ISSN
1916-694X

2010;
Volume 1 (Number 1): Pages 9-14

ORIGINAL
RESEARCH

Unintentional
uterine hyperactivity and perinatal outcomes following labor induction with
intravaginal administration of sustained-release dinoprostone insert

Hyun PARKa, Jung Yeol HANb,*
Hyun Kyong AHNb, June Seek CHOIb,   Sung Il CHOc, E. Yadira VELÁZQUEZ-ARMENTAd,
Alejandro A. NAVA-OCAMPOd,e

aDepartment of Obstetrics and Gynecology, Kangnam
Cha Hospital, College of Medicine, Pochon Cha University, Seoul, Korea; bThe
Korean Motherisk Program, Division of Maternal Fetal Medicine, Department of
Obstetrics and Gynecology, Cheil Hospital & Women’s Healthcare Center,
Kwandong University, College of Medicine, Seoul, Korea; cSchool of
Public Health, Seoul National University, Seoul, Korea; dPharmaReasons,
Toronto, Canada; eDepartment of Pharmacology & Toxicology,
Faculty of Medicine, University of Toronto, Toronto, Canada

*Corresponding author:
[email-masked]

ABSTRACT

Objective: To evaluate the
perinatal outcomes of pregnant women who underwent labor induction with
intravaginal administration of controlled-release dinoprostone who
involuntarily progressed to uterine hyperstimulation. Methods: In a retrospective cohort study design, the perinatal
outcomes of 388 pregnant women who received intravaginal administration of
controlled-release dinoprostone for cervix ripening at a community hospital
were analyzed. Uterine hyperactivity was considered as present if the
cardio-tocogram registered more than 5 uterine contractions within 10 minutes
at any time post-induction. Women were grouped according to the presence or
absence of uterine hyperactivity. Results:
26.3% (n= 102) developed uterine hyperactivity and 73.7% (n= 286) did not. In
the former group, the incidence of vaginal deliveries within 12 hours
post-induction and cesarean sections was marginally higher than among women who
did not progress to uterine hyperactivity. However, the indications of cesarean
sections were not different between both groups. The incidence of postpartum
hemorrhage and of babies admitted to the neonatal intensive care unit was
similar between groups (P >0.05). Conclusions:
Uterine hyperactivity induced by intravaginal administration of
controlled-release dinoprostone may increase the rate of cesarean sections
without increasing the frequency of neonatal adverse outcomes.

Key words

Cervical ripening; Labor induction; Uterine
hyperactivity

RÉSUMÉ

Objectif: Évaluation des effets périnataux de
l’administration intra-vaginale de dinoprostone à libération contrôlée pour
l’induction du travail ayant par ailleurs entraîné une hyperstimulation
utérine.  Méthodes: Cette étude rétrospective a
été effectuée sur 388 femmes ayant reçu une administration intra-vaginale de
dinoprostone à libération contrôlée pour accélérer la maturation du col utérin
au cours du troisième trimestre de la grossesse dans un hôpital de ville. Une
hyperstimulation utérine a été considérée présente lorsque la cardiotocographie
avait enregistré plus de 5 contractions utérines par 10 minutes à tout moment
après l’induction du travail. Les femmes ont été groupées d’après la survenue
ou non d’une hyperstimulation utérine. Résultats:
26,3% (n= 102) des femmes ont présenté une hyperstimulation utérine et 73,7%
(n= 286) n’en ont pas présenté. Dans le premier groupe l’incidence des
naissances par voie vaginales durant les premières 12 heures après l’induction
du travail et des césariennes était marginalement plus élevée que dans le
groupe qui n’avait pas présenté d’hyperstimulation utérine. Les indications des
césariennes n’étaient cependant pas différentes entre les deux groupes.
L’incidence des hémorragies du postpartum et des nouveau-nés adressés à l’unité
de soins intensifs néonataux était similaire (P >0,05). Conclusions: Une hyperstimulation utérine faisant suite à
l’administration intra-vaginale de dinoprostone à libération contrôlée est
susceptible d’augmenter la fréquence des césariennes sans par ailleurs
accroître l’incidence des effets défavorables chez les nouveau-nés.

