol 2004;104:7619. [74] Bevan CD, Ridgway GL, Rothermel CD. Ecacy and safety of azithromycin as monotherapy or combined with metronidazole compared with two standard multidrug regimens for the treatment of acute pelvic inammatory disease. J Int Med Res 2003;31:4554. [75] Scholes D, Stergachis A, Heidrich FD, et al. Prevention of pelvic inammatory disease by screening for cervical chlamydial infection. N Engl J Med 1996;334:13626.

Med Clin N Am 92 (2008) 11151141

Breast Disease: Benign and Malignant

Angela L.W. Meisner, MPHa, M. Houman Fekrazad, MDb, Melanie E. Royce, MD, PhDb,*
Population Science, Cancer Health Disparities and Cancer Control, Cancer Research and Treatment Center, University of New Mexico, Albuquerque, NM 87131, USA b Division of Hematology/Oncology, Department of Internal Medicine, Cancer Research and Treatment Center, University of New Mexico, Albuquerque, NM 87131, USA
a

Breast diseases, both benign and malignant, are common. Typically, young women present with more benign pathologies; however, breast malignancies can occur in young women, especially in those harboring mutations in the BRCA genes, other inherited genetic syndromes associated with increased risk of breast cancer, or familial predisposition for breast cancer. In all women aged 40 and over presenting with abnormalities of the breast, a primary breast cancer should be ruled out because it is the leading cancer among women in developed countries.

Benign diseases of the breast Epidemiology Benign breast disease (BBD) is a heterogeneous group of pathologies with the majority related to benign brocystic breast changes. It is widely accepted that BBD is common, though the incidence is sparsely documented in the literature and is probably quite underestimated. It is challenging to approximate the incidence of BBD, given that it is not associated with a grave prognosis, and that not all women who have BBD see a physician. It is generally accepted that approximately 90% of women have brocystic changes, and that these are more pronounced in women of reproductive age. Prevalence and cumulative incidence rates of BBD may be estimated using

* Corresponding author. University of New Mexico, MSC 08-4630, UNM Cancer Research and Treatment Center, 900 Camino de Salud N.E., Albuquerque, NM 87131-0001. E-mail address: MRoyce@salud.unm.edu (M.E. Royce). 0025-7125/08/$ - see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2008.04.003 medical.theclinics.com

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results from autopsy and cohort studies, respectively [1,2]. A forensic autopsy study by Bartow ands colleagues found benign cysts in 61% of the Caucasian women observed [3]. In 1997, Goehring and Morabia [1] conducted a meta-analysis to determine the incidence rate per 100,000 women-years for the two most common BBD in women: brocystic change and broadenoma. For brocystic change, the incidence rate per 100,000 women-years was 137 for ages 25 to 29 years, 411 for ages 40 to 44 years, and 387 for ages 48 to 49, producing a slightly skewed, bell-shaped curve. For broadenoma, the incidence rate per 100,000 women-years for broadenoma was 115 for ages 20 to 24 years, then a gradual decrease to less than 5 for women older than 50 years. Using this analysis, the study authors estimated the cumulative incidences were 8.8% and 2.2% for biopsy-proven brocystic change and broadenoma in women older than 65 years, respectively [1]. Etiology Changes in hormone levels throughout womens reproductive cycles and lives contribute to the dierentiation of the breast structure and cellularity. Therefore, risk of BBD is commonly associated with menopausal and hormonal status [2]. In premenopausal women who have BBD, underlying endocrinologic issues must be addressed. The following may be considered risk factors for BBD with diering degrees of association: oral contraceptives, age at rst live birth, nulliparity, breastfeeding, age at menopause, socioeconomic status, education, race and family history of breast cancer [1]. For many women such changes are normal, without an identiable cause. Common symptoms and pathology in benign breast disease Breast tissue is heterogeneous, containing ducts and lobules, stroma, and fat. Any one of these structures can be aected by benign processes. Fig. 1 illustrates the anatomy of the breast. Mastalgia Ninety percent of the time, mastalgia or breast tenderness/pain is benign [4]. There are two general types of mastalgia: cyclic or noncyclic. Cyclic mastalgia occurs because of hormonal changes during the menstrual cycle. Approximately 2 weeks before menses, hormonal changes trigger an increase in breast size and volume, and then they return to baseline a week afterward. The premenstrual changes in the breast can be heralded by mastalgia, and is often referred to as mastitis or brocystic disease; however, in reality it represents a normal condition of the breast. Some authors have found that symptoms associated with cyclic breast changes can be alleviated to varying degrees by reducing caeine intake (coee, tea, cola and chocolate), vitamin E cream application, or by taking evening primrose oil [5]. Relief may not be immediate, but symptoms generally improve

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Fig. 1. Anatomy of the female breast.

within 3 to 4 months. Others, however, have suggested these treatments may be ineective, and recommend instead a well-tting bra, axseed, and topical nonsteroidal anti-inammatory gel as treatments for mastalgia [6]. Noncyclic mastalgia is more common in older women and is not related to the menstrual cycles. It may be related to a variety of medications such as estrogen replacement, thiazide diuretics, and digoxin. Medications typically associated with mastalgia and those used to treat it are listed in Boxes 1ab. When a woman presents with mastalgia, a thorough history and physical examination is necessary to rule out any underlying pathology. Mammography, breast ultrasound or breast biopsy may be warranted for diagnostic purposes.

Box 1a. Medications associated with mastalgia Oral contraceptives Hormone replacement therapy Antidepressants Digoxin Methyldopa Spironolactone Oxymetholone Chlorpromazine

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Box 1b. Medications used to treat mastalgia Oral contraceptives Danazol Tamoxifen Toremifene Bromocriptine Nonsteroidal anti-inammatory drugs Acetaminophen Magnesium Evening primrose oil

Mastitis Mastitis is a condition in which the breast is inamed, and it may or may not be caused by an underlying infection. The breast is often erythematous, warm, and tender. Mastitis is usually unilateral, and may be confused with inammatory breast cancer. There are several types of mastitis, including, but not limited to, puerperal or lactational, periductal or mammary duct ectasia, and idiopathic granulomatous lobular mastitis (IGLM). Puerperal or lactational mastitis is an acute infection of the mammary ducts, and is almost exclusively seen in lactating females. The inammation is generally in a wedge distribution, but may eventually spread throughout the breast [7]. In addition to the tender, inamed breast, other systemic symptoms may occur, such as fever, chills, fatigue, and body aches [8]. The organism responsible is usually Staphylococcus aureus and it generally enters the body through a dry, cracked nipple of a nursing mother. In most cases, the infant is the source of the infection by harboring the infectious organism in the oropharynx. The infection is treated appropriately with antibiotics, such as penicillins, cephalosporins, erythromycin, clindamycin, ciprooxacin, or vancomycin. Left untreated, it may lead to breast abscess requiring surgical drainage. Necrosis may also develop, producing brous scars and nipple retraction, a presentation that can mimic an underlying breast carcinoma [7]. In nursing mothers, mastitis may also occur as a noninfectious inammation caused by the increase in milk in the breasts. Although mastitis mostly occurs in lactating women, it may occur at other times. Periductal mastitis, also called mammary duct ectasia, is not a disease and is not associated with lactation [8,9]. Perimenopausal and postmenopausal women are more likely to present with mammary duct ectasia than premenopausal women [8]. Mammary duct ectasia is a benign lesion of the breast that has been described in infants, prepubertal boys and girls, and adult men and women. In children and adolescents, the lesion is usually unilateral. The patient presents with nipple discharge, which may be bloody. Histologically, there is

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dilatation of the mammary ducts, periductal brosis, and inammation. Infectious and inammatory causes have been implicated in the etiology. Ultrasound ndings are usually suggestive, revealing dilated mammary ducts radially located around the nipple. The process is usually self-limited; therefore, surgery is not recommended if the diagnosis is certain [10]. IGLM is a rare benign breast disease that often mimics infection or carcinoma. Patients may present with impressive signs and symptoms that may include an irregular, inamed, and painful breast mass, peau dorange, nipple retraction, and no evidence of infection [11,12]. Despite dramatic ndings in the breast, enlarged axillary lymph nodes are an uncommon sign of IGLM [12]. Care must therefore be taken not to confuse this condition with breast cancer to avoid inappropriate treatment. The exact etiology is unknown and response to treatment can be variable. Treatment often involves several months of anti-inammatory medications such as nonsteroidal anti-inammatory drugs (NSAIDs) or prednisone. More severe or persistent cases may require a course of immunosuppressant such as cyclosporine or methotrexate. After medical therapy, some may require excision of any residual microabscesses. Subareolar abscess, which typically aect smokers, presents with pain and redness of the nipple areolar complex. The abscess is generally polymicrobial. Treatment includes incision and drainage, and may occasionally necessitate antibiotics. Nipple discharge and nipple abnormalities Seventy percent of women have nipple discharge at some point during their lives. Many medications can be associated with galactorrhea, as enumerated in Box 2. Galactorrhea or milky discharge may be associated with hypothyroidism or pituitary adenomas, and assessment of thyroid stimulating hormone (TSH) and prolactin levels may be revealing of etiology. Multiduct nipple discharge, especially if the discharge is milky, or cloudy green or yellow, is not an indication for surgical biopsy because the discharge is usually benign; however, a spontaneous bloody or serous nipple discharge is concerning for underlying problems. Approximately a third of these discharges are malignant, so evaluation should be more extensive. Galactography or mammary duct excision should be performed, and most often will reveal an intraductal papilloma, a benign growth of the breast ducts, which is the most common cause of a bloody nipple discharge. This lesions appearance on galactography is that of a smooth, lobulated, intraluminal lling defect or a solitary obstructed duct [13]. Congenital inversion of the nipples occurs in many women, particularly those who have large breasts. It may be confused as a symptom of breast cancer [7]. Nipple inversion can also occur later in life as a result of scarring from acute mastitis. Nipple inversion, unless associated with other breast ndings, is usually not a signicant problem other than perhaps causing diculty with nursing.

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Box 2. Medications commonly associated with galactorrhea Drugs that block dopamine receptors Butyrophenones Metoclopramide Phenothiazines Risperidone Selective serotonin reuptake inhibitors Thioxanthenes Tricyclic antidepressants Drugs that deplete dopamine Methyldopa Reserpine Drugs that inhibit release of dopamine Codeine Heroin Morphine Antihistamines Cimetidine Drugs that stimulate lactotrophs Oral contraceptives Verapamil
Adapted from Leung AK, Pacaud D. Diagnosis and management of galactorrhea. Am Fam Physician 2004;70(3):544; with permission. Copyright 2004 American Academy of Family Physicians. All Rights Reserved.

Skin conditions such as eczema or dermatitis may occur on the nipple and areola. Management approaches are similar to other parts of the body, with topical corticosteroids being the mainstay of treatment. Pagets disease of the nipple presents as a persistent dermatitis of the nipple with a red, oozing, crusted lesion, which is often unresponsive to topical steroid and antibiotics. Rarely, it can occur in both breasts [14]. This is an uncommon type of pathology that must not be dismissed simply as eczema, because over 95% are associated with an underlying breast cancer [15]. Most patients diagnosed with Pagets disease are over age 50, but a few cases have been diagnosed in women in their 20s [15]. Surgery is the most common form of treatment, but the specic treatment often depends on the characteristics of the underlying breast carcinoma. An algorithm for investigation of nipple discharge is shown in Fig. 2. Fat necrosis Fat necrosis presents as a rm mass generally associated with a history of trauma, surgery, or radiation therapy of the breast, though it can occur for

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Spontaneous nipple discharge

Investigations Clinical examination Mammography

Abnormal Single-duct discharge

Normal

Multiple duct discharge Investigate as for mass lesion or mammographic Suspicious* or troublesome Not suspicious or troublesome

Distressing symptoms

No distressing symptoms

Surgery

Reassurance Surgery Reassurance

Fig. 2. Investigation of nipple discharge. * Suspicious means discharge that is bloodstained or contains moderate or large amounts of blood on testing, is associated with a mass, or is a new development in women older than age 50 and is not thick or cheesy. (From Dixon MJ, Bundred NJ. Diagnosis and management of benign breast diseases. In: Harris JR, Lippman ME, Morrow M, et al, editors. Diseases of the breast. 2nd edition. Philadelphia: Lippincott Williams and Wilkins; 2000. p. 48; with permission.)

unknown reasons. Perimenopausal women who are obese and have large breasts are more likely to develop fat necrosis. It is typically found in the supercial region of the breast as a rm, nontender, irregular mass, which may result in skin retraction [8]. Clinically and mammographically, it may be dicult to distinguish it from a carcinoma of the breast. The diagnosis is usually made by breast biopsy. Fibrocystic changes Fibrocystic change is a heterogeneous group of changes rather than a single entity, aecting the stromal and glandular tissues of the breast. Pathologically, these changes are characterized by the formation of cysts, stromal brosis, and a variety of proliferative lesions [7]. The term brocystic disease is also commonly used to describe these lesions, but the morphologic changes that occur are not consistent with the denition of a disease. These changes are present in up to 90% of women and represent the normal changes in the breast, generally occuring between the ages of 20 and 40 years. Symptoms of brocystic change, such as palpable lumps or nipple discharge, may be initially confused with characteristics of carcinoma [7]. In premenopausal women, symptoms usually occur in conjunction with the menstrual cycle. Typically, postmenopausal women and adolescent girls do not experience symptoms related to brocystic changes, although it has been reported among in older women. Fibrocystic changes can be classied as either nonproliferative or proliferative based on pathologic ndings. Nonproliferative changes such as cysts, apocrine metaplasia, brosis, intraductal hyperplasia, and broadenomas

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do not increase the risk of developing breast cancer. Proliferative lesions, on the other hand, may slightly increase the risk for breast cancer by 1.5 to 2 times that of the general population. Examples of proliferative lesions without atypia include orid hyperplasia, sclerosing adenosis, and intraductal papillomatosis. If a patient has epithelial ductal hyperplasia with moderate or orid proliferation of ductal cells, she has a 1.6 times higher risk of developing breast cancer. The relative risk increases to 2 if she has a family history of breast cancer [16]. Additionally, breast cancer risk increases if there are more than four layers of myoepithelial and epithelial cells [7]. When the proliferative lesion is associated with atypia, the risk for breast cancer is even higher. Women who have atypical ductal or lobular hyperplasia are at 4.5 to 5 times increased risk for developing breast cancer compared with the general population; or a hazard ratio of 5.80, after adjusting for breast density, ethnicity, and family history [17]. With the addition of a positive family history of breast cancer, the risk doubles to 8 to 10 times that of the general population. Nonproliferative changes such as cysts and broadenomas are commonly encountered. Patients may experience symptoms for which they seek medical attention, or a discrete lesion may be seen on breast imaging. Cysts are uid-lled lesions generally found in the terminal duct or lobule, and may appear with apocrine metaplasia [7,8,16,18]. Pain may or may not be a presenting symptom. Most women who report pain usually experience it in the upper and outer quadrant of the breast, and the pain is usually bilateral. Fibroadenomas are grossly pseudoencapsulated lesions found in the stroma and ducts. Fibroadenomas are bilateral in about 10% of patients. Adolescent girls and young women are more likely to exhibit broadenomas than older adult women [8]. Fibroadenomas can vary in size from a few millimeters to several centimeters [19]. Epithelial hyperplasia is a type of proliferative change that is not obvious by physical examination. It is the result of proliferation of the myoepithelial and epithelial cell layer of the ductal system of the breast or, more frequently, the lack of apoptosis in the ductal lumen [7]. There are three levels of ductal cell proliferation: mild, moderate, and orid [8,20]. Atypia may or may not be present [7]. When present, atypia can be either an atypical ductal hyperplasia (ADH) or atypical lobular hyperplasia [8]. These proliferative lesions share similar characteristics with their in situ counterpart [7]. Ductal carcinoma in situ (DCIS) is a noninvasive form of breast cancer and is discussed further under the malignant breast disease section of this article. Lobular carcinoma in situ (LCIS), although it sounds like cancer is in general considered a form of benign proliferative breast disease. Women who have LCIS are at a 15% to 35% increased risk for developing breast cancer over the next 15 years. Although many women have undergone bilateral prophylactic mastectomy for this condition, close clinical follow-up may suce. Alternatively, chemoprevention, such as with tamoxifen, can be considered as a risk-reduction strategy. In women

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who have LCIS and who subsequently develop a breast cancer, the most common histologic type is an inltrating ductal carcinoma rather than an inltrating lobular carcinoma, and the risk for developing breast cancer is equal in either breast. Evaluation of benign breast disease When evaluating breast abnormalities, one of the most important considerations is to exclude breast cancer. The clinical context may provide direction as to whether breast cancer should be low or high in the dierential diagnosis, with the clear understanding that there are always exceptions to the rule. Mammogram Mammograms are radiographs of the breast whose sensitivity is highly dependent on breast density. As breast density increases, the sensitivity of a screening mammogram diminishes from 98% in women who have fatty breasts to 55% in those who have the densest breasts [20]. In general, denser breasts are found in younger compared with older women, and premenopausal compared with postmenopausal women. In a dense breast, a mass may be missed on mammogram. Thus, other breast imaging modalities such as an ultrasound or MRI may be required, especially in younger women, to better examine a lesion, especially if index of suspicion is high for a malignancy. Calcications are best seen on mammogram. Fat necrosis [8] and brocystic change [7] on mammography may appear as a mass or dense tissue, with or without associated calcications. In broadenomas, the calcications often appear as popcorn [8,21]. The detection of microcalcations and other abnormalities on routine screening mammography has increased the rate of atypical hyperplasia diagnoses. An estimated 12% to 17% of biopsies performed for evaluation of a mammographic abnormality resulted in a nding of atypical hyperplasia [8]. Ultrasound Ultrasound is often a useful adjunct in evaluating breast abnormalities, and may even be the initial breast imaging modality used, especially for a young woman who has very dense breasts. It can very easily dierentiate between cystic and solid lesions, as in a simple cyst versus a broadenoma; however, it is not a good way to evaluate calcications, especially when it is not associated with a mass. Ultrasound is not an eective method of screening the entire breast, and is best used to examine a targeted area of the breast. Breast magnetic resonance imaging MRI imaging is being used with increasing frequency by breast specialists for both diagnostic and screening purposes. This is because MRI imaging is quite sensitive and can help detect breast cancer that is both clinically and mammographically occult [22]; however, breast MRI is not a substitute

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for mammography; rather it is an adjunct to it. Although quite sensitive, MRI has limited specicity, in the range of 65% to 79%, because of the enhancement of benign lesions such as broadenomas, fat necrosis, and certain types of brocystic changes. Indeed, women who are also screened with breast MRI tend to have more biopsies than women screened with mammography alone. Unfortunately there are reports of women undergoing unnecessary mastectomies on the basis of MRI ndings without subsequent histologic demonstration of a malignancy in the resected breast specimen [23]. Cost is another important issue to consider regarding the use of MRI. Physicians should therefore use breast MRI only for a select group of women or clinical scenarios, and should recognize the benets and pitfalls of this test when ordering it for their patients. Current recommendations for the use of breast MRI are to evaluate a breast lesion in patients who have: (1) equivocal mammographic or physical examination ndings;, (2) malignant axillary adenopathy and unknown site of primary tumor; and (3) extensive or locally advanced cancer undergoing neoadjuvant systemic therapy, typically chemotherapy [23]. As a screening tool, it should be limited to women at increased lifetime risk (greater than 20%) of developing breast cancer [23]. MRI is particularly helpful in women who have a high likelihood of developing breast cancer at an early age (eg, BRCA mutation carriers), because the denser breasts of young women generally decrease the sensitivity of a mammogram. Tissue sampling When the clinical examination or imaging of a breast abnormality are inconclusive, a tissue or cytologic diagnosis should be obtained. There are several ways to do this. One is to obtain a ne needle aspiration (FNA). Cysts are particularly amenable to this type of cytologic evaluation because it serves a dual purposedfor diagnosis and symptom management [16]. In many cases a lesion is not amenable to FNA, and a biopsy is required for tissue diagnosis. Core biopsy is preferred over excisional or incisional biopsy, unless the lesion is not amenable for this procedure or it is denite that the lesion is benign. For instance, when the symptom-causing lesion is clearly a broadenoma, it can be treated surgically by removing the lesion entirely. Treatment strategies for benign breast disease Treatment for BBD is directed at symptom control and prevention of more serious problems that might arise from the lesion if left untreated. In general, most brocystic changes in the breast do not require any treatment, and get better with time. Lifestyle modications Lifestyle modications can be encouraged, not only because they could alleviate the symptoms related to BBD, but also because of the benets

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related to general health and well-being. Eating a low-fat diet [24] and avoiding caeine may be used to treat brocystic change, particularly if pain is exhibited [25]. Although a direct association has not been denitively established, smoking cessation and regular exercise is encouraged. Women who experience fat necrosis should wear an extra supportive brassiere. Medications BBD with infectious etiology, such as an abscess or mastitis, are treated with antibiotics; however, duration of therapy depends on the severity of symptoms and response to treatment. Commonly patients require at least 1 week of oral antibiotics. The choice of antibiotic depends on the suspected etiologic organism, usually gram-positive cocci. Acute mastitis is also treated with warm compresses. In lactational mastitis, breastfeeding should continue while the patient is treated for the mastitis [8]. Anti-inammatory medications can also be used either as a pain reliever or to treat noninfectious forms of BBD. A brief course of NSAIDs can be very useful in managing pain related to brocystic changes as well as other BBD. In IGLM, NSAIDs and celecoxib can be quite useful, although the condition requires a longer duration of therapy compared with noninfectious mastitis. Because several of the changes associated with BBD depend on hormonal uctuations, oral contraceptives may be useful in its treatment. This may also help prevent development of further lesions, or at the very least, help modulate their size, thus further alleviating the symptoms [7]. In women who are deemed at intermediate to high risk of developing breast cancer, chemoprevention risk-reduction strategies include tamoxifen (for either pre- or postmenopausal women) [26] or raloxifene (for postmenopausal women only) [27]. Determination or calculation of breast cancer risk is discussed further under the section of malignant breast diseases of this article. Surgery Surgical drainage of an abscess is performed to prevent the spread of the infection and for symptomatic relief of discomfort/pain [7]. Fibroadenomas, when symptomatic, can be excised completely. Alternatively, if a patient is less than 35 years old and the breast mass is not disrupting quality of life, a core biopsy can be performed, primarily to establish that there is not a more ominous pathology to worry about, and then the condition can be managed conservatively [8,21]. Fig. 3 depicts an algorithm for evaluation and management of a palpable mass. Less invasive forms of surgery to manage broadenomas are in use in certain centers in the United States. One such technique is cryoablation, which freezes the lesion in situ. The cells, which have been killed by the cryoablation procedure, are eventually cleared by macrophages. This process does

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Fig. 3. Diagnostic algorithm for patients with palpable breast masses. (Reprinted from Evaluation of palpable breast masses. Am Fam Physician 2005;71:1736; with permission. Copyright 2005 American Family Physicians. All Rights Reserved.)

take time, so the mass from the broadenoma may remain palpable for a long time after treatment.

Malignant diseases of the breast Epidemiology In the United States, breast cancer is the second most common cancer after skin cancers, and is the second leading cause of death from cancer in women after lung cancer. In 2007, 178,480 women will be diagnosed with breast cancer and 40,460 women will die of their disease [28]. At the current rate, 1 out of 8 American women will develop breast cancer at some point in their lifetimes [29,30]. After increasing since 1980, female breast cancer incidence rates leveled o from 2001 to 2003, likely a reection of the saturation of mammography use and reduction in the use of hormone replacement therapy [28,31]. Even more noteworthy is that mortality from breast cancer has been on the decline since the early 1990s, partly because of early diagnosis and improvements in adjuvant therapy.

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Etiology Many factors inuence the risk of developing breast cancer. Female gender and age are two risk factors that all too often are underemphasized, probably because there is nothing one can do to inuence them. Other commonly recognized factors are genetics, family history of breast cancer, personal history of a prior cancer or prior biopsies disclosing atypia or LCIS, and use of hormone replacement therapy. The contributions to the risk of developing breast cancer by some of these factors are briey described. Personal characteristics Female gender is the primary risk factor for developing breast cancer, with a female-to-male risk ratio of about 135 to 1. Age is the second leading risk factor. In American women, the probability of developing breast cancer is 1 in 210 at age 39 or younger, to approximately 1 in 25 for ages 40 to 60 years, to as high as 1 in 15 for those 70 years and older [28]. Age at rst birth, early menarche, and late menopause are other factors that are weakly associated with an increased relative risk of developing breast cancer. Prior personal history of cancer is another inuencing factor. For instance, women who have a personal history of endometrial or ovarian carcinoma have greater than twice the risk of developing breast cancer as that of women who do not have such a history. Risk of a recurrence from a prior personal history of a breast cancer is clearly a concern, but it also puts the woman at a higher risk of developing a second breast cancer, either in the ipsilateral or contralateral breast. Women who have no prior history of breast cancer and who have had breast biopsies that reveal benign proliferative changes are also at increased risk of developing breast cancer. The risk is even more signicant when proliferative changes are associated with atypia, especially if there is also a family history of atypical hyperplasia or breast cancer in rst-degree relatives [16]. As previously mentioned, LCIS on previous biopsy is a marker for risk of developing invasive breast carcinoma in either breast. Hormone replacement therapy In postmenopausal women, the benets of hormone replacement therapy (HRT) for menopausal symptoms are controversial, primarily because of the increased risk of developing breast cancer. On average, HRT use is estimated to increase the annual rate of breast cancer to approximately 2% above that for women not using it [32]. In the landmark Womens Health Initiative (WHI) study, more women taking HRT in the form of combined estrogen and progestin developed breast cancer than those taking placebo [33]. After an average of 5.6 years, 245 of the 8506 women on HRT and 185 of the 8102 women on placebo developed breast cancer. Of the total cancers, 349 cases were invasive; there were 8 additional cases of invasive

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breast cancer for every 10,000 women over 1 year caused by HRT. Overall, the study authors found a 24% increase in the relative risk for breast cancer caused by HRT. HRT for management of problematic menopausal symptoms may be reasonable, but should be used for the shortest possible duration and with the lowest dose. Common and potential life-threatening side eects of HRT should be discussed with the patients. Family history and genetic predisposition The majority of patients who develop breast cancer, up to 85% of cases, do not have a family history of breast cancer; however, if a womans mother, sister, or daughter has a history of breast cancer, her risk increases by approximately twice the population risk. Even more signicantly, if a woman has two rst-degree relatives aected, her relative risk increases by more than four to six times compared with someone without a family history. Moreover, bilateral breast cancer in a rst-degree relative may increase risk by more than six times. Only approximately 5% of breast cancer cases can be considered as inherited forms of breast cancer, and an additional 10% to 15% can be considered to have a familial predisposition. All are autosomal dominant and tend to be highly penetrant. Bilaterality is common, where breast cancer diagnosis can either be synchronous or metachronous. It is often forgotten that 50% of hereditary breast cancer is inherited from the paternal side. Carriers of a germ-line mutation have a 1.5% to 4% per year risk of developing breast cancer. The best-characterized genetic risk factors are represented by germ-line mutations in BRCA1and BRCA2. These tumorsuppressant genes are associated with a much higher risk of breast and ovarian cancers [34,35]. Claus and colleagues [36] estimated that 36% of breast cancer cases in women aged 20 to 29 years could be attributed to a single dominant susceptibility gene, whereas only 1% of women diagnosed with breast cancer over the age of 80 have such a gene mutation. The lifetime risk of breast cancer in female carriers of BRCA1 mutation is estimated to be 36% to 87%, and 45% to 84% in carriers of BRCA2 mutation. Additionally, BRCA2 mutations are associated with a 6% lifetime risk of breast cancer among male carriers [34]. Breast cancer risk assessment tools Optimal public health gains from breast cancer risk-reduction strategies depend on the ability to accurately assess an individuals risk for developing breast cancer. Several models of risk assessment exist. It is important to remember that these models assess probability of developing breast cancer, not of dying from it. Two currently accepted breast cancer risk assessment models are the Gail model and the Claus model. Both were designed primarily to provide risk assessments for Caucasian women, so caution must be taken when applying them to women of other races.

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The Gail model estimates the risk of developing an invasive breast cancer over the next 5 years and a womans lifetime [37]. It considers ve factors: (1) current age; (2) age at menarche; (3) previous breast biopsies, taking into account if any of those biopsies demonstrated atypia; (4) age at rst live birth; and (5) history of breast cancer in rst-degree relatives. Disadvantages of this model are that it does not evaluate age at which a family member was diagnosed, and whether the disease occurred in both breasts. Thus, it underestimates the risk for patients who might harbor a BRCA mutation. Furthermore, the Gail model does not apply to women who have LCIS, DCIS, or personal history of breast cancer. The Claus model is weighted toward identifying women at risk for breast cancers related to a genetically inherited risk. It calculates age-specic and cumulative risk of developing breast cancer for a woman who has a rstdegree family history of breast cancer based on the age of the relative at diagnosis and the relationship to the woman at risk [36]. Like the Gail model, the Claus model does not consider other cancers that may signal a hereditary component, such as ovarian cancer and male breast cancer. Of all the breast cancer risk assessment tools, the Gail model is the most user-friendly and readily available. For individuals who would like to personally assess their risk, a computerized risk assessment tool based on the Gail model is available on the Web at http://www.cancer.gov/bcrisktool [38]. The CancerGene software from University of Texas Southwestern, which estimates Gail risk, Claus risk, and the statistical model BRCAPRO, may also be found at http://www4.utsouthwestern.edu/breasthealth/cagene [39]. BRCAPRO is another program used to determine an individuals risk of carrying a BRCA mutation, but is not used to estimate the risk of developing breast cancer. BRCAPro assess the risk of a BRCA mutation based on personal and family history of breast cancer and ovarian cancer [40]. It also takes into account male breast cancer, ages of breast cancer onset, and the total number of family members who have never developed breast or ovarian cancer. The BRCAPRO software may be downloaded from http://astor. som.jhmi.edu/BayesMendel/brcapro.html [41]. The risk of harboring a genetic mutation is best determined by a genetic counselor rather than a general practitioner, mainly because of the extensive counseling that is required before genetic testing. Malignant breast pathologies There are several ways of classifying malignant breast pathologies. One method is to classify them as either invasive or noninvasive. Although some noninvasive forms of breast cancer may become invasive over time, invasive breast cancers are more concerning because they have the ability to metastasize to distant sites and other organs at the outset. Another way of classifying breast pathologies is by their histologic subtypes. The

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most common histologic type of breast cancer is ductal, followed by lobular carcinoma. Some histologic types, such as tubular or mucinous, have a more favorable biology, whereas those with squamous or sarcomatous dierentiation have a more aggressive behavior. Although often of ductal histology, a particularly aggressive form of breast cancer is inammatory breast carcinoma. This type of breast cancer has a rapid course from a normal to abnormal looking breast in days to weeks, and is often misdiagnosed as mastitis, which often leads to delay in initiation of appropriate therapy. Fortunately, these aggressive histologic types and forms of breast cancer are less frequent than the garden variety type of breast cancer. Noninvasive breast carcinoma There are two subtypes of noninvasive carcinoma, DCIS and LCIS, although the latter is considered more frequently as a marker or risk rather than a cancer. DCIS is by far more common than LCIS, and more importantly, is clearly a malignant lesion. In DCIS, cancer cells proliferate within the mammary ductal-lobular system. DCIS can present as either a mass or pleomorphic microcalcications. Because it is noninvasive, it is less likely to produce overt changes in the contour of the breast or skin changes, but can occasionally be associated with nipple ndings such as a discharge. Five pathologic subtypes have been identied: comedo, papillary, micropapillary, cribriform, and solid. A positive biopsy for DCIS increases the risk of subsequent development of an invasive ductal carcinoma by 8 to 10 times, possibly higher in comedo type DCIS. Standard of care is resection with negative margins followed by radiation therapy to the ipsilateral breast. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-17 trial, which prospectively randomized 818 patients to either radiation therapy or no radiation therapy following lumpectomy, showed that radiation after lumpectomy reduces the incidence of tumor recurrence in the ipsilateral breast by about half [42]. In women who have estrogen receptor or progesterone receptor positive (collectively referred to as hormone-receptor positive) DCIS, tamoxifen for 5 years is also recommended. The NSABP B-24 study, involving 1804 women who had DCIS randomized to receive either tamoxifen or placebo following their local therapy, showed that the addition of tamoxifen is more eective than local therapy alone in preventing invasive and noninvasive ipsilateral breast tumor recurrences [43]. In LCIS, solid proliferation of uniform small cells occurs within multiple breast lobules. There is diuse involvement throughout the breast tissue, and it should be considered to be present in both breasts. Although LCIS shares features of its natural history with DCIS, LCIS is a more indolent form of in situ breast carcinoma than DCIS. For this reason, there is no compelling reason to surgically treat LCIS [44]. Negative surgical margins are not required, because it is presumed to be multicentric [45]. A woman

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who has a nding of LCIS has 10 times the risk of developing invasive breast cancer compared with her counterpart without this diagnosis. Thus, these women are particularly good candidates for chemoprevention strategies with either tamoxifen or raloxifene, the latter recommended only in postmenopausal women. Additionally, elective bilateral mastectomy is an option, but because this is more invasive and a permanent procedure, it should be a personal choice for the patient. Furthermore, follow-up is more intensive, depending on age and clinical scenario, such as whether patients decide to take chemoprophylaxis, undergo a bilateral mastectomy, or choose close surveillance. Invasive breast carcinoma Invasive breast cancers usually are epithelial tumors of ductal or lobular origin. Inltrating ductal carcinoma is the most common form of invasive breast cancer, and accounts for about 75% of patients who have breast cancers. Typically, it presents as a hard palpable mass, although with increasing use of screening mammography more cancers of this type are diagnosed at a nonpalpable stage. Inltrating lobular carcinoma has a much lower incidence and composes about 15% of invasive breast cancer. It has a tendency to be more multifocal. Other invasive histologies of epithelial origin, such as tubular, medullary, and papillary carcinomas, as well as nonepithelial breast tumors such as breast lymphoma, are much less common, and together account for less than 10% of all invasive breast cancers. Pattern and tempo of metastasis for invasive breast carcinomas can be quite unpredictable. In general, they metastasize to regional axillary lymph nodes rst. Frequent sites of distant metastasis include the bone, lung, and liver. The brain as a sole site of metastasis is uncommon, occurring in less than 5% of patients presenting with a recurrence. Metastasis to the meninges (ie, leptomeningeal disease or LMD) can occur and is particularly dicult to manage. Similarly dicult to manage is metastasis to serosal surfaces or peritoneal carcinomatosis. This particular type of metastasis is more commonly associated with inltrating lobular carcinoma. Molecular markers in the tumor are increasingly used in clinical practice to discern both prognosis and probability of response to a given therapy. Currently, tumor expression of the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) are routinely assessed in every newly diagnosed breast cancer. All three have important prognostic and predictive implications. ER and PR are valuable markers of disease-free survival and potential response to hormonal therapy. Patients who have hormone receptor-positive breast cancers in general have a more indolent course with fewer numbers of recurrences; however, they also tend to have a long natural history, so that very late recurrences, 10 to 15 years later, are not uncommon. More importantly, treatment with anti-estrogen therapies such tamoxifen or an aromatase inhibitor can eectively decrease the risk of recurrence. Based on the results from the

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Breast Cancer Prevention Trial (BCPT or P1 Trial), 5 years of tamoxifen compared with placebo reduced the risk of developing invasive breast cancer by 49% (P!.00001) in women at increased risk for breast cancer. The relative reduction in risk was greater in women who had a history of LCIS (56%) or atypical hyperplasia (86%) [46]. In patients diagnosed with breast cancer, treatment with tamoxifen improves breast cancer specic survival compared with placebo [47]. HER2 overexpression occurs in 20% to 30% of breast cancers, and is associated with increased incidence of recurrence and shortened survival. Patients who have HER2-positive breast cancer are candidates for treatment with the anti-HER2 monoclonal antibody trastuzumab. The addition of trastuzumab to standard therapy in early-stage and advanced disease has been shown to improve outcomes with fewer recurrences and deaths, respectively [48]. As more is learned about the biology of breast cancer, it is hoped that discovery of other molecular markers will be useful not only in providing prognosis, but also in tailoring therapy to specic abnormalities found in an individuals tumor. Evaluation and diagnosis of breast cancer Suspicious breast symptoms or ndings must be carefully evaluated to rule out a malignancy. Several modalities may be used for evaluation, most of which are complimentary. History and physical examination History and physical examination are key to the evaluation and diagnosis of any lesion suspicious for a breast cancer. Other tests are important and useful adjuncts, but understanding the clinical scenario is a critical rst step. Careful history will often lead a clinician to raise or lower the level of suspicion, and thus inuence how vigorously additional testing is pursued. Physical examination should include inspection of the patient in the upright as well as supine positions. Unless there is an obvious explanation, signicant size discrepancy or asymmetry of the breast, dimpling, nipple retraction or inversion, scaling, skin erythema, edema (peau dorange), or ridging should be considered abnormal and merit further evaluation. Examination of the supraclavicular, infraclavicular, and axillary lymph nodes is a part of routine physical examination. Once the patient is in the supine position with the ipsilateral arm extended over the head, the breast parenchyma can be compressed against the chest wall. This may reveal abnormalities not seen previously, such as a breast mass. Although not all breast cancers present with a mass, when a hard, often painless mass is noted, further evaluation is warranted. The same is true for a spontaneous bloody nipple discharge. In summary, all palpable breast masses should be evaluated by a physician to determine if further work-up is warranted.

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Monthly self-breast examination (SBE) as a prevention strategy is still generally presented as an option for women beginning at age 18 years, although no strong data support its ecacy in the early detection of breast cancer. In fact, studies indicate that SBE increases the incidence of diagnostic interventions as well as patient anxiety without altering the incidence of breast cancer mortality. If a woman wishes to do monthly SBE, she should be carefully taught how to do it properly. Clinical breast examination in women age 19 to 40 years is recommended approximately every 3 years, and yearly for women aged 40 years and older [49]. Diagnostic mammogram and other breast imaging techniques In the past, breast cancer most commonly presented as a palpable mass found by the patient. Currently most breast cancers are detected mammographically, when the mass may be quite small in size and nonpalpable. Thus, screening mammograms are important in the detection of breast cancer at an early stage. The American Cancer Society recommends that women in their 20s and 30s have clinical breast examinations every 3 years, and women aged 40 and older should have yearly bilateral mammograms and clinical breast examinations. In high-risk patients, such as BRCA1 and BRCA2 mutation carriers, heightened screening should begin at age 25, or 10 years earlier than the earliest age in which breast cancer presented in a family member. These women should best be followed at a high-risk breast clinic if one is available. (See the article by Zebrack and Brown elsewhere in this issue for additional breast cancer screening guidelines.) Diagnostic mammography, which takes additional views of the breast or lesion, is commonly recommended for symptomatic patients or women who have abnormal screening mammogram. It is also recommended for breast cancer follow-up (ie, post-lumpectomy) and after breast augmentation surgery. As an adjunct to mammography, ultrasonography can be particularly useful in younger patients or women who have brocystic breasts. Its main use remains in distinguishing solid from cystic lesions. It can be very operator-dependent, and is most useful when one can indicate which area of the breast needs further investigation. It is not a useful screening method for the entire breast because this would be quite time-consuming, and areas of the breast can be easily missed. High-risk patients who are good candidates for MRI screening include women who have very dense breasts, women who have a personal history of breast cancer not initially visualized by mammography, and women who have a strong familial or genetic predisposition for breast cancer (eg, carriers of BRCA1 or BRCA2 mutation). As a screening modality, MRI is quite sensitive, but its specicity is signicantly lower than that of mammography. As a consequence, more than twice as many unnecessary biopsies are performed, because many more abnormalities are picked up that turn out to benign on further evaluation [50]. When breast cancer is

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diagnosed, MRI can be a very useful tool in determining the extent of the lesion, including assessment of whether there is chest wall or regional lymph node involvement. It is thus a useful adjunct for surgical planning and to determine whether the patient may be better served by undergoing neoadjuvant therapy initially, or for recommending mastectomy rather than lumpectomy. Breast implants create limitations with regard to use of conventional breast cancer screening modalities. For instance, implants may make it difcult to adequately compress the breast during mammography for adequate viewing of the breast parenchyma. Given that the type, size, and placement of the breast implants dier, modication of screening practices depends on what nding/abnormality the clinician is investigating. Increasingly, MRI is used for evaluation of suspicious breast lesions in patients who have implants. Diagnostic procedures for histologic diagnosis Similar procedures used for BBD are also used in evaluating lesions suspected of breast cancer. Although FNA remains a useful procedure for masses such as simple cysts, it is no longer the standard for initial evaluation of many palpable breast masses. It is still useful, however, in the evaluation of suspicious regional lymph nodes or in the younger patient who has a simple cyst. The reason FNA is used less frequently for evaluating suspicious masses is that cytology alone cannot distinguish invasive carcinoma from noninvasive disease, and histologic conrmation of invasion requires a biopsy. Core needle biopsy (CNB) is the preferred initial diagnostic procedure for breast lesions suspicious for a malignancy. The main advantage of CNB is the ability of a surgical pathologist to distinguish between invasive cancer and DCIS, based on architectural information provided by the larger tissue sample obtained in a CNB. Because a lesion can be heterogeneous, image-guided CNB is preferred over a blind biopsy even in palpable lesions, because this increases the probability of getting representative samples of the lesion. In a nonpalpable lesion, it is a way to assure that the appropriate area has been sampled. Ultrasonography, mammography, and MRI may all be used to perform image-guided CNB, although ultrasound is most commonly used. Complete surgical removal of a palpable breast lesion is referred to as an excisional biopsy, whereas surgical sampling (or incomplete removal) of the lesion is referred to as an incisional biopsy. Excisional or incisional biopsies are indicated if the following situations arise: (1) neither CNB nor FNA is technically feasible, (2) nondiagnostic attempts by CNB or FNA, or (3) pathology is discordant with radiographic imaging. It is best to avoid excisional biopsy to establish histologic diagnosis of cancer, because this often means two dierent surgeries for the patientdone for diagnosis and the other for denitive therapy or axillary staging.

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Staging The standard staging system is that of the American Joint Committee on Cancer (AJCC). The system is based on primary tumor size (T), lymph node involvement (N), and whether there is evidence of metastatic disease on presentation (M) [51]. Breast cancer is broadly categorized into ve stages, in which noninvasive disease is Stage 0 (Tis N0 M0), small tumors 2 cm or smaller without lymph node involvement is Stage I (T1 N0 M0), whereas metastatic disease is Stage IV (any T any N M1). Stage II is subdivided into a and b, and Stage III is subdivided into a, b, and c, to reect increasing tumor size or number of lymph node involvement. The axilla is the principal drainage site for the breast. The size of the primary tumor has a positive correlation with the odds of nodal involvement. The number of metastatic axillary lymph nodes is a very signicant prognostic factor in breast cancer. Among patients who have positive axillary lymph node involvement, those who have the least number of involved nodes (ie, one to three positive axillary nodes) do best. Immunohistochemistry staining for cytokeratin will detect an additional 10% to 20% of cases of carcinoma involving the lymph nodes originally assessed to be uninvolved by standard histology. Use of this technology is reected in the current AJCC breast cancer staging (ie, N0 (i)). Staging workup in patients who have low probability of metastasis (ie, small tumors or negative nodes) requires only laboratory work and chest radiography; however, in higher-staged patients, staging workup may require CT and bone scans. Positron emission tomography (PET) scan is currently not recommended as a routine staging procedure for newly diagnosed breast cancer. Treatment Management of breast cancer requires a multimodality approach, including surgery, radiation, and systemic therapy. Surgery and radiation therapy are considered local therapies and are used for management of the primary tumor and to decrease risk of local recurrence. Systemic therapy modalities, such as chemotherapy, anti-estrogen therapy, and biologic therapy, are used to manage micrometastatic disease and decrease the risk of developing distant metastasis. Surgical therapy Initial surgical assessment involves determining whether the tumor is operable or not. This is predicated on whether the entire tumor, along with sucient margins plus axillary nodes, can be removed without signicant morbidity to the patient. If the patient is operable, then the next decision is to determine if the patient can be oered breast conservation surgery (ie, lumpectomy), or if a mastectomy is required. Lumpectomy is often followed with radiation therapy, and this must be taken into consideration

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during the surgical planning. Total or simple mastectomy involves removal of the breast parenchyma, including the nipple-areolar complex, with no lymph node dissection. A modied radical mastectomy involves resection of the breast parenchyma and axillary nodes lateral to and behind the medial border of the pectoralis minor. An essential component of breast cancer surgery is axillary assessment. There are two methods currently in use: sentinel lymph node biopsy (SLNB), and axillary lymph node dissection (ALND). Sentinel lymph nodes are the rst nodes that receive drainage from tumors. The technique involves injecting radiocolloid, blue dye, or both, into the breast and allowing it to travel into the draining lymph nodes. Afterward, the initial draining lymph nodes are identied and removed. Additional lymph nodes are subsequently removed (ie, ALND) only if the SLN is found to have metastatic deposits of cancer. This procedure results in less morbidity to the patient compared with initially performing ALND, which involves removal of level I (closest to the breast) and II (bordering the pectoralis muscle) axillary nodes. ALND is required if there is clinical suspicion of lymph node involvement. After axillary surgery, patients may experience paresthesias or lymphedema, which may be a long-term problem for some patients. Fig. 4 illustrates the anatomy of the breast lymph nodes. Radiation therapy Radiation therapy is indicated for patients who have breast cancer who have: (1) undergone breast conservation, (2) large primary tumors greater than 5 cm, (3) skin or chest wall involvement, or (4) multiple lymph node involvement (four or more lymph nodes). Typically, the whole breast is

Fig. 4. Anatomy of the breast lymph nodes.

