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Combination of tocolytic agents for inhibiting preterm labour

(Protocol)
Nardin JM, Carroli G, Alfirevic Z
This is a reprint of a Cochrane protocol, prepared and maintained by The Cochrane Collaboration and published in The Cochrane
Library 2006, Issue 4
http://www.thecochranelibrary.com
Combination of tocolytic agents for inhibiting preterm labour (Protocol)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
T A B L E O F C O N T E N T S
1 HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1 ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1 BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3 OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3 METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6 ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8 WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8 HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9 CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9 DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9 SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
i Combination of tocolytic agents for inhibiting preterm labour (Protocol)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Protocol]
Combination of tocolytic agents for inhibiting preterm labour
Juan Manuel Nardin
1
, Guillermo Carroli
1
, Zarko Alfirevic
2
1
Centro Rosarino de Estudios Perinatales, Rosario, Argentina.
2
School of Reproductive and Developmental Medicine, Division of
Perinatal and Reproductive Medicine, The University of Liverpool, Liverpool, UK
Contact address: Juan Manuel Nardin, Centro Rosarino de Estudios Perinatales, Pueyrredon 985, Rosario, Santa Fe, 2000, Argentina.
jmnardin@crep.com.ar. jmnardin@yahoo.com.
Editorial group: Cochrane Pregnancy and Childbirth Group.
Publication status and date: Edited (no change to conclusions), published in Issue 1, 2009.
Citation: Nardin JM, Carroli G, Alfirevic Z. Combination of tocolytic agents for inhibiting preterm labour. Cochrane Database of
Systematic Reviews 2006, Issue 4. Art. No.: CD006169. DOI: 10.1002/14651858.CD006169.
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A B S T R A C T
This is the protocol for a review and there is no abstract. The objectives are as follows:
To assess the effects on maternal, fetal and neonatal outcomes of any combination of tocolytic drugs for the treatment of pretermlabour
when compared to any other treatment, no treatment or placebo.
B A C K G R O U N D
Preterm birth can be defined simply as birth before 37 completed
weeks of gestation (Bryce 2005); however, it refers to a complex
situation that affects not only the baby, but the mother and the
family, with substantial costs for health services (Petrou 2005). It
accounts for 5% to 11% of births in the world, but represents
the single largest cause of mortality and morbidity for newborns
and a major cause of morbidity for pregnant women (NHMRC
2000). More than nine million neonatal deaths occur each year,
98% of themin developing countries (Costello 2003). It has been
estimated that preterm birth is responsible for 60% to 80% of
early neonatal deaths (age under one week) and 28% of all neona-
tal deaths worldwide. The other causes include severe infections,
complications of asphyxia and congenital abnormalities (45 coun-
tries; 96,797 deaths) (Lawn 2005). According to mortality statis-
tics for the year 2003, in England and Wales, immaturity related
conditions are the main causes of death between birth and one
year of age (46% of all causes) and are responsible for almost 62%
of deaths during the early neonatal period. More than 92% of
deaths for all age groups are related to a birthweight less than 2500
g (ONS 2005). For the year 2002, the National Centre for Health
Statistics in the United States found an infant mortality rate of
60.3 per 1000 for newborns with birthweight less than 2500 g
compared with only 2.4 per 1000 for those that weighed more
than 2500 g (NCHS 2004).
Data from developed countries showed an increase in the inci-
dence of pretermbirths during the last decade. Apopulation-based
study in Denmark, with national data from all deliveries during
a 10-year period, showed that the overall proportion of preterm
deliveries increased by 22% from 1995 to 2004 (from 5.2% to
6.3%). Known risk factors for pretermbirth, such as in vitro fertil-
isation, multiple pregnancies, and elective deliveries, also increased
and were associated with a higher risk of preterm delivery. Spon-
taneous preterm deliveries in primiparous women at low risk rose
51% (from 3.8% to 5.7%) during this time compared with 20%
(2.7% to 3.2%) in low-risk multiparous women (Langhoff-Roos
2006).
