Original Research

Vaginal Misoprostol Compared With Buccal

Misoprostol for Termination of
Second-Trimester Pregnancy
A Randomized Controlled Trial
Ragip A. Al,

MD,

and Omer E. Yapca,

MD

OBJECTIVE: To compare the efficacy of vaginal misoprostol with buccal misoprostol for second-trimester
termination of pregnancies.
METHODS: In a randomized trial, we compared 400
micrograms vaginal and buccal misoprostol every 3 hours
for up to six doses for induction of labor at 1324 weeks
of gestation with a live fetus and intact membranes.
Women who had a uterine scar were excluded from
the study. The primary outcome of the study was
induction-to-abortion interval. Based on a two-tailed a
of 0.05, we planned to include 65 patients per group to
detect a 50% difference in the primary outcome with
a power of 80%.
RESULTS: From January 2014 to December 2014, 172
women were screened and 130 were randomized: 65
vaginal and 65 buccal misoprostol. Characteristics of
patients were similar between groups. Patients administered vaginal misoprostol compared with buccal misoprostol had a shorter induction-to-abortion interval
(25617 hours compared with 40629 hours, P5.001) and
a higher abortion rate within both 24 hours (41 [63%]
compared with 27 [42%] P5.014) and 48 hours (59
[91%] compared with 44 [68%], P5.001). Complete abortion rates were similar in both groups (vaginal 51 [78%]
compared with buccal 54 [83%]). The incidence of side
effects was similar for both groups. The perceived pain
was higher in the buccal group, but the small difference
did not appear to be clinically meaningful.
From the Department of Obstetrics and Gynecology, Atatrk University Faculty
of Medicine, Erzurum, Turkey.
Corresponding author: Ragip A. Al, MD, Cigdem Mah, 1561. Sokak, Segmen
sitesi A Blok No 7/25, 06530 Cankaya, Ankara, Turkey; e-mail: atakanal@
gmail.com.
Financial Disclosure
The authors did not report any potential conflicts of interest.
2015 by The American College of Obstetricians and Gynecologists. Published
by Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0029-7844/15

VOL. 126, NO. 3, SEPTEMBER 2015

CONCLUSION: Vaginal compared with buccal misoprostol administration has a shorter induction-toabortion interval for second-trimester termination of
viable pregnancies. However, both administration routes
are equally effective for induction of termination.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov,
www.clinicaltrials.gov, NCT02048098.
(Obstet Gynecol 2015;126:5938)
DOI: 10.1097/AOG.0000000000000946

LEVEL OF EVIDENCE: I

ermination of second-trimester pregnancy consists

of 1015% of induced abortions worldwide.1 Misoprostol is the drug of choice as a single agent for medical termination of second-trimester pregnancy because
of its high efficacy, low cost, and ease of use.2,3
The ideal dosing regimen of misoprostol is uncertain at present. It can be administered by vaginal,
sublingual, oral, or buccal routes for medical abortion.
Vaginal misoprostol is more effective than the oral
route in the second trimester.4,5 Sublingual misoprostol
has comparable effectiveness and safety with the vaginal route.2,6 In the only published study comparing
vaginal with buccal administration, the median times
from induction to abortion were similar for both
groups.7 Direct comparison of the two routes was limited, however, because both groups receiving an initial
dose of vaginal misoprostol. Successful outcomes were
reported with buccal misoprostol for first-trimester
abortion.8 It has a lower peak plasma concentration
than all other routes and produces a uterine response
similar to vaginal administration.9,10
The efficacy of misoprostol varies depending on
the cause of termination. It is more effective for
intrauterine fetal demise, with a shorter induction-todelivery interval, than when it is administered for
termination of ongoing pregnancy.5,11,12 Women with

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593

premature rupture of membranes (PROM) also constitute a different group, in whom the process of labor
has started before induction.
To this end, a randomized trial comparing buccal
misoprostol with vaginal misoprostol as a single agent
for the management of second-trimester abortion with
a live fetus and intact membranes was conducted.