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radiated, with a boost to the tumor bed. Regional lymph node-bearing areas such as the axilla and supraclavicular fossa are also radiated when a patient has multiple lymph node involvement, because these areas are at high risk for local recurrence. Newer techniques such as partial breast irradiation radiate only a select portion of the breast. Though used in some centers for selected patients, they are still considered investigational and should not be used routinely in clinical practice. Common side eects of radiation therapy include skin changes and fatigue. Systemic therapy Breast cancer is considered a systemic disease; thus systemic therapy is an essential component of treatment to increase chances for cure and survival. Systemic therapy in operable breast cancer is typically given postoperatively or adjuvantly. Some patients who are candidates for systemic therapy may elect to receive all or some of their treatment in the preoperative or neoadjuvant setting. Often this is done to shrink the tumor and allow for an increased rate of breast conservation. This approach also allows for assessment of tumor response to a given therapy. In patients who are initially deemed inoperable, either because of locally-advanced or metastatic disease, systemic therapy is the mainstay of treatment. Chemotherapy, anti-estrogen therapy (also referred to as endocrine or hormone therapy), and biologic therapy with molecularly targeted agents are all under the umbrella of systemic therapy. In the adjuvant or neoadjuvant setting, chemotherapy is typically given for a xed number of cycles, whereas in metastatic disease the number of cycles is less dened, and depends on the patients response and tolerance to the treatment. Chemotherapies commonly used in breast cancer include anthracyclines and taxanes. Examples of anthracylines include adriamycin and epirubicin; examples of taxanes include paclitaxel and docetaxel. Common side eects of chemotherapy include alopecia, nausea/vomiting, mucositis, lowering of blood counts, fatigue, and peripheral sensory neuropathy. Long-term toxicities include cardiomyopathy, secondary leukemia, and premature menopause. Anti-estrogen or endocrine therapy is used in patients whose tumors are hormone-receptor positivedestrogen receptor (ER) or progesterone receptor (PR) positive. When used in the adjuvant setting, it is typically given for 5 years, though in some patients it may used for up to 10 years. As with chemotherapy, duration of endocrine therapy in the metastatic setting is variable from a few months to years. Commonly used endocrine therapies include tamoxifen, and aromatase inhibitors such as anastrozole, letrozole, exemestane, and fulvestrant. Common side eects of endocrine therapy include hot ashes, night sweats, mood lability, increased risk of thromboembolic events, increased risk of uterine cancer, and osteoporosis. Because endocrine therapy has a specic molecular target, the ER, it can be considered a form of targeted therapy.

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To date, there are only two other molecularly targeted agents approved by the Food and Drug Administration (FDA) for the treatment of breast cancer: trastuzumab and lapatinib. Both target the HER2 receptor. Lapatinib also targets the epidermal growth factor receptor (EGFR), although a correlation between treatment response and EGFR targeting has not been clearly demonstrated in breast cancer. Trastuzumab is a humanized monoclonal antibody that has been shown to improve outcomes in both adjuvant [52,53] and metastatic treatment of breast cancer [54]. Common toxicities associated with trastuzumab include infusion reactions and cardiomyopathy. Rarely, it may be associated with pulmonary pneumonitis. Lapatinib is a small molecule tyrosine kinase inhibitor (TKI) that has been shown to be useful in the management of metastatic disease [55]. Common toxicities associated with lapatinib include diarrhea and rash. Other types of targeted therapy are currently being investigated, and should hopefully be part of the breast cancer armamentarium in the near future. Breast cancer outcomes Much progress has been achieved in the management of breast cancer. Women diagnosed with breast cancer today have a higher likelihood of surviving their cancer compared with women diagnosed in the 1970s or 1980s. Indeed, death from breast cancer has been declining since the 1990s. This is likely because of eective screening, with breast cancer being diagnosed at earlier stages, when there is a higher chance for cure, and development of eective adjuvant therapies. Because the curability of breast cancer is very much correlated to stage of diagnosis, it is essential for the primary care physician (PCP) to be vigilant about screening and early detection. It is also important for the PCP to make timely referrals when appropriate (eg, genetic counseling and screening in women who have strong family history, or further workup of suspicious breast lesions when there is uncertainty about how best to proceed). Although much progress has been made, there is much that remains unknown. For instance, the recognition that not all breast cancers are the same has made it apparent that more needs to be known about the dierent tumor biologies. New discoveries in this arena are likely to make a huge impact on the management of breast cancer in the future.

Acknowledgments The authors would like to acknowledge and thank James Swan at the University of New Mexico, Department of Biology, for his help with the illustrations.

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References
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[24] Mishra SK, Sharma AK, Salila M, et al. Ecacy of low fat diet in the treatment of benign breast disease. Natl Med J India 1994;7(2):602. [25] Russell LC. Caeine restriction as initial treatment for breast pain. Nurse Pract 1989;14(2): 367, 40. [26] Fisher B, Costantino J, Wickerham DL, et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 2005;97(22):165262. [27] Vogel VG, Costantino JP, Wickerham DL, et al. Eects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial. JAMA 2006;295:272741. [28] Jemal A, Siegel R, Ward E, et al. Cancer Statistics, 2007. CA Cancer J Clin 2007;57(1):4366. [29] Dobson R. Breast cancer incidence in US has fallen for rst time in 20 years. BMJ 2007; 335(7625):849. [30] Weir HK, Thun MJ, Hankey BF, et al. Annual report to the nation on the status of cancer, 19752000, featuring the uses of surveillance data for cancer prevention and control. J Natl Cancer Inst 2003;95(17):127699. [31] Jemal A, Clegg LX, Ward E, et al. Annual report to the nation on the status of cancer, 19752001, with special feature regarding survival. Cancer 2004;101:327. [32] Manson JE, Martin KA. Clinical practice. Postmenopausal hormone-replacement therapy. N Engl J Med 2001;345(1):3440. [33] Chlebowski RT, Hendrix SL, Langer RD, et al. Inuence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Womens Health Initiative Randomized Trial. JAMA 2003;289(24):324353. [34] Garber JE, Ot K. Hereditary cancer predisposition syndromes. J Clin Oncol 2005;23(2): 27692. [35] Greene MH. Genetics of breast cancer. Mayo Clin Proc 1997;72(1):5465. [36] Claus EB, Risch NJ, Thompson D. Age at onset as an indicator of familial risk of breast cancer. Am J Epidemiol 1990;131:96172. [37] Gail MH, Brinton LA, Byar DP, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 1989; 81:187986. [38] National Cancer Institute. breast cancer risk assessment tool. Available at: http://www. cancer.gov/bcrisktool. Accessed March 16, 2008. [39] University of Texas Southwestern Medical Center and the BayesMandel Group at Johns Hopkins University. CancerGene with BRCAPRO, MMRpro, and PancPRO. Available at: http://www4.utsouthwestern.edu/breasthealth/cagene. Accessed March 16, 2008. [40] Parmigiani G, Berry DA, Aguilar O. Determining carrier probabilities for breast cancersusceptibility genes BRCA1 and BRCA2. Am J Hum Genet 1998;62:14558. [41] Parmigiani G, Wang W, Blackford A. BRCAPRO. Available at: http://astor.som.jhmi.edu/ BayesMendel/brcapro.html. Accessed March 8, 2008. [42] Fisher B, Costantino J, Redmond C, et al. Lumpectomy compared with lumpectomy and radiation therapy for the treatment of intraductal breast cancer. N Engl J Med 1993;328: 15816. [43] Fisher B, Land S, Mamounas E, et al. Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the National Surgical Adjuvant Breast and Bowel Project experience. Semin Oncol 2001;28(4):40018. [44] Fisher ER, Land SR, Fisher B, et al. Pathologic ndings from the National Surgical Adjuvant Breast and Bowel Project: twelve-year observations concerning lobular carcinoma in situ. Cancer 2004;100(2):23844. [45] Reis-Filho JS, Pinder SE. Non-operative breast pathology: lobular neoplasia. J Clin Pathol 2007;60(12):13217.

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[46] Ganz PA, Day R, Ware Je JR, et al. Base-line quality-of-life assessment in the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial. J Natl Cancer Inst 1995;87(18):137282. [47] Early Breast Cancer Trialists Collaborative Group (EBCTCG). Eects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomized trials. Lancet 2005;365(9472):1687717. [48] Baselga J, Perez EA, Pienkowski T, et al. Adjuvant trastuzumab: a milestone in the treatment of HER-2-positive early breast cancer. Oncologist 2006;11(Suppl1):412. [49] Smith RA, Cokkinides V, Eyre HJ. American Cancer Society guidelines for the early detection of cancer, 2006. CA Cancer J Clin 2006;56:1125. [50] Orel SG. MR imaging of the breast. Radiol Clin North Am 2000;38(4):899913. [51] Singletary SE, Allred C, Ashley P, et al. Revision of the American Joint Committee on Cancer staging system for breast cancer. J Clin Oncol 2002;20(17):362836. [52] Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353(16):167384. [53] Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353(16):165972. [54] Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344(11):78392. [55] Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355(26):273343.

Med Clin N Am 92 (2008) 11431161

Pelvic Masses
Spencer P. Barney, MDa,*, Carolyn Y. Muller, MDa, Karen D. Bradshaw, MDb
a

Department of Obstetrics and Gynecology, University of New Mexico Health Science Center, 2211 Lomas Blvd. NE, Albuquerque, NM 87131, USA b Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9032, USA

Much fear and anxiety surround the evaluation of masses within the female pelvis, driven mainly by the potential of missing a malignancy. The limitations of physical examination, the apparent invasiveness of such examinations, and the patients perception of malignant risk can further heighten provider anxiety. The impact of invasive diagnostics on fertility in premenopausal women adds another layer of complexity to the diagnostic dilemma. This article reviews key concepts in a common-sense approach to diagnosing and managing pelvic masses in women of all age groups. Pelvic cystic masses are a common occurrence in women of all age groups, with approximately 8% of asymptomatic women aged 25 to 40 who were randomly sampled from a population register having a cyst larger than 2.5 cm [1]. Another study found that of women aged 50 and older, 18% had a nding of a unilocular ovarian cyst of 10 cm or less [2]. Given these ndings, all practitioners who care for women will, at some point in their careers, encounter the nding of a pelvic mass. Pelvic masses often are asymptomatic and found at the time of routine health care visits, during screening for other unrelated complaints, or when evaluating a specic gynecologic complaint. This article assists primary care providers in the targeted evaluation, management, and appropriate referral of women with a newly identied pelvic mass. Dierential diagnosis The initial evaluation of a pelvic mass requires a consideration of the multiple organ systems present within the female pelvis and an adequate understanding of female pelvic anatomy. The reproductive organs include
* Corresponding author. E-mail address: sbarney@salud.unm.edu (S.P. Barney). 0025-7125/08/$ - see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2008.04.007 medical.theclinics.com

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the vagina, cervix and uterus, fallopian tubes, and ovaries. Nonreproductive organs within the female pelvis include bowel (both large and small intestines), bladder, ureters, nerves, vascular structures, lymph nodes, and muscles. Any anatomic structure that resides in the female pelvis has the capacity to form a pelvic mass, so a variety of potential sources must be taken into consideration when the diagnosis of a pelvic mass is made. Because most pelvic masses within the female pelvis originate from the reproductive structures, this article specically focuses on the diagnosis of masses of these organs. A list of common masses, both benign and malignant, is found in Table 1.

Clinical evaluation Physical examination Every evaluation should begin with a thorough history and physical examination. The history should include menstrual history, location, qualication, and quantication of pain, if present, fever, and any noted change in bowel or bladder habits. Age and family history of cancer should be included in every history because they are the two most important risk factors for the development of ovarian cancer. The physical examination can be somewhat directed by the information elicited when obtaining the patient history. A thorough abdominal and pelvic examination is critical in determining the dierential diagnosis. The pelvic examination includes a speculum examination and an evaluation of any purulent vaginal discharge followed by a bimanual and rectovaginal examination. Stool should be tested for blood. The location, consistency, mobility, and size of any masses palpated should be documented, along with location and characteristics of any pain elicited when performing the examination. Texture of the pelvic oor, including xation, thickened tissue planes, or nodularity, should be noted.
Table 1 Dierential diagnosis of common causes of a pelvic mass Cervix and uterus Benign Pregnancy Leiomyoma Adenomyoma Nabothian cyst Uterine polyp Hydrometra Pyometra Malignant Endometrial Cancer Leiomyosarcoma Cervical cancer Fallopian tube Benign Hydrosalpinx Tubo-ovarian abscess Ectopic pregnancy Paraovarian cyst Ovaries Benign Functional cyst Endometrioma Polycystic ovaries Fibroma; brothecoma Torsion Mature cystic teratomas Benign cystadenomas Malignant Ovarian cancer Borderline tumor Metastatic cancer Nongynecologic Benign Appendicitis Bowel adhesions Diverticulitis Urinary retention

Malignant Fallopian tube cancer

Malignant Colorectal cancer Lymphoma Carcinomatosis

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Endometrial biopsy should be performed on any perimenopausal or postmenopausal woman who presents with associated abnormal bleeding. Any visible masses on the cervix or protruding from the vagina should be biopsied. This initial examination aids in establishing the dierential diagnosis. Many physicians rely on imaging and do only a supercial examination or no examination at all (the electronic pelvic examination), but imaging cannot replace the additional useful information obtained by clinical hands-on evaluation and may result in a narrowed and erroneous diagnosis. For example, a mass can seem to represent a degenerating broid on a CT scan obtained during an emergency room visit for abdominal pain, but a thorough examination could reveal a normal sized uterus separate from a mass and additional nodularity within the cul-de-sac, which would increase the clinical suspicion of an ovarian malignancy. Should the diagnosis be made solely on the CT suggestion of a degenerating broid, treatment could be delayed, appropriate referrals not made, and survival subsequently compromised for that patient. Despite the need for a thorough examination, studies have shown that the physical examination is not reliable as a diagnostic tool in and of itself. Padilla and colleagues [3] showed that even under ideal circumstances, the sensitivity of the pelvic examination is only 51%. This study attempted to eliminate diculties, such as patient discomfort and anxiety, that are found in awake patients by assessing the eectiveness of examinations performed on anesthetized patients before surgery. Even this control does not eliminate diculties caused by variables such as patient habitus, scars, or other ndings, however, which can make assessment of pelvic masses more dicult. A similar study, also by Padilla and colleagues [4], showed the importance of experience when performing a pelvic examination under the same optimal examination conditions. The accurate identication of uterine size, contour, and adnexal pathology during pelvic examinations under general anesthesia was 70.2% for attending gynecologists, 64.0% for residents, and 57.3% for medical students when compared with surgical ndings. They also found that uterine assessment seemed to be more accurate than adnexal assessment. Because even in the most experienced hands under optimal examination conditions pelvic examination does not always accurately assess pelvic pathology, other diagnostic studies such as ultrasound, used in tandem with the initial history and physical examination, are necessary to achieve a more complete evaluation of the pelvis. Ultrasound Transabdominal and transvaginal ultrasounds are still the leading modalities used to visualize female pelvic anatomy and examine pelvic masses. Generally, transabdominal and transvaginal ultrasound should be performed to assess the adnexa adequately. The transabdominal ultrasound gives an overall assessment of organ size and anatomy, whereas the transvaginal ultrasound, with its higher image resolution, gives more detailed information

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about pelvic structures and masses. Many characteristic ndings seen on ultrasound help to dierentiate benign from malignant masses. Benign masses are more often smooth in contour and have a single, thin-walled cyst with minimal vascularity (Fig. 1). Malignant masses, on the other hand, often show thick walls or septations, solid components such as mural nodules, increased vascularity, and increased pelvic uid or frank ascites (Fig. 2). Other nonmalignant masses, such as hemorrhagic cysts, endometriomas, and mature teratomas, have their own characteristic ndings on ultrasound. After visualizing the mass generally, it is important to determine if the mass is intraovarian or extraovarian, which often can be accomplished by visualizing the ipsilateral ovary. The distinction is important because most extraovarian masses are benign [5]. Most pelvic malignancies arise from ovarian tissue; however, most intraovarian masses are benign, especially in premenopausal women. The ve most common masses seen within the ovary are simple functional cysts, mature teratomas (dermoid), endometriomas, corpus lutea, and hemorrhagic cysts [5]. A normal premenopausal ovary averages 3.5 2 1.5 cm; a postmenopausal ovary measures 1.5 0.75 0.5 cm [6]. Any postmenopausal ovary that is twice as large as the contralateral ovary is concerning [7]. For unilocular cysts (single cysts without septations or solid components), ovarian size does not correlate well with the risk for malignancy, however. Studies show that unilocular ovarian cysts smaller than 5 to 10 cm had no ndings associated with malignancy on ultrasound and were likely benign or had a low malignant potential, even in postmenopausal patients [2,8]. Many of these cysts stayed the same size or resolved spontaneously over a prolonged period of time. Of those that had spontaneous resolution (69%), most resolved within 3 months. Apart from the size, another aspect of a pelvic mass that can be evaluated by ultrasound is its consistency. Cysts that have septae, excrescences, papillations, or solid areas are signicantly more concerning for malignancy than

Fig. 1. A single cystic structure without any solid components is more characteristic of a benign mass.

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Fig. 2. Masses that have solid components, septations, or irregular borders are more characteristic of malignant masses.

simple cysts with a smooth contour. One study of a mixed population of pre- and postmenopausal patients showed that among women with unilocular cysts, only 0.3% (1/296) of cysts were malignant, whereas 8% (20/229) that were classied as multilocular were found to be malignant. Multilocular tumors with solid components and solid tumors were much more likely to be malignant than those without solid components [9]. More recent studies conrm this nding that unilocular and even multilocular cysts without solid components are most often benign [10,11]. Vascularization is another aspect of a mass that can be characterized sonographically. Malignancies are much more likely to have neovascularization and often are found to have a low resistive index (RI) on Doppler ow imaging of the mass. The RI is dened as the dierence between the peak systolic and the maximum end diastolic ow velocity in arterial vessels divided by the peak systolic ow velocity. New vessels associated with malignancy have little smooth muscle in the arterial wall; they have less resistance to ow and subsequently a lower RI. Benign cysts, on the other hand, generally do not have this same neovascularization. At our institution we use a cut-o of 0.4 when looking at the RI of ovarian masses. Anything below this number has a higher suspicion of being malignant. The uterus also can be visualized sonographically, which is helpful when evaluating for abnormal or postmenopausal bleeding or evaluating for or characterizing presumed broids. Generally, in postmenopausal patients the endometrial thickness or stripe should measure less than 5 mm (Fig. 3). In premenopausal patients, measurement of the endometrial stripe is generally of little value because there is a large variation in the endometrial thickness throughout the menstrual cycle. Fibroids typically have a characteristic appearance on ultrasound. They are generally round, well-circumscribed masses with a circumferential blood ow pattern (Fig. 4). These characteristics can vary, and broids can have degenerative changes, including calcications or cystic degeneration. Such degeneration and necrosis can be seen as

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Fig. 3. The endometrial stripe is a measurement of the thickness of the endometrium. It is considered a double-layer thickness because it contains both sides of the endometrium surrounding the endometrial canal, which is generally a potential space. In the previous gure, the endometrial stripe is measured in two separate areas outlined by the marks shown.

broids outgrow their blood supply. Smaller broids can be seen and mapped out using transvaginal ultrasound. Large broids often are better visualized and measured transabdominally given the shallow depth of penetration of the transvaginal transducer, which makes it less eective at evaluating large masses. Submucosal broids and endometrial polyps may be better visualized with a sonohysterogram, in which saline is instilled within the endometrial cavity to allow for better visualization of the space (Fig. 5). It may be dicult to distinguish pedunculated serosal broids from ovarian masses unless the ipsilateral ovary can be well visualized separate from the mass or unless bridging vessels are seen between the uterus and the mass. Hemorrhagic cysts occur when bleeding occurs in a functional cystd typically at the time of ovulation. They can vary widely in appearance. As the clot organizes, it forms brin strands that can be mistaken for septations. The dierence between septations and brin strands is determined by

Fig. 4. Fibroids are generally well circumscribed, as demonstrated in the previous image. They can vary in echogenicity from being hypoechoic (solid arrows) to hyperechoic (hollow arrows).

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Fig. 5. A sonohistogram is used to identify lesions such as endometrial polyps, submucosal broids, or focal endometrial hyperplasia. In the previous gure, saline was instilled into the uterus to better visualize an endometrial polyp. The picture on the left shows the lower uterine segment before instillation of saline. The picture on the right is the same uterus after saline has been placed into the endometrial canal. The white arrow indicates an endometrial polyp that was the likely cause of uterine bleeding.

the number seen and their ultrasonographic characteristics. Septations are usually limited in number, whereas brin strands are innumerable. The brin strands are generally much thinner and tract over less distance than do septations. Given these initial ndings, hemorrhagic cysts can bedand at times aredmistaken for neoplastic masses. The dierence is that hemorrhagic cysts nearly always resolve spontaneously over a short time period of 2 to 8 weeks (Fig. 6) [12]. The appearance of these cysts can vary greatly as they continue to reabsorb. The brin strands disappear, and the retracting thrombus can appear as a solid structure on the sidewall of an otherwise

Fig. 6. Hemorrhagic cysts change over time as the clot organizes and then is reabsorbed, as this series demonstrates. (A) Fibrin strands from organized clot can be seen within the cyst. (B) Ultrasound performed just 4 days later. You can already see the dierence in the areas where the clot has started to reabsorb, forming larger anechoic areas. (C) Follow-up ultrasound done 3 months later. At that time a normal ovary with multiple follicles was seen.

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normal appearing cyst. This variance stresses the value of re-examination and reimaging of equivocal pelvic masses within a 6- to 8-week period. Endometriomas are another example of a pelvic mass that can take on multiple ultrasonographic appearances. These masses can be found in association with endometriosis, although endometriosis itself is not reliably seen on ultrasound. They can occur in a large range of ages and often are present for long periods of time unless they are surgically excised. Most endometriomas are represented on ultrasound by diuse, homogeneous, low-level echoes. Occasionally, these masses can vary in appearance and contain septations or hyperechoic wall foci and nodularity [5]. There may be some overlap between the ultrasound appearance of endometriomas and that of hemorrhagic cysts, and endometriomas may contain an apparent solid component caused by brin or clot. In one study, 17 of 58 surgically proven endometriomas (29.3%), which measured larger than 2 cm, had no mention of endometrioma or hemorrhagic cyst on the prospective dierential diagnosis. In this article, ultrasonographic ndings that were atypical included retracted clots that appeared as solid components without any blood ow, areas with heterogeneous internal echoes, or areas of central calcication [13]. CT CT is generally not recommended for initial evaluation of pelvic masses because ultrasound is less expensive and better at evaluating masses of gynecologic origin and results in no exposure to radiation. CT is most helpful as a second line study for in-depth evaluation of the abdomen and pelvis when malignancy is suspected; CT studies should be ordered by a specialist after referral. More pelvic abnormalities are being initially found on CT evaluation because it is becoming a more common rst-line tool for the evaluation of patients with various symptoms who present to the emergency department [14]. CT is less operator-dependent than ultrasound and often has round-the-clock availability that may be lacking for ultrasound evaluation. Because of its availability, many gynecologic abnormalities, which normally would have been evaluated by ultrasound, are initially being found during these evaluations (Fig. 7). Many are incidental ndings during CT evaluation of nonpelvic complaints, whereas others may be the cause of the pelvic pain or other complaints that initially led to the CT. Historically, given the comfort of gynecologists with ultrasound ndings, these CT images would be followeddat times unnecessarilydwith ultrasound for evaluation. Many of these conditions, such as hemorrhagic ovarian cysts, pelvic inammatory disease, cystic teratomas, endometriosis, broids, and endometrial or ovarian cancers, have ndings that can be reliably recognized on CT (Fig. 8) [15]. If these masses have a characteristic diagnostic appearance, then reimaging is not necessary. Patel and Dubinsky [16] described three instances in which reimaging with ultrasound is useful after pelvic CT ndings of an abnormality: (1) evaluation of the mass in

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Fig. 7. (A) Initial CT of a patient who presented to the emergency room for abdominal pain and was thought to have diverticulitis. The CT was read as having a septated left adnexal cyst (white arrow). (B) Follow-up transvaginal ultrasound 3 weeks later showed that the multicystic structure was composed of four anechoic structures. Resistive indices were all within acceptable limits.

relationship to ovarian tissue, (2) better clarication of the vascularity of the mass, especially for noncontrasted CT images, and (3) evaluation for indications that are uniquely suited to ultrasound evaluation, such as pregnancy or follow-up for a suspected ectopic pregnancy. In most other instances, immediate reimaging by ultrasound of abnormalities found on CT is not necessary. Follow-up imaging (ultrasound evaluation at some future point to re-evaluate ndings) of these abnormalities may still be clinically indicated. MRI MRI, much like CT, has little place in the initial evaluation of pelvic masses. Like CT, it can be used for further evaluation of masses suspected to be malignant. Chang and colleagues [17] dened some instances when MRI is useful after sonographic evaluation, including the evaluation of large masses that are not well visualized by transvaginal ultrasound and indeterminate pelvic masses in which the origin of the pelvic mass cannot be determined by ultrasound. Patel [12] similarly stated that adnexal ndings that cannot be classied condently should be followed-up with MRI for further evaluation. MRI also can be helpful for the evaluation of small masses found within soft tissue, such as masses felt along the vaginal sidewall, if not well characterized by ultrasound. Traditionally, MRI has been the modality of choice for uterine ndings felt to be adenomyosis, and this application continues to be appropriate. Studies currently show that

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Fig. 8. (A) This patient presented to the emergency room with right lower quadrant pain, and a CT was obtained to rule out appendicitis. The mass marked by the white arrow was identied and described as fat containing. with mural soft tissue components. Findings were consistent with a dermoid cyst. (B) Follow-up ultrasound was obtained. It described a focal increased echogenicity with shadowing. These ndings conrmed the diagnosis of a dermoid cyst.

transvaginal ultrasound also has adequate image resolution to diagnose adenomyosis, as long as the sonographer has sucient experience and training [18]. In cases in which an experienced sonographer is available, the relative cost and availability of ultrasound make it an ideal rst-line choice for the evaluation of pelvic pain suspected to be adenomyosis. MRI is useful in assessing an adnexal mass in pregnancy, in which exposure to radiation is avoided and palpation and sonographic visualization are dicult. As the gestation progresses, the adnexa are moved out of the pelvis and may not be adequately evaluated by transabdominal sonography. Because surgical intervention in pregnancy is reserved for acute complications or malignant suspicions, MRI may be helpful in further characterizing the mass and evaluating the safety of waiting until after delivery to intervene.

Tumor markers The most commonly used tumor marker for ovarian cancer is CA-125, which is a serum glycoprotein that is elevated in 80% of women with epithelial ovarian cancer [19]. No single tumor marker (including CA-125) has been found to be reliably helpful for screening purposes, however. Instead, tumor markers are used as a tool to help assess likelihood of ovarian cancer in someone found to have a suspicious mass, especially in postmenopausal patients. Because many benign diseases, including nongynecologic

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conditions and physiologic ovulatory events, can increase CA-125, it is of limited value in premenopausal women and should not be obtained unless interpretation of the result is understood by the practitioner. Elevated results and normal results should be interpreted with caution and in conjunction with the clinical scenario and cancer risk assessment. Findings such as pelvic inammatory disease, adenomyosis, endometriosis, pregnancy, menstruation, and functional cysts can increase the serum CA-125 level. On the other hand, a negative CA-125 result does not rule out ovarian cancer. Up to 50% of early malignancies and 20% to 25% of late stage cancers are found to have normal CA-125 values [20]. The greatest use of CA-125 is to assess the eectiveness of surgery and other treatments or monitor for recurrence of ovarian cancer when the diagnosis is histologically known. Other tumor markers have been studied, including CA-15.3 [21], which showed a high specicity and positive predictive value, and CA-19.9 [22], which had a high association with mucinous-type tumors. Neither of these markersdeither individually or in conjunction with CA-125dseemed to show a signicant increase in detection of cancer over CA-125 combined with physical examination and ultrasound. A urry of translational genomic and proteomic research eorts has yielded promising biomarkers for early detection of ovarian cancer, such as He-4, mesothelian, osteopontin, lysophospatidic acid, kallikreins, and soluble epidermal growth factor receptor [23]. Although not ready for clinical use, active validation studies are underway to dene a panel that will have optimal sensitivity and specicity proles to improve early diagnosis of ovarian cancer. If a germ cell tumor is of concern because of a solid mass seen in a premenopausal woman, then lactate dehydrogenase, alpha-fetoprotein, and human chorionic gonadotropin levels can be helpful. Obtaining a human chorionic gonadotropin value is essential to rule out pregnancy, either intrauterine or ectopic, as the cause of a pelvic mass.

Management Initial management of a pelvic mass is based on patient age, size and characteristics of the mass, and ndings on ultrasound and laboratory tests. The initial evaluation should focus on ruling out malignancy, torsion, or rupture. It is important to decide which masses require surgery and which do not. Some masses may require further management by a specialist, although many masses or cysts can be dealt with medically or conservatively in a generalist setting. This section explores the management of adnexal massesdafter initial evaluationdstratied by age. Adolescents A human chorionic gonadotropin level should be obtained in every adolescent or woman of childbearing age to rule out pregnancy as the primary

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cause of a pelvic mass. This is especially true if a history of irregular menses or missed menses is elicited in the initial interview. An ectopic pregnancy can be life threatening if not promptly diagnosed early in the growth process. Once pregnancy is ruled out, then clinical examination and ultrasound ndings can be reviewed. Because the risk of malignancy is low in this age group and the desire to preserve fertility is high, many masses can be followed expectantly. Any simple cystic mass that is smaller than 10 cm should be followed expectantly unless symptoms, such as signicant pain, suggest torsion. During the reproductive years, 70% of cysts of this size resolve spontaneously [24]. Generally, follow-up ultrasound in approximately 2 to 3 months is a reasonable time period to look for resolution of, or change in, a cystic mass. If there does not seem to be resolution within 3 months or if the mass is growing or seems to be more complex, then referral to a gynecologist may be warranted. It has been a common practice to prescribe oral contraceptive pills for the treatment of women with simple cysts. The use of oral contraceptive pills for treatment of ovarian cysts, however, has been shown to have no eect. A Cochrane Review in 2006 concluded that treatment with combined oral contraceptives did not hasten resolution of functional cysts in any trial [25]. Most of these cysts resolve on their own if followed expectantly. Some providers use oral contraceptives for women with ovarian cysts, not to treat the cyst but with the hope that use will prevent new cysts from forming while awaiting the resolution of the cyst in question. The use of oral contraceptive pills for this indication is not well studied. Fine needle aspiration of cysts is another traditionally used method of treatment that has not been found to be useful. The diagnosis of cancer based on cytologic ndings is not sensitive enough to warrant routine aspiration as part of the evaluation for pelvic masses, and the resolution rate of cysts after aspiration is not statistically dierent than cysts followed expectantly [26,27]. Any cyst larger than 10 cm or any cyst with septations or solid components should undergo further evaluation. The use of CA-125 in adolescents is of limited value because of its nonspecic nature. Endometriosis, pelvic inammatory disease, pregnancy, and even functional ovarian cysts can elevate CA-125. The American College of Obstetricians and Gynecologists advises that in premenopausal women with symptoms, a CA 125 measurement has not been shown to be useful in most circumstances [20]. Because of this difculty, the American College of Obstetricians and Gynecologists recommends a CA-125 level of more than 200 U/mL as a threshold in average-risk premenopausal women for referral to a gynecologic oncologist. Although solid masses are concerning and often require surgical management, most are still benign. Dermoid cysts, or mature cystic teratomas, which are more common in younger, reproductive-aged women, are almost universally benign [28]. One concern of large cysts, or any large mass of the ovary, is that of torsion, which refers to the twisting of the ovary around its ligamentous

PELVIC MASSES

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support. Torsion can result in venous obstruction of the ovary and cause engorgement and eventually ischemia because of diminished blood ow. Torsion often presents as intermittent sharp pain. Evaluation should begin with a pelvic examination and ultrasound to evaluate blood ow of the ovary in question. Ultrasound imaging, however, is not an infallible way to diagnose torsion, so clinical suspicion should guide the evaluation. Studies need to be completed quickly and followed by urgent surgical management, when indicated, to help salvage the ovary and preserve ovarian function. When surgery is performed soon after discovery of torsion, the vessels can be untwisted and the ovary, along with fertility, can be preserved. Pelvic inammatory disease is also more prevalent in adolescent and young adult women. It can lead to tubo-ovarian abscesses and adhesions and can be a cause of long-term infertility if not diagnosed and treated early. Women generally present with pelvic pain and a history of fever or purulent vaginal discharge or both. They often have an elevated white blood cell count because of the infectious process. Infection and the inammatory response are what lead to abscesses and eventually scarring and tubal occlusion if not treated in a timely fashion. Gonorrhea and chlamydia cultures should be obtained during the evaluation of pelvic inammatory disease because they are often the primary causes. Premenopausal women The principles that direct management of pelvic masses in adolescents also apply to most premenopausal women. As patients age, however, the risk of ovarian malignancy increases. As patients approach menopause, the suspicion of malignancy also should increase proportionately. As in adolescents, evaluation begins with a human chorionic gonadotropin test to rule out pregnancy. Risk of ectopic pregnancy also increases as patients age because of the increased likelihood that they have had pelvic inammatory disease or pelvic surgery, which can cause scarring around the fallopian tubes, so attention should be paid to this possibility. A history of previous ectopic pregnancy should place this diagnosis higher on the dierential until pregnancy is ruled out or until an intrauterine pregnancy has been conrmed. With the increased use of rst trimester ultrasound in pregnancy and the increased sensitivity of ultrasound equipment, the incidence of diagnosis of pelvic masses during pregnancy has increased. Most of these masses resolve spontaneously by the second trimester [29,30]. In most cases, early surgical management is unwarranted. The risk of malignancy of an ovarian mass encountered during pregnancy is between 2% and 3% [30]. As in other pelvic masses, the malignant potential can be evaluated with the same ultrasound guidelines used for nonpregnant women, with solid tumors with irregular vascularity carrying a higher risk of malignancy. If pelvic masses persist into the second trimester, then consideration should be given to the possible need for surgical intervention. Surgery is more likely necessary if, after

1156

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evaluation, there remains a strong suspicion of malignancy, the mass is large (O 10 cm) or symptomatic, or there is an increased concern for torsion, rupture, or obstruction of labor [30]. In nonpregnant patients, once a mass has been detected by physical examination, an ultrasound should be used for characterization of the mass. In limited instances, a CA-125 test may be useful. Ultrasound appearance combined with tumor size has been found to be the best predictor of malignancy in premenopausal women. In postmenopausal women, CA-125 combined with ultrasound appearance is the best predictor of malignancy [31]. A CA-125 test values in premenopausal women can be elevated because of several nonmalignant causes, and it is not a reliable marker for malignancy in this age group. These guidelines apply to premenopausal women of average risk for ovarian malignancy. Women with a hereditary high risk of premenopausal ovarian cancer and a pelvic mass should be referred for a more comprehensive evaluation for ovarian malignancy. Women with known BRCA2 or BRCA1 mutations have a 26% to 50% lifetime risk of developing ovarian cancer and a 3% to 23% risk of developing cancer by age 50, respectively [32]. Family history of cancer is critical when assessing these women, as is a personal history of premenopausal breast cancer. Pelvic masses that are suspected to be caused by uterine broids, based on ultrasound or CT ndings, do not require evaluation with CA-125. Most broids can be followed expectantly if symptoms are well tolerated. In any woman over the age of 35 years with abnormal bleeding, an endometrial biopsy should be performed to rule out endometrial cancer. If the endometrial biopsy shows malignant cells, then the patient should be referred to a gynecologic oncologist. Once cancer has been ruled out, bleeding associated with broids can be treated with oral contraceptive pills or endometrial ablation, depending on the size and number of broids present. Large broids that cause pain or other symptoms, such as incontinence, can be treated surgically and should be referred to a gynecologist. Many broids begin to regress after menopause and can be treated expectantly until menopause if surgery is not desired or is deemed unsafe because of a patients medical status. Solid adnexal masses, although not often malignant in premenopausal women, generally require surgical intervention and warrant referral to a gynecologist. These recommendations apply to average-risk premenopausal women. The decision for referral to a gynecologic oncologist is based on several other criteria discussed later in this article. Postmenopausal women Previously, conventional wisdom held that postmenopausal ovaries did not produce cysts; however, this is not the case. Along with the increasing use of sonography, the diagnosis of unilocular cysts in postmenopausal patients is also increasing. The malignant potential of a unilocular cyst in

PELVIC MASSES

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postmenopausal women, like that of premenopausal women, is low [2,8]. These cysts should be evaluated initially with ultrasound and a CA-125. If the CA-125 is normal (! 21 U/mL or ! 35 U/mL, depending on the laboratory), then the cyst can be followed by repeat ultrasound. Any blood ow seen within the mass also can be evaluated. A resistance index of less than 0.4 is associated with neovascularization and is more concerning for malignancy. Any cysts with true complex septations or solid components found in postmenopausal women require surgical exploration. Again, a CA-125, according to the previous guidelines, can help determine if the mass should be approached by a general gynecologist or if it should be referred to a gynecologic oncologist for surgical management or presumed ovarian cancer. It should be noted that 50% of early-stage ovarian cancers have a normal CA-125, so clinical risk assessment, examination ndings, and ultrasound characteristics of the ovarian mass should work in conjunction with laboratory values to dictate the presumed risk for malignancy. Referral guidelines As a general guideline, women with ovarian cancer have a better outcome and a longer survival rate if the initial surgery is performed by a gynecologic oncologist [20,21,33,34]. Appropriate surgical staging in presumed earlystage ovarian malignancies upstages the cancer in more than 30% of cases, thus changing the treatment recommendations and likelihood of survivorship [35,36]. In more advanced cases, adequate cytoreductive surgery that results in microscopic residual disease followed by appropriate chemotherapy improves survival [34,37]. This makes referral to the proper physician

Box 1. Guidelines for referral to a gynecologic oncologist Premenopausal women  Very elevated CA-125 (> 200 U/mL)  Ascites  Evidence of abdominal or distant metastasis  Family history of one or more rst-degree relatives with ovarian or breast cancer Postmenopausal women  Elevated CA-125 (> 35 U/mL)  Ascites  Nodular or xed pelvic mass  Evidence of abdominal or distant metastasis  Family history of one or more rst-degree relatives with ovarian or breast cancer

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of vital importance for best patient outcome. The American College of Obstetricians and Gynecologists has developed guidelines to aid in the referral process [20]. These guidelines vary slightly for premenopausal versus postmenopausal women, as listed in Box 1. Meeting any one of these criteria warrants referral to a gynecologic oncologist. Following these referral guidelines was shown to capture 70% of ovarian cancer in premenopausal women and 94% of ovarian cancers in postmenopausal women [38]. This same study showed that strict adherence to the referral guidelines did tend to overrefer patients who were later found to have benign masses with a positive predictive value of 33.8% in premenopausal women and 59.5% in postmenopausal women. The guidelines presented in this article relate most to women at average risk for ovarian cancer. Fig. 9 displays a basic algorithm for referral of patients based on initial ndings of an adnexal mass. All providers should recognize that women deemed at high risk for ovarian cancer because of signicant family history, personal history, or premenopausal

Adnexal Mass on Physical Exam

Ultrasound Premenopausal Postmenopausal

Cystic (Simple)

Solid (Complex)

Solid (Complex)

Cystic (Simple)

< 10cm

> 10cm

Referral

> 10cm

> 5cm < 10cm Follow-up ultrasound in 2-3 months > 35* CA 125 < 5cm

< 35*

Follow-up ultrasound in 2-3 months

Fig. 9. Algorithm for referral of patients based on initial ndings of an adnexal mass. * American College of Obstetricians and Gynecologists guidelines specify this value for referral to a gynecologic oncologist; however, this value is laboratory dependent. At our institution we use a cut-o of 21.

PELVIC MASSES

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breast cancer or known BRCA mutation carrier status with symptoms or an adnexal mass should be managed by a gynecologic oncologist.

Summary Initially, evaluation of any pelvic mass begins with a thorough history and physical examination, which should include a pelvic examination to determine the location, size, and characteristics of the mass. The rst-line imaging modality for evaluation of any pelvic mass is ultrasound, which can aid in further dening the characteristics of the mass and evaluating its potential for malignancy. Pregnancy always must be excluded in reproductive-aged women. Most masses in premenopausal women are benign and, after appropriate evaluation, can be managed conservatively. Tumor markers such as CA-125 are not generally helpful in the evaluation of a pelvic mass in premenopausal patients but can be useful in evaluating postmenopausal patients with a pelvic mass. Management can be directed based on these ndings and may vary depending on patient age. Any mass that needs surgical management should be referred to a gynecologist. If malignancy is of concern, then referral to a gynecologic oncologist should be made to enhance a patients likelihood of survival.

Acknowledgments We would like to thank Rebecca Hall, PhD, and Benjamin Brooks, MD, for helping to provide the ultrasound and CT images, respectively.

References
[1] Borgfeldt C, Andolf E. Transvaginal sonographic ovarian ndings in a random sample of women 2540 years old. Ultrasound Obstet Gynecol 1999;13(5):34550. [2] Modesitt SC, Pavlik EJ, Ueland FR, et al. Risk of malignancy in unilocular ovarian cystic tumors less than 10 centimeters in diameter. Obstet Gynecol 2003;102(3):5949. [3] Padilla LA, Radosevich DM, Milad MP. Accuracy of the pelvic examination in detecting adnexal masses. Obstet Gynecol 2000;96(4):5938. [4] Padilla L, Radosevich DM, Milad MP. Limitations of the pelvic examination for evaluation of the female pelvic organs. Int J Gynaecol Obstet 2005;88(1):848. [5] Brown D. A practical approach to the ultrasound characterization of adnexal masses. Ultrasound Q 2007;23(2):87105. [6] Adams Hillard PJ. Benign diseases of the female reproductive tract: symptoms and signs. In: Berek JS, editor. Novacs gynecology. 13th edition. Philadelphia: Lippincott Williams & Wilkins; 2002. p. 351420. [7] Herrmann UJ. Sonographic patterns of ovarian tumors. Clin Obstet Gynecol 1993;36(2): 37583. [8] Nardo LG, Kroon ND, Reginald PW. Persistent unilocular ovarian cysts in a general population of postmenopausal women: is there a place for expectant management? Obstet Gynecol 2003;102(3):58993.

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[9] Granberg S, Wikland M, Jansson I. Macroscopic characterization of ovarian tumors and the relation to the histological diagnosis: criteria to be used for ultrasound evaluation. Gynecol Oncol 1989;35(2):13944. [10] Valentin L. Gray scale sonography, subjective evaluation of the color Doppler image and measurement of blood ow velocity for distinguishing benign and malignant tumors of suspected adnexal origin. Eur J Obstet Gynecol Reprod Biol 1997;72(1):6372. [11] Valentin L. Prospective cross-validation of Doppler ultrasound examination and gray-scale ultrasound imaging for discrimination of benign and malignant pelvic masses. Ultrasound Obstet Gynecol 1999;14(4):27383. [12] Patel M. Practical approach to the adnexal mass. Radiol Clin North Am 2006;44(6):87999. [13] Asch E, Levine D. Variations in appearance of endometriomas. J Ultrasound Med 2007; 26(8):9931002. [14] Broder J, Warshauer DM. Increasing utilization of computed tomography in the adult emergency department, 20002005. Emerg Radiol 2006;13(1):2530. [15] Kalish GM, Patel MD, Gunn ML, et al. Computed tomographic and magnetic resonance features of gynecologic abnormalities in women presenting with acute or chronic abdominal pain. Ultrasound Q 2007;23(3):16775. [16] Patel MD, Dubinsky TJ. Reimaging the female pelvis with ultrasound after CT: general principles. Ultrasound Q 2007;23(3):17787. [17] Chang SD, Cooperberg PL, Wong AD, et al. Limited-sequence magnetic resonance imaging in the evaluation of the ultrasonographically indeterminate pelvic mass. Can Assoc Radiol J 2004;55(2):8795. [18] Dueholm M, Lundorf E. Transvaginal ultrasound or MRI for diagnosis of adenomyosis. Curr Opin Obstet Gynecol 2007;19(6):50512. [19] Carlson KJ, Skates SJ, Singer DE. Screening for ovarian cancer. Ann Intern Med 1994; 121(2):12432. [20] ACOG. ACOG Committee Opinion: Number 280, December 2002. The role of the generalist obstetrician-gynecologist in the early detection of ovarian cancer. Obstet Gynecol 2002; 100(6):14136. [21] Schutter EM, Davelaar EM, Van Kamp GJ, et al. The dierential diagnostic potential of a panel of tumor markers (Ca 125, CA 153, and CA 724 antigens) in patients with a pelvic mass. Am J Obstet Gynecol 2002;187(2):38592. [22] Gadducci A, Cosio S, Carpi A, et al. Serum tumor markers in the management of ovarian, endometrial and cervical cancer. Biomed Pharmacother 2004;58(1):2438. [23] Bast RC, Badgwell D, Lu Z, et al. New tumor markers: CA125 and beyond. Int J Gynecol Cancer 2005;15(Suppl 3):27481. [24] Curtin J. Management of the adnexal mass. Gynecol Oncol 1994;55(3 Pt 2):S426. [25] Grimes DA, Jones LB, Lopez LM, et al. Oral contraceptives for functional ovarian cysts. Cochrane Database Syst Rev 2006;(4):CD006134. [26] Zanetta G, Lissoni A, Torri V, et al. Role of puncture and aspiration in expectant management of simple ovarian cysts: a randomized study. BMJ 1996;313(7065):11103. [27] Higgins RV, Matkins JF, Marroum MC. Comparison of ne-needle aspiration cytologic ndings of ovarian cysts with ovarian histologic ndings. Am J Obstet Gynecol 1999; 180(3 Pt 1):5503. [28] Ayhan A, Bukulmez O, Genc C, et al. Mature cystic teratomas of the ovary: case series from one institution over 34 years. Eur J Obstet Gynecol Reprod Biol 2000;88(2):1537. [29] Guintoli RL II, Vang RS, Bristow RE. Evaluation and management of adnexal masses during pregnancy. Clin Obstet Gynecol 2006;49(3):492505. [30] Leiserowitz GS. Managing ovarian masses during pregnancy. Obstet Gynecol Surv 2006; 61(7):46370. [31] Roman LD, Muderspach LI, Stein SM, et al. Pelvic examination, tumor marker level, and gray-scale and Doppler sonography in the prediction of pelvic cancer. Obstet Gynecol 1997;89(4):493500.

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[32] Finch A, Beiner M, Lubinski J, et al. Salpingo-oophorectomy and the risk of ovarian, fallopian tube and peritoneal cancers in women with a BRCA1 or BRCA2 mutation. JAMA 2006;296(2):18592. [33] Earle CC, Schrag D, Neville BA, et al. Eect of surgeon specialty on processes of care and outcomes for ovarian cancer patients. J Natl Cancer Inst 2006;98(3):17280. [34] Bristo RE, Tomacruz RS, Armstrong DK, et al. Survival eect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol 2002;20(5):124859. [35] Young RC, Decker DG, Wharton JT, et al. Staging laparotomy in early ovarian cancer. JAMA 1983;250(22):30726. [36] Young RC. Initial therapy for early ovarian carcinoma. Cancer 1987;60(Suppl 8):20429. [37] Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006;354(1):3443. [38] Im SS, Gordon AN, Guttin BM. Validation of referral guidelines for women with pelvic masses. Obstet Gynecol 2005;105(1):3541.

