doi:10.1111/jog.12910 J. Obstet. Gynaecol. Res. Vol. 42, No.

3: 246–251, March 2016

Vaginal misoprostol versus intravenous oxytocin for the

management of second-trimester pregnancies with
intrauterine fetal death: A randomized clinical trial

Zhila Abediasl1,2, Mahdi Sheikh1, Parichehr Pooransari3, Zahra Farahani1 and Farah Kalani2
1
Maternal, Fetal and Neonatal Research Center, Tehran University of Medical Sciences, 3Shohadaye Tajrish Hospital, Shahid Beheshti
University of Medical Sciences, Tehran, and 2Shariati Hospital, Hormozgan University of Medical Sciences, Bandar-Abbas, Iran

Abstract
Aim: The aim of this study was to compare vaginal misoprostol versus intravenous (i.v.) oxytocin in the manage-
ment of pregnancies with second-trimester intrauterine fetal death (IUFD).
Methods: This randomized clinical trial was conducted on 85 pregnant women with IUFD and unripe cervix
who were admitted for labor induction. Forty were randomly allocated to receive 200 mcg vaginal misoprostol
every 12 h, and 45 were randomly assigned to receive high-dose i.v. oxytocin (starting from 6 mU/min to reach
the maximum dose of 40 mU/min). This study is registered at www.irct.ir (IRCT201307159568N5).
Results: The induction-to-delivery interval in the misoprostol group (10.5 ± 5.3 [range 4–27] h) was significantly
lower than that in the oxytocin group (14 ± 6.8 [range 4–30] h) (P = 0.009). The total hospital stay in the misoprostol
group (22.6 ± 9.5 [range 12–48] h) was significantly lower than that in the oxytocin group (35.3 ± 16.4 [range 12–72]
h) (P = 0.000). Although the successful induction rate was higher in the misoprostol group, this was not significant
(95% vs 86.7%, P = 0.1). Placenta retention occurred more in the oxytocin group (20% vs 5%, P = 0.03).
Conclusion: Both vaginal misoprostol and high-dose i.v. oxytocin are highly effective in labor induction in
second-trimester pregnancies with IUFD and an unripe cervix. However, vaginal misoprostol seems to be supe-
rior to i.v. oxytocin.
Key words: demise, fetus, induction, intrauterine fetal death, labor.

Introduction which is increasingly being used because of its efficacy

Intrauterine fetal death (IUFD) is the death of a product
of human conception before the complete expulsion or
extraction from its mother.1 IUFD is a stressful situation
for the mother, her family and for health-care providers
and it occurs in 1% of pregnancies.2 The management
of IUFD remains challenging. There are two options in
caring for these patients: (i) waiting for the onset of labor
(as most women will spontaneously labor within 3
weeks of IUFD; however, the development of dissemi-
nated intravascular coagulation, severe hemorrhage
and maternal death remains a serious concern with
expectant management); and (ii) induction of labor,
and safety.2,3
Oxytocin is one of the oldest and most common induc-
tion and cervical-ripening agents used worldwide, espe-
cially prior to the introduction of prostaglandins.4
Before 24 weeks of gestation, the uterus is less responsive
to the usual infusion concentrations of oxytocin, however
the American College of Obstetricians and Gynecologists
(ACOG) has suggested that high-dose oxytocin infusion
is comparable to other methods and is an acceptable
choice.5 Misoprostol is a synthetic prostaglandin-E1 ana-
logue that has been used effectively for labor induction in
the second trimester of pregnancy.6 Although misopros-
tol is still not approved by the US Food and Drug

Received: June 21 2015.

Accepted: October 21 2015.
Reprint request to: Dr Mahdi Sheikh, Maternal, Fetal and Neonatal Research Center, Vali-asr Teaching Hospital, Imam Khomeini Hospital
Complexes, Keshavarz Blvd, Tehran, 1419733141, Iran. Email: mahdisheikh@gmail.com

