International Journal of Gynecology and Obstetrics 130 (2015) 214218

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International Journal of Gynecology and Obstetrics

journal homepage: www.elsevier.com/locate/ijgo

REVIEW ARTICLE

Misoprostol versus prostaglandin E2 gel for labor induction in premature

rupture of membranes after 34 weeks of pregnancy
Yan Zhang, Jun Wang, Yan Yu, Cui Xie, Meiqun Xiao, Lirong Ren
Baoan Maternal and Child Health Hospital, Shenzhen, Guangdong Province, China

a r t i c l e

i n f o

Article history:
Received 16 September 2014
Received in revised form 2 April 2015
Accepted 26 May 2015
Keywords:
Cervical ripening
Labor induction
Misoprostol
Prostaglandin E2 gel
Premature rupture of membranes

a b s t r a c t
Background: Both misoprostol and prostaglandin E2 (PGE2) gel are used for labor induction in women with premature rupture of membranes (PROM). Objectives: To evaluate studies comparing the effects of misoprostol and
PGE2 gel in labor induction. Search strategy: Databases including Medline, Embase, and the Cochrane Central
Register of Controlled Trials were searched for relevant papers. Selection criteria: Randomized controlled trials
comparing the use of misoprostol and PGE2 gel for labor induction in women with PROM were included. Data
collection and analysis: For meta-analyses, the MantelHaenszel method was used for dichotomous data, and
the inverse variance method was used for continuous data. Main results: Four randomized controlled studies
(n = 615) were included. There were no signicant differences between the two groups in the induction-todelivery interval (mean difference 4.44 hours; 95% condence interval [CI] 9.35 to 0.48), rate of cesarean delivery (odds ratio [OR] 0.90; 95% CI 0.441.85), and rate of neonatal intensive care unit admission (OR 0.89;
95% CI 0.571.38). Women receiving misoprostol had a signicantly higher rate of tachysystole than did those
receiving PGE2 gel (OR 4.84; 95% CI 2.469.54). Conclusions: Misoprostol is as efcacious and safe as PGE2 gel
for labor induction in women with PROM.
2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction
Premature rupture of membranes (PROM)dened as rupture of
membranes prior to the onset of birthoccurs in 3%18.5% of all pregnancies [1]. The longer the interval from rupture of membranes to delivery, the higher the incidence of chorioamnionitis and neonatal sepsis
[2]. Labor induction in women with PROM at term, or near term with
evidence of fetal lung maturity, is supported by evidence [3]. For patients with an unfavorable cervix, several cervical ripening methods
are available. The options include expectant management and labor induction using misoprostol, oxytocin, or dinoprostone (prostaglandin
E2) [4]. Active management reduces the infectious morbidity associated
with a conservative management approach, but it is associated with a
high cesarean delivery rate, especially if titrated oxytocin is being used
in women with an unfavorable cervix [5]. A meta-analysis [6] shows
that misoprostol is both effective and safe for the induction of labor in
women with PROM at term. Among the prostaglandins, prostaglandin
E2 has been identied as an effective ripening agent [7].
In China, misoprostol and prostaglandin E2 gel are two commonly
used methods of labor induction in women with PROM. Several randomized studies have compared their effects in labor induction. The
Corresponding author at: Department of Obstetrics, Baoan Maternal and Child Health
Hospital, No 21, Yuan 2nd Road, Baoan District, Shenzhen, Guangdong Province, 518000,
China. Tel.: +86 755 27812637; fax: +86 755 27834718.
E-mail address: lirongren2014@163.com (L. Ren).

aim of the present study was to evaluate the results from randomized
trials comparing the effectiveness and safety of misoprostol and prostaglandin E2 gel for cervical ripening and labor induction in women with
PROM after 34 weeks of pregnancy.

2. Materials and methods

2.1. Sources
The present study involved a systematic review of the literature to
identify all published randomized clinical trials that evaluated the use
of misoprostol versus prostaglandin E2 gel for labor induction among
women with PROM. The literature search was carried out in Medline
(via Ovid), Embase (via Ovid), Cochrane Central Register of Controlled
Trials (via Ovid), ClinicalTrials.gov, and ve biomedical databases originating from China: China National Knowledge Infrastructure, Wanfang
Data, VIP, and Chinese Biomedical Literature. The latest search was conducted on March 5, 2014.
The following keywords were used in the search: misoprostol,
labor induction, cervical ripening, prostaglandin E2, and premature rupture of membranes. The OR operator was used to combine
labor induction and cervical ripening; AND was used to search
for various combinations of the keywords. No restriction was posed on
the date or language of the publications. The references listed in all relevant articles were evaluated to nd more potential papers.

http://dx.doi.org/10.1016/j.ijgo.2015.04.031
0020-7292/ 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

Y. Zhang et al. / International Journal of Gynecology and Obstetrics 130 (2015) 214218

215

variables, overall odds ratios (ORs) and 95% CIs were estimated using
xed-effects models. P b 0.05 was considered statistically signicant.