Med Clin N Am 92 (2008) 11631192

Basic Infertility Including Polycystic Ovary Syndrome

Maryse Brassard, MDa, Youssef AinMelk, MDb, Jean-Patrice Baillargeon, MD, MSca,*
a

Division of Endocrinology, Department of Medicine, Universite de Sherbrooke, 3001, 12th North Avenue, Sherbrooke, QC J1H 5N4, Canada b Department of Obstetrics and Gynecology, Universite de Sherbrooke, 3001, 12th North Avenue, Sherbrooke, QC J1H 5N4, Canada

Infertility is the inability of a couple to conceive after 12 months of unprotected and frequent intercourse. It aects about 10% to 15% of couples [1]. Cycle fecundability is the probability that a single cycle will result in pregnancy and is approximately 20% in normal couples [2]. It typically decreases with age. The fertility rate in developed countries has declined in recent years and can be attributed mainly to delayed childbearing. The eect of aging on female fertility is clear: In women, the fertility peak is between the ages of 20 and 24 years, decreases slightly by age 32, and then declines progressively and more rapidly after age 40 [3,4]. Decreasing fertility is associated with increasing pregnancy wastage. Spontaneous miscarriage increases from 10% in younger women to 40% at age 40, even with assisted reproductive technology. This increase is due to progressive follicular depletion and a high incidence of abnormalities in aging oocytes, mainly aneuploidy. In addition to age, other factors that inuence fertility include lifestyle (smoking, alcohol, caeine, drugs, and body mass index) and the timing and frequency of intercourse. Normal sperm can survive at least 3 days, but an oocyte can be fertilized for only 12 to 24 hours. The major causes of infertility include tubal and peritoneal pathology (30%40%), ovulatory dysfunction (15%), and male factor (30%40%) [5]. Uterine and cervical factors are uncommon. Patients without an

This work was supported by Personal Award #12131 to Jean-Patrice Baillargeon from the Fonds de la recherche en sante du Quebec. * Corresponding author. E-mail address: jp.baillargeon@usherbrooke.ca (J-P. Baillargeon). 0025-7125/08/$ - see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2008.04.008 medical.theclinics.com

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identiable cause are classied as unexplained infertility (10%). Ovulatory dysfunction and unexplained infertility have the best prognosis. This article reviews the evaluation and treatment of female infertility.

Initial evaluation The evaluation should be initiated after 12 months of unprotected intercourse, at which time 85% of couples attempting conception will have been successful [6]. In women between 35 and 40 years of age, assessment should be considered after 6 months. In such females with oligomenorrhea or amenorrhea, or a history of pelvic infection or chemotherapy [1], assessment should be considered sooner. Initial evaluation includes a complete medical history, physical examination, and screening tests for cervical dysplasia and sexually transmitted infections, including gonorrhea and chlamydia. Basic testing consists of semen analysis, documentation of ovulation (eg, midluteal phase progesterone level above 6.5 ng/mL followed by menstrual bleeding within 2 weeks), and a hysterosalpingogram to assess possible tubal factors. If an obvious cause, such as oligoanovulation, is determined during initial clinical evaluation, semen analysis and hysterosalpingogram can be postponed until after resolution of this condition, assuming that infertility persists. The next steps in the evaluation of female infertility are based on the most probable causes initially identied. These are discussed in this article and summarized in Fig. 1.

Tubal and peritoneal pathology Tubal factors Approximately 20% of female infertility results from tubal disease. This disease can be suspected by a history of pelvic infection disease (PID), tubal or pelvic surgery, or ectopic pregnancy. Infection by Chlamydia trachomatis is one of the main causes of tubal injury, which can ultimately lead to tubal occlusion or adnexal adhesions. Subclinical salpingitis is even more common than symptomatic PID, and can occur despite appropriate antibiotic therapy. The incidence of tubal disease is 10% after one episode of PID and 54% to 75% after three episodes [7]. The mechanism involves anatomic abnormalities in the tubes that prevent the union of sperm and ovum. The classic methods for evaluation of tubal patency are hysterosalpingography (HSG) and laparoscopy with chromotubation. HSG is performed by injecting water-soluble contrast through the cervix into the uterus. HSG images the uterine cavity and reveals the internal architecture and patency of the tubal lumen. Laparoscopy is regarded as the denitive test for the evaluation of tubal factors. It provides more detailed information, such as

INFERTILITY AND THE PCOS

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Domapine agonist Lthyroxine Insulin sensitization Ovulation inductors

Prolactin Ovulatory cycles No TSH Androgens Yes

Hyper Hypo PCOS

Not pregnant Male factor Semen analysis Tubal assessment Abnormal Tubal damage Endometriosis Normal

Pregnant

Donor insemination IVF Surgery Medical or surgical treatment

Not pregnant Unexplained infertility

Pregnant

Ovulation inductorsIUI

GonadotropinsIUI

Fig. 1. Algorithm for investigation and treatment of infertile women. IUI, intrauterine insemination; IVF, in vitro fertilization; PCOS, polycystic ovary syndrome; TSH, thyroid-stimulating hormone.

pelvic anatomy, adhesions, and endometriosis. Laparoscopy also oers the opportunity to treat disease at the time of diagnosis. Chlamydia antibody testing has been shown to be as predictive as HSG, or even laparoscopy, for the detection of tubal pathology [8]. The role of chlamydia antibody tests in the evaluation of the infertile women has not yet been dened, but may prove useful as a pretest to select women who warrant earlier or more detailed evaluations [2,9]. The treatment options for tubal factors include reconstructive surgery and in vitro fertilization (IVF). In selected cases, a microsurgical procedure, such as mbriolysis and mbrioplasty, may be used. In most cases, especially in older women, IVF is more ecient and more eective [10]. Uterine factor Abnormalities of the uterine cavity are a relatively uncommon cause of infertility. Abnormalities include congenital malformations, such as a septum or bicornuate uterus, leiomyomas, intrauterine adhesions (Ashermans syndrome), and endometrial polyps. Uterine abnormalities more commonly aect pregnancy outcome than fertility. Assessment of the uterine cavity can be obtained by HSG, transvaginal ultrasound (for uterine malformations

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and myomas), sonohysterography (for submucosal myomas and endometrial polyps), hysteroscopy (the denitive method for diagnosis and treatment of intrauterine pathology), MRI, and laparoscopy. The management of uterine myoma in infertile women must be individualized. The decision for surgical treatment varies depending on age and duration of infertility after excluding other infertility factors [11]. It appears that submucous myomas can lower the rate of pregnancy and implantation [12]. In one study, myomectomy for a submucous myoma increased the pregnancy rate from 27.2% (no treatment) to 43.3% (myomectomy), though there was no improvement in the pregnancy rate following myomectomy in locations outside the uterine cavity. For intrauterine adhesions (ie, synechiae), predisposing events can usually be identied, such as pregnancy termination or postpartum curettage. The presence of adhesions can be conrmed by HSG, though hysteroscopy is considered the preferred technique for diagnosis and treatment [13]. Hysteroscopy is also appropriate for diagnosis and treatment of uterine septum. Cervical factor Cervical mucus is important in the reproductive process. Estrogen stimulates cervical mucus while progesterone inhibits its production and permeability. The traditional postcoital test, the Sims-Huhner test, has a poor predictive value for infertility and its utility has been debated. Routine postcoital testing is not recommended [6]. Because there is no good method for diagnosing infertility due to cervical factor, that diagnosis is usually a one of exclusion when ovulation and semen analyses are normal and the tubes are patent. It is usually included in unexplained infertility (see Fig. 1). Common treatments for cervical factor infertility bypass the cervix and include intrauterine insemination and IVF. Endometriosis There is a higher incidence of endometriosis in infertile women (25% 48%) as compared with all women in the reproductive age group (3%10%) [2]. Despite this association, a causal link between endometriosis and infertility has not been clearly demonstrated and management of infertility associated with endometriosis remains challenging. In severe endometriosis, pelvic adhesions can clearly distort the relationship of the tubal mbria and ovarian follicles with resulting infertility. In minimal and mild endometriosis, mechanisms that cause reproductive failure are subtler and remain controversial. They include alterations in peritoneal uid as a result of inammatory factors (macrophages, cytokines, and growth factors). Such alterations can aect ovum maturation, fertilization, or implantation. Endocrine and ovulatory abnormalities are among other mechanisms that may cause reproductive failure in minimal and mild endometriosis [14,15].

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Fecundity in women with untreated endometriosis is only 2% to 3% per cycle, far below the normal monthly rate of 20%. The medical treatment of endometriosis with a period of ovulation suppression does not improve subsequent fecundity and fertility [2]. Conservative surgical therapy, such as ablation of endometriosis implants, can improve the fecundity in patients with severe disease by up to 50%, but is still controversial in patients with mild endometriosis. A randomized trial of laparoscopic ablation treatment for minimal or mild endometriosis demonstrated a signicant increase in the rate of pregnancy [16]. Thirty-six weeks after surgery, 29% of treated women achieved an ongoing pregnancy compared with 17% of those who were not treated. However, a smaller Italian trial with similar design and laparoscopic ablation therapy showed no eect on live birth rate [17]. Other approaches to consider for treatment of endometriosis are expectant management, superovulation with intrauterine insemination for young patients (!35 years old), or IVF for older women (O35 years old). For more advanced cases, IVF preceded by 3 months of medical treatment for endometriosis is suggested.

Ovulatory dysfunction Ovulatory dysfunction is associated with infertility and is usually manifested either by oligomenorrhea, dened as eight or fewer menstrual periods per year, or amenorrhea, dened as the absence of menstrual bleeding. This lack of menstrual periods may be classied as primary or secondary. Primary amenorrhea refers to absence of menses by the age of 14 years in the absence of secondary sexual characteristics or by the age of 16 years in the presence of secondary sexual characteristics. Secondary amenorrhea applies to women who have not menstruated for at least 6 months but who have previously menstruated. Furthermore, it is estimated that about 10% of normal menstrual cycles of 35 days or less are actually anovulatory. The causes of ovulatory dysfunction are discussed below. Hypogonadotropic hypogonadism Hypogonadism is dened as an abnormal decrease in the functional capacity of the gonads and is classied as hypergonadotropic or hypogonadotropic, depending on whether the disease is of gonadal or pituitary/ hypothalamic origin. In the presence of abnormal sex hormones and gamete production, low levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are indicative of hypogonadotropic disease, whereas high levels reect a hypergonadotropic hypogonadism. Causes of hypogonadotropic hypogonadism are listed in Box 1. Patients with Kallmann syndrome have hypogonadotropic hypogonadism along with anosmia. The clinical feature of anosmia relates to the embryologic development of gonadotrophin-releasing hormone (GnRH)

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Box 1. Causes of hypogonatotropic hypogonadism Kallmann syndrome Functional hypothalamic amenorrhea, including eating disorders, intense exercise, stress from systemic disease Iatrogenic causes from drugs, pituitary surgery, cranial radiation Tumors of the central nervous system Sheehans syndrome, trauma Inltrative disorders of the pituitary Hyperprolactinemia

neurones. Kallmann syndrome is a genetically heterogeneous condition and aects 1 in 70,000 females [18]. In addition to anosmia, other possible features of Kallmann syndrome include unilateral renal agenesis, synkinesia (mirror movements), hearing loss, midline facial defects, cryptorchidism, and bone abnormalities [1921]. Recently, scientists have isolated the KAL gene as a cause of at least some forms of Kallmann syndrome [2225]. Functional hypothalamic amenorrhea is one of the most frequently encountered forms of ovulation dysfunction. This endocrine disorder is due to a deciency of pulsatile GnRH secretion unrelated to hypothalamicpituitary organic lesions nor endocrine or systemic diseases [26,27]. Based on the degree of GnRH suppression, these women can present with dierent clinical proles that vary from an inadequate luteal phase, to anovulation with menstrual irregularity, to hypothalamic amenorrhea [27]. The incidence of functional hypothalamic amenorrhea ranges from 15% to 48% [28,29] of women with secondary amenorrhea. In clinical practice, functional hypothalamic amenorrhea is often associated with stressors (metabolic, physical, or psychologic), with weight loss due to decreased caloric intake, or with intensive physical exercise [26]. Statistics show that the prevalence of reproductive dysfunction is 6% to 79% in athletic women [30]. Suppression of gonadotrophin release may occur when there is acute [31,32] or chronic [33,34] systemic disease, which can acutely suppress the hypothalamic-pituitary-gonadal (HPG) axis. Chronic systemic illnesses most associated with hypothalamic-pituitary dysfunction include chronic renal failure and AIDS. Acute illnesses, in turn, may lead to transient forms of either hypogonadotropic or hypogonadotropic hypogonadism [35,36]. In fact, suppression of the GnRH pulse generator in response to the physiologic stress of any severe illness inhibits the release of pituitary gonadotropins [31,32] in the same way that excessive exercise does. A few drugs are incriminated in the pathogenesis of hypogonadotrophic hypogonadism. Opioid use is the most common cause of iatrogenic hypogonadism, and it may have a toxic eect on the reproductive axis. The mechanism of amenorrhea in opioid users is probably attributable to

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opioid-induced hypothalamic GnRH suppression [37]. Other drugs causing infertility are certain psychotropic drugs, such as phenothiazines and risperidone, which block prolactin-inhibiting dopamine release [38,39]. Also, anabolic androgenic steroids can cause hyperandrogenism and menstrual irregularity. Most central causes of hypogonadism that are organic in nature can be attributed to pituitary and hypothalamic lesions. Other causes of structural etiology include inltrative diseases, such as sarcoidosis, histiocytosis, and hemochromatosis; head trauma; pituitary apoplexy; and cranial irradiation or surgery. Tumors of the central nervous system, such as craniopharyngiomas, germinomas, and other extrasellar germ cell tumors, may interfere with FSH secretion and lead to ovulatory function failure. Patients who have low levels of other hormones, symptoms of a pituitary tumor (such as frontal headache or reduced visual elds), or increased prolactin levels not due to medication, warrant pituitary MRI. Pituitary imaging is also required when drug-related hyperprolactinemia is associated with one of these factors. The impact of elevated prolactin on the gonads is hypothesized to result from disruption of normal GnRH pulsatility and consequent alterations in the secretion of FSH and LH [40]. The clinical expression is anovulation, with either amenorrhea or oligomenorrhea in most women, as well as galactorrhea and decreased libido. Hyperprolactinemia can be divided into pituitary and nonpituitary causes. Pituitary causes include prolactinsecreting adenomas, nonsecreting pituitary tumors or cysts, and idiopathic hyperprolactinemia. Any disruption of the pituitary stalk, usually by macroadenomas, can lead to failure of the normal hypothalamic suppression of prolactin by dopamine. Nonpituitary causes of hyperprolactinemia are common and include pregnancy, hypothyroidism, and dopamine-antagonist drug therapy (eg, phenothiazines and metoclopramide). Some women with polycystic ovary syndrome (PCOS) have mild hyperprolactinemia [41]. Treating prolactinomas or idiopathic hyperprolactinemia with dopamine agonists reduces tumor size and prolactin levels, normalizes abnormal sexual function, and improves fertility. Hypergonadotropic hypogonadism Premature ovarian failure (POF) is diagnosed when sex steroid deciency, elevated gonadotropins, and amenorrhea are found in women under the age of 40 [4244]. Spontaneous 46,XX POF is not a rare condition. The age-specic incidence is approximately 1 in 250 women by age 35 and 1 in 100 by age 40 [43]. In around 10% of patients, the disorder is familial [45]. POF most commonly presents as secondary amenorrhea, though it may present rarely as primary amenorrhea with variable degree of secondary sexual characteristics. As estrogen deciency progresses, vasomotor symptoms and symptoms of atrophic vaginitis eventually become prominent. Women suering from POF are at increased risk of developing a variety

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of comorbidities [46,47] and nearly double their age-specic mortality risk [48]. They are decient in sex steroids and therefore have a signicantly increased risk of osteoporosis [49,50], particularly in those who have developed POF before achieving peak adult bone mass. The risk of cardiovascular disease in POF suerers is also signicantly increased [51,52], which is probably caused by lower high-density lipoprotein cholesterol and higher insulin resistance than those of age-matched premenopausal women [53]. The most troublesome aspect of the disorder for these young women is infertility [54]. Previously, they were considered as irreversibly sterile. However, accumulating evidence has demonstrated that the infertility associated with POF is not absolute. Up to 50% of young women with 46,XX spontaneous POF have remaining follicles in their ovaries [55,56] and are probably more aected by follicular dysfunction than follicular depletion. Studies in women with POF have demonstrated that up to 20% of patients ovulate spontaneously during 4 months of observation, nearly 50% have intermittent ovarian follicle function (as dened by serum estradiol O50 pg/mL) [56], and 5% to 10% unexpectedly became pregnant some time after diagnosis [57,58]. But ovulations are unpredictable, making appropriate timing of intercourse or insemination impossible. There is no evidence that such treatments enhance the pregnancy rate in patients with POF [57]. There are a variety of causes of POF: chromosomal and genetic abnormalities, autoimmune disease, viral infections, and iatrogenic therapies, such as pelvic surgery, chemotherapy, and radiotherapy. In the majority of cases, however, no etiologic factor can be identied [59]. In fetuses with 45,XO karyotype (Turners syndrome), ovaries develop normally in utero. Due to the absence of the second X chromosome, accelerated follicle atresia occurs from week 18 of pregnancy onwards or over the rst few postnatal months and years, leading to POF [60,61]. Mosaicism, typically 45,XO/46,XX or 46,XX/47,XXX, is more common and characterized by a milder clinical phenotype [62]. Other genetic mutations have also been associated with POF [63,64]. However, in the past 3 decades, much evidence has accumulated to suggest that autoimmune mechanisms are involved in pathogenesis of up to 30% of cases of POF [65,66]. Autoimmune lymphocytic oophoritis is a clearly established mechanism of 46,XX spontaneous POF, which can present in an isolated manner or as part of the autoimmune polyendocrinopathy syndrome, type 1 [67]. Women less than 40 years old with 4 or more months of amenorrhea should have an FSH measured with a repeat in 1 month if it is elevated. If two levels are in the menopausal range (O40 IU/L by radioimmunoassay), POF is diagnosed. These women should have a karyotype [44] and thyroid function studies [68] performed. Hypothyroidism, as well as adrenal insuciency, is associated in 3% of cases [69]. Other invasive procedures do not change management or prognosis.

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Providing hormone replacement to induce regular menses is probably indicated in these women to normalize symptoms and decrease the risk of osteoporosis associated with estrogen deciency, to reduce the risk of adenocarcinoma with an eective progestin replacement, and possibly to improve chances of spontaneous pregnancy [70]. However, the eectiveness of this strategy to improve fertility has not been conrmed [71]. Ovulatory dysfunction without hypogonadism Polycystic ovary syndrome Introduction. Dened by Stein and Leventhal [72] in 1935, PCOS is now thought to be the most prevalent endocrine disorder in young women, aecting 6% to 10% [7377] of women of childbearing age and accounting for 70% of anovulatory subfertility [78]. In a British population study, 37% of amenorrheic and 90% of oligomenorrheic women treated for infertility had PCOS [79]. Also, PCOS is one of the major causes of infertility overall, aecting up to 20% of infertile couples in some studies [80,81]. Its diagnosis is important not only for the short-term fertility issue, but also for long-term considerations, such as metabolic or insulin resistance syndrome and its associated consequences. Diagnosis and clinical presentation. Based on criteria established during the European Society of Human Reproduction & Embryology/American Society for Reproductive Medicine (ESHRE/ASRM) consensus conference in Rotterdam in 2003 [82], PCOS is diagnosed in the presence of two factors among the following: menstrual irregularity, hyperandrogenism (clinical or biochemical), and polycystic ovaries after excluding other secondary causes of hyperandrogenism, such as congenital adrenal hyperplasia (CAH), Cushings syndrome, hyperprolactinemia, or an androgen-secreting tumor. This denition has been revised in a published Androgen Excess Society guideline, which recommends that hyperandrogenism be mandatory for the diagnosis of PCOS [83]. Menstrual irregularity typically manifests at the time of menarche in women with PCOS, and menarche may be delayed. Some may have normal menses at rst and then develop menstrual irregularity later in life, often after weight gain. Aected women are typically anovulatory with resulting oligomenorrhea or amenorrhea. Heavy bleeding in this situation is typical of anovulatory menses. Infertility in PCOS is mostly related to this chronic absence or low rate of ovulation, but also to an increased rate of early pregnancy loss. Hyperandrogenism is usually a presenting feature of the syndrome, manifested clinically by hirsutism (excess pigmented body hair with a male distribution), acne, and male-pattern alopecia. Evidence of virilization, such as clitoromegaly, increased muscle mass, and deepening of the voice should raise concern for androgen-secreting neoplasm of the ovary or

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adrenal gland, but can also be the result of hyperthecosis, a rare and extreme form of PCOS. Circulating androgens, especially testosterone and androstenedione, are found to be elevated in 50% to 90% of patients, depending upon the androgen measured and technique employed [84]. The ultrasound criteria for polycystic ovaries [82] are based on the presence of 12 or more 2- to 9-mm follicles in each ovary, or ovarian volume greater than 10 mL. A recent prospective systematic study screened 400 unselected reproductive-aged women in the United States to determine the prevalence of PCOS and performed a phenotyping of the women involved [77]. The proportion of overweight and obese women with PCOS seems to be the same as in the general population. Though the proportion of women with the syndrome is similar in normal and obese patients, obese women often have more severe hormonal and metabolic abnormalities [85]. Indeed, obesity increases the degree of insulin resistance typically found in PCOS women, which plays a key role in PCOS pathophysiology, as discussed below. Pathogenesis. The pathogenesis of PCOS has been controversial. Most experts agree that hyperandrogenemia is the central feature of PCOS [83]. Studies found that greater than 60% of the circulating levels of androgens were of ovarian origin, and about 40% were of adrenal source [86]. Furthermore, increased adrenal and ovarian androgen responses to stimulation by LH [87,88] or corticotropin [89,90], respectively, were found in vivo in women with PCOS. Insulin resistance is also a common characteristic of PCOS, both in obese and nonobese aected women [91]. Insulin resistance primarily refers to impaired action of insulin on glucose metabolism, in the presence of normal insulin binding [92]. In turn, the resulting compensatory hyperinsulinemia [9199], or increased insulin action, leads to exaggerated eects of insulin on other actions, including stimulation of androgen secretion by ovarian and adrenal cells [88,100104]. Insulin can also directly inhibit sex-hormonebinding globulin (SHBG) production [105], increasing the active testosterone fraction. The ovarian and adrenal androgenic hyperresponsiveness to LH and corticotropin that characterizes PCOS women may result from increased chronic insulin stimulation. Indeed, this androgenic hyperresponsiveness has been shown to persist after prolonged LH or corticotropin suppression [88,106,107], but to improve after insulin sensitization (with weight loss, metformin, or peroxisome proliferator-activated receptor g agonists) [108112]. Moreover, our group found that PCOS women, who were nonobese, normoinsulinemic, and normally insulin-sensitive, normalized their hyperandrogenemia with a pure insulin-lowering agent (diazoxide) [113]. These results demonstrated that even normal insulin levels contribute to PCOS hyperandrogenemia. Altogether, these ndings suggest that women may develop PCOS because of increased sensitivity of their androgenic pathway to insulin,

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and not just hyperinsulinemia. This increased sensitivity might be improved with insulin sensitization or reduction [114]. It is probable that only a minority of women with PCOS have a defect severe enough to cause a typical syndrome without insulin resistance. Most women with PCOS must develop insulin resistance with compensatory hyperinsulinemia to further aggravate insulin stimulation of androgen production and express the syndrome. Thus, classical insulin resistance and compensatory hyperinsulinemia are not necessary to develop PCOS, but they favor the clinical expression of PCOS and may result from the same factors as for the general population, which are obesity and a genetic predisposition to insulin resistance. As shown in Fig. 2, the combination of elevated levels of androgens and obesity is thought to lead to increased formation of extraglandular estrogen, termed estrone. This hormone exerts a positive feedback on LH secretion and negative feedback on FSH secretion. Studies have provided conicting results on the ability of insulin to increase the pulsatory rate of GnRH [115121]. It is possible that PCOS women have a higher sensitivity to insulin-stimulated LH production, but that this defect is attenuated in obese women because of other factors, such as leptin resistance, other adipokynes, and higher testosterone levels. In some studies, circulating concentrations of FSH are within the normal range in women with PCOS [122124], but the normal intercycle rise in serum FSH levels is lacking. The increased level

Hypothalamus-Pituitary LH secretion FSH secretion Plasma FSH level Adipose tissue Extraglandular aromatisation Chronic anovulation Follicle maturation

Acyclicestrogen (estrone)

Plasma LH level

Stimulation of stroma Ovary and theca

Obesity Androgen excess

Cyclicestrogen (estradiol)

Adrenal androgen

Fig. 2. Proposed mechanism for the initiation and perpetuation of chronic anovulation in the PCOS. (Adapted from Mishell Jr DR, Davajan V, editors. Reproductive endocrinology, infertility, and contraception. 2nd edition. Philadelphia: Davis; 1986; with permission of Blackwell Publishing; and from Yen SCC, Jae RB, Barbieri RL, et al, editors. Reproductive endocrinology. 4th edition. Philadelphia: Saunders; 1999; with permission of Elsevier Health.)

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of LH can lead to hyperplasia of the ovarian stroma and theca cells and increased ovarian androgen production, which in turn provides more substrate for peripheral aromatization and perpetuates the chronic anovulation. Deregulation of local follicle regulatory systems by androgens and other factors impedes normal follicular growth, resulting in follicular arrest at the 4- to 8-mm diameter size [125]. A dominant follicle (ie, 1825 mm in diameter) does not develop, and therefore ovulation does not occur. Complications. In addition to infertility, patients with PCOS are at risk for many other complications. The overall risk of type 2 diabetes mellitus (T2D) is increased in PCOS, particularly in women with a rst-degree relative with T2D [126129]. In a study of 122 obese women with PCOS, 45% had either impaired glucose tolerance (35%) or T2D (10%) [130]. All obese women with PCOS should have frequent assessment of glucose tolerance. This association is less clear in lean women. Fasting plasma glucose for detecting abnormal glucose tolerance was shown to be insensitive in women with PCOS as compared with oral glucose tolerance test (OGTT) [131]. Thus, we recommend performing an OGTT to screen this population. This recommendation was recently stated in an Androgen Excess Society position article, which also recommends repeating OGTTs every 2 years [132]. A recent meta-analysis comparing the risk of pregnancy and neonatal complications in women with PCOS to controls found that those with PCOS demonstrated a signicantly higher risk of developing gestational diabetes (odds ratio [OR] 2.94), pregnancy-induced hypertension (OR 3.67), preeclampsia (OR 3.47) and preterm birth (OR 1.75). Their babies have signicantly higher perinatal mortality (OR 3.07), unrelated to multiple births [133]. Most of these complications have been strongly associated with obesity in the general population, as recently demonstrated in large register study [134]. The importance of weight loss before conception should therefore be strongly emphasized, not only to increase pregnancy rates but also to prevent deleterious eects on the pregnancy outcome. Clinical management of PCOS Lifestyle modications. Women with obesity and PCOS demonstrate improved ovulation and menses with weight reduction, which may be considered as primary therapy for infertility before the use of ovulation-inducing agents [135]. In many overweight and obese women with PCOS, weight loss alone is often associated with a reduction in serum-free testosterone concentrations, resumption of ovulation, and pregnancy [136139]. This is likely related to improvement of the hyperinsulinemic state, concomitant with an increase in SHBG levels, as shown in most of the studies that reported these parameters [140143]. Lifestyle modication, including a weight-reducing diet and exercise, is recommended as rst-line therapy for all obese women with PCOS. A small weight loss of 5% to 10% of total body weight was shown to be eective for

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inducing ovulation in many women [139]. Pharmacologic therapy should ideally be considered only if lifestyle modications fail to resolve spontaneous ovulatory cycles after 3 to 6 months [144]. Ovulation-induction agents. Clomiphene citrate (CC) was the rst ovulation inductor and is still the most common one used for ovulation induction. It is a nonsteroidal selective estrogen receptor modulator that releases estrogen inhibition on FSH production at the pituitary level. By increasing FSH levels, it favors follicle recruitment, induction of FSH receptors at the cell surface of granulosa cells, and eventually selection of one or multiple dominant follicles. This drug is taken for 5 days starting on the third or fth day of the menstrual cycle, following either a spontaneous or induced bleeding with progesterone withdrawal. CC is initially begun at a dose of 50 mg daily for 5 days and, if ovulation does not occur in the rst cycle of treatment, the dose is increased to 100 mg and, subsequently, to a maximum of 150 mg. The couple should be advised to have intercourse at least every other day for 1 week beginning the last day of medication. The response to treatment should be monitored. Conversion of a uniphasic to a biphasic basal temperature curve suggests ovulation has occurred, but this should not be used by the couple as an indicator for beginning to have frequent intercourse as the temperature rise occurs up to 4 days after ovulation. The occurrence of ovulation can also be accurately conrmed by a midluteal serum concentration greater than 6.5 ng/mL (ideally greater than 10 ng/mL). Adding transvaginal ultrasonographic monitoring and urinary LH testing is costly and does not appear to improve pregnancy rates signicantly [145]. Transvaginal ultrasound monitoring may be done in the very rst CC cycle to exclude hyperresponse [146]. CC is indicated as rst-line therapy for women with PCOS desiring pregnancy. Based on a meta-analysis in PCOS women, CC doubles the odds of clinical pregnancy as compared with no treatment or placebo [147,148]. Indeed, a cumulative pregnancy rate of up to 73% can be achieved in women with PCOS when CC is repeated for up to nine ovulatory cycles [149]. Side eects are infrequent, dose-dependent, and rarely interfere with therapy. They include hot ashes, blurred vision, exaggerated symptoms of ovulation, and inhibition of estrogen-mediated endometrial growth. The most signicant risk with CC is multiple pregnancy, which occurs in up to 6% of pregnancies [147]. CC has been the preferred fertility treatment in PCOS women for decades because of its low cost, few side eects, and simplicity of administration. The aromatase inhibitor letrozole is another ovulation-inductor drug that is gaining popularity because its side eects appear to be less severe than those of CC. For example, with letrozole, patients experience less of a decrease in cervical mucus, less thinning of the endometrial lining, and less emotional irritability. At the doses usually used for ovulation induction, side eects can include hot ashes, nausea, and vomiting. Insulin-sensitizing agents. Insulin sensitizers, namely metformin and thiazolidinediones, are benecial in controlling both short- and long-term

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issues in PCOS. However, thiazolidinediones are contraindicated during pregnancy because they were found to decrease progesterone levels and impair fetal growth in animal studies. Metformin is a biguanide whose primary mechanism of action is the reduction of hepatic gluconeogenesis, which pathologically increases in insulin-resistant states and thereby produces fasting hyperinsulinemia. Recent studies in women with PCOS have suggested that this may be a safe and eective means of improving the metabolic prole and reproductive function in both lean and obese women with PCOS. The favorable eect of metformin on hyperandrogenemia and ovulation in PCOS may stem from metformin-induced reduction of insulin levels, which reduces ovarian and adrenal secretions of androgens, reduces pituitary secretion of LH, and increases SHBG levels [114]. Accumulating evidence has shown that the rationale for metformin use in PCOS makes sense, and it has been shown to improve ovulation rates in women with PCOS [150,151]. A randomized trial comparing the eectiveness of metformin to CC administration as rst-line treatment in nonobese anovulatory women with PCOS found ovulation rates were not dierent between the groups, whereas the pregnancy rate was signicantly higher in the metformin group (15.1% versus 7.2%) [152]. Ovulation and pregnancy rates with the use of metformin increased steadily during the 6 months of the study with a number needed to treat of three for inducing a pregnancy. In contrast, CC showed higher ecacy initially, but this declined over time [113]. More recently, the same investigators did another head-to-head randomized controlled trial of CC versus metformin as rst-line treatment in infertile anovulatory patients with PCOS. They reported treatment with CC or metformin for 6 months resulted in cumulative pregnancy rates of 49% with CC and 63% with metformin, a dierence that was not signicant [153]. Furthermore, use of metformin during early pregnancy has been shown to reduce rst-trimester pregnancy loss [154,155], which can be as high as 30% to 50% in women with PCOS [156,157]. Finally, metformin induces normal ovulation, such that the risk of multiple gestation is no more than in the general population [147]. Despite such promising initial results, further studies are needed to conrm whether metformin has any benet over CC as an initial treatment in PCOS. The recent Pregnancy in Polycystic Ovarian Syndrome (PPCOS) study [147] brought additional controversy to the subject. In this study, 626 infertile women with PCOS received CC plus placebo, extended-release metformin plus placebo, or a combination of extended-release metformin and CC for up to 6 months. The results suggested that the live birth rate achieved with CC was higher for women who received CC alone (22.5%) or in combination with metformin (26.8%) than for women who received metformin alone (7.2%). Unfortunately, the PPCOS study used an extended-release formulation that demonstrated none of the expected metabolic benets of this insulin sensitizer, especially the absolute change

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in plasmatic insulin concentration and homeostasis model assessment of insulin resistance, both from baseline and compared with CC. The change in body mass index was statistically signicant but minor (0.6 [ 2.2]; 95% CI, 0.90.2 [P!.001]). In the absence of the expected metabolic improvements with metformin, it is not surprising that fertility parameters did not improve. The cumulative rate of ovulation after 6 months in the metformin group was only 29%, as compared with 63% and 55% in the two studies from Palomba and colleagues [152,153] and 58% after 3 to 6 months in a meta-analysis of four randomized controlled trials [150]. Thus, the PPCOS study should probably not be considered the denitive study for the choice of the best pharmacologic rst-line therapy in PCOS anovulatory women. In summary, the rst-line agent for the treatment of PCOS should be chosen by the physician after considering the discussed available data and consulting with the patient. There is no rm recommendation as to which agent should be used for initial therapy. We generally prefer metformin as a rst treatment, as it intervenes at the source of the disease and treats the metabolic abnormalities in PCOS. Even more importantly, metformin acts more slowly and tends to reduce appetite, which allow for lifestyle changes and weight loss before pregnancy. Other endocrine or metabolic disorders Congenital adrenal hyperplasia. CAH is an inherited recessive disorder of adrenal steroidogenesis, usually resulting from deciency of one of the ve enzymes required for synthesis of cortisol in the adrenal cortex. The clinical manifestations reect the severity of the enzymatic defects. The most prevalent disorders are caused by 21-hydroxylase deciency (w90% of cases [158161]), followed by 11b-hydroxylase deciency and 3b-hydroxysteroid dehydrogenase deciency accounting for most of the remaining cases. The adrenal precursors produced proximal to the enzymatic defect accumulate and are converted into androgens, resulting in symptomatic hyperandrogenism. Nonclassical or late-onset 21-hydroxylase deciency is one of the most common autosomal-recessive diseases and is more frequent than cystic brosis. It ranges in prevalence from 1% to 10%, depending on the ethnicity of the patient [162]. Nonclassical forms of CAH have clinical features similar to those of patients diagnosed with PCOS (ie, menstrual irregularity, hyperandrogenism, infertility, and polycystic ovaries). Consequent anovulation, in association with sexual dysfunction [163], is responsible for impaired fertility in these women. Another explanation for their subfertility is high glucocorticoid levels in treated women [164,165]. Finally, CAH women often develop insulin resistance, due to high levels of androgens or exogenous glucocorticoids, with superimposed PCOS. Patients with mild forms of 21-hydroxylase deciency might ovulate with adequate cortisol replacement and conceive spontaneously. Nevertheless, in more severe forms of CAH, fertility and childbirth rates are compromised despite treatment [163,165167].

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In nonclassical CAH women, follicular early-morning measurement of serum 17-hydroxyprogesterone concentration is the most likely to show an elevation. Levels greater than 800 ng/dL (24 nmol/L) are diagnostic of 21-hydroxylase deciency, whereas patients with levels greater than 400 ng/dL (12 nmol/L) and less than 800 ng/dL should be addressed with a provocative test with corticotropin (250 mg intravenously) [65]. A lower cuto 17- hydroxyprogesterone level of 200 ng/dL (6 nmol/L) for CAH screening may be more appropriate if early-morning samples cannot be obtained. The diagnosis of 21-hydroxylase deciency is then made if 17-hydroxyprogesterone levels are greater than 1000 ng/dL (30 nmol/L) 1 hour after administration of corticotropin. The other enzymatic defects that result in nonclassical CAH can be similarly tested with measurements of corticosteroid products proximal to the blockade following provocative testing [168]. The fundamental aim of endocrine therapy for CAH is to provide replacement of the decient hormones, especially in the severe classical forms. Dexamethasone is the corticosteroid of choice for all forms of CAH [169]. CC and other assisted reproduction techniques may be added if glucocorticoid therapy alone is ineective in restoring fertility [170]. Virilizing tumors. Both benign and malignant adrenal tumors can produce androgens, including testosterone, many steroid intermediates, and, rarely, cortisol. Approximately 50% to 60% of adrenal cancers are functional. The most frequent presentation is Cushings syndrome with or without virilization. Androgen-secreting adrenal tumors are more frequently malignant than benign. Nearly all patients have very high serum dehydroepiandrosterone sulphate concentrations and the values do not fall in response to highdose dexamethasone. Ninety-ve percent of adrenal carcinomas are larger than 5 cm in diameter. Androgen-producing carcinomas lead to virilization in women: male-pattern baldness, deepening voice, breast atrophy, clitoral hypertrophy, increased libido, oligomenorrhea or amenorrhea, total testosterone concentrations over 200 ng/dL, and characteristic ultrasound or CT ndings. Ovarian virilizing tumors typically secrete predominantly androstenedione and are thus characterized by a disproportionate elevation of plasma androstenedione relative to testosterone, resulting in anovulation. When a virilizing tumor is suspected, conrmatory imaging is required and the treatment is surgical resection. Adrenal failure and Cushings syndrome. Both adrenal failure and Cushings syndrome may cause infertility. If adrenal insuciency is suspected, the 250-mg corticotropin stimulation test should be performed as a screening measure. The maximal plasma cortisol level following acute corticotropin stimulation should be 20 mg/dL or above [171]. Hormonal supplementation with hydrocortisone generally permits restoration of fertility. Puerperal mortality/morbidity in women with adrenal failure can be prevented by

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both mineralo- and glucocorticoid replacement with higher doses during stressful periods, such as labor, delivery, and surgery. In Cushings syndrome, the excess cortisol and androgen levels suppress gonadotropin secretion, impair LH response to GnRH [172,173], and, in some cases of Cushings disease due to pituitary tumor, also result in hyperprolactinemia, which suppresses ovulatory LH surge [174176]. The insulin resistance due to cortisol excess may also cause a typical PCOS. Cushings syndrome can be diagnosed, when the clinical suspicion is high, with the administration of 1 mg of dexamethasone at 11 PM and measurement of serum cortisol at 8 AM the next morning [177], which should be less than 2 ug/dL in normal subjects [178]. Twenty-fourhour urinary cortisol excretion also provides a direct and reliable practical measure of cortisol secretion [179,180]. Concern should be raised if the result is a twofold increase compared with normal laboratory values. Cause-specic treatment has a high likelihood of improving fertility, as well as improving maternal and perinatal outcomes in case of Cushings syndrome diagnosed during pregnancy. Other endocrine disorders. Overt hypo- or hyperthyroidism may result in oligomenorrhea, amenorrhea, and anovulatory infertility, whereas subclinical hypothyroidism may result in menorrhagia and luteal phase defect. Subclinical hypothyroidism is dened as thyroxine and tri-iodothyronine levels in the normal range with thyroid-stimulating hormone (TSH) above the upper limit of the reference value, typically greater than 3.5 IU/L. Surprisingly, subclinical or mild hyperthyroidism is rarely associated with infertility [181], but more severe hypothyroidism can cause infertility. According to routine screening studies in infertile populations, 2.3% to 5.1% have abnormal thyroid function tests in this more severe range [182,183]. Thyroid hormones have direct eects on granulosa cells, luteal cells, and oocytes, indicating a direct interference with normal ovarian function [184]. Several studies conrmed that subclinical hypothyroidism or euthyroidism in patients with thyroid antibodies may also adversely aect the mother or fetus [185,186], and substitutive treatment with levothyroxine has been shown to lower the chance of miscarriage and premature delivery in these particular women [187]. Women with subclinical hypothyroidism should then be treated before pregnancy, aiming for a TSH of 2.5 IU/L or less to optimize fertility and ensure normal thyroid hormone levels for the fetus. Diabetic women have a higher incidence of secondary hypogonadotropic amenorrhea, more so if body mass index is low and glycosylated hemoglobin (HbA1c) is higher than normal [188]. In women with diabetes mellitus desiring pregnancy, prepregnancy counseling is essential and adequate glycemic control before conception is critical to diminish the risk of spontaneous abortion [189,190], fetal abnormalities, macrosomia, and other pregnancy complications [191,192]. Thus, diabetic women should aim for an HbA1c below 6%, or below 7% if the risk of hypoglycemic episodes is

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too high, before getting pregnant. The possibility of associated PCOS should also be questioned in this population. General diagnostic approach of anovulatory disorders Anovulatory infertility should be suspected in all women who have oligomenorrhea or amenorrhea and have not been able to conceive despite unprotected and timely intercourse. The use of a questionnaire is a key element of the evaluation (Box 2), in addition to a thorough physical examination, including calculation of the patients body mass index and assessment for signs of potential causes of infertility. Patients should be evaluated for abnormalities of the thyroid gland, galactorrhea, and signs of androgen excess (hirsutism, acne, male-pattern baldness). All women should typically have FSH, LH, prolactin, TSH, and fasting glucose levels checked. Women with signs of androgen excess or menstrual irregularity should be tested with levels of total and calculated free testosterone, as well as 17-hydroxyprogesterone or dehydroepiandrosterone sulphate levels to rule out CAH or androgen-secreting tumors (Fig. 3). Screening tests for Cushings syndrome (24-hour urinary cortisol excretion or 1-mg dexamethasone suppression test) should be reserved for cases with high clinical suspicion. Glycemic control should be assessed in diabetic women with HbA1c.

Box 2. History taking in infertile women Fertility history: duration of infertility, prior pregnancies (including miscarriage), previous infertility testing and/or treatment, frequency of intercourse Gynecologic history: pelvic inammatory disease, broids, endometriosis, cervical dysplasia; surgery of the cervix, ovary, uterus, fallopian tube or abdomen; prior contraceptive use (including intrauterine device); uterine abnormalities Menstrual history: age at menarche, cycle length, regularity and bleeding heaviness; presence of symptoms suggestive of menopause or hyperandrogenism (see text) Change in body weight, galactorrhea, Cushings symptoms, symptoms of dysthyroidism Family diseases: birth defects, reproductive failure, hyperandrogenism Other medical and surgical history: radiation or chemotherapeutic agents Regular medications, drug use (including tobacco, alcohol, other recreational drug use), occupational exposures, exercise, and dietary habits

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Fig. 3. Algorithm for initial evaluation of hyperandrogenic disorders. 17(OH)Pg, 17ahydroxyprogesterone; ACTH, corticotropin; DHEAS, dehydroepiandrosterone sulphate; Stim., stimulation; T testo., total testosterone.

Unexplained infertility Unexplained infertility is dened as the failure to conceive for a couple in whom no denitive cause for infertility can be found. In such cases, basic tests for ovulation, fallopian tube patency, and semen analysis are normal. It is a state of relative inability to conceive. In such cases, the need to include a diagnostic laparoscopy in the basic tests is controversial [2,193]. The incidence of unexplained infertility varies with the population studied and the criteria used. It ranges from 10% to 30% in all infertile couples. The cycle fecundity in unexplained infertility is about 2% to 4%, which is far below the normal rate of 20%. With increasing age of the female partner and increasing duration of infertility (O3 years), conception is even less likely. The proposed treatments of unexplained infertility are empiric. The goal of treatment is to increase monthly fecundity and hasten pregnancy by increasing the gamete density (superovulation). Recommended treatments have included controlled ovarian hyperstimulation with CC (even in ovulatory female) for 3 to 6 months, alone or with intrauterine insemination, or by gonadotropins with or without intrauterine insemination. The cycle fecundability varies from 8.3% with CC plus intrauterine insemination to 17.1% with gonadotropins plus intrauterine insemination [193,194]. IVF can be the last resort of treatment, but caution about the increased risk of multiple births and ovarian hyperstimulation syndrome should be applied with these treatments.

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Assisted reproductive technology Assisted reproductive technology procedures can be divided into several categories, namely IVF, intracytoplasmic sperm injection, gamete intrafallopian transfer, cryopreserved embryo transfer, and donor oocyte or embryo. The indications for IVF are tubal factor infertility, endometriosis, male factor infertility (IVF or intracytoplasmic sperm injection), unexplained infertility, ovarian failure, and diminished ovarian reserve [147]. The main problem with the accessibility of IVF is the high cost with less than 10% of infertile couples undergoing such treatment [195]. The risk of multiple gestation is increased in assisted reproductive technology cycles. In 2006 in the United States, 33% of multiple gestations in women under 35 were a result of IVF. Of these multiple gestations, approximately one third were twins. During the use of assisted reproductive techniques, the risk for spontaneous abortion is about 17% and for ectopic pregnancy 2% [195]. It is recommended that no more than two embryos be transferred in women under 35 and more than two only in older women. In Europe, many in the eld have suggested that multiembryo transfers be discouraged for all women, no matter the age. The success rate of assisted reproductive technology varies with age. In 2003 in the United States, the percentage of cycles resulting in live births were 37% for women younger than 35 years, 30% for women age 35 to 37 years, 20% for women age 38 to 40 years, and 11% for women age 40 to 41 years [195]. In Canada in 2003, the clinical pregnancy rates per cycle started were 31% in IVFintracytoplasmic sperm injection cycles [196]. It was estimated that the number of IVFintracytoplasmic sperm injection cycles cycles per million population per annum is 269 in the United States, 270 in Canada, 784 in France, and 1791 in Denmark [196]. Summary Infertility is a common disorder that has major consequences on womens well-being. Aected women eagerly seek answers and eective therapy. The most common cause of medically treatable infertility is the polycystic ovary syndrome. This syndrome is common in young women and is the cause of anovulatory infertility in 70% of cases. It is therefore an important condition to screen and manage in primary care medical settings. In the past 10 years, insulin sensitization with weight loss or metformin has been shown to be a safe and eective treatment for PCOS infertility that eliminates the risk of multiple pregnancy and may reduce the risk of early pregnancy loss as compared with ovulation-inductor drugs. The authors believe metformin should be considered as rst line therapy because it has the advantage to allow for normal single ovulation, for reduced early pregnancy loss, and, most importantly, lifestyle modications and weight loss before pregnancy. Losing weight not only improves fertility but also reduces adverse pregnancy outcomes associated with obesity.

