Professional Documents
Culture Documents
2018
Abstract
Aim: To test whether Premaquick biomarkers were superior to modified Bishop score for preinduction cer-
vical assessment at term.
Methods: A multicenter, double-blind randomized clinical trial in 151 nulliparous, cephalic presenting and
singleton pregnancies was conducted. The cervix was considered ‘ripe’ when at least two out of three Pre-
maquick biomarkers are positive or a Bishop score of ≥6. Main outcome measures were proportion of
women who were administered or had additional prostaglandin E1 analogue (PGE1) as a preinduction agent
and incidence of uterine rupture. The trial was registered in PACTR registry with approval number
PACTR201604001592143. Analysis was performed by intention-to-treat principle.
Results: The need for initial PGE1 analogue (77.6% vs 98.7%, risk ratio [RR] =0.47, 95% confidence intervals
[95% CI] =0.38–0.59, P < 0.001) and additional PGE1 analogue for cervical ripening after one insertion
(44.7% vs 68.0%, RR = 0.63, 95% CI = 0.46–0.86, P = 0.004) was significantly lower in Premaquick group.
There was no significant difference in incidence of uterine rupture (0% vs 1.4%, RR = 0.000, P = 0.324); however,
the frequency of transition to labor was statistically higher in Premaquick group (44.7% vs 22.7%, RR = 1.59, 95%
CI = 1.17–2.15, P = 0.004). Interval from start of induction to any type of delivery, need for oxytocin aug-
mentation, vaginal delivery, number of women with cesarean section for failed induction and number of
infants admitted to neonatal intensive care unit were similar between the two groups (P > 0.05).
Conclusion: Preinduction cervical assessment with Premaquick was significantly associated with higher fre-
quency of transition to labor and reduced need for PGE1 analogue when compared to modified Bishop
score. Further similar trials in other settings are necessary to strengthen or refute this observation.
Key words: cervical assessment, induction, labor, modified Bishop score, Premaquick.
period between August 2016 and September 2017. method or modified Bishop score method. Group allo-
Women were recruited by the researchers in the labor cation was predetermined and placed in sequentially
ward when they were admitted for induction of labor. numbered, sealed, opaque envelopes with a piece of
paper inside bearing the label ‘Premaquick’ or ‘Bishop
Study design score’. Following allocation, all the women underwent
This was a randomized double-blind trial. Consecu- cervical assessment by Premaquick and modified
tive women admitted to the Obstetrics units of the Bishop score, but clinical management of the women
recruiting hospitals for induction of labor at term was based on the group she belonged following the
(37 completed weeks of gestation to 42 weeks of ges- randomization.
tation) participated in the study. Women who gave We used a modified Bishop score, which has five
informed consent were assigned with the aid of parameters and 0–13 points. Thus, cervical dilatation,
computer-generated random numbers (block size cervical effacement assessed by cervical length, consis-
four, 1: 1 randomization ratio) to have preinduction tency, position and station of the presenting part were
cervical assessment and induction of labor based on assessed. All Premaquick evaluations were performed
the Premaquick or modified Bishop score. Assign- by trained obstetrics care providers. When necessary,
ments were concealed by sequentially numbered opa- participants were re-examined by the same person.
que envelopes prepared by a person not involved in The cervix was considered unripe if the Bishop
the clinical care of the women. score was <6 or Premaquick was negative. In cases
with an unripe (unfavorable) cervix (when Bishop
Study population score was <6 or Premaquick was negative), 50 μg of
These were all consenting pregnant women seen in misoprostol (cytotec Pfizer comprimidos misoprostol,
the labor and delivery suite for induction of labor at lot b13221) was administered intravaginally every 6 h
term during the period of the study and who met the for a maximum of four doses. No further oxytocics
inclusion criteria, until the calculated minimum sam- were administered when uterine contractions reached
ple size was reached. a frequency of 3 in 10 min. If cervical ripening was
not achieved, cesarean section was performed after
Inclusion criteria the 4th dose of misoprostol. In cases with a ripe cervix
Nulliparous pregnant women scheduled for induction (when Bishop score was >6 or Premaquick was posi-
of labor at or beyond 37 weeks of gestation with a tive), oxytocin infusion was commenced (using stan-
singleton pregnancy in cephalic presentation, absence dard induction protocol of the hospital). Thus,
of labor (labor defined as the presence of regular and intravenous oxytocin (10 IU in 1 L of isotonic saline
painful uterine contractions) and intact membranes or 5% dextrose in water) administration was started
were eligible for inclusion. using the manual drip pawns at 10 drops per min
and increased every 30 min by 10 drops per min to a
Exclusion criteria maximum of 60 drops per min and given for a maxi-
Exclusion criteria were previous uterine scars, multi- mum of 16 h. If the woman had not reached the active
parity and premature rupture of membranes. The phase by the end of this period, cesarean section was
dates of the confinements were calculated according performed.
