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7/25/2019 jurnal bagus obgyn
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1thebmj BMJ2015;350:g217 doi: 10.1136/bmj.h217
Centre or Womens HealthResearch, University oLiverpool and LiverpoolWomens Hospital, Liverpool LSS, UKSchool o Social andCommunity Medicine, Universityo Bristol, Bristol BS PS, UK
Correspondence to:Z Alfirevic [email protected]
Additional material is publishedonline only. To view please visitthe journal online ( http://dx.doi.org/./BMJ.h)
Cite this as: BMJ;:hdoi: ./bmj.h
Accepted: December
Labour induction with prostaglandins: a systematic review and
network meta-analysis
Zarko Alfirevic,Edna Keeney,Therese Dowswell,Nicky J Welton,Sofia Dias,Leanne V Jones,Kate Navaratnam,Deborah M Caldwell,
ABSTRACT
OBJECTIVES
To assess the effectiveness and saety o
prostaglandins used or labour induction.
DESIGN
Systematic review with Bayesian network meta-
analysis
DATA SOURCES
The Cochrane Pregnancy and Childbirth Groups
Database o Trials (which incorporates the results o a
broad generic search or all pregnancy and postpartum
trials). Sources included are CENTRAL, Medline,Embase, NHS Economic Evaluation Database, CINAHL,
relevant journals, conerence proceedings, and
registries o ongoing trials.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES
Randomised clinical trials o prostaglandin or
prostaglandin analogues used or third trimester
cervical ripening or labour induction versus placebo or
no treatment, alternative prostaglandin dose or
administration, or a different type o prostaglandin. We
included studies recruiting women with a viable etus,
but had no other restrictions relating to indication or
labour induction or language o publication. Outcomes
assessed were serious neonatal morbidity (trialist
defined) or perinatal death; serious maternal
morbidity (trialist defined) or death; vaginal delivery
not achieved within hours, caesarean section, and
uterine hyperstimulation with etal heart rate changes.
RESULTS
randomised clinical trials were included (
women) in the review. Maternal and neonatal mortality
and serious morbidity were rarely reported and are
summarized narratively. Unresolved inconsistency was
observed or the hyperstimulation outcome. Relative
to placebo, the odds o ailing to achieve a vaginal
delivery were lowest or vaginal misoprostol ( g)
(odds ratio . (% credible interval . to .)),
with a % absolute probability o event (% credible
interval % to %). Compared with placebo, odds o
caesarean section were lowest or titrated oral
misoprostol solution (
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evidence, both direct and indirect, a network meta-anal-
ysis produces estimates o the relative effects o each
treatment compared with all others in the network,
even i not all treatments have been directly compared
with each other. It is then possible to calculate the prob-
ability o one treatment being the best or a specific out-
come; in this way different treatment options can be
ranked rom best to worst or each outcome.
In this paper we present a network meta-analysis to
quantiy the effects and saety o different prostaglan-
dins used or labour induction. Originally conceived as
a standalone investigation, it is now also part o a larger
project looking at all methods or labour induction
(PROSPERO :CRD).
Methods
Search strategy and selection criteria
To identiy potentially eligible trials, we searched the
Cochrane Pregnancy and Childbirth Groups Database
o Trials (which incorporates the results o a broad
generic search or all pregnancy and postpartum trials).
Sources searched were CENTRAL, Medline, Embase,
NHS Economic Evaluation Database, CINAHL, relevant
journals, conerence proceedings, and registries o
ongoing trials. The ull text o every relevant trial report
was obtained and assigned to a topic depending on the
intervention beore adding to the database. This
approach leads to a more specific search. We then
screened all reports assigned to the induction o
labour topic. The detailed search strategy, along with
reerences or all reports identified by the search, are in
appendices . Inormation relating to the characteris-
tics o the included studies and different doses and reg-
imens used are outlined in appendices and . Thelatest search was completed in March .
We included all randomised clinical trials comparing
a prostaglandin or prostaglandin analogue used or
third trimester cervical ripening or labour induction
with placebo or no treatment, with the same prosta-
glandin administered by a different route or dose, or
with a different type o prostaglandin. We included only
studies recruiting women with a viable etus but had no
other restrictions relating to indication or labour
induction, language, or date o publication.
We included different types o prostaglandin or
prostaglandin analogue: vaginal prostaglandin Eas
tablets, gel, pessary, or sustained release pessary; intra-cervical prostaglandin E; prostaglandin F gel; vagi-
nal misoprostol tablet (dose
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treatment effect estimates to inormally assess agree-
ment. Studies with or % events in all arms were
excluded rom the analysis because these studies pro-
vide no evidence on relative effects.For studies with
a or % events in one arm only, we planned to
analyze the data without continuity corrections where
computationally possible. To avoid double counting o
events, multi-arm trials were analysed in their original
orm without the need to combine treatment arms.
