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

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University Hospital (KAUH) Institu- active labor was achieved, no further the independent Student t test, with
tional Review Board. All women admitted misoprostol was given. If contractions P <.05 indicating statistical significance.
to the KAUH (Jeddah, Saudi Arabia) for subsequently became inadequate, ox-
whom induction of labor was indicated ytocin augmentation was provided at R ESULTS
by their attending obstetrician, who met least 2 hours after the last misoprostol A total of 160 women were enrolled be-
the eligibility criteria, and from whom dose. Dinoprostone 10 mg vaginal insert tween January 2011 and July 2012, of
written informed consent was obtained (Propess; Controlled Therapeutics, East whom 80 were randomized to the miso-
by the physician were enrolled. Inclusion Kilbride, Scotland) was placed manually prostol and 80 to the dinoprostone vaginal
criteria included singleton pregnancy of in the posterior fornix for a maximum of insert groups (Figure). The groups were
at least 34 weeks’ gestation and a baseline 24 hours or until the establishment of similar for demographic and clinical fac-
Bishop score less than 6. Women with regular uterine activity and then was tors (Table 1). They were 28.8  5.5 years
contraindications for use of either drug, removed. If contractions subsequently of age. Approximately half had previous
previous cesarean section or other uterine became inadequate, oxytocin augmen- deliveries. Three fourths of the women
surgery, severe pregnancy-induced hy- tation was provided at least half an hour had a Bishop score of 3 or less at baseline,
pertension (abnormal liver function tests, after removal of the insert. and postterm was the primary induction
protein >1 g/d, blood pressure of 160/ The primary outcome variable was indication for 93 (58.1%) women.
100 mm Hg), parity of 4 or more, or with successful labor induction, defined as the Women in the misoprostol group
uterine contractions were excluded. proportion of women achieving vaginal received a median of 9 (range, 2e11)
Women were randomized into the delivery within 24 hours after treatment doses (median dose, 340 mg; range,
misoprostol or dinoprostone groups (1:1) initiation. Secondary outcomes included 40e460 mg). In the entire cohort, vaginal
using computer-generated numbers, with interval to delivery from first treatment delivery was achieved within 24 hours in
allocation concealed in opaque envelopes (hours), rate of cesarean delivery, and 100 subjects (62.5%): 44 (42 normal
distributed by the obstetrics ward nurse. need for augmentation with oxytocin. vaginal deliveries and 2 ventouse extrac-
Labor management at the KAUH is Safety assessments included the inci- tions) in the dinoprostone vaginal insert
standardized and includes electronic fetal dence of maternal morbidity and adverse group (55.0%) and 56 (55 normal
monitoring performed 1 hour before and neonatal outcomes. Uterine tachysystole vaginal deliveries and 1 ventouse extrac-
1 hour after the start of induction, which was defined as more than 5 contractions tion) in the misoprostol group (70.0%)
is continued after the beginning of uter- in a 10 minute period without fetal heart (P ¼ .05; power, 50%; relative risk
ine contractions until delivery. Intra- rate changes and uterine hyperstimula- relative risk [RR], 1.5, 95% confidence
muscular or intravenous analgesia is tion as tachysystolic uterine contractions interval [CI], 0.99e2.27) (Table 2).
given for pain relief during labor. Delivery associated with nonreassuring fetal heart Proportions with vaginal delivery
is conducted by in-house staff, usually rate pattern. Nonreassuring fetal heart within 12 hours and interval from first
residents and senior residents under the rate was defined as an abnormal fetal treatment to vaginal delivery were not
care of the on-call consultant. heart rate on electronic monitoring. significantly different between groups.
Oral misoprostol was administered Proportions achieving vaginal delivery
from a 1 mg/mL solution prepared from a within 24 hours were similar between
200 mg misoprostol tablet (Cytotec; Searle S TATISTICAL A NALYSIS groups for women with previous child-
Pharmaceuticals, Leicester, UK) dissolved Several studies comparing oral miso- birth (P ¼ .313); however, the propor-
in 200 mL of water, following the proce- prostol with vaginal prostaglandins for tion of women successfully induced was
dure described in other studies.2 Cutting the induction of labor failed to show a significantly greater for nulliparous
the tablets is difficult and imprecise, and statistically significant difference in rates women in the misoprostol group (24 of
oral misoprostol in solution not only al- of vaginal delivery within 24 hours, with 51, 58.5%) compared with the dino-
lows precise dosing, but also the miso- success rates ranging from 54% to 74%.1 prostone vaginal insert group (12 of 36,
prostol remains active in solution for 24 In the study by Cheng et al, 6 however, 33.3%; P ¼ .027).
hours.2 The starting dose was 20 mg 94% of subjects delivered within In addition, proportions were similar
hourly for 2 doses. In the absence of 24 hours after oral titrated misoprostol, between groups for women with in-
regular uterine activity, the dose was compared with 54% after vaginal miso- dications for induction other than status
increased to 30 mg hourly for 3 doses and prostol. Using an intermediate projec- postterm, whereas significantly more
then 40 mg for 1 dose, 50 mg for 1 dose, tion of 60% delivery within 24 hours misoprostol-treated postterm women
and 60 mg hourly for 4 doses. Before for dinoprostone and 80% for miso- delivered vaginally within 24 hours (37 of
administering the 40 mg and 50 mg doses, prostol would require 82 subjects per 48, 77.1%) compared with dinoprostone-
1 more hour of observation was given. group at alpha ¼ .05 with 80% power. treated women (25 of 45, 55.6%; P ¼
Regular uterine activity is defined Analysis was performed on an intent-to- .028). Although more women in the
as regular uterine contractions every treat basis. Dichotomous variables were dinoprostone vaginal insert group whose
3-5 minutes and lasting 60 seconds or compared between groups using c2 Bishop score at baseline was 4 or 5 had
more. At any time, if establishment of analysis, and continuous variables using successful induction (17 of 20, 85.0%)

