Misoprostol and active management of the third stage of labor

International Journal of Gynecology and Obstetrics (2006) 94, 149 — 155
www.elsevier.com/locate/ijgo
SPECIAL ARTICLE
Misoprostol and active management of the third
stage of labor
N. Prata a,*, S. Hamza b,1, R. Gypson b,1, K. Nada b,1,
F. Vahidnia a, M. Potts a
a
Bixby Program in Population, Family Planning and Maternal Health, School of Public Health, University of
California, Berkeley, USA
b
John Snow Inc, Healthy Mother/Healthy Child, Maadi, Cairo, Egypt
Received 22 December 2005; received in revised form 5 May 2006; accepted 25 May 2006
KEYWORDS
Postpartum
hemorrhage;
Misoprostol;
Active management
of the third stage
of labor
Abstract
Objective: To compare current practices for the active management of the third
stage of labor (AMTSL) with the use of 600 Ag of oral misoprostol. Methods: An
operations research study was designed to compare blood loss with current AMTSL
practices and misoprostol use. Results: Women in the misoprostol group were less
likely to bleed 500 ml or more (adjusted odds ratio, 0.30; 95% confidence interval,
0.16—0.56) compared with those in the current practices group. In the current
practices group 73% women required interventions because of postpartum hemorrhage, compared with 11% in the misoprostol group. Conclusion: In situations where
oxytocin and or ergometrine are not consistently and appropriately used during third
stage of labor, misoprostol should be considered for inclusion in the AMTSL protocol.
D 2006 International Federation of Gynecology and Obstetrics. Published by
Elsevier Ireland Ltd. All rights reserved.
1. Introduction
* Corresponding author. 314 Warren Hall, Berkeley, CA 947207360, USA. Tel.: +1 510 643 4284; fax: +1 510 643 8236.
E-mail address: [email protected] (N. Prata).
1
At the time of the study the authors were working for The
Healthy Mother Healthy Child Project; implemented by John
Snow Inc. in Egypt under United States Agency for International
Development (USAID) Contract No. 263-C-00-98-0041-00.
In Egypt, although the maternal mortality ratio
decreased from 174 to 84 per 100,000 live births
between 1992—1993 and 2000, for a 52% reduction,
the distribution of causes of death has not changed
[1]. According to the National Maternal Mortality
Study conducted in Egypt in 2000, postpartum
hemorrhage (PPH) alone was responsible for 27%
0020-7292/$ - see front matter D 2006 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd.
All rights reserved.
doi:10.1016/j.ijgo.2006.05.027
150
of all maternal deaths, making it the leading
contributor to maternal mortality in that country.
Routine active management of the third stage of
labor (AMTSL) has been recommended for vaginal
deliveries in hospital settings [2,3]. It involves
prophylactic administration of uterotonic agents
before delivery of the placenta, early cord clamping and cutting, and controlled umbilical cord
traction. Recommended uterotonics are oxytocin
(10 IU administered intramuscularly or intravenously or an infusion of 20 IU intravenously) or ergometrine (0.2 mg intramuscularly or intravenously) [4].
In contrast, in expectant management of the third
stage of labor, placental delivery is spontaneous or
aided by gravity or nipple stimulation—without the
use of uterotonics.
In Egypt, the most recent essential obstetric
care protocol for physicians, published by the
Ministry of Health and Population, describes both
active and expectant management of the third
stage of labor [5]. For active management, the
recommended uterotonic drug is oxytocin (5 IU)
administered intramuscularly at the time of the
delivery of the anterior shoulder. The protocol
suggests that oral tablets of ergometrine have little
effect on postpartum blood loss. Controlled cord
traction, i.e., traction on the cord combined with
upward counterpressure applied to the lower
segment of the uterus, is recommended by the
protocol to reduce blood loss and shorten the third
stage of labor. However, the protocol does not
encourage cord clamping immediately after delivery because of the perceived small effect on the
incidence of PPH, and it may deprive the newborn
of needed hemoglobin.
Misoprostol, an E1 prostaglandin analogue, is a
potent uterotonic agent whose usefulness is increasingly recognized in obstetric and gynecologic
practice, including in the control of PPH [6—8].
