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European Journal of Obstetrics & Gynecology and

Reproductive Biology 138 (2008) 135140

Comparing two dinoprostone agents for cervical ripening

and induction of labor: A randomized trial
Anna Maria Marconi a,*, Patrizia Bozzetti a, Alberto Morabito b, Giorgio Pardi a
Department of Obstetrics & Gynecology, DMSD San Paolo, University of Milano, Via A. di Rudini 8, 20142 Milano, Italy
Department of Statistics, DMSD San Paolo, University of Milano, Via A. di Rudini 8, 20142 Milano, Italy
Received 16 July 2006; received in revised form 6 August 2007; accepted 8 August 2007


Objective: To compare dinoprostone gel and insert in achieving successful vaginal delivery in nulliparous and multiparous women.
Study design: 220 nulliparous and 100 multiparous with a Bishop score 7 were randomized to receive dinoprostone either gel or insert for
cervical ripening. The main outcome measures were the rate and latency of vaginal delivery.
Results: In nulliparous women no significant differences were found between the gel and insert groups in the rate of vaginal delivery (85.6%
vs. 80.7%) delivery 12 (36.8% vs. 32.9%) and 24 h (85.3% vs. 93.4%) regardless of the preinduction Bishop score. Nulliparous with
Bishop score 4 treated with the insert had a decreased risk ( p < 0.05) of post partum hemorrhage (4.8%) when compared with nulliparous
treated with gel (16.7%). On the contrary, in multiparous the time to delivery interval was significantly shorter in the gel treated group
(9.9  4.9 h vs. 13.1  5 h; p < 0.001) with more patients delivering vaginally 12 h (75% vs. 37.5%, p < 0.001), regardless of the
preinduction Bishop score.
Conclusion: Both dinoprostone gel and insert are efficient in achieving cervical ripening and successful labor in nulliparous and multiparous.
In multiparous, however, the gel significantly reduces the time to vaginal delivery with more patients delivering vaginally 12 h, regardless of
the Bishop score.
# 2007 Elsevier Ireland Ltd. All rights reserved.

Keywords: Induction of labor; Dinoprostone; Parity

1. Introduction However, most comparative randomized clinical trials

have not drawn definitive conclusions about the relative
Labor induction is among the most frequent procedures effectiveness with regard to parity [2,3,6]. Furthermore, in
performed in pregnant women and many studies have most studies the induction regimen is not comparable: the
demonstrated that cervical ripeness is one of the most slow release dinoprostone insert is either repeated or
important factors in predicting successful labor induction followed by gel administration, if labor does not start [5,9
[1]. Thus far, prostaglandins, particularly PGE, have been 12]. Similarly, for the dinoprostone gel the variability,
shown to be the most effective agents in achieving cervical among studies, concerns both dose and administration
ripening [1]. The effects and properties of PGE2 route [3,69].
(dinoprostone) have been extensively investigated and The purpose of our prospective randomized study was
many studies have compared the efficacy of the different to compare the efficacy of dinoprostone gel and insert in
formulations available (gel vs. slow release insert) [212]. promoting cervical maturation and achieve vaginal
delivery. Results are presented in terms of route of

delivery, induction latency and maternal and neonatal side
Preliminary account of this work was presented at the 2003 Annual
Meeting of the Society for Gynecologic Investigation, Washington, DC.
effects in nulliparous (N) and multiparous (M) patients,
* Corresponding author. Tel.: +39 02 503 23064; fax: +39 02 936 50639. analyzed separately, and according to the preinduction
E-mail address: (A.M. Marconi). Bishop score.

0301-2115/$ see front matter # 2007 Elsevier Ireland Ltd. All rights reserved.
136 A.M. Marconi et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 138 (2008) 135140