The outlook for a baby born at 36 weeks of gestation is quite
different to that of a baby born at 26 weeks but both would be
1 Combination of tocolytic agents for inhibiting preterm labour (Protocol)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
labelled preterm (Copper 1993). Interventions that are appropri-
ate at 26 weeks may not necessarily be appropriate at 36 weeks
and vice versa. Considering all preterm births together in a single
group would inevitably lead to clinical practice guidelines that are
inappropriate for a large number of mothers and babies (NHMRC
2000). Spontaneous pretermlabour and pretermrupture of mem-
branes are responsible for about two-thirds of pretermbirths, with
the remainder due to medical interventions after maternal or fe-
tal indications (Lumley 1993). Neonatal respiratory distress syn-
drome (a condition in which the baby’s lungs are not developed
enough to take in the air they need), bronchopulmonary dyspla-
sia (a chronic lung disease which can follow respiratory distress
syndrome), intraventricular haemorrhage (bleeding into the nor-
mal fluid spaces (ventricles) within the brain and also used to re-
fer to bleeding in areas near the ventricles even if the blood is
not within them), sepsis (generalized infection or infection of the
blood stream), cerebral palsy (an injury to the brain resulting in
children being unable to use some of the muscles to walk, talk, eat
or play in the normal way), intellectual impairment (limitations in
mental function and in skills such as communicating, taking care
of oneself, and social skills), blindness and deafness (Anotayanonth
2004), and their impacts on parents, families and society, are to
a large extent related to the consequence of neonatal immaturity
following preterm birth.
Amulti-level modelling of hospital service utilisationand cost pro-
file of preterm birth using data from 117,212 children, divided
into four subgroups by gestational age at birth (less than 28 weeks,
28 to 31 weeks, 32 to 36 weeks and 37 weeks or greater), showed
that the cumulative cost of hospital inpatient admissions, includ-
ing the initial birth admission, averaged at £17,819.94 for chil-
dren born at less than 28 weeks’ gestation; £17,751.00 for children
born at 28 to 31 weeks’ gestation; £5376.39 for children born at
32 to 36 weeks’ gestation; and £1658.63 for children born at 37
weeks’ gestation or greater. The adjusted number of hospital in-
patient admissions, inpatient days and costs over the first 10 years
of life was 130%, 77% and 443% higher for children born at less
than 28 weeks’ gestation than for children born at term (Petrou
2005).
Antenatal corticosteroids reduce the burden of
prematurity
Twenty-one studies including data on over 4200 babies were in-
cluded in the recently updated Cochrane systematic review assess-
ing antenatal administration of corticosteroids (Roberts 2006): 24
mg of betamethasone or dexamethasone administered to women
expected to give birth pretermwas associated with a significant re-
duction in mortality (relative risk (RR) 0.69, 95% confidence in-
terval (CI) 0.58 to 0.81), respiratory distress syndrome (RR 0.66,
95% CI 0.59 to 0.73) and cerebroventricular haemorrhage (RR
0.54, 95%CI 0.43 to 0.69) and other relevant neonatal outcomes.
Data derived from the randomised trials of postnatal surfactant
therapy indicate that the benefits of postnatal surfactant are en-
hanced by antenatal corticosteroid administration (Jobe 1994).
Furthermore, treatment with antenatal corticosteroids was associ-
ated with less developmental delay in childhood (RR 0.49, 95%
CI 0.24 to 1.00) and a trend towards a decrease in cerebral palsy
at two to six years of age (RR 0.60; 95%CI 0.34 to 1.03) (Roberts
2006). The cost and duration of neonatal care was also reduced in
the corticosteroids groups (RCOG 2004). The international data
continue to support unequivocally the use and efficacy of a single
course of antenatal corticosteroids using the dosage and interval
of administration specified in the NIH 1994 Consensus Develop-
ment Conference on the Effect of Corticosteroids for Fetal Mat-
uration on Perinatal Outcomes report (NICHHD 1994).