Mots clés

Maturation du col
utérin; Induction du travail; Hyperstimulation utérin

RESUMEN

Objetivo: Evaluar los resultados perinatales de las
mujeres embarazadas que recibieron dinoprostona de liberación controlada para
inducción del parto y que involuntariamente progresaron a hiperestimulación
uterina. Métodos: En una cohorte
retrospectiva, el estudio analizó los resultados perinatales de 388 mujeres
embarazadas que recibieron dinorpostona de liberación controlada por vía
intravaginal para inducir la apertura del cérvix, en un hospital comunitario.
Se consideró la presencia de hiperactividad uterina si el cardio-tocograma
mostraba, en cualquier momento posterior a la inducción del parto, más de 5
contracciones uterinas en 10 minutos. El análisis de los resultados consideró
dos grupos de mujeres: las que tuvieron hiperestimulación uterina y los de las
que no la presentaron. Resultados:
26.3% (n= 102) desarrollaron hiperactividad uterina y 73.7% (n= 286) no la
presentaron. En el primer grupo, la incidencia de partos vaginales dentro de
las primeras 12 horas post-inducción así como de cesáreas debido a intolerancia
fetal incrementaron marginalmente en comparación al segundo grupo. Sin embargo,
las indicaciones de cesárea fueron similares. La incidencia de hemorragia
postparto y la frecuencia de bebés que requirieron cuidados intensivos también
fueron semejantes (P >0.05). Conclusiones:
La hiperactividad uterina secundaria a la administración de dinoprostona de
liberación controlada puede incrementar el número de cesáreas sin incrementar
la frequencia de efectos neonatales adversos.

Palabras clave

Apertura
cervical; Inducción del parto; Hiperestimulación uterina

INTRODUCTION

Intravaginal administration of prostaglandin E2 (PGE2) is a
standard method of labor induction, and different formulations containing PGE2
have been developed [1]. Dinoprostone administered as a controlled-release
formulation of 5 mg is released over a period of 12 hours at a slow and
constant rate [2]. Uterine hyperactivity, however, may appear after the
vaginal administration of dinoprostone, potentially increasing the rate of
adverse perinatal outcomes. Slow-release dinoprostone has been in Korea for
several years and has been administered to a large number of women even in
non-specialized centers. However, the incidence of adverse maternal and fetal
outcomes is yet unknown. We therefore designed the present study in order to
estimate the incidence of adverse perinatal outcomes in women who underwent
labor induction with dinoprostone.

METHODS

Patients

With previous approval by the Institutional Research Board,
the study was performed at a community hospital, Cheil Hospital & Women’s
Healthcare Center, Seoul, Korea. In a retrospective cohort study design, the
clinical records of women who delivered over a period of 1 year were reviewed.

Selection criteria

The inclusion and exclusion criteria were similar to those
previously reported elsewhere [3]: patients admitted to the labor room for dinoprostone
induction with a singleton, cephalic fetus of at least 36 weeks gestation with
an initial Bishop score less than 6. The files of 388 women who were physically
examined on admission to the labor room and underwent continuous fetal
monitoring by cardiotocography until delivery contained sufficient information
satisfying the inclusion criteria. There were no cases of women induced with
dinoprotone who had a greater than 2 cm cervix dilation, a history of prior
cesarean delivery or hysterotomy, ruptured membranes, intrauterine growth
restriction, known fetal anomalies, evidence of chorioamnioitis, placenta
previa, suspected abruption, or a non-reassuring fetal heart pattern.
Therefore, no cases were excluded from the study.