to the duration of amenorrhea based on last men- Active phase was defined as dilatation of at least
strual period and checked by an ultrasound examina- 4 cm. Once in labor, women were cared for as per
tion performed before 20 weeks of gestation. NAUTH, Nnewi, Nigeria obstetric protocols. For the
purpose of this study, other hospitals adopted the
Procedure hospital protocol of NAUTH (as stated earlier). Mem-
Following a written informed consent, a cervical swab branes were ruptured when the cervix was at least
sample for assay of Premaquick was taken before dig- 80% effaced: (cervical lenght <0.5cm) and dilated at
ital cervical examination for Bishop score in all the eli- least 4 cm, and the fetal head well applied to the cer-
gible participants. Thereafter, a trained obstetrics care vix. If the progress of labor halts at <1 cm cervical
provider opened sequentially numbered, sealed, opa- dilatation per hour in the course of the process of
que envelopes containing the participants’ group induction of labor, oxytocin infusion in incremental
assignment and participants were randomly allocated, doses, as per protocol above, was commenced. How-
in a 1:1 ratio, to be assessed by either Premaquick ever, the oxytocin augmentation was delayed until
the duration from the last dose of misoprostol admin- delivery, need for oxytocin augmentation, interval
istration was at least 4 h to minimize the risk of hyper- from start of induction to beginning of active phase,
tonus or hyperstimulation syndrome. Continuous vaginal delivery, number of women with cesarean
electronic fetal heart rate monitoring with cardiotoco- section for failed induction, meconium staining of the
graph was used in all cases. amniotic fluid, Apgar score at 1 min and number of
The sample for the Premaquick test was simulta- infants admitted to neonatal intensive care unit.
neously obtained from the posterior fornix of the
vagina with a Dacron swab (supplied by the manu- Sample size determination
facturers), and was analyzed, and evaluated at the Sample size calculations were based on the expecta-
bedside. The technique was performed by placing the tion of a comparable effect as observed by Park et al.5
lower end of the Dacron swab stick in the posterior who compared Bishop score in determining the
fornix of the vagina for 30 s (to allow for swab satura- requirement for prostaglandin administration for pre-
tion) during a sterile speculum examination. Following induction cervical ripening in nulliparae at term.
collection, the swab was inserted into a tube containing Using the mean number of doses of prostaglandin per
1 mL of extraction buffer containing proprietary con- woman during entire period of serial induction of
centrations. Three drops of the extraction buffer (con- 0.84 0.56 and 0.47 0.70 in the Bishop score study
taining the cervical secretion) were dropped into each and transvaginal ultrasound groups, respectively,
of the sample wells. The results were interpreted after with a mean difference of 0.37 and a standard devia-
10 min waiting time with the sample wells placed in tion of 0.56, an α of 0.05, and power of 0.8, Epi info
flat horizontal position. Three biomarkers (total IGFBP- 2016 version 7.0 (Centers for Disease Control and Pre-
1, native IGFBP-1 and IL-6) were tested. The detection vention) and Stata PASS version 10 (NCSS) both yielded
limit of the two versions of IGFBP-1: total IGFBP-1 a sample size of 48 women per group (60 assuming a
and native IGFBP-1B were 40 ng/mL and 20 ng/mL 25% drop out rate).
of recombinant IGFBP-1, respectively.
Following the tests, the outcome measures were Statistical analysis
assessed in the women by the investigators or Following entry, checking and cleaning of the data, the
research assistants who were not aware of the inter- randomization code was broken. Epi info 2016 version
vention or group assignment. The Premaquick was 7.0 and Stata PASS version 10 were used for analysis.
defined to be positive when at least two of the three Student’s t-test was used for analyzing continuous var-
(2/3 rule) biomarkers were positive. The investigators iables. The statistical significance of differences
were blinded to the results of the Premaquick assay. between groups for continuous variables was assessed
The Bishop score for the participant was obtained and differences in proportions were assessed using
through a single digital vaginal examination, with Mantel–Haenszel or Fisher’s exact test. The analysis
scoring modified by the use of cervical length instead was based on the intention-to-treat principle. The value
of percentage as a score component for cervical efface- of P < 0.05 was considered statistically significant.
ment. The parameters recorded at pelvic examination
also included the state of fetal membranes. The collec- Ethical consideration
tion of specimen for Premaquick assay consistently Our study does not violate the policies and/or proce-
preceded each digital cervical examination for the dures established by journal such as those described
assessment of the modified Bishop score. in ‘Specific Inappropriate Acts in Publication Process’.
