Journal of

Clinical Medicine

Article
Use of Vaginal Dinoprostone (PGE2) in Patients with Premature
Rupture of Membranes (PROM) Undergoing Induction of
Labor: A Comparative Study
Nuria López-Jiménez 1 , Fiamma García-Sánchez 1 , Rafael Hernández Pailos 1 , Valentin Rodrigo-Álvaro 1 ,
Ana Pascual-Pedreño 1 , María Moreno-Cid 1 , Antonio Hernández-Martínez 2, * and Milagros Molina-Alarcón 3

1 Department of Obstetrics and Gynecology, La Mancha Centro Hospital, 13600 Alcazar de San Juan, Spain;
[email protected] (N.L.-J.); [email protected] (F.G.-S.); [email protected] (R.H.P.);
[email protected] (V.R.-Á.); [email protected] (A.P.-P.); [email protected] (M.M.-C.)
2 Department of Nursing, Physiotherapy and Occupational Therapy, Faculty of Nursing,
University of Castilla-La Mancha IDINE, Camilo José Cela, 14, 13071 Ciudad Real, Spain
3 Department of Nursing, Physiotherapy and Occupational Therapy, Faculty of Nursing,
University of Castilla-La Mancha IDINE, Av. de España, s/n, 02001 Albacete, Spain;
[email protected]
* Correspondence: [email protected]

Abstract: Purpose: To evaluate the effect and safety of vaginal dinoprostone in pregnant women
with PROM who undergo induction of labor (IoL). Materials and Methods: Prospective observational





 study conducted at La Mancha Centro hospital from 1 February 2019, to 30 August 2020. Obstetric and
Citation: López-Jiménez, N.;
neonatal variables of 94 pregnant women with PROM who underwent IoL with vaginal dinoprostone
García-Sánchez, F.; Pailos, R.H.; were analyzed, and the results were compared with 330 patients without PROM who also underwent
Rodrigo-Álvaro, V.; Pascual-Pedreño, IoL. Bivariate and multivariate analyses were performed using binary and multiple linear regression.
A.; Moreno-Cid, M.; Results: A total of 424 women were included in this study. A greater response to cervical ripening
Hernández-Martínez, A.; (Bishop score > 6) with PGE2 was observed in the PROM group (odds ratio (OR) 2.73, 95% confidence
Molina-Alarcón, M. Use of Vaginal interval (CI) 1.50–4.99, p = 0.001), as well as a shorter total duration of IoL (mean difference (MD)
Dinoprostone (PGE2 ) in Patients with 2823.37 min (min), 95% CI 1257.30–4389.43, p < 0.001). Cesarean sections were performed in 28.7%
Premature Rupture of Membranes
(n = 27) of patients in the PROM group vs. 34.2% (n = 113) of patients in the non-PROM group,
(PROM) Undergoing Induction of
with no significant differences (OR 0.87%, 95% CI 0.47–1.60, p = 0.652). There were no significant
Labor: A Comparative Study. J. Clin.
differences in changes in the cardiotocographic record (CTG), postpartum hemorrhage (PPH), uterine
Med. 2022, 11, 2217. https://
rupture, or adverse neonatal outcomes between the two groups. Conclusions: The use of vaginal
doi.org/10.3390/jcm11082217
dinoprostone in pregnant women undergoing IoL with PROM is safe for the mother and the fetus,
Academic Editor: Yariv Yogev shortens the total delivery time, and does not increase the risk of cesarean section compared with
Received: 14 February 2022 pregnant women undergoing IoL without PROM.
Accepted: 14 April 2022
Published: 15 April 2022 Keywords: premature rupture of membranes (PROM); induction of labor (IoL); PGE2 ; cesarean
section; delivery time
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
1. Introduction
Premature rupture of membranes (PROM) is defined as the rupture of the fetal mem-
branes before the onset of regular uterine contractions [1]. This condition can occur in term
Copyright: © 2022 by the authors. fetuses (≥37 weeks of gestation) and preterm fetuses (PPROM, <37 weeks of gestation) with
Licensee MDPI, Basel, Switzerland. an incidence of approximately 8% and 3%, respectively [2]. Its etiology is multifactorial, but
This article is an open access article the gestational age at which it occurs provides information regarding the underlying cause.
distributed under the terms and Regarding full-term fetuses, it may be due to physiological weakening of the membranes
conditions of the Creative Commons
combined with the shear forces created by uterine contractions with the onset of labor [1].
Attribution (CC BY) license (https://
In the case of preterm fetuses, its association with intra-amniotic infection has been reported
creativecommons.org/licenses/by/
in 25–40% of pregnant women [3–5].
4.0/).