2. Materials and methods every 15 min up to a maximum dose of 32 mU/min.

Amniotomy was performed simultaneously, before or after,
This prospective randomized study was performed at the at the discretion of the attending clinician.
Department of Obstetrics and Gynecology, DMSD San Abnormal fetal heart rate was defined by the presence of
Paolo, University of Milano (Italy). The Department Board persistent severe variable decelerations, persistent late
approved the protocol. Written informed consent was decelerations or bradicardia with absent variability [14].
obtained from all pregnant women. Maternal blood loss was assessed with a plastic bag
The study took place from June 2001 to March 2003 and with a graded funnel-shaped tube (Biogyn s.n.c., Mirandola
all women requiring induction of labor were evaluated for MO, Italy).
entry into the study. Inclusion criteria were: (1) Bishop score For a beta of 0.10 and an alpha of 0.05 and a rate of
7; (2) gestational age 37 weeks; (3) singleton pregnancy; cesarean delivery in the gel and insert groups of 1234%, 84
(4) no previous uterine surgery and (5) absence of patients were required in each group. Analysis was by intent
contraindications to vaginal delivery. Gestational age was to treat. Data are presented as mean  S.D. and median
calculated from the last menstrual period and confirmed by when appropriate. Coxs proportional hazard model was
routine sonography at 20 weeks gestation. used to evaluate the impact of treatment, parity and
320 patients met the inclusion criteria (220 nulliparous preinduction Bishop score on the time to vaginal delivery
and 100 multiparous) and were randomly assigned by means interval. Proportional hazard assumptions were graphically
of a phone call randomization with stratification by parity to tested. KaplanMeier estimates of the mean time to vaginal
receive dinoprostone either gel (Prepidil 0.5 intracervical or delivery were performed. The differences between Kaplan
1 mg intravaginal, Pharmacia Italia S.p.A., Milano, Italy) or Meier curves were tested by the log-rank test. Differences
insert (Propess 10 mg, Ferring S.p.A., Milano, Italy). between means were analyzed with a Students t test for
Patients randomized to the gel received 0.5 mg intra- unpaired samples whereas proportional data were analyzed
cervical when the Bishop score was 4 or 1 mg intravaginal by Fishers two tailed exact test using Statistica for
when the Bishop score was 57 with a maximum of three Windows. p-Values <0.05 were considered significant.
doses, 6 h apart if spontaneous labor had not occurred or the
Bishop score was 7.
Patients randomized to the vaginal insert received the 3. Results
10 mg controlled-release dinoprostone insert as a single dose:
the insert was removed after 12 h if labor had not started. 320 women were randomized: 161 in the gel group (111
Either PB or AMM assessed the initial Bishop score (BS): N and 50 M) and 159 in the insert group (109 N and 50 M).
the attending physician performed subsequent management. Table 1 presents maternal age, gestational age and Bishop
In each patient, the fetal heart rate and uterine activity score at the beginning of induction in the two groups
were recorded continuously for at least 30 min prior to according to parity. No significant differences were present.
dinoprostone administration and for at least 60 min after. If Indications for labor induction included: oligohydram-
active labor (regular uterine contractions occurring every 2 nios (amniotic fluid index 5); prelabor rupture of the
3 min) started during the ripening phase, no further gel dose membranes (PROM); post-date pregnancy (41 weeks + 3
was administered or the insert was removed, according to the days); intrauterine growth restriction (IUGR: diagnosed
allocation group. when fetal abdominal circumference was below the 10th
Amniotomy and/or oxytocin was performed: (a) in the gel percentile; only cases with umbilical Doppler waveforms
group, during the preinduction period when the BS was >7; within the normal range were included); gestational
(b) in both groups, if active labor did not start at the end of hypertension and gestational diabetes; non-reassuring
the preinduction period regardless of the BS; in these CTG; other maternal indications including thrombophilia,
patients it was performed 69 h after the last dose of gel or cholestasis, psychological indication, fever (Table 1). The
30 min to 3 h after the removal of the insert (this 3 h delay time interval between PROM and the beginning of the
was dependent on the activity of the labor and delivery ward) cervical ripening was not different in the gel (12.4  2.8 h)
and (c) in patients in labor for augmentation when cervical and insert (12.8  1.9) groups ( p = 0.5).
dilatation, assessed every 2 h, had not increased by at least In the insert group, there were 15 accidental expulsions
2 cm in nulliparous and 3 cm in multiparous, according to (between 2:45 and 11:40 h after application) and in 4
our local protocol. nulliparous, since active labor did not already start, it was
Treatment failure, as in (a) and (b), was considered when reapplied. In the nulliparous patients the insert was removed
the patient was not in labor after at least 6 h of oxytocin after 8.32  4.01 h with a significant increase of the BS
administration. Uterine tachysystole was diagnosed when (6.5  1.9; p < 0.001 vs. BS at induction); similarly, in the
more than five contractions were present in 10 min for at multiparous patients it was removed after 9.2  4.48 h with
least 20 min [13]. a significant increase of the BS (7.4  0.3; p < 0.001 vs. BS
Oxytocin was begun at 2 mU/min and doubled every at induction). The number of vaginal examinations
15 min up to 16 mU/min when the increase was of 2 mU performed to complete the preinduction process was
A.M. Marconi et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 138 (2008) 135140 137