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experienced uterine tachysystole and hy-


FIGURE perstimulation accompanied by shiv-
Trial profile 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
Rouzi. Hourly titrated oral misoprostol. Am J Obstet Gynecol 2014.
all scores were 7 or greater at 5 minutes.
No neonates from the dinoprostone
group had neonatal intensive care unit
compared with the misoprostol group Similar proportions of patients treated (NICU) admission, compared with 6
(13 of 21, 61.9%), the difference was not with oxytocin were successfully induced in from the misoprostol group (7.5%;
statistically significant (P ¼ .095). both groups (P ¼.45); however, in subjects P ¼ .028). NICU admission was based
Although the induction success was who did not receive oxytocin, significantly on neonatal hypoglycemia because of
similar in misoprostol group women more (41 of 44, 93.2%) who were treated maternal type 1 diabetes (n ¼ 3), growth
with baseline Bishop scores of 3 or less with misoprostol delivered vaginally restriction (n ¼ 2), and meconium
compared with 4-5 (P ¼ .346), signifi- within 24 hours compared with those aspiration (n ¼ 1). The 6 infants were
cantly more women with a baseline treated with dinoprostone (21 of 34, discharged home in good condition.
Bishop score of 3 or less in the miso- 61.8%; P < .001).
prostol group had successful induction Cesarean delivery was performed in C OMMENT
(43 of 59, 72.9%) compared with women twice as many women in the dinoprostone Although misoprostol is not approved
with low scores in the dinoprostone (n ¼ 18) compared with the misoprostol for labor induction, its comparative cost
group (27 of 60, 45.0%; P ¼ .002). This group (n ¼ 9), approaching statistical advantage over dinoprostone combined
was reflected by a significantly lower significance (22.5% vs 11.3%; P ¼ .057). with greater satisfaction with oral ad-
success rate within the dinoprostone Cesarean deliveries were performed less ministration contributed to its wide-
group subjects who had low (45.0%) than 24 hours after treatment in 7 subjects spread off-label use for this indication.
compared with high (85.0%) Bishop in the dinoprostone group (38.9%), ACOG states that “no studies indicate
scores at baseline (P ¼ .002). compared with 6 in the misoprostol group that intrapartum exposure to misopros-
Oxytocin was used in fewer patients in (66.7%). The small numbers preclude tol has any long-term adverse health
the misoprostol group (n ¼ 36, 45.0%) meaningful comparisons. consequences to the fetus in the absence
compared with the dinoprostone group Frequencies of maternal adverse events of fetal distress, nor is there a plausible
(n ¼ 46, 57.5%); however, the difference were similar between groups (Table 3). biologic basis for such a concern.”1
was not statistically significant (P ¼ .114). One woman in the misoprostol group Numerous studies have explored the

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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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A metaanalysis compared a fixed 20-


