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Article history:
Received 13 September 2014
Received in revised form 24 January 2015
Accepted 24 January 2015
Available online xxxx
Keywords:
Gestational diabetes pregnancy
Pregnancy
Screening
Type 2 diabetes mellitus
a b s t r a c t
Gestational diabetes mellitus (GDM) is dened as any carbohydrate intolerance rst diagnosed during
pregnancy. The prevalence of GDM is about 25% of normal pregnancies and depends of the prevalence of
same population to type 2 diabetes mellitus. It is associated with adverse outcome for the mother, the fetus,
neonate, child and adult offspring of the diabetic mother. Detection of GDM lies on screening, followed as
necessary by diagnostic measures. Screening can either be selective, based upon risk stratication or universal.
Timely testing enables the obstetrician to assess glucose tolerance in the presence of the insulin-resistant state
of pregnancy and permits treatment to begin before excessive fetal growth has occurred. Once a diagnosis of
GDM was made close perinatal surveillance is warranted. The goal of treatment is reducing fetal-maternal
morbidity and mortality related with GDM. The exact glucose values needed are still not absolutely proved.
The decision whether and when to induce delivery depends on gestational age, estimated fetal weight, maternal
glycemic control and bishop score. Future research is needed regarding prevention of GDM, treatment goals and
effectiveness of interventions, guidelines for pregnancy care and prevention of long term metabolic sequel for
both the infant and the mother.
2015 Elsevier B.V. All rights reserved.
1. Introduction
Gestational diabetes mellitus (GDM) is dened as any carbohydrate
intolerance rst diagnosed during pregnancy [1]. It is associated with
adverse outcome not only for the mother, but also for the fetus, neonate,
child and adult offspring of the diabetic mother. Maternal consequences
include increased rate of operative and cesarean delivery, hypertensive
disorders during pregnancy and future risk for type 2 diabetes mellitus
(T2DM) as well as other aspects of the metabolic syndrome, such as
obesity, cardiovascular morbidities and recurrent GDM [24]. Also,
there are maternal implications secondary to a delivery of a macrosomic
or large for gestational age (LGA) fetus, such as an increased rate of
cesarean delivery, postpartum hemorrhage (PPH), birth trauma and
shoulder dystocia [4,5].
As today, GDM is dened as carbohydrate intolerance of variable
severity with onset or rst recognition during pregnancy. The denition is applicable regardless of whether insulin is used for treatment
or the condition persists after pregnancy. It does not exclude the
Abbreviations: BMI, body mass index; DM, diabetes mellitus; GCT, glucose challenge
test; GDM, gestational diabetes mellitus; IUFD, intrauterine fetal death; LGA, large for gestational age;OGTT, oral glucose tolerance test; PPH, postpartumhemorrhage; T2DM, type2 diabetes mellitus.
Corresponding author at: President Elect EAPM Chairman FIGO GDM Initiative
Committee Professor of Obstetrics and Gynecology Director, Division of Maternal Fetal
Medicine, Helen Schneider Hospital for Women, Rabin Medical Center, Sackler Faculty of
Medicine, Tel Aviv University, Tel Aviv, Israel. Tel: + 972 3-9377400; fax: + 972-39377402; Mobile: +972 528888899.
E-mail address: hodroyal@inter.net.il (M. Hod).
http://dx.doi.org/10.1016/j.cca.2015.01.021
0009-8981/ 2015 Elsevier B.V. All rights reserved.
Please cite this article as: Ashwal E, Hod M, Gestational diabetes mellitus: Where are we now?, Clin Chim Acta (2015), http://dx.doi.org/10.1016/
j.cca.2015.01.021
2. Epidemiology
Table 1
Risk factors for gestational diabetes mellitus.
Advanced maternal age
Maternal obesity
High parity
Previous delivery of a macrosomic infant
Family history of type 2 diabetes mellitus.