246 © 2015 Japan Society of Obstetrics and Gynecology


Administration (FDA) for this indication, the World
Health Organization (WHO) and a Cochrane review sug-
gest that vaginal misoprostol is an effective treatment for
termination of non-viable pregnancies before 24 weeks.7,8
Despite many studies that have assessed and com-
pared the efficacy, side-effects and doses of misoprostol
and oxytocin in the induction of labor in pregnancies
with live fetuses during the second and third gestational
trimesters, studies regarding the use of misoprostol and
oxytocin in the induction of labor in pregnancies with
early IUFD are limited.2,3,7–9 The dose, route and use of
induction agents in women with IUFD are different from
those with live fetuses; there is a possibility of dissemi-
nated intravascular coagulation complicating IUFD and
jeopardizing the woman’s life.3 However, the success
rate is higher and the abortion time is shorter in dead-
fetus pregnancies compared to live-fetus pregnancies.10
Two Cochrane Reviews, the WHO, and FIGO have
recognized the limitations and paucity of randomized
clinical trials regarding the proper management of IUFD
and have indicated that future research efforts should be
directed towards determining the optimal route, dose
and frequency of administration of prostaglandins in
the management of IUFD.2,3,7–9 In addition, the optimal
intravenous (i.v.) oxytocin concentration and dosing reg-
imens in the management of second-trimester IUFD are
yet to be defined.11 We therefore conducted this study
to compare the success rate, efficacy and side-effects of
vaginal misoprostol versus i.v. oxytocin in labor induc-
tion in women with early IUFD.
Methods
Study population and study design
This randomized, open-label trial was conducted on 85
pregnant women with confirmed IUFD who were ad-
mitted for labor induction at Shariati Hospital, Bandar
Abbas, Iran, from January 2013 through January 2014.
The inclusion criteria were: pregnant women with
documented IUFD, a gestational age of 15–24 weeks,
and a Bishop score < 4. Exclusion criteria were: multiple
pregnancies, any contraindication for induction of
labor (including maternal cardiac disease, clinical
chorioamnionitis, placenta previa, vasa previa, cord pro-
lapse, invasive carcinoma of the cervix and previous
myomectomy), having a history of two or more cesarean
sections, and a Bishop score ≥ 4.
After explaining the whole procedure, informed writ-
ten consent was obtained from the participants. The
women were then randomly allocated to one of two
© 2015 Japan Society of Obstetrics and Gynecology
Misoprostol vs oxytocin in IUFD
groups: the vaginal misoprostol group or the i.v. oxyto-
cin group (Fig. 1).
A computerized random-number generator was used
for sequence generation, which was carried out by M.S.
Simple randomization was used in this study. We used
consecutive opaque envelopes for the concealment of al-
location, which was performed by F.K. The envelopes
were opaque when held to the light, and opened sequen-
tially and only after the participant’s name and other de-
tails had been written on the appropriate envelope. The
implementation of assignments was carried out by Z.A.
The primary outcome of our study was the time of
induction-to-delivery interval. Secondary outcomes were
the success rate, duration of admission, post-partum
hemorrhage and complications of labor induction.
Due to the setting of our center, the direct measure-
ment of blood loss during labor was not possible, there-
fore post-partum hemorrhage was diagnosed primarily
through visual and clinical estimation when blood loss
resulted in dizziness, palpitation and tachycardia in the
patient. However, because this definition is not accurate,
only those patients who had a confirmed postsurgical
decline of 10% or more in the baseline hematocrit level
were defined as having post-partum hemorrhage.
This study was approved by the research deputy and
the ethics committee of Hormozgan University of Medi-
cal Sciences (Reference ID: 88–84-32). This study is regis-
tered at the Iranian Registry of Clinical Trials (www.irct.
ir), which is a Primary Registry in the WHO Registry
Network (Registration Number: IRCT201307159568N5).
Protocol
In the randomly assigned vaginal misoprostol group, the
dose and route of misoprostol administration were cho-
sen based on the WHO recommendations in the Repro-
ductive Health Library commentary.9 The starting dose
was 200-mcg misoprostol vaginal tablets. The tablet was
wet with a drop of water for injection and inserted into
the posterior fornix of the vagina using a speculum and
a spatula. After 12 h, if the conception products were
not expelled and the effective uterine contractions
(>3 contractions/10 min) were not established, another
dose of 200-mcg misoprostol vaginal tablets was inserted,
reaching a maximal total dose of 400 mcg. If labor was not
established within 24 h of induction, this was regarded as
failed induction. In case of induction failure in this group,
high-dose i.v. oxytocin was used as the second-line treat-
ment and if no response was obtained after 6 h, the patient
was considered a candidate for hysterotomy.
In the randomly assigned i.v. oxytocin treatment
group, based on the ACOG recommendations,
247
Z. Abediasl et al.
high-dose i.v. oxytocin was used.5 The oxytocin infusion
was given in 500 cm3 of 5% dextrose with the starting
oxytocin dose of 6 mU/min. If no effective uterine con-
tractions were noted, the dose was increased at a rate
of 6 mU/min at 45-min intervals to reach a maximal
dose of 40 mU/min. If labor was not established within
24 h of induction, this was regarded as failed induction.
In case of induction failure in this group, 200 mcg
misoprostol was inserted vaginally as the second-line
treatment and if no response was obtained after 6 h, the
patient was considered a candidate for hysterotomy.
In both groups, in case of incomplete expulsion of the
placenta or significant vaginal bleeding in the third stage
of labor, uterine curettage was performed.
Statistical analysis
The sample size was calculated for a power of 80%,
α = 0.05, β = 20%, and a standard effect size of 0.84. All
the statistical analyses were performed using SPSS ver-
sion 18. Data were displayed using mean, standard devi-
ation (SD) and range. Mean comparisons between the
248
Figure 1 Flow chart of the study
showing randomization of patients.
two groups were performed using the t-test for indepen-
dent samples. Furthermore, Χ2 analysis, Fisher’s exact
test, the independent-samples T-test, and one-way
analysis of variance were used to examine the relation
between maternal drugs and demographic factors in
the two groups. The level of statistical significance was
set at P-value < 0.05.
Results
Descriptive statistics
This study was conducted on 85 pregnant women with
IUFD between the gestational ages of 15 and 24 weeks.
One hundred pregnant women agreed to participate in
the study, 15 of whom were excluded due to having
one or more of the exclusion criteria; 40 women were
randomly assigned to receive vaginal misoprostol and
45 were randomly assigned to receive i.v. oxytocin for
the induction of labor.
The mean ± SD for maternal age was 26.4 ± 5.1 years; ges-
tational age was 18.9 ± 2.2 weeks; duration from cessation of
© 2015 Japan Society of Obstetrics and Gynecology
 Misoprostol vs oxytocin in IUFD

