Research www.AJOG .

org

OBSTETRICS
Randomized clinical trial between hourly titrated oral
misoprostol and vaginal dinoprostone for induction of labor
Abdulrahim A. Rouzi, MB, ChB, FRCSC; Sharifa Alsibiani, MD; Nisma Mansouri, MD;
Nawal Alsinani, MD; Khalid Darhouse, MRCOG

OBJECTIVE: The objective of the study was to compare the efficacy and achieved within 24 hours in 100 women (62.5%): 44 in the dino-
safety of hourly titrated oral misoprostol with vaginal dinoprostone insert. prostone group (55.0%) and 56 in the misoprostol group (70.0%) (P ¼
.05). The proportion of women who achieved vaginal delivery within
STUDY DESIGN: Subjects were randomized into hourly titrated oral
24 hours was significantly greater for nulliparous women in the
misoprostol or dinoprostone 10 mg vaginal insert. Misoprostol was
misoprostol group (24 of 51, 58.5%) compared with the dinoprostone
given as 20 mg hourly for 2 doses. In the absence of regular uterine
group (12 of 36, 33.3%; P ¼ .0270). Significantly more women with
contractions, the dose was increased to 30 mg hourly for 3 doses and
baseline Bishop score of 3 or less in the misoprostol group had suc-
then 40 mg for 1 dose, 50 mg for 1 dose, and 60 mg hourly for 4 doses.
cessful induction (43 of 59, 72.9%) compared with the dinoprostone
Before the 40 and 50 mg doses, 1 more hour of observation was given.
group (27 of 60, 45.0%; P ¼ .002). Frequencies of maternal adverse
The primary outcome variable was vaginal delivery within 24 hours.
events were similar between groups.
Safety assessments included the incidence of maternal morbidity and
adverse neonatal outcomes. CONCLUSION: Hourly titrated oral misoprostol can provide an effica-
cious and safe substitute for the expensive dinoprostone vaginal insert.
RESULTS: A total of 160 women was enrolled in the study. The groups
were similar for demographic and clinical factors. Vaginal delivery was Key words: hourly, misoprostol, oral, titrated

Cite this article as: Rouzi AA, Alsibiani S, Mansouri N, et al. Randomized clinical trial between hourly titrated oral misoprostol and vaginal dinoprostone for induction of
labor. Am J Obstet Gynecol 2014;210:56.e1-6.

I nduction of labor for both elective

reasons and clinical indications con-
tinues to increase worldwide. Miso-
prostol, a synthetic prostaglandin E1
analog, can be administered orally, sub-
lingually, buccally, intravaginally, or
rectally and is used for both cervical
ripening and labor induction. According
From the Department of Obstetrics and
Gynecology, King Abdulaziz University, Jeddah,
Saudi Arabia.
Received May 22, 2013; revised July 4, 2013;
accepted Aug. 26, 2013.
This study was supported by the Deanship of
Scientific Research, King Abdulaziz University,
grant 5 / 11/ 430.
The authors report no conflict of interest.
Presented in oral format at the Annual Clinical
Meeting of the Society of Obstetricians and
Gynecologists of Canada, Calgary, AB, Canada,
June 11-14, 2013.
Reprints: Abdulrahim Rouzi, MB, ChB,
PO Box 80215, Jeddah 21589, Saudi Arabia.
aarouzi@gmail.com.
0002-9378/$36.00
ª 2014 Mosby, Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ajog.2013.08.033
to the American College of Obstetricians
and Gynecologists (ACOG), there is
extensive clinical experience with miso-
prostol, and a large body of published
reports supports its safety and efficacy
when used appropriately.1
A Cochrane review of 56 randomized
clinical trials (RCTs) of oral misoprostol
with a total of 11,590 women concluded
that this treatment is as effective as vaginal
misoprostol for inducing vaginal delivery
and results in fewer caesarean deliveries
compared with vaginal dinoprostone.2
Based on their review, the authors rec-
ommended a dose of oral misoprostol in
solution (OMS) of 20-25 mg; however, a
specific regimen was not supported, and
trials that included fixed and titrated
doses were pooled.