Table 1
Maternal age, gestational age and Bishop score at the time of induction
(mean  S.D.) and clinical indication for induction
Gel Insert
Number of patients 161 159
Nulliparous 111 (68.9%) 109 (66.7%)
Multiparous 50 (31.1%) 50 (33.3%)
Maternal age (years) 31  4.7 30.3  5.1
Nulliparous 30.05  4.3 29.4  4.7
Multiparous 33.1  4.9 32.1  5.6
Gestational age (weeks) 39.6  1.3 39.6  1.4
Nulliparous 39.6  1.4 39.6  1.4
Multiparous 39.7  1.3 39.8  1.3
Fig. 1. KaplanMeier plot of time to vaginal delivery stratified by parity
Bishop score at induction 4.1  1.2 4.0  1.1 and treatment group in patients with Bishop score 4 (solid line: M with
Nulliparous 3.9  1.1 3.9  1.2 gel; hatched line: M with insert; solidhatched line: N with gel; dotted line:
Multiparous 4.5  1.1 4.1  1.1 N with insert).
Nulliparous at first pregnancya 87 (78.4%) 85 (78%) (4.9%) nulliparous had vacuum assisted vaginal delivery
Multiparous with >1 delivery 14 (28%) 9 (18%) regardless of preinduction Bishop score or treatment. The %
Indication for induction
of cesarean section was higher, although not significant, in N
Oligohydramnios 41 35 and M with unfavourable cervix with no treatment based
Premature rupture of membranes 33 22 differences. Overall, only three cesarean sections were
Postdate pregnancy 22 30 performed for failed induction, all in nulliparous with BS
Gestational hypertension 21 24 4 (one in the gel and two in the insert groups).
Intrauterine growth restriction 17 17
Gestational diabetes 9 8
27 patients (25 of which nulliparous) had a 0 change of
Non-reassuring CTG 6 6 BS at the end of the preinduction period (22 in the insert and
Other maternal medical conditions 12 16 5 in the gel group): even though 16/27 remained with a BS
Absence of spontaneous or voluntary pregnancy termination.
4, amniotomy/oxytocin was performed and 21/27 deliv-
ered vaginally (15 within 24 h). Only six cesarean sections
were performed in these patients, two for failed induction
significantly higher in the gel than in the insert groups (both in nulliparous).
(1.9  1.04 vs. 1.3  0.5; p < 0.001). At vaginal delivery, we found no differences in the mean
Two patients in the gel group and two patients in the blood loss (273  230 ml in the gel group and 253  232 in
insert group had complications. In the insert group, uterine the insert group), however more patients with an unfavour-
tachysystole with abnormal fetal heart rate tracings able cervix in the gel treated group had a post partum
developed within 2 h from induction, the ripening agent hemorrhage (PPH) and this was mainly due to nulliparous.
was removed and, after the fetal heart rate had recovered, The median hospital stay was not different in the gel and
amniotomy was performed and both patients delivered insert groups (4 days) regardless of parity: 26/30 patients in
vaginally after approximately 3 and 5 h, respectively. In the the gel group and 26/35 in the insert group with a hospital
gel group, one multiparous patient had uterine tachysystole stay >4 days had an unripe cervix (BS  4) (Table 3).
with abnormal fetal heart rate: vaginal washing was
performed, fetal heart rate recovered and she delivered
vaginally approximately after 4 h. In the other patient, fetal
heart rate abnormalities appeared with no evidence of
uterine tachysystole: she underwent a cesarean section and
the umbilical cord was found having two true knots.
No maternal side effects (nausea, vomiting, fever and
diarrhea) were reported in any patient.
Time to vaginal delivery is presented as a KaplanMeier
plot stratified by parity and treatment in Fig. 1 (patients with
Bishop score 4) and Fig. 2 (Bishop score 57). When Coxs
regression analysis was performed we found that the time to
vaginal delivery interval was independently correlated to
treatment ( p < 0.02), parity ( p < 0.001) and preinduction
Fig. 2. KaplanMeier plot of time to vaginal delivery stratified by parity
Bishop score ( p < 0.001) (Table 2). Multiparous with BS 57 and treatment group in patients with Bishop score 57 (solid line: M with
treated with gel had the shortest time to delivery interval gel; hatched line: M with insert; solidhatched line: N with gel; dotted line:
(Table 3); no differences were present in nulliparous. 9/183 N with insert).
138 A.M. Marconi et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 138 (2008) 135140