ACochrane systematic reviewthat assesses the effectiveness and sa-
fety of a repeat dose(s) of prenatal corticosteroids, given to women
who remain at risk of preterm birth seven or more days after an
initial course of prenatal corticosteroids (Crowther 2000), showed
that fewer infants in the repeat dose(s) of corticosteroids group had
severe lung disease compared with infants in the placebo group
(RR 0.64, 95% CI 0.44 to 0.93; one trial, 500 infants). This evi-
dence is supported by a recently published randomised controlled
trial including 982 women (Crowther 2006), which shows that
fewer babies exposed to repeat corticosteroids had respiratory dis-
tress syndrome (RR 0.82, 95% CI 0.71 to 0.95), severe lung dis-
ease (RR 0.60, 95% CI 0.46 to 0.79), needed less oxygen therapy,
and had shorter duration of mechanical ventilation than those in
the placebo group. However, the current data on long-term out-
comes are insufficient to assert whether this intervention is related
to benefits and risks that continue into childhood and beyond and,
therefore, further assessment should be considered to incorporate
routine use of repeat course(s) of antenatal corticosteroids in clin-
ical practice (Crowther 2000; Crowther 2006; NIH 2000).
Tocolytic therapy
Tocolytic agents include a wide range of drugs that can inhibit
labour, slow down or suppress the contractions of the uterus. In
situations where clinical considerations make it desirable to in-
stall tocolytic treatment to prolong pregnancy, the primary out-
come considered is time gained allowing (a) the fetus to mature
more before being born; (b) enhance lung maturation by antena-
tal corticosteroid administration; and (c) time for in-uterus trans-
fer to a tertiary care centre with neonatal intensive care facilities
(Anotayanonth 2004; NHMRC 2000). The overall goal is to ei-
ther avoid preterm birth where appropriate or to minimise its ef-
fects and ensure that babies are born in the best conditions possi-
ble with reduced morbidity and mortality of the neonate, reduced
morbidity inthe mother andimprovedlong-termfamily outcomes
(ONS 2005). A variety of tocolytic treatments have been used
to inhibit uterine activity in women in preterm labour. Agents
used include beta-adrenergic receptor agonists (betamimetics),
2 Combination of tocolytic agents for inhibiting preterm labour (Protocol)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
prostaglandin inhibitors, calcium channel blockers, oxytocin re-
ceptor antagonists and magnesiumsulphate (Anotayanonth 2004;
Crowther 1998; Crowther 2002; Duckitt 2002; Gaunekar 2004;
King 2003; King 2005; Papatsonis 2005). The ideal tocolytic
agent should be easy to administer, inexpensive, without signifi-
cant maternal, fetal or neonatal side-effects, and effective at de-
laying preterm birth, at least long enough to permit the use of
prenatal corticosteroids (Crowther 2002). There is considerable
variation in the type of tocolytic agent used in different parts of
the world.
Although there is evidence that some of these groups of tocolytic
agents could decrease the number of womeninpretermlabour giv-
ing birth within 48 hours when compared to placebo and, there-
fore, increase the chances of receiving a full course of antenatal
corticosteroids with a safe margin of at least 24 hours before birth,
the percentage of side-effects and withdrawals fromtreatment, and
the lack of benefits observed for other long-term outcomes and
more robust short-term neonatal outcomes, leads to the decision
to use tocolytic therapy for inhibiting preterm birth to be based
on an imprecise balance between risks and benefits. Some factors
relevant in determining the likelihood of adverse effects with com-
monly used tocolytics are (i) mechanism of drug action; (ii) target
tissues; (iii) dosage and route of administration; (iv) pharmacoki-
netics and pharmacodynamics.
Tocolytic agents that affect contractile proteins
The tocolytics currently in use affect myometrial contractility by
one of two major pathways: they affect either the contractile pro-
teins (usually the phosphorylation of myosin) by generation or
alteration of an intracellular messenger or they inhibit the syn-
thesis of, or block the action of, a known myometrial stimulant.
The first group is represented by the betamimetics, nitric oxide
donors, magnesium sulphate and the calcium channel blockers.
The betamimetics (ritodrine, isoxsuprine, terbutaline, salbutamol,
hexoprenaline and orciprenaline), by binding with cell membrane
beta-adrenergic receptors, lead to an increase in intracellular cyclic
adenosine monophosphate that inhibits the ability of myosin light
chain kinase to phosphorylate myosin. Nitric oxide donors pro-
duce a similar response through cyclic guanosine monophosphate.