The World Health Organization rec-
ommendation of a fixed OMS dose of
25 mg every 2 hours for labor induction
based on moderate-quality evidence and
strong recommendation3 was recently
supported by the International Federa-
tion of Gynecology and Obstetrics.4
However, trials continue in efforts to
identify the optimum treatment regimen.
Misoprostol has a short half-life (20-
40 minutes) following oral administra-
tion. It reaches peak serum concentration
in 30 minutes, followed by a rapid decline
to low levels by 120 minutes, with a more
gradual decline thereafter.5 Compared
with 2 hour dosing, hourly titrated oral
misoprostol dosing may provide a more
steady state drug level within the zone of
therapeutic efficacy, which may result in
improved clinical outcome. There are
limited data, however, regarding the use
of hourly titrated oral misoprostol. Based
on pharmacokinetics, previously pub-
lished regimens, and the incidence of side
effects, we hypothesized that stepwise
hourly titrated oral misoprostol is effi-
cacious and safe.
The objective of this study was to
compare the efficacy and safety of a
stepwise protocol of hourly titrated oral
misoprostol with vaginal dinoprostone
insert in women scheduled for labor
induction.
M ATERIALS AND M ETHODS
This open-label randomized trial was
approved by the King Abdulaziz

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www.AJOG.org
University Hospital (KAUH) Institu-
tional Review Board. All women admitted
to the KAUH (Jeddah, Saudi Arabia) for
whom induction of labor was indicated
by their attending obstetrician, who met
the eligibility criteria, and from whom
written informed consent was obtained
by the physician were enrolled. Inclusion
criteria included singleton pregnancy of
at least 34 weeks’ gestation and a baseline
Bishop score less than 6. Women with
contraindications for use of either drug,
previous cesarean section or other uterine
surgery, severe pregnancy-induced hy-
pertension (abnormal liver function tests,
protein >1 g/d, blood pressure of 160/
100 mm Hg), parity of 4 or more, or with
uterine contractions were excluded.
Women were randomized into the
misoprostol or dinoprostone groups (1:1)
using computer-generated numbers, with
allocation concealed in opaque envelopes
distributed by the obstetrics ward nurse.
Labor management at the KAUH is
standardized and includes electronic fetal
monitoring performed 1 hour before and
1 hour after the start of induction, which
is continued after the beginning of uter-
ine contractions until delivery. Intra-
muscular or intravenous analgesia is
given for pain relief during labor. Delivery
is conducted by in-house staff, usually
residents and senior residents under the
care of the on-call consultant.
Oral misoprostol was administered
from a 1 mg/mL solution prepared from a
200 mg misoprostol tablet (Cytotec; Searle
Pharmaceuticals, Leicester, UK) dissolved
in 200 mL of water, following the proce-
dure described in other studies.2 Cutting
the tablets is difficult and imprecise, and
oral misoprostol in solution not only al-
lows precise dosing, but also the miso-
prostol remains active in solution for 24
hours.2 The starting dose was 20 mg
hourly for 2 doses. In the absence of
regular uterine activity, the dose was
increased to 30 mg hourly for 3 doses and
then 40 mg for 1 dose, 50 mg for 1 dose,
and 60 mg hourly for 4 doses. Before
administering the 40 mg and 50 mg doses,
1 more hour of observation was given.
Regular uterine activity is defined
as regular uterine contractions every
3-5 minutes and lasting 60 seconds or
more. At any time, if establishment of
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active labor was achieved, no further
misoprostol was given. If contractions
subsequently became inadequate, ox-
ytocin augmentation was provided at
least 2 hours after the last misoprostol
dose. Dinoprostone 10 mg vaginal insert
(Propess; Controlled Therapeutics, East
Kilbride, Scotland) was placed manually
in the posterior fornix for a maximum of
24 hours or until the establishment of
regular uterine activity and then was
removed. If contractions subsequently
became inadequate, oxytocin augmen-
tation was provided at least half an hour
after removal of the insert.