Table 2
Cox regression analysis
Hazard ratio Standard error z p > [z] [95% Confidence interval]
Treatment 0.7706115 0.0883825 2.27 0.023 0.6154744 0.9648527
Parity 2.002239 0.2592057 5.36 0.000 1.553535 2.580541
Bishop score 2.034914 0.2627192 5.50 0.000 1.579978 2.620844

Neonatal outcome is presented in Table 4: there were no with an unripe cervix went into labour after the first
differences in the mean birthweight and in the percentage of intracervical gel.
babies 2500 grams between the gel and insert treated Furthermore, once in progress, the preinduction is
patients. 19 babies were admitted in the NICU, only 5 of brought until delivery has been accomplished; amniotomy
which for delivery related problems. and/or oxytocin is started either when the BS is >7 or when
regular uterine contractions are not present at the end of the
ripening process, independent of the BS. Other authors
4. Comment chose to repeat the preinduction after 24 h if labor did not
start or the BS did not improve [5,912] even though the
This is the largest prospective randomized study ripening process should determine changes in histologic
comparing two dinoprostone agents, gel and insert, in characteristics and biochemical composition of the cervix
achieving cervical ripening and successful delivery in which not necessarily imply the onset of uterine contractions
nulliparous and multiparous patients analyzed separately. [16]. These authors report repetition of induction rates
We studied 320 patients, mostly (68.7%) nulliparous. varying from 3% (10) to 53% (9) with the insert and from
Our protocol does not allow more than one insert 16% (10) to 34% (9) with the gel without any evident benefit.
application (unless accidentally removed before the start In our study, >80% of the patients delivered vaginally
of uterine contractions with a BS < 7) and more than three regardless of parity, treatment and preinduction BS. Other
administration of gel: intracervical vs. intravaginal route is authors have reported similar high rate both for the insert
dependent on the BS, based upon the observation that [2,5,7,8] and the gel [5,7,8,17]. However, when compared to
intracervical administration is particularly effective when other studies, we report higher rates of vaginal delivery
the cervix is unfavourable (BS  4) [15]. As a matter of within 12 h regardless of parity [10,17], treatment
fact, 34% of the nulliparous and 44% of the multiparous [6,10,11,17] or preinduction BS [11,12]: this was mainly

Table 3
Data at delivery and hospital stay according to parity and to the Bishop score at the time of induction in the gel and insert groups
BS  4 p BS 57 p
Gel Insert Gel Insert
Number of patients (%) 111 (68.9%) 109 (68.6%) NS 50 (31.1%) 50 (31.4%) NS
Nulliparous 87 (78.4%) 80 (73.4%) 24 (48%) 29 (58%)
Multiparous 24 (21.6%) 29 (26.6%) 26 (52%) 21 (42%)
Vaginal delivery (%) 96 (86.5%) 89 (81.6%) NS 48 (96%) 47 (94%) NS
Nulliparous (% of N) 72 (82.8%) 62 (77.5%) 23 (95.8%) 26 (89.7%)
Multiparous (% of M) 24 (100%) 27 (93.1%) 25 (96.1%) 21 (100%)
Hours from induction to VD 15.3  7.7 15.6  7.1 NS 9.6  4.4 12.3  4.9 0.006
Nulliparous 16.5  8 16.1  7.7 11.5  4.8 12.9  5.6
Multiparous 11.9  5.7 14.5  5.5 7.8  3.1 11.5  3.8 0.001
Cesarean section 15 (13.5%) 20 (18.3%) NS 2 (4%) 3 (6%) NS
Nulliparous (% of N) 15 (17.2%) 18 (22.5%) 1 (4.2%) 3 (10.3%)
Multiparous (% of M) 0 2 (6.9%) 1 (3.8%) 0
Amniotomy/Oxytocin for induction 45 (40.5%) 43 (39.4%) NS 7 (14%) 10 (20%) NS
Nulliparous (% of N) 36 (41.4%) 35 (43.8%) 5 (20.8%) 6 (20.7%)
Multiparous (% of M) 9 (37.5%) 8 (27.6%) 2 (7.7%) 4 (19%)
Post partum hemorrhage (500 ml)a 14 (14.6%) 4 (4.5%) 0.03 6 (12.5%) 7 (15.2%) NS
Nulliparous (% of N) 12 (16.7%) 3 (4.8%) 0.05 3 (13%) 6 (23.1%)
Multiparous (% of M) 2 (8.3%) 1 (3.7%) 3 (12%) 1 (4.8%)
Hospital stay >4 days 26 (23.4%) 27 (24.8%) NS 3 (6%) 9 (18%) NS
Nulliparous 25 (28.7%) 23 (28.7%) 3 (12.5%) 7 (24.1%)
Multiparous 1 (4.2%) 4 (13.8%) 0 2 (9.5%)
At vaginal delivery.
A.M. Marconi et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 138 (2008) 135140 139

