International Journal of Gynecology and Obstetrics 129 (2015) 227–230

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International Journal of Gynecology and Obstetrics

journal homepage: www.elsevier.com/locate/ijgo

CLINICAL ARTICLE

Double-blind randomized controlled trial comparing misoprostol and

oxytocin for management of the third stage of labor in a Nigerian hospital
Abdulkarim O. Musa a, Munir’deen A. Ijaiya b,⁎, Rakiya Saidu b, Abiodun P. Aboyeji b, Abiodun A. Jimoh b,
Kikelomo T. Adesina b, Ishaq F. Abdul b
a
Department of Obstetrics and Gynecology, Federal Medical Centre, Lokoja, Nigeria
b
Department of Obstetrics and Gynecology, University of Ilorin/University of Ilorin Teaching Hospital, Ilorin, Nigeria

a r t i c l e i n f o a b s t r a c t

Article history: Objective: To compare the efficacy of oral misoprostol with that of oxytocin for active management of the third
Received 6 August 2014 stage of labor (AMTSL). Methods: A double-blind randomized control trial was undertaken at a center in Ilorin,
Received in revised form 18 December 2014 Nigeria, between January and June 2013. Every other eligible patient (in the first stage of labor at term, to have
Accepted 10 March 2015 a spontaneous vaginal delivery, and no/low risk of postpartum hemorrhage [PPH]) were randomly assigned
with computer-generated random numbers to receive oral misoprostol (600 μg) plus placebo injection or oral
Keywords:
placebo plus oxytocin injection (1 mL of 10 IU) in the third stage of labor. The primary outcome was amount
Adverse effects
Efficacy
of blood loss during delivery. Results: Mean postpartum blood loss was 325.85 ± 164.72 mL in the 100 patients
Intramuscular oxytocin given misoprostol and 303.95 ± 163.33 mL in the 100 patients given oxytocin (P = 0.391). PPH (≥500 mL blood
Oral misoprostol loss) was recorded in 15 (15.0%) patients given misoprostol and 14 (14.0%) given oxytocin (P = 0.841).
Third stage of labor Shivering, pyrexia, and diarrhea were all significantly more common in the misoprostol group (P b 0.01 for
all). Conclusion: The efficacy of oral misoprostol was similar to that of intramuscular oxytocin. Adverse effects as-
sociated with misoprostol were transient and self-limiting. Thus, oral misoprostol is efficacious and a good alter-
native to oxytocin for AMTSL.
Pan African Clinical Trials Registry: PACTR201407000825227.
© 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction and misoprostol—that cause contraction and retraction of the uterus

after delivery, thereby minimizing blood loss [8]. However, the use of
Obstetric hemorrhage is a leading cause of maternal mortality, caus- ergometrine is discouraged because of adverse effects (e.g. increased
ing 127 000 deaths annually worldwide [1]. Nearly all maternal deaths blood pressure, nausea, and vomiting); oxytocin and misoprostol are
are due to postpartum hemorrhage (PPH) and are preventable [2]. considered to be effective and to have acceptable adverse effects [9].
There are nearly 14 million cases of PPH each year [2]. The contribution Both a WHO multicenter randomized controlled trial [10] and a
of PPH to maternal mortality is disproportionately higher in low- Cochrane systematic review [11] on the use of misoprostol for AMTSL
resource countries, particularly in rural settings with limited infrastruc- showed that there is a higher risk of severe PPH among women taking
ture, availability of skilled delivery attendants, and access to uterotonic misoprostol than among those taking oxytocin. By contrast, recent stud-
agents for management of PPH [3,4]. ies [8,12–16] have found no significant difference in the amount of
Active management of the third stage of labor (AMTSL) has been blood loss between misoprostol and oxytocin groups.
shown to prevent PPH. A systematic review [5] established that risk of Although WHO regards oxytocin as the gold standard for PPH
PPH can be reduced by 60% when AMTSL is implemented. Further- prevention and misoprostol as an alternative in low-resource settings
more, WHO and other international agencies recommend that AMTSL [6,10], further studies comparing misoprostol and oxytocin for AMTSL
should be offered to all women who deliver with a skilled birth atten- in different settings with robust methods will add to the existing evi-
dant [6,7]. The evaluation of individual components of AMTSL has fo- dence. The aim of the present study was to compare the efficacy and
cused on uterotonic drugs—e.g. ergometrine, oxytocin, syntometrine, adverse effects of oral misoprostol with those of oxytocin for AMTSL.