Magnesium sulphate and calcium channel blockers (nifedipine,
nicardipine, verapamil, diltiazem) lower intracellular calcium by
preventing an influx of calcium ions, thereby reducing the activity
of myosin light chain kinase and inhibiting the phosphorylation
of myosin (Caritis 2005).
Tocolytic agents that block the action of
myometrial stimulants
Oxytocin and prostaglandins are the major endogenous my-
ometrial stimulants. Atosiban is an oxytocin receptor antago-
nist. It binds to the receptor in the myometrium and other ges-
tational tissues, thus, preventing the oxytocin-induced increase
in inositol triphosphate, the messenger that increases intracel-
lular calcium and causes myometrial contractions and up-regu-
lates prostaglandin production. Prostaglandins are produced in
the myometrium and other gestational tissues. Agents such as in-
domethacin inhibit the cyclo-oxygenase (COX) enzymes, which
are key to the production of these prostaglandins. General in-
hibitors of both the COX-1 (constitutive) and COX-2 (inducible)
enzymes include indomethacin and sulindac. Selective COX-2 in-
hibitors include agents such as nimesulide and rofecoxib (Caritis
2005).
In vitro studies have demonstrated that simultaneous blockage of
these different pathways could result in an additive or even syner-
gistic effect capable of potentiating the uterine relaxation induced
by each single drug and, most importantly, allow a reduction of
the therapeutic concentration needed for each single drug (Doret
2003). However, it is unlikely that additional effects or synergy of
effects could take place in other tissues if, for instance, a specific
oxytocin receptor antagonist, only active on breast myoepithelial
cells outside the uterus, is combined with any other group of to-
colytic agents (Goodwin 1996; Goodwin 1998). Based on these
assumptions, a combination of agents of two of these different
groups could be used to improve myometrial effects without an
increment in maternal or neonatal side-effects, or both, or to re-
duce the dosage and time of administration of one or more of
them, thereby leading to a decrease in maternal and fetal side-
effects without decreasing the tocolytic effect magnitude. Patho-
logical effects, though, might also occur as a result of non-physi-
ological effects in various tissues. Examples of non-specific effects
include the nausea associated with atosiban or perhaps magnesium
sulphate, and the oedema noted with calcium channel blocker us-
age. Pulmonary oedema associated with tocolytic therapy has been
reported with beta-agonists, magnesium sulphate and the calcium
channel blockers.
O B J E C T I V E S
To assess the effects on maternal, fetal and neonatal outcomes of
any combination of tocolytic drugs for the treatment of preterm
labour when compared to any other treatment, no treatment or
placebo.
M E T H O D S
Criteria for considering studies for this review
Types of studies
3 Combination of tocolytic agents for inhibiting preterm labour (Protocol)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Any adequate published, unpublished or ongoing randomised
controlled trial that compares a combination of tocolytic agents,
administered by any route or any dose, for inhibiting preterm
labour versus any other treatment, no intervention or placebo. We
will exclude quasi-randomised controlled trials.
Types of participants
Pregnant women assessed as being in spontaneous preterm labour
(see definitions below) and considered suitable for tocolytic agents.
Types of interventions
The following groups of comparisons will be assessed for inclusion.
1. Combination of tocolytic drugs versus any other
combination of tocolytic agents
2. Combination of tocolytic drugs versus any other tocolytic
agent alone
3. Combination of tocolytic drugs versus any other
intervention
4. Combination of tocolytic drugs versus no intervention
5. Combination of tocolytic drugs versus placebo
Types of outcome measures
Five primary outcomes were chosen as being most representative
of the clinically important measures of ineffectiveness and com-
plications.
