International Journal of Gynecology and Obstetrics (2006) 92, 10 — 18
Misoprostol in preventing postpartum hemorrhage:A meta-analysis
Epidemiology and Biostatistics, School of Public Health, University of California at Berkeley,Berkeley, CA, USA
Received 25 May 2005; received in revised form 3 October 2005; accepted 4 October 2005
Objective: To assess misoprostol’s ability to prevent postpartum hemorrhage
(PPH) where no alternatives exist. Comparison to oxytocics demonstrates how
similarly misoprostol achieves a level of effectiveness—obtainable only in
hospitals—in remote locations around the world. Method: Using the Mantel—
Haenszel fixed-effects model and the DerSirmonian and Laird random-effects
model, summary statistics indicated that misoprostol’s excess risk of PPH was only4% when compared to oxytocics. Result: This risk difference was well within therange of expected results for all uterotonic agents and does not warrant brandingmisoprostol as an inferior drug. Conclusion: Conventional uterotonic drugs shouldnot be used to set the lowest-accepted level of effectiveness in settings wherethey are entirely unsuitable. Continuing to weigh the benefits of one effectivedrug against another only delays the distribution of misoprostol in countries whereit is the only feasible choice and must be measured against no treatment at all. D 2005 International Federation of Gynecology and Obstetrics. Published by ElsevierIreland Ltd. All rights reserved.
quarter of these deaths . Most of these deathsoccur in the resource-poor countries of Africa and
The World Health Organization (WHO) estimated that
Asia, particularly in rural areas. Not surprisingly,
529,000 women died from obstetric causes in 2000
records of maternal mortality are poor or non-
. Postpartum hemorrhage (PPH), which afflicts
existent where it most often occurs, which implies
approximately 14 million women annually, caused a
that even these sobering estimates are greatlyunderestimated. Indeed, data in remote regions areso scarce and the methods of collection so varied thatthe WHO warns against the formulation of confidence
E-mail address: colangenbach@yahoo.com.
intervals around the available estimates.
0020-7292/$ - see front matter D 2005 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijgo.2005.10.001
Misoprostol in preventing postpartum hemorrhage: A meta-analysis
PPH is defined as blood loss of 500 mL or more
developing countries, where it is most needed.
within 24 h of delivery, but, this quantity is
Misoprostol’s value as a prophylactic uterotonic
extremely difficult to identify outside of a con-
drug lies in its ability to prevent PPH and reduce
trolled trial setting. Even trained physicians are
maternal mortality where no alternatives exist.
reported to typically underestimate blood loss by
Comparison to oxytocics should serve only to
about half While there are a few known risk
demonstrate how similarly misoprostol achieves a
factors, PPH occurrence is random, making it
level of effectiveness—obtainable only in hospi-
impossible to predict in both low and high risk
tals—in remote locations around the world. To
populations. Furthermore, blood loss can be rapid.
date, this is the largest meta-analysis ever con-
In developing countries, where nearly half the
ducted on the efficacy of misoprostol for the
women deliver without the aid of a skilled birth
attendant , there is simply not enough time toseek treatment for PPH, and in most cases none isto be had. The only way to help women without
access to trained attendants is through preventa-tive measures.
A literature search was conducted for all random-
The most successful method for reducing PPH,
ized control trials (RCT) which tested misoprostol’s
Active Management of the Third Stage of Labor
efficacy in preventing PPH. The electronic data-
(AMTSL), requires prophylactic uterotonic drugs
base PubMed (National Library of Medicine,
which are unsuitable for use in the remote loca-
Bethesda, MD) was searched for published articles,
tions where prevention is most needed. Nonethe-
along with the Cochrane CENTRAL database and the
less, this nearly universal method has set the
Population Council’s bibliographic website
precedent for a standard of care unavailable in
developing countries. The uterotonic drugs used in
ing terms used were: misoprostol and postpartum
AMTSL trials include oxytocics: oxytocin (Syn-
hemorrhage, coupled with: prevention and active
tocinonR, Alliance Pharmaceuticals, Chippenham,
management. References from published articles
UK or PitocinR, King Pharmaceuticals, Bristol, TN),
were pursued and primary authors contacted in
ergometrine malate (MethergineR, Novartis Phar-
order to uncover any unpublished RCTs. The search
maceuticals, East Hanover, NJ) and combinations of
was conducted irrespective of language of publica-
the two (SyntometrineR, Alliance Pharmaceuticals,
tion or geographic region. All studies matching the
Chippenham, UK) all of which must be administered
inclusion criteria and published before May 2005
by injection, which not only requires a sterile
needle, syringe and accurate dosing, but someoneto administer it. In addition, oxytocics are light-sensitive and require refrigeration to remain phar-macologically active, which limits their use to areas
with refrigeration and reliable sources of energyand increases their cost.