J. Clin. Med. 2022, 11, 2217. https://doi.org/10.3390/jcm11082217 https://www.mdpi.com/journal/jcm

J. Clin. Med. 2022, 11, 2217 2 of 11

Induction of labor (IoL) is currently one of the most frequently performed procedures
in obstetrics departments. In Europe, the induction rate varies between 6.8 and 33% [6].
The latest review carried out by Cochrane in 2017 was in favor of induction of labor (IoL)
for PROM at term after demonstrating a reduction in the risk of maternal infectious and
neonatal morbidity compared with expectant management [2]. However, it did not establish
a recommendation for the safest induction method for this (oxytocin or prostaglandins);
hence, its management remains controversial. Furthermore, several studies, including meta-
analyses of randomized clinical trials, have not shown a statistically significant benefit in
women with PROM for using any type of prostaglandin versus oxytocin [7–10]. By contrast,
some studies have documented the efficacy and safety of the use of vaginal dinoprostone
prior to the use of oxytocin for labor induction, with an increase in the rate of vaginal
delivery within 24 h compared with labor induction with IV oxytocin alone (78.5% vs.
63.3%; relative risk (RR) 1.23; 95% CI, 1.09–1.39; p = 0.01) [11].
One of the most feared effects of the use of prostaglandins in patients with ruptured
membranes is uterine hyperstimulation (6.2%) and the possible associated disorders regard-
ing the fetal heart rate (FHR) (6.9%) [12]. Although societies such as the SEGO (Spanish
Society of Obstetrics and Gynecology) [13] and the ACOG (American College of Obste-
tricians and Gynecologists) [1] do not contraindicate the use of dinoprostone to initiate
labor induction in patients with unfavorable Bishop scores, it is remarkable to note that the
Propess® product data sheet recommends not using this product in pregnant women with
PROM because of the limited experience of its use in this population and the possibility
that its release is higher and more variable than in patients without PROM [12,14], possibly
entailing more risks than in patients with intact membranes.
Therefore, to provide more evidence regarding the effect and safety for the mother
and the fetus of vaginal dinoprostone in the induction of labor in patients with PROM, we
analyzed and compared the perinatal results in pregnant women with PROM undergoing
IoL in the first 24 h vs. pregnant women undergoing IoL without PROM.

2. Materials and Methods

2.1. Patients and Methods
A prospective observational study was carried out from 1 February 2019 to 20 August 2020
at La Mancha Centro hospital in Alcázar de San Juan (Ciudad Real), Spain. This study was
approved by the hospital’s clinical research ethics committee (CEIC) with protocol number
102-C. All patients who participated in the study did so voluntarily and anonymously after
agreeing to participate and signing an informed consent form.
The study population included a total of 424 singleton pregnancies undergoing IoL
with vaginal dinoprostone (PGE2 ). A comparative study was conducted between patients
undergoing IoL with PROM (n = 94) and patients with IoL for other reasons (n = 330)
without PROM.

2.2. Inclusion and Exclusion Criteria

The inclusion criteria were singleton pregnancies with cephalic presentations, ≥34 weeks
of gestation, a baseline Bishop score ≤6 points, and the need for cervical ripening prior
to the induction of labor with vaginal dinoprostone (PGE2 ). There were no restrictions
regarding parity or history of previous cesarean section. Patients with labor induction
without PGE2 , multiple gestations, noncephalic presentations, and stillbirths, along with
patients who did not consent to participate in the study, were excluded.

2.3. Information Sources

For data collection, a specific computerized database was created. The information
was obtained from personal clinical interviews and the data recorded in the partograms
and medical records of the patients. Cervical characteristics prior to induction (Bishop
score) and the cervical length measured by transvaginal ultrasound were recorded by the
gynecologist responsible for the delivery room that day. The guidelines of the International
J. Clin. Med. 2022, 11, 2217 3 of 11

Society of Ultrasound in Obstetrics and Gynecology (ISUOG) [15] and the Fetal Medicine
Foundation (FMF) [16] were used for the measurement of cervical length. The main
independent variable analyzed was the existence of the premature rupture of membranes
(PROM), while the dependent variables were the obstetric and neonatal results obtained
after IoL. Table 1 shows the sociodemographic and obstetric characteristics of the pregnant
women studied according to the presence or absence of PROM.

Table 1. Demographic characteristics of the study population according to PROM status.

Variable PROM 1 (n= 94) Non-PROM 1 (n = 330) p-Value

Maternal characteristics
Maternal age (years) * 32.29 (4.83) 33.10 (5.16) 0.174
Pregestational weight (kg) * 66.68 (12.95) 69.82 (14.84) 0.062
Antepartum weight (kg) * 78.47 (14.53) 80.82 (14.91) 0.178
Pregestational Body Mass Index
29.43 (4.70) 30.20 (5.31) 0.203
(BMI) (kg/m2 ) *
Obstetrical characteristics
Previous cesarean delivery
No 85 (90.4%) 292 (88.5%)
0.597
Yes 9 (9.6%) 38 (11.5%)
Parity
Primiparity 21 (22.3%) 123 (37.3%)
0.007
Multiparity 73 (77.7%) 207 (62.7%)
Preexisting or gestational diabetes
No 91 (96.8%) 294 (89.1%)
Preexisting diabetes 0 (0%) 4 (1.2%) 0.154
Gestational diabetes 3 (3.2%) 32 (9.7%)
Hypertensive state in pregnancy
No 92 (97.9%) 292 (88.5%)
Chronic hypertension 2 (2.1%) 6 (1.8%)
Gestational hypertension 0 (0%) 18 (5.5%) 0.043
Preeclampsia 0 (0%) 13 (3.9%)
Preeclampsia with severe features 0 (0%) 1 (0.3%)
Fetal Growth Restriction (FGR)
No 94 (100%) 310 (93.9%)
0.014
Yes 0 (0%) 20 (6.1%)
Gestational age at birth (weeks)
<37 + 0 days 12 (12.8%) 3 (0.09%)
<0.001
≥37 + 0 days 82 (87.2%) 327 (99.1%)
Cervical length prior to IoL 2
21.27 (8.10) 28.04 (9.11) <0.001
(CL) *, millimeters (mm)
Bishop score on admission 2.13 (1.53) 2.81 (1.45) <0.001
Prepartum Amniotic Fluid Index (AFI)
Normal 78 (83%) 270 (81.8%)
Oligoamnios 15 (16%) 34 (10.3%) 0.025
Hydramnios 1 (1.1%) 26 (7.9%)
* Mean (Standard Deviation). 1 PROM: Premature Rupture of Membranes. 2 IoL: Induction of Labor.

