Tocolytics for preterm premature rupture of membranes

(Protocol)

Seibel-Seamon J, Berghella V, Baxter J, Grimes-Dennis J

This is a reprint of a Cochrane protocol, prepared and maintained by The Cochrane Collaboration and published in The Cochrane
Library 2008, Issue 2
http://www.thecochranelibrary.com

Tocolytics for preterm premature rupture of membranes (Protocol)

Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Tocolytics for preterm premature rupture of membranes (Protocol) i

Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Protocol]

Tocolytics for preterm premature rupture of membranes

Jolene Seibel-Seamon1 , Vincenzo Berghella2 , Jason Baxter1 , Jacqueline Grimes-Dennis1

1 Departmentof Obstetrics and Gynecology, Thomas Jefferson University, Philadelphia, USA. 2 Director, Division of Maternal Fetal
Medicine, Thomas Jefferson University, Philadelphia, USA

Contact address: Jolene Seibel-Seamon, Department of Obstetrics and Gynecology, Thomas Jefferson University, 834 Chestnut Street,
Suite 400, Philadelphia, PA 19107, USA. joleneseibel@yahoo.com.

Editorial group: Cochrane Pregnancy and Childbirth Group.

Publication status and date: New, published in Issue 2, 2008.

Citation: Seibel-Seamon J, Berghella V, Baxter J, Grimes-Dennis J. Tocolytics for preterm premature rupture of membranes. Cochrane
Database of Systematic Reviews 2008, Issue 2. Art. No.: CD007062. DOI: 10.1002/14651858.CD007062.

Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effectiveness of administering tocolytic therapy to women with early preterm premature rupture of membranes for
prophylaxis or for treatment of contractions.

