Contraception 89 (2014) 187 192

Original research article

Buccal misoprostol for treatment of fetal death at 1428 weeks of

pregnancy: a double-blind randomized controlled trial,
Hillary Bracken a,, Nguyen Thi Nhu Ngoc b , Erika Banks c , Paul D. Blumenthal d ,
Richard J. Derman e , Ashlesha Patel f , Marji Gold c , Beverly Winikoff a
Buccal misoprostol for IUFD Research Group
a
Gynuity Health Projects, New York, NY 10010, USA
Center for Research and Consultancy in Reproductive Health, 16D Luy Ban Bich. Tan thoi Hoa Tan Phu, Hochiminh City, Vietnam
c
Albert Einstein College of Medicine, Bronx, NY 10461, USA
d
Family Planning Services and Research, Stanford University, Stanford, CA 94305-5317, USA
e
Christiana Care Health System, Department of OB/GYN Research, Newark, DE 19718, USA
f
Department of Obstetrics and Gynecology, JH Stroger Jr. Hospital of Cook County, Chicago, IL 60622, USA
Received 26 July 2013; revised 6 November 2013; accepted 15 November 2013

Abstract
Objective: To assess whether buccal misoprostol is effective for the treatment of intrauterine fetal death.
Study Design: This double-blind randomized trial was conducted at five tertiary-level hospitals in the United States and Vietnam. One
hundred fifty-three women with an intrauterine fetal death at 1428 weeks of pregnancy received either 100 mcg buccal misoprostol or
200 mcg buccal misoprostol every 6 h for a maximum of 8 doses. The main outcome measure was the fetal-placental delivery rate within
48 hours of prostaglandin commencement without any additional intervention.
Results: Most of the women (140/153) were recruited at the study site in Vietnam. Expulsion of both fetus and placenta within 48 hours of
prostaglandin commencement without any additional interventions occurred in 61.8% (47/76) of women receiving misoprostol 100 mcg and
77.9% (60/77) of women receiving misoprostol 200 mcg. The 200 mcg dose was significantly more effective than the 100 mcg dose at
expelling the fetus and placenta within 48 h [RR 0.68 (95% CI: 0.500.92; p=.03)]. The mean time to expulsion was significantly shorter
using the 200 mcg dose (18.511.9 h) than the 100 mcg dose (23.912.5 h) (p=.02). Most women in both groups found the procedure
satisfactory or very satisfactory (100 mcg: 76.7% (56/73); 200 mcg: 89.5% (68/76) [RR 0.86 (95% CI: 0.741.00)].
Conclusion: Buccal misoprostol is an effective method for medical induction of labor after intrauterine fetal demise. A 200 mcg dose is
significantly more effective than 100 mcg for evacuating the uterus within 48h. The treatment is highly acceptable to women.
Implications: Administration of 200 mcg buccal misoprostol every six hours is an effective and acceptable method to effect the delivery of a
demised fetus at 1428 weeks that can be feasibly implemented in a wide variety of settings.
2014 Elsevier Inc. All rights reserved.
Keywords: Buccal misoprostol; Intrauterine fetal demise

1. Introduction

Conflicts of interest: The authors declare no conflicts of interest.

Clinical Trial Registration: The study is registered with Clinical
Trials.gov, NCT 00671060.
Corresponding author. Gynuity Health Projects, New York, NY
10010. Tel.: + 1 212 448 1230; fax: + 1 212 448 1260.
E-mail address: hbracken@gynuity.org (H. Bracken).

0010-7824/$ see front matter 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.contraception.2013.11.014

Globally, access to healthcare and differing methodologies for the classification of fetal demise contribute to wide
variation in rates of fetal death in utero [1]. Timely evacuation can both avoid emotional distress and reduce the
possibility of developing disseminated intravascular coagulapathy (DIC) [2,3]. Intrauterine fetal demise (IUFD) may be
managed surgically with dilatation and evacuation (D&E) or

