Types of studies

All published, unpublished and ongoing randomised controlled trials comparing different magnesium sulphate regimens when administered to women as the only tocolytic therapy in the setting of threatened preterm labour were included. Quasi‐randomised trials were eligible for inclusion but none were identified. Cross‐over and cluster‐randomised trials were not eligible for inclusion. Conference abstracts were included.

Types of participants

Women thought to be in preterm labour with a singleton or multiple pregnancy and administered magnesium sulphate for the prevention of preterm birth were included. Women who had a planned preterm birth or preterm induction of labour were not included.

Types of interventions

Intervention: intravenous or oral magnesium sulphate given alone for tocolysis.

Comparison: alternative dosing regimens of magnesium sulphate given alone for tocolysis.

Trials examining treatment regimens including magnesium sulphate co‐administered with alternative tocolytic agents were not included.

Types of outcome measures

Clinically relevant outcomes for trials of tocolysis for inhibiting preterm labour have been pre‐specified following consultation with the editors and authors of the individual reviews.

Consensus was reached on a set of six ‘core’ outcomes, which are highlighted below. These have been included in all tocolysis reviews. In addition to these core outcomes, individual teams may include other outcomes as necessary.

Electronic searches

We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register by contacting the Trials Search Co‐ordinator (30 September 2015).

For full search methods used to populate the PCG Trials Register including the detailed search strategies for CENTRAL, MEDLINE, Embase and CINAHL; the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service, please follow this link to the editorial information about the Cochrane Pregnancy and Childbirth Group in The Cochrane Library and select the ‘Specialized Register ’ section from the options on the left side of the screen.

Briefly: the Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co‐ordinator and contains trials identified from:

1. monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);

2. weekly searches of MEDLINE (Ovid);

3. weekly searches of Embase (Ovid);

4. monthly searches of CINAHL (EBSCO);

5. handsearches of 30 journals and the proceedings of major conferences;

6. weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.

Search results are screened by two people and the full texts of all relevant trial reports identified through the searching activities described above are reviewed. Based on the intervention described, each trial report is assigned a number that corresponds to a specific Pregnancy and Childbirth Group review topic (or topics), and is then added to the Register. The Trials Search Co‐ordinator searches the Register for each review using this topic number rather than keywords. This results in a more specific search set that review authors then fully account for in the relevant review sections (Included, Excluded, Awaiting Classification or Ongoing).

Searching other resources

We searched the reference lists of retrieved studies.

We did not apply any language or date restrictions.

Selection of studies

Two review authors independently assessed for inclusion all the potential studies identified as a result of the search strategy. We resolved any disagreement through discussion or, if required, we consulted the third author.

Data extraction and management

We designed a form to extract data. For eligible studies, two review authors extracted the data using the agreed form. We resolved discrepancies through discussion or, if required, we consulted the third author. The data were entered into Review Manager software (RevMan 2014) and checked for accuracy.

When information regarding any of the above was unclear, we attempted to contact authors of the original reports to provide further details.

Assessment of risk of bias in included studies

Two review authors independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved any disagreement by discussion or by involving the third author.

Measures of treatment effect

Unit of analysis issues

Women are the unit of analysis for maternal outcomes. For trials involving multiple pregnancies, we planned that the unit of analysis would be per infant for fetal, neonatal and child outcomes. As infants from multiple pregnancies are not independent, we planned to use cluster‐trial methods in the analyses, where the data allowed and where multiples made up a substantial proportion of the trial population, to account for non‐independence of variables (Gates 2004). Multiple pregnancies did not make up a substantial proportion of the trial population in each included study. Additionally, the presentation of data in the included studies did not allow use of cluster‐trial methods in the analyses. In future updates, if identified studies include sufficient multiple pregnancy data, cluster‐trial methods will be used for analyses to account for non‐independence of variables.

In future updates, where a trial has multiple arms (more than two comparisons) and is included in the same meta‐analysis, the number of events and the sample size from one of the groups will be divided by the number of arms compared in the trial. This will ensure that no participants are double counted. If a subgroup analysis is being undertaken then the overall summary statistic will not be reported.

Dealing with missing data

For included studies, we noted levels of attrition. We explored the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis.

For all outcomes, we carried out analyses, as far as possible, on an intention‐to‐treat basis, i.e. we attempted to include all participants randomised to each group in the analyses, and all participants were analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial was the number of participants randomised minus any participants whose outcomes were known to be missing.

Assessment of heterogeneity

We assessed statistical heterogeneity in each meta‐analysis using the Tau², I² and Chi² statistics. We regarded heterogeneity as present if an I² was greater than 30% and either the Tau² was greater than zero, or there was a low P value (less than 0.10) in the Chi² test for heterogeneity. 

Assessment of reporting biases

In future updates of this review, if there are 10 or more studies in the meta‐analysis, we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually. If asymmetry is suggested by a visual assessment, we will perform exploratory analyses to investigate it.

Data synthesis

We carried out statistical analysis using the Review Manager software (RevMan 2014). We used fixed‐effect meta‐analysis for combining data where it was reasonable to assume that studies were estimating the same underlying treatment effect: i.e. where trials were examining the same intervention, and the trials’ populations and methods were judged sufficiently similar. In future updates, if there is clinical heterogeneity sufficient to expect that the underlying treatment effects differ between trials, or if substantial statistical heterogeneity is detected, we will use random‐effects meta‐analysis to produce an overall summary, if an average treatment effect across trials is considered clinically meaningful. The random‐effects summary will be treated as the average range of possible treatment effects and we will discuss the clinical implications of treatment effects differing between trials. If the average treatment effect is not clinically meaningful, we will not combine trials.

Where random‐effects analyses are used, the results will be presented as the average treatment effect with 95% confidence intervals, and the estimates of  Tau² and I².

Subgroup analysis and investigation of heterogeneity

We planned to perform comparisons for different types of regimens; including differences in route of administration, loading and maintenance doses, duration of treatment, timing of treatment and the possibility of repeat dosing. Given the data available in included studies was limited, we performed a comparison of different regimens with respect to dose (high‐dose versus low‐dose). If we identify studies including data that allow further comparisons to be made, these will be included in future updates.

We did not identify substantial heterogeneity. However, if we identify substantial heterogeneity in future updates, we will investigate it using subgroup analyses and sensitivity analyses. We will consider whether an overall summary is meaningful, and if so, use random‐effects analysis to produce it.

Maternal and pregnancy characteristics are likely to affect health outcomes of both mother and child.

We will carry out planned subgroup analyses, where sufficient data are available, based on:

• significant factor(s) contributing to or precipitating preterm labour: including presence or absence of preterm prelabour rupture of membranes;

• multiple versus singleton pregnancy;

• gestational age at time of randomisation and treatment: less than 28 weeks', 28 weeks' to less than 34 weeks', 34 weeks' to less than 37 weeks' or 37 weeks' or more;

• use of antenatal corticosteroids for fetal lung maturation: in 50% or more of the study population or in less than 50% of the study population.

Subgroup analysis will be restricted to the review's primary outcomes.

We will assess subgroup differences by interaction tests available within RevMan (RevMan 2014), and we will report the results of subgroup analyses quoting the Chi² statistic and P value, and the interaction test I² value.

Sensitivity analysis

In future updates, sensitivity analysis will be performed where necessary to investigate the effect of trial quality, as defined by allocation concealment and other 'Risk of bias' components, by excluding studies determined as 'high risk of bias' for these components. Sensitivity analyses will be restricted to primary outcomes examined.