2. Materials and methods

⁎ Corresponding author at: Department of Obstetrics and Gynecology, Faculty of Clinical
Sciences, College of Health Sciences, University of Ilorin, Ilorin, Kwara State, Nigeria.
Tel.: +234 8033801565, +234 8057068400. In the present double-blind randomized control trial, women at-
E-mail address: [email protected] (M.’A. Ijaiya). tending the labor ward of the Department of Obstetrics and Gynecology

http://dx.doi.org/10.1016/j.ijgo.2015.01.008
0020-7292/© 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

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228 A.O. Musa et al. / International Journal of Gynecology and Obstetrics 129 (2015) 227–230

of the University of Ilorin Teaching Hospital, Ilorin, Nigeria, were en- incidence of a prolonged third stage of labor (N30 minutes), the need
rolled between January 1 and June 30, 2013. Eligible participants were for manual removal of placenta, the use of additional oxytocin, and
at term, were advanced in the first stage of labor, were to have a spon- the occurrence of adverse effects (nausea, vomiting, diarrhea, shivering,
taneous vaginal delivery, and had no or low risk of PPH. The exclusion and temperature ≥38 °C).
criteria were grand multiparity (≥ 5 deliveries), multiple pregnancy, The study data were entered into a personal computer and analyzed
uterine fibroids, polyhydramnios, pre-eclampsia or eclampsia, chronic via SPSS version 18.0 (SPSS Inc, Chicago, IL, USA). Analyses were per
maternal illnesses (e.g. hypertension, cardiac disease, and asthma), protocol: women were included when they had definitely received
and prepartum hemorrhage (e.g. placenta previa and placental the allocated intervention and full data were available. Efficacy in each
abruption). Additionally, patients who had previously had PPH, had group was determined by the proportion of participants with a blood
received oxytocin and/or misoprostol other than in the third stage loss of 500 mL of more and the proportion of those who had additional
of labor, were to undergo a planned instrumental vaginal delivery, oxytocic drugs. Statistical significance was determined via the χ2 test,
had prolonged rupture of membranes, or had anemia (hemoglobin Student t test, relative risks (RRs) with 95% confidence intervals (CIs),
b100 g/L) were excluded. Study approval was obtained from the Ethical and relative differences with 95% CIs, as appropriate. P b 0.05 was
Research Committee of the hospital and the National Agency for Food taken to be statistically significant.
and Drug Administration and Control as per the trial protocol. Informed
consent was obtained from all participants. 3. Results
Eight research assistants were trained by the lead researcher (A.O.M.)
for 2 weeks before the study began. The research assistants were second- Of the 200 study participants included in analyses, 100 had received
year registrars, two from each of the four subunits of the department oral misoprostol and 100 received intramuscular oxytocin for AMTSL
who were in charge of the labor ward during working hours and on- (Fig. 1). Baseline demographic and clinical variables were similar across
call periods. The training covered patient selection, the randomization groups (Table 1).
process, administration of research medications, the gravimetric method Table 2 shows the results for the primary outcome. The third stage of
of blood loss estimation and other outcome assessments, vital signs as- labor was longer in the oxytocin group than in the misoprostol group,
sessment, blood sample collection, and appropriate completion of the in- but the difference was not significant (Table 3). The decrease in hemo-
formation data form. globin concentration was slightly greater in the misoprostol group, but
Sample size calculations established that 100 participants were it did not differ significantly (Table 3). There were no cases of manual
necessary in both groups to achieve 80% power, with a significance removal of the placenta in the misoprostol group, and two cases in the
level of 0.05 and a 10% attrition rate. Patient selection was based on oxytocin group (P = 0.1552). Regarding adverse effects, diarrhea, shiv-
a multistage sampling technique. In stage 1, systematic random sam- ering, and pyrexia were significantly more common among women in
pling was used to select every other eligible patient on admission to the misoprostol group (P b 0.01 for all) (Table 3). Nausea was reported
the labor ward. In stage 2, participants were allocated to receive oral only in the oxytocin group.