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H. Bracken et al. / Contraception 89 (2014) 187192

labor induction with a variety of products including vaginal

placement of prostaglandin E2 vaginal suppositories,
misoprostol and/or oxytocin. Surgery is often expensive,
potentially dangerous in settings with limited resources or a
lack of trained providers, and is more difficult as the pregnancy becomes more advanced. Induction with misoprostol
is a safe and effective option particularly in low-resource
settings. Unlike other prostaglandins, misoprostol is stable
at room temperature and very inexpensive. A systematic
review found vaginal misoprostol as effective as, or more
effective than, other prostaglandin preparations (including
gemeprost [Cervagem], prostaglandin E2, and prostaglandin
F2 alpha) and oral misoprostol for induction of labor in the
second or third trimester for women following fetal death [4].
Pretreatment with mifepristone appears to significantly
reduce the time to expulsion and side effects when compared to misoprostol alone [57]. However, mifepristone is
expensive and not available in many settings so a safe,
effective misoprostol alone regimen is still a desirable
treatment option.
Studies of misoprostol alone for IUFD have examined
different modes of administration (oral, vaginal and sublingual). The use of buccal misoprostol for this indication is
less studied. Researchers have evaluated buccal routes for
labor induction [8,9] and induction of first and second trimester abortion either alone or after pre-treatment with
mifepristone [1012]. Pharmacokinetic studies show that the
buccal route results in a serum concentration curve similar in
shape to the curve associated with vaginal administration, the
most commonly used route for IUFD [13,14]. Buccal administration may also be more acceptable to women as it does
not necessitate frequent vaginal exams [13].
Our study documented the efficacy and side effect profile
of two regimens (100 mcg and 200 mcg) of buccal misoprostol. A 100 mcg tablet is the smallest dose commercially
available in many settings and eliminates the need to cut or
dissolve tablets in solution, which may result in inaccurate or
variable dosing.

2. Methods
This double-blind randomized trial was approved by the
institutional review boards of Montefiore Medical Center,
Stanford University, Stroger Hospital, Christiana Health
System, the Huong Vuong Hospital in Ho Chi Minh City,
Viet Nam and the Allendale Investigational Review Board,
an independent review board. Women who sought medical
care for possible fetal demise in pregnancies of between 14
and 28 weeks at the five hospitals from December 2008 to
December 2011 were screened. Confirmation of fetal demise
and final gestational age were determined by ultrasound.
Women were excluded if they had known allergies or other
contraindications to the use of misoprostol; placental
abruption with active hemorrhage, complete placenta previa,
extreme uterine structural anomalies, or other contradictions

to vaginal delivery of the fetus; presentation in active labor

(moderate to severe contractions every 10 minutes or less);
history of prior uterine incision; or four or more previous
deliveries. All subjects provided written informed consent.
At enrollment, a medical history and physical examination
were performed. Women were randomized to one of two study
groups. Both women and providers were blinded to the
treatment allocation. The groups were created by Gynuity
Health Projects using a simple randomization sequence
generated by computer with blocks of 10. Randomization
was stratified by study site. A research assistant prepared
numbered and sealed randomization packets before beginning
enrollment. Each packet contained eight individually labeled
dose envelopes. Each woman was administered a randomization envelope containing two tablets (either Group 1: a 100
mcg misoprostol tablet with a placebo pill made to resemble
a 100 mcg tablet, or Group 2: two 100 mcg misoprostol tablets).
The woman was instructed to hold the tablets in her cheeks
for 20 minutes, after which she swallowed any remaining
medication. Study drug was administered at 6-hourly intervals,
for a maximum of 8 doses (either 800 or 1600 mcg depending
on treatment arm). A woman was not administered the next
dose if she was experiencing active labor. If at 48 hours the fetus
and placenta remained undelivered, the case was considered a
failure for purposes of the study, and the woman was treated
according to established practice at the facility including
surgical termination, expectant management or repeating the
induction. No prophylactic medications were used for
management of the gastrointestinal side effects of misoprostol.
Women remained in the hospital for the duration of
treatment. Patients were monitored for basic vital signs as
well as every two hours for pain, cervical dilation, uterine
contractility, and signs of possible complications. Pain
management was according to the standard practice at each
facility. No cervical osmotic dilators or laminaria were
administered prior to trial entry for cervical preparation.
Women who expelled the fetus within the study period were
provided with a single dose of 200 mcg buccal misoprostol
after expulsion of the fetus for placental management.
Patient acceptability was assessed in an exit interview
conducted prior to hospital discharge when the woman was
fully stable. Satisfaction with the procedure was measured
using a validated five-point Likert scale.
The primary outcome was the fetal-placental delivery rate
within 48 hours of misoprostol commencement without any
additional intervention. Rates of success were compared
across study arms. We anticipated that given the pharmacokinetic profile of buccal administration, results would be
similar to those found with vaginally administered misoprostol. A systematic review conducted by one of the study
authors gave us no reason to think that either of the two
treatment doses would be superior to the other [15]. Thus, we
designed the study as a separate, non-comparative efficacy
study. In order to have 80% power (alpha=.05) to demonstrate that each misoprostol regimen was 95%, 5%,
effective, we calculated that we would need to enroll 73