Both fixed and random effects models (accounting
or the correlations induced between trial-specific
effects in multi-arm trials) were considered on the basis
o model fit. Goodness o fit was measured using the
posterior mean o the residual deviance, the degree o
between-study heterogeneity, and the deviance inor-
mation criterion. In a well fitting model the posterior
mean residual deviance should be close to the number
o data points.Heterogeneity was reported as the
posterior median between-trial standard deviation ()
with its % credible interval. Differences o points
or deviance inormation criterion were considered
meaningul.
Consistency between the different sources o evi-
dence was explored statistically by comparing the fit o
a model assuming consistency with a model which
allowed or inconsistency.I the inconsistency model
had the smallest posterior mean residual deviance, het-
erogeneity, or deviance inormation criterion value then
this indicates potential inconsistency in the data.
Where model fit was indicative o inconsistency, we
firstly planned to restrict analysis to those trials with
adequate allocation concealment. I this did not resolve
apparent inconsistency we planned urther subgroup
analyses using potential treatment effect modifiersidentified as being unevenly distributed across the
treatments. The impact o removing placebo and
no-treatment nodes rom the network was also exam-
ined in sensitivity analyses, because o the possibility
that such trials may have included lower risk popula-
tions than head-to-head comparisons o active treat-
ments.
Full details o priors and convergence checks are
given in appendix , but they are briefly summarized
here. Vague prior distributions were specified or treat-
ment effect and heterogeneity parameters. Convergence
was assessed using the Brooks-Gelman-Rubin diagnos-
tic plotsand was satisactory by simulationsor all outcomes. A urther simulation sample o at least
iterations post-convergence was obtained on
which all reported results were based.
Relative treatment effects are reported as posterior
median odds ratios and % credible intervals. We cal-
culated the probability o each treatment being first,
second, third, etc, most effective or each outcome. As
this metric can be unstable, the posterior median o the
ranking o each treatment (and % credible intervals)
are also reported, with the convention that the lower
the rank the better the treatment. The absolute proba-
bility o an event on each treatment was also calculated
by applying the log odds ratios to the log odds esti-mated rom a synthesis o reerence treatment (placebo)
arms.We used this to inorm the calculation o the
number needed to treat to harm (all events considered
here are undesirable). For the interested reader, poste-
rior median risk ratios are also reported in appendix
(table ).
Results
The search identified studies ( reports) poten-
tially eligible or inclusion in the review. O these,
studies were excluded (see fig or reasons or exclu-
sion). We included studies in the systematic review,
and data were available or at least one o our outcomes
or women. The data used in the analyses are
reported in appendix (tables ).
The complete comparison networksincluding
randomised controlled trials o prostaglandins exam-
ining different regimens, no treatment, and pla-
ceboare presented in figure or ailure to achieve
vaginal delivery in hours, caesarean section, uter-
ine hyperstimulation, serious neonatal morbidity or
perinatal death, and serious maternal morbidity or
death.
Vaginal delivery not achieved within -hours
Afer the exclusion o trials with zero events in all arms,
trials were available or network analysis. There were
no trials remaining that compared prostaglandin F.
Meaningul differences were observed in posterior
mean residual deviance and deviance inormation
Studies identified through searching Cochrane Pregnanyand Childbirth Group database of trials (n=; reports)
No of arms relating to different treatments (n=): No treatment (n=) Placebo (n=) Vaginal prostaglandin Etablet (n=) Vaginal prostaglandin Egel (n=) Vaginal prostaglandin Epessary (slow release) (n=) Prostaglandin Fgel (n=) Intracervical prostaglandin E(n=) Vaginal prostaglandin Epessary (normal release) (n=)
Vaginal misoprostol (dose
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VagPGEtablet = Vaginal prostaglandin Etablet; VagPGEgel = Vaginal prostaglandin Egel; VagPGEpessarySR = Vaginal prostaglandin Epessary (slow release);cxPGE = Intracervical prostaglandin E; VagPGEpessary = Vaginal prostaglandin Epessary (normal release); VagPGF gel = Vaginal prostaglandin Fgel;VagMiso mcg
OMisomcg
VagMiso>mcg
VagMiso
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criterion values, suggesting that, or the ull network,
the inconsistency model is preerred over the consis-
tency model (appendix , table ). To explore the source
o the observed inconsistency, we conducted a pre-spec-
ified sensitivity analysis examining the effect o remov-
ing trials at high risk o bias rom the network. The
random effects model, excluding these trials, provided
an adequate fit to the data (appendix , table ), and
reported results are based on this model, with trials
(Table, and fig ).