MATERIALS AND METHODS

The study was an open-label, randomized clinical trial
carried out at Ataturk University Hospital between
January 2014 and December 2014. Approval was
obtained by the institutional review board of the
Ataturk University Faculty of Medicine before the
beginning of the study.
Women admitted to the hospital for secondtrimester medical abortion because of fetal abnormality or maternal medical complications were eligible
for inclusion if they had a live singleton fetus at 1324
weeks of gestation, no uterine contractions, and
a Bishop score less than 5. Women were excluded if
they had a history of prostaglandin allergy, a scar on
the uterus, a uterine abnormality, or PROM. Gestational age was determined either on the basis of certain menstrual date confirmed by ultrasonography or
by ultrasound dating if the menstrual dates were
uncertain or differed more than 7 days from ultrasonography. Premature rupture of membranes was diagnosed by history, physical examination, or placental
alpha microglobulin-1 biomarker test.
All eligible women admitted to the hospital
during the study period were invited to participate
in the study; those who gave informed consent were
consecutively enrolled. At enrollment, medical history, hemoglobin (Hb) level, and Rh-antigen status
were assessed and a physical examination including
Bishop scoring was performed. Cervical length was
measured by transvaginal ultrasonography. All participants then were randomly assigned to either
vaginal or buccal induction treatment. Randomization
was performed by means of a computerized random
number generator in single blocks. Group allocation
was predetermined by a physician who was not
involved in the study before patient enrollment and
placed in consecutively numbered and sealed opaque
envelopes. When a woman was recruited into the
study, she was given a sequential study number
according to the sequence of entry into the study.
The principal investigator was contacted and opened
the sealed envelope bearing the study number of the
participant for the purpose of treatment allocation.
Women were randomized to receive 400 micrograms buccal misoprostol or 400 micrograms vaginal

594

Al and Yapca

misoprostol every 3 hours for up to six doses until

delivery took place. Vaginal tablets were introduced
with moisture. Women in the buccal group were
instructed to place tablets between their teeth and
buccal wall and let them completely dissolve without
chewing or swallowing whole. The treatment was
withheld if the patient had strong uterine contractions.
If abortion had not occurred within 24 hours after the
beginning of the treatment, a second course of 400
micrograms misoprostol every 3 hours up to six doses
was administered by the initially assigned route. If
abortion had not occurred within 48 hours after the
beginning of the study, it was considered a treatment
failure, and the primary physician and the woman
were then given the option to choose from other
induction methods or to continue the protocol.
Investigators, nursing stuff, and resident physicians were involved in patient care. Inductions took
place in the obstetrics ward. Blood pressure, pulse
rate, temperature, and side effects were recorded
every 3 hours by the nursing stuff. Diclofenac sodium
(75 mg intramuscularly) and metoclopramide (10 mg
intramuscularly) were provided for pain and nausea
according to patient request.
We applied a standard treatment protocol for the
management of the third stage of labor. Once fetal
expulsion occurred, all participants received highdose oxytocin, 20 units in 1,000 mL of isotonic saline
at 100 mL per hour, until delivery of the placenta.
Spontaneous expulsion of the placenta was awaited up
to 2 hours after the delivery of the fetus. If the
placenta was delivered spontaneously, it was examined to check whether the abortion was complete. If
necessary, exploration and evacuation of the uterus
were performed. If the placenta was not expulsed
within 2 hours, it was removed with Winter placental
forceps and blunt curettage. Curettage is not performed routinely. Patients were discharged 24 hours
after abortion if there were no complications. At
discharge, Hb level was assessed.
The pain related to treatment was evaluated by
visual analog scale (VAS) scoring. The intensity of
perceived pain is a highly subjective experience and
can vary from one individual to another. The subjective experience of pain is profoundly modulated by
past experience and future expectations about a nociceptive stimulus.13 Because participants might have
had delivery or abortion experiences before the study,
we assessed both expected and perceived pain from
the procedure. The expected pain from the procedure
was measured just after the randomization process,
and perceived pain was recorded 12 hours after the
placenta and fetus had been completely removed. We