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[128] Colilla S, Cox N, Ehrmann D. Heritability of insulin secretion and insulin action in women with polycystic ovary syndrome and their rst degree relatives. J Clin Endocrinol Metab 2001;86(5):202731. [129] Ehrmann D, Kasza K, Azziz R. Eects of race and family history of type 2 diabetes on metabolic status of women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005;90(1):6671. [130] Ehrmann DA, Barnes RB, Roseneld RL, et al. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care 1999;22(1):1416. [131] Gagnon C, Baillargeon J. Suitability of recommended limits for fasting glucose tests in women with polycystic ovary syndrome. CMAJ 2007;176(7):9338. [132] Salley K. Position statement: glucose intolerance in polycystic ovary syndrome a position statement of the Androgen Excess Society. J Clin Endocrinol Metab 2007;92(12): 454656. [133] Boomsma CM, Eijkemans MJ, Hughes EG, et al. A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome. Hum Reprod Update 2006;12(6):67383. [134] Chu SY, Bachman DJ, Callaghan WM, et al. Association between obesity during pregnancy and increased use of health care. N Engl J Med 2008;358:144453. [135] Balen A, Dresner M, Scott A. Should obese women with polycystic ovary syndrome receive treatment for infertility? BMJ 2006;332:4345. [136] Pasquali R, Antenucci D, Casimirri F, et al. Clinical and hormonal characteristics of obese amenorrheic hyperandrogenic women before and after weight loss. J Clin Endocrinol Metab 1989;68(1):1739. [137] Bates G, Whitworth N. Eect of body weight reduction on plasma androgens in obese, infertile women. Fertil Steril 1982;38(4):4069. [138] Guzick D, Wing R, Smith D, et al. Endocrine consequences of weight loss in obese, hyperandrogenic, anovulatory women. Fertil Steril 1994;61(4):598604. [139] Huber-Buchholz M, Carey D, Norman R. Restoration of reproductive potential by lifestyle modication in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone. J Clin Endocrinol Metab 1999;84:14704. [140] Moran L, Noakes M, Clifton P. Dietary composition in restoring reproductive and metabolic physiology in overweight women with polycystic ovary syndrome. J Clin Endocrinol Metab 2003;88:8129. [141] Kiddy D, Hamilton-Fairley D, Seppala M. Diet-induced changes in sex hormone binding globulin and free testosterone in women with normal or polycystic ovaries: correlation with serum insulin and insulin-like growth factor-I. Clin Endocrinol (Oxf) 1989;31:75763. [142] Kiddy D, Hamilton-Fairley D, Bush A. Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 1992;36:10511. [143] Hamilton-Fairley D, Kiddy D, Anyaoku V. Response of sex hormone binding globulin and insulin-like growth factor binding protein-1 to an oral glucose tolerance test in obese women with polycystic ovary syndrome before and after calorie restriction. Clin Endocrinol (Oxf) 1993;39:3637. [144] Baillargeon J, Iuorno M, Nestler J. Insulin sensitizers for polycystic ovary syndrome. Clin Obstet Gynecol 2003;46(2):32540. [145] Smith YR, Randolph JF Jr, Christman GM, et al. Comparison of low-technology and high-technology monitoring of clomiphene citrate ovulation induction. Fertil Steril 1998;70(1):1658. [146] Kousta E, White D, Franks S. Modern use of clomiphene citrate in induction of ovulation. Hum Reprod Update 1997;3(4):35965. [147] Legro R, Barnhart H, Schal W. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007;356:55166. [148] Hughes E, Collins J, Vandekerckhove P. Clomiphene citrate for ovulation induction in women with oligo-amenorrhoea. Cochrane Database Syst Rev 2000;(2):CD000056.

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[149] Imani B, Eijkemans MJ, te Velde ER, et al. Predictors of chances to conceive in ovulatory patients during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility. J Clin Endocrinol Metab 1999;84(5):161722. [150] Kashyap S, Wells G, Rosenwaks Z. Insulin-sensitizing agents as primary therapy for patients with ploycystic ovarian syndrome. Hum Reprod 2004;19(11):247483. [151] Lord J, Flight I, Norman R. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ 2003;327(7421):9513. [152] Palomba S, F.Orio J, Falbo A. Prospective parallel randomized, double-blind, doubledummy controlled clinical trial comparing clomiphene citrate and metformin as the rstline treatment for ovulation induction in nonobese anovulatory women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005;90:406874. [153] Palomba S, Orio F Jr, Falbo A, et al. Clomiphene citrate versus metformin as rst-line approach for the treatment of anovulation in infertile patients with polycystic ovary syndrome. J Clin Endocrinol Metab 2007;92(9):3498503. [154] Jakubowicz DJ, Iuorno MJ, Jakubowick S, et al. Eects of metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol Metab 2002;87:5249. [155] Baillargeon JP, Legro RS. Should metformin be used as front-line therapy for fertility in women with PCOS. Sexuality, Reproduction and Menopause 2007;5(2):179. [156] Balen AH, Tan SL, MacDougall J, et al. Miscarriage rates following in vitro fertilization are increased in women with polycystic ovaries and reduced by pituitary desensitization with buserelin. Hum Reprod 1993;8:95964. [157] Sagle M, Bishop K, Ridley N, et al. Recurrent early miscarriage and polycystic ovaries. BMJ 1988;297:10278. [158] Speiser P, White P. Congenital adrenal hyperplasia. N Engl J Med 2003;349:77688. [159] Merke DP, Bornstein SR, Avila NA, et al. NIH conference. Future directions in the study and management of congenital adrenal hyperplasia due to 21-hydroxylase deciency. Ann Intern Med 2002;136:32034. [160] Merke D, Cutler GJ. New ideas for medical treatment of congenital adrenal hyperplasia. Endocrinol Metab Clin North Am 2001;30:12135. [161] White P, Speiser P. Congenital adrenal hyperplasia due to 21-hydroxylase deciency. Endocr Rev 2000;21:24591. [162] Speiser P, Dupont B, Rubinstein P. High frequency of nonclassical steroid 21-hydroxylase deciency. Am J Genet 1985;37:65067. [163] Mulaikal R, Migeon J, Rock J. Fertility rates in female patients with congenital adrenal hyperplasia due to 21-hydroxylase deciency. N Engl J Med 1987;316:17882. [164] Bradford J. Pharmacological treatment of the paraphilias. American Psychiatric Press Review of Psychiatry 1995;14:75577. [165] Helleday J, Siwers B, Ritzen EM, et al. Subnormal androgen and elevated progesterone levels in women treated for congenital virilizing 21-hydroxylase deciency. J Clin Endocrinol Metab 1993;76:9336. [166] Holmes-Walker DJ, Conway GS, Hoour JW, et al. Menstrual disturbance and hypersecretion of progesterone in women with congenital adrenal hyperplasia due to 21-hydroxylase deciency. Clin Endocrinol (Oxf) 1995;43:2916. [167] Kuhnle U, Bullinger M, Schwartz H. The quality of life in adult female patients with congenital adrenal hyperplasia: a comprehensive study of genital malformations and chronic disease on female patients life. Eur J Pediatr 1995;154:70816. [168] Greenspan F, Gardner D. Basic & clinical endocrinology. In: Rosen M, Cedars M, editors. Female reproductive endocrinology & infertility. 7th edition. New York: Lange Medical Books/Mc Graw Hill; 2004. [169] Birnbaum M, Rose L. The partial adrenocortical hydroxylase deciency syndrome in infertile women. Fertil Steril 1979;32(5):53641. [170] Lo J, Grumbach M. Pregnancy outcomes in women with congenital virilizing adrenal hyperplasia. Endocrinol Metab Clin North Am 2001;30(1):20729.

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[171] Kehlet H, Binder C. Value of an ACTH test in assessing hypothalamic-pituitaryadrenocortical function in glucocorticoid-treated patients. BMJ 1973;2:14752. [172] Boccuzzi G, Angeli A, Bisbocci D, et al. Eect of synthetic luteinizing hormone releasinghormone (LHRH) on the release of gonadotropins in Cushings disease. J Clin Endocrinol Metab 1975;40:8925. [173] Sakakura M, Takebe K, Nakagawa S. Inhibition of luteinizing hormone secretion induced by synthetic LHRH by long-term treatment with glucocorticoids in human subjects. J Clin Endocrinol Metab 1975;40:7749. [174] Jurney T, deRuyter H, Vigersky R. Cushings disease presenting as amenorrhea with hyperprolactinemiadreport of two cases. Clin Endocrinol (Oxf) 1981;14:53946. [175] Lamberts S, DeLange S, Stefanko S. Adrenocorticotropin-secreting pituitary adenomas originate from the anterior or the intermediate lobe in Cushings disease: dierences in regulation of hormone secretion. J Clin Endocrinol Metab 1982;54:28691. [176] Rodriguez S, Alger M, Forsbach G, et al. Amenorrhea-galactorrhea associated with Cushings disease due to pituitary tumor. J Endocrinol Invest 1981;4:3740. [177] Nugent C, Nichols T, Tyler F. Diagnosis of Cushings syndrome; single dose dexamethasone suppression test. Arch Intern Med 1965;116:1726. [178] Blethen S, Chasalow F. Overnight dexamethasone suppression test: normal responses and the diagnosis of Cushings syndrome. Steroids 1989;54(2):18593. [179] Crapo L. Cushings syndrome: a review of diagnostic tests. Metabolism 1979;28(9):95577. [180] Mengden T, Hubmann P, Muller J, et al. Urinary free cortisol versus 17-hydroxycorticosteroids: a comparative study of their diagnostic value in Cushings syndrome. Clin Investig 1992;70(7):5458. [181] Goldsmith R, Sturgis S, Lerman J. Menstrual pattern in thyroid disease. J Clin Endocrinol Metab 1952;12:846. [182] Stratford G, et al. Value of thyroid function tests in routine screening of women investigated for infertility. Hum Fertil (Camb) 2000;3:2036. [183] Lincoln S, Ke R, Kutteh W. Screening for hypothyroidism in infertile women. J Reprod Med 1999;44:4557. [184] Wakim AN, Polizotto SL, Buo MJ, et al. Thyroid hormones in human follicular uid and thyroid hormone receptors in human granulosa cells. Fertil Steril 1993;59:118790. [185] Davis L, Leveno K, Cunningham F. Hypothyroidism complicating pregnancy. Obstet Gynecol 1988;72:10812. [186] Glinoer D, Riahi M, Grun JP, et al. Risk of subclinical hypothyroidism in pregnant women with asymptomatic autoimmune thyroid disorders. J Clin Endocrinol Metab 1994;79: 197204. [187] Negro R, Formoso G, Mangieri T, et al. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: eects on obstetrical complications. J Clin Endocrinol Metab 2006;91(7):258791. [188] Kjaer K, Hagen C, Sando SH, et al. Epidemiology of menarche and menstrual disturbances in an unselected group of women with insulin-dependent diabetes compared to controls. J Clin Endocrinol Metab 1992;75:5249. [189] Miodovnik M, Lavin J, Knowles H. Spontaneous abortion among insulin dependent diabetic women. American Journal of Obstetrics & Gynecology 1984;150(4):3726. [190] Miodovnik M, Skillman C, Holroyde J. Elevated maternal glycohemoglobin in early pregnancy and spontaneous abortion among insulin dependent diabetic women. Am J Obstet Gynecol 1985;153:43942. [191] Bigazzi M, Ronga R, Lalcrajan I. A pregnancy in an acromegalic woman during bromocriptic treatment: eects on growth hormone and prolactin in the maternal, fetal, and amniotic compartments. J Clin Endocrinol Metab 1979;48:912. [192] Fuhrmann K, Reiher H, Semmler K. The eect of intensied conventional insulin therapy before and during pregnancy on the malformation rate in ospring of diabetic mothers. Exp clin endocrinol 1984;83:1737.

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[193] Guzick D, et al. Ecacy of treatment for unexplained infertility. Fertil Steril 1998;70: 20713. [194] Deaton J, Gibson M, Blackmer K. A randomized controlled trial of clomiphene citrate and intrauterine insemination in couples with unexplained infertility or surgically corrected endometriosis. Fertil Steril 1990;54:10838. [195] CDC, CfDC, ASfR Medicine, et al. Assisted reproductive technology success rates. Atlanta (GA): US Department of Health and Human Services and CDC; 2005. [196] Gunby J, Daya S. Assisted reproductive technologies (ART) in Canada: 2003 results from the Canadian ART register. Fertil Steril 2007;88(3):5509.

Med Clin N Am 92 (2008) 11931225

Medical Issues from Preconception Through Delivery: A Roadmap for the Internist
Michael P. Carson, MDa,b,*, Deborah Ehrenthal, MDc,d
Jersey Shore University Medical Center, 1945 Route 33, Neptune, NJ 07753, USA Departments of Medicine and OB/Gyn, UMDNJdRobert Wood Johnson Medical School, Clinical Academic Building, Suite 1400, 125 Paterson Street, New Brunswick, NJ 08901, USA c Department of Obstetrics and Gynecology, Womens Health Programs Christiana Care Health Services, Inc., 4755 Ogletown-Stanton Road, Newark, DE 19718, USA d Thomas Jeerson University College of Medicine, Jeerson Medical College Oce of the Dean, 1025 Walnut Street, Philadelphia, PA 19107, USA
b a

Women of childbearing age.bear children. It has been said that most internists would be comfortable managing a womans medical problems during pregnancy, if only she werent pregnant. However, preconception planning does not address pregnancy. It is simply excellent primary care with attention to reproductive potential. The percentage of women with medical issues during pregnancy has increased from 15% to 36% [1,2]. This increase means that it is even more important that internists be aware of these issues and how they should be addressed because the best time to solve such problems is before conception. We also have the chance to identify concerns that arose during a prior pregnancy and decrease the risk of future complications related to that issue. Those two points are the focus of this article. We are on the cusp of a change within internal medicineprimary care where the list of expected preventive interventions and recommendations, such as those aimed at reducing the risk of heart disease and osteoporosis, will be expanded to include eorts to reduce the risk of medical morbidity and poor pregnancy outcomes. We hope this article helps readers recognize obstetric and medical issues that can be addressed to achieve these goals. We provide data regarding the risks, and for some we provide specic

* Corresponding author. Jersey Shore University Medical Center, 1945 Route 33, Neptune, NJ 07754. E-mail address: MPCarson@meridianhealth.com (M.P. Carson). 0025-7125/08/$ - see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2008.04.010 medical.theclinics.com

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management plans both before conception and during an ongoing pregnancy. Our goal is to provide a roadmap to practicing internists so they can be more comfortable helping patients prepare for pregnancy and provide collaborative prenatal care with their obstetricians. To borrow terms from the preoperative evaluation, we wont clear them, but we will optimize the patient before pregnancy, encourage optimal timing of childbearing, and minimize risks during a pregnancy. Importance of preconception health care Over the past several decades, infant mortality in the United States has declined, but the rate of decline has recently leveled and remains between 6.5 and 7 deaths per 1000 live births [3]. The United States ranks a disappointing 28th internationally in infant mortality [4]. Signicant ethnic disparities exist as well, with rates among non-Hispanic blacks consistently twice that of nonHispanic whites [5,6]. Prior national and local eorts to improve infant mortality rates focused on improving health care during the prenatal period. However, there is compelling evidence that addressing and modifying key maternal health risks before conception leads to improved pregnancy outcomes [710]. Preconception care is dened as the period before a rst pregnancy or the period between pregnancies, the interconception period. Such care has been recommended by the American College of Obstetricians and Gynecologists since 1995 and was a part of the Healthy People 2000 goals, but has not yet become a routine part of womens health care [10,11]. The fraction of women currently receiving preconception counseling and interventions designed to decrease their risk of poor pregnancy outcomes is small, even among women who have had a prior problem pregnancy [1215]. In 2006 the Centers for Disease Control and Prevention published recommendations to improve preconception health and health care [16]. These recommendations identied 14 targeted preconception risk factors and outlined 10 recommendations to improve preconception health: (1) individual responsibility across the life span, (2) consumer awareness, (3) preventive visits, (4) intervention for identied risks, (5) interconception care, (6) prepregnancy checkups, (7) health insurance coverage for women with low incomes, (8) public health programs and strategies, (9) research, and (10) monitoring of improvements. The barriers to preconception care are not well known. One study found that even when women and clinicians were made aware of pregnancy risks at the time of a negative pregnancy test, rates at which these risks were addressed did not improve [17]. Another found the majority of women surveyed at their annual examination recognized the importance of optimizing their health before conception. However, these women had deciencies in their knowledge of risk factors that have an impact on maternal and fetal health, which suggests that physicians are not routinely providing preconception care [13]. In spite of a concerted national eort by such

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organizations as the March of Dimes, surveys still nd low awareness of folic acid and low use of folic acid among women of childbearing age [14]. Even women with chronic medical problems and with frequent contact with health care providers do not routinely have pregnancy risks assessed. One study of diabetic women found only 52% recalled counseling about glycemic control and 37% about contraceptive advice [15]. Because of high rates of unplanned pregnancy, integrating discussions about reproductive plans into routine health care for women is needed. Internists and other primary care physicians can and should play a major role in providing appropriate contraception for those not planning a pregnancy and optimal management for those who desire to conceive. Chronic health problems, including obesity, hypertension, diabetes, and depression, all contribute to increased risk for pregnancy complications and poor outcomes. While medical comorbidities carry specic risks, other factors increase the likelihood of adverse outcomes, including black ethnicity; single, divorced, or separated marital status; insucient prenatal care; lower educational levels; and lack of adequate health insurance. Higher risks are also seen for women with unplanned pregnancies and those with a short interpregnancy interval [18]. Behavioral risks, including tobacco, alcohol, and drug use; sedentary lifestyle; and poor nutrition, are known to play a major role in these poor outcomes. General preconception recommendations The main goals of preconception care and counseling are to identify potential future pregnancy risks, provide counseling about the potential impact of these risks on a womans health and future pregnancy, identify interventions that could improve the chances of a good outcome, and discuss pregnancy planning options. This section addresses the 14 risk factors identied by the Centers for Disease Control and Prevention. All women of childbearing age should be encouraged to develop a reproductive plan. This is especially important for women with known health risks. Women with some medical illnesses, such as severe pulmonary hypertension, Eisenmengers syndrome, or Marfans syndrome with aortic involvement, are at very high risk for mortality during a pregnancy and should to be counseled about the risk of signicant morbid complications, including death. Others, such as women with diabetes, can decrease the risk of major congenital anomalies if steps are taken to plan pregnancy at a time when their disease is well controlled. Women who smoke or use alcohol or other substances should be advised about their potential impact on fetal anomalies and pregnancy outcomes overall. Good nutritional status, a healthy weight, regular exercise, and attention to routine dental care are all important components of good preconception health. Important issues that should be addressed in the preconception period are shown in Box 1. All women should be advised to take supplemental folic acid

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Box 1. Risk factors that can be modied to decrease pregnancy-related morbidity  Obesity, diabetes, hypertension: Optimize maternal disease.  Other medical problems, such as sexually transmitted disease, hypothyroidism, phenylketonuria, and HIV: Diagnose and treat to decrease maternal and fetal morbidity.  Medications such as isotretinoins, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, statins: Should be avoided.  Medications such as antiepileptic drugs and oral anticoagulant: Modify or minimize dosage in the rst trimester when appropriate.  Rubella, varicella, hepatitis B: Assess needs for immunization/ vaccination.  Drug, alcohol, or tobacco use: Provide counseling and support for cessation.  Inadequate folic acid intake: Ensure 400 mcg/d.  Short interpregnancy interval: Counsel patient regarding the health benets of a longer interpregnancy interval.  Psychosocial risks, such as depression, low income, lack of social support: Identify patients at risk and refer to appropriate resources. in the form of a multivitamin containing at least 400 mcg of folic acid daily. Immunity to rubella, hepatitis B, and varicella should be veried and vaccines should be updated as needed. Screening for infectious risks, such as HIV and other sexually transmitted infections, should be completed and addressed before conception. Women with phenylketonuria should be advised that adherence to a low phenylalanine diet before conception and continued throughout their pregnancy will lead to improved outcomes. Finally, women should be asked about their use of herbs, over-the-counter medications, and prescription medications, and advised about the risk of inappropriately stopping indicated medications without discussing the consequences with their physician. Substance abuse, including tobacco use, alcohol use, and illicit drug use, aects large numbers of women and should be screened for and addressed because management is typically simpler if the substance abuse is identied before pregnancy. Nicotine replacement can decrease fetal nicotine exposure compared with continued smoking [19]. In addition, screening for psychosocial and socioeconomic risks before conception helps identify women with depression, housing and food instability, lack of social support, domestic violence, or lack of health insurance. Referral to appropriate resources can help decrease global stress and improve social support before pregnancy.

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Women with prior problem pregnancies should receive advice based on their obstetric history. Women with a history of a baby with a neural defect should take 4 mg of folic acid daily. Women with a personal or family history of genetic disorders may benet from genetic counseling before conception. Finally, and perhaps most importantly, internists should be proactive regarding pregnancy timing and birth spacing as 50% of pregnancies are unplanned. Work with all women of childbearing age, especially those with medical conditions, by discussing eective contraceptive options. An array of contraceptive options are available for women to aid in timing their pregnancies. Eectiveness among contraceptives varies (Table 1). The choice of contraceptive method for women with medical issues requires a careful weighing of the risks and benets of the method, including the acceptability of the method and the risks associated with an unplanned pregnancy. Most women are candidates for highly eective long-acting reversible contraceptives, including intrauterine devices and contraceptive implants, both of which have very few contraindications. The safety of combination hormonal contraceptives when used by women with medical problems depends upon the specic health risk and the hormone used. The World Health Organizations Medical Eligibility Criteria for Contraceptive Used3rd edition is a helpful resource and is available on-line (http://www.who.int/reproductivehealth/publications/mec/) [20]. Prescribing during pregnancy A healthy fetus depends upon a healthy mother. There are only about 30 medications that have been proven to be teratogenic, so most can be given when indicated. Organogenesis is completed by 13 weeks gestation. Once the woman enters the second trimester, there is virtually no chance that commonly used medications will cause a permanent physical deformity in the fetus. Thus, starting from that period, the known benets of a medication
Table 1 Eectiveness of common contraceptive methods Level of eectiveness Very eective (0%1% failure) Contraceptive method Vasectomy, female sterilization, etonogestrel subdermal implant 68 mg, copper-bearing intrauterine device, levonorgestrel intrauterine device Combined oral contraceptive pills, patches, vaginal rings, depot medroxyprogesterone acetate injection, progesterone only pills while breast-feeding Condoms, diaphragms, cervical caps, spermicides, coitus interruptus

Eective as commonly used (2%12% failure); very eective when used correctly and consistently Only somewhat eective as commonly used (15%30% failure); eective when used correctly and consistently

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to the pregnant woman should be weighed against the potential eects on the fetus. The US Food and Drug Administration (FDA) categorization for drug use during pregnancy is overly simplistic and should not be the only source relied upon to decide if the medication should be used during pregnancy. The FDA descriptions state that any medication in class A through D may be used when the potential benet justies the potential risk, and this is particularly true for seizure disorders. However, a study of a large database found that documentation regarding the potential impact of a medication on pregnancy was lacking [21]. Rather than thinking if medications are safe or not, consider the benets and whether the use of the medication is justied or warranted. For example, if gastroesophageal reux is particularly severe and other measures have failed, it is reasonable to recommend the pregnant woman use an H2-receptor blocking agent. One helpful approach is that developed by the obstetric medicine faculty at Brown University involving four questions that guide the clinician and the patient through the decision-making process (Box 2) [22]. Such a tool combined with an oce resource, such as the book Drugs in Pregnancy and Lactation, enables one to address most situations [23]. Diagnostic imaging The upper limit of recommended fetal radiation exposure is 5.0 rad. A single maternal x-ray imparts less than 0.0007 rad, meaning that 70,000 maternal x-rays would be needed before you reach the upper limit of safe

Box 2. Approach to prescribing during pregnancy Question 1. Is the medication necessary or is the symptom to be treated self-limited and/or amenable to nonpharmacological management? Corollary: Is it a could use or a should use medication? Question 2. What are the possible consequences for the mother and fetus if the medication is not given? Corollary: A healthy fetus depends on a healthy mother. Question 3. What data are available on the safety of this medication in pregnancy and is there a similar drug with better safety data available that could be used instead? Corollary: Dont say no when the answer is I dont know. Use a reference or colleague to determine what data exist about a medication. Question 4. How is the patients (and the providers) understanding and value system affecting decisions about the use of this medication in pregnancy?

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exposure [24]. This can be a useful statistic to quote when trying to ease patient concerns. Environmental background fetal radiation exposure is 0.1 to 0.3 rad over 9 months. This helps put in perspective that a CT scan of the head imparts 0.006 rad to the fetus; abdominal or pelvic CT about 2.0 rad; and an abdominal x-ray about 0.4 rad. Maternal MRI studies have not been shown to carry any risks for the fetus and are occasionally used to image a fetus with a complex anatomic abnormality. Intravenous contrast does not pose a risk to the fetus or breast-fed infant. The amount of iodine or gadolinium that gets into the breast milk is insignicant and breast-feeding should not be interrupted [25]. Chronic hypertension Hypertension is one of the most common issues for which internists are consulted and complicates 2% to 3% of pregnancies. The four categories of hypertensive disorders during pregnancy and the denitions are outlined elsewhere [26]. Chronic hypertension is dened as blood pressure exceeding 140/90 mm Hg before pregnancy or before 20 weeks gestation. New onset of elevated blood pressure readings after 20 weeks gestation mandates the consideration and exclusion of preeclampsia. Potential impact on pregnancy Preeclampsia occurs in 2% to 10% of all pregnancies, and hypertension is the leading cause of medically indicated prematurity. Up to 22% of women with chronic hypertension develop preeclampsia, a multisystem syndrome related to abnormal placental development that can aect the mother, or the fetus, or both mother and fetus [27]. Preeclampsia typically occurs in the third trimester (after 26 weeks) and is dened as new elevations of blood pressure (systolic blood pressure O140 mm Hg or diastolic blood pressure O90 mm Hg) with proteinuria greater than 300 mg every 24 hours. Abnormal placental development (placentation) is felt to be the cause of preeclampsia, which can aect any maternal organ system. Placental insuciency may manifest as intrauterine growth restriction or low amniotic uid. Disorders of placentation also include gestational hypertension, placental abruption, and placental infarctions seen on pathology reports. Close monitoring can usually prevent severe maternal complications. However, the downside of early detection is that it may require preterm delivery, putting the newborn at risk for all of the related short- and long-term morbidities. Pregnancy planning In normal pregnancy, the mean arterial pressure drops 10 to 15 mm Hg over the rst half of pregnancy. In women with mild chronic hypertension (ie, systolic blood pressure 140160 mm Hg, diastolic blood pressure

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90100 mm Hg), this decrease in blood pressure may obviate the need for medication. However, diastolic blood pressure greater than 110 mm Hg has been associated with an increased risk of placental abruption and intrauterine growth restriction [26]. Therefore, antihypertensive therapy should be initiated if the systolic blood pressure is greater than 160 mm Hg or the diastolic blood pressure is greater than 100 mm Hg. First-trimester exposure to angiotensin-converting enzyme inhibitors was associated with cardiac and renal defects. Therefore, avoid these and angiotensin receptor blocking agents in women of childbearing age [28]. Three treatment options are available in cases of mild chronic hypertension before pregnancy:  Hold antihypertensive medication with subsequent close observation of blood pressure. Because blood pressure decreases during pregnancy, and no data support the use of medication in patients with pressures less than 160/100 mm Hg, the authors recommend this option most often.  If a woman is on an agent not recommended for use in pregnancy, such as an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocking agent, she may be switched to an alternative antihypertensive agent preferred for use in pregnancy.  If a woman is on an agent acceptable for use in pregnancy, and use is indicated, she may continue her current antihypertensive therapy. Ideally, women should be seen, and medication changes made, before pregnancy. This allows for assessment of the blood pressure response and tolerability before pregnancy. Labetalol is our preferred medication. The starting dose is 100 or 200 mg by mouth twice a day, with a maximum of 2400 mg per day. At doses above 600 mg, we usually give it three times a day. Methyldopa has the most data regarding safety in pregnancy, but it often requires three-times-a-day or four-times-a-day dosing and side eects are frequent. The starting dose is 250 mg by mouth twice a day up to a maximum of 1000 mg a day divided twice a day to four times a day. Both of these medications are compatible with breast-feeding. If there are issues with intolerance or side eects, other options include nifedipine or metoprolol. Atenolol, propanolol, and diuretics should typically be avoided. Antepartum care and monitoring No interventions have been found to prevent preeclampsia. Failed interventions include normalization of blood pressure, calcium supplementation, and aspirin. Eighty-one milligrams of aspirin and/or calcium supplementation do not carry signicant risks, but aggressive blood pressure control may be associated with decreased birth weight and could theoretically decrease placental perfusion. One randomized trial of calcium supplementation (1.5 g/d) in women with low calcium intake [!600 mg] found that

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supplementation decreased eclampsia, the severity of preeclampsia, and neonatal mortality [29]. However, another randomized trial found no benet in women with adequate dietary calcium [30]. Calcium supplementation did not prevent severe preeclampsia in preterm patients with mild preeclampsia [31]. Randomized trials of aspirin are also conicting. Although one randomized controlled trial in low-risk women found that aspirin decreased preeclampsia [32], another randomized controlled trial of high-risk patients (pregestational insulin-treated diabetes mellitus, chronic hypertension, multifetal gestations, and women who had had preeclampsia during a previous pregnancy) did not nd any benet [27]. Meta-analyses have concluded that calcium or aspirin may be helpful, only to be contradicted by randomized controlled trials. Antepartum care of women with hypertension consists of establishing a baseline and then monitoring pressures every 1 to 2 months early in pregnancy and more frequently later on. The fetus should be monitored for growth with serial ultrasounds. Additional antepartum care should include:  Pregnancy-induced hypertension laboratory tests: complete blood cell count, serum urea nitrogen, creatinine, transaminases, bilirubin, and a 24-hour urine for protein and creatinine clearance. Repeat these later if there are changes in maternal blood pressure.  Home blood pressure monitoring. Check about once per day. If systolic blood pressure is greater than 140 mm Hg or diastolic blood pressure is greater than 90 mm Hg, then recheck in 30 to 60 minutes. If still elevated, call provider. These changes should prompt a repeat of the pregnancy-induced hypertension laboratory tests.  History at each visit: Educate patient and ask about the signs and symptoms of preeclampsia (headache, changes in vision, swelling of the hands or face, right upper abdominal pain). See her every 8 weeks initially.  Examination: Take blood pressure; examine the fundi for vasospasm; check reexes; look for edema of the hands/face or new pretibial edema; check for liver tenderness.  Fetal ultrasounds: Obstetrician should obtain fetal ultrasounds for growth at 18 to 20 weeks gestation and then again at 28 to 32 weeks [33]. If the blood pressure begins to rise, the frequency of visits should increase to every 1 to 2 weeks. Normalization of blood pressure will not stop or prevent preeclampsia and it could mask a useful clinical indicator. Determine if it is the normal increase seen between 20 and 40 weeks, or if she is becoming preeclamptic. Use the following to help determine which category ts your patient.  Obtain the history and focused examination as listed above, and obtain a new set of maternal laboratory tests. The obstetrician should schedule an ultrasound to assess fetal growth and amniotic uid index as indicators of placental health. Doppler assessments of the uterine artery blood

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ow pattern may show evidence of abnormal placentation, but this is generally deferred to the obstetrician.  If you suspect preeclampsia, consider hospital admission to monitor the patient and fetus, and obtain a 24-hour urine. If outpatient monitoring is reasonable, ask the obstetrician to schedule fetal testing twice each week. Typically this will be a biophysical prole early in the week and a nonstress test later that week.  The only cure for preeclampsia is delivery of the placenta. If the pregnant patient is beyond 37 weeks gestation, then the decision is easy. Close monitoring for preeclampsia classied as mild is considered when delivery will result in a preterm infant. Collaboration with the obstetrician and a perinatologist is preferable if at all possible. If the fetus has not shown adequate growth over a 2-week period or has intrauterine growth restriction, or if the mother has severe disease, then consider delivery. Postpartum Blood pressure may remain labile and elevated after delivery. In these cases, use a sliding scale blood pressure regimen to facilitate discharge with a plan that can avoid the blood pressure dropping too low at home. Labetalol is a preferred medication as it can be dosed frequently and is compatible with breast-feeding. A reasonable regimen is for labetalol 200 mg orally three times a day. Advise the patient to: 1. Take her own blood pressure three times a day, before each dose. If the systolic blood pressure is less than 140 mm Hg AND the diastolic is less than 90 mm Hg then do NOT take that dose. 2. Repeat this for each dose. Typically women come o of the medication within 2 weeks. If the laboratory tests are trending toward the normal range, the patient may be discharged with outpatient follow-up. Typically, blood pressure and/or laboratory normalization will occur by 6 weeks postpartum, but it may take longer in those with severe abnormalities. Document normalization of any and all laboratory abnormalities attributed to preeclampsia. If they dont normalize or worsen, then one should carry out an evaluation for an underlying medical disorder [34]. Some long-term maternal issues are probably associated with abnormal placentation syndromes. The adjusted hazard ratio of developing coronary artery, cerebrovascular, or peripheral artery disease at least 90 days after the delivery discharge date was 2.0 (95% CI 1.72.2) in those with a placental syndrome relative to those without it. The hazard ratio was 3.1 if they had the syndrome and poor fetal growth, and it was 4.4 with intrauterine fetal death [35]. These women can benet from close follow-up, risk assessment (weight, smoking, cholesterol, diet, exercise), and modication of risks associated with cardiovascular disease.

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Future pregnancies Early or severe preeclampsia, intrauterine growth retardation, three rsttrimester losses, or one second-trimester loss have been associated with placental thrombosis, thrombophilias, and antiphospholipid antibodies. Therefore, such women should be screened. These tests include anticardiolipin antibody IgG, IgA, and IgM; antibeta-2-glycoprotein-1 IgG, IgA, and IgM; and a lupus anticoagulant (essentially a modied active partial thromboplastin time). Randomized trials in women with antiphospholipid antibody syndrome and pregnancy loss are generalized to anyone with the antiphospholipid antibody syndrome. Protein C, antithrombin, and protein S deciencies are rare. However protein S levels are always low during pregnancy and the actual threshold below which a deciency is felt to be signicant is not entirely clear. A functional activated protein C resistance can develop in 60% of pregnant women. So, if testing is indicated, defer it until after pregnancy [36]. While associated with thrombosis and preeclampsia, factor V Leiden and the prothrombin gene mutation have not been shown to increase the recurrence risk of either [3739], nor is there any data supporting treatment with anticoagulants in people with these mutations. While controversial, we do not test for factor V Leiden and prothrombin gene mutation because we did not nd data showing that a positive test requires an alteration in the management plan. Women with abnormal placentation syndromes should have a placental pathologist review the organ. The presence of infarcts or extensive thrombosis suggests that an anticoagulant (heparin) may be of some utility during the next pregnancy. A number of small case series and retrospective studies suggest that heparin can decrease the risk of recurrence, but no randomized trials validate the ecacy or safety of anticoagulants versus no treatment. However, we believe that abnormal placental pathology is a phenotypic/clinical event that obviates the need for further serologic testing in a woman with a placental syndrome. In this setting, consideration should be given to treating the patient during future pregnancies with empiric anticoagulation along the lines of treatments for women with antiphospholipid antibodies. While empiric, the risk of low molecular weight heparin (LMWH) complications is low compared with the morbidity of prematurity that can last a lifetime. Newer data support this approach as one randomized controlled trial found that LMWH reduced the risk of preeclampsia in angiotensin-converting enzyme deletion homozygote women with a prior history of a placental syndrome [40]. Thyroid disease Potential impact on pregnancy Hypothyroidism during pregnancy is associated with low birth-weight infants [41,42], impaired psychomotor development [43], and delivery at

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or before 34 weeks of gestation [44]. In addition, the fetal death rate among 209 women with thyrotropin greater than 6 mU/L was 3.8%, versus 0.9% in the 9197 women with thyrotropin less than 6 mU/L (odds ratio 4.4, 95% CI 1.99.5) [45]. Hyperthyroidism in women of childbearing age is due to Graves disease 95% of the time. Graves disease typically becomes less active as the pregnancy progresses, but sometimes can present or become more active during pregnancy. Uncontrolled hyperthyroidism has been associated with premature delivery, perinatal death, and neonatal morbidity [46]. Pregnancy planning It is important to identify women with thyroid disease, to discuss with them their reproductive plans, to monitor laboratory tests, and to adjust their dose to normalize the thyrotropin before pregnancy. Hypothyroid patients who conceive after gonadotropin stimulation or with oral medications for ovulation induction typically do not need additional thyroid supplementation compared with those who conceive spontaneously [47]. Propylthiouracil is the preferred rst-line agent for the treatment of hyperthyroidism, but methimazole should be used if there are any contraindications to propylthiouracil. The priority is controlling maternal disease. Long-term follow-up of children with in utero propylthiouracil exposure show no long-term physical or intellectual eects [48]. Nonselective betaadrenergic blocking agents (propanolol) can be used when indicated for severe disease during pregnancy, but attempt to taper the dose quickly. Antepartum monitoring Hypothyroid patients should have thyrotropin checked each trimester and the dose adjusted accordingly. Because the level of thyroid binding globulin increases throughout pregnancy, one should use the thyrotropin and/or free thyroxine levels to monitor hypothyroid patients, recheck the thyrotropin 4 weeks after any dose changes, and use pregnancy-specic reference ranges for thyrotropin and free thyroxine values. Total thyroxine in combination with resin tri-iodothyronine uptake is also reliable. To minimize medication exposure, adjust the propylthiouracil or methimazole so that the hormone levels are in the high-normal range and recheck maternal hormone levels 1 to 2 weeks after dose adjustments. When hormone levels are stable, check laboratory tests monthly as the medication requirements often decrease near term. High doses of propylthiouracil or methimazole can cause a hypothyroid goiter in the fetus and a thyroid-stimulating immunoglobulin can cause a hyperthyroid goiter. Consider an ultrasound of the fetal thyroid gland around 30 weeks gestation. This examination is to detect a fetal goiter that could limit neck exion during a vaginal delivery.

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Postpartum If the dose of thyroid hormone was increased, it can be decreased to the prepregnancy levels or continue the current dose. In either case, check thyrotropin about 4 weeks after delivery to guide management. Women with Graves disease may see a reactivation of the disease. Women on propylthiouracil may breast-feed, but they should talk with their pediatrician regarding monitoring of the newborns thyroid status. Diabetes mellitus and gestational diabetes Potential impact on pregnancy There is no better example of the need for internists to address medical issues before conception than diabetes, nor does anyone have a better opportunity. Uncontrolled disease poses a signicant risk to the fetus and is correlated with the glycosylated hemoglobin test (HbA1c) at the time of conception. If the value is greater than 7%, the risk of a major congenital anomaly doubles to 5% with all major organs being at risk. The risk is 23% with an HbA1c of 8.6% or more [49]. While preconception control is important, only 52% of diabetics recalled counseling about preconception control [15]. Unfortunately, by the time such patients see the obstetrician, the opportunity to prevent fetal defects by optimizing diabetic control has been lost. Pregnancy planning Diabetics should be asked about their reproductive plans early and often. Ensure they are using a highly reliable form of contraception if they do not desire pregnancy. Be sure she is familiar with the diet, and increase the frequency of her glucose checks and oce visits. Insulin is the best choice for women who require medication and are planning pregnancy. Neutral protamine Hagadorn (NPH) insulin and regular insulin have been used the longest, the new rapid-acting insulins oer patients more exibility, and there is only limited data regarding the use of insulin glargine during pregnancy. A regimen with NPH and regular is preferred, but rapid-acting insulin can be substituted for regular if it improves glycemic control. In properly selected patients with type 1 diabetes mellitus, an insulin pump is also an option, but nothing surpasses an educated and motivated patient. The priority is the best achievable glycemic control with the HbA1c less than 7% before conception. Regular appointments with an ophthalmologist are important because retinopathy may initially worsen with improved glycemic control, and any necessary laser retinal treatments should be administered. Diabetics are at increased risk for preeclampsia and therefore they should be counseled and monitored as prescribed in the section on hypertension. For women with a long history of diabetes, cardiovascular testing for occult disease should be considered.

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Women with a history of gestational diabetes or who delivered a macrosomic infant (O4500 g) should be screened annually for diabetes and be advised to undergo early screening for gestational diabetes in subsequent pregnancies. The value of working toward achieving a healthy weight through diet and exercise should be emphasized. Antepartum monitoring Sugar levels should be checked four times a day, fasting and 2 hours after each meal. Postmeal glucose checks have been associated with a lower risk of obstetric morbidity [50]. We have our patients send faxes with sugar measurements every week and return for oce visits each month. The goals are fasting sugar levels % 95 mg/dL and 2-hour postprandial values of % 120 mg/dL (or 1-hour values of %140 mg/dL) [51]. If the sugar levels are elevated for 3 consecutive days, then we consider adding medication. When required, insulin is the best option in the rst trimester. Glyburide was given to women with gestational diabetes after 11 weeks gestation, and it was not detected in the cord blood of 200 newborns [52]. Metformin is used for women with polycystic ovary syndrome, but, because of better safety data regarding insulin and glyburide, we generally stop it after the rst trimester. Monitor for preeclampsia as outlined in the section on hypertension. A single study found that metformin is equivalent to insulin for the treatment of gestational diabetes, but long-term follow-up is necessary, and it is not yet endorsed by national organizations [53]. Postpartum Fifty percent to 70% of women diagnosed with gestational diabetes eventually develop type 2 diabetes mellitus. Conrm that all patients with gestational diabetes have a 2-hour 75-g glucose tolerance test 6 to 8 weeks after delivery. If it is normal, they should have their sugar levels assessed each year. If they are diabetic or glucose intolerant, then address diet, exercise and weight-loss issues; see them every 3 months; and monitor them so that the HbA1c is less than 7%. Depression Potential impact on pregnancy Untreated maternal depression has been associated with inadequate nutrition, poor weight gain, poor compliance with prenatal care, marital discord and divorce, diculty caring for other children, loss of employment, substance abuse, dangerous risk-taking behavior, and maternal suicide [54,55]. The eects of maternal disease on the ospring include preterm birth, lower birth weight, smaller head circumference, lower Apgar scores, and poor performance on neurologic exams (motor skills, activity, coordination) [5658].

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Pregnancy planning As with other issues, the best strategy with depression is to control the disease before pregnancy. First, nonpharmacologic interventions should be considered and initiated if appropriate, including interventions to discourage alcohol, nicotine, or caeine; and to promote good sleep hygiene, stress management, identication of support systems, and close monitoring. Women and their physicians often abruptly stop medications when they discover a woman is pregnant. It is important to remember that generally the magnitude and specic negative eects the disease can have on the patient and her family are obvious and greater than the potential medication eect on the fetus. However, this is a complex situation. Fluoxetine does not increase the risk of fetal anomalies, but when used in the third trimester may be associated with neonatal irritability and poor adaptation [59]. Firsttrimester paroxetine exposure was shown to increase the risk of atrial and ventricular septal defects by 1%, but buproprion did not [60]. A case-control study found that use of selective serotonin reuptake inhibitors after 20 weeks gestation increased the risk of persistent pulmonary hypertension of the newborn (PPHN) [59]. The estimate of the absolute risk of PPHN is at most 1%. Amitriptyline also inhibits serotonin reuptake, but there were not enough women in the study to determine if an association exists between amitriptyline and PPHN. Regardless, the absolute risk of PPHN is much smaller than the risk that a woman with major depression will experience an exacerbation of her disease during pregnancy. Data show that 26% of women with major depression experience an exacerbation of their disease during pregnancy even if they continue medications, and 68% suer a relapse if they stop them [61]. In spite of the concern about PPHN associated with selective serotonin reuptake inhibitors, we cant ignore the risks of withholding the medication. Talk with your patient and determine how she thinks shell do o of the medication, review the 68% risk of recurrence o the medication, and the association between selective serotonin reuptake inhibitors and PPHN. Discuss how untreated depression or anxiety will aect her relationships and her ability to function in the workplace and at home as a caregiver. When medications are indicated, understand that there is no best choice as none have been shown to be teratogenic and neonatal abstinence syndromes can occur after exposure to selective serotonin reuptake inhibitors or tricyclic antidepressants, such as amitriptyline. It is reasonable to start a selective serotonin reuptake inhibitor, such as uoxetine, or a tricyclic, such as amitriptyline, as a rst-line medication. Consider nortriptyline or selective serotonin reuptake inhibitors other than paroxetine as second-line medications. If intolerance or side eects are signicant issues, one can consider buproprion as a third-line agent. Its a complex area, but we have better data on the benets of the medication and the risk of untreated disease than ever before.

