CLINICAL ARTICLE

Accepted Article
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. Ali3, Eman A. Hussein1, Bahaa Hammad1, Wesam S. Deeb4

1
Department of Obstetrics and Gynecology, Kasr Al-Ainy Hospital, Cairo University,

Cairo, Egypt
2
Department of Obstetrics and Gynecology, Al Azhar University, Cairo, Egypt
3
undergraduate student, Al Azhar University, Cairo, Egypt
4
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

Keywords: Egypt; Elective cesarean delivery; Intraoperative blood loss; Misoprostol;

Postpartum hemorrhage; Randomized controlled trial; Rectal route

Synopsis: Preoperative administration of misoprostol significantly reduced

intraoperative and postoperative blood loss during and after cesarean delivery.

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1002/ijgo.12922
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 Abstract

Objective: To assess the safety and efficacy of preoperative rectal misoprostol for
Accepted Article
the prevention of intraoperative and postoperative blood loss in women undergoing

elective 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 ug rectal misoprostol at urinary catheter insertion

plus 400 ug rectally after abdominal closure (preoperative group, n=100) or 800 ug of

rectal misoprostol after abdominal closure (postoperative group, n=100). Primary

outcome was intraoperative blood loss.

Results: Intraoperative blood loss was significantly lower in the preoperative

misoprostol 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 preoperative group (–6.8 vs –12.8% and –6.05 vs

–17.8%, respectively; P<0.001).

Conclusion: Preoperative rectal administration of misoprostol significantly reduced

intraoperative and postoperative blood loss during and after elective cesarean

delivery.

ClincalTrial.gov ID: NCT03680339. Date of registration 9/2018

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 1 Introduction

The incidence of cesarean delivery has increased in both high- and low-income
Accepted Article
countries, ranging from 20%–30% worldwide [1]. Postpartum hemorrhage (PPH)

accounts for 50% of maternal mortality in low-income countries [2]. Blood loss during

cesarean delivery is almost double the amount lost during vaginal delivery (1000 mL

vs 500 mL) [3].

Various uterotonics are used to minimize intraoperative and postoperative bleeding

during cesarean, including oxytocin, methylergometrine 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, sublingual, 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 acidity and the bacterial

microenvironment [7]. Sublingual route has the highest peak concentration [7], 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, they are also

associated with the highest incidence of adverse effects due to high peak

concentration [8]. Rectally administered misoprostol is associated with slower

absorption, lower peak concentration levels, and reduced adverse effects compared

with the oral and sublingual routes [9].

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 Most previous studies involving misoprostol have investigated PPH after vaginal
Accepted Article
delivery. Some studies have reported on the prevention 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 criteria were

hypertension; diabetes; heart, kidney, or liver disorders; known allergy to

misoprostol; contraindication to use of misoprostol; or women who had undergone

any previous uterine surgery, such as myomectomy. Women at higher risk of

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 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

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excluded.

Before surgery, all women underwent full history-taking and careful examination to

ensure adherence to the inclusion and exclusion criteria. 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 ug rectal misoprostol just after spinal anesthesia and

insertion of the urinary catheter and another 400 ug rectally after closure of the

abdomen (preoperative group) or 800 ug 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) intramuscularly. 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 obstetrician with over five

years of experience. All procedures were performed using the Munro-Kerr method

through a Pfannenstiel incision, immediate cord clamping after delivery of the baby,

double-layer closure of the uterus, and closure of the abdomen in layers.

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 Intraoperative blood loss was calculated using two methods and considered mean

amount lost. The first method used the formula:

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Blood loss = estimated blood volume (EBV) x 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].

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 Data were coded and entered using SPSS version 25 (IBM, Armonk, NY, USA).

Data were summarized using mean ± SD, median, minimum and maximum for
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numerical data, and frequency (count) and relative frequency (percentage) for

categorical data. Comparisons between numerical variables were done using the

nonparametric Kruskal-Wallis and Mann-Whitney tests. For comparing 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 neonatal 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

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 additional uterotonics compared with the postoperative group (7 vs 21, P<0.001)

(Table 2).
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Although preoperative hemoglobin and hematocrit levels were comparable in both

groups, the decrease to postoperative levels was significantly less among women in

the preoperative misoprostol 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 and 12 hours after the procedure

(Figures 2 and 3), or the need for blood transfusion (P=0.819) (Table 2).

4 Discussion

Preoperative administration of rectal misoprostol (400 ug after

anesthesia/catheterization and 400 ug following abdominal closure) significantly

reduced intraoperative blood loss during cesarean delivery. The drop in both

hemoglobin and hematocrit levels was significantly lower in women who received

misoprostol preoperatively. Furthermore, administration of preoperative misoprostol

achieved less blood loss during the first 24 hours after the procedure compared with

women in the postoperative group who received rectal misoprostol only after closure

of the abdomen.