Also, the protocol for this research project was approved
Outcome assessment by NAUTH Ethics committee and other recruiting hospi-
The primary endpoints were the number of women tals (approval number: NAUTH/CS/66/vol 9/143,
with unripe cervix, that is, the number of women approval date: July 25, 2017) and it conforms to the
who were administered PGE1 analogue (misoprostol) provisions of the Declaration of Helsinki (as revised
as a preinduction agent, the number of women who in Tokyo 2004), available at http://www.wma.net/en/
were administered additional prostaglandin (miso- 30publications/10policies/b3/index.html. The study
prostol) as a preinduction agent after one dose and was registered with the pan African Clinical trial
uterine rupture. The secondary endpoints included registry at www.pactr.org with approval number
frequency of transition to labor during cervical ripen- PACTR201604001592143, with a date of registration
ing, interval from start of induction to any type of of April 18, 2016.
Randomized (n=151)
Allocation
Allocated to Premaquick (n=76) Allocated to Bishop score (n=75)
♦ Received allocated intervention (n=76) ♦ Received allocated intervention (n=75)
♦ Did not receive allocated intervention (n=0 ) ♦ Did not receive allocated intervention (n=0)
Follow-Up
Lost to follow-up (n=0) Lost to follow-up (n=0)
Analysis
Analysed (n=76) Analysed (n=75)
♦ Excluded from analysis (n=0) ♦ Excluded from analysis (n=0)
♦ Protocol strict (n=73) ♦ Protocol strict (n=70)
♦ Protocol violations (n=3) ♦ Protocol violations (n=5)
Figure 1 Flow chart of the women in Premaquick vs Bishop score study. PROM, premature rupture of membranes.
in nulliparae at term. In another randomized con- length value that is most likely to indicate benefit
trolled trial by Bartha et al.,4 it was concluded that the from a cervical ripening agent prior to induction of
use of transvaginal ultrasound instead of Bishop score labor.17 This result is very interesting because need-
for preinduction cervical assessment to choose induc- less use of prostaglandin agents could trigger uterine
tion agent significantly reduces the need for intracer- hyperactivity and uterine hyperstimulation, which
vical prostaglandin treatment without adversely can jeopardize the perinatal life, increase operative
affecting the success of induction. However, the major intervention and hospital costs.
problem of transvaginal ultrasound is that both the Although both methods have not been directly
equipment and skill are not readily available in low- compared in any randomized studies, few prospective
resource settings and there is no clear cutoff cervical studies have compared the effects of pIGFBP-1 and
Bishop score. Dogl et al.13 revealed that pIGFBP-1 pre- Kosinska-Kaczynska et al.16 found a positive association
dicts both the spontaneous onset of labor and success- between cervical pIGFBP-1 and vaginal delivery fol-
ful induction in post-term pregnancy than Bishop lowing induction of labor. Their findings are in sharp
score. Consistent with Dogl et al., Vallikkannu et al.14 similarity to ours, although our study population is
found pIGFBP-1 to be a moderately strong indepen- exclusive of nulliparous women and more than 65%
dent predictor of successful induction and neither had their labor induction for post-date pregnancy. Thus,
Bishop score nor transvaginal ultrasound (TVUS) of the cervical pIGFBP-1 is a better tolerated test and a stron-
cervical length was independently predictive of vaginal ger predictor of a transition to successful labor in nulli-
delivery (P > 0.05). Similarly, Cheung et al.15 and paras with intact membranes than the Bishop score.
This trial also showed that the rate of transition to been confirmed in studies included in a recent
labor was statistically higher in the Premaquick group Cochrane systematic review.23 This is an interesting
than in women assessed by Bishop score method. The finding with higher tendency to have very high
reason for this finding was not clear. However, it obstetrics significance. In the index study, women
could be as a result of the cutoff value of Bishop score assessed by the Bishop score method, 76.1% of
used in the study which was <6. However, other pre- women needed to proceed to an oxytocin infusion,
vious studies20,21 used ≤4, but a more recent random- which, in settings like ours without electronic infusion
ized clinical trial by Bansiwal et al.22 used <6 as a pumps, can be the most hazardous part of the induc-
cutoff. In some studies, misoprostol has been used tion procedure for the fetus. There could be varied
both for cervical ripening and induction, with regular instabilities in the rates of infusion when manual drip
doses of misoprostol used in place of the oxytocin pawns are used. Furthermore, the intrapartum use of
infusion characteristic of most induction protocols. oxytocin in low-income settings is closely associated
The misoprostol used for ripening may be contribu- with neonatal morbidity and mortality and uterine
tory to the transition to labor. rupture.24 Therefore, the safety of the Bishop score for
The fear that misoprostol could be dangerous to the preinduction cervical ripening assessment has the
fetus because of irreversible hyperstimulation has not dangers of the oxytocin infusion on the flipside.