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Antepartum monitoring Elicit the symptoms that indicate her disease is aring, see her at least once a trimester to inquire about those symptoms, and be sure that she is also following up with her mental health professional if she has one. Because of the risk of PPHN, you can consider tapering or stopping the medication by 20 weeks gestation if her disease is stable and she is functioning well. After that, follow her monthly, inquire about the specic symptoms, and consider restarting the medication if symptoms come back. A randomized pilot trial of light therapy administered to 10 pregnant women demonstrated an improvement in scores on a depression scale similar to that seen with medication use [62]. A randomized trial of interpersonal psychotherapy for 50 pregnant women reported 60% had full recovery [63]. For refractory disease, electroconvulsive therapy can be considered during pregnancy [64]. Postpartum Twenty-ve percent of women with a history of depression worsen postpartum. Intrapersonal psychotherapy has been shown to be helpful. Close follow-up with monthly oce visits should be considered. Sertraline and paroxetine have the lowest secretion into breast milk. If medications are necessary during lactation, the mother should monitor the babys behavior and use that to guide treatment and any decisions to interrupt breast-feeding. Thrombosis, antiphospholipid antibodies Patients that require special consideration before and during pregnancy include those with prior venous thromboembolism (VTE) without the need for chronic anticoagulation, those with antiphospholipid antibody associated obstetric morbidity, patients on lifelong anticoagulation, and those with a prior stroke or transient ischemic attack (TIA). Potential impact on pregnancy In women with a history of prior VTE, the risk of recurrence during pregnancy varies by study, but appears to be 7.5% to 12%, and the risk in the puerperium is 15% [65,66]. For nonpregnant patients with a history of VTE, factor V Leiden and the prothrombin gene mutation have not been associated with an increased risk of recurrence versus controls [38,67,68]. However, cohort studies following relatives of women with a history of VTE found the absolute risk of VTE during pregnancy associated with protein C, protein S, or antithrombin deciencies to be 4.1% versus 0.5% of controls, and the rate for factor V Leiden was 3.9% versus 1.4% of controls [69,70]. An oft-quoted study by Brill-Edwards that attempted to evaluate the risk of recurrence without thromboprophylaxis was

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limited by the exclusion of women with a known thrombophilia before enrollment, but not after; and women felt to be too high risk by the investigators [71]. The magnitude of this risk is controversial. Randomized controlled trials have shown that women with the antiphospholipid antibody syndrome and three or more pregnancy losses are more likely to have a successful pregnancy when treated with heparin and 81-mg aspirin during subsequent pregnancies [72,73]. Clinical events that should prompt testing include pregnancy loss (two or more rst-trimester losses or one second-trimester loss), early or severe preeclampsia, placental abruption, and intrauterine growth retardation. Women with the syndrome should be treated with prophylactic unfractionated heparin (UFH) or LMWH and 81 mg of aspirin. Corticosteroids should be avoided [74]. Pregnant patients with an indication for chronic anticoagulation are typically those with the antiphospholipid antibody syndrome, those with a history of recurrent VTE without an obvious trigger, or those with mechanical heart valves. In these patients, warfarin should be avoided in the rst trimester because it is teratogenic. The data regarding risk of recurrent stroke or TIA during pregnancy is insucient, which makes this a dicult issue to address in terms of counseling. Pregnancy planning The treatment recommendations for women with prior VTE are based on data from cohort studies rather than randomized trials. The risks of UFH and LMWH that must be reviewed with the patients include type I and type II heparin-induced thrombocytopenia (HIT), and a 10% decrease in bone density may occur in 2% to 2.5% of women, regardless of the type of heparin used [75]. HIT is rare. However, in one study, eight of nine aected patients developed a thrombosis [76]. Generally we recommend that women with a past history of a symptomatic VTE should start receiving LMWH at prophylactic doses when they nd out they are pregnant. Enoxaparin 40 mg daily or dalteparin 5000 units daily are reasonable. If UFH is used because of cost issues, then the doses are 5000 units twice a day in the rst trimester, 7500 units twice a day in the second, and 10,000 units twice a day in the third. As neuraxial anesthesia may not be administered to a woman who took LMWH within 24 hours, such patients should be changed to UFH at about 36 weeks gestation (10,000 units twice a day). When possible, the heparin should be withheld for 24 hours before delivery. Otherwise, check an active partial thromboplastin time if they arrive in labor, resume the medication 24 hours after a cesarean section or 12 hours after a vaginal delivery, and then continue until she is 6 weeks postpartum. The management of women with a prior supercial venous thrombosis or an upper extremity thrombosis related to an indwelling venous catheter is not clear.

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Women with the antiphospholipid antibody syndrome should be started on 81-mg aspirin, and UFH or LMWH at prophylactic doses as soon as they are pregnant. Peripartum management is the same as above. Women with a history of VTE on chronic anticoagulation have some choices. They should all be counseled about the risk of warfarin embryopathy, be aware of contraceptive options to plan their pregnancies, and be advised to check a pregnancy test as soon as they believe they are pregnant. It is reasonable to (1) put them on full-dose weight-based LMWH before conception, or (2) wait until they are pregnant, then stop the warfarin and put them on fulldose LWMH (or UFH if cost is an issue). When using UFH you may either (1) use a weight-based UFH regimen [77] (333 U/kg then 250 U/kg every 12 hours) or (2) admit, place them on a drip, and titrate it to a partial thromboplastin time of 60 to 80 seconds. Once the active partial thromboplastin time is therapeutic with a stable drip rate for 24 hours, convert them over to subcutaneous dosing twice a day. Monitor the 6-hour postinjection active partial thromboplastin time, adjust the dose in 1000-unit increments, and check the active partial thromboplastin time every week. Women on LMWH should have antifactor Xa levels checked to monitor the dosing. If the patient has a mechanical heart valve, then there are really two options based on American College of CardiologyAmerican Heart Association guidelines [78]. Because of anecdotal experience with valve thrombosis during pregnancy, we prefer to admit them for UFH once they are pregnant, resume coumadin in the second trimester (international normalized ratio O3.0), and then admit them again at about 34 weeks gestation to convert back to UFH for the remainder of the pregnancy. In this case, the UFH is dosed every 8 hours, the active partial thromboplastin time is checked 4 hours after the injection, and the active partial thromboplastin time should run closer to 80 seconds. The second option is to continue with UFH for the entire pregnancy. We prefer not to use LWMH in pregnant patients with mechanical heart valves. Women with a history of stroke or TIA not associated with antiphospholipid antibody syndrome should receive 81 mg of aspirin. All women should receive aggressive deep vein thrombosis prophylaxis with pneumatic compression boots for cesarean section in combination with early ambulation and heparin. Antepartum monitoring Once the heparin is initiated, a complete blood count should be obtained after 7 and 14 days to monitor for HIT. All women should take calcium and vitamin D supplementation. Postpartum VTE may still occur during the postpartum period. Women on prophylactic anticoagulation for maternal issues should continue their therapy

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for 6 weeks. We recommend UFH or LMWH because it is dicult to titrate the warfarin to the narrow therapeutic window of an international normalized ratio between 1.5 and 2.0. Warfarin is compatible with breast-feeding and should be resumed after delivery in women with indications for chronic anticoagulation.

Asthma Potential impact on pregnancy Asthma complicates approximately 6.5% of pregnancies. Case control studies and analysis of discharge data found that uncontrolled disease is associated with preeclampsia, preterm delivery, slightly lower birth weights (56 g), and preterm labor [79,80]. An analysis of hospital discharge data found that acute respiratory diseases and asthma were associated with preterm rupture of membranes, with a stronger association among blacks [81]. A randomized trial in pregnant asthmatics found inhaled beclomethasone decreased readmission rates from 33% to 12% [82]. These data support treatment and control of the disease to decrease maternal and fetal morbidity. Important physiologic changes are the increase of minute ventilation, because of a progesterone-mediated increase in tidal volume causing the normal PaCO2 to be 28 to 32 mm Hg; and a 70% decrease of functional residual capacity when supine (this is important before intubation, so supplemental oxygen should be administered), while spirometry and lung volumes are unchanged. Pregnancy planning The management of acute and chronic asthma in pregnancy is essentially unchanged. Patient education is important because a pharmacy database study found that use of asthma medications declined in the rst trimester [83]. Patients (and occasionally physicians) stop medications out of concern that they will adversely aect the fetus. Caution her that stopping medication could lead to an acute exacerbation, hospitalization, and administration of much higher doses of the medications. Talk to your patient about her reproductive plans and educate her about the risks of uncontrolled asthma. Inhaled steroids should be continued if necessary. Budesonide is FDA category B and is therefore preferred, but other forms are acceptable. Inhaled beta-agonists should be used as they would for nonpregnant patients. Nasal steroids can be used if theyll control allergies that could exacerbate asthma and thereby avoid the need for systemic medications. Any absorption will be minimal and the placenta should break down the medication before it reaches the fetus. One study of leukotriene inhibitors found no association between their use and

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congenital abnormalities or obstetric morbidity [84]. So, if other medications fail to control maternal disease, the use of leukotriene inhibitors should be considered, but we prefer to use them as adjunctive therapy when inhaled steroids are not adequate. Educate patients about the use of peak ow monitoring as an early warning system and tell her to call you in the event that she plans to become pregnant or unexpectedly nds that she is. Antepartum monitoring The course and treatment of asthma is not altered by pregnancy and one should look for the same typical triggers, such as reux and nasal congestion, as they are common during pregnancy. Use nonpharmacological means to treat reux, such as elevation of the head of the bed, avoidance of caeine (coee, tea, chocolate), consumption of smaller and more frequent meals, and avoidance of alcohol and tobacco. Proton pump inhibitors may be used, but the H2-anatgonists have been around longer so we prefer them. Rhinitis can be treated with nasal saline or budesonide, but avoid pseudoephedrine in the rst trimester. Treatment of acute exacerbations is the same as for nonpregnant patients. Maternal chest radiographs should be obtained when indicated. If she required high-dose steroids for more than 2 weeks in the past year, then she should receive stress doses at the time of vaginal or cesarean delivery. Postpartum If medication doses were altered during pregnancy, especially in women with reux, be prepared to adjust them to the prepregnancy levels. Maternal asthma and maternal smoking during pregnancy are independently associated with the development of bronchiolitis in term, nonlow birth weight infants without preexisting cardiac or pulmonary disease [85]. Excess weight and obesity Potential impact on pregnancy The impact of obesity and being overweight can be seen across a broad range of reproductive issues and is important to consider when planning a pregnancy [86,87]. Prior to conception, overweight and obese women are more likely to have comorbidities, such as diabetes and hypertension, which can have signicant implications for preconception care as well as potential pregnancy outcomes. Health care providers should take the opportunity to counsel women about the impact of excess weight and obesity on their reproductive risks as well as the importance of weight loss before conception [87,88]. Weight loss can lead to improved fertility as well as more favorable pregnancy outcomes [89,90].

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Women with an elevated body mass index are at risk of loss early in pregnancy [91], stillbirth (intrauterine fetal demise after 20 weeks gestation), and an increased risk of congenital anomalies, including neural tube defects [9295]. Pregnancy planning Pregnancy planning for women whose body mass index falls outside of the normal range involves weight loss, folic acid supplementation, and screening for and management of medical comorbidities. No evidence yet supports folic acid supplementation beyond the 400- to 800-mg level in the absence of a prior neural tube defect or gastric bypass surgery. Women with hypertension and diabetes should be sure they are not using angiotensinconverting enzyme inhibitors, angiotensin receptor blockers, and statins. Recommendations for women with diabetes and hypertension are addressed in detail in specic sections in this article. Weight loss, even in the range of 5% to 10% of body weight, has been found to improve menstrual regularity and improve fertility in obese women with polycystic ovary syndrome [90,96]. However, it is important to counsel women about the use of weight-loss medications during pregnancy. None of the currently available weight-loss medications are considered to be safe during pregnancy, so they should be stopped before attempting conception. Women who have undergone bariatric surgery see improved fertility rates with weight loss, but should delay pregnancy for at least the 12- to 18-month postoperative period of rapid weight loss. This delay requires a discussion of reliable contraception. Pregnancy after this time is not associated with increased maternal or fetal risks [95,97], and women can expect a lower risk of complications compared with their prior pregnancies [89,98]. Pregnancy outcomes following restrictive procedures are encouraging. There are no related prospective randomized studies, but cohort data show decreased likelihood of gestational diabetes, gestational hypertensive disorders, cesarean section delivery, and fetal macrosomia compared with historical controls. Women with a gastric band should be monitored by their surgeon because adjustment of the band may be needed. With the Roux-en-Y gastric bypass, food bypasses the duodenum and may not come into contact with intrinsic factor. This means women who have had this procedure should be sent for bloodwork, including ferritin; vitamins A, B12, and D; calcium; and prothrombin time; and have any abnormalities corrected before conception. These women may require parenteral repletion of iron, vitamin B12, or oral supplementation of fat-soluble vitamins [88,99]. Antepartum monitoring The Institute of Medicine recommendations for weight gain during pregnancy are followed by the American College of Obstetricians and Gynecologists and are adjusted for women whose body mass index is outside of the

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normal range with suggested weight gain of 15 to 25 lb for women who are overweight and 15 lb for women who are obese [100]. It is has been well established that dieting to achieve weight loss during pregnancy should not be recommended, though individual nutritional counseling may be of tremendous benet in limiting weight gain and avoiding gestational diabetes [100,101]. Following that, we do not alter the diet when some of our patients with gestational diabetes and a body mass index of more than 30 lose weight if they have seen a dietician, eat an appropriate diet, and feel well. Obesity makes antenatal monitoring less reliable by complicating estimation of fetal weight, acquisition of high-quality ultrasound images, and interpretation of the a-fetoprotein to determine risk of neural tube defects [87]. Women who are overweight or obese are more likely to develop gestational diabetes, hypertensive disorders of pregnancy, obstructive sleep apnea, and urinary tract infections during pregnancy [87,102,103]. Early screening for gestational diabetes at entry to prenatal care should be considered with follow-up screening later in pregnancy if initial tests are negative [88]. Peri- and postpartum Cesarean delivery is more common for women who are obese and there is an increase in perioperative morbidity, including anesthesia-related complications, endometritis, wound infection or dehiscence, and thrombophlebitis [87]. The American College of Obstetricians and Gynecologists recommends antibiotic prophylaxis to prevent wound infection for all cesarean sections [88]. Babies born to obese mothers show higher rates of fetal macrosomia and are at increased risk for shoulder dystocia [103]. Graduated compression stockings and early mobilization are recommended to prevent the deep vein thrombosis. There is insucient data to support heparin use except for those with prior thromboembolic disease [87,88,104]. Monitoring for resolution of pregnancy complications is important and women with gestational diabetes should undergo an oral glucose tolerance test 6 weeks postpartum to identify the 7% who will continue to have impaired glucose tolerance or frank diabetes [105]. Women should be counseled about the importance of returning to their prepregnancy weight and the importance of healthy diet and physical activity. Advanced maternal age Potential impact on pregnancy The average maternal age at delivery in the United States has increased steadily over the past 2 decades [3]. Birth rates are lower for women over 35, but in 2005 they constituted over 14% of childbearing women in the United States (Fig. 1) [3]. The term advanced maternal age is used to describe women who are 35 or older at the estimated date of delivery, but the eects of age do not demonstrate a threshold eect. Older women are

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Fig. 1. Birth rates by age of mother: United States, 1990 and 2005. (From Centers for Disease Control and Prevention. National Center for Health Statistics, National Vital Statistics System. Available at: http://www.cdc.gov/nchs/products/pubs/pubd/hestats/prelimbirths05/prelimbirths05. htm and http://www.cdc.gov/nchs/data/nvsr/nvsr52/nvsr52_23.pdf. Accessed July 18, 2008.)

more likely to enter pregnancy with pre-existing medical problems, including diabetes and hypertension, and this is likely to explain some of their higher risks. However, studies attempting to control for confounding found that maternal age remains an independent risk factor for low birth weight, prematurity, gestational diabetes, abruption, and perinatal mortality [97,99]. Fertility remains stable until age 30 when a signicant decline is seen [98]. Linked to lower fertility is a miscarriage rate that rises exponentially after age 30. The increased risk for Downs syndrome and other chromosomal abnormalities is well known and is linked to these high rates of miscarriage [9799,106]. The risk of a chromosomal abnormality for women delivering at age 20 is 1 in 526, but for women delivering at 45 it is 1 in 21 [98]. Increasing paternal age, often associated with maternal age, is associated with increased rates of autosomal dominant genetic disorders, such as Marfans syndrome and achondroplasia [98]. Autism-related disorders are associated with advanced maternal and paternal age [107]. Pregnancy planning Pregnancy planning for the older woman includes a frank discussion of her expectations for future fertility and the theoretic benets of conception sooner rather than later. Medical comorbidities as well as other health risks should be specically addressed to help assess the potential impact of these health risks on pregnancy, the impact of pregnancy on the health risks, and to develop plans to optimize her health before conception. Genetic risks are of major concern for this age group and an exploration of the womans (or couples) plans regarding genetic screening are best done while planning the pregnancy. Referral for genetic counseling, consultation with an

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obstetrician, or both should be considered, especially if there has been a prior adverse outcome. Antepartum monitoring The American College of Obstetricians and Gynecologists recommends screening all women for fetal chromosomal abnormalities [108]. The specic approach must be customized based on the availability of resources in the community. Women who present during the rst trimester have the option of integrated rst-trimester screening with nuchal translucency and biochemical markers. Women found to have an elevated risk can then undergo chorionic villus sampling or second-trimester amniocentesis. Women who present to care after the rst trimester should be oered a multiple marker screen or an amniocentesis. No specic guidelines recommend a dierent antepartum management approach for older women based solely on their risk related to advanced maternal age. Older women are more likely to develop pregnancy complications, including gestational diabetes and gestational hypertensive disorders, as well as placenta previa and abruption [97,99,106]. The current approach to prenatal care is dictated by their comorbidities and pregnancy complications. However, due to the increased rates of late preterm death, some researchers are exploring the strategy of antepartum surveillance after 37 weeks gestation to prevent late stillbirth [109].

Prior adverse outcomes Women who have had a poor pregnancy outcome have an elevated risk of future adverse events. Preconception planning includes an exploration of prior obstetric history and identication of evidence-based interventions that could improve the chances for a subsequent healthy pregnancy. In this section, we discuss several adverse outcomes that are important for the internist to understand to help guide preconception counseling and recommendations. Prior pregnancy loss Women who have had two to three consecutive spontaneous abortions are considered to have recurrent pregnancy loss and should be evaluated to determine the underlying cause [110,111]. Most losses are during the pre-embryonic or embryonic period. Pregnancy loss during the rst or early-second trimester can be due to number of underlying causes, including genetic abnormalities, hormonal and metabolic abnormalities, abnormal uterine anatomy, infection, environmental causes, occupational and personal habits, and autoimmune disorders. Other than antiphospholipid antibodies, thrombophilias are not associated with rst-trimester losses.

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Recognizing that an evaluation will identify the underlying cause in fewer than 50% of couples, these women should be referred to an obstetrician/ gynecologist during the preconception period for a complete evaluation and for recommendations about strategies to improve the chances of carrying a future pregnancy to term. The American College of Obstetricians and Gynecologists recommends women with three or more spontaneous abortions before the 10th gestational week and women with one or more unexplained fetal deaths at or beyond the 10th week be tested for lupus anticoagulant and anticardiolipin antibody. Those with repeated positive testing should consider anticoagulation with low-dose aspirin and heparin, as discussed in the section above on thrombosis and antiphospholipid antibodies. Chromosomal analysis may be helpful to identify balanced translocations, as would imaging to identify abnormal uterine structure with corrective surgery if an abnormality, such as a uterine septum, is identied [111]. Fetal loss, or loss at or beyond 14 weeks, is much less common and the underlying cause may be dicult to determine. A stillbirth is dened as in utero fetal death after 20 weeks gestation and occurs at a rate of about 6.5 per 1000 births. About half occur before 28 weeks gestation and 20% at or near term. Underlying causes are again broad and include birth injuries, such as uterine rupture or malpresentation; placental lesions, such as abruption; cord prolapse; hydrops fetalis; complications of multiple gestations; lethal congenital conditions; and infection. Maternal characteristics associated with stillbirth include diabetes, obesity, advanced age, antiphospholipid syndrome, and stress [112]. At the time of the stillbirth, a thorough evaluation of the mother and the fetus provides information for the mother and the providers about the cause of the stillbirth. Though the optimal evaluation of a stillbirth remains controversial, currently recommended tests and procedures include, in addition to a thorough medical and obstetric history, a fetal autopsy, placental evaluation, karyotype, indirect Coombs test, serologic test for syphilis, screen for fetal-maternal hemorrhage, toxicology screen, and parvovirus serology. Some recommend a screen for a lupus anticoagulant for all cases. Others recommend it if there is evidence of placental insuciency, placental infarction, recurrent loss, or a personal or family history of thrombosis [110,112]. Prior preterm labor Preterm birth, dened as delivery before 37 weeks gestation, is the leading cause of infant mortality in the United States [113]. Preterm birth can be a result of spontaneous premature labor or a result of a medically indicated preterm birth due to a maternal or a fetal indication. Though many risk factors for spontaneous preterm labor have been identied, there is little understanding of the underlying etiology. Rates of preterm delivery in the United

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States were 12.7% in 2004 [3]. Women with a history of a prior preterm delivery are at a twofold higher risk during subsequent pregnancies [114]. Prevention of recurrent preterm labor is thus dicult. Addressing maternal risk factors, such as tobacco use and others described in this article, are of tremendous importance. In addition, recent studies have identied the use of 17a hydroxyprogesterone caproate to be eective in decreasing rates of spontaneous preterm labor among women carrying singleton pregnancies who were at high risk due to a history of prior preterm labor [115,116]. This is a new intervention and the optimal route of drug delivery, as well as its role in the primary prevention of preterm labor, has yet to be dened. It is, however, the most promising intervention to date and women with a history of preterm labor should receive care at a facility with access to this and other state-of-the-art interventions if possible. While there are no good tests to predict preterm labor, ultrasonography to measure cervical length between weeks 16 and 24 can be helpful in identication of women at risk for recurrent preterm birth [114]. Prior neural tube defect Women who have a history of delivering a baby with a neural tube defect are at increased risk for a defect in subsequent children and folic acid supplementation at high doses is recommended to prevent recurrence. An oral dose of 4.0 mg daily during the month before conception and for the rst 3 months of pregnancy is recommended [117]. Ecacy of this intervention is high. However, studies have found that a surprisingly small fraction of women with a prior child with a neural tube defect recall receiving this advice [93].

Summary If appropriately educated, internists are positioned to act as the rst line of defense in the pre- and interconception periods. They can identify and address past medical and obstetric issues to modify risks before pregnancy. Evidence related to smoking, asthma, diabetes, obesity, and thyroid disease shows that control of these before pregnancy will result in a lower risk of complications. By identifying and creating a plan for high-risk patients, providers can better prepare for and, it is hoped, avoid last-minute scrambling that is the result of inadequate pregnancy planning. Every physician need not become an expert, but data support the need for increased surveillance and intervention by primary caregivers. Providers should be familiar with areas where practical interventions exist, provide a guide on how to address the issues, and provide appropriate guidance to the patient (Appendix). Again, in this era of heightened awareness, we hope that this article will serve as a roadmap to practicing internists so they will incorporate pregnancy planning into their everyday care.

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Appendix Useful resources  2006 recommendations from the Centers for Disease Control and Prevention: Recommendations to improve preconception health and health cared United States: a report of the CDC/ATSDR Preconception Care Work Group and the Select Panel on Preconception Care, MMWR, April 21, 2006/55 (RR06);123. Available at: http://www.cdc.gov/ mmwR/preview/mmwrhtml/rr5506a1.htm. Accessed May 8, 2008.  Contraception: World Health Organization. Medical eligibility criteria for contraceptive use, 2004. Available at: http://www.who.int/reproductive-health/ publications/mec/. Accessed May 8, 2008. Emergency Contraception. Available at: http://ec.princeton.edu/ and http://www.womenshealth.gov/faq/econtracep.htm. Accessed July 18, 2008.  Pregnancy planning for women with chronic medical problems: Rosene-Montella K, Keely EJ, Lee RV, et al, editors. Medical care of the pregnant patient. 2nd edition, Womens health series. Philadelphia: American College of PhysiciansAmerican Society of Internal Medicine, 2007. Ehrenthal DB, Homan MK, Adams Hillard PJ, editors. Menstrual disorders, Womens health series, Philadelphia: American College of PhysiciansAmerican Society of Internal Medicine, 2006. American Diabetes Association. Preconception care of women with diabetes. Diabetes Care 2004; 27:S768. Morell, MJ. Epilepsy in women. Am Fam Physician. 2002;66(8):148994. Lampe, MA. Human immunodeciency virus-1 and preconception care. Matern Child Health J 2006;10(Suppl 7):1957.  Statistics for pregnancy outcomes in your state: March of Dimes. Available at: http://www.marchofdimes.com/ peristats/. Accessed May 8, 2008.  Medications in pregnancy Briggs GG, Freeman RF, Yae SJ. Drugs in pregnancy and lactation (hardcover). 7th edition. Philadelphia: Lippincott Williams & Wilkins; 2005.

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[111] American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 24: management of recurrent pregnancy loss, February 2001. (Replaces technical bulletin no. 212, September 1995). American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 2002;78(2):17990. [112] Silver RM, Varner MW, Reddy U, et al. Work-up of stillbirth: a review of the evidence. Am J Obstet Gynecol 2007;196(5):43344. [113] Callaghan WM, MacDorman MF, Rasmussen SA, et al. The contribution of preterm birth to infant mortality rates in the United States. Pediatrics 2006;118(4):156673. [114] Spong CY. Prediction and prevention of recurrent spontaneous preterm birth. Obstet Gynecol 2007;110(2 Pt 1):40515. [115] American College of Obstetricians and Gynecologists. ACOG committee opinion. Use of progesterone to reduce preterm birth. Obstet Gynecol 2003;102(5 Pt 1):11156. [116] Meis PJ, Klebano M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alphahydroxyprogesterone caproate. N Engl J Med 2003;348(24):237985. [117] Recommendations for the use of folic acid to reduce the number of cases of spina bida and other neural tube defects. MMWR Recomm Rep 1992;41(RR14):17.

Med Clin N Am 92 (2008) 12271237

Prescribing Medications Safely During Pregnancy

William F. Rayburn, MD, MBA1,*, Adanna C. Amanze, MD2
Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of New Mexico Health Sciences Center, 4th Floor, Ambulatory Care Center, 2211 Lomas Blvd. NE, Albuquerque NM 87106, USA

Medication use has changed among women of reproductive age in the United States. New products are being marketed directly to the consumer, increased concerns about safety and ecacy are apparent, public education has increased, and more prescription medications have been granted nonprescription status by the US Food and Drug Administration (FDA). Reproductive-age women increasingly are relied on to provide their internist or other primary health care provider with an accurate description of drugs they use. Although not widely practiced, drug regimens for chronic illnesses are best assessed and altered in the preconception period. Pregnancy is being diagnosed earlier because of the widespread availability of sensitive, over-the-counter home pregnancy tests. Unfortunately, because risks from many medications when taken during pregnancy are often unknown, there may be either a voluntary or involuntary cessation or an underreporting of medications. Most internists and their patients adopt a conservative approach to medication use during pregnancy, especially in the rst trimester. This article oers internists practical guidelines for prescribing medications when pregnancy is either anticipated or already discovered. Those medications studied most during human pregnancy and believed to pose the least risk are discussed along with limitations in knowledge when
* Corresponding author. Department of Obstetrics and Gynecology, MSC 10 5580, 1 University of New Mexico, Albuquerque NM 87131-0001. 1 Having a pharmacology background, he is the author of many studies reporting drug trials during pregnancy and of several texts dealing with drug therapy during pregnancy. 2 Before her subspecialty training, she was an active practitioner of general obstetrics and gynecology. E-mail address: wrayburn@salud.unm.edu (W.F. Rayburn). 0025-7125/08/$ - see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2008.04.006 medical.theclinics.com

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considering which medication is safest. Strategies are proposed to counsel patients who require a specic medication and desire to become or already are pregnant. Prenatal medications Medications commonly taken prenatally include vitamins, iron preparations, calcium, analgesics, antibiotics, and antacids. Over-the-counter drugs account for approximately half of the medications, and acetaminophen remains the most commonly taken medication during pregnancy. Antibiotics are the most commonly prescribed drugs. Although tobacco, alcohol, and illicit substance use tends to decrease as pregnancy progresses, prescription medications are taken the same or more often during gestation. According to our experience, the mean number of medications consumed during the second and third trimesters, 3.3 and 4.1 respectively, is signicantly higher than the number (2.6) taken before pregnancy [1]. Given the abundance of medications available, it is unclear why there is a paucity of scientic information about their potential adverse eects on pregnancy. Risks and experience during pregnancy with new drugs are usually not well explored. As a result, practitioners often rely on older drugs during gestation because a larger body of information has been reported about them. These older medications may not be preferred after patients deliver. Special considerations during pregnancy Conrmation of pregnancy and accurate gestational dating are critical in determining susceptibilities. In utero exposure to a drug may be divided into three periods of fetal development: (1) ovum, from fertilization to implantation, (2) embryo, from the second through the eighth week, and (3) fetus, from the eighth completed week until delivery. An all or none eect (spontaneous abortion or not) is believed to result from exposure during the rstdor ovumdperiod. The second period, or embryo, encompasses the most critical time with respect to structural malformations, because it involves organogenesis. Any specic harmful eect relates to the timing and duration of drug exposure during this relatively brief but critical time of development. Drug absorption is not signicantly aected by pregnancy, but serum concentrations of albumin for drug binding are lower than when nonpregnant. Pharmacokinetic changes during pregnancy include a higher volume of distribution, lower maximum plasma concentration, lower steady serum state concentration, shorter plasma half-life, and higher clearance rate [2]. Virtually all drugs and their end products cross the placenta, with unbound concentrations of the drug being similar or, with chronic therapy, sometimes higher in fetal than maternal serum. A few drugs have a high molecular weight that prohibits transplacental passage in signicant amounts (eg, glyburide, interferon, thyroid supplements, and insulin).

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Despite being infrequent, detrimental eects may occur with certain drugs when taken beyond the rst 8 weeks of organogenesis. Cells continue to divide in the hematologic, reproductive, and central nervous systems. Few medications are implicated in restricting fetal growth or reducing organ size. There is minimal or no consistent information in humans about longterm eects, such as learning or behavior problems (functional teratogenesis), that may result from chronic prenatal exposure to a certain medication. Individual susceptibility is also dose dependent. Fetal risk to a constant dose of a medication may not be obvious in a small sample of cases but could be biologically signicant in a larger population. An increase in the daily dose of certain medications (eg, anticonvulsants, insulin, or thyroid supplementation) may be necessary during pregnancy to maintain serum concentrations in a therapeutic nonpregnant range. The only drugs suspected of prolonging gestation are the b-adrenergics, which stimulate uterine-relaxing b2-agonist receptors. No drug is known to directly shorten gestation, although a few have been questioned, including ergotamine and b-adrenergic blockers. Problems with studies in humans and animals All medications to be approved by the FDA must undergo animal studies to determine possible teratogenic eects. Animals used to study alterations on the fetus include rodents (fertility, birth defects, birth weights, behavior), rabbits (birth defects), baboons (uterine blood ow), and sheep (uterine blood ow, maternal and fetal cardiovascular eects, fetal hypoxia and acidosis). Doses are often much higher than typically used (per body weight or surface area) to test the systems for any possible detrimental reproductive harm. Although such studies may be helpful, if ndings indicate no additional risk, their results do not reliably predict the human response. Few medications are linked with abnormal fetal development. Major structural defects are apparent at birth in approximately 3% of all pregnancies and approximately 4.5% of all children by 5 years of age [2]. A cause or proposed mechanism for the defect can be determined in less than half of cases. Expert consensus on the safety of such agents often does not exist and may be impossible to achieve. In addition to the period of fetal development and the dose of the medication, other factors to consider when determining fetal risk include the exact identity of the medication, duration of therapy, underlying illness, other drugs, and the genetic susceptibility of the mother and fetus (eg, nicotine and cleft palate). Conclusions from human studies about birth defects must be interpreted cautiously. Results of retrospective and uncontrolled studies and individual case reports or small series may overestimate the fetal risk to a specic drug or a combination of medications. Case reports do not establish causation. Dierentiating between risks of a specic drug and hazards from a maternal illness can be dicult in explaining an unfavorable pregnancy outcome (eg,

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stillbirth: enoxaparin versus thrombophilia; fetal growth restriction: azathioprine versus underlying illness, b-blocker versus hypertension; spontaneous abortion: bupropion versus cigarette smoking; fetal distress: cholesyramine versus cholestasis). It is necessary to distinguish between the natural prevalence ratedthe rate at which the defect occurs in a populationdand the additional risk potentially attributable to a drug. Studies of large populations are required, yet usually unattainable, to determine the relative risk from specic potential teratogens. Assessing neurobehavioral eects from in utero exposure to centrally acting drugs is dicult, especially beyond the immediate neonatal period. The dose, osprings age and gender, and behavior test system must be considered. Doses in animals are often so high as to cause a toxic eect and result in adverse events in ospring.

Counseling the expectant mother In conjunction with an obstetrician, counseling before or during pregnancy about continuing or beginning a medication should be undertaken in an open, supportive, and informative manner. Most conditions involve drug exposures at low levels of relative and absolute risks. Strategies for prescribing medications in pregnancy are summarized in Box 1. Examples of questions for internists to ask about prenatal exposure to a medication are listed in Box 2. A detailed fetal ultrasound examination is often

Box 1. Strategies for prescribing medications during pregnancy (examples shown in parentheses)  Avoid multiple medications if possible and choose those that are safe (anticonvulsants, antihypertensives)  Determine what is the best method to monitor therapy (asthma: peak ow meters; hypertension: portable blood pressure monitors; diabetes: glucometers)  The healthiest mother is most likely to deliver the healthiest infant  Focus on the underlying disorder, not on the drug alone, to explain any additional risk to the fetus (hypertension and fetal growth restriction, seizures and childhood seizures, systemic lupus and fetal growth restriction)  Only a few drugs are clearly linked with specic birth defects (phenytoin, warfarin, alcohol, methotrexate, diethystilbestrol, cis retinoic acid, valproic acid, carbamazepine)  Experience with rst-trimester exposure for any drug is often too limited in humans to be considered safe

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Box 2. Examples of questions to ask about prenatal exposure to a medication      WHEN was the medication taken? WHY was the medication taken? HOW long was the medication taken? WHAT other drugs or substances were taken? WHERE do I nd more information?

recommended to accurately date the pregnancy and, if possible, screen for any structural defects. Further methods of early fetal evaluation, such as screening tools for aneuploidy in the rst and second trimester, are not predictive of direct eects from drugs. Many sources of information about potential teratogens are available as publications [35]. Table 1 lists references of computerized databases on teratogenic information about specic drugs. We nd the Reprotox reference [6] to be most helpful. To avoid liability, pharmaceutical manufacturers do not encourage prescribing their drugs during pregnancy unless the benet outweighs the risk. Marketing of a medication for specic use during pregnancy is unrealistic from the business perspective, because it requires much investment in time and cost to conduct research on a vulnerable population that is limited in number. Examples of standard statements in the Physicians Desk Reference about any medication include the following:
Reproductive studies, performed in rats and mice at maternally toxic dose levels, revealed no evidence of impaired fertility or harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. As animal reproduction studies are not always predictive of human response, (name of medication) should be used during pregnancy only if clearly needed.

These statements are inconclusive and redirect attention to the obstetrician or internist for prescription decision making.
Table 1 Examples of references of databases on teratogenic information Organization Web site

National Library of Medicine www.nlm.nih.gov Organization of Teratogen Information Services www.otis.pregnancy.org Pharmaceutical companies www.pharmacy.org/company.html Poison control centers www.poison-control.com Pregnancy exposure registries www.fda.gov/womens/registries/default.htm Reproductive toxicology center http://reprotox.org Physicians Desk Reference http://www.pdr.net/login/Login.aspx

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Table 2 Examples of rst-line, second-line, and contraindicated agents in treating medical illnesses during pregnancy Drugs/medical illnesses Analgesics Antithyroid Antiacne First-line agents Acetaminophen Propylthiouracil Benzoyl peroxide Topical clindamycin Topical erythromycin Topical metronidazole Adenosine B-adrenergic blockers Calcium channel blockers Digoxin b2 agonist Inhaled corticosterioids Penicillins Cephalosporins Macrolides Second-line agents Opioids Methimazole Contraindicated NSAIDs O 48 hours I-131 Isotretinoin

Antiarrhythmics

Quninidine Amiodarone Flecainide

Antiasthmatics

Antibacterials

Anticoagulants

Anticonvulsants

Heparin Low molecular weight heparin Lamotrigine Gabapentin

Oral corticosterioids Anticholinergic agents Methylxanthines Leukotriene modiers Sulfonamides Tetracycline Trimethoprim Doxycycline Nitrofuratoin Quinolones Metronidazole Gentamycin Clindamycin Warfarin

Antidepressants

Antidiabetic Antidiarrheal Antiemetics

Antifungals Antihypertensives

Selective serotonin reuptake inhibitors Tricyclic antidepressants Insulin Glyburide Loperamide Pyridoxine Doxylamine with pyridoxine Antacids Topical imidazole Methyldopa Labetalol Nifedipine Corticosteroids

Valproate Carbamazepine Phenytoin Barbiturates Wellbutrin Cymbalta Benzodiazepines Metformin Kaopectate Promethazine Metoclopracamide Ondansetron Nystatin Fluconazole Propranolol Atenolol Diuretics Hydralazine

ACE inhibitors

Anti-inammatory

(continued on next page)

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Table 2 (continued ) Drugs/medical illnesses Antimigraine First-line agents Acetaminophen Metoclopramide Second-line agents Acetaminophen codeine Acetaminophen caeine Opioids Selective serotonin agonists Contraindicated NSAIDs O 48 hours

Antiparasitic Antipsoriatic Antipsychotic

Lindane 1% Permethrin 5% Calcipotriene Cyclosporin A Haloperidol

Retin-A derivatives Methotrexate sodium Clozaril Zyprexa Seroquel Risperdal Valacyclovir Famciclovir Rifampin Ethambutol Pyrazinamide Benzodiazepines

Antiviral Antitubercular

Acyclovir Isoniazid

Streptomycin

Anxiolytics

Bronchitis

Chemotherapeutics Constipation

Buspirone Zolpidem Antihistamines Acetaminophen Decongestants Cough suppressants Contraindicated Psyllium

Antibiotics

Gastroesophageal reux Hemorrhoids

Antacids

Lactulose Sorbitol Glycerin Rantidine Lansoprazole Pantoprazole

Immunosuppressants

Psyllium Hydrocortisone suppositories Glucocorticoids Azathioprine Cyclosporin Tacrolimus 5-aminosalicylic acid

Mycophenolate mofetil Sirolimus Cyclophosphamide Leunomide Sulfasalazine Corticosteroids Metronidazole Antibiotics

Inammatory bowel

Inuenza

Acetaminophen Decongestants Cough suppressants

(continued on next page)

1234 Table 2 (continued ) Drugs/medical illnesses Intrahepatic cholestasis Mood stabilizers Pneumonia

RAYBURN & AMANZE

First-line agents Antihistamines Ursodeoxycholic acid Cholestyramine Lamotrigine Acetaminophen Erythromycin Azithromycin Ceftriaxone Methadone

Second-line agents Phenobarbital

Contraindicated

Valproate Carbamazepine

Polysubstance abuse Ethanol Tobacco Heroin Respiratory infection Upper respiratory Sinusitis

Vasomotor rhinitis

Acetaminophen Decongestants Amoxicillinclavulanate Cefuroxime Saline nasal spray Steroid nasal spray Saline nasal spray Ipratropium Steroid nasal spray

Benzodiazepines Buprenorphine Nicotine replacement Bupropion Cough suppressants Ipratropium

Antabuse

Abbreviation: NSAIDs, nonsteroidal anti-inammatory drugs.

The FDA dened ve risk categories (A, B, C, D, X) that are used by manufacturers to rate their products for use during pregnancy. The approximate frequency of medication in each risk category is 2% for A, 50% for B, 38% for C, 3% to 5% for D, and 1% to 5% for X [3]. Ratings range from A for drugs that show no evidence of damage to the fetus, to D and X for drugs that are denitely teratogenic. The D rating is generally reserved for drugs (eg, secobarbital, doxycycline, lorazepam) with no safer alternatives. The X rating means there is absolutely no reason to take the drug in pregnancy (eg, oral contraceptives, benzodiazepines, misoprostol). These FDA categories are outdated, however, and often do not reect the degree to which available information has ruled out risk to the fetus. A major initiative is underway to make these categories obsolete and provide more informative drug labeling for clinicians and their pregnant patients. Pregnancy labels of the future likely will address three important areas: (1) clinical considerations, (2) summary risk assessment, and (3) data to support the assessment. The goals of the initiative are to highlight clinical considerations relevant to making prescribing decisions for a particular medication for pregnant women, including disease risk and the risk of no treatment. This label also will include information that may assist

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clinicians when counseling women whose fetuses are inadvertently exposed to medications in early gestation. The summary risk assessment section may be a narrative text that articulates, as best can be determined, the risk of exposure based on animal and human data. Fetal eects from specic medications We compiled a list in Table 2 of rst-line, second-line, and contraindicated agents in treating medical illnesses during pregnancy. A drug was selected as being rst line if there had been much clinical experience to be considered safe or if the reported experience was sucient to suggest no additional risk. Table 3 describes fetal eects from drugs listed in Table 2 as being contraindicated. Most human data involve small series or case reports that, although helpful, may be biased or reect the pregnancys background risk for birth defects. Case reports of malformations after prenatal exposure to a certain drug may include exposures to other agents and a lack of uniformity of abnormalities, which makes their association with a single agent unlikely.
Table 3 Examples of contraindicated drugs and their known adverse eects on the developing human fetus Drugs ACE inhibitors Antabuse Chemotherapeutics Doxycycline I-131 Immunosuppressants Mycophenolate mofetil Sirolimus Cyclophosphamide Leunomide Live-attenuated virus Methotrexate NSAIDs Quinolones Retin-A derivatives Streptomycin Tetracycline Thalidomide Warfarin First-trimester fetal eects Cardiac/CNS malformations Congenital malformations Abortion, anomalies Fetal thyroid development Embryopathy Same as above Same as above Same as above Embryopathy IUGR, miscarriage, cranial anomalies Cardiac, gastroschisis, miscarriage Toxic to developing cartilage CNS, cardiac, facial anomalies Otoxicity None known Limb reduction (gastrointestinal/ cardiac/renal defects) Skeletal defects Second- and third-trimester fetal eects Oligohydramnios, IUGR, renal failure Hypoplastic gonads, IUGR Eect on bone growth CNS development

Same as above Premature ductal closure Toxic to developing cartilage Stillbirth, mental retardation None known Staining of teeth

CNS defects/microhemorrhages

Abbreviations: CNS, central nervous system; IUGR, intrauterine growth restriction; NSAIDs, nonsteroidal anti-inammatory drugs.

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Principles of maintenance drug therapy are the same as in the nonpregnant state. Knowledge about one or two medications for each disorder is recommended. Certain drugs may need to be prescribed either in a higher dose or more frequently to obtain therapeutic concentrations in the expanded intravascular volume during pregnancy. Side eects from medications, such as nausea, fatigue, and gastrointestinal disturbance, may mimic symptoms from physiologic changes during pregnancy. For most drugs, typical doses are not anticipated to increase the risk of congenital anomalies. Dissimilarities in the dose and the route of delivery also limit interpretation. For example, short-term administration of a drug given intravenously or sublingually makes it dicult to relate risk when the same medication is taken orally or vaginally in a lower dose either for a longer period or at a different period of gestation. Randomized controlled trials of drugs are rare during pregnancy, and prospective cohort investigations are uncommon. Because a control population is often not possible, it is also dicult to separate any additional risk from the medication and the underlying disease. Care of gravid women with signicant medical problems should include an assessment of the potential risk not only to the fetus but also to the patients. Occasionally, alternative therapies exist that may be safer to a developing fetus. Although the lowest eective dose is to be prescribed, inadequate treatment may lead to minimal benet and potentially greater risk to the pregnancy. Although information about prescription drug use is often scant, assessing risks associated with over-the-counter medications and natural food products is even more dicult. It should be emphasized, however, that these medications should be taken as directed by the product label. A review of the PDR for Non-Prescription Drugs reveals little or no information about reproductive hazards for most of these medications [7]. Many agents contain multiple ingredients, both active and inactive, which compounds counseling about pregnancy risks. Doses may not be included in the product labeling, although the dose is usually low. Summary Medications are taken during gestation at the same frequencydor more oftendas before pregnancy. Testing to assess overall fetal well-being is not predictive of a drugs eects. Few drugs are major teratogens during early gestation, but heightened vigilance is crucial to protect pregnant patients. Detrimental eects can occur beyond the critical embryo stage as cells continue to divide in the developing hematologic, reproductive, and central nervous systems. Listed in this article are medications believed to be rst line, second line, or contraindicated in treating pregnant women for certain illnesses. In general, when prescribing medications during pregnancy, the primary care physician should typically follow the same principles as for a nonpregnant patient.

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References
[1] Splinter M, Nightingale B, Sawgraves R, et al. Medication use during pregnancy by women delivering at a tertiary university hospital. South Med J 1997;90:498502. [2] American College of Obstetricians and Gynecologists. Teratology. ACOG Educ Bull 1997; 236:8779. [3] Physicians desk reference. 62nd edition. Montvale (NJ): Medical Economics; 2008. [4] Briggs GG, Freeman RK, Yaee FJ. Drugs in pregnancy and lactation: reference guide to fetal and neonatal risk. 7th edition. Baltimore (MD): Williams & Wilkins; 2005. [5] Briggs GG, Freeman RK, Yaee FJ. ReproTox database, vol. 13, no. 1. Bethesda (MD): Reproductive Toxicology Center; 2000. [6] ReproTox. Bethesda, MD, Reproductive Toxicology Center. Available at: http://reprotox. org/. Accessed January 24, 2008. [7] PDR for nonprescription drugs. 29th edition. Montvale (NJ): Medical Economics; 2008.