H. Bracken et al. / Contraception 89 (2014) 187192

women with second-trimester fetal death in each arm of the

study, or 146 women total. The sample size also provided
80% power (alpha=.05) to detect a significant difference
between treatments should the treatment arms differ in
effectiveness by a sizeable margin (i.e. 10%).
Results for the two treatment arms are presented separately. Differences between the two groups were compared
using the chi-square (or Fischers exact) and Students t-test
for categorical and continuous variables, respectively. All
analyses were performed using SPSS Version 19.0. Time to
expulsion was analyzed by survival methods, i.e. Kaplan
Meier and log rank test. The analysis was intent-to-treat.
According to the protocol, the data and safety monitoring
committee conducted one interim analysis when approximately two-thirds of the study sample (98 of 146 women)
had completed participation. The review committee was
blinded to the treatment assignments. Early termination of
the study was not recommended.

3. Results
153 women were enrolled: 76 were randomly assigned
to receive 100 mcg buccal misoprostol, and 77 to receive
200 mcg buccal misoprostol (Fig. 1). Most of the women
were recruited at the study site in Vietnam (140 of 153). One
woman assigned to the 100 mcg group was withdrawn after

189

the administration of 2 doses of misoprostol when she

developed preeclampsia. One woman assigned to the 200
mcg arm was determined to be ineligible after enrollment
due to a gestational age of 12 weeks. All women were
included in the final outcome analysis.
The average gestational age at time of demise was
approximately 18 weeks (Table 1). No significant difference
in maternal age, gestational age or parity between the two
groups was present at the time of randomization. In almost
all cases (100 mcg: 95.9% or 71/76; 200 mcg: 96.1% or
73/77) membranes were intact at the time of enrollment.
There was a significant difference between the two groups in
the number of women with recorded dilation at the time of
enrollment (100 mcg: 6.6% or 5/76; 200 mcg: 0; p=.02): Five
women in the 100 mcg study arm were dilated 11.5cm.
Expulsion of both fetus and placenta within 48 hours of
prostaglandin commencement without any additional interventions occurred in 61.8% (47/76) of women receiving
misoprostol 100 mcg and 77.9% (60/77) of women receiving
misoprostol 200 mcg (Table 2). Rates for both arms were
well below the hypothesized efficacy rate of 955%. The
difference between the two groups was statistically significantly different (RR: 0.68; 95% CI: 0.500.93; p=.03)
(Table 2). In one case where the fetus and placenta were
successfully expelled within the study period, tissue in the
cervix was removed by forceps three days after discharge
from the study. She was considered a treatment success.

Fig. 1. CONSORT Flow Diagram.

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H. Bracken et al. / Contraception 89 (2014) 187192

Table 1
Background characteristics (n, %)

Age (y)
Mean (SD)
Range
Primiparous
Gestational age at time of demise (weeks)
mean (SD) (range)
Fetal age at time of demise
1418 weeks
1923 weeks
2428 weeks
Presentation at time of enrollment
Chorioamnionitis at time of enrollment
Vaginal bleeding
Painful contractions
Cervix dilated* (n, %)
1 cm
1.5 cm
Membranes intact

100 mcg (n=76)

200 mcg (n=77)

p-value

25.6 (5.6)
1741
55 (72.4)

25.8 (5.9)
1647
60 (77.9)

.93
.43

18.4 (3.6) (14.1428.0)

17.5 (3.4)(12.7126.43)

.14

39 (51.3)
24 (31.6)
13 (17.1)

49 (63.6)
23 (29.9)
5 (6.5)

0
0
0
5 (6.6)
4
1
71 (95.9)