TABLE 3 25 mg 2 hour dose or titrated oral miso-
Maternal adverse events prostol with vaginal prostaglandins for
Variable Dinoprostone (n [ 80) Misoprostol (n [ 80) P value induction of labor and failed to show a
Uterine tachysystole 7 (8.75) 9 (11.25) .597 statistically significant difference in rates
of vaginal delivery within 24 hours.2
Uterine hyperstimulation 5 (6.25) 7 (8.75) .549
Within each study, similar delivery out-
Shivering 0 4 (5.0) .120 comes were achieved in each group. Our
Vomiting 1 (1.25) 2 (2.5) 1.0 success rate in the entire cohort was
Nausea 1 (1.25) 3 (3.75) .620 similar to what is reported in the litera-
ture (63%); however, the 15% difference
Pyrexia 6 (7.5) 2 (2.50) .276
between dinoprostone (55%) and miso-
Data are number (percentage).
prostol (70%) subjects bordered on sta-
Rouzi. Hourly titrated oral misoprostol. Am J Obstet Gynecol 2014.
tistical significance (P ¼ .05).
Cheng et al,6 in 2008, reported that
vaginal delivery within 24 hours was
The median dosage of misoprostol vaginal dinoprostone.9 The original in- achieved in 94.1% of 101 women ran-
used was 150 mg (range, 50e400 mg). duction protocols used by Hofmeyr et al7 domized to hourly titrated oral miso-
Hofmeyr et al,8 in 2001, reported the for OMS and vaginal dinoprostone were prostol, compared with 53.8% of 106
results of a multicenter RCT in Johan- followed. The proportion of vaginal de- women treated with vaginal misoprostol
nesburg, South Africa, and Liverpool, liveries within 24 hours was similar in (P < .01). The misoprostol protocol
United Kingdom, between the novel the 3 groups (55% in the Foley’s catheter used 20 mg hourly for 4 doses and then
2 hour titrated OMS and 2 doses of 2 mg and misoprostol group, 60% in the 40 mg hourly for 4 doses and 60 mg
vaginal dinoprostone given 6 hours apart. misoprostol group, and 60% in the hourly until adequate uterine contrac-
Oral misoprostol solution was given as dinoprostone group). tions occurred. If contractions subse-
20 mg every 2 hours for 2 doses (Liver- In 2003, Dällenbach et al10 published quently became inadequate, hourly
pool) or 3 doses (Johannesburg) and an RCT between titrated oral misopros- doses of misoprostol solution were star-
increased to 40 mg every 2 hours until tol (20 mg given every 2 hours for 2 doses ted at 10 mg, which could be increased
adequate uterine contractions were ach- and increased to 40 mg every 2 hours for to 20 mg or 40 mg based on uterine
ieved. No statistically significant differ- a maximum of 10 doses) and vaginal responsiveness. Induction failure was
ences were seen in the vaginal delivery dinoprostone (2 mg twice, 6 hours defined as not entering into the active
within 24 hours (OMS: 62%, vaginal apart). The median misoprostol dose phase after 36 hours of misoprostol
dinoprostone: 64%). The median and was 240 mg (range, 40e475 mg). There treatment with a maximal cumulative
maximum doses of OMS used were not was no statistical significant difference dosage of 1600 mg.
reported. between the 2 groups in the proportion These researchers continue to report
In 2003, the same research group from of vaginal deliveries within 24 hours high success rates with hourly titrated
South Africa reported a 3 arm RCT (56% in the misoprostol group and 62% oral misoprostol.11 In the first study, the
comparing Foley’s catheter and titrated in the dinoprostone group; RR, 0.90, median dose was 180 mg, with the
misoprostol, titrated misoprostol, and 95% CI, 0.72e1.14). highest total cumulative dose reaching
1120 mg.6 The median dose in the second
study was higher (280 mg) in nulliparous
TABLE 4 women than in multiparous women
Neonatal outcomes (160 mg).11
Variable Dinoprostone (n [ 80) Misoprostol (n [ 80) P value In contrast, our stepwise protocol was
more conservative by using 10 mg in-
Nonreassuring fetal heart rate 20 (25.0) 10 (12.5) .043
crements, adding an hour of observation
Meconium-stained liquor 8 (10.0) 8 (10.0) 1.00 before giving the 40 mg and 50 mg doses
Birthweight, g 3194.5  498.1 3148.4  450 .54 and setting the maximum dose at 460 mg.
Perinatal death 1 (1.25) 1 (1.25) 1.00 This might have contributed to our
lesser proportion of vaginal deliveries
Apgar score <7 at 1 min 7 (8.75) 10 (12.5) .442
within 24 hours compared with those
Apgar score <7 at 5 min 0 0 1.00 studies by Cheng et al.6,11
NICU admission, n (%) 0 6 (7.5) .028 Thaisomboon et al12 compared hourly
NICU, neonatal intensive care unit. titrated misoprostol dosing (20 mg hourly
Rouzi. Hourly titrated oral misoprostol. Am J Obstet Gynecol 2014. orally for 4 doses and then 40 mg
hourly for a maximum of 8 hours) with