2.4. Induction of Labour Protocol at the Study Center

Pregnant women who presented with an unfavorable cervix at the beginning of the
IoL (Bishop score of ≤6) underwent a prior cervical ripening process with the adminis-
tration of vaginal prostaglandins (PGE2 ) using the Propess® slow-release system (Ferring
Pharmaceuticals, Saint-Prex, Switzerland). This system contains 10 mg of PGE2 released at
a rate of 0.3 mg/h over 24 h.
J. Clin. Med. 2022, 11, 2217 4 of 11

Fetal indications for IoL included the following: non-reassuring fetal heart rate
(NRFHR), oligohydramnios, polyhydramnios, fetal growth restriction (FGR), small for
gestational age, and macrosomia. Maternal indications for IoL included the following:
maternal diseases, such as gestational or pregestational diabetes, cholestasis, chronic hyper-
tension or hypertensive diseases of pregnancy, and poor obstetric history.
The diagnosis of patients with PROM was made by vaginal examination, after ob-
serving the leakage of amniotic fluid through the cervical orifice and its accumulation
in the posterior vaginal fornix, or by a positive test for the protein insulin-like growth
factor-binding 1 (IGFBP-1) in the vaginal fluid. These patients underwent IoL starting from
34 weeks of gestation. We carried out prior cervical ripening with PGE2 if the patient had a
Bishop score of ≤6 and the rupture of membranes occurred within the first 24 h. Antibiotic
prophylaxis was only administered for GBS infection if the patient had a positive screening
or if the screening status was unknown.
Once the vaginal device was placed, the pregnant woman underwent fetal heart rate
(FHR) monitoring for 2 h. After insertion, if any alteration in the FHR pattern (according
to the classification criteria for FHR tracings proposed by the National Institute of Child
Health and Human Development, NICHD) [17] or uterine tachysystole (defined as the
presence of more than five contractions every 10 min) was observed, the device was
removed immediately. If no alteration occurred, FHR monitoring was performed at 12 and
24 h, and the device was removed when the woman reached favorable cervical ripening
(Bishop score of >6), dilation of 3–4 cm with regular uterine contractions, or after 24 h
regardless of the Bishop score. By contrast, in selected cases, women with a favorable
Bishop score at the beginning of induction (>6) were directly stimulated with intravenous
oxytocin perfusion and amniotomy.
Specifically, oxytocin was administered intravenously via an infusion pump at a dose
of 2 milliunits/minute with a period between dose increments of 15 min until reaching regu-
lar uterine dynamics (3–4 contractions/10 min) or a maximum dose of 20 milliunits/minute
(120 mL/h).

2.5. Statistical Analysis

All analyses were conducted using the program SPSS v24.0 (Chicago, IL, USA). A
descriptive analysis was performed with mean and standard deviation (SD) for quantitative
variables and absolute and relative frequencies for categorical variables. We carried out
a bivariate analysis to determine the sociodemographic and clinical differences between
the group of women with PROM and the group of women without PROM. Bivariate
and multivariate analyses were then carried out to analyze the effect of PROM on the
different perinatal outcomes analyzed. For this, binary logistic regression or multiple
linear regression was used depending on whether the result variable was categorical or
quantitative in nature. On the basis of this, odds ratios (OR)/adjusted odds ratios (AOR)
or mean differences (MD)/adjusted mean differences (aMD) were estimated with their
respective 95% confidence intervals.

3. Results
A total of 1353 deliveries took place at La Mancha Centro hospital during the study
period, of which 445 (32.89%) underwent IoL with PGE2 . After applying the exclusion
criteria, 424 pregnant women were recruited into the study. Of these, 94 (22.17%) underwent
IoL for PROM, and 330 (77.83%) women underwent IoL for another indication without
PROM. Figure 1 shows the flowchart of the patients included in the study.
J. Clin. Med. 2022, 11, x FOR PEER REVIEW 5 of 11

J. Clin. Med. 2022, 11, 2217 5 of 11

underwent IoL for PROM, and 330 (77.83%) women underwent IoL for another indication
without PROM. Figure 1 shows the flowchart of the patients included in the study.

Figure
Figure 1.
1. Flow
Flowchart
chartof
ofthe
theselection
selectionprocess
processofofthe
thepatients
patientsstudied.
studied.1 IoL: Induction
1 IoL: of of
Induction Labour. 2
Labour.
PROM:
2 PROM:Premature
PrematureRupture
RuptureofofMembranes.
Membranes.