fetal movements till induction was 5.8 ± 4.5 days;

induction-to-delivery time was 12.4 ± 6.5 h (range 4–30 h);
and the duration of total hospital stay was 29.3 ± 14.9 h
(range 12–72 h). Induction failure occurred in eight
(9.4%) women; 51 women (60%) had a gestational age
< 20 weeks; 41 (48.2%) were nulliparous; eight (9.4%)
had a history of one previous cesarean section;
52 (61.1%) had a Bishop score ≥ 2; 11 (12.9%) required
curettage due to retained placenta; and three (3.5%)
experienced post-partum hemorrhage. Hypotension,
uterine rupture, chorioamnionitis, hydric intoxication,
and fever/shivering were not observed in any of
the participants.
There were no statistically significant differences be-
tween the women who received vaginal misoprostol
and those who received i.v. oxytocin for labor induction
(Table 1).

Effect of treatment allocation on main study

outcomes
The mean ± SD for the duration of induction-to-delivery
interval in the vaginal misoprostol group was 10.5 ±
5.3 h (range 4–27 h). This was significantly lower than
the duration of induction-to-delivery interval in the i.v.
oxytocin group, which was 14 ± 6.8 h (range 4–30 h)
(Fig. 2). The duration of hospital stay in the vaginal miso-
prostol group was 22.6 ± 9.5 h (range 12–48 h). This was
significantly lower than the duration of hospital stay in
the i.v. oxytocin group, which was 35.3 ± 16.4 h (range
12–72 h). The successful induction rate was higher in
the vaginal misoprostol group compared to the i.v.
oxytocin group; however, this was not statistically signif-
icant (95% vs 86.7%, P = 0.1) (Table 2).
Effect of treatment allocation on complications of
labor induction
Retention of the placenta occurred significantly more in
the oxytocin group compared to the misoprostol group
Figure 2 Kaplan–Meier curve comparing the induction-to-
delivery interval between the groups treated with vagi-
nal misoprostol (thick line) and i.v. oxytocin (thin line).
(20% vs 5%, P = 0.03). Also, post-partum hemorrhage oc-
curred more in the oxytocin group compared to the mi-
soprostol group; however, this was not statistically
significant (4.4% vs 2.5%, P = 0.6). No other complica-
tions occurred in either of the groups (Table 2).
Discussion
Oxytocin is a neurohypophysial hormone produced by
the hypothalamus and secreted by the posterior pitui-
tary gland.12 Diluted oxytocin for i.v. use was first sug-
gested in 1943 for the induction of labor by Page et al.
and it soon gained great attention in obstetrics.13 Oxyto-
cin was synthesized in 1954 to be the first synthesized
polypeptide hormone.14 Oxytocin has since been widely