BACKGROUND
Preterm premature rupture of membranes (PPROM) is defined
as rupture of the chorioamniotic membranes before the onset of
labor prior to 37 weeks of gestation. It is further classified by
gestational age: midtrimester PPROM (less than 24 weeks), early
PPROM (24 to 34 weeks), and near-term PPROM (34 to 37
weeks). Less than 1% of pregnancies are affected by midtrimester
PPROM, 2% to 5% by early PPROM, and 2% to 8% by near-
term PPROM (ACOG 2007). The etiology of PPROM is not
well understood but likely to be multifactorial. Associated condi-
tions include smoking, lower socioeconomic status, sexually trans-
mitted diseases, vaginal bleeding and uterine distention (Canavan
2004). Possible mechanisms that could explain these associations
include choriodecidual infection/inflammation, decreased mem-
brane collagen content, collagen degradation, membrane stretch
or programmed amniotic cell death (Parry 1998).
PPROM contributes to both maternal morbidity and perinatal
morbidity and mortality. The major cause of perinatal morbid-
ity and mortality associated with PPROM is premature deliv-
Tocolytics for preterm premature rupture of membranes (Protocol)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ery. Overall, it accounts for about one third of all preterm births
(Kaltreider 1980). The related morbidities associated with pre-
maturity include respiratory distress syndrome (RDS), intraven-
tricular haemorrhage (IVH), necrotizing enterocolitis (NEC) and
infection. Other complications include placental abruption, cord
prolapse and fetal distress. PPROM is strongly associated with ma-
ternal infectious morbidity with an increase in chorioamnionitis,
endometritis and bacteraemia.
In order to reduce the effects of prematurity, early PPROM (24 to
34 weeks) is best served with conservative management. In con-
servative management of early PPROM, the use of adjunctive an-
tibiotic treatment has been recommended. The goal of adjunctive
antibiotics is to prevent or treat ascending infection and prolong
pregnancy. The choice and regimen of antibiotics have varied but
the combination of ampicillin/amoxicillin and erythromycin has
been associated with significant maternal and neonatal benefits.
Another Cochrane review showed a reduction in preterm birth
within 48 hours and a reduction in preterm birth within seven days
when antibiotics were given to women with PPROM. Neonatal
benefits included a decrease in infection, surfactant use, oxygen
1
therapy and abnormal cerebral ultrasound scan. Maternal benefits We will include all published randomized controlled trials, unpub-
included a reduction in chorioamnionitis (Kenyon 2003). lished randomized controlled trials and quasi-randomized con-
trolled trials evaluating tocolytics in women with early preterm
In addition to antibiotics, corticosteroid therapy administration
premature rupture of membranes (PPROM), i.e. PPROM be-
is recommended for women with early PPROM. Corticosteroid
tween 24 and 34 weeks gestation.
administration is associated with a reduction in RDS, IVH, NEC,
respiratory support and intensive care admissions without any
significant increase in maternal or neonatal infection (Roberts Types of participants
2006). The National Institute of Health consensus conference
Pregnant women with singleton pregnancies and a gestational age
of 1994 recommended single course corticosteroid administra-
between 24 and 34 weeks who are diagnosed with PPROM. The
tion in patients with PPROM before 32 weeks. Group B strep-
women will be classified in regards to the presence or absence of
tococcus (GBS) screening also should be performed on women
contractions.
with PPROM and intrapartum GBS prophylaxis should be initi-
ated based on the 2002 revised guidelines from the CDC (Schrag
2002). Types of interventions
Tocolytic therapy (labor-inhibiting medications) are often used in We will include any tocolytic therapy compared to no tocolytic,
women who have preterm labor with intact membranes. Other another tocolytic or placebo. Tocolysis will be classified in regards
Cochrane reviews have addressed the efficacy of tocolytics as pre- to prophylaxis or treatment. Example of tocolytics include be-
ventive and maintenance therapy in this clinical setting (Dodd tamimetics, calcium channel blockers, cox inhibitors, oxytocin re-
2006; Gaunekar 2004; Nanda 2002; Papatsonis 2005). In theory, ceptor antagonists and magnesium sulfate. The use of interven-
tocolytic therapy should also prolong pregnancy in women with tions like antibiotics and corticosteroids will also be reported.
early PPROM. However, the use of tocolytics in women with early
PPROM is still controversial and practice varies among physicians.
Types of outcome measures
Many physicians use tocolytic therapy as a prophylactic measure
and others initiate tocolysis only with the onset of contractions.
There is also a variety of tocolytic therapy to choose from includ-
Primary outcomes
ing betamimetics, calcium channel blockers, cox inhibitors, oxy-
tocin receptor antagonists and magnesium sulfate. Each of these 1. Perinatal mortality (stillbirth, neonatal and infant mortality)
medications also have the potential for adverse maternal and fetal
effects. Common maternal side effects include gastrointestinal up-
Secondary outcomes
set, electrolyte abnormalities, arrhythmias and pulmonary edema.
Fetal side effects are uncommon but oligohydramnios and con-
striction of the ductus arteriosus are specific to the cox inhibitors. 1. Neonatal morbidity
Currently, there is insufficient evidence to suggest a role for to-
1.1 Birthweight (less than 1500 grams)
colytic therapy in women with early PPROM.
1.2 Length of stay in neonatal intensive care unit hospital
1.3 Requiring ventilation (number and number of days)
1.4 Respiratory distress syndrome
OBJECTIVES 1.5 Sepsis
To assess the effectiveness of administering tocolytic therapy to 1.6 Apgar score (less than seven at five minutes)
women with early preterm premature rupture of membranes for 1.7 Necrotizing enterocolitis
prophylaxis or for treatment of contractions. 1.8 Intraventricular haemorrhage (Grade 3/4)

2. Latency (time until delivery)

METHODS 2.1 Prolongation of labor for 48 hours
2.2 Prolongation of labor for seven days