All RCTs which assessed misoprostol efficacy in
Misoprostol (CytotecR, Pfizer, New York, NY), a
preventing PPH during third trimester vaginal births
prostaglandin E1 analog, registered for the pre-
were reviewed for inclusion in this analysis. All
vention and treatment of gastric ulcers, is well-
studies, irrespective of dose, route of administra-
known for its off-label use as a uterotonic agent. It
tion (with the exception of vaginal administration
is inexpensive (one 200 g tablet is approximately
due to its infeasibility after a vaginal birth) or type
US$1 comes in tablets which can be admin-
of control substance, were included. Three out-
istered orally, rectally or sublingually, and does not
comes were selected before analysis began: blood
require refrigeration, dark storage or administra-
loss z500 mL, blood loss z1000 mL and the need
tion by an attendant. However, many studies have
for additional uterotonic agents. Because the side
found it to be slightly less effective than oxytocics
effects of all uterotonic drugs have been well
in controlled clinical settings. This circumstance
has had the result of branding misoprostol as an
ison to the life threatening alternative of PPH, side
inferior drug , despite repeated praise for
effects were not considered a relevant outcome for
the feasibility of its use in resource-poor settings
A total of 31 relevant studies were identified,
The objective of this review is to analyze all
but only 22 were selected for inclusion in the meta-
existing trial data in order to reframe the current
analysis. Six studies were excluded due to miso-
debate surrounding the use of misoprostol in
prostol being administered vaginally or after
.5 mg or Oxytocin 10 units orErgometrine 500 mg
a New studies since last meta-analysis.
Misoprostol in preventing postpartum hemorrhage: A meta-analysis
All doses and routes of administration were
pooled for three reasons. First, patients within
studies were already included in other trials
individual studies did not always receive the same
and could not be used independently. A final trial
was eliminated because it reported a pilot study
it impossible to distinguish between methods.
Although the pooling of patients given oxytocics
The studies which were included consisted of
of varying administrations has been heavily criti-
five placebo-controlled trials and 26 drug
cized, especially in the WHO multi-center trial
where intravenous and intramuscular administra-
but in two instances , where three different
heterogeneity only strengthened this meta-analy-
oxytocics were tested, two arms were excluded
sis. As oral, rectal and sublingual routes are known
from the meta-analysis since they could not be
to have slower up-take than intravenous or intra-
pooled and analyzed against the misoprostol arm
muscular injections, testing the three slowest
simultaneously. For these two trials, the oxytocin
methods against the two fastest biased the results
arm was selected for the analysis since it is the
against finding a similar relative risk. Therefore,
most common prophylactic uterotonic drug. Seven
the difference between misoprostol and oxytocics
found in this analysis was actually greater than if
published subsequent to the only other meta-
misoprostol had only been administered by its
analysis on the efficacy of misoprostol, published
fastest method (sublingual and oxytocics by
their slowest (intramuscularly). Second, numerousstudies on the efficacy of different oxytocics foundno significantly statistical difference in blood lossbetween them And third, comparison of
misoprostol to each of these individual drugs hasalready been well documented ; given these
Data were extracted from each study by the author,
caveats, the purpose of this analysis was to
who was not blinded. A validity analysis was
compare misoprostol to the de facto standard of
conducted to assess the methodological aspects of
care (i.e. the collective efficacy of any drug
each trial. Studies were scored from 0 to 10, using a
approved for PPH prevention), rather than any
For each outcome, a pooled risk ratio (RR) was
1) A research objective appropriate for this
calculated comparing misoprostol to oxytocics or
placebo. The Mantel—Haenszel fixed-effects model
2) Explicit inclusion and exclusion criteria
was used instead of the inverse-variance method
3) Exclusion of patients with labor augmentation
due to sparse outcome data. The test for hetero-
geneity was based on weights provided by the
inverse-variance method. When heterogeneity was
5) Reported baseline similarity between groups
detected, the DerSirmonian and Laird random-
effects model was used. Sensitivity analyses were
conducted to investigate the influence of individual
studies on the summary statistic by omitting each
9) No losses to follow-up before each outcome
study in turn. Egger’s weighted regression and
Begg’s rank correlation, where odds ratios were
10) Criteria for administration of additional ute-
plotted against study size, were used for the
detection of publication bias for each outcome.