Table 1 Participant demographics in the vaginal misoprostol and intravenous oxytocin groups
Demographics Vaginal misoprostol Intravenous P-value
n = 40 oxytocin n = 45
Maternal age (years) (mean ± SD) 27.3 ± 4.2 26.1 ± 3.4 0.7 (NS)
Gestational age (weeks) (mean ± SD) 18.5 ± 2.2 19.3 ± 2.2 0.18 (NS)
Duration from cessation of fetal movements till induction 5.2 ± 4.3 6.4 ± 4.7 0.19 (NS)
(days) (mean ± SD)
Gestational age < 20 weeks [number (%)] 28 (70%) 23 (51.1%) 0.08 (NS)
Bishop score ≥ 2 [number (%)] 26 (65%) 26 (57.7%) 0.32 (NS)
Nulliparity [number (%)] 19 (47.5%) 22 (48.8%) 1 (NS)
History of one CS [number (%)] 3 (7.5%) 5 (11.1%) 0.5 (NS)
CS, cesarean section; NS, non-significant; SD, standard deviation.

© 2015 Japan Society of Obstetrics and Gynecology 249

Z. Abediasl et al.
Table 2 Comparison of main outcomes and complications between the two treatment groups
Outcome
Induction-to-delivery interval (h) (mean ± SD)
Total hospital stay (h) (mean ± SD)
Successful induction rate [number (%)]
Placenta retention requiring curettage [number (%)]
Post-partum hemorrhage [number (%)]
*Statistically significant. NS, non-significant; SD, standard deviation.
used and is approved by the FDA and recommended by
the ACOG for labor induction.4,5 However, before 24
gestational weeks, the uterus is relatively unresponsive
to the usual doses of oxytocin. This could be due to the
low numbers of oxytocin receptors, which begin to ap-
pear at 13 weeks of gestation and increase throughout
pregnancy to reach the maximum levels at term.12,15
In our study, in the pregnancies with second-trimester
IUFD and unripe cervix, the induction of labor with
high-dose i.v. oxytocin was an effective method with
a high (86.7%) successful induction rate and an
induction-to-delivery interval of 14 ± 6.8 h with no po-
tentially fatal complications, such as uterine rupture, hy-
persensitivity reactions, sever hypotension, or water
intoxication. In the study by Yapar et al., 36 women
(55.5% with IUFD) received high-dose i.v. oxytocin for
second-trimester pregnancy termination. This was asso-
ciated with a 97.3% success rate and induction-
to-delivery interval of 12.2 ± 14.4 h, with one case of
uterine rupture and maternal death.15 Two other studies
that were conducted on pregnant women with IUFD
and unfavorable cervix at ≥18 gestational weeks also
reported a success rate of more than 96% in the i.v. oxy-
tocin group; however, the induction-to-delivery intervals
were much higher than those in our study. No fatal com-
plications were observed in these studies.16,17 The lower
successful induction rate in our study could be due to the
differences in the definition of successful induction and
in the gestational ages of the participants; in our study,
we defined successful induction as delivery within a
24-h period while in the other studies, a 48-h period
was used.15–17 Also, the longer induction-to-delivery
times observed in the studies by Nakintu16 and Bugalho
et al.17 seem to be due to the use of low-dose i.v. oxytocin
in their studies, while in our study and in the study by
Yapar et al.,15 high-dose oxytocin was used.
Misoprostol is a synthetic prostaglandin E1 analogue
that has mucosal protective properties. It was originally de-
veloped in the 1970s for the prevention of peptic ulcers.18
Since the early 1990s, misoprostol has been widely used
in obstetrics. The WHO in its Reproductive Health Library
250
Vaginal misoprostol n = 40 Intravenous oxytocin n = 45 P-value
10.5 ± 5.3 (range 4–27) 14 ± 6.8 (range 4–30) 0.009*
22.6 ± 9.5 (range 12–48) 35.3 ± 16.4 (range 12–72) 0.000*
38 (95%) 39 (86.7%) 0.1 (NS)
2 (5%) 9 (20%) 0.03*
1 (2.5%) 2 (4.4%) 0.6 (NS)
commentary recommended the use of 200 mcg vaginal mi-
soprostol every 12 h for labor induction and indicated that