3.1.
3.1. Characteristics
Characteristics ofof the
the Women
Women Undergoing
Undergoing IoL IoL with
with PROM
PROM and and without
without PROM
PROM
Both
Both groups
groups presented
presented similar
similar baseline
baseline variables.
variables. InInthe
thegroup
groupof ofpatients
patientswithwithPROM,
PROM,
2
the mean age was 32.29 years (SD = 4.83), and the pre-pregnancy BMI was 29.43 kg/m2 (SD
the mean age was 32.29 years (SD = 4.83), and the pre-pregnancy BMI was 29.43 kg/m
=(SD
4.70). In theInnon-PROM
= 4.70). the non-PROM group, the mean
group, age was
the mean age 33.10 yearsyears
was 33.10 (SD =(SD5.16), and the
= 5.16), andpre-
the
2 (SD = 5.31). Regarding parity, a greater number of
pregnancy BMI was 30.20 kg/m2 (SD = 5.31). Regarding parity, a greater number of multip-
pre-pregnancy BMI was 30.20 kg/m
multiparous
arous patientspatients was observed
was observed in the PROM
in the PROM group (n group
= 73,(n77.7%)
= 73, 77.7%)
vs. the vs. the non-PROM
non-PROM group
group (n = 207, 62.7%), although the result was non-significant (p = 0.07).
(n = 207, 62.7%), although the result was non-significant (p = 0.07). Statistically significant Statistically
significant differences
differences were foundwere foundhypertension
regarding regarding hypertension
in pregnancy, in which
pregnancy, whichfrequent
was more was more in
frequent in non-PROM patients (n = 38, 11.5% vs. n = 2, 2.1%; p = 0.043); intrauterine
non-PROM patients (n = 38, 11.5% vs. n = 2, 2.1%; p = 0.043); intrauterine growth restriction, growth
restriction,
which which
was more was more
frequent frequentwith
in patients in patients
PROM (n with
= 20,PROM (n n
6.1% vs. = =20, 6.1%p vs.
0.0%; n = 0.0%;
= 0.014); ges-
p = 0.014); gestational age at birth (<37 weeks’ gestation), which was
tational age at birth (<37 weeks’ gestation), which was greater in the PROM group (n greater in the PROM
= 12,
group (n = 12, 12.8%) than in the non-PROM group (n = 3, 0.09%) (p < 0.001); cervical length
12.8%) than in the non-PROM group (n = 3, 0.09%) (p < 0.001); cervical length at the begin-
at the beginning of the IoL, which was lower in the PROM group (21.27 mm, SD = 8.10) than
ning of the IoL, which was lower in the PROM group (21.27 mm, SD = 8.10) than in the non-
in the non-PROM group (28.04 mm, SD = 9.11) (p < 0.001); and the prepartum Amniotic
PROM group (28.04 mm, SD = 9.11) (p < 0.001); and the prepartum Amniotic Fluid Index
Fluid Index (AFI) (p = 0.025). No statistically significant differences were observed between
(AFI) (p = 0.025). No statistically significant differences were observed between both groups
both groups for the rest of the variables. Table 1 lists all the analyzed sociodemographic
for the rest of the variables. Table 1 lists all the analyzed sociodemographic variables of the
variables of the patients included in the study according to their PROM status.
patients included in the study according to their PROM status.
J. Clin. Med. 2022, 11, 2217 6 of 11

3.2. Obstetric Outcomes According to PROM Status

A greater response to cervical ripening with PGE2 (Bishop score > 6) was observed
in the group of patients with PROM vs. the non-PROM group (OR 2.73, 95% CI 1.50–4.99,
p = 0.001) in the multivariate analysis. This difference was statistically significant for the
nulliparous group, whereas it was not significant for the multiparous group. In addition,
the time recorded with PGE2 and the total duration of IoL were significantly shorter in
the PROM group: MD 1884.52 min (min) (95% CI 752.09–3016.96, p = 0.001) and MD
2823.37 min (95% CI 1257.30–4389.43, p < 0.001), respectively. A significantly higher risk of
developing chorioamnionitis was observed in patients with PROM than in patients without
PROM (OR 5.36, 95% CI 1.18–24.42, p = 0.030). Within the group of pregnant women with
PROM, 71.28% (n = 67) had a vaginal delivery compared with 65.76% (n = 217) of the
group without PROM, although this result was not significant (OR 0.87%, 95% CI 0.47–1.60,
p = 0.652). No statistically significant differences were found in the bivariate or multivariate
analyses between the two groups in terms of the presence of meconium, intrapartum fever,
category II–III FHR pattern, postpartum hemorrhage (PPH), uterine rupture, or maternal
admission to the ICU. All the obstetric variables studied are provided in detail in Table 2.

Table 2. Obstetric outcomes in the study population according to PROM.

PROM 1 Non-PROM 1 Univariate Analysis Multivariate Analysis **

Variable
(n = 94) (n = 330) OR/MD 95% CI p-Value OR/MD 95% CI p-Value
Bishop score >6 after PGE2
No 26 (27.7) 161 (48.8)
2.49 (1.51–4.11) <0.001 2.73 (1.50–4.99) 0.001
Yes 68 (72.3) 169 (51.2)
Nulliparous Bishop score >6 after PGE2
No 19 (20.2) 116 (35,2)
3.62 (2.01–6.54) <0.001
Yes 54 (57.45) 91 (27.6)
Multiparous Bishop score >6 after PGE2
No 7 (7.45) 45 (13.6)
1.15 (0.43–3.07) 0.774
Yes 14 (14.9) 78 (23.6)
Time with PGE2 373.92 1884.52
418.51 (310.22) 792.42 (420.50) <0.001 0.001
(min) * (281.40–466.43) (752.09–3016.96)
Total duration of 442.35 2823.37
903.03 (525.73) 1345.38(653.9) <0.001 <0.001
IoL (min) * (297.29–597.41) (1257.30–4389.43)
Duration of 2nd −13.94 −274.51
104.50 (82.61) 90.56 (78.35) 0.209 0.45
stage (min) * (−35.79–7.83) (−542.58–6.43)
Type of delivery
Vaginal delivery 67 (71.3) 217 (65.8)
0.77 (0.47–1.28) 0.316 0.87 (0.47–1.60) 0.652
Cesarean delivery 27 (28.7) 113 (34.2)
Meconium
No 86 (91.5) 278 (84.2)
0.50 (0.23–1.09) 0.080 0.64 (0.26–1.57) 0.327
Yes 8 (8.5) 52 (15.8)
Reason for cesarean delivery
Arrest of labor 12 (12.8) 27 (8.2) 1.64 (0.80–3.38) 0.178 2.32 (0.95–5.69) 0.066
Failed induction 4 (4.3) 32 (9.7) 0.41 (0.14–1.20) 0.105 0.51 (0.15–1.74) 0.282
Cephalopelvic
5 (5.3) 11 (3.3) 1.63 (0.55–4.81) 0.377 1.42 (0.40–5.12) 0.588
disproportion
Emergent 6 (6.4) 43 (13) 0.45 (0.19–1.10) 0.082 0533 (0.20–1.41) 0.206
J. Clin. Med. 2022, 11, 2217 7 of 11

Table 2. Cont.