Most of the women (n=140) were recruited at the Vietnam

study site. We analyzed the results from the Vietnam site
separately in order to control for any inter-site differences.
Expulsion of both fetus and placenta within 48 hours of
prostaglandin commencement without any additional interventions occurred in 64.3% (45/70) of women receiving
misoprostol 100 mcg and 81.4% (57/70) of women receiving
misoprostol 200 mcg (Fischers exact p=.02).
Among women with successful complete delivery of both
fetus and placenta, delivery was achieved in a median of 20.8
hours (range: 5.6747.00) with the 100 mcg regimen and
14.4 hours (range: 0.8347.00) with the 200 mcg regimen
(Fig. 2). There was a significant difference in the percent
of women who delivered within 24 h in the two groups
(100 mcg: 39.5% (30/76); 200 mcg: 64.9% (50/77); RR:
0.60; 95% CI: 0.440.84; p=.002) (Table 2).
The rate of complete expulsion of the fetus alone also
differed significantly across groups [100 mcg: 65.8% (50/
76); 200 mcg: 84.4% (65/77); RR: 0.46; 95% CI: 0.25
0.83]. A few women who successfully expelled the fetus
then required interventions in addition to the single 200 mcg

0
0
0
0 (0)

.02

73 (96.1)

.97

dose to expel the placenta (100 mcg: 3 women; 200 mcg:

4 women) [RR: 0.75 (95% CI: 0.173.24) p=0.70].
Six women received treatment for bleeding or a suspected
pelvic infection. Two women in the 200 mcg arm and one
woman in the 100 mcg arm received oxytocin IV after
expulsion of the fetus when bleeding reached 100250 ml.
One woman in the 100 mcg arm and one woman in the 200
mcg arm received presumptive treatment with antibiotics for
a suspected infection. One woman in the 200 mcg arm had a
continued hospitalization after discharge from the study as a
failure of expulsion. As per the protocol, she then received
the hospitals standard of care for this indication including
laminaria, pitocin and additional misoprostol to induce
delivery. The woman delivered 96 hours after her discharge
from the study.
Rates of side effects in both study arms were low
(Table 3). There was no significant difference between the
two groups in vomiting, chills, headache, and pain. There
were significantly more women who experienced diarrhea
among those receiving 200 mcg misoprostol compared to
those who received 100 mcg (100 mcg: 10.7% or 8/76; 200

Table 2
Delivery interval characteristics (n, %)
100 mcg (n=76)

200 mcg (n= 77)

RR (95% CI)

Fetal and placental expulsion within 48 hours with study drug alone

47 (61.8)

60 (77.9)

Fetal and placental expulsion within 24 hours with study drug alone

30 (39.5)

50 (64.9)

0.68 (0.500.92)
p=.03
0.68 (0.440.84)
p=.002

Induction to delivery interval among women with successful procedure (hours)

Mean
Median
Range

23.9 (12.5) a
20.8
(5.6747.00)

18.5 (11.9) b
14.4
(0.8347.00)

In one case, tissue was removed with forceps three days after delivery.
a
n=47.
b
n= 60.

p=.02

H. Bracken et al. / Contraception 89 (2014) 187192

191

4. Discussion

Fig. 2. Time from misoprostol administration to delivery of fetus and placenta. Survival curve of the percentage of pregnancies that were undelivered
for each of the two study regimens. Log rank test p=.001.

mcg: 32.5% or 25/77; p=.001). In all cases, diarrhea was

either mild or moderate.
Analgesic usage was not significantly different between
the two groups. Narcotic analgesia was required in 2.6%
(or 2/76) of women in the 100 mcg group and 6.4% (or 5/77)
of women in the 200 mcg arm (p=0.25). No woman received
an epidural.
Almost all women in both study groups were satisfied or
very satisfied with the treatment (100 mcg: 76.7% or 56/73;
200 mcg: 89.5% or 68/76). Women in the lower dose arm
were more likely to find the procedure unsatisfactory or very
unsatisfactory (100 mcg: 21.9% or 16/73; 200 mcg: 7.8% or
6/77; RR: 1.61; 95% CI: 1.172.21; p=0.02). Most women
found the pain associated with the induction less than or
same as expected. While most women found the side effects
acceptable, significantly more women in the 100 mcg arm
found the side effects unacceptable or very unacceptable
(100 mcg: 16.0% or 12/75; 200 mcg: 3.9% or 3/77) (RR:
1.73; 95% CI: 1.272.36; p=.012). Women in the 100 mcg
arm were more likely to find the duration of treatment
unacceptable or very unacceptable (100 mcg: 17.1% or 12/
70; 200 mcg: 8.1% or 6/74; p=.09) and the length of the
hospitalization the worst aspect of the procedure (100 mcg:
18.9% or 14/74; 200 mcg: 7.8% or 6/77; p=.06).