Primary outcomes
• Serious maternal outcomes (see definitions below)
• Short-term and long-term serious infant outcome (see
definitions below)
• Birth before 48 hours of trial entry
• Preterm neonate delivered without full course of antenatal
steroids (see definitions below) completed at least 24 hours before
birth
• Perinatal death after trial entry
Secondary outcomes
Maternal
• Adverse drug reaction
• Discontinuation of therapy because of maternal side-effects
• Need for additional tocolytics
• Recurrence of labour
• Caesarean section birth
• Antepartum haemorrhage
• Postpartum haemorrhage
• Length of hospital stay
• Breastfeeding
• Satisfaction with treatment
• Quality of life at 12 to 24 months after the birth (measured
by validated instruments)
• Psychological aspects of mother and family
Infant/child
• Birth before seven days of trial entry
• Birth before 28 completed weeks
• Birth before 34 completed weeks
• Birth before 37 completed weeks
• Pregnancy prolongation (interval between randomisation
and birth)
• Gestational age at birth
• Birthweight
• Apgar score less than seven at five minutes
• Respiratory distress syndrome
• Use of mechanical ventilation
• Duration of mechanical ventilation
• Persistent pulmonary hypertension of the neonate
• Intraventricular haemorrhage
• Intraventricular haemorrhage - grade three or four
• Periventricular leukomalacia
• Chronic lung disease
• Necrotising enterocolitis
• Retinopathy of prematurity
• Neonatal jaundice
• Neonatal sepsis
• Fetal death
• Neonatal death
• Infant death
Health service use
• Admission to neonatal intensive care unit
• Neonatal length of hospital stay
• Treatment associated costs
Definitions
• Preterm labour: the presence of regular uterine contractions
on a preterm pregnancy (with intact or ruptured membranes)
with or without cervical dilatation.
• Full course of corticosteroids: 24 mg of betamethasone
intramuscularly (IM) divided in two to four doses, given in 24
hours, 20 to 24 mg of dexamethasone IM divided in four to six
doses given in 24 hours, or 2 g of hydrocortisone intravenously
divided in four doses given in 24 hours.
• Serious maternal outcomes: death, cardiac arrest,
respiratory arrest, admission to intensive care unit.
• Short-term and long-term serious infant outcome:
determined by the presence of any of the following: death or
4 Combination of tocolytic agents for inhibiting preterm labour (Protocol)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
chronic lung disease (need for supplemental oxygen therapy at
36 weeks’ postmenstrual age); grade three or four intraventricular
haemorrhage or periventricular leukomalacia; major
sensorineural disability at two years of age defined as any one or
more of the following: severe or profound vision impairment,
sensorineural deafness requiring hearing aids, moderate or severe
cerebral palsy or developmental delay/intellectual impairment
(defined as developmental quotient or intelligence quotient less
than two standard deviations below the mean).
Search methods for identification of studies
Electronic searches
We will contact the Trials Search Co-ordinator to search the
Cochrane Pregnancy and Childbirth Group’s Trials Register.
The Cochrane Pregnancy and Childbirth Group’s 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 37 journals.
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 ’Search strategies for identification of studies’ section
within the editorial 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 reviewusing these codes rather than keywords.
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. 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 two review authors
(JM Nardin, Z Alfirevic) will extract the data independently using
the agreed form. We will resolve discrepancies through discussion.
We will use the Review Manager software (RevMan 2003) to dou-
ble enter all the data or a subsample.
When information regarding any of the above is unclear, we will
attempt tocontact authors of the original reports toprovide further
details.
Assessment of methodological quality of included
studies
Two review authors (JM Nardin, Z Alfirevic) will assess indepen-
dently the validity of each study using the criteria outlined in
the Cochrane Handbook for Systematic Reviews of Interventions
(Higgins 2005). Methods used for generation of the randomisa-
tion 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-
domisation, 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:
(A) blinding of participants (yes/no/unclear);
(B) blinding of caregiver (yes/no/unclear);
(C) blinding of outcome assessment (yes/no/unclear).
Measures of treatment effect
We will carry out statistical analysis using the Review Manager
software (RevMan 2003). We will use fixed-effect meta-analysis
5 Combination of tocolytic agents for inhibiting preterm labour (Protocol)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
for combining data in the absence of significant heterogeneity if
trials are sufficiently similar.
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 standardised mean difference to combine trials that measure
the same outcome, but use different methods. If there is evidence
of skewness, this will be reported.