2.2. Study selection

Studies were included if women with PROM who underwent labor
induction were randomly assigned to two groups: misoprostol and
prostaglandin E2 gel. Observational and retrospective studies were excluded. Because the outcome measures involved different ways of delivery, there was no requirement for the outcome assessment to be
blinded. Studies were excluded if the participants in the two intervention groups also received other concurrent induction agents, such as
oxytocin or placebo. Studies in which participants received prostaglandin E2 in a form other than a gel (e.g. pessary) were also excluded. However, because the administration of oxytocin in labor is routine
following both misoprostol and prostaglandin E2 gel, studies were not
excluded if oxytocin was given after the last dose of misoprostol or prostaglandin E2 gel. Studies with three or more intervention groups were
not excluded if there were two groups comparing misoprostol and prostaglandin E2 gel. For such studies, only the relevant data were obtained.
Two authors (Y.Z. and C.X.) independently processed the studies
they considered eligible to decide whether to include them and retrieve
the relevant data. Disagreements were resolved by consensus.
The primary outcomes were the induction-to-delivery interval and
the rate of cesarean delivery. The secondary outcomes were the rates
of tachysystole and neonatal intensive care unit (NICU) admission.
Quality assessment was performed on each study using the following criteria: random sequence generation (selection bias), allocation
concealment (selection bias), blinding of participants and personnel
(performance bias), incomplete outcome data (attrition bias), and selective reporting (reporting bias). Publication bias was not calculated
because the present review included only four studies.
Statistical analyses were performed using Review Manager 5.2
(Cochrane Collaboration, Oxford, UK). The I2 statistic was calculated to
evaluate study heterogeneity. For meta-analyses, the MantelHaenszel
method was used for dichotomous data, and the inverse variance method was used for continuous data. Because the induction-to-delivery interval is a continuous variable, random-effects models were adopted to
estimate the overall mean difference and 95% condence interval (CI)
while adjusting for variations in the Bishop Score, misoprostol dose,
and frequency and route of misoprostol administration. Because cesarean delivery, tachysystole, and NICU admission are dichotomous

3. Results
3.1. Identied studies
Four studies [811] with 615 patients in total were identied as
eligible for inclusion in the present meta-analysis (Fig. 1, Table 1).
Fig. 2 presents the quality assessment. All studies reported the
induction-to-delivery interval, the rate of cesarean delivery, and
the rate of NICU admission. Two of the four studies [8,9] also reported the rate of tachysystole.

3.2. Induction-to-delivery interval

The induction-to-delivery interval did not differ signicantly between the two groups (mean difference 4.44 hours [95% CI 9.35
to 0.48). The heterogeneity was signicant (P b 0.001), with I2 estimated
at 94%. The forest plot can be seen in Fig. 3.

3.3. Rate of cesarean delivery

The rates of cesarean delivery did not differ signicantly between
the two groups (OR 0.90 [95% CI 0.441.85]). The heterogeneity was signicant (P = 0.07); the estimate of I2 was 57%. The forest plot is provided in Fig. 4. All four studies showed separately that no signicant
difference exists in the cesarean delivery rate of women who received
misoprostol and those who received prostaglandin E2 gel.

3.4. Rate of tachysystole

The misoprostol group had a signicantly higher rate of tachysystole
than the prostaglandin E2 gel group (OR 4.84 [95% CI 2.469.54]). The
heterogeneity was not signicant (P = 0.88); the estimate of I2 was
0%. The forest plot is shown in Fig. 5.

Fig. 1. Study selection ow chart. Abbreviations: PROM, premature rupture of membranes; RCT, randomized controlled trial.

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Table 1
Randomized trials included in the meta-analysis.
Study

Number of
participants

Pregnancy
duration

Intervention

Controls

Outcomes

Ayad 2002 [8]

n = 238

N36 weeks

Vaginal misoprostol at 50 g

Vaginal PGE2 gel at 0.5 mg

Frohn et al. 2002 [9]

n = 109

34 weeks

Nagpal et al. 2009 [10]

n = 61

3742 weeks

Chaudhuri et al. 2011 [11]

n = 207

37 weeks

Vaginal misoprostol at 50 g
(maximum of two doses)
Oral misoprostol at 50 g every
4 hours (maximum of three doses)
Vaginal misoprostol at 25 g
(maximum of ve doses)

Vaginal PGE2 gel at 2.5 mg every

6 hours (maximum two doses)
Vaginal PGE2 gel at 0.5 mg every
6 hours (maximum two doses)
Vaginal PGE2 gel at 0.5 mg every
6 hours (maximum two doses)

Cesarean delivery, induction-to-delivery

interval, tachysystole, NICU admission
Cesarean delivery, tachysystole, inductionto-delivery interval, NICU admission
Induction-to-delivery interval, cesarean
delivery, NICU admission
Induction-to-delivery interval, cesarean
delivery, NICU admission

Abbreviations: PGE2, prostaglandin E2; NICU, neonatal intensive care unit.