misoprostol is an effective and safe alternative to surgical
evacuation in the management of second-trimester IUFD.9
In the current study, in the pregnancies with second-
trimester IUFD and an unripe cervix, the induction of la-
bor with 200 mcg vaginal misoprostol every 12 h was an
effective method with a high (95%) successful induction
rate and an induction-to-delivery interval of 10.5 ± 5.3 h.
The complications of induction were rare in this group
(<5%) and potentially fatal complications, such as uter-
ine rupture, hypersensitivity reactions, and hypotension,
were not observed. In the study by Yapar et al., 49 preg-
nant women (46% with IUFD) received 200-mcg vaginal
misoprostol for second-trimester pregnancy termination.
This was associated with a 77.5% success rate and an
induction-to-delivery interval of 24 ± 22.2 h with no fatal
complications.15 In the above-mentioned study, more
than half of the pregnant women who received miso-
prostol had live-fetus pregnancies and, as indicated by
other studies, labor induction with misoprostol is associ-
ated with a less successful induction rate and a longer
induction-to-delivery interval in live-fetus pregnancies
compared to dead-fetus pregnancies.10 In three other
studies that included pregnant women with IUFD at
≥18 gestational weeks, two used high doses of vaginal
misoprostol (maximum dose of 750–800 mcg) and one
used low doses of vaginal misoprostol (maximum dose
of 400 mcg).16,17,19 There was a 100% successful induc-
tion rate with both misoprostol doses with a median
induction-to-delivery interval of 14–15 h in the high-
dose treatment and 12.6 h in the low-dose treatment,
while the induction complications were rare (less than
5%) with no fatal complications.16,17,19
In the current study, although both induction agents
were highly effective, vaginal misoprostol was superior
to high-dose i.v. oxytocin in the labor induction of
second-trimester IUFD with an unripe cervix. Induction
with vaginal misoprostol was associated with a shorter
induction-to-delivery interval, a shorter duration of hos-
pital stay and a lower complication rate. These results
© 2015 Japan Society of Obstetrics and Gynecology

were in accordance with other studies conducted on
pregnant women with IUFD at ≥18 gestational weeks
in Uganda and Norway.16,17 However, our results were
different from the study by Yapar et al., which showed
that high-dose i.v. oxytocin was more effective than vag-
inal misoprostol in the termination of second-trimester
pregnancies.15 This might be due to the inclusion of
live-fetus pregnancies in their study.
Although 200 mcg vaginal misoprostol every 12 h
and high-dose i.v. oxytocin (starting from 6 mU/min
and incrementally increased to reach a maximum dose
of 40 mU/min) are both highly effective in labor induc-
tion in second-trimester pregnancies with IUFD and an
unripe cervix, vaginal misoprostol seems to be superior
to i.v. oxytocin because it is associated with a shorter
induction-to-delivery interval, a shorter duration of to-
tal hospital stay and lower complication rates. In our
study, these doses of vaginal misoprostol and i.v. oxyto-
cin were safe and were not associated with developing
potentially life-threatening conditions. However, the
sample size was too small to reach a conclusion regard-
ing drug safety, as grave complications caused by these
drugs are rare; therefore, more studies with larger num-
bers of patients are required to confirm these results and
to evaluate the safety of these drugs.
Acknowledgments
This research was funded by the Maternal, Fetal and
Neonatal Research Center, Tehran University of Medical
Sciences and Hormozgan University of Medical Sciences.
Disclosure
The authors declare that they have no conflicts of
interest.
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