Table 4
Birthweight, and neonatal outcome in the study groups
Gel Insert p
Birthweight (grams) [range] 3238  475 [17804300] 3286  509 [19304630] NS
Nulliparous 3204  463 3259  489
Multiparous 3316  495 3346  551
Birthweight 2500 g 13 (8.1%) 9 (5.7%) NS
Cesarean section for fetal heart rate abnormalities 9 (5.6%) 6 (3.8%) NS
Apgar  7 at 1 7 (4.3%) 6 (3.8%) NS
Apgar  7 at 50 1 (0.6%) 1 (0.6%)
Umbilical arterial pH < 7.00 1a (0.6%) 1a (0.6%) NS
Meconium stained amniotic fluid 3 (1.9%) NS
Transfer to neonatal intensive case unit 8 (5%) 11 (6.9%) NS
For delivery related problems 3 (1.9%) 2 (1.2%)
Delivered by vacuum.

due to multiparous treated with gel, independently of the differences in operative vaginal delivery, rate of oxytocin
Bishop score. Similarly, almost 90% of the patients who augmentation or other post partum complications.
delivered vaginally, delivered within 24 h regardless of We are aware that misoprostol is much more cost-
parity and this is the highest percentage reported thus far in effective (same efficacy with very low costs) however its use
similar studies. Also, the time to delivery interval is shorter is still associated with the observation of significant side
in our study when compared to others both in the gel [2,5] effects [2022]. Furthermore, compared to the results of our
and insert [2,18] groups. Both observations might be study it does not seem to offer big advantages in terms of
partially explained by the fact that others allowed repetition cesarean section rate and time to delivery intervals [19,23]
of the preinduction [5,11,12] which most likely has even though only a randomized trial could confirm this
lengthened the whole process. However, it is worth noting observation.
that the rate of vaginal delivery within 24 h is higher also In conclusion, our study shows that both dinoprostone gel
than that reported by Stewart et al. [17] in a gel group treated and insert are efficient in achieving cervical ripening and
with immediate oxytocin (76% in nulliparous and 89% in successful vaginal delivery both in nulliparous and multi-
multiparous) and by Bolnik et al. [19] in an insert group parous with negligible maternal and fetal/neonatal side
treated with immediate oxytocin (81%). effects. In multiparous, however, the gel significantly and
Conversely, we had a low cesarean section rate, correctly powered reduces the time to vaginal delivery with
particularly in multiparous (2% in the gel group and more patients delivering vaginally within 12 h, regardless of
4% in the insert group), regardless of the BS. Even though the Bishop score. The insert seems more convenient in
this study is underpowered to detect the cesarean section nulliparous patients, especially when the preinduction BS is
rate differences, we found (to achieve a significant result 4, given its handiness: one administration, possible
we should have enrolled 1555 patients in each arm) the application overnight, easy removal in case of side effects,
cesarean section rate in these patients is comparable with less vaginal examinations and, most important, decreased
rates obtained in low risk patients in spontaneous labour at risk of post partum hemorrhage.
our institution (13.7%). A possible explanation for this is
the large use of amniotomy/oxytocin: on the whole, 63%
of our patients received either further induction or Acknowledgments
augmentation and this might have increased the number
of successful vaginal delivery on one side, and reduced the The authors wish to thank Camilla De Gasperi, MD,
number of cesarean section for failed induction on the Maria Nobile De Santis, MD and Simona Vailati, MD for
other side. their precious help in collecting the data forms.
Nulliparous with an unfavorable cervix treated with gel
had an increased rate of post partum blood loss 500 ml
when compared to insert treated women. Even though References
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