Maternal short stature
Polycystic ovary disease
High levels of saturated fat in the diet
Prior GDM
Prior neonatal death
Prior cesarean delivery
Previous stillbirth or congenital malformations
High blood pressure during pregnancy
Multiple pregnancy
Please cite this article as: Ashwal E, Hod M, Gestational diabetes mellitus: Where are we now?, Clin Chim Acta (2015), http://dx.doi.org/10.1016/
j.cca.2015.01.021
Table 2
Risk stratication for selective screening and diagnosis of GDM.
Risk
Criteria
Low
1.
2.
3.
4.
5.
6.
Average
1.
2.
High
1.
2.
3.
4.
5.
Recommended screening
Should be tested in a single (OGTT) or two stage manner (GCT & OGTT),
as soon as possible in pregnancy, and if diabetes is not diagnosed, testing
should be repeated at 2428 weeks or if clinical suspicion arises
(2 h vs. 3 h), the actual cutoffs and whether 1 or 2 high values are
necessary [37].
One of the major controversies is the determination of the diabetic
threshold in screening and diagnosis. Previous studies have shown
that the current criteria, may lead to under diagnosis and that treating
women with lower hyperglycemic levels, that are not diagnostic for
diabetes, can lower associated morbidity [3841].
The major aw in the GDM diagnostic criteria is that they have been
based on the risk of future hyperglycemia, and not merely on clinical
squeal. In order to address this issue, the Hyperglycemia and Adverse
Pregnancy Outcome (HAPO) study rst demonstrated an association
between increasing levels of fasting, 1-hour and 2-hour plasma glucose
post a 75 g OGTT to outcomes of birth weight above the 90th percentile,
cord blood serum C-peptide level above the 90th percentile, primary
cesarean delivery, neonatal hypoglycemia, preterm delivery, shoulder
dystocia, intensive neonatal care admission, hyperbilirubinemia and
preeclampsia. Since the results show that there is no apparent glycemic
level cut off for complications but rather a continuum [42]. The International Association of Diabetes and Pregnancy Study Groups (IADPSG)
developed recommendations for the diagnosis and classication of
hyperglycemia in pregnancy to translate the HAPO results into clinical
practice [43]. On the basis of the HAPO data, the panel suggested that
a 75-g OGTT be performed and that GDM be diagnosed if any one of
the values for fasting plasma glucose, 1-h glucose, or 2-h glucose
equaled or exceeded the diagnostic threshold in Table 2. Even though
these recommendations were the rst evidence-based guidelines for
GDM which correlate maternal glucose concentrations to perinatal
outcomes, they have not achieved universal acceptance; they were
endorsed by the American Diabetes Association and by the National
Academy of Clinical Biochemistry [44] along with several countries.
However, the American College of Obstetricians and Gynecologists
recommends that GDM be diagnosed with either the NDDG or the
Carpenter and Coustan criteria [5]. Of note, an NIH Consensus Development Conference was held in 2013 to assess the available data regarding
Table 3
Diagnosis of GDM by an oral glucose tolerance test.
Criteria
O'Sullivan
NDDG
Coustan and Carpenter
WHO
IADPSG
Steps
2
2
2
1
1
Increased values to
consider pathology
2
2
2
1
1
100
100
100
75
75
Glucose threshold
Fasting
1h
2h
3h
90 (5.0)
105 (5.8)
95 (5.3)
126 (7.0)
92 (5.1)
165 (9.2)
190 (10.6)
180 (10.0)
180 (10.0)
145 (8.1)
165 (9.2)
155 (8.6)
140 (7.8)
153 (8.5)
125 (6.9)
145 (8.1)
140 (7.8)
Please cite this article as: Ashwal E, Hod M, Gestational diabetes mellitus: Where are we now?, Clin Chim Acta (2015), http://dx.doi.org/10.1016/
j.cca.2015.01.021
Table 4
Goals of glycemic control during pregnancy.