Med Clin N Am 92 (2008) 12391252

Domestic Violence and Rape

Julianne S. Toohey, MDa,b,*
a

Division of Maternal Fetal Medicine, University of California, Irvine Medical Center, 101 The City Drive, Bldg. 56, Orange, CA 92868, USA b Department of Obstetrics and Gynecology, University of California, Irvine, School of Medicine, 101 The City Drive, Bldg. 56, Orange, CA 92868, USA

Domestic violence and sexual assault No compilation of womens health care is complete without confronting domestic violence and sexual assault. Long recognized as a health care and physician issue, intimate partner violence continues to be one of the most frequent causes for injury and death to women in the United States and worldwide. According to the Commonwealth Fund survey in 1998, 31% of women reported either physical or sexual abuse from a husband or boyfriend. One in ve American women also reported being raped during their lifetime [1]. Accurate information is dicult to compile, and it is understood that many of these crimes are simply not reported. Studies in this area also are fraught with sampling biases. US Department of Justice statistics reveal that intimate partner violence is primarily a crime against women, who were 85% of the victims reported in 2001. Murders and the most serious injuries are more common against women. In the year 2000, approximately three women per day were murdered in the United States by a spouse or boyfrienddfor a total of 1247 [2]. Although it seems that the numbers of rapes have been dropping since the 1970s, 3 to 4 per 10,000 rapes against women continue to be reported to the police each year in the United States [3,4]. The National Institute of Justice and the Centers for Disease Control and Prevention survey compiled in 2000 conrmed these disturbing numbers, with 25% of women admitting to being raped during their lifetime but only one in ve women reporting this crime. The number of women suering from nonlethal assault and emotional trauma can only be extrapolated from these data, which are staggering in their implications.
* Division of Maternal Fetal Medicine, University of California, Irvine Medical Center, 101 The City Drive, Bldg. 56, Orange, CA 92868. E-mail address: jtoohey@uci.edu 0025-7125/08/$ - see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2008.04.005 medical.theclinics.com

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TOOHEY

Cycle of violence Since Lenore Walkers initial description in 1979, much has been written regarding the cyclical and often predictable behavior observed in violent relationships, notably the three interacting phases of the cycle of violence known as (1) the tension-building phase, (2) the violent episode, and (3) the honeymoon phase. The complex psychology and sociology involved in domestic violence is beyond the scope of this article. However, it is important for health care professionals to realize that these phases tend to escalate over time, with the violent episode increasing in severity and frequency and the honeymoon or violence-free phase decreasing in length. The interaction of this cyclical behavior in relation to intergenerational dynamics is beginning to be better appreciated. Abused children grow up to have an increased risk for victimization and violent behavior and psychologic and school problems. Abused wives age to become abused elders. Intimate partner violence is a smaller photograph of family violence as a whole and violence in the community at large [5]. Domestic violence includes many forms of abuse of power and control. Women often state that although the physical component of domestic violence is frightening and dangerous, the psychologic abuse is often what is most dicult to recover from. This form of abuse includes threats, intimidation, humiliation, and constant reminders of past sorrows or mistakes. Fear of hurting or kidnapping the children is often a primary concern, as are threats to report a woman to immigration authorities if she happens to be undocumented. Threats to hurt either pets or people a woman loves may be coupled with threats of suicide by the batterer. Living in constant terror has obvious long-term eects on a persons coping skills, response to stress, and the ability to trust and maintain a healthy relationship. The physical abuse seen in these relationships ranges from a slap or push to repeated beatings and death. Domestic violence also may involve sexual abuse that can include rape, degrading acts, violent sex, or sex without protection against pregnancy, HIV, and other sexually transmitted diseases. Control of the familys nances is often central to the dysfunctional dynamics of the couple and inuences the options available to the victim. Economic control can occur regardless of whether a woman works outside of the home and includes control over the checking account, use of the car, and access to food, transportation, shelter, and help.

Risk factors Studies reveal that women and men of all ages, sexual orientation, ethnic, religious, and educational backgrounds, and socioeconomic levels are at risk for intimate partner violence. Despite this broad range, however, several risk factors have been identied [6]. Women who are noted to be unusually dependent on their partners are at increased risk of being victims, including

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women who are isolated geographically or culturally from other support systems, such as women who live in rural areas, immigrants, or women who do not speak the community language. Women with disabilities or chronic illnesses are at high risk because these conditions increase their dependence on their spouse. Teenagers and pregnant women are particularly vulnerable [7,8]. The proles of batterers are also varied, with several characteristics noted. Dutton [9,10] has written extensively on the psychologic prole of the batterer and has shed light on the complex and poorly understood problems and disorders faced by these men. Most, if not all, of these individuals were also victims of emotional and physical abuse. Learned helplessness and disassociation in childhood and adolescence lead to a profound lack of selfesteem with diculty in properly identifying and expressing emotion. Many batterers have serious challenges at work or are unemployed. The role of alcohol and drug abuse in these cases is extensive and complicates identication and recovery [9,10]. Pregnancy and domestic violence Pregnancy has been clearly shown to be a time of increased risk, with many relationships becoming actively violent at this time [11]. Homicide is a major contributor to maternal mortality, although it is rarely included in maternal mortality surveillance systems [12]. The rape-related pregnancy rate in the United States is 5% per rape among victims of reproductive age, resulting in more than 32,000 unwanted pregnancies each year [13]. It is unclear why violence increases during pregnancy. Speculations include a plummeting of coping skills caused by increased stress on relationships during pregnancy and the postpartum period. Several studies have noted an incidence of active violence in approximately 19% to 23% of patients in a prenatal care clinic [14,15]. Pregnant women have more injuries to the breast and abdomen and have been noted to suer increased incidence of pregnancy loss, preterm delivery, and low birthweight infants [1618]. Physicians who care for pregnant women need to keep in mind the various ways that domestic violence can present during this time, including vaginal bleeding, preterm labor, placental abruption, and complaints of decreased fetal movement. Pregnancy is also known to be a time when women are more apt to seek medical help. They may begin questioning their dicult relationships and fear safety for their child and the future of the family. The frequent contact between patients and their physicians that results from multiple prenatal care visits likely plays an important role. Trust is more easily built, and physicians have many opportunities for education and noting inappropriate interactions, bruises, or depression in their patients. Likewise, primary care physicians who follow women for chronic illness may have greater success in properly identifying and beginning appropriate treatment of violence.

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TOOHEY

Unfortunately, it is unclear whether physicians have risen to the challenge of this opportunity [19,20]. Health care providers need to remember that any violence during pregnancy is a foretelling of the risk to a child in that family. One in six neonates in the United States goes home to a family with active violence [21]. It is also understood that when a mother is battered, there is a 50% chance that the children in the home are also abused. It is estimated that 3.3 million children between the ages of 3 and 17 years witness parental abuse in the United States every year. Because of serious long-term psychologic, educational, and sociologic consequences seen in children of violent homes, the denition of child abuse in various states has expanded to include witnessing physical abuse between parents. Barriers to diagnosis Despite the known risks to such large numbers of women in our country and the known burden to our society, physicians continue to have diculty adequately identifying women in trouble. Primary care clinics and emergency rooms are estimated to have high percentages of patients suering from domestic violence, with estimates of approximately 5% to 19% and 50%, respectively [2224]. One in four women who attempts suicide is a victim of abuse. Several studies have revealed that only a fraction of battered women are correctly identied in these settings. Some studies have estimated that only 1 in 25 battered women are correctly identied in an emergency room and even less in the clinic or oce setting [25,26]. Why is this so? Several barriers stand in the way of proper diagnosis. Clearly, women are reluctant in many cases to disclose such intimate and frightening details, especially after chronic abuse. They fear repercussions by the batterer and the social and legal complications. Highly successful or educated women are often ashamed to admit they have such loss of control at home. Because of their damaged self-esteem, some women even suspect that they may deserve the treatment and consider themselves poor wives or mothers. Perhaps most importantly, batterers are often the sole source of support for the family, and their arrest or absence would leave the family destitute. Financial concerns are clearly a frequent reason why women remain in violent relationships. The psychology of an abused woman is complicated and not clearly understood by health care providers. It is dicult to imagine the consequences of chronic emotional and physical battery with the attendant loss of selfcondence, emotional maturity, and support systems. These women are often not able to take the dicult steps necessary to leave an abusive relationship and navigate the court system while continuing to provide for their family. The ability to trust in others who are willing to help is decient. The fact that violence is clearly cyclical in naturedwith lengths of time that are relatively peacefuldmakes leaving a dicult step. Women continue to hope

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for better times and blame the behavior on stress, alcohol, or drug use. Although physicians often wonder how and why women stay in these relationships, it is actually more remarkable that women are able to leave at all. Physicians are responsible for several barriers to proper diagnosis. Frequently they are not aware of the scope of this problem and do not aord it the attention it deserves. It is important to remember that few, if any, medical conditions in your practice are seen as frequently as violence. Physicians lack of appreciation that all women are at risk plays an important role in their failure to identify victims properly. Physicians attitudes may be that although this is an unfortunate problem, it is not their concern or in their jurisdiction. They may feel that that they are not able to provide any help in this regard or question the usefulness of their intervention. Lack of knowledge about how to proceed if they do identify an abused patient is often what keeps health care providers from addressing the issue. It has been noted that although many health care providers understand that violence is an important health care issue, they do not wish to screen patients [2729]. Time constraints are clearly a factor that aects the correct identication of these patients. Practitioners have little time in modern oce practices to instill trust and address the multitude of issues that confront patients. Because of the large numbers of women aected and the serious implications of this diagnosis, an improved eort in this regard is justied. Physicians need to confront the fact that if they are rarely identifying cases of domestic violence, the likelihood is that they are frequently missing this diagnosis. Despite the fact that women are reluctant to share this information, it is believed that the most signicant reason why health care providers do not detect violence is that they do not ask questions [2729]. Universal screening Because of the large numbers of women who are aected by domestic violence and the serious implications of this condition, universal screening of all women and men who present to a health care setting is recommended. Too often, health care providers forget that all women are at risk and do not realize that rarely can they properly identify battered women. Asking pertinent questions regarding a history of violence to all patients removes any prejudice from the process of whom to question. Universal screening also is a way for physicians to educate the public and communicate to patients that this is a common problem and that they are not alone. Several studies have noted that screening does assist health care providers in identifying victims of violence [3032]. Despite the fact that in recent years physicians have been more aware of the magnitude of domestic violence, few are routinely screening their patients, even if they are at high risk [33]. Screening can be simple and ecient. The process may depend on the setting and personnel available, and time should be spent by all providers on

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how best to incorporate screening into their practice. Screening can begin by including a few questions on the written health screen that is given new patients, such as (1) Have you ever been in a violent relationship? (2) Are you currently in a violent or dicult relationship? (3) Are you afraid you or your children might be hurt by your partner? Clearly some patients are reluctant to impart such information in a written format, and this tool should not take the place of face-to-face questioning by either the physician or nurse. Although not all women feel comfortable disclosing their problems, it may be surprising how often women disclose information when asked kindly and without judgment. If a woman asks why she is being screened for violence, share with her that because it is a frequent cause of injury to women, all patients are asked. This answer often leads to a discussion of the problem and may result in women relating how they are concerned about a sister, a daughter, or a friend. Physicians should not underestimate their power in how they educate patients in the oce. Patient screening always must be conducted in private. Although this may sound obvious, many women present with their partners or family members, and the provider may be uncertain about how to proceed. All patients deserve private time with their physicians. We would not expect a teenager to disclose problems or questions of an intimate nature with their parents present, and we usually aord them this privacy. Adult women deserve similar consideration. A simple solution is to systematically ensure private time with all new patients in the oce practice and periodically with established patients. If a partner has serious objections to this routine, your suspicions should be aroused. Addressing the possibility of domestic violence with patients with any suspicious bruising, aect, or interaction is vital. Ask patients what happened to them and follow with, In my experience, when a patient has a bruise like this, someone has hurt her. Did anyone hurt you? Are you ok? Depending on how suspicious you are, you should educate patients about the risks of violence in an intimate relationship and how common the problem is. Even if patients deny any violence, provide them with information about local support groups and assure them that if they ever need to talk, they are free to call at any time. Documenting your concern and ndings and any action taken is important. If you have concerns about violence, schedule another appointment in the near future to reassess the situation. The question of screening men for domestic violence must be considered, especially in the primary care setting. Although most victims are women, heterosexual and homosexual men also can be victims. Screening men for inappropriate anger and violent behavior may be even more helpful in this setting. Examples of useful questions are as follows: (1) Are you worried about controlling your anger? (2) Have you ever regretted your behavior at home when you were angry? (3) Do you need help controlling your anger? Always screen for alcohol and drug abuse. Referral to batterers treatment groups, anger management programs, or individual psychotherapy

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or psychiatry can be valuable, although few physicians routinely employ such options. Ideally we could identify individuals with control and anger management issues and refer them for proper help before serious entanglements with law enforcement. Signs and symptoms Several presenting signs and symptoms of domestic violence are common. Battered women often present to a primary care clinic with vague complaints, such as sleeping diculties, appetite changes, and chronic pain. Depression, anxiety disorders, and suicide attempts are strong indicators of abuse and alcohol or illicit drug use. Conditions associated with stress are common, including irritable bowel syndrome, tachycardia, temporomandibular joint disorders, and headaches. Health care providers also need to consider domestic violence when patients present with chronic back or knee pain and adult-onset seizures that may be the result of falls or head trauma. Acute injuries, such as broken bones, bruises, chipped or broken teeth, and lacerations, must be investigated fully. They may be the result of being pushed down a ight of stairs, thrown against a wall, or punched with a st. Pregnant patients may present with vaginal bleeding, preterm labor, stillbirth, or placental abruption. The variety of presentations of domestic violence ensures that virtually every health care professional, regardless of specialty, will be confronted with this issue. The use of the health care system itself often provides some clues about domestic violence, such as inappropriate use of the emergency room, frequently changing providers, or missed appointments. Physical examination Common ndings on the physical examination include bruises on the upper arms bilaterally, which are the result of being grabbed and shaken violently. Parallel lines that are the result of being hit with a baseball bat can be seen, as can crescent-shaped lacerations from being punched by a st wearing a heavy ring. Any other type of bruising or laceration requires close investigation. Oral injuries are common and often overlooked by physicians and dentists. Petechiae on the roof of the mouth can be the result of forced oral copulation. Scalp lacerations or hematomas are often hidden by hair. Physicians should document all injuries carefully using a body chart and photographs when possible. In most cases, a police photographer should be used. Of special note, strangulation attempt is often missed, as are its implications. Any attempted strangulation is a murder attempt and deserves special consideration by physicians and law enforcement. Unfortunately, signs can be missed until a day or so after the assault. Presenting signs include hoarseness, petechiae on the face (especially around the eyes), conjunctival

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hemorrhages, and bruising around the eyes. Bruising or swelling can be present around the throat, but it is often absent, especially during the rst few hours. Physicians need to rule out a fractured hyoid bone or trachea with radiographs. All patients who have suered strangulation attempt need to be watched for any signs of aspiration pneumonia, which may not present for 24 to 48 hours. Safety assessment When patients discloses that they are victims of violence, an immediate assessment of safety must take place, regardless of whether a patient has a current injury. A detailed history of the violence, including the frequency and severity of injury, assists you in how to proceed. Determine the last time the patient was injured and what he or she thinks the likelihood of injury is in the near future. Find out with whom the patient lives and, if there are children, whether there is risk of child abuse. Information regarding the whereabouts of the batterer and the children is vital. This type of discussion is dicult for physicians, who have other patients to attend to and have little assistance or resources to address these matters. Calling on colleagues at the local battered womens shelter for guidance is invaluable. Counselors with much experience can speak to patients in an emergency over the phone to help ascertain history, level of risk, and options. In some facilities, a domestic violence response team or social services can be of help. After initial assessment, the patient, counselor, and physician decide on the next best possible step. If a patient is injured and requires treatment, admission to the hospital may be best, which allows time for further planning. Remember that any attempt to leave a violent relationship clearly increases the risk of injury because of the perception of loss of control by the batterer. The most lethal time for battered women is when they have recently left a relationship. If the danger is considered to be signicant, it is imperative that patients be counseled not to go to a parents or family members home or any other place where they could be found. All too often, police reports indicate a serious escalation of violence that includes the family members or friends who tried to give shelter or help. This sad nding is a reminder of why shelters are so valuable in our communities and how important it is to maintain the condentiality of their locations. Shelters for battered women Battered womens shelters often provide extraordinary support. Most physicians are unaware of the multitude of services available or the dedicated and talented individuals who are trained to help victims recover and redirect their lives. Legal assistance with navigating the challenging court and custody issues is often available, as is individual counseling.

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Preparations for future work or education are often begun, and mentoring and parenting skills can be improved. Although it is true that few scientic data are available regarding the outcomes of physician intervention in domestic violence, data are emerging [34]. One report that compared varying levels of encounters during the postpartum period at an urban public health prenatal clinic noted a signicant decrease in the severity of abuse even after a brief intervention [35]. Studies conducted at the University of California, Irvine, School of Social Ecology revealed that 93% of graduates from Human Options, a shelter for battered women and their children in Orange County, were free of violence after 5 years [36,37]. More data are needed on the eectiveness of programs, gaps in services, and batterers treatment programs. This kind of information should be an inspiration to health care providers that although domestic violence seems overwhelming, involvement and action can make a dierence. One of the greatest concerns regarding domestic violence is the damage to children and the help they require [38,39]. Shelters have been pioneers in recognizing the extraordinary needs in this area. Our school systems are inadequately equipped to handle these concerns, and many women do not have the resources to fund their mental health needs. The eect on the children in a family emphasizes the progression and multiplication of the cycle of violence and reminds us of the importance of timely intervention. Communities have great needs with confronting the long-term consequences of violence on our children. Physicians should remember that active participation in their community shelters can be invaluable, as can their involvement on a state and local government level to ensure continued nancial assistance. Insucient data are available regarding the success of batterers treatment programs with regards to the percentage of men who are no longer violent after completion. It is encouraging that great improvements have been made regarding attendance and completion of these programs and court documentation of compliance. One of the barriers to success is related to the lack of aordable alcohol and drug treatment programs in our communities. Legal considerations Most states have mandatory reporting laws for health care providers, which continue to be controversial topics and are the subject of much debate. The American College of Obstetricians and Gynecologists currently does not support mandatory reporting laws for physicians because of their concern that women may be placed in greater danger and may delay seeking medical help if needed for an injury. Although these concerns are real and should not be taken lightly, failure to report such a serious crime has its own risks. Mandatory reporting is a conrmation that domestic violence is a crime and that all people have the right to live free of violence, especially in their

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own homes. Once victims have been identied by a physician as having an injury, their lives and the lives of their children may already be in danger. It is a tragedy that women have been found to be battered for years, receiving medical care at various facilities with no active intervention. Women are often not equipped in these dicult relationships to seek help on their own, and immediate assistance from doctors and law enforcement is required to face this complex social entanglement. Advances in law enforcement education and court intervention in domestic violence are encouraging and contribute to my belief that reporting is helpful in many communities. Mandatory reporting of these crimes is consistent with the requirement that physicians have to report all injuries that are the result of a crime. Reporting gang-related injuries or assault by a stranger while ignoring assault by a spouse or boyfriend is inappropriate. It is helpful to remember that reporting child abuse was not mandatory until relatively recently. Although we all acknowledge that the systems in place are not perfect, few of us would agree that physicians should be free to fail to report to authorities when a child has been abused. All health care providers need to be aware of their own states laws regarding mandatory reporting of domestic violence. Continued dialog and research in this area by all individuals who work in this eld will hopefully elucidate the best course of action. Rape The examination of a rape victim requires special consideration. Physicians play a vital role in providing a safe, nonjudgmental, and sensitive environment in which to assess, document, and treat a victim of rape. Physicians should be familiar with their own states requirements and forms, and it is important to use the sexual assault evidence collection kit provided by the local sheri-coroner. Victims can be retraumatized in the emergency room during the medical examination and the forensic evidence collection. Therefore, this examination should be performed by health care personnel who are knowledgeable about the proper procedure and collection of evidence that is vital to the investigation of this crime [40,41]. In many areas, a highly trained sexual assault nurse examiner is available. Your local police department or emergency room can provide information regarding options in your area. Often, however, it is left to physicians on call to at least begin proceedings and direct the proper procedure. Patients should be examined as soon as possible after an assault and after assessment for life-threatening injuries. Social services or the rape intervention team at the hospital should be present. Provide a private, quiet place to help calm patients and ensure proper dignity and respect. The history should be taken before patients disrobe, if possible. Because the history will serve as an adjunct to a victims police statement, avoid any speculation on your part and use her words to describe the event. It is important to document current

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birth control use, recent vaginal infections, medications, and the time of previous consensual sexual intercourse. Rape is a violent crime, and many types of physical evidence may be transferred from the assailant to the victim. Clothing should be examined while still on the patient. Document any tears, stains, hairs, dirt, sand, bers, or other material that may be present. A Woods lamp may be used to look for semen. Clothing should be labeled and placed in a paper bag for forensics. Fingernail scrapings can be collected by using a nail cleaner over a sheet of paper, which is also placed in a plastic bag. Document any signs of general body trauma with notes and photographs. It is usually best to use the police photographer in these cases and in cases of domestic violence. Note the size, depth, shape, and color of bruises, lacerations, and bite marks, including any material such as bers held within. Examine the head carefully because hair often hides injury. Genital trauma may or may not be present when a rape has occurred. Lack of genital trauma does not rule out forced penetration, and a physician may be asked to clear this misconception in court. The forensic kit should contain swabs that are collected from the vagina and rectum, and instructions are given with the kit as to proper collection. Cultures should be taken for sexually transmitted diseases, and blood should be drawn for syphilis and HIV testing with the patients consent. The HIV test is repeated in 6 months. It is important to obtain a pregnancy test and oer emergency contraception (Plan B), which is eective up to 120 hours after the assault. Ensure that the required forms have been followed and submitted. The chain of custody of rape materials has presented numerous problems in court. Ensure that the specimens obtained are handled by as few people as possible and that receipts are used to document the chain of custody. Failure to do so can result in evidence not being admissible in court. Summary Violence is sadly a frequent component of our patients lives. The response of the health care community has been variable and unfortunately lacking in many sectors because of barriers we face in the oce or emergency room setting. Keep materials and referrals in your oce for your patients. Information and pertinent phone numbers are useful to keep in the restrooms for privacy. The March of Dimes provides brochures and information that can be copied free of charge and are available in many languages. Practice universal screening and education of both men and women. Careful documentation of your concerns and your ndings and safety assist you in navigating the various options available to you and your patients. Be knowledgeable of the mandatory reporting laws in your state and keep in mind the high incidence of child abuse when a mother is battered.

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Prevention of trauma and the long-term consequences of domestic violence is an important component to the health care we give our patients. Involve yourself in community eorts to curb violence and educate the public on these issues. Establish a working relationship with your local shelters and counselors. It is imperative that all physicians know how to access the resources in their community. This can assist you in not feeling so alone when facing these challenging patients. Not every victim is ready for your help, and discouragement is common in dealing with domestic violence; however, the gratication of being a part of a familys recovery and future is a powerful reminder of why we are physicians. Additional resources
Oce for Victims of Crime. US Department of Justice, 810 Seventh Street NW, Eighth Floor, Washington, DC 20531. Phone: 202-307-5983; Fax: 202-514-6383. Available at: www.ovc.gov. Violence Against Women Oce. U.S. Department of Justice, 810 Seventh Street NW, Washington, DC 20531. Phone: 2023076026; Fax: 2023052589. Available at: www.usdoj.gov/ovw. Sexual Assault Resource Service (SARS). Available at: www.sane-sart.com. International Association of Forensic Nurses. Available at: www.forensicnurse.org. National Alliance of Sexual Assault Coalitions. Available at: www.taasa.org. Rape, Abuse and Incest National Network (RAINN). Available at: www.rainn.org.

References
[1] Scott Collins K, Schoen C, Joseph S, et al. Health concerns across a womans lifespan: the Commonwealth Fund 1998 survey of womens health. Available at: http://www.cmwf.org/ usr_doc/Healthconcerns_surveyreport.pdf. Accessed July 9, 2008. [2] Tjaden P, Thoennes N. Full report of the prevalence, incidence and consequences of violence against women. Available at: http://www.ncjrs.gov/pdles1/nij/183781.pdf. Accessed July 9, 2008. [3] Rennison CM. Intimate partner violence, 19932001. Available at: http://www.ojp.usdoj. gov/bjs/pub/pdf/ipv01.pdf. Accessed July 9, 2008. [4] Maston C, Klaus P. Criminal victimization in the United States. Available at: http://www. ojp.usdoj.gov/bjs/pub/pdf/cvus05.pdf. Accessed July 9, 2008. [5] Walker L. The battered woman. New York: Harper & Row; 1979. [6] Berrios D, Grady D. Domestic violence: risk factors and outcomes. West J Med 1991;155:1335. [7] Quinlivan J. A prospective cohort study of the impact of domestic violence on young teenage pregnancy outcomes. J Pediatr Adolesc Gynecol 2001;14(1):1723. [8] McFarlane J, Parker R, Soeken K. Abuse during pregnancy: frequency, severity, perpetrator and risk factors of homicide. Public Health Nurs 1995;12(5):2849. [9] Dutton D, Golant S. A psychological prole of the batterer. New York: Basic Books; 1995. [10] Dutton D. The domestic assault of women. Vancouver (BC): University of British Columbia Press; 1995. [11] McFarlane J. Abuse during pregnancy: the horror and the hope. AWHONNS Clin Issues Perinat Womens Health Nurs 1993;4(3):35062. [12] Dannenbuer A, Cortes D, Lawson H, et al. Homicide and other injuries as causes of maternal death in New York City, 1987 through 1991. Am J Obstet Gynecol 1995;172:155764.

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[13] Holmes M, Resnick H, Kilpatrick D, et al. Rape-related pregnancy: estimates and descriptive characteristics from a national sample of women. Am J Obstet Gynecol 1996; 175:3205. [14] Cambell J, Poland M, Waller J, et al. Correlates of battering during pregnancy. Res Nurs Health 1992;15:21926. [15] Hillard P. Physical abuse in pregnancy. Obstet Gynecol 1985;66:18590. [16] MacFarland J, Parker B, Soeken K. Assessing for abuse during pregnancy: severity and frequency of injuries and associated entry into prenatal care. J Am Med Assoc 1992;267: 31768. [17] Huth-Bocks A, Levendosky A, Bogat G. The eects of domestic violence during pregnancy on maternal and infant health. Violence Vict 2002;17(2):16985. [18] Rodriguez T, Rocha L, Barros H. Physical abuse during pregnancy and preterm delivery. Am J Obstet Gynecol 2008;198(2):23940. [19] Parsons L, Zaccaro D, Wells B. Methods of and attitudes toward screening obstetrics and gynecology patients for domestic violence. Am J Obstet Gynecol 1995;173:3817. [20] Sachs C. Failure of the mandatory domestic violence reporting law to increase medical facility referral to police. Ann Emerg Med 1998;31(4):48894. [21] MacFarlane J. Battery during pregnancy: tip of the iceberg revealed. Women Health 1989; 15(3):6984. [22] McCauley J, Kern D, Kolondner K, et al. The Battery Syndrome: prevalence and clinical characteristics of domestic violence in primary care internal medicine practices. Ann Intern Med 1995;123(10):73746. [23] Kraemer A, Lorenzon D, Mueller G. Prevalence of intimate partner violence and health implications for women using emergency rooms and primary care clinics. Womens Health Issues 2004;14(1):1929. [24] Dearwater S, Coben J, Cambell J, et al. Prevalence of intimate partner violence in women treated at community hospital emergency department. JAMA 1998;280(5):4338. [25] Stark E, Filcraft A. Women at risk: domestic violence and womens health. Thousand Oaks (CA): Sage; 1996. [26] Eisenstat S, Bancroft L. Domestic violence. N Engl J Med 1999;341:88692. [27] Sachs C. Should physicians be required to report domestic violence to the police. West J Med 2000;173(4):225. [28] Richardson J, Feder G, Eldridge S, et al. Women who experience domestic violence and women survivors of childhood sexual abuse: a survey of health professionals attitudes and clinical practice. Br J Gen Pract 2001;51(467):46870. [29] Chez R, Jones R. The battered woman. Am J Obstet Gynecol 1995;173:6779. [30] Feldhaus K, Koziol-Mclain J, Ambury H, et al. Accuracy of 3 brief screening questions for detecting partner violence in the emergency department. JAMA 1997;277:135761. [31] Wirst W, McFarlane J. The eectiveness of an abuse assessment protocol in public health prenatal clinics. Am J Public Health 1999;89(8):121721. [32] Thackey J, Stelzner S, Down S, et al. Screening for intimate partner violence. J Interpers Violence 2007;22:65970. [33] Klap R, Tang L, Wells K, et al. Screening for domestic violence among adult women in United States. J Gen Intern Med 2007;22(5):57984. [34] Wathen C, MacMillan H. Interventions for violence against women: scientic review. JAMA 2003;289:589600. [35] McFarlane J, Soeken K, Wiist W. An evaluation of interventions to decrease intimate partner violence to pregnant women. Public Health Nurs 2000;17(6):44351. [36] Jarvis K, Novaco R. Post shelter adjustment of children from violent families. J Interpers Violence 2006;21(8):104662. [37] Hans-Rowbottom K, Gordon E, Jarvis K, et al. Life constraints and psychological wellbeing of domestic violence shelter graduates. J Fam Violence 2005;20(2):10921.

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[38] MacFarlane J, Go J, OBrien J. Behavior of children who are exposed and not exposed to intimate partner violence: an analysis of 330 black, white and Hispanic children. Pediatrics 2003;112(3):2027. [39] Jarvis K, Gordon E, Novaco R. Psychological distress of children and mothers in domestic violence emergency shelters. J Fam Violence 2005;20(6):2027. [40] Cabaniss M, Scott S, Copeland L. Gathering evidence for rape cases. Contemp Ob Gyn 1985;16074. [41] Governors Oce of Emergency Services. California medical protocol for examination of sexual assault and child sexual abuse victims. Available at: http://www.oes.ca.gov/Operational/ OESHome.nsf/PDF/California%20Medical%20Protocol%20for%20Examination%20of%20 Sexual%20Assault%20&%20Child%20Sexual%20Abuse%20Victims,%20July%202001/ $le/protocolbook.pdf. Accessed July 9, 2008.

Med Clin N Am 92 (2008) 12531271

Menopause and the Menopausal Transition

Kirsten J. Lund, MD*
University of Colorado, Department of OB-GYN, Denver, CO, USA

The onset of menopause is a signicant life event for women, carrying with it medical, psychosocial, and cultural signicance. More broadly, the perimenopausal transition, dened as the time between the onset of menstrual irregularity and the menopause, can be a challenging time for both patient and health care provider. The menopausal transition, and the years of life spent in the menopausal state, bring with them issues related to both quality of life, and disease prevention and management. Both are intrinsically important to patients, and the challenge to the caregiver is to balance the interests of preventing disease, taking into account individual risk factors, with maintaining quality of life in a way that addresses each patients goals and desires. Although those who care for older women may have diverse training backgrounds, it is important for all to have an integrated understanding of the issues surrounding menopause. The proportion of the female population who are in the peri- and postmenopausal age group continues to increase because of two separate but synergistic factors: First, medical advances have resulted in increased life expectancy and in particular the prolongation of relatively disease-free life. Healthy women typically spend one third of their lives in a menopausal state. Second, the postwar baby boom of the 1940s and 1950s has led to an absolute increase in the over-50 population. Menopausal patients are better educated about this phase of life and have more resources available to them than ever before. Pharmaceutical and advertising dollars are increasingly targeting the older population, and women want and need their providers to assist them in deciphering available information and making optimal health care choices.

* University of Colorado, Dept of OB-GYN, Academic Office 1, 12631 E 17th Street, Rm 4221, MS B198-2, PO Box 6511, Aurora, CO. E-mail address: kirsten.lund@uchsc.edu 0025-7125/08/$ - see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2008.04.009 medical.theclinics.com

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Denition and diagnosis of menopause Menopause is traditionally dened as having occurred when a woman does not have a spontaneous menstrual period for 12 months. Because this denition is a retrospective diagnosis it has limited clinical utility, particularly for patients who are not yet fully menopausal but who suer from menopausal symptoms. More recently, the menopausal transition has been divided into stages in an eort to provide clinicians, researchers, and patients a more objective and relevant means by which to discuss the reproductive aging process [1]. Early perimenopause is dened as a change in menstrual cycle length of more than 7 days from baseline cyclicity. One or more skipped menstrual periods, or greater than 60 days of amenorrhea, constitutes late perimenopause. Early menopause is the 5 years after menopause onset, followed by late menopause, which continues until death.

Age of menopause The median age of menopause has been fairly consistent over centuries and across modern epidemiologic studies and generally falls between 50 to 52 years of age. There is striking consistency in the age of menopause across geographic and cultural groups despite signicant disparities in other measures of reproductive health such as age of menarche and childbirth [2]. However, there is a large distribution around this median, with most women experiencing menopause between the ages of 44 and 55. Factors associated with an earlier age of menopause include smoking; a diet high in vegetables, bers, and cereals (as opposed to a high-protein, high meat diet); autoimmune disorders such as type I diabetes; nulliparity; and low body mass index [35]. Although clinical impression suggests that mothers and daughters experience similar menopausal transitions, it is dicult to control for social, racial, and behavioral factors to arrive at the true contribution of genetic factors to the age of menopause. There is no association between use of hormonal contraceptives and age of menopause. Although results of controlled studies have suggested that hysterectomy is associated with earlier age at menopause, the diagnosis of menopause after hysterectomy is impossible to make in the classical way, ie, 12 months of amenorrhea. The posthysterectomy diagnosis is based on serum follicle-stimulating hormone (FSH) measurements, which may uctuate signicantly during the perimenopausal transition and not accurately reect true menopause [6]. Cohort studies have suggested that women who have undergone unilateral oophorectomy may enter menopause slightly earlier than the average [7]. There is no evidence that tubal ligation independently aects the age at menopause, although the majority of women undergoing sterilization are multiparous, itself a factor in age at menopause.

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Physiology of menopause The physiology of menopause is exceedingly complex and may vary considerably among patients. However, depletion of ovarian follicles throughout the female lifespan, or decreasing ovarian reserve, is the basis for reproductive aging and the menopausal transition. The decrease in number of ovarian follicles occurs throughout life but accelerates in the later reproductive years and leads to hormonal alterations that can be observed as early as the fourth decade of life. Although the complex nature of feedback between the ovary and the hypothalamicpituitary axis makes it dicult to understand fully the endocrinology of the reproductive aging process, perhaps the most straightforward of the early changes is a decrease in ovarian secretion of inhibin B [8]. This peptide hormone is responsible for negative feedback to the pituitary and the suppression of FSH in the early part of each menstrual cycle. A decrease in inhibin B results in higher early-cycle FSH levels and, because ovarian follicles respond to FSH by growing and secreting estradiol, higher circulating estradiol levels in response to the higher FSH. In this way, and despite the overall depletion of ovarian follicles in perimenopausal patients, higher early-cycle FSH levels actually act to stimulate the perimenopausal ovary and thereby preserve normal levels of serum estradiol through the earlier stage of menopause [9]. It is only after the absolute depletion of ovarian follicles renders the ovary unable to respond even to high tonic FSH levels that estradiol levels begin to decrease. Alterations in pituitary gonadotropin levels may render ovulation intermittent, leading to the variability in cycle length characteristic of the perimenopause.

Preventive health concerns General Menopausal patients should have an identied care provider, or team of care providers, who are familiar with the full range of health care concerns of older women. Although many internists are comfortable with femalespecic health issues and may be experienced and comfortable performing annual gynecologic examinations, others may prefer patients see a gynecologist for their breast and pelvic examination and discussion of specic issues such as hormone replacement therapy. Conversely, some gynecologists are familiar with general health maintenance screening recommendations although others may prefer that their patients have an internist who can follow their patients nongynecologic medical conditions. Regardless, all women deserve access to periodic, comprehensive health maintenance reviews in addition to care for their specic medical conditions. Because the needs of menopausal patients may change over time, the annual health maintenance examination should be a mainstay of menopausal care.

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Coronary artery/vascular disease Cardiovascular disease (CVD) remains the leading overall cause of death in women, with 27.2% and 7.5% of all female deaths in 2004 caused by heart disease and stroke, respectively [10]. An estimated 47 million women, or 37% of the total American female population, suer from CVD [11]. Although the burden of CVD morbidity and mortality among women is clearly signicant, research into the prevention and treatment of this disease in women historically has been lacking. The risk factors, epidemiology, prevention, and treatment of CVD are similar between men and women, although there are dierences. Recently, the number of quality prospective studies that include women has increased, and evidence-based guidelines for prevention and treatment of CVD in women are now available. The key nonmodiable risk factors for cardiovascular disease in women are age and family history. In general, women develop clinically evident cardiovascular disease at a later age than men. Although acute cardiovascular events are rare in nonobese, nondiabetic premenopausal women, they increase markedly after the menopause [12]. Modiable cardiovascular risk factors include hypertension, dyslipidemia, obesity, diabetes/glucose intolerance, cigarette smoking, poor diet, and lack of physical activity. The rst four of these risk factors are components of the metabolic syndrome, which is in itself a strong predictor of cardiovascular morbidity and mortality [13]. Because most risk factors for CVD are modiable, signicant reduction in cardiovascular morbidity and mortality is feasible. Lifestyle interventions for prevention of CVD in women that have been shown to be useful and eective include smoking cessation, physical activity of moderate intensity for 30 minutes per day, maintenance of appropriate weight, and following a heart-healthy diet. More specic eective risk factor interventions include maintaining optimal blood pressure and lipid levels through lifestyle approaches and, when necessary, pharmacotherapy [14]. Aspirin has been shown to be eective in the secondary prevention of cardiovascular disease in both men and women [15]. However, there are limited data on the role of low-dose aspirin in primary prevention of cardiovascular disease in women. The largest single randomized trial to address this issue indicates that among women 45 and older, there is a nonsignicant reduction in all major cardiovascular events of 9% with use of low-dose aspirin. However, there is a signicant 17% reduction in risk of stroke. Among women 65 and older there were signicant reductions in all categories of cardiovascular events, including a 30% reduction in ischemic stroke and a 34% reduction in myocardial infarction [16]. In general, aspirin should not be used for primary prevention of heart disease in women under the age of 65 unless individual health benets are judged to outweigh risks, which primarily involve bleeding episodes such as hemorrhagic stoke and gastrointestinal bleeding.

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Osteoporosis Osteoporosis is the most prevalent bone disorder among elderly women. Worldwide it is estimated that there are 9 million osteoporotic fractures per year, leading to 5.8 million person-years of disability or loss of life [17]. Although hip fractures are the most serious of these, spinal and distal forearm fracture contribute signicantly to the overall burden of this disease. Perhaps even more importantly, because the number of women with osteopenia is much greater than that of women with osteoporosis, and because each standard deviation below mean bone density doubles fracture risk, the overall burden of fractures related to low bone density is likely much greater than the above estimates, which address only fractures caused by osteoporosis [18]. Overall bone density at any given time reects the balance between bone formation and resorption. Bone is formed most rapidly in the early reproductive years, and bone density peaks at or before age 30. Any diminution in bone accrual during these early years will lead to decreased lifetime maximum bone density and higher risk for osteoporosis in the later years. Although bone density gradually decreases after peak, in women there is a marked increase in bone loss in the rst few years after the menopause. Risk factors for osteoporosis are many, but perhaps the most important are age, dietary calcium intake and hormone status during adolescence, and heritability. In fact, genetic factors likely account for 70% to 75% of the variation in bone density among menopausal patients [19]. As a result, clinical screening for osteoporosis should begin with a thorough family, dietary, and menstrual history. Additional risk factors for low bone density include low current or past calcium and vitamin D intake, excess alcohol intake, sedentary lifestyle, low lean body mass, smoking, white or Asian ethnicity, and premenopausal estrogen deciency (eg, amenorrhea, surgical oophorectomy). There are also many chronic medical conditions that predispose to osteoporosis, generally beyond the scope of this chapter. Because many of these risk factors involve lifestyle, each is potentially modiable with appropriate counseling. Recommended calcium intake for menopausal women is 1000 to 1500 mg/ day, with 400 to 800 IU of vitamin D [20]. Weight-bearing exercise has been shown to improve bone density at the hip and spine. In addition, regular exercise is associated with improved muscle strength and balance, which may reduce the incidence of falls in individuals susceptible to fragility fractures [21]. Screening for osteoporosis should take into account individual patient risk factors. In general, the most accurate and reproducible way to measure bone density is by dual electron x-ray absorptimetry (DEXA) scan with measurements taken at the spine and hip. Diagnosis of low bone density is made by comparing patient bone density with that of an average young adult at peak bone mass and converting this measurement into standard

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deviations above or below the latter value. Such a measurement is known as a T-score and is the recommended terminology for discussing and dening bone density in menopausal women. For younger populations it is useful to compare bone density with that of an average patient of the same age, also known as a Z-score. Such a comparison may identify individuals who, though not frankly osteopenic or osteoporotic, are signicantly behind their peers and may have secondary, nonage-related causes of low bone density. Osteoporosis is dened as bone density that is greater than 2.5 standard deviations below reference, or a T-score of greater than 2.5; osteopenia is dened as bone density between 1 to 2.5 standard deviations below reference. Although screening recommendations vary among various governing bodies, in general all patients over the age of 65 and younger patients with signicant risk factors such as long-term steroid use should receive bone density screening. Treatment options for low bone density include lifestyle and pharmacologic interventions. Smoking cessation and moderation of alcohol intake should be strongly encouraged. Calcium, especially when combined with vitamin D, is associated with improved bone mass. Several pharmacologic therapies reduce the incidence of osteoporotic fractures. Estrogen therapy, with or without progestins, reduces both bone loss and fractures compared with placebo and may be particularly eective in the early menopausal years, when the rate of bone loss is greatest and when patients may choose estrogen therapy for management of menopausal symptoms [22]. However, because estrogen and progestin have been associated with adverse events such as myocardial infarction and stroke, alternative osteoporosis prevention therapies should be considered for patients who do not have another indication for taking estrogen. Selective estrogen-receptor modulators (SERMs), which have agonist properties in bone but antagonist properties in the breast and endometrium, have shown promise for preventing fractures without inducing untoward estrogen-related side eects. In particular, raloxifene increases bone density and decreases the rate of vertebral fractures (although prolonged follow-up has failed to nd an eect on nonvertebral fractures) without increasing uterine bleeding or breast cancer rates [23,24]. Bisphosphonates, which inhibit osteoclasts and thereby reduce bone resorption are highly eective at improving bone density and reducing osteoporotic fractures. Fracture reductions of up to 50% compared with placebo have been observed with alendronate; risedronate and ibandronate have also been shown to be ecacious in randomized trials [25]. Bisphosphonates may cause gastrointestinal side eects, although compliance has been enhanced by weekly and even monthly dosing. For many women, bisphosphonates are the rst-line therapy for osteoporosis treatment. Finally a number of other pharmacologic interventions may prevent osteoporotic fractures, but for a variety of reasons their use has not become widespread in the American market. These include parathyroid hormone, calcitonin, and strontium ranelate. Table 1 summarizes nonhormonal

MENOPAUSE AND THE MENOPAUSAL TRANSITION

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Table 1 Nonhormonal therapies for treatment of osteoporosis Generic name Raloxifene Alendronate Risedronate Ibandronate Etidronatea Zoledronic acid Parathyroid hormone Calcitonin Strontium ranelateb
a b

Brand name Evista Fosamax Actonel Boniva Didronel Reclast Forteo Fortical Protelos

Dose 60 mg 70 mg 35 mg 150 mg 400 mg 5 mg 20mcg 200 IU 2g

Route Oral Oral Oral Oral Oral IV SQ Intranasal Oral

Frequency Daily Weekly Weekly Monthly Daily Yearly Daily Daily Daily

O-label use in osteoporosis. Not currently available in United States.

treatments for osteoporosis. The use of drug therapy for osteopenia is controversial, although many products are US Food and Drug Administration approved for Prevention and treatment of osteoporosis implying approval of their use in osteopenia at provider discretion. Malignancy Cancer deaths account for 22% of total mortality in women, second only to cardiovascular deaths. Malignancy rates generally increase with age; the bulk of cancers in women occur in the menopausal age group. The most common cancers in women are, in descending order, breast, lung, colorectal, and uterine cancer. Of these, the highest mortality is associated with lung cancer, followed by breast and colorectal cancer [26]. Cigarette smoking is thought to contribute to 90% of lung cancer deaths in women [27], and smoking cessation is the cornerstone of lung cancer prevention. However, the incidence of lung cancer in never-smokers is approximately double among women as compared with men [28]. The epidemiology and pathophysiology of nonsmoking-related lung cancer is not well understood. The US Preventive Service Task Force does not recommend screening for lung cancer in asymptomatic people, in part because although such screening (which may include computed tomography scanning, sputum cytology, or chest radiography) may identify lung cancers at an earlier stage, there is no evidence of an impact on mortality and a substantial risk for false-positive results and unnecessary invasive procedures. Breast cancer remains the most commonly diagnosed nonskin cancer in women, although advances in detection and treatment have reduced mortality rates signicantly over the last decade. Risk factors for breast cancer are primarily nonmodiable in menopausal patients and include age, family history, early age at menarche, late age at rst childbirth (or nulliparity), and lack of breastfeeding. However, obesity confers a 40% increase in risk of breast cancer in menopausal women [29], and alcohol consumption

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increases risk by about 10% for each daily drink [30]; these risk factors are modiable with counseling. Patients with a strong family history of breast cancer (one or more rst-degree relatives) should be considered for genetic testing, particularly for the BRCA-1 and -2 germ line mutations. Such patients may be oered intensied surveillance, chemoprevention such as tamoxifen or aromatase inhibitors, or prophylactic surgery (bilateral oophorectomy or mastectomy). Screening recommendations for breast cancer center on monthly breast self-examination, yearly clinical breast examination, and mammography every 1 to 2 years for women over 40. Despite the generally accepted utility of the above screening methods, it has been extremely dicult to show outcome benets in controlled studies. Because it is in the nature of screening tests to generate a high number of false-positive results, may women who do not have breast cancer undergo invasive testing as a result of clinical or mammographic ndings [31]. Based on this information it is reasonable not to recommend breast self-examination especially in younger women. Other screening modalities, such as ultrasound scan and magnetic resonance imaging, may improve the specicity of breast cancer screening, but their utility has not yet been established. Colorectal cancer remains the third most commonly diagnosed cancer in women. Risk factors for colon cancer include family history, age, sedentary lifestyle, high dietary intake of animal products and low dietary ber intake, and tobacco and alcohol use. Although some of these risk factors are modiable, direct evidence of benet through risk factor modication is scarce. Although there is evidence to support physical activity as a means of colon cancer prevention, studies of diet modication have been inconclusive [32,33]. In general, colon cancer screening should begin at age 50 (earlier for selected patients with family history) and may include fecal occult blood testing, sigmoidoscopy, or colonoscopy. Because they are more likely to have an identied care provider and to use other cancer screening methods such as Pap smears and mammography, women undergo colon cancer screening at higher rates than men, and their survival rates are slightly higher [26,34].

