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A randomized controlled trial of the safety and efficacy of preoperative rectal

misoprostol for prevention of intraoperative and postoperative blood loss at
elective cesarean deliv...

Article  in  International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics · July 2019
DOI: 10.1002/ijgo.12922

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Received: 31 January 2019    Revised: 18 April 2019    Accepted: 12 July 2019    First published online: 25 July 2019

DOI: 10.1002/ijgo.12922

CLINICAL ARTICLE
Obstetrics

A randomized controlled trial of the safety and efficacy

of preoperative rectal misoprostol for prevention of
intraoperative and postoperative blood loss at elective
cesarean delivery

Ahmed M. Maged1,* | Tarek Fawzi1 | Mohamed A. Shalaby1 | Ahmed Samy1 | 

Mohamed A. Rabee1 | Ahmed S. Ali2 | Eman A. Hussein1 | Bahaa Hammad1 | 
Wesam S. Deeb3

1
Department of Obstetrics and
Gynecology, Kasr Al-Ainy Hospital, Cairo
University, Cairo, Egypt
2
Al Azhar University, Cairo, Egypt
3
Department of Obstetrics and
Gynecology, Fayoum University, Fayoum,
Egypt
*Correspondence
Ahmed M. Maged, 11 Eid Mostafa Street,
Haram, Giza, Egypt.
Email: prof.ahmedmaged@gmail.com
Abstract
Objective: To assess the safety and efficacy of preoperative rectal misoprostol for the
prevention of intraoperative and postoperative blood loss in women undergoing elec-
tive cesarean delivery.
Methods: A single-­blind randomized controlled trial of 200 full-­term pregnant women
scheduled for elective cesarean delivery. Computer-­generated randomization allocated
women to receive 400 μg rectal misoprostol at urinary catheter insertion plus 400 μg
rectally after abdominal closure (preoperative group, n=100) or 800 μg of rectal mis-
oprostol after abdominal closure (postoperative group, n=100). Primary outcome was
intraoperative blood loss.
Results: Intraoperative blood loss was significantly lower in the preoperative misopros-
tol group compared with the postoperative group (528.7 ± 114.8 mL vs 788.6
± 165.8 mL; P<0.001). Blood loss during the first 24 hours after delivery was also lower in
the preoperative group (199.3 ± 84.5 mL vs 302.9 ± 125.6 mL; P<0.001). Fewer women in
the preoperative group needed additional uterotonics (7 vs 21; P<0.001). After delivery,
the decrease in both hemoglobin and hematocrit levels was significantly less in the preop-
erative group (−6.8 vs −12.8% and −6.05 vs −17.8%, respectively; P<0.001).
Conclusion: Preoperative rectal administration of misoprostol significantly reduced intra-
operative and postoperative blood loss during and after elective cesarean delivery.
ClinicalTrial.gov ID: NCT03680339. Date of registration 9/2018

KEYWORDS
Egypt; Elective cesarean delivery; Intraoperative blood loss; Misoprostol; Postpartum hemorrhage;
Randomized controlled trial; Rectal route

1 | INTRODUCTION Postpartum hemorrhage (PPH) accounts for 50% of maternal mor-

tality in low-­income countries.2 Blood loss during cesarean delivery
The incidence of cesarean delivery has increased in both high-­ is almost double the amount lost during vaginal delivery (1000 mL
and low-­income countries, ranging from 20% to 30% worldwide.1 vs 500 mL).3