Cluster-randomised trials
We will include cluster-randomisedtrials inthe analyses along with
individually randomised trials. Their sample sizes will be adjusted
using the methods describedinGates 2005 using anestimate of the
intracluster correlation co-efficient (ICC) derived fromthe 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-randomised trials and individually randomised trials, we
plan to synthesise the relevant information. We will consider it
reasonable to combine the results from both if there is little het-
erogeneity between the study designs and the interaction between
the effect of intervention and the choice of randomisation unit is
considered to be unlikely.
We will also acknowledge heterogeneity in the randomisation unit
and performa separate meta-analysis. Therefore the meta-analysis
will be performed in two parts as well.
Intention-to-treat analysis
We will analyse 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 analysed in the group to which they were
randomised, and there is sufficient information in the trial report,
we will attempt to restore them to the correct group.
Assessment of heterogeneity
We will apply tests of heterogeneity between trials, if appropriate,
using the I² statistic. If we identify high levels of heterogeneity
among the trials, (exceeding 50%), we will explore it by prespeci-
fied subgroup analysis and performsensitivity analysis. The use of
a random-effects model recommended by some authors to over-
come the problemof heterogeneity is still debatable (Deeks 2001;
Villar 2001), therefore, no summary estimator that could lead to
wrong assumptions will be used in this situation.
Subgroup analyses
We will conduct planned subgroup analyses classifying whole trials
by interaction tests as described by Deeks 2001. Subgroup analy-
ses for the main outcomes will be based on the following charac-
teristics:
1. gestational age (less than 28 weeks of gestation versus 28
weeks and above);
2. intact versus ruptured membranes;
3. single versus multiple pregnancy.
Sensitivity analyses
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.
A C K N O W L E D G E M E N T S
As part of the pre-publication editorial process, this protocol has
been commented on by four peers (an editor and three referees
who are external to the editorial team), one or more members
of the Pregnancy and Childbirth Group’s international panel of
consumers and the Group’s Statistical Adviser.
6 Combination of tocolytic agents for inhibiting preterm labour (Protocol)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
R E F E R E N C E S
Additional references
Anotayanonth 2004
Anotayanonth S, Subhedar NV, Garner P, Neilson
JP, Harigopal S. Betamimetics for inhibiting preterm
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14651858.CD004352.pub2]
Bryce 2005
Bryce J, Boschi-Pinto C, Shibuya K, Black RE, WHO Child
Health Epidemiology Reference Group. WHO estimates
of the causes of death in children. Lancet 2005;365(9465):
1147–52.
Caritis 2005
Caritis S. Adverse effects of tocolytic therapy. BJOG: an
international journal of obstetrics and gynaecology 2005;112
(Suppl 1):74–8.
Copper 1993
Copper RL, Goldenberg RL, Creasy RK, DuBard MB,
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birth weight and gestational age-specific neonatal mortality.
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Costello 2003
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pregnancy and outcomes for newborn infants in developing
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Crowther 1998
Crowther CA, Moore V. Magnesium maintenance therapy
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labour. The Cochrane Database of Systematic Reviews
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14651858.CD000940]
Crowther 2000
Crowther CA, Harding J. Repeat doses of prenatal
corticosteroids for women at risk of preterm birth for
preventing neonatal respiratory disease. The Cochrane
Database of Systematic Reviews 2000, Issue 2.[Art. No.:
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Crowther 2002
Crowther CA, Hiller JE, Doyle LW. Magnesium sulphate for
preventing preterm birth in threatened preterm labour. The
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Crowther 2006
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Indicates the major publication for the study
W H A T ’ S N E W
Date Event Description
20 September 2008 Amended Converted to new review format.
8 Combination of tocolytic agents for inhibiting preterm labour (Protocol)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
H I S T O R Y
Protocol first published: Issue 4, 2006
C O N T R I B U T I O N S O F A U T H O R S
Juan M Nardin was primarily responsible for the development of the protocol. Guillermo Carroli and Zarko Alfirevic contributed to
the development of the protocol, and reviewed the final draft.
D E C L A R A T I O N S O F I N T E R E S T
None known.
S O U R C E S O F S U P P O R T
Internal sources
• The University of Liverpool, UK.
External sources
• World Health Organization, Switzerland.
9 Combination of tocolytic agents for inhibiting preterm labour (Protocol)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.