Contrariwise, misoprostol causes both cervical ripen- of Premaquick, two biomarkers (native IGFBP1 and
ing and uterine contractions. As a result, more total IGFBP1) have never been evaluated for assess-
women progress through to vaginal birth without ment of induction of labor. Previous studies have only
requiring an oxytocin infusion, which has potential tested phosphorylated IGFBP-1 compared with
safety benefits in the use of Premaquick for preinduc- Bishop score and or TVUS13–16 or TVUS compared
tion cervical assessment. with Bishop score,4,5 and very recent Cochrane sys-
Although neonatal morbidity did not differ signifi- tematic review by Ezebialu et al. indicated that direct
cantly between the two intervention groups, this comparisons between Bishop score and pIGFBP-1 and
study had insufficient power to detect anything other IL-6 for assessing preinduction cervical ripening
than major differences in rare outcomes. Although among parturients at term gestations was yet to be
babies born to women assessed by the Bishop score carried out.17 We have only tested the kits in cervi-
had a higher number of adverse infant outcomes, the covaginal secretions, which is another strength to our
difference was not statistically significant. For study as it makes the technique useful in facilities
instance, women in the Bishop score group had more without need for speculum. Evidence has shown that
often number of meconium-stained liquor, which was parity is a robust predictor of successful induction of
also a common cause of cesarean section in that labor; therefore, identical populations of nulliparous
group. The direct smooth muscle effect of misoprostol women were used in this study so as to attain a suit-
on the fetal intestine, may be responsible for the able comparison of the two preinduction cervical
meconium staining of the liquor since more women assessment methods.26 Additionally, this is a multi-
received multiple courses of prostaglandin agents in center study thus make the findings more generaliz-
the Bishop score group. able to the general population. It is our belief that this
In settings without access to electronic fetal moni- study expands current literature by providing perfor-
toring, meconium-stained liquor is an important clini- mance metrics for the novel Premaquick for preinduc-
cal sign of fetal compromise and so might, in itself, be tion cervical assessment.
an indication for cesarean sections in these high-risk Despite these strengths, our study has some limita-
inductions. Although not associated with fetal hyp- tions. The obstetrics care providers were not masked
oxia, meconium-stained liquor does carry risks of as this was necessary so as to know when to com-
meconium aspiration and so can cause clinically sig- mence oxytocin agents. However, we think that it is
nificant neonatal morbidity. unlikely that knowledge of intervention arms by
One mechanisms of action of Premaquick for prein- obstetrics care providers may have influenced out-
duction cervical assessment was that IGFBP-1 and IL- comes assessed since double-blinding (study investi-
6 concentration in ripe cervices (determined by Bishop gators and participants) was still achieved because
score) is four times higher than in unripe cervices, each method was performed simultaneously on the
and IGFBP-1 has been shown to predicts both sponta- same individual participants throughout the study,
neous labor onset and successful induction than with only the obstetrics care provider on duty
Bishop score and cervical length which perform knowing the particular method the women were
equally well.13,25 Ideally, the obstetrics advantage of randomized to receive and the study investigators
Premaquick for preinduction cervical assessment was only performing outcome assessments. This there-
that it appears to be a more objective assessment than fore decreased the risk of bias. Furthermore, it
Bishop score and it may not require instrument just as would have been necessary to show the differences
Bishop score and could even be assessed by the in parturition outcomes between modified Bishop
patient herself since the Premaquick kits could be self- score and the conventional Bishop unfortunately
administered. It will also obviate the need for multi- only the modified Bishop score was the routine
ple vaginal examinations commonly seen in Bishop method of preinduction cervical assessment in the
score assessment and thus could be useful in women study hospitals.
with HIV/AIDS in pregnancy and hepatitis B or C Another possible limitation was our use of 50 μg of
virus in pregnancy. misoprostol for cervical ripening as the preformed
The strengths of our study are as follows: To the 25 μg tablet of misoprostol was rarely available at the
best of our knowledge, this is the first study to date time of the trial. However, a recent PROBAAT-II mul-
on Premaquick vs Bishop score method coupled with ticenter Dutch study by Eikelder et al.27 and Uruguay
its randomized design. Among the three biomarkers study by Conde et al.28 used similar (50 μg) dose.
16. Kosinska-Kaczynska K, Bomba-Opon D, Bobrowska K et al. of oxytocin and misoprostol for PPH prevention? Int J
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