102  |  wileyonlinelibrary.com/journal/ijgo

© 2019 International Federation of Int J Gynecol Obstet 2019; 147: 102–107
Gynecology and Obstetrics
Maged ET AL.
Various uterotonics are used to minimize intraoperative and post-
operative bleeding during cesarean, including oxytocin, methylergo-
metrine and prostaglandins.4 Misoprostol, a synthetic prostaglandin
E1 analog, is widely used in obstetrics for the prevention and control
of blood loss. The benefits of misoprostol (cervical dilation and uterine
contractions) and its adverse effects (nausea, vomiting, diarrhea, fever,
and chills) are dose dependent.5 Misoprostol is affordable and widely
available, easily administered via multiple routes (vaginal, rectal, sub-
lingual, and oral), and has a good safety profile if properly administered
and monitored, all of which make it the standard treatment option for
PPH in low-­resource settings.6
Misoprostol administered vaginally is affected by vaginal acid-
ity and the bacterial microenvironment. 7 Sublingual route has the
7
highest peak concentration, the shortest onset of action owing
to avoidance of first-­pass metabolism in the liver and the greatest
bioavailability among all routes of administration; however, it is
also associated with the highest incidence of adverse effects due
8
to high peak concentration. Rectally administered misoprostol
is associated with slower absorption, lower peak concentration
levels, and reduced adverse effects compared with the oral and
sublingual routes.9
Most previous studies involving misoprostol have investigated
PPH after vaginal delivery. Some studies have reported on the pre-
vention of PPH after cesarean delivery, but only a few have looked at
minimizing intraoperative blood loss.
The aim of the present study was to assess the safety and
efficacy of preoperative rectal misoprostol for the prevention of
intraoperative and postoperative blood loss in women undergoing
elective cesarean delivery.
2 | MATERIAL AND METHODS
A single-­blind, randomized controlled trial of full-­term pregnant
women who attended Kasr Al-­Ainy Hospital, Cairo, Egypt, between
September 2nd 2018 and February 16th 2019. The study was
approved by the ethical committee of the obstetrics and gynecology
department of Kasr Al Ainy Hospital, Cairo University. All participants
provided written informed consent following discussion of the risks
and benefits of the study.
Two hundred pregnant women at 37–41 weeks of pregnancy,
carrying a singleton healthy fetus, and scheduled for elective lower-­
segment cesarean delivery under spinal anesthesia were recruited
to the study. Inclusion criteria were maternal age 20–35 years, body
mass index 25–30, normal coagulation profile, and normal amniotic
fluid volume assessed using the amniotic fluid index. Exclusion cri-
teria were hypertension; diabetes; heart, kidney, or liver disorders;
known allergy to misoprostol; contraindication to use of misopros-
tol; or women who had undergone any previous uterine surgery,
such as myomectomy. Women at higher risk of intraoperative blood
loss or PPH, such as those with hemoglobin levels less than 9 g/dL,
antepartum hemorrhage, history of PPH, or uterine fibroids were
also excluded.
|
      103
Before surgery, all women underwent full history-­taking and care-
ful examination to ensure adherence to the inclusion and exclusion cri-
teria. Transabdominal ultrasonography and laboratory investigations
were performed such as blood count, liver and kidney function tests,
and coagulation profile.
On the day of surgery, women were randomized using computer-­
generated random numbers to receive 400 μg rectal misoprostol
just after spinal anesthesia and insertion of the urinary catheter, and
another 400 μg rectally after closure of the abdomen (preoperative
group) or 800 μg of rectal misoprostol after closure of the abdomen
(postoperative group). Both groups received 5 IU oxytocin (Syntocinon;
Novartis, Basel, Switzerland) intravenously, in addition to 0.2 mg
(1 mL) of ergometrine (Methergine; Novartis, Basel, Switzerland) intra-
muscularly. Both groups also received an intravenous infusion of 20 IU
oxytocin diluted in 500 mL of lactated Ringer's solution at a rate of
125 mL per hour.3 The participants, outcome assessor, and statistician
were blinded to the randomization.
Cesarean deliveries were performed by an experienced obstetri-
cian with over 5 years of experience. All procedures were performed
using the Munro-­Kerr method through a Pfannenstiel incision, imme-
diate cord clamping after delivery of the baby, double-­layer closure of
the uterus, and closure of the abdomen in layers.
Intraoperative blood loss was calculated using two methods and
considered mean amount lost. The first method used the formula:
Blood loss = estimated blood volume (EBV) × preoperative
hematocrit − postoperative hematocrit∕preoperative hematocrit.
Estimated blood volume was the weight in kilograms multiplied by
85.3 The second method of calculation was by weighing the towels
and dressings before and after the procedure and adding the volume
of fluid inside the suction apparatus.
The primary outcome parameter was intraoperative blood loss.
Secondary outcomes were occurrence of primary PPH (defined as
bleeding >1000 mL during the first 24 hours after the operation), need
for additional uterotonics, need for blood transfusion, and changes in
vital signs during the operation.
Sample size calculation was done using volume of blood
loss at cesarean since it was the primary outcome of our study.
Mean ± SD blood loss at cesarean was 324 ± 167 mL according
to Chaudhuri et al.10 We calculated that the minimum sample size
needed was 86 participants in each arm to be able to reject the
null hypothesis with 90% power at α=0.05 using one-­way analysis
of variance and a test ratio between the two groups of 1:1. We
recruited 100 women into each group to compensate for a 15%
dropout rate. Sample size calculation was done using G*Power
software version 3.1.2. 11
Data were coded and entered using SPSS version 25 (IBM,
Armonk, NY, USA). Data were summarized using mean ± SD,
median, minimum and maximum for numerical data, and frequency
(count) and relative frequency (percentage) for categorical data.
Comparisons between numerical variables were done using the non-
parametric Kruskal-­Wallis and Mann-­Whitney tests. For comparing
 |
104       Maged ET AL.