PROM 1 Non-PROM 1 Univariate Analysis Multivariate Analysis **

Variable
(n = 94) (n = 330) OR/MD 95% CI p-Value OR/MD 95% CI p-Value
Intrapartum fever
No 88 (93.6) 313 (94.8)
0.75 (0.28–1.97) 0.560 0.60 (0.20–1.80) 0.362
Yes 6 (6.4) 16 (4.8)
Missing data 1 (0.3)
Intrapartum chorioamnionitis
No 89 (94.7) 323 (97.9)
3.03 (0.91–10.17) 0.072 5.36 (1.18–24.42) 0.030
Yes 5 (5.3) 6 (1.8)
Missing data 1 (0.3)
CTG 2 : NICHD 3 2
No 68 (72.3) 234 (70.9)
0.93 (0.55–1.55) 0.787 0.90 (0.51–1.57) 0.702
Yes 26 (27.7) 96 (29.1)
CTG 2 : NICHD 3 3
No 91 (96.8) 312 (94.5)
0.57 (0.17–1.98) 0.378 0.55 (0.15–2.06) 0.372
Yes 3 (3.2) 18 (5.5)
Postpartum hemorrhage 4
No 87 (92.6) 304 (92.1)
1.06 (0.44–2.56) 0.891 0.91 (0.33–2.51) 0.852
Yes 7 (7.4) 23 (7.0)
Missing data 3 (0.9)
Uterine rupture 5
No 93 (98.9) 327 (99.1)
3.52 (0.29–56.75) 0.376 NC 0.994
Yes 1 (0.3) 1 (0.3)
Missing data 2 (0.6)
Blood loss >3.5 (l)
No 90 (95.7) 308 (93.3)
0.57 (0.16–1.98) 0.377 0.84 (0.21–3.45) 0.814
Yes 3 (3.2) 18 (5.5)
Missing data 1 (1.1) 4 (1.2)
ICU 6 admission
No 93 (98.9) 326 (98.8)
3.50 (0.22–56.58) 0.377 0.67 (0–54.31) 0.858
Yes 1 (1.1) 1 (0.3)
Missing data 3 (0.9)
Need for transfusion
No 90 (95.7) 318 (96.4)
1.32 (0.34–5.10) 0.682 1.57 (0.30–8.13) 0.592
Yes 3 (3.2) 8 (2.4)
Missing data 1 (1.1) 4 (1.2)
OR: odds ratio; MD: mean difference; CI: confidence interval. 1 PROM: Premature rupture of membranes. 2 CTG:
cardiotocography. 3 NICHD: CTG classification based on the system proposed by the National Institute of Child
Health and Human Development. 4 Postpartum hemorrhage: defined as more bleeding than expected with signs
and symptoms of hypovolemia, for which the gynecologist had to initiate uterotonic drugs. 5 Uterine rupture:
complete rupture of all uterine layers, including the serosal layer. 6 ICU: Intensive Care Unit. NC: Not calculated.
* Mean (Standard Deviation). ** Multivariate analysis adjusted for previous cesarean delivery, maternal age,
pregestational BMI, Bishop score at admission, neonatal weight, regional analgesia, oxytocin stimulation, parity,
hypertensive state in pregnancy, preexisting or gestational diabetes, and gestational age.

3.3. Neonatal Morbidity

In the group with PROM, APGAR test scores of <7 at 1 min were obtained in 3.2%
(n = 3) of the neonates. No infants with APGAR scores of <7 at 5 min were recorded
in this group. Regarding treatment, 12.8% (n = 12) required admission to the neonatal
intensive care unit (NICU), and 3.2% (n = 3) required type III–IV neonatal resuscitation
at birth. In the group of non-PROM pregnant women, APGAR scores of <7 at 1 min and
5 min were obtained in 2.7% (n = 9) and 0.6% (n = 2) of neonates, respectively. In terms
of treatment, 10.3% (n = 34) required NICU admission, and 2.4% (n = 8) required type
III–IV neonatal resuscitation at birth. No statistically significant differences were observed
between the groups in the bivariate or multivariate analysis in any of the neonatal variables
J. Clin. Med. 2022, 11, 2217 8 of 11

collected. Additionally, no cases of neonatal sepsis were recorded in either group, despite
the intrapartum diagnosis of chorioamnionitis. Table 3 shows the neonatal results in the
study population according to their PROM status in detail.

Table 3. Neonatal outcomes in the study population according to PROM.