Criteria for considering studies for this review

3. Preterm birth
3.1 Less than 34 weeks
3.2 Less than 32 weeks
Types of studies
3.3 Less than 28 weeks

Tocolytics for preterm premature rupture of membranes (Protocol) 2

Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
4. Maternal morbidity
4.1 Endometritis
4.2 Chorioamnionitis
Search methods for identification of studies
Electronic searches
We will contact the Trials Search Co-ordinator to search the
Cochrane Pregnancy and Childbirth Groups Trials Register.
The Cochrane Pregnancy and Childbirth Groups Trials Register
is maintained by the Trials Search Co-ordinator and contains trials
identified from:
1. quarterly searches of the Cochrane Central Register of
Controlled Trials (CENTRAL);
2. monthly searches of MEDLINE;
3. handsearches of 30 journals and the proceedings of major
conferences;
4. weekly current awareness search of a further 36 journals
plus monthly BioMed Central email alerts.
Details of the search strategies for CENTRAL and MEDLINE,
the list of handsearched journals and conference proceedings, and
the list of journals reviewed via the current awareness service can
be found in the Specialized Register section within the edito-
rial information about the Cochrane Pregnancy and Childbirth
Group.
Trials identified through the searching activities described above
are given a code (or codes) depending on the topic. The codes are
linked to review topics. The Trials Search Co-ordinator searches
the register for each review using these codes rather than keywords.
In addition, we will search CENTRAL (The Cochrane Library),
MEDLINE (1966 to current) and EMBASE (1974 to current)
using the search strategies listed in Appendix 1.
We will not apply any language restrictions.
Data collection and analysis
Selection of studies
We will assess for inclusion all potential studies we identify as a
result of the search strategy. Independently, three review authors
will assess all studies for inclusion in the review using the inclusion
criteria. We will resolve any disagreement through discussion or,
if required, consult an outside person.
Data extraction and management
We will design a form to extract data. At least three review authors
will extract the data using the agreed form. We will resolve dis-
crepancies through discussion. We will use the Review Manager
Tocolytics for preterm premature rupture of membranes (Protocol)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
software (RevMan 2003) to double enter all the data or a subsam-
ple.
When information regarding any of the above is unclear, we will
attempt to contact authors of the original reports to provide further
details.
Assessment of risk of bias in included studies
Assessment of methodological quality of included studies
We will assess the validity of each study using the criteria outlined
in the Cochrane Handbook for Systematic Reviews of Interven-
tions (Higgins 2005). Methods used for generation of the ran-
domization sequence will be described for each trial.
(1) Selection bias (randomisation and allocation
concealment)
We will assign a quality score for each trial, using the following
criteria:
(A) adequate concealment of allocation: such as telephone ran-
domization, consecutively-numbered, sealed opaque envelopes;
(B) unclear whether adequate concealment of allocation: such as
list or table used, sealed envelopes, or study does not report any
concealment approach;
(C) inadequate concealment of allocation: such as open list of
random-number tables, use of case record numbers, dates of birth
or days of the week.
(2) Attrition bias (loss of participants, for example,
withdrawals, dropouts, protocol deviations)
We will assess completeness to follow up using the following cri-
teria:
(A) less than 5% loss of participants;
(B) 5% to 9.9% loss of participants;
(C) 10% to 19.9% loss of participants;
(D) more than 20% loss of participants.
(3) Performance bias (blinding of participants, researchers
and outcome assessment)
We will assess blinding using the following criteria:
(1) blinding of participants (yes/no/unclear);
(2) blinding of caregiver (yes/no/unclear);
(3) blinding of outcome assessment (yes/no/unclear).
Measures of treatment effect
We will carry out statistical analysis using RevMan 2003. We will
use fixed-effect meta-analysis for combining data in the absence
3
of significant heterogeneity if trials are sufficiently similar. If het-
erogeneity is found, this will be explored by sensitivity analysis
followed by random-effects if required.
Dichotomous data
For dichotomous data, we will present results as summary relative
risk with 95% confidence intervals.
Continuous data
For continuous data, we will use the weighted mean difference if
outcomes are measured in the same way between trials. We will use
the standardized mean difference to combine trials that measure
the same outcome, but use different methods. If there is evidence
of skewness, this will be reported.
Unit of analysis issues
Cluster-randomised trials
We will include cluster-randomized trials in the analyses along
with individually randomized trials. Their sample sizes will be ad-
justed using the methods described in Gates 2005 using an es-
timate of the intracluster correlation co-efficient (ICC) derived
from the trial (if possible), or from another source. If ICCs from
other sources are used, this will be reported and sensitivity analyses
conducted to investigate the effect of variation in the ICC. If we
identify both cluster-randomized trials and individually random-
ized trials, we plan to synthesize the relevant information. We will
consider it reasonable to combine the results from both if there is
little heterogeneity between the study designs and the interaction
between the effect of intervention and the choice of randomiza-
tion unit is considered to be unlikely.
We will also acknowledge heterogeneity in the randomization unit
and perform a separate meta-analysis; therefore, the meta-analysis