The primary outcome variable was
successful labor induction, defined as the
proportion of women achieving vaginal
delivery within 24 hours after treatment
initiation. Secondary outcomes included
interval to delivery from first treatment
(hours), rate of cesarean delivery, and
need for augmentation with oxytocin.
Safety assessments included the inci-
dence of maternal morbidity and adverse
neonatal outcomes. Uterine tachysystole
was defined as more than 5 contractions
in a 10 minute period without fetal heart
rate changes and uterine hyperstimula-
tion as tachysystolic uterine contractions
associated with nonreassuring fetal heart
rate pattern. Nonreassuring fetal heart
rate was defined as an abnormal fetal
heart rate on electronic monitoring.
S TATISTICAL A NALYSIS
Several studies comparing oral miso-
prostol with vaginal prostaglandins for
the induction of labor failed to show a
statistically significant difference in rates
of vaginal delivery within 24 hours, with
success rates ranging from 54% to 74%.1
In the study by Cheng et al, 6 however,
94% of subjects delivered within
24 hours after oral titrated misoprostol,
compared with 54% after vaginal miso-
prostol. Using an intermediate projec-
tion of 60% delivery within 24 hours
for dinoprostone and 80% for miso-
prostol would require 82 subjects per
group at alpha ¼ .05 with 80% power.
Analysis was performed on an intent-to-
treat basis. Dichotomous variables were
compared between groups using c2
analysis, and continuous variables using
JANUARY 2014 American Journal of Obstetrics & Gynecology
Obstetrics Research
the independent Student t test, with
P <.05 indicating statistical significance.
R ESULTS
A total of 160 women were enrolled be-
tween January 2011 and July 2012, of
whom 80 were randomized to the miso-
prostol and 80 to the dinoprostone vaginal
insert groups (Figure). The groups were
similar for demographic and clinical fac-
tors (Table 1). They were 28.8  5.5 years
of age. Approximately half had previous
deliveries. Three fourths of the women
had a Bishop score of 3 or less at baseline,
and postterm was the primary induction
indication for 93 (58.1%) women.
Women in the misoprostol group
received a median of 9 (range, 2e11)
doses (median dose, 340 mg; range,
40e460 mg). In the entire cohort, vaginal
delivery was achieved within 24 hours in
100 subjects (62.5%): 44 (42 normal
vaginal deliveries and 2 ventouse extrac-
tions) in the dinoprostone vaginal insert
group (55.0%) and 56 (55 normal
vaginal deliveries and 1 ventouse extrac-
tion) in the misoprostol group (70.0%)
(P ¼ .05; power, 50%; relative risk
relative risk [RR], 1.5, 95% confidence
interval [CI], 0.99e2.27) (Table 2).
Proportions with vaginal delivery
within 12 hours and interval from first
treatment to vaginal delivery were not
significantly different between groups.
Proportions achieving vaginal delivery
within 24 hours were similar between
groups for women with previous child-
birth (P ¼ .313); however, the propor-
tion of women successfully induced was
significantly greater for nulliparous
women in the misoprostol group (24 of
51, 58.5%) compared with the dino-
prostone vaginal insert group (12 of 36,
33.3%; P ¼ .027).
In addition, proportions were similar
between groups for women with in-
dications for induction other than status
postterm, whereas significantly more
misoprostol-treated postterm women
delivered vaginally within 24 hours (37 of
48, 77.1%) compared with dinoprostone-
treated women (25 of 45, 55.6%; P ¼
.028). Although more women in the
dinoprostone vaginal insert group whose
Bishop score at baseline was 4 or 5 had
successful induction (17 of 20, 85.0%)
56.e2
Research Obstetrics
FIGURE
Trial profile
Rouzi. Hourly titrated oral misoprostol. Am J Obstet Gynecol 2014.
compared with the misoprostol group
(13 of 21, 61.9%), the difference was not
statistically significant (P ¼ .095).