PROM 5 Non-PROM 5 Univariate Analysis Multivariate Analysis **

Variable
(n = 94) (n = 330) OR 95% CI p-Value OR 95% CI p-Value
APGAR 1 score <7 at 1 min
No 91 (96.8%) 321 (97.3%)
1.18 (0.31–4.43) 0.811 1.70 (0.37–7.83) 0.494
Yes 3 (3.2%) 9 (2.7%)
APGAR score <7 at 5 min
No 94 (100%) 328 (99.4%)
NC 0.997 2.54 (NC) 1
Yes 0 (0%) 2 (0.6%)
NICU 2 admission
No 82 (87.2%) 296 (89.7%)
0.78 (0.39–1.58) 0.499 1.24 (0.47–3.28) 0.661
Yes 12 (12.8%) 34 (10.3%)
REA 3 III–IV
No 91 (96.8%) 322 (97.6%)
1.33 (0.34–5.10) 0.681 3.77 (0.68–21.33) 0.133
Yes 3 (3.2%) 8 (2.4%)
U. artery 4 pH <7.20 at birth
No 86 (91.5) 282 (85.5)
0.50 (1.19–1.31) 0.158 0.87 (0.30–2.54) 0.795
Yes 5 (5.3) 33 (10.0)
Missing data 3 (1.2) 15 (4.5)
U. artery 4 pH < 7.10 at birth
No 90 (95.8) 313 (94.85)
1.74 (0.16–19.40) 0.653 NC 0.957
Yes 1 (0.3) 2 (0.6)
Missing data 3 (1.2) 15 (4.55)
OR: odds ratio; CI: confidence interval. 1 APGAR: Scoring system for the newborn (Appearance, Pulse, Grimace,
Activity, Respiration). NICU 2 : Neonatal intensive care unit. 3 REA: Degree of neonatal resuscitation required at
birth. 4 U. artery: Umbilical artery. 5 PROM: Premature rupture of membranes. ** Multivariate analysis adjusted
for neonatal weight, NICHD classification, meconium, intrapartum fever, prematurity, previous cesarean delivery,
general anesthesia, Fetal Growth Restriction (FGR), hypertensive state in pregnancy, preexisting or gestational
diabetes, oxytocin stimulation, and gestational age.

4. Discussion
The objective of this study was to evaluate the effect and safety of vaginal dinoprostone
(PGE2 ) in pregnant women who underwent IoL with PROM. To do this, we prospectively
compared the perinatal outcomes of 94 pregnant women needing to undergo IoL because
of PROM vs. 330 patients requiring IoL without PROM. The results of this study report
an increased response to cervical ripening with PGE2 in patients with PROM, as well as a
shorter time needed with vaginal PGE2 and a shorter total duration of IoL compared with
pregnant women undergoing labor induction without PROM. There were no significant
differences between the two groups regarding the type of delivery, abnormalities in the
CTG, uterine rupture, postpartum hemorrhage, low APGAR scores, or admission to the
neonatal ICU. Although a higher risk of suspected intrapartum chorioamnionitis was
observed in the PROM group (OR 5.36, 95% CI 1.18–24.42), no cases of neonatal sepsis were
recorded in either group.
Our results are consistent with those observed in the literature. Wang et al. [18]
reported a shorter induction-to-delivery time in the PROM group vs. inductions without
PROM with the use of vaginal dinoprostone (18.76 ± 13.03 h vs. 24.36 ± 17.75 h, p < 0.0001).
They also reported a lower rate of cesarean sections (26.89 vs. 33.58%, p = 0.001) and a
higher number of vaginal deliveries in 24 h (54.38 vs. 45.48%, p < 0.0001) and 48 h (71.90
vs. 63.16%, p <0.0001), without reporting any cases of maternal or fetal infection. Likewise,
Kehl et al., reported similar results for the induction of labor with PROM with vaginal
misoprostol and considered this to be a safe method [19]. In a review carried out by Matt
J. Clin. Med. 2022, 11, 2217 9 of 11

Shirley in 2018 on the efficacy, safety, and tolerability of vaginal dinoprostone in IoL [20],
fewer adverse events were reported with the use of PGE2 than with vaginal misoprostol
preparations (11.4% vs. 4.0%, p < 0.001). A peer-reviewed meta-analysis published in
2015 found up to a threefold decrease in the risk of uterine hyperstimulation with vaginal
dinoprostone use compared with vaginal misoprostol doses of ≥50 µg (OR 2.73, 95% CI
1.08–7.40) [21].
Regarding the finding of a higher risk of intrapartum chorioamnionitis in pregnant
women with PROM, we consider that the time that the pregnant woman remains with
ruptured membranes acts as an independent risk factor in the development of a possible
intra-amniotic infection and should not be attributed to the effect of the vaginal dinopro-
stone itself [22,23]. Another important aspect to take into account is that the premature
rupture of the membranes itself is an independent factor that stimulates the labor pro-
cess and has been widely described [10]; hence, it can influence the time needed with
Propess® , and the total IoL may end up being shorter compared with that in pregnant
women without PROM.
Some studies, such as that by Lyrenäs et al. [14], have studied the rate of PGE2 release
in patients undergoing IoL with both intact membranes and the premature rupture of
membranes. In both groups, this release was observed to be safe and effective, without
evidence of a “loading dose” (the release of an excessive amount of PGE2 over a short
period of time). In patients with PROM, because of the increase in vaginal pH, a greater
release of PGE2 by the device was observed. However, because of the changes in the
ionization that the PGE2 molecule undergoes with an increase in pH, its vaginal absorption
is lower, so the expected risk of uterine hyperstimulation is reduced.
This study has some limitations to consider. First, it is important to clarify that during
the labor process, a suspicion of chorioamnionitis (also called intra-amniotic infection,
IAI) [24] can only be established based on clinical criteria (fever of ≥39.0 ◦ C (102.2 ◦ F) or
two measurements of ≥38 ◦ C (102.02 ◦ F) plus evidence of fetal tachycardia or a maternal
white cell (WBC) count >15,000/mm3 in the absence of corticosteroids and ideally showing
a left shift or purulent-appearing fluid coming from the cervical os visualized by speculum
examination). For confirmation, the detection of Gram-positive bacteria in the amniotic
fluid; a low level of amniotic glucose; or histopathological evidence of the infection of
the placenta, fetal membranes, or the umbilical cord is needed [24]. A limitation of our
study is the impossibility of obtaining a confirmatory diagnosis through a placental study
after delivery in pregnant women with suspected IAI. However, we believe that there was
no actual case, as no cases of neonatal infection/sepsis were observed in the population
studied. On the other hand, we should note that a higher proportion of multiparous
patients was observed for pregnant women with PROM, which may have influenced the
shorter induction times. However, the authors believe that the risk of bias is low because a
multivariate analysis was carried out to control for confounding bias. Finally, the sample
size of our population is limited, which can make it difficult to obtain significant results for
some rare adverse events, such as uterine rupture, which has a low reported frequency of
occurrence [25].
Regarding strengths, it should be noted that this is a prospective study with well-
defined and agreed-upon variables, as well as the use of a uniform induction protocol and
well-detailed doses of oxytocin. In addition, taking into account the scant evidence on
dinoprostone use for PROM, we believe that the results of this study could contribute to the
performance of meta-analyses with greater statistical power to study rare adverse events,
such as uterine rupture, thus enabling the establishment of strong recommendations on the
most appropriate method of cervical ripening and induction in this group of patients.