will be performed in two parts as well.
Dealing with missing data
We will analyze data on all participants with available data in the
group to which they are allocated, regardless of whether or not
they received the allocated intervention. If in the original reports
participants are not analyzed in the group to which they were
randomized, and there is sufficient information in the trial report,
we will attempt to restore them to the correct group.
Tocolytics for preterm premature rupture of membranes (Protocol)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Assessment of heterogeneity
We will apply tests of heterogeneity between trials, if appropriate,
using the I-squared statistic. If we identify high levels of hetero-
geneity among the trials (exceeding 50%), we will explore it by
prespecified subgroup analysis and perform sensitivity analysis. A
random-effects meta-analysis will be used as an overall summary
if this is considered appropriate.
Subgroup analysis and investigation of heterogeneity
We will conduct planned subgroup analyses classifying whole trials
by interaction tests as described by Deeks 2001.
We plan to carry out the following subgroup analyses.
1. Women who received steroids compared with women who
did not
2. Women who received antibiotics compared with women
who did not
3. A comparison of each tocolytic type (agent)
4. Women who received tocolysis for prophylaxis compared to
treatment
5. Duration of tocolytic (less than 48 hours compared to
greater than 48 hours)
Sensitivity analysis
We will carry out sensitivity analysis to explore the effect of trial
quality. This will involve analysis based on an A, B, C or D rating
of selection bias and attrition bias. Studies of poor quality will be
excluded in the analysis (those rating B, C or D) in order to assess
for any substantive difference to the overall result.
We will carry out sensitivity analysis to explore the effect of trial
quality assessed by concealment of allocation, by excluding studies
with clearly inadequate allocation of concealment (rated C).
ACKNOWLEDGEMENTS
Steve Gichuhi, MD.
As part of the pre-publication editorial process, this protocol has
been commented on by three peers (an editor and two referees
who are external to the editorial team), a member of the Pregnancy
and Childbirth Groups international panel of consumers and the
Groups Statistical Adviser.
4
 REFERENCES
Additional references
ACOG 2007
American College of Obstetricians and Gynecologists
(ACOG). Premature rupture of membranes. ACOG
Practice Bulletin. Washington (DC): American College of
Obstetricians and Gynecologists (ACOG), 2007.
Canavan 2004
Canavan TP, Simhan HN, Caritis S. An evidence-based
approach to the evaluation and treatment of premature
rupture of membranes: Part I. Obstetrical and Gynecological
Survey 2004;59(9):66977.
Deeks 2001
Deeks JJ, Altman DG, Bradburn MJ. Statistical methods
for examining heterogeneity and combining results from
several studies in meta-analysis. In: Egger M, Davey Smith
G, Altman DG editor(s). Systematic reviews in health care:
meta-analysis in context. London: BMJ Books, 2001.
Dodd 2006
Dodd JM, Crowther CA, Dare MR, Middleton P. Oral
betamimetics for maintenance therapy after threatened
preterm labour. Cochrane Database of Systematic Reviews
2006, Issue 1. [Art. No.: CD003927. DOI: 10.1002/
14651858.CD003927.pub2]
Gates 2005
Gates S. Methodological Guidelines. In: the Editorial
Team. Pregnancy and Childbirth Group. About The
Cochrane Collaboration (Collaborative Review Groups
(CRGs)) 2005, Issue 2.
Gaunekar 2004
Gaunekar NN, Crowther CA. Maintenance therapy with
calcium channel blockers for preventing preterm birth after
threatened preterm labour. Cochrane Database of Systematic
Reviews 2004, Issue 3. [Art. No.: CD004071. DOI:
10.1002/14651858.CD004071.pub2]
Harding 2001
Harding JE, Pang J, Knight DB, Liggins GC. Do antenatal
corticosteroids help in the setting of preterm rupture of
membranes?. American Journal of Obstetrics and Gynecology
2001;184:1319.
Higgins 2005
Higgins JPT, Green S, editors. Cochrane Handbook
for Systematic Reviews of Interventions 4.2.4 [updated
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Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
March 2005]. In: The Cochrane Library, Issue 2, 2005.
Chichester, UK: John Wiley & Sons, Ltd.
Kaltreider 1980
Kaltreider DF, Kohl S. Epidemiology of preterm delivery.
Clinical Obstetrics and Gynecology 1980;23(1):1731.
Kenyon 2003
Kenyon S, Boulvain M, Neilson J. Antibiotics for preterm
rupture of membranes. Cochrane Database of Systematic
Reviews 2003, Issue 2. [Art. No.: CD001058. DOI:
10.1002/14651858.CD001058]
Nanda 2002
Nanda K, Cook LA, Gallo MF, Grimes DA. Terbutaline
pump maintenance therapy after threatened preterm
labor for preventing preterm birth. Cochrane Database of
Systematic Reviews 2002, Issue 4. [Art. No.: CD003933.
DOI: 10.1002/14651858.CD003933]
Papatsonis 2005
Papatsonis D, Flenady V, Cole S, Liley H. Oxytocin
receptor antagonists for inhibiting preterm labour. Cochrane
Database of Systematic Reviews 2005, Issue 3. [Art. No.:
CD004452. DOI: 10.1002/14651858.CD004452.pub2]
Parry 1998
Parry S, Strauss JF 3rd. Premature rupture of the fetal
membranes. New England Journal of Medicine 1998;338
(10):66370.
RevMan 2003
The Cochrane Collaboration. Review Manager (RevMan).
4.2 for Windows. Oxford, England: The Cochrane
Collaboration, 2003.
Roberts 2006
Roberts D, Dalziel S. Antenatal corticosteroids for
accelerating fetal lung maturation for women at risk of
preterm birth. Cochrane Database of Systematic Reviews 2006,
Issue 3. [DOI: 10.1002/14651858.CD004454.pub2]
Schrag 2002
Schrag S, Gorwitz R, Fultz-Butts K, Schuchat A. Prevention
of perinatal group B streptococcal disease. Revised
guidelines from CDC. MMWR. Recommendations and
Reports 2002; Vol. 51, issue RR11:122.
Indicates the major publication for the study
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APPENDICES