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www.AJOG.org Obstetrics Research
static dosing (50 mg of misoprostol orally more frequently in the misoprostol group, 3. World Health Organization. WHO recom-
every 4 hours up to 12 hours) in a small the rates of these and other maternal mendations for induction of labour, 2011. Avail-
able at: http://whqlibdoc.who.int/publications/
study (32 women/group) reported in outcomes were not significantly different 2011/9789241501156_eng.pdf. Accessed Feb.
2012. The 24 hour delivery rate was between groups. Similarly, other studies 24, 2013.
28.1% and 46.9% in the titrated and reported no difference in maternal side 4. International Federation of Gynecology and
static dose groups, respectively, despite a effects between oral misoprostol and Obstetrics. Misoprostol recommended dos-
significantly higher mean total miso- vaginal dinoprostone treatment.1 Our ages, 2012. Available at: http://www.figo.org/
files/figocorp/Misoprostol_Recommended%
prostol dose given subjects in the titrated NICU admission rates of 7.5% in the oral 20Dosages%202012.pdf. Accessed March 29,
group (236.2 vs 103.1 mg; P ¼ .001). misoprostol group and none in the dino- 2013.
Our 45% oxytocin augmentation rate prostone group are within reported 5. Tang OS, Gemzell-Danielsson K, Ho PC.
in the oral misoprostol group is within ranges. NICU admission rates ranging Misoprostol: pharmacokinetic profiles, effects
reported ranges. In one study, a 74.7% from 0% to 12% have been reported on the uterus and side-effects. Int J Gynecol
Obstet 2007;99:S160-7.
24 hour vaginal delivery rate was ach- following labor induction with oral miso- 6. Cheng S, Ming H, Lee JC. Titrated oral
ieved when 50 mg oral misoprostol was prostol16,10,12 and 0.5% to 12% following compared with vaginal misoprostol for labor in-
followed by up to 3 100 mg doses every vaginal dinoprostone induction.14,15,16 duction. Obstet Gynecol 2008;111:119-25.
4 hours; however, 97.8% of the subjects Women and clinicians were not blin- 7. Hofmeyr GJ, Matonhodze B, Alfirevic Z,
were also given oxytocin.13 Lower oxy- ded to the allocated treatment, which Campbell E, de Jager M, Nikodem C. Titrated
oral misoprostol solution—a new method
tocin augmentation rates of 10.9-46.9% raises the possibility of bias in clinical of labor induction. S Afr Med J 2001;91:
were reported in other titrated-dosing management decisions. However, such 775-6.
studies.6,8,12 an effect can operate in either direction 8. Hofmeyr GJ, Alfirevic Z, Matonhodze B,
Uterine hyperstimulation has been a and is minimized by our standard labor Brocklehurst P, Campbell E, Nikodem VC.
concern with vaginal misoprostol; in ward management policies. Other limi- Titrated oral misoprostol for induction of labor: a
multi-center, randomized trial. BJOG 2001;108:
fact, the authors of a recent systematic tations of our RCT include the small 952-9.
review of 121 trials concluded that size. In addition to limitations on the 9. Matonhodze BB, Hofmeyr GJ, Levin J. La-
further research on the vaginal route primary endpoint, the disadvantages of bour induction at term—a randomised trial
should not be performed.14 In the RCTof small studies are particularly evident comparing Foley catheter plus titrated oral
Cheng et al,6 which enrolled more than when assessing safety, in which detecting misoprostol solution, titrated oral misoprostol
solution alone, and dinoprostone. S Afr Med J
200 women, no cases of hyperstimula- a significant increase in adverse events 2003;93:375-9.
tion occurred following titrated oral that have a low background incidence 10. Dällenbach P, Boulvain M, Viardot C, Irion O.
misoprostol administration, compared can require an unachievable number of Oral misoprostol or vaginal dinoprostone for
with 11.3% following vaginal misopros- subjects. labor induction: a randomized controlled trial.
tol. In one study, when dinoprostone was In conclusion, despite the small sam- Am J Obstet Gynecol 2003;188:162-7.
11. Cheng SY, Hsue CS, Hwang GH, Chen W,
compared with oral and vaginal miso- ple size, our labor induction with hourly Li TC. Comparison of labor induction with
prostol, significantly different uterine titrated oral misoprostol approached titrated oral misoprostol solution between
hyperstimulation rates occurred (8.9%, statistical significance, supporting the nulliparous and multiparous women. J Obstet
16.5%, and 21.4%; P ¼ .004).15 potential use of hourly titrated oral Gynaecol Res 2010;36:72-8.
Other studies reported greater hyper- misoprostol for labor induction. Subse- 12. Thaisomboon A, Russameecharoen K,
Wanitpongpan P, Phattanachindakun B,
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JANUARY 2014 American Journal of Obstetrics & Gynecology 56.e6


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