categorical data, the χ2 test was used. An exact test was used when
the expected frequency was less than 5. P<0.05 was considered
­statistically significant.
3 |  RESULTS
A flowchart of the participants through the study is given as Figure 1.
Baseline characteristics of the study participants were similar in terms
of age, parity, BMI, gestational age, and number of and indication for
previous cesarean deliveries (Table 1).
There was no significant difference between the two groups
regarding neonatal birth weight, induction of anesthesia to
extraction interval, duration of the cesarean procedure, or neona-
tal outcome including Apgar scores at 1 and 5 minutes and NICU
admission (Table 1).
Intraoperative blood loss was significantly lower in women
who received misoprostol preoperatively compared with those in
the postoperative group (528.7 ± 114.8 mL vs 788.6 ± 165.8 mL,
P<0.001). Blood loss during the first 24 hours after delivery was
also significantly lower in the preoperative group (199.3 ± 84.5 mL
vs 302.9 ± 125.6 mL, P<0.001). Fewer women in the preoperative
group needed additional uterotonics compared with the postopera-
tive group (7 vs 21, P<0.001) (Table 2).
Although preoperative hemoglobin and hematocrit levels were
comparable in both groups, the decrease to postoperative levels
was significantly less among women in the preoperative miso-
prostol group compared with the postoperative group for both
hemoglobin (−6.8 vs −12.8%, P<0.001) and hematocrit (−6.05 vs
−17.8%, P<0.001) (Table 2).
There was no significant difference between the two groups
regarding mean arterial blood pressure and heart rate changes during

Enrollment Assessed for eligibility (n=230)

Excluded (n=30)
♦ Not meeting inclusion criteria (n=20)
♦ Declined to participate (n=3)
♦ Other reasons (n=7)

Randomized (n=200)

Allocation
Allocated to intervention (n=100) Allocated to intervention (n=100)
♦ Received allocated intervention (n=100) ♦ Received allocated intervention (n=100)
♦ Did not receive allocated intervention (give ♦ Did not receive allocated intervention (give
reasons) (n=0) reasons) (n=0)

Follow-up
Followed up (n=100) Followed up (n=100)

Analysis
Analysed (n=100) Analysed (n=100)

F I G U R E   1   Flow chart of participants through the study.

Maged ET AL. |
      105

T A B L E   1   Characteristics of the participants, cesarean procedure, and neonates.a

Characteristics Preoperative group (n=100) Postoperative group (n=100) P value

Age, y 27.3 ± 4.4 27.6 ± 4.8 0.93

Parity 2.3 ± 0.9 2.4 ± 0.9 0.48
Body mass index 28.5 ± 2.7 28.4 ± 3.0 0.8
Gestational age, wk 38.8 ± 1.1 38.8 ± 1.1 0.7
Number of previous cesareans 1.6 ± 0.5 1.7 ± 0.7 0.18
Indication for cesarean 0.712
Repeat cesarean 49 46
Malpresentation 40 39
Cephalopelvic disproportion 7 9
Other 4 6
Neonatal birth weight, g 3289 ± 512 3351 ± 601 0.521
Induction of anaesthesia to extraction interval, min 3.9 ± 1.1 4.2 ± 1.2 0.428
Duration of cesarean, min 44.8 ± 13.9 46.8 ± 15.1 0.232
Neonatal outcome
Apgar score, 1 min 7.04 ± 1.49 7.12 ± 1.38 0.418
Apgar score, 5 min 8.69 ± 1.06 8.79 ± 1.04 0.350
NICU admission 9 10 0.833
Cause of NICU admission 0.412
Respiratory distress syndrome 5 7
Transient tachypnea 2 2
Neonatal jaundice 2 1
a
Values are presented as mean ± SD or number.

and 12 hours after the procedure (Figs 2 and 3), or the need for blood The present study found that misoprostol administration prior to
transfusion (P=0.819) (Table 2). the start of the cesarean was associated with less need for additional
uterotonics. This finding was supported by previous studies.8,14,15

4 | DISCUSSION

Preoperative administration of rectal misoprostol (400 μg after anesthe- T A B L E   2  Comparison of outcome parameters between the
preoperative and postoperative groups for rectal administration
sia/catheterization and 400 μg following abdominal closure) significantly
of misoprostol.
reduced intraoperative blood loss during cesarean delivery. The drop in
both hemoglobin and hematocrit levels was significantly lower in women Preoperative Postoperative
Outcome group (n=100) group (n=100) P value
who received misoprostol preoperatively. Furthermore, administration
of preoperative misoprostol achieved less blood loss during the first Estimated blood loss, mL 528.7 ± 114.8 788.6 ± 165.8 <0.001
24 hours after the procedure compared with women in the postoperative Blood loss during first 199.3 ± 84.5 302.9 ± 125.6 <0.001
group who received rectal misoprostol only after closure of the abdomen. 24 h, mL