Although the induction success was
similar in misoprostol group women
with baseline Bishop scores of 3 or less
compared with 4-5 (P ¼ .346), signifi-
cantly more women with a baseline
Bishop score of 3 or less in the miso-
prostol group had successful induction
(43 of 59, 72.9%) compared with women
with low scores in the dinoprostone
group (27 of 60, 45.0%; P ¼ .002). This
was reflected by a significantly lower
success rate within the dinoprostone
group subjects who had low (45.0%)
compared with high (85.0%) Bishop
scores at baseline (P ¼ .002).
Oxytocin was used in fewer patients in
the misoprostol group (n ¼ 36, 45.0%)
compared with the dinoprostone group
(n ¼ 46, 57.5%); however, the difference
was not statistically significant (P ¼ .114).
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Similar proportions of patients treated
with oxytocin were successfully induced in
both groups (P ¼.45); however, in subjects
who did not receive oxytocin, significantly
more (41 of 44, 93.2%) who were treated
with misoprostol delivered vaginally
within 24 hours compared with those
treated with dinoprostone (21 of 34,
61.8%; P < .001).
Cesarean delivery was performed in
twice as many women in the dinoprostone
(n ¼ 18) compared with the misoprostol
group (n ¼ 9), approaching statistical
significance (22.5% vs 11.3%; P ¼ .057).
Cesarean deliveries were performed less
than 24 hours after treatment in 7 subjects
in the dinoprostone group (38.9%),
compared with 6 in the misoprostol group
(66.7%). The small numbers preclude
meaningful comparisons.
Frequencies of maternal adverse events
were similar between groups (Table 3).
One woman in the misoprostol group
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experienced uterine tachysystole and hy-
perstimulation accompanied by shiv-
ering, vomiting, and nausea after 3 doses.
Treatment was interrupted for 6.5 hours,
during which time her condition stabi-
lized. At that time the subject was given
dinoprostone and underwent an un-
eventful vaginal delivery of a 3540 g male
infant after an additional 19 hours. More
infants in the dinoprostone group had a
nonreassuring fetal heart rate (n ¼ 20,
25.0%) before delivery compared with
the misoprostol group (n ¼ 10, 12.5%;
P ¼ .043) (Table 4).
There was one perinatal death in each
group; both women were undergoing
induction because of congenital anom-
alies. The woman in the dinoprostone
group underwent cesarean delivery ap-
proximately 20 hours after treatment,
and the woman in the oral misoprostol
group had a vaginal delivery after
approximately 23 hours. A third subject
with a fetus with congenital anomalies,
also in the misoprostol group, under-
went vaginal delivery approximately
29 hours after the start of induction.
Proportions of neonates with an
Apgar score less than 7 at 1 minute were
similar between groups (P ¼ .442), and
all scores were 7 or greater at 5 minutes.
No neonates from the dinoprostone
group had neonatal intensive care unit
(NICU) admission, compared with 6
from the misoprostol group (7.5%;
P ¼ .028). NICU admission was based
on neonatal hypoglycemia because of
maternal type 1 diabetes (n ¼ 3), growth
restriction (n ¼ 2), and meconium
aspiration (n ¼ 1). The 6 infants were
discharged home in good condition.
C OMMENT
Although misoprostol is not approved
for labor induction, its comparative cost
advantage over dinoprostone combined
with greater satisfaction with oral ad-
ministration contributed to its wide-
spread off-label use for this indication.
ACOG states that “no studies indicate
that intrapartum exposure to misopros-
tol has any long-term adverse health
consequences to the fetus in the absence
of fetal distress, nor is there a plausible
biologic basis for such a concern.”1
Numerous studies have explored the
www.AJOG.org Obstetrics Research
effectiveness and safety of oral miso-
TABLE 1 prostol for labor induction. Study design
Baseline characteristics and subject characteristic variations
Variable Dinoprostone (n [ 80) Misoprostol (n [ 80) P value complicate outcome comparisons, and
Age, y 29.1  5.6 (19e49) 28.4  5.4 (19e46) .42 contribute to the motivation to perform
additional studies in the specific settings
Gestation, wks 39.9  1.8 (35e42) 39.9  1.8 (34e42) .96
in which safe and effective treatments
BMI, kg/m 2
32.8  8.1 (19.0e88.5) 32.5  5.3 (23.2e48.1) .81 will be applied.