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 Lower intraoperative and postoperative blood loss can be explained because the oral

and sublingual routes allow rapid absorption and reach peak level after 12 minutes,
Accepted Article
with a 20–30-minute half-life [12]; in contract, the vaginal and rectal routes are

associated with a slower absorption rate and a peak level after 60 minutes [13]. This

means that by the end of the cesarean procedure, misoprostol has reached its

highest bioavailability [6].

Elsedeek [8] investigated the value of preoperative administration of rectal

misoprostol at cesarean delivery and reported decreased intraoperative and

postpartum blood loss, resulting in higher hemoglobin and hematocrit levels in the

study group compared with the placebo group. However, the main disadvantage of

the study was the use of only towel weighing to estimate blood loss.

The present study found that misoprostol administration prior to the start of the

cesarean was associated with less need for additional uterotonics. This finding was

supported by previous studies [8,14,15].

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

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 general, and timing with catheterization before skin incision would allow enough time

for absorption (maximum levels are reached within 40–60 minutes, although other
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studies have reported 20 minutes [8,16] to effect intrapartum and postpartum blood

loss without causing adverse effects to the unborn baby [8,16].

El-Refaey and Rodeck [14] and Abd-Ella et al. [17] demonstrated the greater

efficiency of preoperative compared with postoperative misoprostol administration to

reduce blood loss. However, they reported higher rates of adverse effects with

preoperative use of misoprostol. We suggest that these adverse effects were related

to the higher dose (600 μg) used in their studies.

Ragab et al. [6] confirmed that use of preoperative rectal misoprostol was associated

with reduced intraoperative and postoperative blood 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 misoprostol administration

reduced bleeding at cesarean delivery, the present study has several strengths: (1)

rectal administration was proved effective for the reduction of intraoperative bleeding

and no neonatal adverse effects were observed; (2) the administration dose was

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 revised; and (3) two methods of blood loss estimation were employed, allowing

greater accuracy.
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The present study is not without limitation. Absence of double blinding and the

relatively small sample size to demonstrate the benefits of misoprostol in minimizing

PPH are limitations.

In conclusion, use of preoperative rectal misoprostol to minimize 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.

Author contributions

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-analysisa and manuscript revision. WSD: data analysis revision

and manuscript revision.

Conflicts of interest

The authors have no conflicts of interest.

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 REFERENCES

[1] Sweed MS, El-Saied MM, Abou-Gamrah AE, et al. Rectal vs. sublingual
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misoprostol before cesarean section: double‑ blind, three‑ arm , randomized

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and after elective cesarean delivery. Int J Gynecol Obstet 2012;118:149–52

[9] Khan RU, El-Refaey H. Pharmacokinetics and adverse-effect profile of rectally

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 [16] Tang OS, Gemzell-Danielsson K, Ho PC. Misoprostol: pharmacokinetic

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Figure legends

Figure 1. Flow chart of participants through the study.

Figure 2. Change in mean arterial blood pressure in the preoperative and

postoperative rectal misoprostol groups.

Figure 3. Change in heart rate in the preoperative and postoperative rectal

misoprostol groups.

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 Table 1.

Characteristics of the participants, cesarean procedure, and neonates.a

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Characteristics Preoperative Postoperative P value
group (n=100) group (n=100)
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 3.9 ± 1.1 4.2 ± 1.2 0.428
interval, min
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.

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 Table 2.
Comparison of outcome parameters between the preoperative and postoperative groups for rectal
administration of misoprostol.
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Outcome Preoperative Postoperative P value
group (n=100) group (n=100)
Estimated blood loss, mL 528.7 ± 114.8 788.6 ± 165.8 <0.001
Blood loss during first 24 hours, mL 199.3 ± 84.5 302.9 ± 125.6 <0.001
Hemoglobin gm/dL
Preoperative 11.7 ± 1.7 11.7 ± 1.6 0.875
Postoperative 10.9 ± 1.4 10.2 ± 1.5 0.041
Percentage change –6.8 –12.8 <0.001
Hematocrit %
Preoperative 34.7 ± 4.7 34.8 ± 4.9 0.826
Postoperative 32.6 ± 4.2 28.6 ± 4.6 0.032
Percentage change –6.05 –17.8 <0.001
Need for additional uterotonics 7 21 <0.001
Need for blood transfusion 2 3 0.819

a
Values are presented as mean ± SD or number.

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Accepted Article
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)

Figure 1. Flow chart of participants through the study.

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 120

110
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100

90
mm Hg

80 Preoperative
misoprostolGroup
70
Postoperative
60 misoprostol group
50

40

Figure 2. Change in mean arterial blood pressure in the preoperative and postoperative rectal
misoprostol groups.

120
115
110
105
beat/min.

100
95 Preoperative misoprostol
90
85 Postoperative
80 misoprostol
75
70

Figure 3. Change in heart rate in the preoperative and postoperative rectal misoprostol groups.

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