Quality-of-life concerns Menstrual disturbances The perimenopausal transition is associated with, and in fact is dened by, changes in normal menstrual cyclicity. Although minor uctuations may be taken in stride, abnormal uterine bleeding in the perimenopausal woman is a common reason for primary care presentation and gynecologic consultation. Changes in endometrial proliferation are common and reect a relative deciency in progesterone, which inhibits proliferation, and a relative excess of estrogen, which causes it. Because of endocrine changes

MENOPAUSE AND THE MENOPAUSAL TRANSITION

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leading to elevated resting FSH levels, estradiol secretion by the ovary is maintained at levels that equal or even exceed premenopausal levels [9]. Postovulatory corpus luteum function is less robust such that peak serum levels, as well as number of days, of luteal-phase progesterone production may decrease. Finally, because progesterone is produced only during ovulatory cycles, patients who are intermittently anovulatory are exposed to additional unopposed estrogen. It is this relatively high-estrogen, lowprogesterone state that may be the cause of three of the gynecologic symptoms associated with the menopausal transition: Endometrial hyperplasia, growth of uterine broids, and dysfunctional uterine bleeding. With the exception of hyperplasia, these conditions are entirely benign yet are the cause of many hysterectomies performed in the perimenopausal years [35]. Endometrial hyperplasia or overgrowth of the uterine lining is most commonly a result of unopposed, or inadequately opposed, estrogen. Although perimenopausal patients are generally at some risk for hyperplasia, any condition that raises circulating estrogen levels above baseline increases hyperplasia risk. These risk factors include obesity, chronic anovulation of the estrogenized or PCOS type, infertility/nulliparity, or, less commonly, estrogen-secreting tumors. Patients with heavy or irregular bleeding during perimenopause should be screened for hyperplasia. The rst-line test for endometrial hyperplasia in perimenopausal women remains outpatient endometrial biopsy, which can be performed by either the primary provider or specialist. Although transvaginal ultrasound evaluation of endometrial thickness has proved useful in menopausal patients, this has not denitively been shown in pre- and perimenopausal populations. If conrmed, endometrial hyperplasia without cytologic atypia may be treated with progestins (oral or intrauterine) with a follow-up biopsy to conrm resolution. In cases of cytologic atypia, there is signicant risk of underlying malignancy, and hysterectomy is the recommended treatment [36]. Uterine broids are extremely common, with prevalence of more than 50% in the perimenopausal population [37]. Most uterine broids are asymptomatic or cause minimal symptoms. When they are large enough to cause mass eect, or when they impinge on the uterine cavity and cause irregular bleeding, patients may present for treatment. Options for broid treatment are myriad; the treatment that is best for an individual patient depends on her treatment goals and her views on the relative merits of surgery and medical therapy. When broids cause no or mild symptoms, many patients respond well to the reassurance that there is no malignancy and that generally broids will cease to grow after menopause. Expectant management is most appropriate in many cases. Occasionally, and especially if broid symptoms are exacerbated by hormonal imbalance, symptoms will be controlled with oral progestins or oral contraceptive pills. Other medical treatments shown to be eective for symptomatic broids are mifepristone, a synthetic progesterone receptor modulator, and leuprolide acetate, a gonadotropin-releasing hormone agonist [38,39]. If patients are close to

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menopause, a temporary course of such agents may bridge them through to menopause. For those patients who are more symptomatic (signicant anemia, diculty maintaining hygiene during menses, signicant mass symptoms), more invasive alternatives may be appropriate. Uterine broid embolization and ultrasound broid ablation are viable treatment options, as are surgical myomectomy or hysterectomy. It should be emphasized, however, that uterine broids are extremely prevalent and in the majority of cases do not require invasive treatment. Abnormal bleeding patterns in the perimenopausal population are exceedingly common. As noted above, this may be caused by a combination of anovulation, elevated estrogen levels, and perhaps anatomic abnormalities such as broids. When hyperplasia and anatomic lesions have been ruled out, most cases of dysfunctional uterine bleeding will respond well to hormonal management. For healthy nonsmokers, low-dose oral contraceptives, taken either cyclically or continuously, provide an adequate dose of progestin to control endometrial growth and, in the case of cyclic pills, provide a measure of menstrual predictability. Patients who have a contraindication to oral estrogen (smoking, poorly controlled hypertension, clotting disorders) or who suer estrogen-dependent symptoms, such as headache, may take progestin-only medications such as medroxyprogesterone acetate or norethindrone acetate. Although these products may be administered in a cyclic fashion, this method may in fact exacerbate irregular bleeding because it does not reliably suppress ovulation. Continuous progestin therapy by contrast induces amenorrhea or unpredictable (but generally light) atrophic bleeding. Finally, intrauterine progestins (levonorgestrel intrauterine system, marketed as Mirena) are highly eective both for endometrial protection as well as contraception. Patients who do not tolerate systemic hormone therapy tend to do well with intrauterine progestin therapy because serum levels of progestin are much lower with this delivery system. Finally, it is imperative for care providers to remember that patients are at risk for pregnancy until they have completed the entire menopausal transition. Unintended pregnancies are not uncommon in the late reproductive years and can have signicant eects on patients lives. The advent of many eective, long-term contraceptive methods, discussed in Chapter 2, has made it easier to provide older women with eective contraception through the menopausal transition. Vasomotor instability Of the many symptoms of menopause that may aect quality of life, the most common are symptoms related to thermoregulation, specically hot ashes and night sweats. The prevalence of such symptoms varies according to ethnic and cultural background but ranges from 18% to 46% of the menopausal population [40]. Asian women in general appear to have the lowest rates of symptomatic vasomotor instability, followed by white Caucasian,

MENOPAUSE AND THE MENOPAUSAL TRANSITION

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Hispanic Caucasian and African (including African American) women. In addition, the prevalence and intensity of hot ashes varies across the menopausal transition, peaking in the peri- and early postmenopausal years. Interestingly, 20% of premenopausal women report signicant hot ashes, which may reect the physiology of the hot ash as being one of relative rather than absolute change in circulating estrogen levels. Lifestyle interventions may be eective in ameliorating vasomotor symptoms in menopausal women. Exercise has been found to be associated with fewer hot ashes, although a recent cohort study found that only women with a history of major depression nd that exercise is of benet [41,42]. Patients may also change their environment by altering their thermostat or wearing fewer bedclothes. The most eective pharmacologic intervention for treatment of vasomotor symptoms is estrogen therapy with or without progestins. Estrogen therapy remains an indicated and acceptable treatment for vasomotor symptoms. Estrogen regimens reduce frequency and intensity of hot ashes by 70% and 90%, respectively, with 3 months of therapy [43]. Because of increased numbers of menopausal patients and increasing interest in developing new estrogen replacement products, there are many dosing and delivery regimens for systemic estrogen or hormone therapy. Table 2 summarizes the currently available options for systemic hormone therapy. Although recent controversies surrounding the use of estrogen in menopausal patients have led to increased interest in the role of nonpharmacologic and alternative medical therapies, nothing has been found to equal estrogen for treatment of vasomotor symptoms. Phytoestrogens such as soy isoavones have not reliably been proven to be of use [44]. Pharmacologic alternatives to estrogen include gabapentin, clonidine, and selective serotonin reuptake inhibitors; Table 3 contains information on those compounds the ecacy of which is supported by randomized, placebocontrolled trials [4551]. However, use of all of nonestrogenic compounds is limited by a high incidence of side eects (specics vary with class of drug) and resultant discontinuation of therapy. Urogenital atrophy Symptoms of urogenital atrophy, including vaginal dryness and dyspareunia, are quite common after menopause and can pose signicant quality-of-life issues especially among sexually active women. Unlike symptoms of vasomotor instability, which peak in the late perimenopausal and early menopausal stages, the prevalence of atrophic symptoms increases throughout menopause and appears to be correlated with absolute, rather than relative, levels of estradiol. Nonpharmacologic interventions for vaginal dryness and dyspareunia include over-the-counter vaginal lubricants that include ingredients such as propylene glycol, glycerin, and mineral oil. Although there is evidence that dietary soy can alter the histology of the lower genital tract, particularly

1264 Table 2 Systemic hormone therapy regimens Contents ESTROGENSa Conjugated equine estrogens Synthetic conjugated estrogens Estradiol Esteried estrogens Estropipate Estradiol acetate Estradiol Brand name Premarin Cenestin, Enjuvia

LUND

Dose 0.31.25 mg 0.31.25 mg 0.51 mg 0.32.5 mg 0.751.5 mg 0.451.8 mg 0.0140.1 mg

Route Oral Oral Oral Oral Oral Oral Patch

Frequency Daily Daily Daily Daily Daily Daily 12x/ week

Estradiol gel

Estradiol spray PROGESTINS Medroxyprogesterone Provera acetate Norethindrone acetate Aygestin Micronized Prometrium progesterone COMBINATION THERAPY Estradiol/drospirenone Angeliq Estradiol/norgestimate Prefest Ethinyl estradiol/ FemHRT norethindrone acetate Conj. equine estrogens/ Prempro medroxyprogesterone
a

Estrace Menest Ortho-Est, Ogen Femtrace Climara, Menostar, Estraderm, Vivelle, Alora, Esclim Elestrin, Estrogel, Divigel, Estrasorb Evamist

0.253 mg 1.53 mg 2.55 mg 5 mg 200 mg

Transdermal Transdermal Oral Oral Oral

Daily Daily Daily Daily Daily

1 mg/0.5 mg 1 mg/0.09 mg 2.55 mcg/ 0.51 mg 0.30.625 mg/ 1.55 mg

Oral Oral Oral Oral

Daily Daily Daily Daily

Must be used with a progestin in women with a uterus.

the maturation index, direct eects on vaginal symptoms and function have not been studied [52] Estrogen preparations are eective for treating symptoms of urogenital atrophy. Table 4 summarizes available local estrogen therapy options. Estrogen therapy results in measurable changes in
Table 3 Nonhormonal treatments for vasomotor symptoms Generic name Gabapentin Venlafaxine Citalopram Fluoxetine Paroxetine Sertraline Clonidine
a

Brand name Eexor Celexa Prozac Paxil Zoloft Catapres

Dose 9002400 mg 37.5150 mg 1030 mg 1030 mg 1020 mg 50 mg 0.1 mg

Frequency Divided TID Daily Daily Daily Daily Daily Daily

% decrease in hot ash scorea 70 Up to 61 NS NS 4656 47 37

NS, Not consistently better than placebo. Combined measure of frequency and severity.

MENOPAUSE AND THE MENOPAUSAL TRANSITION

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Table 4 Vaginal estrogen preparationsa Contents Conjugated equine estrogen cream Estradiol tablets Estradiol ring Brand name Premarin Vagifem Estring, Femring Dose 0.52 g/day 0.25 mg 0.050.1 mg/day Frequency 2x/week 2x/week 90 days

a Although systemic progestin is not required for endometrial protection, development of uterine bleeding is a risk and should be monitored.

cytology, histology, and pH and reduces symptoms [53,54]. For patients who choose not to or cannot take systemic estrogen, vaginal estrogen therapies are equally eective. Vaginal estradiol and conjugated estrogen creams, estradiol tablets, and time-release estradiol rings are signicantly more eective than nonhormonal gels or placebo. Studies suggest that vaginal creams may be associated with higher rates of endometrial stimulation and systemic symptoms (such as breast tenderness) than tablets or the ring [55]. Urinary incontinence Urinary incontinence aects up to 25% of all adult women, with increasing incidence with age and represents a signicant challenge for those whom it aects [56]. Despite the overall aging of the population and the proportional increase in the prevalence of incontinence, it remains a dicult subject for patients to discuss with their family or health care providers. Risk factors for stress incontinence include increasing age, obesity, smoking, diabetes, previous vaginal childbirth, and previous hysterectomy [57]. The majority of patients seeking care for incontinence suer from stress or urge incontinence, though mixed incontinence is also common. The etiology of stress urinary incontinence is complex and may result from a decrease in function of the urethra itself, or of the supporting pelvic musculature. It is characterized by loss of urine with exertion such as cough, sneeze, or other elevation in intra-abdominal pressure. Eective treatments for stress incontinence may vary by patient, depending on the anatomic defect, and include pelvic oor muscle strengthening, weight loss, selective serotonin/norepinephrine inhibitors such as duloxetine, and pelvic reconstructive surgery [5860]. Urinary urgency and urge incontinence results from over activity of the detrussor muscle and may be treated with behavioral therapy or anticholinergic drugs [61]. For patients with mixed incontinence, treatment of one component may signicantly improve quality of life.

The role of hormone therapy in menopause Because many of the health and quality-of-life consequences of menopause seem to be directly related to changing ovarian steroid hormone

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levels, hormone therapy (HT), including estrogen-only and estrogenprogestin combinations, has been a cornerstone of menopausal management for more than 50 years. HT was prescribed initially for treatment of menopausal symptoms, and there is ample evidence that estrogen, or estrogenprogestin combinations, alleviate such symptoms as hot ashes and urogenital atrophy. In time, large observational studies suggested that women who chose to take HT experienced signicantly lower rates of certain health outcomes, particularly cardiovascular events [62,63]. Further investigations into the role of estrogen in prevention of cardiovascular disease included nonhuman primate studies and measurements of surrogate markers in humans. These studies conrmed that estrogen therapy improved lipid proles and delayed atherosclerotic plaque formation after menopause [64,65]. However, quality randomized studies in humans were largely lacking until the last decade. In 2002 the results of the Womens Health Initiative (WHI) trial were published after early termination of the study. This was a large randomized trial of menopausal patients designed to evaluate strategies to reduce the incidence of heart disease, breast cancer, and other secondary outcomes such as osteoporotic fracture and other cancers. The HT component of the WHI was terminated after an average of 5.2 years of patient followup, instead of the planned 8.5 years duration, because the number of invasive breast cancers in the treatment group exceeded the safety boundary and because the hoped-for protective eect of HT on cardiovascular events was not apparent [66]. This study, which was publicized widely in the popular media, had perhaps the greatest single eect on HT prescribing patterns of any study to date. A follow-up study of estrogen-only therapy in the same study found similarly that CVD events were not prevented, although the breast cancer rates in patients taking estrogen alone were not elevated [67]. As a result of these publications, many patients, and many physicians, abandoned HT altogether. Since the publication of the WHI studies, much attention has been focused on why there is a discrepancy between observational trials, which generally support the use of HT on grounds of CVD and osteoporosis prevention, and the WHI, which failed to nd evidence of overall benet. Although the biases inherent in nonrandomized trials may account for some dierence (women who choose HT tend to be healthier, better educated, and more auent), there are also signicant dierences in patient selection within the observational trials and the WHI. Patients in the WHI were much older, with an average age at randomization of 63 (range, 50 to 79), were excluded if they suered severe menopausal symptoms, and were required to be o HT before beginning the study [68]. Critics argue that the study of patients in this age group is not clinically useful, because most patients who initiate HT do so during the early menopausal transition when symptoms are greatest. Many subanalyses focusing on the younger cohort of the WHI have failed to nd adverse cardiac outcomes among

MENOPAUSE AND THE MENOPAUSAL TRANSITION

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this subset, and in fact women in their 50s who took estrogen appear to have less coronary artery calcication than controls [69]. Since the publication of these trials, there has been great interest in developing alternative doses, delivery systems, and medications for HT use. Many new products are now available including transdermal and intravaginal delivery systems, lower-dose traditional HT, and selective SERMs. All aim to attenuate the potential health risks of HT while still conferring benets. There are no adequately powered trials to indicate whether any of these alternatives is superior to traditional oral HT. Given the current state of research into the risks and benets of HT in menopause, it is dicult to make sweeping statements about the utility of these drugs. Although HT should not be initiated solely for primary prevention of heart disease or other diseases, the remainder of the decision making rests with the individual patient and provider. Women who choose HT should have a thorough personal and family medical history to delineate health risk factors that may be aected by hormones. They should have a clear rationale for treatment, usually alleviation of menopausal symptoms such as hot ashes, and the lowest dose that provides control of symptoms should be used. The decision to continue HT should be revisited yearly, and therapy should be discontinued when symptoms resolvedusually in 1 to 3 years after menopause. Summary Older women face complex issues and choices regarding health maintenance and symptom management. Primary care providers are uniquely suited to guide women through the menopausal transition and into the later years. Providers must educate patients as to their risks for major adverse health outcomes such as vascular disease, malignancy, and osteoporotic fracture. Appropriate lifestyle interventions, screening tests, and, when appropriate, pharmacologic therapies should be used. Menopausal symptoms should be taken seriously and treated with respect, as the multitude of treatment options for conditions such as abnormal bleeding, vasomotor instability, urogenital atrophy, and urinary incontinence renders almost all women candidates for some type of eective therapy. Finally, maintaining a continuous relationship and ongoing dialogue with patients as they navigate the menopausal years will ensure that they receive optimal, tailored medical care and enhanced satisfaction. References
[1] Soules MR, Sherman S, Parrott E, et al. Executive summary: Stages of Reproductive Aging Workshop (STRAW). Fertil Steril 2001;76(5):8748. [2] Morabia A, Costanza MC. International variability in ages at menarche, rst livebirth, and menopause. World Health Organization Collaborative Study of Neoplasia and Steroid Contraceptives. Am J Epidemiol 1998;148(12):1195205.

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[3] Meschia M, Pansini F, Modena AB, et al. Determinants of age at menopause in Italy: results from a large cross-sectional study. ICARUS Study Group. Italian Climacteric Research Group Study. Maturitas 2000;34(2):11925. [4] Parazzini F. Determinants of age at menopause in women attending menopause clinics in Italy. Maturitas 2007;56(3):2807. [5] Nagel G, Altenburg HP, Nieters A, et al. Reproductive and dietary determinants of the age at menopause in EPIC-Heidelberg. Maturitas 2005;52(34):33747. [6] Farquhar C. The association of hysterectomy and menopause: a prospective cohort study. BJOG 2005;112(7):95662. [7] Hardy R, Kuh D. Reproductive characteristics and the age at inception of the perimenopause in a British National Cohort. Am J Epidemiol 1999;149(7):61220. [8] MacNaughton J, Banah M, McCloud P, et al. Age related changes in follicle stimulating hormone, luteinizing hormone, oestradiol and immunoreactive inhibin in women of reproductive age. Clin Endocrinol (Oxf) 1992;36(4):33945. [9] Santoro N, Brown JR, Adel T, et al. Characterization of reproductive hormonal dynamics in the perimenopause. J Clin Endocrinol Metab 1996;81(4):1495501. [10] Minino A. Deaths: nal data for 2004. Hyattsville (MD): National Center for Health Statistics; 2007. [11] American Heart Association. Heart disease and stroke statisticsd2008 update. Dallas (TX): American Heart Association; 2008. [12] Collins P, Rosano G, Casey C, et al. Management of cardiovascular risk in the perimenopausal women: a consensus statement of European cardiologists and gynecologists. Climacteric 2007;10(6):50826. [13] Malik S, Wong ND, Franklin SS, et al. Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults. Circulation 2004;110(10):124550. [14] Mosca L. Guidelines for prevention of cardiovascular disease in women: a summary of recommendations. Prev Cardiol 2007;10(4 Suppl 3):1925. [15] Antithrombotic Trialists Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324(7329):7186. [16] Cook NR, Lee IM, Gaziano JM, et al. Low-dose aspirin in the primary prevention of cancer: the Womens Health Study: a randomized controlled trial. JAMA 2005;294(1):4755. [17] Johnell O. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int 2006;17(12):172633. [18] Pasco JA, Seeman E, Henry MJ, et al. The population burden of fractures originates in women with osteopenia, not osteoporosis. Osteoporos Int 2006;17(9):14049. [19] Flicker L, Hopper JL, Rodgers L, et al. Bone density determinants in elderly women: a twin study. J Bone Miner Res 1995;10(11):160713. [20] Keen R. Osteoporosis: strategies for prevention and management. Best Pract Res Clin Rheumatol 2007;21(1):10922. [21] Weatherall M. Prevention of falls and fall-related fractures in community-dwelling older adults: a meta-analysis of estimates of eectiveness based on recent guidelines. Intern Med J 2004;34(3):1028. [22] Torgerson DJ, Bell-Syer SE. Hormone replacement therapy and prevention of nonvertebral fractures: a meta-analysis of randomized trials. JAMA 2001;285(22):28917. [23] Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA 1999;282(7):63745. [24] Siris ES, Harris ST, Eastell R, et al. Skeletal eects of raloxifene after 8 years: results from the continuing outcomes relevant to Evista (CORE) study. J Bone Miner Res 2005;20(9): 151424.

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[25] Black DM, Thompson DE, Bauer DC, et al. Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial. FIT Research Group. J Clin Endocrinol Metab 2000;85(11):411824. [26] U.S. Cancer Statistics Working Group. United States Cancer Statistics: 19992004 Incidence and Mortality Web-based Report. 2007. Available at: www.cdc.gov/uscs. Accessed January 30, 2008. [27] CDC. Lung cancer risk factors. Available at: http://www.cdc.gov/cancer/lung/basic_info/ risk_factors.htm. Accessed June 23, 2008. [28] Wakelee HA, Chang ET, Gomez SL, et al. Lung cancer incidence in never smokers. J Clin Oncol 2007;25(5):4728. [29] Reeves GK, Pirie K, Beral V, et al. Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study. BMJ 2007;335(7630):1134. [30] Smith-Warner SA, Spiegelman D, Yaun SS, et al. Alcohol and breast cancer in women: a pooled analysis of cohort studies. JAMA 1998;279(7):53540. [31] Gotzsche PC, Nielsen M. Screening for breast cancer with mammography. Cochrane Database Syst Rev 2006;18(4):CD001877. [32] Samad AK, Taylor RS, Marshall T, et al. A meta-analysis of the association of physical activity with reduced risk of colorectal cancer. Colorectal Dis 2005;7(3):20413. [33] Park Y, Hunter DJ, Spiegelman D, et al. Dietary ber intake and risk of colorectal cancer: a pooled analysis of prospective cohort studies. JAMA 2005;294(22):284957. [34] Geiger TM, Miedema BW, Geana MV, et al. Improving rates for screening colonoscopy: analysis of the health information national trends survey (HINTS I) data. Surg Endosc 2008;22(2):52733. [35] Whiteman MK, Hillis SD, Jamieson DJ, et al. Inpatient hysterectomy surveillance in the United States, 20002004. Am J Obstet Gynecol 2008;198(1):34, e317. [36] Trimble CL, Kauderer J, Zaino R, et al. Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Cancer 2006;106(4):8129. [37] Parker WH. Etiology, symptomatology, and diagnosis of uterine myomas. Fertil Steril 2007; 87(4):72536. [38] Scialli AR, Jestila KJ. Sustained benets of leuprolide acetate with or without subsequent medroxyprogesterone acetate in the nonsurgical management of leiomyomata uteri. Fertil Steril 1995;64(2):31320. [39] Fiscella K, Eisinger SH, Meldrum S, et al. Eect of mifepristone for symptomatic leiomyomata on quality of life and uterine size: a randomized controlled trial. Obstet Gynecol 2006; 108(6):13817. [40] Freeman EW, Sherif K. Prevalence of hot ushes and night sweats around the world: a systematic review. Climacteric 2007;10(3):197214. [41] Hammar M, Berg G, Lindgren R. Does physical exercise inuence the frequency of postmenopausal hot ushes? Acta Obstet Gynecol Scand 1990;69(5):40912. [42] Thurston RC, Joe H, Soares CN, et al. Physical activity and risk of vasomotor symptoms in women with and without a history of depression: results from the Harvard Study of Moods and Cycles. Menopause 2006;13(4):55360. [43] MacLennan A, Lester S, Moore V. Oral estrogen replacement therapy versus placebo for hot ushes: a systematic review. Climacteric 2001;4(1):5874. [44] Lethaby AE, Brown J, Marjoribanks J, et al. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst Rev 2007;17(4):CD001395. [45] Guttuso T Jr, Kurlan R, McDermott MP, et al. Gabapentins eects on hot ashes in postmenopausal women: a randomized controlled trial. Obstet Gynecol 2003;101(2): 33745. [46] Evans ML, Pritts E, Vittingho E, et al. Management of postmenopausal hot ushes with venlafaxine hydrochloride: a randomized, controlled trial. Obstet Gynecol 2005;105(1): 1616.

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[47] Reddy SY, Warner H, Guttuso T Jr, et al. Gabapentin, estrogen, and placebo for treating hot ushes: a randomized controlled trial. Obstet Gynecol 2006;108(1):418. [48] Suvanto-Luukkonen E, Koivunen R, Sundstrom H, et al. Citalopram and uoxetine in the treatment of postmenopausal symptoms: a prospective, randomized, 9-month, placebocontrolled, double-blind study. Menopause 2005;12(1):1826. [49] Stearns V, Slack R, Greep N, et al. Paroxetine is an eective treatment for hot ashes: results from a prospective randomized clinical trial. J Clin Oncol 2005;23(28):691930. [50] Gordon PR, Kerwin JP, Boesen KG, et al. Sertraline to treat hot ashes: a randomized controlled, double-blind, crossover trial in a general population. Menopause 2006;13(4): 56875. [51] Pandya KJ, Raubertas RF, Flynn PJ, et al. Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot ashes: a University of Rochester Cancer Center Community Clinical Oncology Program study. Ann Intern Med 2000;132(10): 78893. [52] Chiechi LM, Putignano G, Guerra V, et al. The eect of a soy rich diet on the vaginal epithelium in postmenopause: a randomized double blind trial. Maturitas 2003;45(4):2416. [53] North American Menopause Society. The role of local vaginal estrogen for treatment of vaginal atrophy in postmenopausal women: 2007 position statement of The North American Menopause Society. Menopause 2007;14(3 Pt 1):35569, quiz 370351. [54] Nilsson K, Risberg B, Heimer G. The vaginal epithelium in the postmenopausecytology, histology and pH as methods of assessment. Maturitas 1995;21(1):516. [55] Suckling J, Lethaby A, Kennedy R. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst Rev 2006;18(4):CD001500. [56] Hannestad YS, Rortveit G, Sandvik H, et al. A community-based epidemiological survey of female urinary incontinence: the Norwegian EPINCONT study. Epidemiology of Incontinence in the County of Nord-Trondelag. J Clin Epidemiol 2000;53(11):11507. [57] Danforth KN, Townsend MK, Liord K, et al. Risk factors for urinary incontinence among middle-aged women. Am J Obstet Gynecol 2006;194(2):33945. [58] Hay-Smith EJ, Dumoulin C. Pelvic oor muscle training versus no treatment, or inactive control treatments, for urinary incontinence in women. Cochrane Database Syst Rev 2006;25(1):CD005654. [59] Ghoniem GM, Van Leeuwen JS, Elser DM, et al. A randomized controlled trial of duloxetine alone, pelvic oor muscle training alone, combined treatment and no active treatment in women with stress urinary incontinence. J Urol 2005;173(5):164753. [60] Lapitan MC, Cody DJ, Grant AM. Open retropubic colposuspension for urinary incontinence in women. Cochrane Database Syst Rev 2003;1(1):CD002912. [61] Nabi G, Cody JD, Ellis G, et al. Anticholinergic drugs versus placebo for overactive bladder syndrome in adults. Cochrane Database Syst Rev 2006;18(4):CD003781. [62] Grodstein F, Stampfer MJ, Manson JE, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med 1996;335(7):45361. [63] Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med 1991;20(1):4763. [64] The Writing Group for the PEPI Trial. Eects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/ Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial. JAMA 1995; 273(3):199208. [65] Clarkson TB. Estrogens, progestins, and coronary heart disease in cynomolgus monkeys. Fertil Steril 1994;62(6 Suppl 2):147S51S. [66] Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benets of estrogen plus progestin in healthy postmenopausal women: principal results From the Womens Health Initiative randomized controlled trial. JAMA 2002;288(3):32133.

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[67] Anderson GL, Limacher M, Assaf AR, et al. Eects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Womens Health Initiative randomized controlled trial. JAMA 2004;291(14):170112. [68] The Womens Health Initiative Study Group. Design of the Womens Health Initiative clinical trial and observational study. Control Clin Trials 1998;19(1):61109. [69] Manson JE, Allison MA, Rossouw JE, et al. Estrogen therapy and coronary-artery calcication. N Engl J Med 2007;356(25):2591602.

Med Clin N Am 92 (2008) 12731293

Urinary Incontinence and Pelvic Organ Prolapse: Diagnosis and Treatment for the Primary Care Physician
Husam Abed, MD, Rebecca G. Rogers, MD*
Division of Urogynecology, Department of Obstetrics and Gynecology, University of New Mexico Health Sciences Center, 4th Floor, Ambulatory Care Center, 2211 Lomas Blvd. NE, Albuquerque NM 87106, USA

Pelvic oor disorders One in nine women undergoes surgery for urinary incontinence or pelvic organ prolapse or both in her lifetime, with increasing incidence with increasing age [1]. The estimated demand for consultations for pelvic oor disorders is anticipated to increase by 30% by the year 2030 [2]. Although not life threatening, urinary incontinence and pelvic organ prolapse are life altering and carry signicant quality-of-life changes. Despite being among the top ten reasons for expenditure of health care dollars, pelvic oor disorders are not typically addressed by primary care physicians. Barriers to diagnosis and treatment include a misunderstanding of the conditions and a commonly held belief that eective treatments are surgical or that an extensive evaluation is required before initiating treatment [35]. In this article, we outline a simplied approach to diagnosis and treatment of women with urinary incontinence or pelvic organ prolapse that can be used by primary care physicians to identify patients with these conditions and initiate treatment for basic problems. Urinary incontinence Denitions and classication Urinary incontinence is a hidden epidemic that consumes approximately $19.5 billion in health care expenditures annually [6]. Dened as the involuntary leakage of urine, incontinence is more common among women than men. Fewer than 50% of women aected by incontinence seek treatment.
* Corresponding author. E-mail address: rrogers@salud.unm.edu (R.G. Rogers). 0025-7125/08/$ - see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2008.04.004 medical.theclinics.com

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Many patients feel that urinary incontinence is a normal part of aging and are embarrassed to discuss this problem with their health care provider. Most cases of incontinence in women are either stress urinary incontinence (SUI)dthe loss of urine associated with coughing, sneezing, exercise, or exertiondor urge urinary incontinence (UUI)dloss of urine preceded by or accompanied by urgency. Many women have mixed incontinence, which is a combination of stress and urge incontinence. Not all women with bladder problems are incontinent; overactive bladder is urinary urgency usually with frequency and nocturia, with or without incontinence, and may severely aect many women. Epidemiology Approximately 38% of women have some type of urinary incontinence [7]. Although not all incontinence is bothersome, an estimated 20% of women aged 45 to 59 years women report daily or severe incontinence and one third report weekly incontinence [7]. A recent study found that the 2-year incidence for development of urinary incontinence was 13.7%, although during the same time frame there was also a 13.9% remission rate [8]. The same study revealed that the peak incidence of frequent SUI and UUI (leak at least once weekly) diers. The peak incidence of SUI is between the ages of 46 and 50, whereas the peak incidence of UUI is older, between the ages of 51 and 55. Reported risk factors for urinary incontinence include age, race, hormonal status, obesity, and history of pregnancy and childbirth. The prevalence of urinary incontinence increases from 15% for the age group 18 to 24 years to 46% for the age group 60 to 64 years [9]. Higher prevalence rates of incontinence are reported for whites and Hispanics compared with African Americans and Asian women [10]. The prevalence of urinary incontinence also increases with increasing body mass index, increased parity, and smoking [10]. Other risk factors not consistently reported include constipation and family history. Pathophysiology and anatomy The lower urinary tract is composed of the bladder, bladder neck, and urethra. It is innervated by the sympathetic and parasympathetic nervous systems and is responsible for urinary storage and evacuation. During the storage phase, the detrusor muscle is relaxed through stimulation of b-adrenergic receptors and inhibition of muscarinic M3-cholinergic receptors, which allows the bladder to ll without signicant increase in intravesical pressure. At the same time, the bladder neck and urethral sphincter are contracted because of stimulation of a-adrenergic receptors, which creates a pressure gradient that prevents urine from leaking through the urethra. As the bladder lls to capacity (350600 mL of uid), bladder stretch receptors are stimulated. Signals are transferred at S2-4 nerve root levels and sent to the spinal cord and brain, which creates awareness of the need to void.

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During evacuation, signals from the pons micturition center to the sacral portion of the spinal cord results in parasympathetic stimulation, which causes the detrusor muscle to contract. At the same time, the internal urethral sphincter is signaled to relax and urination ensues. Diagnosis The rst step to diagnosing urinary incontinence is screening patients for symptoms. Like other embarrassing conditions, women may be reluctant to broach the subject with their primary care provider. Screening questionnaires have been developed that screen for incontinence and simplify the diagnosis of type of incontinence. Use of a questionnaire in clinical practice can allow for easy diagnosis and intervention in many women. The 3 Incontinence Questions questionnaire consists of three questions and has a sensitivity of 0.75 (95% CI, 0.680.81) and a specicity of 0.77 (95% CI 0.690.84) in distinguishing urge from stress incontinence [11]. The Questionnaire for Urinary Incontinence Diagnosis consists of six questions with similar specicities and sensitivities (Appendix 1) [12]. Women who are unresponsive to rst-line treatment after screening may benet from a more in-depth history and physical examination, including pelvic examination, voiding diary, and simple oce testing. The history should include evaluation of medical comorbidities, including diabetes, neurologic disorders, and cognitive impairment, and a complete surgical history, including prior incontinence or prolapse procedures. A review of current medications is important because they can cause incontinence through several dierent mechanisms (Table 1) [13]. During pelvic examination, objective evidence of urine leakage with Valsalva maneuver and cough supports the diagnosis of SUI. Patients also should be evaluated for signicant pelvic organ prolapse by observing the vaginal introitus during straining. During the pelvic bimanual examination, patients can be asked to contract their pelvic musculature or perform a Kegel exercise. Incorporating evaluation and coaching of pelvic oor exercises during the pelvic examination is a simple way to ensure that patients are performing exercises correctly. Some women are unable to correctly contract their pelvic oor muscles and might benet from referral to a physical therapist [14]. Voiding diaries are diagnostic and therapeutic and may point to interventions, including reducing or increasing uid intake and timing of voids. Voiding dairies record volumes and types of uids consumed, frequency and amount of voids, and episodes of incontinence and triggers for incontinence. Normal voided volumes range from 200 to 250 mL per void, with normal voiding frequency ranging from 8 to 12 voids daily with 1 void per night [15]. A sample voiding diary can be downloaded online at http://www.augs.org/Portals/0/Voiding_Diary.pdf. Urinary tract infections can mimic either SUI or UUI; screening for infection in incontinent women with urine dip or urinalysis is important. Although bladder cancers are relatively rare in women, the urine dip or

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Table 1 Examples of various eects of medications on lower urinary tract function Lower urinary tract eect Urethral relaxation Mechanism Decreased urethral pressure Category a-adrenergic blockers Neuroleptics Benzodiazepines Parasympathomimetics Diuretics Anticholinergics Anti-parkinsonians a-agonists b-adrenergic blockers Calcium channel blockers Indirect eect Cough Sedation, delerium, immobility Angiotensive-converting enzyme inhibitors Sedatives Alcohol Examples Doxazosin, prazosin, tamsulosin, terazosin Haloperidol, chlorpromazine, prochlorperazine Alprazolam, clonazepam, diazepam Bethanechol, cisapride Furosemide, hydrochlorothiazide Atropine, hyoscyamine, oxybutynin, tolterodine Carbidopa, levodopa Guanfacine, phenylephrine, clonidine Atenolol, labetalol, propranolol Amlodipine, nifedipine Disopyramide Captopril, enalapril, ramipril, lisinopril Trazadone, lorazepam, quetiapine

Increased intravesical pressure

Detrusor stimulation Increased urine production Urinary retention

ABED & ROGERS

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urinalysis also can screen for hematuria. If hematuria is present, further evaluation should be undertaken. Postvoid residual testing for bladder emptying should be performed in women with history of pelvic surgery, diabetes, or other neurologic disorders. The test can be performed either by catheterization or ultrasound. Although exact agreement on what is considered an elevated postvoid residual varies, residuals of more than 150 mL on two separate occasions warrant further investigation by a subspecialist. More invasive testing, such as urodynamics, is performed by many subspecialists before surgical intervention. Performing these tests is not indicated in most patients interested in starting nonsurgical treatment. Treatment Treatment options for urinary incontinence vary depending on whether the diagnosis of stress or urge incontinence is made, although the two disorders do share several behavioral and physical therapy interventions. Strategies to prevent development of urinary incontinence are not well dened. Cesarean delivery on demand is advocated by some as a protective intervention for development of urinary incontinence. The Term Breech Trial, which randomized women to vaginal versus cesarean delivery for breech presentation infants, is the single randomized trial that followed women postpartum for pelvic oor changes. Although a protective eect of cesarean delivery in preventing urinary incontinence was found at 3 months after delivery (RR 0.62; 95% CI, 0.410.93) the eect was lost at 2 years (RR 0.81; 95% CI, 0.631.06). Until further data are available, the decision to perform cesarean section to prevent pelvic oor problems remains an individual decision between a patient and her provider [16]. Stress urinary incontinence Behavioral and physical and pharmaceutical therapy Management of uid intake may play some role in controlling stress urinary incontinence. It is one of the main coping strategies for up to 38% of women with bothersome urinary incontinence [17]. One study found that reducing uid intake resulted in a signicant reduction in incontinence episodes [18]. Weight reduction also may play a role in the management of SUI, especially in obese women. In one small study, women who experienced weight loss reported a marked improvement in SUI symptoms [19]. Decreased smoking also may be helpful in the treatment of SUI. A retrospective case control study compared women who never smoked to women who currently smoke and showed that the relative risk of urge or stress incontinence increased by a factor of 2.2 for women who previously smoked and by 2.5 for women who currently smoke, compared with never smokers. Risk increased with number of cigarettes smoked and years of smoking [20].

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Pelvic oor exercises are a mainstay of therapy for SUI. Many women can be trained on performing these exercises while performing manual vaginal examination (http://kidney.niddk.nih.gov/kudiseases/pubs/exercise_ez/ #how). A recommended regimen includes three sets of 8 to 12 slow-velocity, maximum intensity pelvic oor muscle contractions sustained for 6 to 8 seconds. The exercises should be performed three to four times a week and continued for at least 15 to 20 weeks [21]. It might take as long as 5 months before clinical improvement is noticed [22]. Learning to perform a properly timed pelvic oor muscle contraction during cough or any activity that causes a SUI episode results in decreased incontinence episodes [23]. Currently, there is no US Food and Drug Administrationapproved pharmacologic therapy for SUI; however, duloxetine, a selective serotonin and norepinephrine reuptake inhibitor antidepressant, has been shown to have some ecacy in the treatment of stress incontinence [24]. Devices Many women use absorptive products, including panty liners or perineal pads, for treatment of mild urinary incontinence. Many women prefer these pads as opposed to incontinence pads for their discreetness, although menstrual pads are not as eective in absorbing uids and managing odor [25]. For women with severe incontinence, diapers are more helpful [26]. Pessaries are silicon devices that can be inserted into the vagina to provide support to the pelvic organs and treat stress incontinence by increasing urethral resistance (Fig. 1). Many women have observed that their stress incontinence improves when a tampon is in place, and tampons are thought to work by a similar mechanism as pessaries by providing urethral support. Pessaries and tampons have been shown to be helpful in controlling SUI during exercise in a randomized trial when compared with no device [27]. Approximately half of women who attempt to use a pessary to treat their stress incontinence continue to use the pessary at 2 years [28]. Some of the reasons for pessary discontinuation include irritation of the vaginal mucosa, with associated discharge, odor, ulcerations, and bleeding. Other devices used for the management of SUI with varying success include the contraceptive diaphragm, intravaginal sponge, urethral plugs, and external urethral occlusive devices [2932]. Despite the lack of strong evidence supporting the role of mechanical devices in the management of urinary incontinence, it is feasible to use such devices because of their low cost, ease of use, and rare side eects [33]. Surgery Patients who fail pelvic oor exercises and devices should be referred to a specialist for evaluation for surgery. Surgery, which remains a major therapeutic option for treatment of SUI, can be in the form of minimally invasive midurethral slings, urethral bulking agents, or retropubic operations.

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Fig. 1. Commonly used pessaries. Upper row (pessaries for incontinence): (A) Incontinence ring. (B) Incontinence ring with support. (C) Incontinence dish. (D) Incontinence dish with support. Lower row (pessaries for prolapse): (E) Ring. (F) Ring with support. (G) Gellhorn. (Courtesy of R. Rogers, MD, Albuquerque, NM.)

Traditional retropubic procedures, such as the Burch procedure, have a lower success rate than traditional fascial sling procedures, both of which require a postoperative catheter, abdominal incisions, and hospital stay [34]. Minimally invasive midurethral slings currently are preferred by most patients and surgeons and oer an outpatient procedure for the treatment of stress incontinence. The slings with proven success are made of polypropylene mesh and travel either from the abdomen through the retropubic space under the urethra (eg, tension-free vaginal tape) or through the obturator foramen and under the urethra (eg, trans-obturator tape). Success rates of 81% subjective and objective cure have been reported with a mean follow-up of 7.6 years [35]. Urge urinary incontinence Prevention and treatment The mainstay of therapies for UUI, in contrast to SUI, is pharmaceutical and behavioral. Surgery does not help UUI, and there are no reports of improvement in UUI symptoms with the use of pessaries. As with SUI, there are also no proven preventive interventions. Behavioral and physical therapy Behavioral interventions for urge urinary incontinence include changing bladder function by altering voiding habits and urge suppression strategies

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and uid management. Behavioral therapy plays an important role in the management of UUI. It has been shown that biofeedback-assisted behavioral training was more eective than oxybutynin in the treatment of UUI, rendering this as an eective, safe, and acceptable conservative treatment with high level of patient satisfaction [36]. Another form of behavioral therapy, timed voids, has been shown to be eective in reducing urinary frequency and increasing voided volume. Bladder drills or timed voids place women on a voiding schedule in which they are prompted by a timer or clock to void rather than responding to the urge to void. Women gradually lengthen the time period between voids [37]. The ecacy of timed voids is proven, with episodes of incontinence reduced by as much as 57% [38]. Limiting uid intake in general or at certain times of the day decreases voiding frequency, urgency, and incontinence episodes [18]. Physiologic evidence suggests that caeine precipitates symptoms of UUI [39], but clinical evidence of the eectiveness of caeine reduction is unclear [40,41]. The role of pelvic oor exercises (Kegel exercises) in the management of UUI is less clear than SUI, yet it has proven better than no treatment, placebo drug, or inactive control [42]. Referral to a physical therapist is warranted if patients are unable to contract their pelvic oor muscles during the pelvic examination or for more help with behavioral training. Some physical therapists may use vaginal electrical stimulation to treat overactive bladder symptoms, although no data support the ecacy of this treatment modality [43]. Pharmacologic therapy Anticholinergic medication is the mainstay of treatment for UUI despite lower ecacy than behavioral therapy for treatment of symptoms [36]. These drugs block the postganglionic muscarinic receptors on the detrusor muscle, thus aecting the contractility of the bladder muscle. A recent Cochrane review found that patients taking anticholinergics were more likely to report cure or improvement than patients taking placebo (56% versus 41%, respectively), with a relative risk for cure or improvement of 1.39 (95% CI 1.281.51). This resulted in patients reporting approximately four fewer leakage episodes and ve fewer voids per week when compared with placebo medications [44]. The most common side eects of anticholinergic therapy include dry mouth, constipation, and blurred vision. Oxybutynin chloride and immediate-release tolterodine are the most widely used agents for treatment of UUI. Both have signicant anticholinergic side affects and require repeated dosing during the day. Anticholinergic side eects are decreased but still present in their extended release forms [45,46]. Recently, three new anticholinergics have become available in the United States. Trospium chloride has decreased lipophilicity with no penetration to the blood-brain barrier and has a theoretic lack of eect on the cognitive function, which is important in treating elderly patients. Because of its receptor selectivity, trospium chloride theoretically may have decreased rates

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of severe dry mouth, although when studied, the overall incidence of dry mouth and short-term adverse events were similar to those of immediate-release oxybutynin [47]. Solifenacin has increased specicity for muscarinic receptors in the urinary bladder compared with salivary glands, resulting in decreased rates of dry mouth [48]. Darifenacin has more M3 specicity (bladder) than M1 (central nervous system) with decreased central nervous system side eects and decreased dry mouth [48]. Overall, these anticholinergic drugs are eective in treating symptoms of UUI. There may be some advantage to the newer agents in reducing side eects, but it must be weighed against the additional expense of these agents. All anticholinergics have a signicant discontinuation rate with long-term use. Other reported treatment options for UUI include acupuncture [49], sacral nerve stimulation [50], and various intravesical therapies, including oxybutynin, atropine, trospium, capsaicin, resiniferatoxin, and botulinum A toxin. None of these is considered rst-line therapy. Mixed incontinence In patients with mixed incontinence, an initial trial of medical or behavioral therapy or both directed at the urge component may be benecial. Alternatively, the initial therapy may be selected based on the patients predominant symptom (SUI or UUI). An algorithm that outlines a suggested management plans for urinary incontinence is included (Fig. 2). Pelvic organ prolapse Denition and classication Pelvic organ prolapse is the herniation of the pelvic organs toward or through the vaginal opening. It is often associated with feelings of pressure and bowel and bladder complaints. Typically prolapse is described by one of the three vaginal sites involved, including the anterior wall (bladder or cystocele), posterior wall (rectum or rectocele), and apex (enterocele) (Figs. 35). Although various classication schemes have been proposed, the standard for measurement of pelvic organ prolapse is the Pelvic Organ Prolapse Quantication (POPQ) scale, which describes the prolapse of the three vaginal compartments in relationship to the vaginal hymen. Overall prolapse is staged according to the most dependent position of the leading edge of prolapse [51]. Recently, a validated and simplied version of the POPQ has been proposed, which consists of four measurements and classies prolapse into four stages in relationship to the hymen (Table 2) [52]. Epidemiology Pelvic organ prolapse is common. The International Continence Society denes pelvic organ prolapse as any stage of prolapse greater than zero. If

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Patient complains of Urinary Incontinence

1. 2. 3. 4.

General assessment Urinary symptoms questionnaire (3IQ or QUID) Assess quality of life or desire for treatment Physical exam: a. Assess prolapse (stage) b. Assess pelvic muscle contraction 5. Check PVR (if patient complains of hesitancy/incomplete voiding, weak stream, history of pelvic surgery, large prolapse, or neurologic disease) 6. UA/culture

Incontinence with: 1. Pain 2. Persistent hematuria 3. Recurrent infection 4. Pelvic irradiation 5. Radical Pelvic surgery 6. Fistula If exam abnormal: 1. PVR (>150 mL) 2. POP stage II + UUI 3. Pelvic mass 4. Abnormal neurologic examination

Urge incontinence (QUID Urge score 4)

Mixed Incontinence

Stress Incontinence (QUID Stress score 6)

1. Pelvic floor exercise 2. Timed voiding (Bladder drills) Can use voiding diary as feedback 3. Anticholinergics: a. Oxybutinin 2.5-5mg q4h b. Tolterodine 2mg BID c. Oxybutinin (extended release) 5-15mg/day d. Tolterodine (long acting) LA 24mg/day

1. Pelvic floor exercise 2. Consider pessary fitting if patient is interested 3. Refer for Physical Therapy for biofeedback/pelvic floor rehabilitation if the patient is unable to do pelvic floor exercise or no improvement on her own

No improvement in 6-8 weeks

Specialized Treatment/Referral Common side effects of anticholinergics: 1. Dry Mouth 2. Constipation Rare SE: Blurred Vision Contraindications to the use of Anticholinergics 1. Closed angle glaucoma 2. Urinary retention (PVR > 150mL) 3. Gastric Retention

Fig. 2. Algorithm for treatment of stress urinary and urge urinary incontinence. (Adapted from Kammerer-Doak DN, Abed H. Practice algorithm: urinary incontinence. The Female Patient. March 2007. p. 489; with permission.)

this denition is used, 27% to 98% of women have pelvic organ prolapse [5358]. Not all prolapse is symptomatic, however. Prolapse above or to the hymen typically is not symptomatic and does not require treatment if not bothersome to patients [59]. The number of women who have prolapse beyond the hymen is much less, aecting only 3% to 6% of women who present for gynecologic care [58,60]. Approximately 200,000 surgeries a year are performed for pelvic prolapse, costing more than $1 billion dollars annually [61,62]. Little is known about the natural history of prolapse. A prospective cohort study of 249 women found that the maximum descent of prolapse waxes and wanes. Although the 3-year incidence of prolapse in this cohort was approximately 40%, prolapse increased by at least 2 cm in 11% and regressed by the same amount in 3% of women, conrming that prolapse is dynamic disease process and that not all prolapse progresses with time [63].