Despite the observation o high between-trials het-
erogeneity ( =. (% credible interval . to .))
(relative to the size o the treatment effect estimates as
measured on the log odds scale), there was strong
evidence that all prostaglandins increased the odds o
achieving a vaginal birth within hours when com-
pared with placebo (Table ). When active treatments
were compared, out o comparisons reached con-
ventional level o statistical significance (fig ). The
absolute probabilities o ailing to achieve a vaginal
birth within hours are shown in table , alongside the
odds ratios relative to placebo. We note that the abso-
lute probability o an event or vaginal misoprostol tab-
let g was % (% credible interval % to %),
closely ollowed by that or titrated (low dose) oral
misoprostol solution (% probability (% to %)).
Figure shows the distribution o the rankings or
each o the prostaglandin treatments. The x axis
reports each o the possible ranks, where position
means the treatment is ranked the highest and position
the lowest. The y axis shows the probability with
which each treatment has been ranked at each o the
possible positions and thereore ully encapsulates the
uncertainty in the treatment rankings. For example,consider vaginal prostaglandin E tablet in the top
lef-hand corner o the figure. For the outcome achiev-
ing vaginal delivery within hours o induction, the
probability o vaginal prostaglandin E tablet being
ranked first is %, the probability o being ranked sec-
ond is around %, peaking at a % probability o
being ranked sixth. We can conclude rom figure that
there is considerable uncertainty in the estimation o
any rank or vaginal prostaglandin Etablet. Note that
this uncertainty is also reflected in the credible interval
around the median rank, which spans rom st to th
best treatment or this outcome.
The best treatment or achieving a vaginal birth
within hours was vaginal misoprostol tablet g,
with a probability o being best o %. The probability
o being ranked in the top three treatments was % or
vaginal misoprostol tablet g and % or titrated
(low dose) oral misoprostol solution. The remaining
treatments all rated lower than a % probability o
being in the top three treatments. The probability o
being ranked in the bottom three (that is, poorest in
terms o achieving a vaginal birth within hours) was
% or vaginal prostaglandin E pessary (normal
release), % or oral misoprostol
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Vaginal prostaglandin Etablet v
Vaginal prostaglandin Egel
Vaginal prostaglandin Epessary (slow release)
Intracervical prostaglandin E Vaginal prostaglandin Epessary (normal release)
Vaginal misoprostol (dose
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included). We note that the results are not materially
different between the ull network ( trials) and the
sensitivity analysis network ( trials).
Table reports the posterior median odds ratios (%credible intervals) or each treatment relative to placebo
(the ull results are reported in appendix , table ). We
note that, or all but vaginal prostaglandin Etablet ver-
sus placebo (Table), the direct and network meta-anal-
ysis results are similar. However, this is consistent with
chance (rom statistical tests we might expect . to
be significant by chance), and we did not observe any
meaningul difference in residual deviance or deviance
inormation criterion values between the inconsistency
and consistency models or caesarean section (appendix
, table ). Relative to the size o the treatment effect esti-
mates, between-trial heterogeneity was observed or this
outcome ( =. (% credible interval . to .)).
When active treatments were compared, six out o
comparisons reached the conventional level o statisti-
cal significance (fig ). With placebo used as the reer-
ence (Table ), five active treatment regimens resulted insignificant reduction in caesarean section, namely vagi-
nal prostaglandin E (gel), vaginal misoprostol tab-
let
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or oral misoprostol tablet g. All other treatments
had a lower probability o being among the top three.
The probability o being ranked in the bottom three
(poorest in terms o risk o caesarean section) was %
or vaginal prostaglandin Epessary (normal release)
and % or oral misoprostol tablet
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Vaginal prostaglandin Etablet v Vaginal prostaglandin E(gel) Vaginal prostaglandin Epessary (slow release) Prostaglandin Fgel Intracervical prostaglandin E Vaginal prostaglandin Epessary (normal release) Vaginal misoprostol (dose
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prostaglandin Epessary (normal release) arm excluded
women with a previous caesarean section (appendix ,
table ). A similar distribution o characteristics was
observed or ailure to achieve vaginal delivery within
hours (appendix , table ).