Misoprostol for Second-Trimester Termination

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planned to perform this assessment with the Face Pain

ScaleRevised.14 However, we faced some challenges
in the understanding and acceptance of the scale by
the patients. We changed it to a VAS after five patients had been recruited. The pain scores of these five
patients were included in our analysis.
The primary outcome measure of the study was the
induction-to-abortion interval. It was defined as the
interval between the time of administration of the first
dose of misoprostol to the time when the fetus was
delivered. Secondary outcome measures were abortion
rate at 24 and 48 hours, requirement for another
intervention, expected and perceived pain VAS scores,
rate of complete abortion, number of misoprostol doses,
difference in Hb level measured at the entry of the study
and after the delivery, side effects, and maternal
complications during the hospitalization period. Complete abortion was defined as expulsion of both the fetus
and placenta completely without instrumental assistance. Diarrhea was defined as more than three episodes
of loose bowel movements. Fever was defined as body
temperature of 38C or more. Abortion rates were calculated according to expulsion time of the fetus.
Sample size calculations were based on the
induction-to-abortion interval. Systemic bioavailability of buccal misoprostol was reported close to oral
misoprostol, and both were lower than that of vaginal
misoprostol.9,10 The effect size was estimated from
previous studies that compared vaginal misoprostol
with oral misoprostol using similar doses and dose
intervals as the current study.15,16 Based on a twotailed a of 0.05, it was determined that 65 patients

per group were required to detect a 50% difference

in the mean induction-to-abortion interval with
a power of 80%.
The analysis was based on the intention-to-treat
principle. The statistical software used for analysis
were Sample Power 3.0 and SPSS 20.0. The
Kolmogorov-Smirnov test was used to check normality of distributions. The data were analyzed with the
Students t test and Mann-Whitney U test for continuous variables and Pearson x2 test or Fishers exact
test for categorical variables. Comparison of perceived pain between the groups was also performed
with analysis of covariance adjusting for expected
pain scores. All the test were two-sided and P values
,.05 were considered statistically significant.

RESULTS
One hundred seventy-two women requesting secondtrimester termination of pregnancy were screened. A
total of 130 eligible patients were recruited the study.
All patients completed the study and were included in
the analysis (Fig. 1). Maternal age, gravidity, parity,
primigravidity, gestational age, cervical length,
Bishop score, predelivery Hb level, and expected pain
VAS scores were not different between the groups
(Table 1).
The mean induction-to-abortion interval was
shorter in the vaginal group compared with the buccal
group (25617 hours compared with 40629 hours
respectively, P5.001). In the vaginal group, abortion
rate at 24 hours (vaginal 41 [63%] compared with
buccal 27 [42%], P5.014) and 48 hours (vaginal
Assessed for eligibiity
(n=172)

Enrollment

Recruited and randomized

(n=130)

Excluded (n=42)
Did not meet inclusion
criteria: 37
Previous cesarean
delivery: 10
Intrauterine exitus: 17
Premature rupture of
membranes: 10
Declined to participate: 5

Allocation
Randomized and received
vaginal misprostol
(n=65)
Follow-up

Randomized and received

buccal misprostol
(n=65)

Treatment failed, received

another induction method*
(n=3)

Treatment failed, received

another induction method*
(n=15)
Analyzed,
vaginal misprostol
(n=65)

Analysis

Analyzed,
buccal misprostol
(n=65)

Fig. 1. Flowchart showing recruitment (based on Consolidated Standards of Reporting Trials). The analyses were performed
according to the intention-to-treat principle. *Included in analysis.
Al. Misoprostol for Second-Trimester Termination. Obstet Gynecol 2015.