3.5. Rate of neonatal NICU admission

Fixed-effects models indicated no signicant difference in terms of
the NICU admission rate between the misoprostol group and the prostaglandin E2 gel group (OR 0.89 [95% CI 0.571.38]). The heterogeneity
was not signicant (P = 0.74); the I2 statistic was 0%. The forest plot
is provided in Fig. 6.
4. Discussion
Misoprostol and prostaglandin E2 gel are both recommended by the
American College of Obstetricians and Gynecologists [12] for labor induction. As a common ripening agent for an unfavorable cervix, prostaglandin E2 gel has several shortcomings: a high price, instability at room
temperature, and an increased risk of infection [13]. By contrast,

misoprostol is less costly and stable at room temperature. It has proven

efcacy and safety, and can simultaneously ripen the cervix and stimulate uterine contractions [1315].
In the present meta-analysis of prospective randomized studies that
included 615 women with PROM after 34 weeks of pregnancy who
underwent labor induction, misoprostol and prostaglandin E2 gel had
similar effectiveness and safety. The induction-to-delivery interval did
not differ signicantly. The misoprostol group had a signicantly higher
rate of tachysystole than the prostaglandin E2 gel group, whereas the
rates of cesarean delivery and NICU admission were similar.
Women with PROM after 34 weeks of pregnancy who received prostaglandin E2 gel for labor induction had a lower risk of tachysystole than
those in the misoprostol group. Similar results are found for the comparison of Foley catheter versus misoprostol for labor induction [16].
Therefore, prostaglandin E2 gel is more appropriate for labor induction

Fig. 2. Quality of the four studies included in the present meta-analysis.

Fig. 3. Impact of the use of misoprostol versus prostaglandin E2 gel for labor induction on the induction-to-delivery interval in women with premature rupture of membranes after
34 weeks of pregnancy. Abbreviations: CI, condence interval; IV, inverse variance; PGE2, prostaglandin E2.

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217

Fig. 4. Impact of the use of misoprostol versus prostaglandin E2 gel for labor induction on the likelihood of cesarean delivery in women with premature rupture of membranes after
34 weeks of pregnancy. Abbreviations: CI, condence interval; M-H, MantelHaenszel test; PGE2, prostaglandin E2.

Fig. 5. Impact of the use of misoprostol versus prostaglandin E2 gel for labor induction on the likelihood of tachysystole in women with premature rupture of membranes after 34 weeks of
pregnancy. Abbreviations: CI, condence interval; M-H, MantelHaenszel test; PGE2, prostaglandin E2.

among women with PROM if there is also an elevated danger of fetal

hypoxemiafor instance, because of post-term pregnancy, chronic disease, fetal growth restriction, oligohydramnios, or pre-eclampsia.
In the present meta-analysis, three studies used misoprostol via the
vaginal route and one study used oral misoprostol. Only one randomized
clinical trial [17] could be found that compared vaginal misoprostol with
oral misoprostol for labor induction in women with PROM. No differences
between the two groups were found in terms of effectiveness and safety.
The present data indicate that misoprostol and prostaglandin E2 gel
have similar effectiveness for labor induction in women with PROM
after 34 weeks of pregnancy. Prostaglandin E2 gel carries a reduced
risk of tachysystole, whereas misoprostol does not increase the rate of
cesarean delivery or NICU admission. Moreover, misoprostol is cheaper
and more stable than prostaglandin E2 gel. Therefore, for labor induction in women with PROM after 34 weeks of pregnancy, misoprostol
is recommended when there is no increased risk of fetal hypoxemia.
The present study has its limitations. It was not possible to fully evaluate adherence to the study protocol for the included studies. Besides,
there was heterogeneity among the studies in terms of the study time

and study population. Moreover, other studies might exist that were
not included in the present meta-analysis.
Unfortunately, none of the four randomized controlled studies addressed the incidence rates of impending uterine rupture, uterine rupture, or fetal distress, which are all associated with tachysystole. In
addition, a longer interval from the rupture of membranes to delivery
is associated with a higher incidence of chorioamnionitis and neonatal
sepsis [2]. Only two randomized controlled trials [9,11] reported the incidence of chorioamnionitis and neonatal sepsis. More attention should
be paid to these outcomes in future studies concerning labor induction
in women with PROM.
The present meta-analysis suggests that misoprostol and prostaglandin E2 gel have similar effectiveness and safety. The induction-todelivery intervals, rates of cesarean delivery, and rates of NICU admission do not differ signicantly. The misoprostol group had a signicantly
higher rate of tachysystole without any harmful outcome. Therefore,
prostaglandin E2 gel is preferable for labor induction among women
with PROM if risk of fetal hypoxemia exists. If not, misoprostol is recommended because of economic concerns and stability.

Fig. 6. Impact of the use of misoprostol versus prostaglandin E2 gel for labor induction on the likelihood of NICU admission in women with premature rupture of membranes after 34 weeks
of pregnancy. Abbreviations: CI, condence interval; M-H, MantelHaenszel test; PGE2, prostaglandin E2.

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Conict of interest
The authors have no conicts of interest.
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