Analysis of the data was performed using STATA
8.0 statistical software package (STATA Corpora-
tion, College Station, TX). The raw data publishedin each article were compiled in two-by-two tables.
A total of 30,017 participants were included in the
For only one study was it necessary to calculate cell
22 studies in the analysis, approximately half of
counts from the reported percentages How-
whom received misoprostol, with the remainder
ever, not every study reported data for each
specified outcome. When no data were provided,
However, in several instances when the studies
the study was dropped from the model.
reported a loss to follow-up for a specific outcome
a One included study only reported outcome measurements for 500 mL.
misoprostol to placebo (n = 1706) produced a RR of
the available data, not the original sample size, to
0.69 (95% CI: 0.53, 0.90). Thus, at this level
avoid the inherent presumption that those lost to
misoprostol demonstrates clear and statistically
follow-up were not cases. Due to the infrequent
significant reduction in the need for therapeutic
incidence of PPH, little difference was found
between the odds ratios (OR) and RR for any
The 15 studies (n = 26,870) comparing misopros-
tol and oxytocics for blood loss N500 mL produced a
Whereas five studies compared misoprostol and
RR of 1.4, which represents an excess risk (or risk
placebo use, only two reported blood loss N500 mL;
difference) of 5% greater incidence of blood loss
thus, no analysis was conducted for this outcome
level. Pooling the four studies reporting blood loss
studies, a comparison of the fixed effects estimate
N 1000 mL and one which only reported blood loss of
and the random effects estimate showed little
N 500 mL (n = 2112), misoprostol’s risk of
difference between the two models. Although it
PPH incidence over the risk of incidence with
initially appeared that the largest trial dom-
placebo was 0.85 (RR). Although misoprostol
inated the pooled estimates, removing this study
appeared to decrease the risk of PPH, this finding
did not significantly alter the results (RR: 1.39; 95%
was not statistically significant (95% CI: 0.63, 1.14).
CI: 1.219, 1.588). Further sensitivity analyses
One included study specifically stated that its
demonstrated that the heterogeneity present in
objective was to measure side effects and was
these models was the effect of the 15 varied
not intended to be an efficacy trial due to its lack
outcomes, not the effect of any single study.
of statistical power , which could help explain
The RR of 1.36 for the 11 studies reporting blood
this lack of significance. Of interest, including that
loss N1000 mL for misoprostol versus oxytocics
study with the three other trials reporting a need
(n = 25,448) only demonstrated a 1% excess risk of
for additional uterotonic agents when comparing
All studies evaluating misoprostol vs. placebo with outcome blood loss N1000 mL. Mantel—Haenszel fixed-
effects model. Heterogeneity chi-squared = 4.09 (df = 4), p = 0.394. I-squared (variation in RR attributable toheterogeneity) = 2.1%. Test of RR = 1: z = 1.08, p = 0.280. **Estimate reported for 500 mL or greater.