Misoprostol can be administered orally, rectally,
vaginally, or sublingually without syringes or intravenous equipment, and it is inexpensive, easy to
store and stable at room temperature [9]. Studies
comparing the results of prophylactic use of
misoprostol for the reduction of blood loss with
conventional uterotonics have concluded that
misoprostol had a positive effect [10—21]. Although
some studies have found that conventional uterotonics were superior to misoprostol, none has
rejected using misoprostol when injectable uterotonics are not available or cannot be properly used
[22,23]. Moreover, the 2003 conference on underused technology to reduce maternal mortality
organized by Parkway Academy of Technology and
Health in Bellagio, Italy, called for a greater
interest in the role of misoprostol in AMTSL [24].
N. Prata et al.
A careful analysis of the management of the
third stage of labor in an Egyptian teaching hospital
showed that only 15% of the women received
adequate AMTSL during the study period [25]. Staff
shortages were given as the main explanation for
the generally inappropriate management of deliveries, and that study’s findings are not unique. It is
in these widespread circumstances that, given its
ease of administration, misoprostol may have an
advantage over conventional, intramuscularly or
intravenously delivered uterotonics.
An operations research study was conducted at
three Egyptian hospitals to compare current AMTSL
practices with the use of 600 Ag of oral misoprostol
as the uterotonic agent.
2. Methods
Menya University Hospital, Assiut University Hospital
and Benha University Hospital were involved in the
study over a period of 6 months. Together, these 3
hospitals employ 73 obstetricians, perform on
average 700 deliveries per month, and have a
maternal mortality ratio of 363 per 100,000 live
births. According to hospital records, about 38% of
maternal deaths are due to PPH and the incidence of
PPH is about 5%.
At each study site, the research period was
divided into two phases, a pre-intervention phase
that occupied the first 3 months and an intervention phase that lasted through the last 3 months of
the study.
During the pre-intervention phase, trained staff
at the participating hospitals obtained informed
consent from women admitted for delivery (inclusion criteria were anticipated vaginal delivery,
gestational age N 36 weeks and ability to give
informed consent) and collected blood for antepartum estimation of hemoglobin concentration.
Women were excluded if they had bronchial
asthma, other chronic disease (e.g., heart disease
and/or diabetes), or any condition that could put
them at higher risk for poor delivery outcomes if
they participated in the study.
After delivery and clamping of the umbilical
cord, a calibrated drape was placed under the
women’s buttocks for blood loss measurement. The
calibrated drape remained in place for approximately 4 h following delivery, and blood loss was
read cumulatively every 20 min. Antepartum,
delivery and postpartum care were given to all
women according to standard practices at the
university hospitals. Postpartum hemoglobin concentration was assessed in women who needed to
be hospitalized for more than 24 h because of PPH.
Misoprostol and active management of the third stage of labor
During the pre-intervention phase, apart from
the use of the drape for blood loss collection,
physicians continued to use the current AMTSL
practices. In the intervention phase, all AMTSL
procedures were still encouraged but the only
uterotonic agent used prophylactically was misoprostol (600 Ag orally).
The same data collection instrument was used at
the three sites, and the data recording was done in
stages (upon admission, soon after delivery, every
20 min after delivery for up to 4 h, and before
discharge) by a physician trained as a clinical
research officer. Data collected from each participant included sociodemographic characteristics,
medical and obstetric history, assessment of blood
loss every 20 min for the first 4 h after delivery,
adverse effects of the intervention, any medication
or other intervention received by the participant
between admission and discharge, and condition of
the newborn. The Egyptian ethics committee
approved the study protocol, and the Healthy
Mother Healthy Child Project, implemented in
Egypt by John Snow Inc. under United States
Agency for International Development (USAID)
Contract No. 263-C-00-98-0041-00, was responsible
for study implementation. The misoprostol used
(Misotac; Sigma Co., Moubarak Industrial City, First
Quarter Quesna, Egypt) was donated by Ventures
Strategies for Health and Development.