Table 3
Side effects as reported by woman after completion of treatment (n, %)

Diarrhea
Nausea
Vomiting
Chills
Headache
Pain

100 mcg (n= 76)

200 mcg (n= 77)

p-value

8 (10.7)
14 (18.7)
7 (9.5)
19 (25.3)
13 (17.3)
68 (90.7)

25 (32.5)
18 (23.4)
12 (15.6)
16 (20.8)
17 (22.1)
72 (93.5)

.001
.56
.33
.57
.54
.56

Buccal misoprostol is an effective method for medical

induction of labor after intrauterine fetal demise. The use of
200 mcg of buccal misoprostol for the induction of labor
between 1428 weeks following intra-uterine fetal demise is
more effective than 100 mcg, with women experiencing
shorter induction to expulsion interval, and an increased
chance expelling the fetus and placenta within 48 h of the
start of the induction. Our result also is consistent with
findings from a systematic review that found that lower (800
mcg or less) cumulative doses of misoprostol were
associated with an increased chance of women not achieving
vaginal birth within 24 h when compared with moderate
doses (8002400 mcg) of misoprostol [4].
Our study found that womens satisfaction with the
induction method and ability to tolerate side effects was
likely related to the success and duration of the induction
process. This finding echoes other studies that found the
duration, rather than the route of drug administration, critical
in determining acceptability to women [4]. Differences in the
time to induction are thus highly clinically significant in this
study, and the higher dose regimen is clearly preferable.
The study has several limitations. Most of the women
were recruited at the Vietnam study site (140 of 153). The
results obtained in a single country, Vietnam, may not be
generalizable. Pain management expectations and availability may differ in different settings. This study was also not
powered to detect a difference in safety outcomes because
major adverse events (e.g., uterine rupture, blood transfusion, infection) are rare. Indeed, no studies of misoprostol for
this indication were powered to detect rates of rare
occurrence of major events. Similar to prior research, no
uterine ruptures occurred, and blood transfusion and/or
treatment for suspected infection was infrequent.
This study was designed as separate non-comparative
efficacy trials. We estimated that the effectiveness of buccal
misoprostol would be approximately 95% in both arms. The
effectiveness of buccal misoprostol was much lower than
anticipated, especially in the low dose arm (100 mcg: 61.8%;
200 mcg: 78.9%). Although not significantly different, due to
the limited sample size, the women's gestation in the 200 mcg
group was lower than in the 100 mcg group and may account
for some of the observed difference in effectiveness between
the two groups. Comparison of success rates across studies is
difficult given variations in dose, route of administration,
interval, study sample (i.e., some studies include both spontaneous intrauterine fetal demise and live fetuses or fetal
demise at different gestational ages), and the use of oxytocin
for augmentation. Still, the success rate in the 200 mcg of our
study (78.9%) is lower than rate of successful evacuation of
the fetus alone in previous studies of 200 mcg vaginal
misoprostol for this indication (98.1%) [15]. Dickinson et al.
found that evacuation of the placenta or placental fragments
in the operating room occurred in over one-third (37.8%) of
cases [15]. Our lower success rate may, in part, be a result of a

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H. Bracken et al. / Contraception 89 (2014) 187192

more conservative study outcome (complete delivery of fetus

and placenta) and a protocol that did not allow additional
interventions for delivery of the placenta. A second study by
the same authors comparing 3 dosages administered
vaginally at 6 hours also found a high rate of placental
retention in all three study arms (200 mcg:25%; 400 mcg:
42%; 600 mcg loading dose plus 200 mcg: 40.8%) [16,17]. If
we consider delivery of the fetus alone the success rate in our
study is slightly higher in both study arms (100 mcg: 65.8%;
200 mcg: 84.2%). A study comparing buccal versus vaginal
misoprostol for induction of second trimester abortion found
the two routes of administration equally effective [12].
Buccal misoprostol is an effective method for medical
induction of labor after intrauterine fetal demise. Induction of
labor to effect the delivery of a demised fetus at 1428 weeks
with 200 mcg buccal misoprostol given every six hours is an
effective and feasible approach that can be implemented in a
wide variety of settings.
Acknowledgments
This study was funded by a grant from the Office of
Orphan Products Development of the United States Food
and Drug Administration.
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