It is possible that these differences were partly due to
poor reporting (that is, inclusion and exclusion criteria
were not always well reported). Nevertheless, subgroup
analyses were conducted or both vaginal delivery and
caesarean section outcomes, in which we removed
trials which had randomized women with previous
caesarean section (either all or some participants). The
findings were robust when these trials were removed
rom the analyses, with titrated (low dose) oral miso-
prostol solution still being the highest ranking treat-
ment or the outcome o caesarean section, and vaginal
misoprostol g remaining the highest ranking
treatment or achieving vaginal delivery within
hours (see appendix , table ). The one noticeable
change in results was the median rank o oral misopros-
tol tablet
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to have contributed to the difficulties in model fitting
and statistical inconsistency observed or this outcome.
In practice, caesarean section and uterine hyperstimu-
lation are clearly relatedone would expect that clini-
cally persistent, clinically important uterine
hyperstimulation will eventually result in caesarean
section.
Conclusions and implications for practice
The best saety profile o low dose misoprostol solution
with reasonable efficacy (median rank ) may have
important implications or clinical practice. It is note-
worthy that this method is currently not recommended
by the World Health Organization, while low dose
( g) oral tablets every hours are recommended
despite the worst overall ranking in our network
meta-analysis. In clinical situations where less re-
quent vaginal administration o misoprostol may be
preerable, particularly in settings with intensive moni-
toring acilities, g vaginal misoprostol tablets may
be a reasonable treatment o choice. Most o the studies
in our network meta-analysis used hourly treatment
regimens, and some opted or less requent administra-
tion ( hourly).
Overall, misoprostol may be the best prostaglandin
or labour induction, as titrated low dose oral solution
seems to be the saest in terms o caesarean section risk,
while vaginal misoprostol tablets ( g) are the most
effective in achieving vaginal delivery within hours
o induction. These findings have important implica-
tions or national and international guidelines or
induction o labour and uture research in this area.
We thank Lynn Hampson, Helen West, and Nancy Medley,Cochrane Pregnancy and Childbirth Group, or their support inpreparing the final draf o this paper.
Contributors : ZA and DMC conceived and designed the originalstudy, and are the study guarantors. ZA contributed to planning thereview and network meta-analysis, data interpretation and writingthe report. EK conducted the statistical analyses and revised thepaper. TD contributed to planning the review, data collection,quality assessment, and writing the report. NJW supervised thestatistical analyses and drafed and revised the manuscript. SDcontributed to and supervised the statistical analyses and revisedthe manuscript. LVJ contributed to data collection, qualityassessment, and writing the report. KN contributed to datacollection and quality assessment and commented on the report.DMC conducted and supervised the statistical analyses and drafedand revised the manuscript.
Funding: The work was supported in part by National Institute or
Health Research, UK, HTA project // (www.netscc.ac.uk). Theviews and opinions expressed therein are those o the authors and donot necessarily relect those o the NIHR, NHS, or Department oHealth. DMC is supported by an MRC Population Health Scientistpostdoctoral ellowship (G). The unders had no role in studydesign, data collection and analysis, decision to publish, orpreparation o the manuscript.
Competing interests: All authors have completed the ICMJE uniormdisclosure orm at www.icmje.org/coi_disclosure.pd (available onrequest rom the corresponding author) and declare: support romNIHR or the submitted work; no financial relationships with anyorganisations that might have an interest in the submitted work in theprevious three years; no other relationships or activities that couldappear to have inluenced the submitted work.
Data sharing: All data and statistical code are available in theappendices provided by the authors.
Transparency: The manuscripts guarantors affirm that the manuscriptis an honest, accurate, and transparent account o the study beingreported; that no important aspects o the study have been omitted;
and that any discrepancies rom the study as planned (and, i relevant,registered) have been explained.
This is an Open Access article distributed in accordance with theCreative Commons Attribution Non Commercial (CC BY-NC .) license,
which permits others to distribute, remix, adapt, build upon this worknon-commercially, and license their derivative works on different terms,
provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/./.
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Appendix . Search strategy used to maintain the
Cochrane Pregnancy and Childbirth Groups Database
o Trials
Appendix . List o studies included in network
meta-analysis
Appendix . List o studies excluded rom network
meta-analysis
Appendix . Description o included studies
Appendix . Description o included studiesdoses
and regimens
Appendix . Tables : Characteristics o trials by
treatment and outcome. Tables : Odds ratios or out-
comes with each treatment. Tables : Model fit and
selection statistics by outcome. Tables : Datafiles
used in OpenBUGS analyses or outcomes. Table :
Posterior median rankings or sensitivity analyses.
Table : Comparison o risk ratios and odds ratios or
vaginal delivery and caesarean section
Appendix . Technical appendix
Appendix . Inconsistency plots