Nulliparous 36 (45.0) 41 (51.3) .43 Hofmeyr et al,7 in 2001, published a
Bishop score 3 60 (75.0) 59 (73.8) .86 pilot study from South Africa on the use
of the new protocol using oral 2 hour
Indication
titrated OMS. The starting dose of 40 mg
Postterm 45 (56.3) 48 (60.0) .63 was discontinued because of uterine
IUGR 5 (6.3) 1 (1.3) .21 hyperstimulation. The dose was changed
PIH 9 (11.3) 7 (8.8) .60 to 20 mg every 2 hours for 3 doses and
increased to 40 mg every 2 hours until
Diabetes 5 (6.3) 5 (6.3) 1.00 adequate uterine contractions were
Oligohydramnios 4 (5) 3 (3.8) 1.00 achieved. If contractions subsequently
PROM 5 (6.3) 3 (3.8) .50 became inadequate, labor augmentation
with hourly misoprostol solution was
Other 7 (8.8) 13 (16.3) .15
started at 5 mg, increased to 10 mg and
Data are mean  SD (range) or number (percentage). then 20 mg, and repeated until adequate
BMI, body mass index; IUGR, intrauterine growth restriction; PIH, pregnancy induced hypertension; PROM, premature rupture uterine contractions occurred. Vaginal
of membranes.
Rouzi. Hourly titrated oral misoprostol. Am J Obstet Gynecol 2014.
delivery in 24 hours was achieved in 14
of 25 women (56%).

TABLE 2
Labor outcomes
Outcome Dinoprostone Misoprostol P value (RR; 95% CI)
Delivered vaginally in 24 h 44/80 (55.0) 56/80 (70.0) .050 (1.273; 0.997e1.626)
Delivered vaginally in 12 h 26/80 (32.5) 18/80 (22.5) .156 (0.692; 0.414e1.159)
First treatment to vaginal birth, mean h 20.2  18.0 (n ¼ 62) 17.6  8.5 (n ¼ 71) .301
Cesarean section 18/80 (22.5) 9/80 (11.3) .057 (0.500; 0.239e1.046)
Subgroups: vaginal delivery in 24 h
Parity
Nulliparous 12/36 (33.3) 24/41 (58.5) .027
Multiparous 32/44 (72.7) 32/39 (82.0) .313
Indication
Postterm 25/45 (55.6) 37/48 (77.1) .028
Other 19/35 (54.3) 19/32 (59.4) .671
Bishop score
3 27/60 (45.0) 43/59 (72.9) .002
4 or 5 17/20 (85.0) 13/21 (61.9) .095
Oxytocin
Yes 23/46 (50.0) 15/36 (41.7) .453
No 21/34 (61.8) 41/44 (93.2) < .001
Data are mean  SD or number (percentage).
Rouzi. Hourly titrated oral misoprostol. Am J Obstet Gynecol 2014.

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Research Obstetrics
TABLE 3
Maternal adverse events
Variable
Uterine tachysystole
Uterine hyperstimulation
Shivering
Vomiting
Nausea
Pyrexia
Data are number (percentage).
Rouzi. Hourly titrated oral misoprostol. Am J Obstet Gynecol 2014.
The median dosage of misoprostol
used was 150 mg (range, 50e400 mg).
Hofmeyr et al,8 in 2001, reported the
results of a multicenter RCT in Johan-
nesburg, South Africa, and Liverpool,
United Kingdom, between the novel
2 hour titrated OMS and 2 doses of 2 mg
vaginal dinoprostone given 6 hours apart.
Oral misoprostol solution was given as
20 mg every 2 hours for 2 doses (Liver-
pool) or 3 doses (Johannesburg) and
increased to 40 mg every 2 hours until
adequate uterine contractions were ach-
ieved. No statistically significant differ-
ences were seen in the vaginal delivery
within 24 hours (OMS: 62%, vaginal
dinoprostone: 64%). The median and
maximum doses of OMS used were not
reported.