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Misoprostol for Second-Trimester Termination

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595

Table 1. Maternal Characteristics

Characteristic
Maternal age (y)
Gravidity
Parity
Primigravida
Gestational age (wk)
Cervical length (mm)
Bishop score
Prelabor
hemoglobin (g/dL)
Expected pain VAS
score

Vaginal
Misoprostol
(n565)

Buccal
Misoprostol
(n565)

2967
2 (1, 10)
1 (0, 9)
19 (29)
1863
3963
2 (0, 4)
12.561.3

2767
2 (1, 11)
1 (0, 6)
21 (32)
1864
3962
2 (0, 4)
12.961.1

.108
.673
.514
.704
.501
.407
.314
.072

4.861.8

4.661.7

.401

VAS, visual analog scale.

Data are mean6standard deviation, median (minimum, maximum), or n (%) unless otherwise specified.

59 [91%] compared with buccal 44 [68%], P5.001)

was significantly higher (Table 2).
A total of 18 (14%) patients for whom treatment
failed were given other induction methods (Table 2).
In the vaginal group, three (5%) patients had extraamniotic Foley catheters applied with 400 micrograms
sublingual misoprostol. In the buccal group, eight
(12%) patients continued treatment by 400 micrograms vaginal misoprostol and seven (11%) by Foley
catheter with 400 micrograms vaginal misoprostol.
The remaining nine (7%) patients for whom treatment
Table 2. Treatment Outcomes

Characteristics
Induction-toabortion time (h)
Abortion in 24 h
Abortion in 48 h
No. of misoprostol
doses
Complete abortion
Other induction
methods
Postpartum
Hb (g/dL)
Change in Hb (g/dL)
(prepost)
Packed red cell
transfusion
Perceived pain
(VAS score)

Vaginal
Group
(n565)

Buccal
Group
(n565)

25617

40629

.001

41 (63)
59 (91)
3 (1, 14)

27 (42)
44 (68)
5 (1, 18)

.014
.001
,.001

51 (78)
3 (5)

54 (83)
15 (23)

.504
.002

11.861.4

11.861.5

.964

0.6 (21, 4.3)

0.8 (20.8, 4.4)

.107

2 (3)
6.661.6

2 (3)
7.361.4

1
.01

Hb, hemoglobin; VAS, visual analog scale.

Data are mean6standard deviation, n (%), or median (minimum,
maximum) unless otherwise specified.

596

Al and Yapca

failed chose to continue treatment with the initially

assigned induction method.
The complete abortion rates were similar between
the groups (vaginal 51 [78%] compared with buccal 54
[83%], P5.504) (Table 2). Prelabor Hb level, postpartum Hb level, and the difference between prelabor
and postpartum values were not different between
the two groups. Two patients had packed red blood
cell transfusion in both of groups: postpartum Hb
concentration fell below 8 g/dL in two patients in
the vaginal group and two women in the buccal group
had a retained placenta with significant hemorrhage.
The perceived pain was higher in the buccal arm
than the vaginal arm (Table 2). The mean difference
between the buccal arm and vaginal arm was 0.7 (95%
confidence interval 0.171.12). Expected pain was significantly related perceived pain (F54.4, P5.038,
r50.18). Perceived pain was still higher in the buccal
group when comparisons between the groups were
performed after adjustment for expected pain
(F57.9, P5.006, partial h250.059).
The median number of misoprostol doses given
was higher in the buccal group. Side effects were
similar between the two groups (Table 3). At least one
side effect was observed in all of the patients. Fifty-five
(84%) women in the vaginal group and 61 (94%) in the
buccal group had more than one side effect (P5.09).