The database was developed using the Epi Info
software system, version 2002 (available from the
Centers for Disease Control and World Health
Organization), and statistical analysis was performed using the Stata Statistical Software, release
8.0 (College Station, Tex, USA). Descriptive statistics were reported and the main outcomes estimated and compared between the two study
phases. Crude odds ratios (ORs) and 95% confidence
intervals (CIs) were estimated for the main study
outcomes. Adjusted ORs were estimated using a
logistic regression model and corresponding P
values (two-sided maximum likelihood test). Mean
blood loss at 20, 40, 60, 80, 100 and 120 min) and
95% CIs were estimated and compared between
study phases. Participants who were enrolled but
then had a cesarean section or an instrumentassisted delivery were excluded from the final
comparison analysis.
3. Results
A total of 2532 women were enrolled in the study,
53% of whom during the pre-intervention phase.
The participants’ sociodemographic as well as
pregnancy and medical history characteristics are
151
Table 1 Selected sociodemographic characteristics
and delivery history of women enrolled in the study
Characteristic
Pre-intervention
Intervention
Total
1343 (53%)
1189 (47%)
(%)
Mean age in
24.8 (5.2)
25.2 (5.2)
years (S.D.)
Parity (%)
0
36.1
34.6
1
29.7
26.0
2
18.3
19.9
3
8.5
8.5
4+
7.4
11.0
Education (%)
Illiterate
44.5
46.7
Literate
55.5
53.3
Ante partum
Hgba (g/dl) (%)
b11
25.0
18.9
z11
75.0
81.1
Antenatal care
visits (%)
None
38.1
37.5
One or more 61.9
62.5
Integrity of
membranes (%)
Intact
76.0
72.3
Ruptured
24.0
27.7
Time from admission to birth (h) (%)
b1
23.0
29.6
1—2.9
29.2
27.4
3—4.9
27.7
25.8
5+
20.1
17.1
25.0 (5.2)
35.4
27.9
19.1
8.5
9.2
45.5
54.5
22.4
77.6
37.8
62.2
74.3
25.1
26.1
28.3
26.8
18.7
a
Hemoglobin measured to 1807 patients only, 57% during
pre-intervention phase.
shown in Table 1. A majority of women (69%) were
aged between 20 and 29 years, with no significant
difference between the study phases, and 46% were
illiterate, with similar distributions in the preintervention (45%) and intervention (47%) phases.
Furthermore, the participants’ parity was similar in
the two study phases.
The pregnancy and medical histories taken upon
admission showed the similarity of the study populations in the two phases. Most women had at least
one antenatal visit. Hemoglobin levels were
assessed for only 1807 women, 57% of whom from
the pre-intervention phase. Less than 1% of women
in either study phase had experienced previous PPH
and retained placenta (data not shown).
The pre-intervention phase consisted in collecting information from current practices in the
management of the third stage of labor. During
this phase, 7% of the participants received no
uterotonic agent, and the remaining 93% received
either oxytocin or ergometrine (Table 2). Of those
receiving oxytocin (n = 609), about 35% received 5 IU
and the remaining received 10 IU or more. Of those
receiving ergometrine (n = 621), about half re-
152
N. Prata et al.
Table 2 History of third stage of labor among
women with vaginal deliveries
Pre-intervention
Early cord clamping
Cord traction
Uterine stage
Use of uteronics
None
Oxytocin or
ergometrine
Misoprostol
Intervention
1326 (53%)
1180 (47%)
96.9
98.4
97.2
99.2
99.4
99.1
7.2
92.8
n/a
n/a
n/a
100.0
ceived 0.4 mg and the remaining received 0.2 mg.
The route of administration for ergometrine was
intramuscular; for oxytocin, it was intramuscular
for those receiving 5 IU and intravenous for those
receiving 10 IU or more. During the intervention
phase, all participants received 600 Ag of misoprostol orally. Unlike the administration of uterotonics, which was not universal, uterine massage,
cord traction and early cord clamping were performed in almost all cases regardless of the study
phase.
The cumulative mean blood loss during each study
phase and respective 95% CIs around the mean are
presented in Fig. 1. On average, women enrolled
during the intervention phase and receiving misoprostol as part of AMTSL lost less blood than those
enrolled during the pre-intervention phase. Fig. 1
also shows that, for each time point after delivery,
the mean blood loss was significantly lower in the
intervention (misoprostol) than in the pre-intervention (current AMTSL practices) phase.