In 2003, the same research group from
South Africa reported a 3 arm RCT
comparing Foley’s catheter and titrated
misoprostol, titrated misoprostol, and
TABLE 4
Neonatal outcomes
Variable
Nonreassuring fetal heart rate
Meconium-stained liquor
Birthweight, g
Perinatal death
Apgar score <7 at 1 min
Apgar score <7 at 5 min
NICU admission, n (%)
NICU, neonatal intensive care unit.
Rouzi. Hourly titrated oral misoprostol. Am J Obstet Gynecol 2014.
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Dinoprostone (n [ 80) Misoprostol (n [ 80)
7 (8.75) 9 (11.25)
5 (6.25) 7 (8.75)
0 4 (5.0)
1 (1.25) 2 (2.5)
1 (1.25) 3 (3.75)
6 (7.5) 2 (2.50)
vaginal dinoprostone.9 The original in-
duction protocols used by Hofmeyr et al7
for OMS and vaginal dinoprostone were
followed. The proportion of vaginal de-
liveries within 24 hours was similar in
the 3 groups (55% in the Foley’s catheter
and misoprostol group, 60% in the
misoprostol group, and 60% in the
dinoprostone group).
In 2003, Dällenbach et al10 published
an RCT between titrated oral misopros-
tol (20 mg given every 2 hours for 2 doses
and increased to 40 mg every 2 hours for
a maximum of 10 doses) and vaginal
dinoprostone (2 mg twice, 6 hours
apart). The median misoprostol dose
was 240 mg (range, 40e475 mg). There
was no statistical significant difference
between the 2 groups in the proportion
of vaginal deliveries within 24 hours
(56% in the misoprostol group and 62%
in the dinoprostone group; RR, 0.90,
95% CI, 0.72e1.14).
Dinoprostone (n [ 80) Misoprostol (n [ 80) P value
20 (25.0) 10 (12.5)
8 (10.0) 8 (10.0)
3194.5  498.1 3148.4  450
1 (1.25) 1 (1.25)
7 (8.75) 10 (12.5)
0 0
0 6 (7.5)
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A metaanalysis compared a fixed 20-
25 mg 2 hour dose or titrated oral miso-
prostol with vaginal prostaglandins for
P value induction of labor and failed to show a
.597 statistically significant difference in rates
of vaginal delivery within 24 hours.2
.549
Within each study, similar delivery out-
.120 comes were achieved in each group. Our
1.0 success rate in the entire cohort was
.620 similar to what is reported in the litera-
ture (63%); however, the 15% difference
.276
between dinoprostone (55%) and miso-
prostol (70%) subjects bordered on sta-
tistical significance (P ¼ .05).
Cheng et al,6 in 2008, reported that
vaginal delivery within 24 hours was
achieved in 94.1% of 101 women ran-
domized to hourly titrated oral miso-
prostol, compared with 53.8% of 106
women treated with vaginal misoprostol
(P < .01). The misoprostol protocol
used 20 mg hourly for 4 doses and then
40 mg hourly for 4 doses and 60 mg
hourly until adequate uterine contrac-
tions occurred. If contractions subse-
quently became inadequate, hourly
doses of misoprostol solution were star-
ted at 10 mg, which could be increased
to 20 mg or 40 mg based on uterine
responsiveness. Induction failure was
defined as not entering into the active
phase after 36 hours of misoprostol
treatment with a maximal cumulative
dosage of 1600 mg.
These researchers continue to report
high success rates with hourly titrated
oral misoprostol.11 In the first study, the
median dose was 180 mg, with the
highest total cumulative dose reaching
1120 mg.6 The median dose in the second
study was higher (280 mg) in nulliparous
women than in multiparous women
(160 mg).11
In contrast, our stepwise protocol was
more conservative by using 10 mg in-
.043
crements, adding an hour of observation
1.00 before giving the 40 mg and 50 mg doses
.54 and setting the maximum dose at 460 mg.