5. Conclusions
Our results suggest that the use of vaginal dinoprostone (PGE2 ) in IoL in pregnant
women with PROM is as safe as that in pregnant women without PROM, both for the
mother and the fetus. A decrease in the total induction time was also observed, as well as
J. Clin. Med. 2022, 11, 2217 10 of 11

a reduced time with dinoprostone in pregnant women with PROM, without significant
differences observed in terms of the type of delivery compared with pregnant women
without PROM.

Author Contributions: Conceptualization and methodology, N.L.-J. and A.H.-M.; software, F.G.-S.;
validation, R.H.P. and V.R.-Á.; formal analysis, A.H.-M.; investigation, N.L.-J.; resources, A.P.-P. and
M.M.-C.; writing—original draft preparation, N.L.-J. and A.H.-M.; writing—review and editing,
A.P.-P. and M.M.-C.; visualization, M.M.-A.; supervision, A.P.-P. and M.M.-C.; project administration,
M.M.-A. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: This study was conducted in accordance with the principles
of the Declaration of Helsinki with regard to studies involving human subjects and in line with Law
14/2007 for biomedical research. The principles of confidentiality and anonymity in the treatment
of the data and the presentation of the results were respected at all times, in line with legislation
(EU) 2016/679 of the European Parliament and Council on 27 April 2016 concerning the protection
of natural persons in terms of the processing of personal data and the free movement of such data.
This study was approved by the hospital’s clinical research ethics committee (CEIC), with protocol
number 102-C.
Informed Consent Statement: Informed consent was obtained from all subjects involved in the
study. Written informed consent was obtained from the patients to publish this paper.
Data Availability Statement: The datasets generated and/or analyzed during the current study are
available from the corresponding author on reasonable request.
Acknowledgments: The authors wish to thank Ingrid de Ruiter for the translation of the initial
manuscript draft.
Conflicts of Interest: The authors declare no conflict of interest.

References
1. ACOG Practice Bulletins. Clinical Management Guidelines for Obstetrician—Gynecologists. Obs. Gynecol. 2020, 133, 168–186.
2. Middleton, P.; Shepherd, E.; Flenady, V.; McBain, R.D.; A Crowther, C. Planned early birth versus expectant management (waiting)
for prelabour rupture of membranes at term (37 weeks or more). Cochrane Database Syst. Rev. 2017, 2017, CD005302. [CrossRef]
[PubMed]
3. Romero, R.; Yoon, B.H.; Mazor, M.; Gomez, R.; Gonzalez, R.; Diamond, M.P.; Baumann, P.; Araneda, H.; Kenney, J.S.; Cotton,
D.B.; et al. A comparative study of the diagnostic performance of amniotic fluid glucose, white blood cell count, interleukin-6,
and Gram stain in the detection of microbial invasion in patients with preterm premature rupture of membranes. Am. J. Obstet.
Gynecol. 1993, 169, 839–851. [CrossRef]
4. Asrat, T. Intra-amniotic infection in patients with preterm prelabor rupture of membranes: Pathophysiology, detection, and
management. Clin. Perinatol. 2001, 28, 735–751. [CrossRef]
5. Kacerovsky, M.; Musilová, I.K.; Khatibi, A.; Skogstrand, K.; Hougaard, D.M.; Tambor, V.; Tosner, J.; Jacobsson, B. Intraamniotic
inflammatory response to bacteria: Analysis of multiple amniotic fluid proteins in women with preterm prelabor rupture of
membranes. J. Matern. Neonatal Med. 2012, 25, 2014–2019. [CrossRef]
6. Zeitlin, J.; Mohangoo, A.; Delnord, M. European Perinatal Health Report: The Health and Care of Pregnant Women and Babies in Europe
in 2010.; Euro-Peristat: Paris, France, 2013.
7. Lin, M.G.; Nuthalapaty, F.S.; Carver, A.R.; Case, A.S.; Ramsey, P.S. Misoprostol for Labor Induction in Women with Term
Premature Rupture of Membranes. Obstet. Gynecol. 2005, 106, 593–601. [CrossRef]
8. McQueen, D.; Neilson, J.P.; Whittle, M.J. Pre-labour rupture of membranes with an unripe cervix: A random trial of management.
J. Obstet. Gynaecol. 1990, 10, 495–498. [CrossRef]
9. Kulhan, N.G.; Kulhan, M. Labor induction in term nulliparous women with premature rupture of membranes: Oxytocin versus
dinoprostone. Arch. Med. Sci. 2019, 15, 896–901. [CrossRef]
10. Hannah, M.E.; Ohlsson, A.; Farine, D.; Hewson, S.A.; Hodnett, E.D.; Myhr, T.L.; Wang, E.E.; Weston, J.A.; Willan, A.R. Induction
of Labor Compared with Expectant Management for Prelabor Rupture of the Membranes at Term. N. Engl. J. Med. 1996, 334,
1005–1010. [CrossRef]
11. Güngördük, K.; Asicioglu, O.; Besimoglu, B.; Güngördük, O.C.; Yildirm, G.; Ark, C.; Şahbaz, A. Labor induction in term premature
rupture of membranes: Comparison between oxytocin and dinoprostone followed 6 hours later by oxytocin. Am. J. Obstet.
Gynecol. 2012, 206, 60.e1–60.e8. [CrossRef]
J. Clin. Med. 2022, 11, 2217 11 of 11