Time of glucose measurement
Fasting
1 h postprandial
2 h postprandial
Target value
mg/dl
mmol/L
95
140
120
5.3
7.8
6.7
5.2.2. Metformin
Oral metformin is the second option for pharmacological noninsulin treatment for GDM. Metformin crosses the placenta and could
affect fetal physiology directly. It improves insulin sensitivity, probably
by activating adenosine monophosphate kinase, and is not associated
with weight gain or hypoglycemia [65]. Reported outcomes of its use
during pregnancy have been favorable [66,67] except for one small,
retrospective cohort study [68] that showed increased rates of perinatal
loss and preeclampsia as compared with insulin treatment.
5.3. Insulin
Approximately 15% of GDM patients will not meet glycemic targets
with diet alone and will require medical intervention with insulin or a
hypoglycemic agent. As mentioned earlier, other than glycemic target
values, after 2930 weeks of gestation (up until which glucose level
were the sole indicator for insulin initiation) the fetal abdominal
circumference can be also used as an indicator for the need to initiate
insulin (or medical) therapy. An abdominal circumference above the
70th percentile should evoke insulin therapy as an additional mean to
the dietary plan [69]. Regular human insulin is mostly prescribed, however, either human regular insulin or rapid acting analogues can be
used, through multiple daily injections or subcutaneous infusion.
Preliminary studies suggest also, that long acting insulin analogues
(e.g. glargine) have a good safety prole during pregnancy [70].
5.3.1. Insulin starting dose
Insulin is dosed according to body weight, between 0.71.0 Units/kg.
With advancing gestational age, the patient becomes more insulin resistant and insulin requirements increase. Between 2032 weeks there is
up to 50% increase from the starting dose of insulin. The average dose
in the rst trimester is 0.7 Units/Kg, 0.8 Units/Kg in the second
trimester, and 0.91 Units/Kg along the third trimester.
5.3.2. Multiple daily injections
There are several protocols to distribute insulin throughout the day,
in several timed daily injections, and according to the glycemic control.
One common regimen involves giving two thirds of the total calculated
insulin dose in the morning (fasting, pre-breakfast), made up of two
parts intermediate-acting to one part regular insulin. The remaining
one third of the total daily insulin dosage should be divided equally as
regular insulin (to be given before dinner) and intermediate-acting
insulin (to be given at bedtime). Another option would be a protocol
of 4 injections a day, combing three doses of regular insulin before
each meal and an intermediate insulin dose before bedtime [71].
5.3.3. Continuous subcutaneous infusion
This mode of administration is as effective as various regimens of
multiple daily injections, in terms of glycemic control, with a lesser
risk of maternal hypoglycemia and an improvement in adverse pregnancy outcome. However, limited data suggests an increased risk for
neonatal hypoglycemia, diabetic ketoacidosis, maternal weight gain
and diabetic retinopathy with the use of an insulin pump [7274].
5.4. Treatment during delivery
5.2.1. Glyburide
The drug increases insulin secretion and diminishes insulin resistance by lowering glucose toxicity. Its onset of action is ~4 h, and duration of action is ~ 10 h. Thus, after achieving the targeted therapeutic
level, glyburide covers the basal requirement as well as postprandial
glucose excursions. The starting dose is 2.5 mg in the morning, increasing to 5 mg if target glucose levels are not met. After 37 days, another
dose of 5 mg in the evening can be added and thereafter, 5 mg increments to a maximum of 20 mg/day. If the patient does not achieve
targeted levels of glycemic control, add long-acting insulin to the regimen or assign the patient to insulin therapy alone [63,64].
Please cite this article as: Ashwal E, Hod M, Gestational diabetes mellitus: Where are we now?, Clin Chim Acta (2015), http://dx.doi.org/10.1016/
j.cca.2015.01.021
Please cite this article as: Ashwal E, Hod M, Gestational diabetes mellitus: Where are we now?, Clin Chim Acta (2015), http://dx.doi.org/10.1016/
j.cca.2015.01.021
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Please cite this article as: Ashwal E, Hod M, Gestational diabetes mellitus: Where are we now?, Clin Chim Acta (2015), http://dx.doi.org/10.1016/
j.cca.2015.01.021