Procedures

Slow-release dinoprostone was only intravaginally
administered if there was a cervical dilatation up to 2 cm, the baby was in
cephalic position and vertex was well applied to the cervix, and a stable fetal
hear and regular fetal movements registered respectively by means of a
tocograph and abdominal palpation were ascertained for at least 30 minutes
before drug administration. The vaginal insert of dinoprostone released the
drug at a rate of 0.3 mg h-1 over a period of 12 hours and could be
retrieved at any time. Uterine hyperactivity was diagnosed when there was a
tachysystole (more than five contractions per ten minute period) [4]. If uterine hyperactivity occurred, the slow-release
tablet was removed within the next 30 minutes. A similar action was performed
if regular uterine contractions, membrane rupture, fetal tachysystole, maternal
systemic adverse effects or no reassuring fetal heart rate pattern was
developed during labor induction. All cases of uterine hyperactivity were
included in the data analysis of pregnancy outcomes, regardless of whether the
slow-release tablet of dinoprostone was removed. In some cases, oxytocin was
co-administered for labor augmentation after 1 hour of removal of the vaginal
slow-release tablet of dinoprostone. However, if labor was not successfully
induced or the cervix was still unfavorable after the first day of a single
administration of dinoprostone alone or in combination with oxytocin, women
underwent either a new course of induction with dinoprostone or cesarean
section, as judged by the treating obstetrician.

Statistical analysis

Maternal age, gestational age, and fetal weigh were compared
between groups by a Student t test, the number of previous pregnancies by a
Mann-Whitney test, and categorical variables (number of NICU admission and of
cases receiving blood volume replacement) by means of either a Chi-square test
or the Fisher’s exact test. The statistical analyses were performed by means of
SPSS v. 10.0.7 (SPSS Inc., Chicago, ILL, USA), and the significant level was
set at a two-tailed P <0.05.

RESULTS

Labor induction with intravaginal administration of
slow-release tablets of dinoprostone was mainly indicated in women with
oligohydramnios followed by women with a prolonged pregnancy (Table
1). The maximum number of doses of dinoprostone given to the women
in the study was three. Of 388 women, 261 (67.3%) delivered vaginally. There
were 26.3% (102/388) of women who developed uterine hyperactivity. Of them, 61
delivered vaginally within the next 12 hours of starting labor induction and 41
underwent cesarean delivery. Within 30 minutes after detection of uterine
tachysystole, the insert was removed and most of tachysystole subsided to
normal or no activity except in 2/102. The incidence of vaginal deliveries
within 12 hours post-induction and cesarean sections was marginally higher In
the group with uterine hyperactivity (P =0.06). However, the indications of
cesarean section did not differ between both groups. In addition, the incidence
of postpartum hemorrhage and of babies admitted to the neonatal intensive care
unit was similar between groups (P >0.05) (Table
2).

Table 1

Obstetric
characteristics of women who used controlled-release PGE2 vaginal insert for
pregnancy induction

Uterine
hyperactivity

Positive

(n=
102)

Negative

(n=
286)

P
value

Maternal
age (mean ± SD)

31.0
± 3.3

30.6
± 3.1

0.33

Gravida
[median (ranges)]

1
(1-4)

1
(1-5)

0.23

Gestational
age (mean ± SD)

39.8
± 1.2

40.0
± 1.1

0.14

Indication
of labor induction: [n (%)]

Oligohydrmanios*

46
(55.1)

116
(40.6)

0.43

Prolonged
pregnancy**

34
(33.3)

115
(40.2)

0.22

Others***

22
(21.6)

55
(19.2)

0.61

Fetal
weight (g) (mean ± SD)

3,330
± 512

3,340
± 451

0.83

*Amniotic
fluid index <5 cm; **Gestational age ≥ 41 weeks; ***Maternal
hypertension, intrauterine growth retardation,

large for gestational age, or
polyhydroamnios.

Table 2

Perinatal outcomes according to
uterine hyperactivity

Uterine
hyperactivity

Positive

(n=
102)

Negative

(n=
286)

P
value

Vaginal
delivery ≤12 h post-treatment

25
(41.0)

57
(29.5)

0.06

Cesarean
sections

41
(40.2)

86
(30.1)

0.06

Labor
failing to progress

30
(73.2)

73
(84.9)

0.54

Fetal
distress

11
(26.8)

13
(15.1)

0.10

NICU
admissions

1
(1.0)

12
(4.2)

0.19

Patients
who required blood transfusion or colloid infusion

2
(2.0)

2
(0.7)