12. Agencia Española de Medicamentos y Productos Sanitarios (AEMPS). Ficha Técnica Propess. Available online: https://cima.
aemps.es/cima/dochtml/ft/62088/FT_62088.html (accessed on 13 December 2021).
13. Sociedad Española de Ginecología y Obstetricia. Rotura Prematura de Membranas. Protocolos ProSEGO 2012. Available online:
https://sego.es (accessed on 13 December 2021).
14. Lyrenas, S.; Clason, I.; Ulmsten, U. In vivo controlled release of PGE2 from a vaginal insert (0.8 mm, 10 mg) during induction of
labour. BJOG Int. J. Obstet. Gynaecol. 2001, 108, 169–178. [CrossRef] [PubMed]
15. Kagan, K.O.; Sonek, J. How to measure cervical length. Ultrasound Obstet. Gynecol. 2015, 45, 358–362. [CrossRef] [PubMed]
16. The Fetal Medicine Foundation. Cervical Assessment. Available online: https://fetalmedicine.org/education/cervical-
assessment (accessed on 13 December 2021).
17. Parer, J.T.; Ikeda, T.; King, T.L. The 2008 National Institute of Child Health and Human Development Report on Fetal Heart Rate
Monitoring. Obstet. Gynecol. 2009, 114, 136–138. [CrossRef]
18. Wang, X.; Zhang, X.; Liu, Y.; Jiang, T.; Dai, Y.; Gong, Y.; Li, Q.; Wang, X. Effect of premature rupture of membranes on time to
delivery and outcomes in full-term pregnancies with vaginal dinoprostone-induced labour. Arch. Gynecol. Obstet. 2019, 301,
369–374. [CrossRef] [PubMed]
19. Kehl, S.; Weiss, C.; Dammer, U.; Baier, F.; Faschingbauer, F.; Beckmann, M.W.; Sütterlin, M.; Pretscher, J. Effect of Premature
Rupture of Membranes on Induction of Labor: A Historical Cohort Study. Geburtshilfe und Frauenheilkd. 2017, 77, 1174–1181.
[CrossRef]
20. Shirley, M. Dinoprostone Vaginal Insert: A Review in Cervical Ripening. Drugs 2018, 78, 1615–1624. [CrossRef] [PubMed]
21. Alfirevic, Z.; Keeney, E.; Dowswell, T.; Welton, N.; Dias, S.; Jones, L.V.; Navaratnam, K.; Caldwell, D.M. Labour induction with
prostaglandins: A systematic review and network meta-analysis. BMJ 2015, 350, h217. [CrossRef]
22. Tran, S.H.; Cheng, Y.W.; Kaimal, A.J.; Caughey, A.B. Length of rupture of membranes in the setting of premature rupture of
membranes at term and infectious maternal morbidity. Am. J. Obstet. Gynecol. 2008, 198, 700.e1–700.e5. [CrossRef]
23. Seaward, P.; Hannah, M.E.; Myhr, T.L.; Farine, D.; Ohlsson, A.; Wang, E.E.; Haque, K.; Weston, J.A.; Hewson, S.A.; Ohel, G.; et al.
International Multicentre Term Prelabor Rupture of Membranes Study: Evaluation of predictors of clinical chorioamnionitis and
postpartum fever in patients with prelabor rupture of membranes at term. Am. J. Obstet. Gynecol. 1997, 177, 1024–1029. [CrossRef]
24. Higgins, R.D.; Saade, G.; Polin, R.A.; Grobman, W.A.; Buhimschi, I.A.; Watterberg, K.; Silver, R.M.; Raju, T.N.; Chorioamnionitis
Workshop Participants. Evaluation and Management of Women and Newborns with a Maternal Diagnosis of Chorioamnionitis.
Obstet. Gynecol. 2016, 127, 426–436. [CrossRef]
25. Chiossi, G.; D’Amico, R.; Tramontano, A.L.; Sampogna, V.; Laghi, V.; Facchinetti, F. Prevalence of uterine rupture among women
with one prior low transverse cesarean and women with unscarred uterus undergoing labor induction with PGE2: A systematic
review and meta-analysis. PLoS ONE 2021, 16, e0253957. [CrossRef] [PubMed]
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