DISCUSSION
The results of our study indicate that 400 micrograms
vaginal misoprostol administered every 3 hours is
equally effective and has a shorter induction-toabortion interval for second-trimester termination of
viable pregnancies than buccal misoprostol given at
the same dose and dosing interval. The rates of side
effects and complete abortion were similar in both
administration routes.
We chose the most common regimen used for
vaginal misoprostol to ensure comparability of the
Table 3. Side Effects

Nausea
Dizziness
Fatigue
Headache
Fever and chills
Diarrhea
Vomiting

Vaginal
Group
(n565)

Buccal
Group
(n565)

16
12
19
15
19
3

16
16
20
24
28
3
2

(25)
(18)
(29)
(23)
(29)
(5)
0

(25)
(25)
(31)
(37)
(43)
(5)
(3)

P
1
.393
.848
.085
.1
1
.094

Data are n (%) unless otherwise specified.

Misoprostol for Second-Trimester Termination

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study with other studies. The success of vaginal

misoprostol at 24 hours and 48 hours was similar to
the previous report.1721 The mean induction-todelivery time for vaginal misoprostol was similar to
some previous reports; however, it was longer than
the other studies.1721 The time interval for buccal
misoprostol was also longer than two previous reports.22,23 These differences may be the result of difference in patient characteristics between previous
studies and the current one. The current study does
not include women with intrauterine fetal demise or
PROM in contrast to the other reports.
Minor side effects were common as reported
previously and at a similar rate in both groups.18,24
We found that perceived pain was higher in the buccal
group than that of the vaginal group. This finding is
somewhat unexpected because the mean peak serum
level of the vaginal route was reported to be approximately half the buccal one.9 It may be related to a longer
induction time in the buccal arm. A longer induction-todelivery time causes a longer duration of pain and exposes the women to side effects for a longer time and
may be more traumatic emotionally. However, the difference between pain scores that was statistically significant is unlikely to be of clinical significance.
A minimum of a 1.3-cm (range 1.01.7 cm) difference
on the VAS represents the smallest measurable change
in acute pain severity that is clinical important.25
There is no evidence that the operative intervention rate for incomplete abortion differs by the route
of misoprostol.2 In the current study, all women
received standardized management of the third stage
of labor. The operative intervention rate was similar
for both groups and was approximately 20%, as reported in previous studies in which the third stage was
managed similarly.2628
This study has a number of strengths. Cervical
length, Bishop scores, rate of primigravidity, and
gestational age were similar between groups. As
potential confounders, women who had intrauterine
fetal demise or PROM were not included in the study.
The results of this study may not be applicable to
these groups.
The study has a limitation on the secondary
outcomes. The findings related to complete abortion
rate, change in Hb level, transfusion rate, pain, and
side effects of the study should be interpreted with
caution because the study is not specifically powered
to assess these outcomes.
The greater bioavailability of vaginal misoprostol
probably explains the results of the current trial.
Meckstroth et al9 compared the serum pharmacokinetics of misoprostol with vaginal compared with

VOL. 126, NO. 3, SEPTEMBER 2015

buccal (400 micrograms) administration in pregnant

women. Systemic bioavailability of vaginally administered misoprostol computed by area under the curve
of serum concentration across time was two times
higher than that of the buccal route.
Although vaginal misoprostol is the most effective
one, women prefer the oral and sublingual routes
because these routes are more convenient, less painful, and give more privacy.1719,29 However, long
induction-to-delivery times are unacceptable to most
women. A combined regimen including both the vaginal and buccal routes improves patient acceptability
and the efficacy of buccal misoprostol. Ellis et al7
found no significant difference between the vaginal
and buccal routes after an initial vaginal dose and
both regimens were highly acceptable. It seems to
be better to use vaginal misoprostol for the first dose
followed by repeated doses of buccal misoprostol.
It has been shown by randomized studies that use
of oral mifepristone 2448 hours before misoprostol
administration significantly shortens the induction-todelivery interval, reduces the total misoprostol dose,
and increases the success rate.22,23 However, it is not
available in most countries, including Turkey. The
long induction intervals with misoprostol used alone
provide additional compelling evidence about the
need to have access to mifepristone for secondtrimester induction.
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