1.00 This might have contributed to our
lesser proportion of vaginal deliveries
.442
within 24 hours compared with those
1.00 studies by Cheng et al.6,11
.028 Thaisomboon et al12 compared hourly
titrated misoprostol dosing (20 mg hourly
orally for 4 doses and then 40 mg
hourly for a maximum of 8 hours) with
www.AJOG.org
static dosing (50 mg of misoprostol orally
every 4 hours up to 12 hours) in a small
study (32 women/group) reported in
2012. The 24 hour delivery rate was
28.1% and 46.9% in the titrated and
static dose groups, respectively, despite a
significantly higher mean total miso-
prostol dose given subjects in the titrated
group (236.2 vs 103.1 mg; P ¼ .001).
Our 45% oxytocin augmentation rate
in the oral misoprostol group is within
reported ranges. In one study, a 74.7%
24 hour vaginal delivery rate was ach-
ieved when 50 mg oral misoprostol was
followed by up to 3 100 mg doses every
4 hours; however, 97.8% of the subjects
were also given oxytocin.13 Lower oxy-
tocin augmentation rates of 10.9-46.9%
were reported in other titrated-dosing
studies.6,8,12
Uterine hyperstimulation has been a
concern with vaginal misoprostol; in
fact, the authors of a recent systematic
review of 121 trials concluded that
further research on the vaginal route
should not be performed.14 In the RCTof
Cheng et al,6 which enrolled more than
200 women, no cases of hyperstimula-
tion occurred following titrated oral
misoprostol administration, compared
with 11.3% following vaginal misopros-
tol. In one study, when dinoprostone was
compared with oral and vaginal miso-
prostol, significantly different uterine
hyperstimulation rates occurred (8.9%,
16.5%, and 21.4%; P ¼ .004).15
Other studies reported greater hyper-
stimulation in women on dinoprostone
compared with oral titrated misoprostol.
In a large study that enrolled 741 sub-
jects, incidence of uterine hyperstimu-
lation was 1.9% and 6.1% in the oral
misoprostol and vaginal dinoprostone
groups16 and was 9% and 14% of 100
subjects in another study.10 In the cur-
rent study, the incidence of uterine hy-
perstimulation was similar between the 2
groups and was within reported ranges
following both misoprostol (8.8%) and
dinoprostone (6.3%) treatment.
An adverse reaction considered related
to misoprostol resulted in switching 1
subject in our study to dinoprostone
because of uterine tachysystole and hy-
perstimulation, shivering, vomiting, and
nausea. Although these events occurred
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more frequently in the misoprostol group,
the rates of these and other maternal
outcomes were not significantly different
between groups. Similarly, other studies
reported no difference in maternal side
effects between oral misoprostol and
vaginal dinoprostone treatment.1 Our
NICU admission rates of 7.5% in the oral
misoprostol group and none in the dino-
prostone group are within reported
ranges. NICU admission rates ranging
from 0% to 12% have been reported
following labor induction with oral miso-
prostol16,10,12 and 0.5% to 12% following
vaginal dinoprostone induction.14,15,16
Women and clinicians were not blin-
ded to the allocated treatment, which
raises the possibility of bias in clinical
management decisions. However, such
an effect can operate in either direction
and is minimized by our standard labor
ward management policies. Other limi-
tations of our RCT include the small
size. In addition to limitations on the
primary endpoint, the disadvantages of
small studies are particularly evident
when assessing safety, in which detecting
a significant increase in adverse events
that have a low background incidence
can require an unachievable number of
subjects.
In conclusion, despite the small sam-
ple size, our labor induction with hourly
titrated oral misoprostol approached
statistical significance, supporting the
potential use of hourly titrated oral
misoprostol for labor induction. Subse-
quent to this comparison with our
standard protocol, further studies focus-
ing on OMS are warranted to more
clearly determine the optimal regimen.-
ACKNOWLEDGMENT
This project was funded by the Deanship of
Scientific Research (DSR), King Abdulaziz
University, Jeddah, under grant 5 / 11 /430. The
authors, therefore, acknowledge, with thanks,
DSR technical and financial support.
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