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Fig. 3. Stage 2 anterior compartment prolapse (cystocele). (Courtesy of R. Rogers, MD, Albuquerque, NM.)

Causes and risk factors The most established risk factors for pelvic organ prolapse include vaginal childbirth, advancing age, and obesity [64]. The risk of developing pelvic organ prolapse from vaginal childbirth has been studied in several epidemiologic studies. The Oxford Family Planning study found that

Fig. 4. Stage 2 posterior compartment prolapse (rectocele). (Courtesy of R. Rogers, MD, Albuquerque, NM.)

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Fig. 5. Stage 4 anterior, apical, and posterior (not shown) prolapse (uterine prolapse or vault prolapse). (Courtesy of R. Rogers, MD, Albuquerque, NM.)

a vaginal parity of two conferred a relative risk of 8.4 of developing prolapse. The Womens Health Initiative had similar ndings, with every additional delivery up to ve deliveries conferring an increased risk of prolapse by 10% to 20%. Not all prolapse changes are attributable to vaginal birth. Some anatomic changes are observed during pregnancy; up to 46% of nulliparous women have been shown to have some prolapse in the late third trimester. Other studies have demonstrated that bladder and urethral mobility increase in pregnancy, with the greatest changes seen in the third trimester [55,6567]. Older women are at increased risk for pelvic organ prolapse. Among 1000 women who presented for an annual gynecologic examination, every
Table 2 Stages of prolapse Stage Stage 1 Stage 2 Stage 3 Description Prolapse in which the given point remains at least 1 cm above the hymenal remnants Prolapse in which the given point descends to an area extending from 1 cm above to 1 cm below the hymenal remnants Prolapse in which the given point descends more than 1 cm past the hymenal remnants but does not represent complete vaginal vault eversion or complete procidentia uteri. It implies that at least some portion of the vaginal mucosa is not everted Complete vaginal vault eversion or complete procidentia uteri. It implies that the vagina and/or uterus is maximally prolapsed with essentially the entire extent of the vaginal mucosa everted

Stage 4

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additional 10 years of age conferred an increase risk of prolapse of 40% [58]. Obesity has been shown in several epidemiologic studies to be associated with an increased risk of prolapse, with overweight and obese women (body mass index of O 25) having a 50% higher chance of developing prolapse [58]. Another survey of more than 2000 women identied vaginal parity, health status, and history of constipation as independent risk factors for symptomatic prolapse, but it did not nd age or increased body mass index to be associated with increased risk [68]. Other risk factors have variable support in the literature, including white or Hispanic race, hysterectomy, occupations that involve heavy lifting, and various obstetric factors, including operative delivery, infant weight, and length of pushing in the second stage of labor [64]. Pathophysiology and anatomy Support of the pelvic organs, including the rectum, bladder, and small bowel, depends on the apical, lateral, and distal attachments of the vaginal canal and the strength and integrity of the levator ani, or pelvic oor. The vagina is supported by a system of endopelvic fascia and supportive ligaments attached to the bony pelvis. Vaginal support can be divided into three levels. Level one support is the attachment of the vaginal apex to the uterosacral ligament complex, which in turn is attached to the sacrum. Level two support includes the lateral attachments of the anterior and posterior vaginal walls to the arcus tendineous fascious pelvis, or pelvic white line. Level two support also encompasses the inherent support of the vaginal tube by the vaginal muscularis, sometimes inappropriately termed vaginal fascia. Level three support is composed of the attachment of the anterior vaginal wall to the symphysis pubis and the posterior wall to the perineal body (Fig. 6) [69]. When all three levels are intact, there is continuous support from the perineum to the sacrum. Disruption may occur at any level of support or at multiple levels, resulting in pelvic organ prolapse. Integrity of the levator ani is essential to this support system by providing a platform on which the pelvic organs rest. Women with symptomatic prolapse commonly have multiple sites of defects and damage to the levator ani. Although descriptions of pelvic organ prolapse are reported in respect to which compartment is aected, the vagina is a continuous organ, and separation of the vagina into anterior, posterior, and apical compartments is somewhat arbitrary. Recent studies have underlined the importance of thinking of the vagina as continuous organ; approximately half of anterior prolapse can be attributed to apical descent [70]. Diagnosis Women with pelvic organ prolapse typically present with complaints of feeling a bulge or something falling out of the vagina. Often patients

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Fig. 6. Level I (suspension) and level II (attachment). In level I, paracolpium suspends vagina from lateral pelvic walls. Fibers of level I extend vertically and posteriorly toward sacrum. In level II, vagina is attached to arcus tendineus fasciae of pelvis and superior fascia of levator animuscles. Vaginal levels of anatomic support. (Adapted from DeLancey JO. Anatomic aspects of vaginal eversion after hysterectomy. Am J Obstet Gynecol 1992;166(6 Pt 1):171724; with permission.)

are concerned that they have a cancerous growth, which prompts them to seek medical attention. Although prolapse can be present for long periods of time before women request treatment, protrusion of the prolapse outside of the vagina often precipitates intervention. Prolapse is associated with myriad bowel and bladder complaints, including pelvic pressure, obstructed voiding and/or defecation, need for splinting (placing ngers in the vagina for support with defecation or urination), urinary or defecatory urgency and frequency, constipation, and urinary and anal incontinence. These symptoms are not useful in diagnosing prolapse, and women with pelvic oor symptoms other than seeing or feeling a bulge should have further investigation before undergoing treatment for prolapse to resolve the other symptoms [59]. The gold standard for diagnosis of pelvic organ prolapse is pelvic examination with measurement of vaginal descent by the POPQ, although completing the full POPQ is not necessary for screening or before initiation of conservative therapy. For the basic examination, a patient is examined in the supine position with the head of the bed at 45 and is asked to perform Valsalva while the vaginal opening is observed for bulging. To ascertain which compartments of the vagina are involved, a split speculum is inserted, and the anterior, posterior, and apical portions of the vagina are observed sequentially (see Figs. 35). Women should be asked to conrm that the degree of prolapse seen on examination is the degree of prolapse that they are experiencing. If a patients history of feeling a ball does not concur with

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the clinical examination, women should be examined while standing to elicit maximum descent. Because prolapse above the hymen does not carry signicant risk and these women are unlikely to have symptoms, the use of screening questions for detection of signicant pelvic organ prolapse may be valid [68]. Examples of questions used to screen patients include Do you usually have a bulge or something falling out that you can see or feel in your vaginal area? [71] and Do you have a sensation that there is a bulge in your vagina or that something is falling out from your vagina? [72]. Because prolapse is often accompanied by urinary or anal incontinence, women with prolapse also should be asked about these other disorders and vice versa. Treatment and prevention Clinical observation is a viable option for most women with pelvic organ prolapse. This approach is supported by recent evidence that even advanced prolapse can regress and that most women with early-stage prolapse are asymptomatic [73]. Asymptomatic patients with stage 1 or 2 disease (prolapse up to 1 cm distal to the hymenal ring) can be reassured that observation is warranted in their situation. Asymptomatic patients with stage 3 or 4 prolapse may need evaluation on regular basis to assess the development or worsening of voiding or defectory symptoms. Obstructed urination or defecation or hydronephrosis from chronic ureteral kinking are all indications for treatment regardless of degree of prolapse [64]. Nonsurgical treatment strategies for pelvic organ prolapse are limited. Because the epidemiologic risk factors for prolapse are not clearly dened, preventive strategies for development of prolapse are likewise not clearly dened. The problem is confounded by the fact that many of the risk factors for development of prolapse occur far in advance of symptomatic clinical presentation. This is particularly true for vaginal birth. For example, the peak age for surgical intervention for prolapse is 55, approximately 20 to 30 years after most women give birth. Cesarean delivery has been proposed as possible prevention strategy for prolapse. Not all multiparous women develop prolapse, however, and widespread implementation of maternal request cesarean delivery would expose the 90% of women not at risk to an unnecessary surgical intervention without sure benet [59]. Although obesity has been linked as a risk factor for development of prolapse, weight loss has not been proven to be a preventive measure. Pelvic oor exercises are other proposed prevention strategies with limited evidence to support their use [74]. The cornerstone of nonsurgical treatment for prolapse is the vaginal pessary (see Fig. 1). Pessaries are silicone devices that support the pelvic organs when inserted into the vagina. Historically, pessaries have been used in elderly women who are poor surgical candidates. Given rates of surgical

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failure of approximately 30%, however, pessaries oer a viable, nonsurgical treatment option for treatment of prolapse. Although there are at least 13 types of commonly used pessaries, most women can be tted and gain relief of symptoms with one of two types of pessary: the ring with support or the Gellhorn. A recent randomized controlled trial determined that patients did not have a preference for the ring or Gellhorn, and both were eective in the treatment of prolapse [75]. Approximately 80% of women who desire a trial of pessary use are successfully tted. Of those tted, approximately 50% continue using the pessary in the intermediate term (1 year) [7678]. Most women can learn to care for the pessary themselves after proper instruction, although a few require ongoing care by the provider. Pessary use may prevent prolapse progression and may prove to be an appropriate prevention strategy in the future [78]. The mainstay of treatment for symptomatic pelvic organ prolapse is surgery. Although a full description of the dierent types of prolapse surgery is beyond the scope of this article, in general, prolapse surgery can be divided into either obliterative procedures, in which the vagina is amputated, or reconstructive procedures, which attempt to restore vaginal anatomy. Obliterative procedures are performed vaginally and have high reported success rates with low morbidity [64]. These procedures are only appropriate in women who do not desire future vaginal intercourse. Multiple dierent reconstructive surgeries have been described for the treatment of prolapse. Little level 1 evidence exists to guide surgical decision making, however, and evidence regarding safety and ecacy of new procedures lags far behind their introduction. Traditional reconstructive repairs are associated with a one in three lifetime risk of repeat surgery with a mean interval between the rst and second surgery of 12.5 years [1]. Because of this high failure rate, new procedures have been introduced using surgical kits and graft materials, which purport to have higher success rates despite limited follow-up or comparative data. In general, abdominal procedures with graft materials have higher success rates at the expense of longer recovery times, higher cost, and longer operating times. Success of vaginal repairs may be improved with the use of graft materials at unknown cost of morbidity in sexual function and bowel and bladder complaints [79].

Summary Pelvic oor disorders are common and costly in terms of health care dollars and patient quality of life. Eective nonsurgical interventions exist for urinary incontinence and pelvic organ prolapse, and many women would benet from these simple interventions. Primary care providers are ideally suited to screen for these problems. Because most patients do not have complicated urinary incontinence or pelvic organ prolapse, primary care

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physicians can safely initiate rst-line treatments, such as instructions on performing pelvic oor exercises, behavioral modication (uid and dietary changes), prescribing anticholinergics, and pessary tting.

Appendix 1 Simple screening tool for stress urinary and urge urinary incontinence

The Questionnaire for Urinary Incontinence Diagnosis None of the time: score 0 Rarely: score 1 Once in a while: score 2 Often: score 3 Most of the time: score 4 All of the time: score 5

Question Do you leak urine (even small drops), wet yourself, or wet your pads or undergarments. 1. When you cough or sneeze? 2. When you bend down or lift something up? 3. When you walk quickly, jog, or exercise? 4. While you are undressing to use the toilet? 5. Do you get such a strong and uncomfortable need to urinate that you leak urine (even small drops) or wet yourself before reaching the toilet? 6. Do you have to rush to the bathroom because you get a sudden, strong need to urinate?

Stress urinary incontinence: score items 1, 2, and 3; stress score R 4. Overactive bladder: score items 4, 5, and 6; urge score of R 6. Mixed urinary incontinence: combined stress score R 4 and urge score of R 6. Modied from Bradley CS, Rovner ES, Morgan MA, et al. A new questionnaire for urinary incontinence diagnosis in women: development and testing. Am J Obstet Gynecol 2005;192(1):66; with permission.

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[46] Van Kerrebroeck P, Kreder K, Jonas U, et al. Tolterodine once daily: superior ecacy and tolerability in the treatment of overactive bladder. Urol 2001;57:41421. [47] Halaska M, Ralph G, Wiedemann A, et al. Controlled, double-blind, multicentre clinical trial to investigate long-term tolerability and ecacy of trospium chloride in patients with detrusor instability. World J Urol 2003;20(6):3929. [48] Dmochowski R. Improving the tolerability of anticholinergic agents in the treatment of overactive bladder. Drug Saf 2005;28(7):583600. [49] Emmons SL, Otto L. Acupuncture for overactive bladder: a randomized controlled trial. Obstet Gynecol 2005;106(1):13843. [50] van Kerrebroeck PE, van Voskuilen AC, Heesakkers JP, et al. Results of sacral neuromodulation therapy for urinary voiding dysfunction: outcomes of a prospective, worldwide clinical study. J Urol 2007;178(5):202934. [51] Bump RC, Mattiasson A, Bo K, et al. The standardization of terminology of female pelvic organ prolapse and pelvic oor dysfunction. Am J Obstet Gynecol 1996;175(1):107. [52] Swift S, Morris S, McKinnie V, et al. Validation of a simplied technique for using the POPQ pelvic organ prolapse classication system. Int Urogynecol J Pelvic Floor Dysfunct 2006; 17(6):61520. [53] Nygaard I, Bradley C, Brandt D. Pelvic organ prolapse in older women: prevalence and risk factors. Obstet Gynecol 2004;104:48997. [54] OBoyle AL, Woodman PJ, OBoyle JD, et al. Pelvic organ support in nulliparous pregnant and nonpregnant women: a case control study. Am J Obstet Gynecol 2002;187:99102. [55] Sze EH, Sherard GB, Dolezal JM. Pregnancy, labour, delivery and pelvic organ prolapse. Obstet Gynecol 2002;100(5pt1):9816. [56] Swift SE. The distribution of pelvic organ support in a population of female subjects seen for routine gynecologic health care. Am J Obstet Gynecol 2000;183:27785. [57] Bland DR, Earle BB, Vitolins MZ, et al. Use of the Pelvic Organ Prolapse staging system of the International Continence Society, American Urogynecologic Society, and Society of Gynecologic Surgeons in perimenopausal women. Am J Obstet Gynecol 1999;181:13247. [58] Swift S, Woodman P, OBoyle A, et al. Pelvic Organ Support Study (POSST): the distribution, clinical denition, and epidemiologic condition of pelvic organ support defects. Am J Obstet Gynecol 2005;192:795806. [59] Bradley CS, Nygaard IE. Vaginal wall descensus and pelvic oor symptoms in older women. Obstet Gynecol 2005;106(4):75966. [60] Samuelsson EC, Arne Victor FT, Tibblin G, et al. Signs of genital prolapse in a Swedish population of women 20 to 59 years of age and possible related factors. Am J Obstet Gynecol 1999;180:299305. [61] Boyles SH, Weber AM, Meyn L. Procedures for pelvic organ prolapse and urinary incontinence. Obstet Gynecol 19791997. Am J Obstet Gynecol 2003;188:10815. [62] Subak LL, Waetjen LE, van den Eeden S, et al. Cost of pelvic organ prolapse surgery in the United States. Obstet Gynecol 2001;99:64651. [63] Bradley CS, Zimmerman MB, Qi Y, et al. Natural history of pelvic organ prolapse in postmenopausal women. Obstet Gynecol 2007;109:84854. [64] Jelovsek JE, Maher C, Barber MD. Pelvic organ prolapse. Lancet 2007;369:102738. [65] Dietz HP, Lanzarone V. Levator trauma after vaginal delivery. Obstet Gynecol 2005;106(4): 70712. [66] Dietz HP, Eldridge A, Grace M, et al. Does pregnancy aect pelvic organ mobility? Aust N Z J Obstet Gynaecol 2004;44(6):51720. [67] DeLancey JO, Kearney R, Chou Q, et al. The appearance of levator ani muscle abnormalities in magnetic resonance images after vaginal delivery. Obstet Gynecol 2003;101:4653. [68] Rortveit Gm, Brown JS, Tham DH, et al. Symptomatic pelvic organ prolapse: prevalence and risk factors in a population-based, racially diverse cohort. Obstet Gynecol 2007; 109(6):1396403.

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[69] DeLancey JO. Anatomic aspects of vaginal eversion after hysterectomy. Am J Obstet Gynecol 1992;166(6 Pt 1):171724. [70] Summers A, Winkel LA, Hussain HK, et al. The relationship between anterior and apical compartment support. Am J Obstet Gynecol 2006;194:143843. [71] Barber MD, Neubauer NL, Klein-Olarte V. Can we screen for pelvic organ prolapse without a physical examination in epidemiologic studies? Am J Obstet Gynecol 2006;195(4):9428, 35. [72] Lukacz ES, Lawrence JM, Buckwalter JG, et al. Epidemiology of prolapse and incontinence questionnaire: validation of a new epidemiologic survey. Int Urogynecol J 2005;16:27284. [73] Handa VL, Garrett E, Hendrix S, et al. Progression and remission of pelvic organ prolapse: a longitudinal study of menopausal women. Am J Obstet Gynecol 2004;190(1):2732. [74] Bo K. Can pelvic oor muscle training prevent and treat pelvic organ prolapse? Acta Obstet Gynecol Scand 2006;85(3):2638. [75] Cundi GW, Amundsen CL, Bent AE, et al. The PESSRI study: symptom relief outcomes of a randomized crossover trial of the ring and Gellhorn pessaries. Am J Obstet Gynecol 2007; 196(4):7884. e18. [76] Maito JM, Quam ZA, Craig E, et al. Predictors of successful pessary tting and continued use in a nurse midwifery pessary clinic. J Midwifery Womens Health 2006;51(2):7884. [77] Clemons JL, Aguilar VC, Sokol ER, et al. Patient characteristics that are associated with continues pessary use versus surgery after 1 year. Am J Obstet Gynecol 2004;191(1):15964. [78] Handa VL, Jones M. Do pessaries prevent the progression of pelvic organ prolapse? Int Urogynecol J 2002;13:34952. [79] Maher C, Baessler K, Glazener CM, et al. Surgical management of pelvic organ prolapse in women. Cochrane Database Syst Rev 2007;3:CD004014.

Med Clin N Am 92 (2008) 12951305

Index
Note: Page numbers of article titles are in boldface type.

A Abscess, breast, 1119 Absorptive products, for urinary incontinence, 1278 Abstinence-only sexuality education, 1038 Abuse, domestic. See Domestic violence. Acute urethral syndrome, 1104 Acyclovir, for herpes simplex virus infections, 10961097 Adhesions, uterine, 1166 Adolescents cervical cancer screening in, 1063, 1066, 1071, 1073 pelvic masses in, 11531155 pregnancy in, 10391040 Adrenal disorders, infertility in, 11771179 Age maternal, pregnancy complications and, 12141216 of menopause, 1254 Agency for Health Care Research and Quality on womens health access, 1000 recommendations of, for sexually transmitted disease, 1084 Alcohol misuse, screening for, 10291030 Amenorrhea, infertility and, 11671180 hypothalamic, 1168 in premature ovarian failure, 11691170 Amitriptyline, for depression, 1207 Amoxicillin, for chlamydial infections, 1091 Anastrozole, for breast cancer, 1137 Androgens, elevated, in polycystic ovary syndrome, 11711172 Anovulation, infertility in, 11671180

Anticholinergic agents, for urinary incontinence, 12801281 Anticoagulants, for thrombotic diseases, 706709 Anti-estrogen therapy, for breast cancer, 1137636 Antiphospholipid antibody syndrome, in pregnancy, 12081211 Antithrombin deciency, in pregnancy, 12081211 Aromatase inhibitors for breast cancer, 1137 for polycystic ovary syndrome, 1175 Aspirin for cardiovascular disease prevention, 10121013, 1256 for preeclampsia, 1200 Assisted reproduction technology, 1182 Asthma, in pregnancy, 1211710 Atypical glandular cells, cervical, 1074 Atypical squamous cells of undetermined signicance, 10711073 Autoimmune disorders, lymphocytic oophoritis, 1170 Azithromycin for chlamydial infections, 1091 for pelvic inammatory disease, 1108 B Bariatric surgery, pregnancy after, 1213 Barrier contraceptive methods, 10511052 Basal cell carcinoma, screening for, 10251026 Battered family members. See Domestic violence. Behavioral therapy, for urinary incontinence, 1277, 12791280

0025-7125/08/$ - see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/S0025-7125(08)00109-0 medical.theclinics.com

1296 Benign breast diseases. See Breast, benign diseases of. Bichloroacetic acid, for genital warts, 1102 Biopsy breast, 1124, 1134 endometrial, 1145 Birth control pills, 10481049 for benign breast disease, 1125 for ovarian cysts, 1154 for uterine broids, 12611262 Bisphosphonates, for osteoporosis, 1258757 Bladder prolapse of, 1281786 training program for, 1280 Bleeding, uterine, in menopause, 12601262 Body mass index, evaluation of, 1014 Bone density test, 1027, 12571258 BRCA gene mutations, 1128 BRCAPRO program, for breast cancer risk assessment, 1129 Breast benign diseases of, 11151126 epidemiology of, 11151116 etiology of, 1116 evaluation of, 11231124 fat necrosis, 11201121 brocystic changes, 11211123 mastalgia, 11161117 mastitis, 11181119, 1125 nipple disorders, 11191120 treatment of, 11241126 cancer of, 11261138 epidemiology of, 1126 etiology of, 11271128 evaluation of, 11321134 genetic factors in, 1128 hormone replacement therapy and, 11271128 in menopause, 12591260 invasive, 11311132 noninvasive, 11301131 outcomes of, 1138 pathology of, 11291132 risk factors for, 11281129 screening for, 10161018, 1260 staging of, 1135 treatment of, 11351138 implants in, 1134 Breastfeeding, mastitis in, 11181119 C CA-125 tumor marker, 1153, 1156 CAGE test, for alcohol misuse, 10291030

INDEX

Calcitonin, for osteoporosis, 1258 Calcium supplementation for osteoporosis, 1027, 12571258 for preeclampsia, 12001201 Cancer adrenal, 1178 breast. See Breast, cancer of. cervical, 10181019, 1024, 10601069 colorectal, 1018, 1260 in menopause, 12591260 ovarian. See Ovary, cancer of. skin, 10251026 uterine, 10241025 Cardiovascular disease in menopause, 1256 screening for, 10111013 Ceftriaxone, for syphilis, 1100 Cephalosporins for gonorrhea, 1093 for pelvic inammatory disease, 11071108 Cervical cancer, screening for, 10181019, 1024, 10601069. See also Pap test. eectiveness of, 10601061 limitations of, 10601061 liquid-based cytology in, 10611062 recommendations for, 10631068 Cervicitis in herpes simplex virus infections, 1094 mucopurulent, 1104 Cervix cancer of. See Cervical cancer. masses of, dierential diagnosis of, 1144 mucus of, 1166 strawberry, in trichomoniasis, 11021103 Cesarean delivery, on demand, for urinary continence preservation, 1277 Chancre, in syphilis, 10971098 Chemotherapy, for breast cancer, 11371138 Chickenpox immunization, 1023 Childrens Health Insurance Program, 994995 Chlamydial infections, 10881091 pelvic inammatory disease in, 1105 screening for, 1026, 10891090 Citalopram, for vasomotor instability, 1264 Claus model, for breast cancer risk assessment, 11281129

INDEX

1297 Cystocele, 1281786 Cysts breast, 11211123 ovarian, 11541157 D Depo-medroxyprogesterone acetate injection, 1047 Depression in pregnancy, 12061208 screening for, 1029 Dermatitis, of nipple, 1120 DHypogonadotropic hypogonadism, 11671169 Diabetes mellitus in polycystic ovary syndrome, 1174 in pregnancy, 12051206 infertility in, 11791180 screening for, 10141016 Diaphragm, 1052 Diary, voiding, in incontinence, 1275 Diet, for polycystic ovary syndrome, 11741175 Diphtheria immunization, 1023 Domestic violence, 12391252 barriers to identifying, 12421243 cycle of, 1240 in pregnancy, 12411242 legal considerations in, 12471248 physical examination in, 12451246 rape in, 12481249 risk factors for, 12401241 safety assessment in, 1246 screening for, 10281029, 12431245 shelters for, 12461247 signs and symptoms of, 1245 statistics on, 1239 Doxycycline for chlamydial infections, 1091 for pelvic inammatory disease, 11071108 Drug(s) in pregnancy, 12271237 teratogenic, 11971198, 12291236 Ductal carcinoma in situ, 11221123, 1130 Duloxetine, for urinary incontinence, 1278 Dysfunctional uterine bleeding, in menopause, 12601262 Dyslipidemia, screening for, 1013 Dyspareunia, in menopause, 12631265

Clindamycin, for pelvic inammatory disease, 11071108 Clomiphene, for polycystic ovary syndrome, 1175 Clonidine, for vasomotor instability, 1264 Colorectal cancer, 1018, 1260 Computed tomography, in pelvic masses, 11501151 Condoms for contraception, 1051 for disease prevention, 10861087 Condyloma lata, 1098 Congenital adrenal hyperplasia, infertility in, 11771178 Contraception, 10371058 abstinence-only sexuality education and, 1038 barriers to using, 10371040 failure of, 1041 initiating, 1055 insurance coverage of, 996 lack of access to, 10381039 methods for, 10411053 barrier, 10511052 birth control pills, 10481049 combined hormonal, 10471048 depo-medroxyprogesterone acetate, 1047 eectiveness of, 10401042, 1197 emergency, 10521053 etonogestrel implant, 1044 intrauterine, 10401044 selection of, 1040 skin patch, 10491050 sterilization, 10451047 vaginal ring, 10501051 myths about, 10541055 oral. See Birth control pills. preconception counseling on, 1197 transition from, 1055 Copper intrauterine device, 1041, 10431044 Core needle biopsy, of breast, 1124 Coronary artery disease in menopause, 1256 screening for, 10111013 Cortisol, abnormal, infertility in, 1178677 Cryotherapy, for genital warts, 1102 Cushings syndrome, infertility in, 11781179 Cyclic mastalgia, 11161117

1298 E Eczema, of nipple, 1120 Education, for womens health, 10041006 Emergency contraception, 10521053 Endometriosis, infertility in, 11661167 Endometrium abnormalities of, in menopause, 12601262 biopsy of, 1145 cancer of, 10241025 hyperplasia of, 1261 Enterocele, 12811288 Epithelial hyperplasia, of breast, 11221123 Erythromycin for chlamydial infections, 1091 for syphilis, 1100 Estrogen replacement. See Hormone replacement therapy. Etonogestrel implant, 1044 Excisional biopsy, of breast, 1124 Exercise for osteoporosis prevention, 1027 for polycystic ovary syndrome, 11741175 for urinary incontinence, 1278, 1280 for vasomotor instability, 1263 Expedited partner therapy, for sexually transmitted diseases, 1088 F Factor V Leiden, in pregnancy, 12081211 Fallopian tube disease of, infertility in, 11641165 interruption of, for sterilization, 10451046 masses of, 1144 Famciclovir, for herpes simplex virus infections, 10961097 Fasting plasma glucose level, as screening test, 1015 Fat necrosis, of breast, 11201121 Fertility, problems with. See Infertility. Fetus, drugs aecting, 11971198, 12291236 Fibroadenomas, of breast, 1122 Fibrocystic changes, of breast, 11211123

INDEX

Fibroids, uterine, 1166, 12611262 Fine needle aspiration, of breast lesions, 1134 Fluoxetine for depression, 1207 for vasomotor instability, 1264 Food and Drug Administration, drug research guidelines of, 9991000 Fractures, in menopause, 1257 Future of Family Medicine project, 10021003 FUTURE studies, of human papillomavirus vaccine, 10751076 G Gabapentin, for vasomotor instability, 1264 Gail model, for breast cancer risk assessment, 11281129 Galactorrhea, 1119 Genetic factors in breast cancer, 1128 in premature ovarian failure, 1170 Genital herpes, 1090, 10941097 Genital warts, 11011102 Gentamicin, for pelvic inammatory disease, 1107 Gestational diabetes, 12051206 Glucose tolerance, impaired, 10151016 Gonadotropin releasing hormone deciency, infertility in, 1168 Gonorrhea, 1090, 10921094, 1105 Government Accountability Oce, research report of, 998999 Graves disease, 12041205

H Health care access to, 994998 costs of, 993994 for underinsured population, 995996 for uninsured population, 994995 Health Resources and Administration, 1000 Healthcare Eectiveness Data and Information Set, recommendations of, for sexually transmitted disease, 1084

INDEX

1299 Hypogonadism hypergonadotropic, 11691171 hypogonadotropic, 11671169 Hypothalamic-pituitary-gonadal axis, dysfunction of, infertility in, 11681169 Hypothyroidism in pregnancy, 12031205 infertility in, 1179 screening for, 1016 Hysterectomy, Pap test after, 1064, 10681069 Hysterosalpingography, in infertility, 11641165 Hysteroscopic sterilization, 10451046

Hearing loss, screening for, 1028 Heparin, for thrombotic diseases, 12091211 Hepatitis A immunization, 1020 Hepatitis B immunization, 1020 HER2 expression, in breast cancer, 1132 Herpes simplex virus infections, 1090, 10941097 Hormone replacement therapy breast cancer and, 11271128 for menopause, 12631267 for osteoporosis, 1258 for premature ovarian failure, 1171 for vasomotor instability, 12631264 Hormone therapy, for breast cancer, 11371138 Hot ashes, in menopause, 12621263 Human immunodeciency virus infection screening for, 1026 sexually transmitted diseases with, 1085 Human papillomavirus cervical cancer due to, 10691071 DNA testing for, 10701071, 10741075 immunization for, 1019, 1021, 1024, 10751077 warts due to, 11011102 11bHydroxylase deciency, infertility in, 11771178 21-Hydroxylase deciency, infertility in, 11771178 Hyperandrogenism, in polycystic ovary syndrome, 11711173 Hypergonadotropic hypogonadism, 11691171 Hyperinsulinemia, in polycystic ovary syndrome, 11721173 Hyperlipidemia, screening for, 1013 Hyperprolactinemia, infertility in, 1169 Hypertension in polycystic ovary syndrome, 1174 in pregnancy, 11991203 screening for, 10111013 Hyperthyroidism in pregnancy, 12041205 infertility in, 1179 screening for, 1016

I Idiopathic granulomatous lobular mastitis, 11181119 Imiquimod, for genital warts, 1102 Immunizations, 10191024, 10311032, 10751077 Incontinence, urinary. See Urinary incontinence. Infections, breast, 11181119 Infertility, 11631192 algorithm for, 1165 anovulatory, 1180 assisted reproductive technology for, 1182 causes of, 11631164 denition of, 1163 diagnosis of, 1180 evaluation of, 1164 in adrenal disorders, 11771179 in cervical mucus abnormalities, 1166 in diabetes mellitus, 11791180 in endometriosis, 11661167 in ovulatory dysfunction, 11671180 in hypergonadotropic hypogonadism, 11691171 in hypogonadotropic hypogonadism, 11671169 in polycystic ovary syndrome, 11711177 in thyroid disorders, 1179 in tubal disease, 11641165 in uterine abnormalities, 11651166 maternal age and, 12141216 unexplained, 1181 Inuenza immunization, 1021

1300 Insulin for diabetes mellitus, 12051206 resistance to, in polycystic ovary syndrome, 11721174 Insulin-sensitizing agents, for polycystic ovary syndrome, 11751177 Insurance for contraceptives, 10381039 inadequate, 994996, 1085 Intimate partner violence. See Domestic violence. Intrauterine devices, 10401044 K Kallmann syndrome, infertility in, 11671168 Kegel exercises, for urinary incontinence, 1278, 1280 L Labetalol, for hypertension, 1200 Laparoscopic tubal sterilization, 1045 Laparoscopy, in tubal inspection, in infertility, 11641165 Lapatinib, for breast cancer, 1138 Letrozole, for polycystic ovary syndrome, 1175 Leuprolide acetate, for uterine broids, 1261 Levooxacin, for chlamydial infections, 1091 Levonorgestrel intrauterine system, 1041, 10431044 Lifestyle modications for benign breast disease, 11241125 for polycystic ovary syndrome, 11741175 for urinary incontinence, 12771278 for vasomotor instability, 1263 Lipid disorders, screening for, 1013 Lobular carcinoma in situ, 11221123, 11301131 Lung cancer, in menopause, 1259 M Magnetic resonance imaging in benign breast disease, 11231124

INDEX

in breast cancer screening, 10171018, 11331134 in pelvic masses, 11511152 Mammary duct ectasia, 11181119 Mammography, 1017, 1123, 1133 Mastalgia, 11161117 Mastitis, 11181119, 1125 Measles-mumps-rubella immunization, 1022 Medicaid, 994996 Melanoma, screening for, 10251026 Meningococcal immunization, 1022 Menopause and menopausal transition, 12531271 age of, 1254 cancer in, 12591260 cardiovascular disease in, 1256 denition of, 1254 diagnosis of, 1254 hormone replacement therapy for, 12651267 menstrual disturbances before, 12601262 osteoporosis in, 12571259 Pap tests after, 10681069, 1073 physiology of, 1255 preventive health concerns in, 12551260 quality-of-life concerns in, 12601265 urinary incontinence in, 1265 urogenital atrophy in, 12631265 vasomotor instability in, 12621263 Menstrual irregularity in menopause, 12601262 in polycystic ovary syndrome, 1171 Metabolic syndrome, screening for, 10131014 Metformin, for polycystic ovary syndrome, 11751177 Methimazole, for hyperthyroidism, 1204 Methyldopa, for hypertension, 1200 Metronidazole for pelvic inammatory disease, 11071108 for trichomoniasis, 1103 Mifepristone, for uterine broids, 1261 MMR (measles-mumps-rubella) immunization, 1022 Morning-after contraception, 10521053

INDEX

1301 dysfunction of, infertility in, 11671180 follicle depletion in, in menopause, 1255 hyperstimulation of, for unexplained infertility, 1181 masses of dierential diagnosis of, 1144 imaging of, 11461147 polycystic disease of, 11711177 premature failure of, 11691170 torsion of, 11541155 virilizing tumors of, 1178 Ovulation-induction agents, for polycystic ovary syndrome, 1175 Oxybutynin, for urinary incontinence, 1280

Mucopurulent cervicitis, 1104 Mucus, cervical, qualities of, in infertility, 1166 Mumps immunization, 1022 Myomas, uterine, 1166, 12611262 N National Ambulatory Care Survey, 1003 National Centers of Excellence in Womens Health, 1006 National Health Interview Survey, 1003 National Institutes of Health, research guidelines of, 998 Neisseria gonorrhoeae infections, 1090, 10921094, 1105 Neisseria meningitidis immunization, 1022 Neural tube defects, risks of, 1218 Nipple disorders, 11191120 Nonsteroidal anti-inammatory drugs for benign breast disease, 1125 for mastitis, 1119 Nucleic acid amplication tests for chlamydial infections, 1089 for gonorrhea, 1092 O Obesity in polycystic ovary syndrome, 11721174 in pregnancy, 12121214 pelvic organ prolapse in, 1283, 1285 screening for, 10131014 Oce of Womens Health, 999 Ooxacin, for chlamydial infections, 1091 Oligomenorrhea, in infertility, 11671180 Opioids, infertility due to, 11681169 Oral contraceptives. See Birth control pills. Osteoporosis in menopause, 12571259 screening for, 10261028 Ovary cancer of referral in, 11571158 screening for, 1024 tumor markers for, 11521153 ultrasonography in, 1156 cysts of, 11541157

P Pagets disease, of nipple, 1120 Pap test, 1019 abnormal results in, 10711075 after menopause, 10681069, 1073 cytology with, 1064 discontinuation of, 1064 eectiveness of, 1060 rst, 1063, 1066 human papillomavirus testing with, 10701071, 10741075 intervals for, 1064, 10661068 method for, 10621063 posthysterectomy, 1064, 10681069 recommendations for, 10631068 versus liquid-based cytology, 10611062 Parathyroid hormone, for osteoporosis, 1258 Paroxetine for depression, 1207 for vasomotor instability, 1264 Pelvic oor disorders, 1273. See also Urinary incontinence. Pelvic oor exercises, for urinary incontinence, 1278, 1280 Pelvic inammatory disease, 11041109 clinical manifestations of, 1105 diagnosis of, 1106 epidemiology of, 1105 masses in, 1155 prevention of, 11081109 risk factors for, 1105 treatment of, 11061108 Pelvic masses, 11431161 clinical evaluation of, 11441145

1302 dierential diagnosis of, 11431144 epidemiology of, 1143 imaging of, 11451152 in adolescents, 11531155 in postmenopausal women, 11561157 in premenopausal women, 11551156 referral guidelines for, 11571159 treatment of, 11531157 tumor markers for, 11521153 Pelvic organ prolapse, 12811288 causes of, 12831285 classication of, 1281 denition of, 1281 diagnosis of, 12851287 epidemiology of, 12811282 pathophysiology of, 1285 treatment of, 12871288 Penicillin G, for syphilis, 1100 Perimenopause, denition of, 1254 Pertussis immunization, 1023 Pessaries for pelvic organ prolapse, 1288 for urinary incontinence, 1278 Physical therapy, for urinary incontinence, 12771278, 1280 Pituitary gland dysfunction, infertility in, 11681169 Placenta, abnormalities of, 1203 Pneumococcal immunization, 1022 Podolox, for genital warts, 1102 Podophyllin, for genital warts, 1102 Polycystic ovary syndrome, 11711177 clinical features of, 11711172 complications of, 1174 diagnosis of, 11711172 pathogenesis of, 11721174 prevalence of, 1171 treatment of, 11741177 Polymerase chain reaction, for herpes simplex virus, 1095 Preconception care, 11941197 Prednisone, for mastitis, 1119 Preeclampsia, 11991203 Pregnancy domestic violence in, 12411242 drug prescriptions in, 12271237 medical issues in, 11931225 advanced maternal age, 12141216

INDEX

antiphospholipid antibodies, 12081211 asthma, 12111212 cervical cancer screening, 1073 depression, 12061208 diabetes mellitus, 1016, 12051206 drug prescriptions, 11971198, 12271237 hypertension, 11991203 imaging, 11981199 obesity, 12121214 polycystic ovary syndrome, 1174 preconception care in, 11941197 prior adverse outcomes, 12161218 sexually transmitted diseases, 1087 syphilis, 1099 thrombosis, 12081211 thyroid disease, 12031205 pelvic organ prolapse during and after, 12831285 prior losses in, 1216715 ultrasonography in, 11551156 unintended prevention of. See Contraception. societal supports for, 10391040 Pregnancy in Polycystic Ovarian Syndrome, 11761177 Premature ovarian failure, 11691170 Preterm labor and birth, 12171218 Preventive health. See also Screening. immunizations in, 10201023, 10311032, 10751077 Probenecid, for pelvic inammatory disease, 1107 Progestins, in emergency contraception, 10521053 Prolactin, elevated, infertility in, 1169 Prolapse, pelvic organ, 12811288 Propranolol, for hyperthyroidism, 1204 Propylthiouracil, for hyperthyroidism, 1204 Protein C deciency, in pregnancy, 12081211 Protein S deciency, in pregnancy, 12081211 Psychologic issues, in domestic violence, 12421243

INDEX

1303 Sertraline, for vasomotor instability, 1264 Sexuality education, 1038 Sexually transmitted diseases, 10831113 acute urethral syndrome in, 1104 barriers to diagnosis and treatment of, 10851086 chlamydial infections, 1026, 10881091, 1105 clinical sequelae of, 1087 epidemiology of, 10841085 gonorrhea, 1090, 10921094 herpes simplex virus infections, 1090, 10941097 human papillomavirus. See Human papillomavirus. mucopurulent cervicitis in, 1104 partner management in, 10871088 pelvic inammatory disease in, 11041109 prevention of, 10861087 reporting requirements with, 1088 screening for, 1026 syphilis, 1090, 10971100 trichomoniasis, 11021103 Shingles vaccination, 1023 Skin cancer, screening for, 10251026 Skin patch, contraceptive, 10491050 Smoking lung cancer due to, 1259 screening for, 10301031 Solifenacin, for urinary incontinence, 1281 Sponge, contraceptive, 10511052 Squamous cell carcinoma, screening for, 10251026 Squamous intraepithelial lesions, cervical, 10721074 State Childrens Health Insurance Program, 994995 Sterilization female, 10451046 male, 10461047 Stillbirth, causes of, 1217 Strangulation attempt, signs and symptoms of, 12451246 Strawberry cervix, in trichomoniasis, 11021103 Streptococcus pneumoniae immunization, 1022 Stress urinary incontinence, 12771279, 1289

R Radiation therapy, for breast cancer, 11361137 Radiography, in pregnancy, 11981199 Raloxifene, for osteoporosis, 1258 Rape victim, examination of, 12481249 Rapid plasma reagin test, in syphilis, 1099 Rectum, prolapse of, 12811288 Reporting, of sexually transmitted diseases, 1088 Research, in womens health, 9981001 Revitalization Act of 1993, 999 Rubella immunization, 1022 S Salpingitis (pelvic inammatory disease), 11041109 Screening, 10111035 for alcohol misuse, 10291030 for breast cancer, 10161018, 1260 for cardiovascular disease, 10111013 for cervical cancer, 10181019, 1024, 10601069 for chlamydial infections, 1089 for colorectal cancer, 1018 for depression, 1029 for diabetes mellitus, 10141016 for domestic violence, 10281029, 12431245 for gonorrhea, 1090 for hearing loss, 1028 for herpes simplex virus infections, 1090 for hypertension, 10111013 for lipid disorders, 1013 for metabolic syndrome, 10131014 for obesity, 10131014 for osteoporosis, 10261028, 12571258 for ovarian cancer, 1024 for sexually transmitted diseases, 1026 for skin cancer, 10251026 for syphilis, 1090 for thyroid disorders, 1016 for urinary incontinence, 1275, 1289 for uterine cancer, 10241025 for vision disorders, 1028 Selective estrogen-receptor modulators for menopause, 1267 for osteoporosis, 1258 Selective serotonin reuptake inhibitors, for depression, 1207

1304 Stroke, screening for, 10111013 Surgery for breast cancer, 11351136 for pelvic organ prolapse, 1288 Sweating, in menopause, 12621263 Syphilis, 1090, 10971100 T Tamoxifen for benign breast disease, 1125 for breast cancer, 1137 Teratogenic drugs, 11971198, 12291236 Tetanus immunization, 1023 Thiazolidinediones, for polycystic ovary syndrome, 11751177 Thrombophilia, 1203, 12081211 Thyroid disorders in pregnancy, 12031205 infertility in, 1179 screening for, 1016 Tinidazole, for trichomoniasis, 1103 Tolterodine, for urinary incontinence, 1280 Torsion, ovarian, 11541155 Trastuzumab, for breast cancer, 1138 Treponemal tests, in syphilis, 10991100 Trichloroacetic acid, for genital warts, 1102 Trichomoniasis, 11021103 Trospium, for urinary incontinence, 12801281 Tubal sterilization, 10451046 Tumor markers, for pelvic masses, 11521153 TWEAK test, for alcohol misuse, 10291030 U Ultrasonography in breast diseases, 1123, 1133 in pelvic masses, 11451150 Underinsured population, 995996 Uninsured population, 994995 Universal health care, 997 Urethra, infection of, 1104 Urge urinary incontinence, 12791281, 1289

INDEX

Urinary incontinence classication of, 12731274 denition of, 12731274 diagnosis of, 12751277 drug-induced, 1276 epidemiology of, 1274 in menopause, 1265 mixed, 1281 pathophysiology of, 12741275 screening for, 1289 stress, 12771279, 1289 treatment of, 12751277 urge, 12791281, 1289 Urinary tract infections, incontinence in, 1275, 1277 Urogenital atrophy, in menopause, 12631265 Uterus abnormalities of, infertility in, 11651166 cancer of, 10241025 endometriosis of, 11661167 masses of, 1156 dierential diagnosis of, 1144 imaging of, 11471150 myomas of, 1166, 12611262 V Vaccinations. See Immunizations. Vagina atrophy of, in menopause, 12631265 contraceptive ring for, 10501051 pelvic organ prolapse into, 12811288 Valacyclovir, for herpes simplex virus infections, 1096 Varicella immunization, 1023 Vasectomy, 10461047 Vasomotor instability, in menopause, 12621263 Venereal disease research laboratory test, in syphilis, 1099 Venlafaxine, for vasomotor instability, 1264 Venous thromboembolism, in pregnancy, 12081211 Violence. See Domestic violence. Virilizing tumors, infertility due to, 1178 Vision disorders, screening for, 1028 Vitamin D, for osteoporosis, 1027, 1258 Voiding diary, in incontinence, 1275

INDEX

1305 research in, 9981001 services needed in, 1002 sexual assault, 12391252 sexually transmitted diseases, 10831113 specialists in, 10011006 urinary incontinence, 12731293 Womens Health Initiative trial, on hormone replacement therapy, 12661267

W Warfarin, for thrombotic diseases, 12101211 Warts, genital, 11011102 Weight reduction, for polycystic ovary syndrome, 11741175 Womens health barriers to, 9931009 breast disease, 11151141 cervical cancer prevention, 10181019, 1024, 10591082 contraception, 10371058 domestic violence, 10281029, 12391252 education for, 10041006 health centers for, 1006 infertility, 11631192 menopause, 10681069, 1073, 12531271 pelvic oor disorders, 12731293 pelvic masses, 11431161 pregnancy. See Pregnancy. preventive, 10111035

X X-rays, in pregnancy, 11981199

Y Yuzpe method, of emergency contraception, 10521053

Z Zoster vaccination, 1023