0.28

NICU: neonatal intensive care unit. Data are
n (%)

DISCUSSION

Prostaglandin E2 is used on a large scale for cervical ripening
and labor induction. However, its administration has been associated with an
increased rate of adverse maternal and fetal events [5] [6]. The administration of PGE2 may result in uterine
hyperactivity and insufficient uteroplacental oxygenation, resulting in fetal
distress [7]. In addition, prostaglandins cross the placenta and
may stimulate the fetal ileum, favoring the passage of meconium [8]. In the present study, one fourth of the women who
underwent uterine stimulation with dinoprostone had uterine hyperactivity.
However, we did not observe any increased risk of adverse maternal or fetal
events.

Sustained-release preparations are designed to produce
relatively slow and uniform absorption of the drug for 8 hours or longer. The
advantage of such preparations are seen in the reduction in frequency of dose
administration, maintenance of therapeutic effect overtime, and a decreased
incidence or intensity of undesired effects by elimination of high peaks in
drug concentration (Cmax) that often occur after administration of
immediate-release dosage forms [9].

Lower Cmax and longer times to reach it are
observed in the vaginal insert of sustained-release dinoprostone in comparison
with the regular formulation of immediate release [2] [10]. The estimated plasma half-life of PGE2 is very
short, less than 15 seconds [11]. These characteristics are expected to induce
cervical ripening with a lower rate of adverse effects. In our study, the high
incidence of uterine hyperactivity was not associated with an increased
incidence of adverse maternal and fetal outcomes. This was most likely due to
the fact that the insert was removed at an appropriate time which limited the
extent of uterine hyperstimulation.

In experimental animal models, the uteroplacental hypoxia
secondary to induced uterine hyperactivity is one of the most common causes of late
deceleration and other adverse fetal outcomes [12] [13]. The risks of uterine hyperstimulation and systemic
adverse effects are known to be related to the dose and plasma concentration of
PG [11] [14]. Furthermore, increasing uterine activity with an
unripe cervix or labor induction with poor preparation of labor is known to
increase the incidence of cesarean deliveries especially in nulliparas [15] [16].

In our study we used a stringent definition of uterine hyperstimulation
and included frequent mild contractions irrespective of pain. That may
partially explain the higher number of cases with uterine hyperactivity
observed in our study in comparison to the approximately 18% reported in
previous studies using a similar PGE2 vaginal insert [17]. In relation to pregnancy outcomes, although the
difference between groups was not statistically significant, there was a higher
rate of cesarean sections among women who progresses to uterine hyperactivity
in comparison to those who did not. This difference was probably secondary to
the higher rate of cases of fetal distress in the former group. Interestingly,
the proportion of babies referred to the NICU was low in spite of the elevated
number of fetuses with non-reassuring heart rates. It is possible that uterine
hyperactivity or fetal distress were overestimated, resulting in some cases of
unnecessary cesarean sections.

There were several limitations that deserve to be mentioned.
The criteria of digital examination for judging cervical ripening probably
exhibited large variations due to the shifts of staff and residents in the
labor ward during the study period. The protocol of labor induction was not
consistent in terms of dosage of dinoprostone. We were unable to objectively
judge the decision in taking a patient for cesarean section since it was
determined by the attending physician during or after the first attempt for
uterine stimulation. However, despite such limitations, our results were
consistent to other reports stating that slow-release dinoprostone has been
associated with a low rate of adverse prenatal outcomes.

In conclusion, our study suggests that intravaginal
administration of a slow-release tablet of dinoprostone is associated with a
high incidence of uterine hyperactivity that can be easily reverted by
extracting the vaginal insert. No increased risk of adverse perinatal maternal
and fetal outcomes was observed.

AUTHORS’ PARTICIPATION

JY H conceived the idea of the study, JY H & SI C
designed the study, H P retrieved the information, JS C analyzed data; all the
authors participated in the discussing the findings and drafting the
manuscript.

ACKNOWLEDGEMENTS

None to declare.

CONFLICT OF INTERESTS/DISCLAIMERS

JY H, EY V-A, & AA N-O are members of the Editorial Board
of the journal.

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