misoprostol plus placebo injection or oral placebo plus oxytocin injec-
tion. Allocation was done by blocked (restrictive), double-blind ran- 4. Discussion
domization using computer-generated random numbers prepared
by an independent statistician. Opaque envelopes containing these In the present double-blind randomized controlled trial, postpartum
random numbers were opened in the third stage of labor. Participants, blood loss and drop in hemoglobin concentration was higher in the mi-
caregivers, and outcome assessors (researchers or research assistants) soprostol group than in the oxytocin group, but the differences were not
were masked to group allocation. Investigators were not masked for significant. These results are in keeping with findings from other centers
data analysis. [8,13–15,18], although Uthman et al. [19] reported a significantly lower
Within 1 minute of delivery of the neonate and clamping of the mean postpartum blood loss with misoprostol than with oxytocin in a
cord, each participant was given an injection and three oral tablets study in Maiduguri, northeastern Nigeria. The reason for the variation
with approximately 50 mL of clean water. Participants assigned to miso- between studies is unknown, but might be related to pharmacokinetics
prostol received three 200-μg tablets of misoprostol (600 μg in total; and geographic differences: the high temperature and probably unfa-
Eprostol 200, Lincoln Pharmaceuticals, Ahmedabad, Gurat, India) and vorable storage conditions in the Maiduguri study might have contrib-
1 mL of placebo by injection (sterile water). Participants assigned to uted negatively to the pharmaceutical stability of oxytocin injection
oxytocin received 1 mL of 10 IU oxytocin (Rotexmedica, Trittau, and thus its effectiveness.
Germany) by injection and three placebo tablets (lactose). In the present trial, no differences in the number of cases of PPH and
The placenta was delivered by controlled cord traction. Irrespective additional oxytocin usage were observed. This finding is in keeping with
of the group allocation, an additional dose of oxytocin was given if the several other studies [8,12,14,15,20–22]. However, a WHO multicenter
uterus was not well contracted after 30 minutes of oxytocic administra- randomized trial [10] found a significant difference: 20% of women
tion, or if there was excessive vaginal bleeding (blood loss ≥500 mL) or given misoprostol had a measured blood loss of at least 500 mL, com-
vomiting within 30 minutes of delivery. pared with 14% of those given oxytocin (RR 1.44, 95% CI 1.35–1.54;
Blood loss at delivery was assessed by the outcome assessor using P b 0.001). Additionally, 15% of women in the misoprostol group and
the gravimetric method [17]. Blood loss estimation was continued 11% in the oxytocin group required additional uterotonics (RR 1.40,
until 1 hour after delivery in both groups. 95% CI 1.29–1.51; P b 0.001) [10].
Maternal blood pressure, pulse, and temperature were recorded The present trial reported no cases of retained placenta in the miso-
immediately after delivery and again after 30 and 60 minutes. Within prostol group and only two cases in the oxytocin group. Similar findings
1 hour of delivery, the patients were asked about the occurrence of have been reported in many other studies [8,14,15,18,20,21], with an
adverse effects such as nausea, vomiting, diarrhea, and shivering. Any incidence of retained placenta of less than 2% in both groups.
adverse effects were noted or observed by the midwife or outcome Shivering, pyrexia, and diarrhea were the most common adverse ef-
assessor. Blood samples were taken before delivery and 24 hours after fects in the present study and were significantly more prevalent among
delivery to assess hemoglobin concentration. women in the misoprostol group. This is a common finding in many
The primary outcome measure was the amount of blood loss during studies that have compared misoprostol with oxytocin [8–10,14,15,18,
delivery. Secondary outcome measures included the change in maternal 20–23], although Afolabi et al. [13] reported no rise in temperature be-
hemoglobin concentration between admission to the labor ward and tween the pre-intervention and post-intervention periods in either
24 hours after delivery, the duration of the third stage of labor, the group in their study in Ile-Ife, Nigeria. The pathogenesis of shivering

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 A.O. Musa et al. / International Journal of Gynecology and Obstetrics 129 (2015) 227–230 229

Fig. 1. Flow of participants through the study.

