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Cochrane Database of Systematic Reviews Protocol - Intervention

Combination of tocolytic agents for inhibiting preterm labour

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Abstract

This is a protocol for a Cochrane Review (Intervention). 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 preterm labour when compared to any other treatment, no treatment or placebo.

Background

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 them in 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 neonatal deaths worldwide. The other causes include severe infections, complications of asphyxia and congenital abnormalities (45 countries; 96,797 deaths) (Lawn 2005). According to mortality statistics 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 incidence of preterm births during the last decade. A population‐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 preterm birth, such as in vitro fertilisation, multiple pregnancies, and elective deliveries, also increased and were associated with a higher risk of preterm delivery. Spontaneous 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 labelled preterm (Copper 1993). Interventions that are appropriate 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 preterm labour and preterm rupture of membranes are responsible for about two‐thirds of preterm births, with the remainder due to medical interventions after maternal or fetal indications (Lumley 1993). Neonatal respiratory distress syndrome (a condition in which the baby's lungs are not developed enough to take in the air they need), bronchopulmonary dysplasia (a chronic lung disease which can follow respiratory distress syndrome), intraventricular haemorrhage (bleeding into the normal fluid spaces (ventricles) within the brain and also used to refer 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.

A multi‐level modelling of hospital service utilisation and cost profile 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, including the initial birth admission, averaged at £17,819.94 for children 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 inpatient 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 included in the recently updated Cochrane systematic review assessing antenatal administration of corticosteroids (Roberts 2006): 24 mg of betamethasone or dexamethasone administered to women expected to give birth preterm was associated with a significant reduction in mortality (relative risk (RR) 0.69, 95% confidence interval (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 enhanced by antenatal corticosteroid administration (Jobe 1994). Furthermore, treatment with antenatal corticosteroids was associated 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 Development Conference on the Effect of Corticosteroids for Fetal Maturation on Perinatal Outcomes report (NICHHD 1994).

A Cochrane systematic review that assesses the effectiveness and safety 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 evidence 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 distress syndrome (RR 0.82, 95% CI 0.71 to 0.95), severe lung disease (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 outcomes 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 clinical 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 install tocolytic treatment to prolong pregnancy, the primary outcome considered is time gained allowing (a) the fetus to mature more before being born; (b) enhance lung maturation by antenatal corticosteroid administration; and (c) time for in‐uterus transfer to a tertiary care centre with neonatal intensive care facilities (Anotayanonth 2004; NHMRC 2000). The overall goal is to either avoid preterm birth where appropriate or to minimise its effects and ensure that babies are born in the best conditions possible with reduced morbidity and mortality of the neonate, reduced morbidity in the mother and improved long‐term family 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), prostaglandin inhibitors, calcium channel blockers, oxytocin receptor antagonists and magnesium sulphate (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 significant maternal, fetal or neonatal side‐effects, and effective at delaying 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 women in preterm labour giving birth within 48 hours when compared to placebo and, therefore, 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 from treatment, 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 commonly used tocolytics are (i) mechanism of drug action; (ii) target tissues; (iii) dosage and route of administration; (iv) pharmacokinetics 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 proteins (usually the phosphorylation of myosin) by generation or alteration of an intracellular messenger or they inhibit the synthesis 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 produce 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 myometrial stimulants. Atosiban is an oxytocin receptor antagonist. It binds to the receptor in the myometrium and other gestational tissues, thus, preventing the oxytocin‐induced increase in inositol triphosphate, the messenger that increases intracellular calcium and causes myometrial contractions and up‐regulates prostaglandin production. Prostaglandins are produced in the myometrium and other gestational tissues. Agents such as indomethacin inhibit the cyclo‐oxygenase (COX) enzymes, which are key to the production of these prostaglandins. General inhibitors of both the COX‐1 (constitutive) and COX‐2 (inducible) enzymes include indomethacin and sulindac. Selective COX‐2 inhibitors 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 synergistic 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 tocolytic 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 reduce 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. Pathological effects, though, might also occur as a result of non‐physiological 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 usage. Pulmonary oedema associated with tocolytic therapy has been reported with beta‐agonists, magnesium sulphate and the calcium channel blockers.

Objectives

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.

Methods

Criteria for considering studies for this review

Types of studies

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 complications.

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 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 review using 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 double enter all the data or a subsample.

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 methodological quality of included studies

Two review authors (JM Nardin, Z Alfirevic) will assess independently 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 randomisation 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 randomisation, 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 criteria:
(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 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‐randomised trials in the analyses along with individually randomised trials. Their sample sizes will be adjusted using the methods described in Gates 2005 using an estimate 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‐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 heterogeneity 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 perform a 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 prespecified subgroup analysis and perform sensitivity analysis. The use of a random‐effects model recommended by some authors to overcome the problem of 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 analyses for the main outcomes will be based on the following characteristics:

  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.