Statistically significant differences were observed between the pre-intervention and the
intervention groups regarding the amount of blood
loss at the two most important cut-off points for
Figure 1
vaginal bleeding after delivery (Table 3). Results
show that, when the blood loss was 500 ml or
greater, women in the misoprostol group were less
likely to incur PPH (adjusted OR, 0.30; 95% CI,
0.16—0.56). The difference between the two
groups was even more pronounced for severe PPH
(adjusted OR, 0.12; 95% CI, 0.02—0.93).
Additional uterotonic agents were given to 73%
of the women who experienced PPH in the preintervention phase, compared with only 11% in the
intervention group. Of the main potentially adverse effects measured 20 min after delivery,
women in the intervention group were consistently
more likely to develop high temperature (z 37 8C),
shivering, nausea and vomiting (Table 3). The
mean temperature of the participants was 37.1
8C in the pre-intervention group and 37.3 8C in the
intervention group, and less than 1% of the
participants needed to be treated for pyrexia.
Although nausea and vomiting affected only a
small number of participants, the number was
significantly higher in the intervention group.
A separate analysis that excluded the women
who did not receive uterotonics in the pre-intervention phase was performed for the main study
outcomes and a slightly but significantly lower
adjusted OR was found (0.36 vs. 0.30). The same
was found regarding the need for additional interventions. Without the women who did not receive
uterotonics, the adjusted OR for a blood loss of 1000
ml or greater was insignificant.
4. Discussion
This study was intended to provide information for
the review and possible revision of the current
Ministry of Health and Population policy in Egypt on
the management of the third stage of labor. It can
Cumulative mean blood loss and 95% confidence intervals according to study period (vaginal deliveries).
Misoprostol and active management of the third stage of labor
Table 3
153
Primary and secondary study outcomes among women with vaginal deliveries
Blood loss Z 500 ml
Blood loss Z 1000 ml
Additional interventions
Among those PPH
Among study participants
Main side effects
Temp. N 37 8C
Shivering
Nausea
Vomiting
Crude OR (95% CI)
Adjusted ORa (95% CI)
(1.6%)
(0.1%)
0.28* (0.17 to 0.47)
0.10** (0.01 to 0.79)
0.30* (0.16 to 0.56)
0.12** (0.02 to 0.93)
2/19
2/1178
(10.5%)
(0.2%)
1.04** (0.01 to 0.27)
0.04** (0.01 to 0.17)
0.02** (0.00 to 0.19)
0.03** (0.00 to 0.19)
280/1178
253/1119
73/1119
39/1115
(23.0%)
(22.6%)
(6.5%)
(3.5%)
2.80*
4.50*
2.90*
2.70**
1.63**
4.03*
3.74*
3.36*
Pre-intervention
(current practice)
Intervention
(misoprostol)
n
(%)
n
(%)
73/1324
11/1324
(5.5%)
(0.8%)
19/1178
1/1178
53/73
53/1324
(72.6%)
(4.0%)
169/1324
79/1297
30/1295
17/1295
(12.7%)
(6.1%)
(2.3%)
(2.3%)
(2.16
(3.45
(1.90
(1.50
to
to
to
to
3.53)
5.89)
4.50)
4.80)
(1.20.to 2.20)
(2.93 to 5.55)
(2.33 to 6.00)
(1.81 to 6.22)
*p b 0.05; **Fisher’s exact test.
a
Adjusted for parity, integrity of membranes, antenatal Hgb and time from admission to birth. Additional interventions among
those with PPH are adjusted for parity, integrity of membranes and time from admission to birth.
also help inform policy makers on the feasibility of
using misoprostol in AMTSL, especially in resourcepoor settings where other uterotonics are unavailable or wherever AMTSL is not practiced. In recent
years, an increasing body of literature has shown
the importance of using uterotonics in AMTSL, and
many international organizations, including FIGO,
recommend that uterotonics be used in all deliveries to decrease PPH-associated morbidity and
mortality. In Egypt, despite the success achieved
in overall reduction of maternal mortality in the
last decade, PPH continues to be the single most
important cause of maternal mortality.