and pyrexia associated with misoprostol is related to a prostaglandin- AMTSL among low-risk patients. It could be useful in low-resource
mediated shift in the hypothalamic set point of the thermoregulatory countries, particularly in rural settings where storage facilities for oxy-
pathway. Genetic variations in a patient’s response to misoprostol tocin are not available.
with regard to fever have also been documented [23]. These adverse
effects are unlikely to pose serious clinical problems to patients because
they are transient and self-limiting.
Table 1
One limitation of the present trial was its small sample size, which Demographic and clinical characteristics of participants.a
meant that it was difficult to assess the significance of some outcome
Characteristics Misoprostol Oxytocin P value
variables that were observed at low frequency. In addition, it is possible
group group
that some investigators became aware of group allocation after patients (n = 100) (n = 100)
developed specific adverse effects associated with one of the drugs.
Demographic
Lastly, high-risk pregnancies that are more likely to have greater blood
Age, y 29.60 ± 4.71 29.50 ± 4.37 0.877
loss were excluded from the study, and an objective assessment of Gestational age, wk 39.38 ± 1.70 39.39 ± 1.43 0.958
both tolerability to the adverse effects of the drugs and patient satisfac- Parity 2.22 ± 1.10 2.22 ± 1.09 N0.99
tion with AMTSL was not made. Birth weight, g 3004.3 ± 430.1 3013.0 ± 47.3 0.886
Clinical
In conclusion, the efficacy of 600 μg of oral misoprostol was found
Pre-delivery hemoglobin 119 ± 11.1 119.5 ± 11.1 0.728
to be similar to that of 10 IU of intramuscular oxytocin for the preven- concentration, g/L
tion of primary PPH. A significantly higher number of patients in the Duration of 2nd stage, min 30.57 ± 23.99 29.42 ± 16.66 0.711
misoprostol group experienced shivering, pyrexia, and diarrhea, but Episiotomy 26(26.0) 33(33.0) 0.197
these effects are generally transient and self-limiting. Therefore,600 μg Minor genital trauma 40(40.0) 32(32.0) 0.184

oral misoprostol is efficacious and a good alternative to oxytocin for a

Values are given as mean ± SD or number (percentage), unless indicated otherwise.

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230 A.O. Musa et al. / International Journal of Gynecology and Obstetrics 129 (2015) 227–230

Table 2
Primary outcome measures.a

Outcome Misoprostol group Oxytocin group Relative difference, RR (95% CI) P value
(n = 100) (n = 100) % (95%CI)

Postpartum blood loss, mL 325.85 ± 164.72 303.95 ± 163.33 7.2 (−9.4 to 23.8) – 0.391
Postpartum blood loss ≥500 mL 15 (15.0) 14 (14.0) – 1.07 (0.55–2.10) 0.841

Abbreviations: CI, confidence interval; RR, relative risk.

a
Values are given as mean ± SD or number (percentage), unless indicated otherwise.

Table 3
Secondary outcome measures.a

Outcome Misoprostol group Oxytocin group Relative difference, RR (95% CI) P value
(n = 100) (n = 100) % (95% CI)

Duration of 3rd stage of labor, min 5.78 ± 3.29 6.76 ± 7.28 −14.5 (−37.4 to 8.4) – 0.212
Hemoglobin concentration, g/L
Before delivery 119.0 ± 11.1 119.5 ± 11.1 −0.48 (−3.2 to 2.2 ) – 0.728
24 h after delivery 110.2 ± 10.4 111.4 ± 14.3 −2.0 (−5.4 to 1.3 ) – 0.461
Reduction 8.8 ± 5.8 8.1 ± 6.0 0.6 (−0.9 to 2.1 ) – 0.491
Intervention
Manual removal of placenta 0 2 (2.0) – NA 0.155
Other surgical intervention 0 0 – NA –
Adverse effect
Nausea 0 3 (3.0) – NA 0.245
Vomiting 0 0 – NA –
Diarrhea 10 (10.0) 0 – NA 0.0035
Shivering 42 (42.0) 15 (15.0) – 2.80 (1.66 to 4.71) b0.001
Pyrexia 16 (16.0) 4 (4.0) – 4.00 (1.38 to 11.54) 0.0095
Temperature, °C
Before delivery 36.57 ± 0.54 36.54 ± 0.44 −0.05 (−0.52 to 0.41) – 0.684
1 h after delivery 37.37 ± 0.62 36.91 ± 0.45 1.5 (1.1–2.0) – b0.001
Rise in temperature 0.80 ± 0.61 0.37 ± 0.49 121.6 (75.7–167.6) – b0.001
Need for additional oxytocin 20 (20.0) 19 (19.0) – 1.05 (0.59 to 1.84) 0.858

Abbreviations: CI, confidence interval; RR, relative risk.

a
Values are given as mean ± SD or number (percentage), unless indicated otherwise.

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