Lower intraoperative and postoperative blood loss can be explained Hemoglobin gm/dL

because the oral and sublingual routes allow rapid absorption and reach Preoperative 11.7 ± 1.7 11.7 ± 1.6 0.875
12
peak level after 12 minutes, with a 20–30-­minute half-­life ; in contrast, Postoperative 10.9 ± 1.4 10.2 ± 1.5 0.041

the vaginal and rectal routes are associated with a slower absorption rate Percentage change −6.8 −12.8 <0.001

and a peak level after 60 minutes. 13

This means that by the end of the Hematocrit, %

cesarean procedure, misoprostol has reached its highest bioavailability.6 Preoperative 34.7 ± 4.7 34.8 ± 4.9 0.826
8
Elsedeek investigated the value of preoperative administration of Postoperative 32.6 ± 4.2 28.6 ± 4.6 0.032
rectal misoprostol at cesarean delivery and reported decreased intra- Percentage change −6.05 −17.8 <0.001
operative and postpartum blood loss, resulting in higher hemoglobin Need for additional 7 21 <0.001
and hematocrit levels in the study group compared with the placebo uterotonics
group. However, the main disadvantage of the study was the use of Need for blood 2 3 0.819
transfusion
only towel weighing to estimate blood loss.
 |
106       Maged ET AL.

Preoperative Postoperative El-­Refaey and Rodeck14 and Abd-­Ella et al.17 demonstrated the
misoprostol group misoprostol group greater efficiency of preoperative compared with postoperative miso-
120 prostol administration to reduce blood loss. However, they reported
higher rates of adverse effects with preoperative use of misoprostol.
110
We suggest that these adverse effects were related to the higher dose
100
(600 μg) used in their studies.
90 Ragab et al.6 confirmed that use of preoperative rectal misoprostol
mm Hg

80 was associated with reduced intraoperative and postoperative blood

70
60
50
40
F I G U R E   2   Change in mean arterial blood pressure in the
preoperative and postoperative rectal misoprostol groups.
No harmful effects on maternal vital signs or fetal/neonatal effects
were observed in the present study. This was evident through similar
maternal vital signs, neonatal Apgar scores, and NICU admission rates
in the two groups.
The rectal route of misoprostol administration was chosen in the
present study to avoid any adverse effects on the mother and fetus.
Rectal administration has slow absorption, a prolonged effect, low peak
levels, and fewer adverse effects. A low dose of 400 μg was chosen to
minimize the adverse effects of misoprostol in general, and timing with
catheterization before skin incision would allow enough time for absorp-
tion (maximum levels are reached within 40–60 minutes, although other
studies have reported 20 minutes8,16 to affect intrapartum and postpar-
tum blood loss without causing adverse effects to the unborn baby.8,16
Preoperative misoprostol Postoperative
misoprostol
120
115
110
105
100
beat/min.
loss without inducing adverse effects compared with postoperative use.
Most of the previous studies evaluating preoperative misoprostol
used the sublingual route of administration, which is associated with
a rapid rise in concentration and a less sustained level than the rectal
route. Some studies that have investigated the rectal route used a less
accurate method for estimating blood loss. The present study used
two methods.
Although previous studies have shown that preoperative miso-
prostol administration reduced bleeding at cesarean delivery, the pres-
ent study has several strengths: (1) rectal administration was proved
effective for the reduction of intraoperative bleeding and no neona-
tal adverse effects were observed; (2) the administration dose was
revised; and (3) two methods of blood loss estimation were employed,
allowing greater accuracy.
The present study is not without limitations. Absence of double
blinding and the relatively small sample size to demonstrate the bene-
fits of misoprostol in minimizing PPH are limitations.
In conclusion, use of preoperative rectal misoprostol to mini-
mize intraoperative blood loss at cesarean delivery is recommended.
However, it should be used with caution, especially if delay in fetal
extraction was expected as in those with marked adhesions.
AU T HO R CO NT R I B U T I O NS
AMM: project design, data analysis, and manuscript writing. TF: data
analysis and manuscript revision. MS, AS, and MAR: data collection and
manuscript revision. ASA: data collection and manuscript writing. EAH:
data analysis and manuscript writing. BH: data re-­analysis and manu-
script revision. WSD: data analysis revision and manuscript revision.
CO NFL I C TS O F I NT ER ES T
The authors have no conflicts of interest.

95
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