The study sites chosen for this operations research study are university hospitals similar in
availability of staff, client volume and maternal
and neonatal outcomes, with similar experience
conducting operations research study in the labor
ward. The study was designed as a quasi experiment,
where the study factor was assessed and compared
between two groups without the use of randomization. These types of studies have limitations. They
do not test for the efficacy of a therapeutic or
prevention measure; they can introduce bias due to
greater attention from the care provider during the
intervention phase; and the lack of randomization
can introduce distortions in the results. However,
the efficacy of misoprostol has been well established
in other studies, some of them reviewed in the
present article, and the superiority of conventional
uterotonics is not being questioned in this study. The
major contribution of this type of design, as in the
present study, is to evaluate the effectiveness of a
planned intervention and suggest program and
policy changes in response to this evaluation.
Results from this study demonstrate that in a
busy hospital misoprostol can offer the optimum
care at delivery. These findings are in contrast to
those reported by Gulmezoglu et al. [22]. Theirs
was a randomized controlled experiment (oxytocin
vs. misoprostol), whereas the present study simply
standardized the btreatment effectQ with misoprostol while maintaining real-life labor ward
conditions. The main goal of this operations
research study was not to assess the efficacy of
uterotonics, but to assess the effectiveness of
implementing a standardized, easy to manage
intervention during the third stage of labor. The
similarity in the participants’ characteristics in the
pre-intervention and intervention phases is reassuring, and the women enrolled in both study
periods would have had a similar likelihood of
experiencing PPH.
This study’s findings about the quality of management of the third stage of labor, particularly
during the pre-intervention phase, are in agreement with what was found by Cherine et al. [25].
Day-to-day practice in delivery rooms can be
inconsistent, especially when uterotonics are used.
Dosages are not standardized and in some cases
uterotonics are not used. Regarding blood loss, the
observed differences were unexpectedly great,
which suggests that careful attention should be
paid to the chemical stability of ergometrine and
oxytocin. Available studies on delivery-related
blood loss do not address this issue and the present
study cannot address it. Moreover, the great
variation in doses and routes of administration of
uterotonics could have affected what constitutes
AMTSL. The difference in the mean blood loss
20 min after delivery is also surprising, given that
the intramuscular and intravenous routes are
expected to cause contractions earlier than the
oral route, and therefore to result in less blood
loss. However, it is difficult to assess how different
the present study population may be from other
154
study populations. To date, there are no available
published results of blood loss in the first 20 min
after prophylactic use of uterotonics. Studies tend
to report total blood loss using cut-off points (i.e.,
500, 750 and 1000 ml).
There exists a possibility of bias among health
care providers, who might have paid greater
attention in the intervention phase, but it cannot
be the only reason for the differences between the
two groups. Other components of active management (uterine massage, cord traction and early
clamping) were almost universally administered
and not significantly different between the two
study phases. Furthermore, the analysis of the
study population without the women who did not
receive uterotonics showed significant differences
between the two groups, and these differences
were in favor of the intervention. There was no
significant difference when severe blood loss
(z 1000 ml) only was considered, but this can be
attributed to the fact that severe PPH occurred in
less than 1% of the participants.
It is clear from the results that 600 Ag of oral
misoprostol can reduce total blood loss after
delivery. The advantage of using misoprostol is its
easy administration, and also the fact that only one
drug regimen is used. The downside of this potent
uterotonic is that women taking misoprostol are at
higher risk for a higher temperature, shivering,
nausea and vomiting. However, none of these
effects are life-threatening; a very small proportion of women require treatment to alleviate them;
and these effects can be easily managed by
delivery room staff. In summary, the benefits from
a substantial decrease in the number of women
that will develop PPH and in need of additional
uterotonics, outweigh the risks of side effects
associated with misoprostol.
In conclusion, misoprostol is a proven, potent
uterotonic agent. In situations where oxytocin and
or ergometrine are not consistently and appropriately used for active management of the third
stage of labor for various reasons (i.e. drug
shortage, shortage of staff to administer i.v./i.m.,
storage and or refrigeration problems, high caseload, etc.), misoprostol should be considered for
inclusion in the protocol for AMTSL.
N. Prata et al.
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