Misoprostol in preventing postpartum hemorrhage: A meta-analysis
All studies evaluating misoprostol vs. placebo with outcome of additional uterotonic agents. Mantel—
Haenszel fixed-effects model. Heterogeneity chi-squared = 1.62 (df = 3), p = 0.654. I-squared (variation in RRattributable to heterogeneity) = 0.0%. Test of RR = 1: z = 2.71, p = 0.007.
from this model produced a statistically insignifi-
many milliliters lost warranted further interven-
cant summary estimate (RR: 1.25; 95% CI: 0.94,
tion. Because rectal administration of misoprostol
0.167), however this outcome was found to be
requires a longer time to reach peak concentration
consistent with the other studies’ findings and was
levels than oral misoprostol it is possible that
many studies intervened with additional uterotonic
The random effects model of the 17 studies
agents before there was adequate time for the
comparing the need for additional uterotonic drugs
misoprostol to take effect. A sub-analysis of oral
in patients who received prophylactic misoprostol
and sublingual misoprostol revealed no statistical
to patients receiving oxytocics (n = 27,566) pro-
difference between misoprostol and oxytocics (RR:
duced a summary RR of 1.23 ). The hetero-
1.13, 95% CI: 0.81, 1.56). This observation strongly
geneity present in this model can, in large part, be
suggests that the rectal misoprostol had, in fact,
explained by the subjective point at which addi-
not yet peaked when additional uterotonic agents
tional uterotonic drugs were administered. Not
were administered. Therefore, inclusion of rectally
only did many studies estimate (as opposed to
administered misoprostol only masked the equiva-
measure) blood loss, but not one specified how
lency of oral and sublingual misoprostol to oxy-
All studies evaluating misoprostol vs. oxytocics with outcome blood loss N500 mL
95% CI = 95% Confidence intervals. M—H pooled RR = Mantel—Haenszel pooled risk ratios.
All studies evaluating misoprostol vs. oxytocics with outcome blood loss N1000 mL. Mantel—Haenszel fixed-
effects model. Heterogeneity chi-squared = 3.64 (df = 10), p = 0.962. I-squared (variation in RR attributable toheterogeneity) = 0.0%. Test of RR = 1: z = 4.41, p = 0.000.
tocics. Despite many misoprostol patients receiving
occurs in 5—18% of live births many trial
doses which had not fully taken effect, only 4%
findings were not statistically significant. The wide
more received therapeutic drugs than patients in
confidence intervals reflected the high probability
of chance in each of these trials. Therefore, the RRof each trial were not definitive estimates, as itwas impossible to distinguish between individual RR
with overlapping confidence intervals. However,the fact that the RR were consistent with individual
Due to the small sample sizes and PPH’s high
studies’ findings, demonstrated that the overall
variability in general (even with oxytocics PPH
risk of PPH when misoprostol was used was only 4%
All studies evaluating misoprostol vs. oxytocics with outcome of additional uterotonic agents. DerSirmonian
and Laird random-effects model. Heterogeneity chi-squared = 343.00 (df = 16), p = 0.000. I-squared (variation in RRattributable to heterogeneity) = 95.3%. Estimate of between-study variance Tau-squared = 0.2171. Test of RR = 1:z = 1.47, p = 0.141.
Misoprostol in preventing postpartum hemorrhage: A meta-analysis
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No. 06-1249 In the Supreme Court of the United States On Petition for a Writ of Certiorari to the Vermont Supreme Court BRIEF OF AMICI CURIAE PRODUCT LIABILITY ADVISORY COUNCIL, INC. AND U.S. CHAMBER OF COMMERCE IN SUPPORT OF PETITIONER Washington, DC 20006(202) 263-3000 1615 H Street, N.W. Washington, D.C. 20062 TABLE OF CONTENTS The Decision Below Thwarts Important
Paxil Litigation Going Strong on Multiple Fronts By C. Richard Newsome, Esq. and Jerri H. Coletti, Esq. Litigation surrounding the antidepressant drug Paxil continues to develop and evolve around the country. During the past year, Plaintiffs won a key victory in the first case to go to trial alleging birth defects caused by Paxil. The second birth defects case ended in dismissal. A large nu