Appendix 1. Search strategies

Database Search strategy

CENTRAL #1MeSH descriptor Fetal Membranes, Premature Rupture explode all trees
#2(rupture* near membrane*) or prom or pprom
#3tocoly*
#4MeSH descriptor Tocolysis, this term only
#5MeSH descriptor Tocolytic Agents explode all trees
#6(#1 OR #2)
#7(#3 OR #4 OR #5)
#8(#6 AND #7)

MEDLINE 1 exp Fetal Membranes, Premature Rupture/

2 exp Tocolytic Agents/
3 Tocolysis/
4 2 or 3
5 1 and 4

EMBASE 1. Premature-Fetus-Membrane-Rupture/
2. Tocolysis/
3. exp Uterus-Spasmolytic-Agent
4. 2 or 3
5. 1 and 4

HISTORY
Protocol first published: Issue 2, 2008

CONTRIBUTIONS OF AUTHORS
Vincenzo Berghella, Jason Baxter, and Jacqueline Grimes-Dennis helped with the initial idea of this review, met several times with the
main author (Jolene Seibel-Seamon) regarding all aspects of the development of the protocol and contributed to the writing and editing
of the protocol.
Jolene Seibel-Seamon (JS) wrote the first draft of the protocol and revised it in response to author and editorial feedback.

Tocolytics for preterm premature rupture of membranes (Protocol) 6

Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DECLARATIONS OF INTEREST
None known.

Tocolytics for preterm premature rupture of membranes (Protocol) 7

Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.