Clinical significance of respiratory distress syndrome and other neonatal morbidities in preterm birth
Respiratory distress syndrome, as a consequence of immature lung development, is a complication of preterm birth and the major cause of early neonatal mortality and morbidity [1, 2]. Infants born very preterm (less than 32 weeks' gestation) often require respiratory support, with significant numbers requiring assisted ventilation, and 9.4% remain dependent on oxygen therapy 28 days after birth and are diagnosed with chronic lung disease . Of infants born very preterm admitted for neonatal intensive care, a substantial proportion (21.6%) will have an intraventricular haemorrhage (IVH) with 5.8% being Grade 3 or 4 IVH; 1.7% will have cystic periventricular leukomalacia; and 4.1% of babies will have severe retinopathy of prematurity . Children born preterm who survive have an increased risk of re-hospitalisation after discharge home and a recognised higher risk of subsequent long-term neurodevelopmental impairments, including cerebral palsy [3, 4], than do children born at term. The personal and emotional costs for affected individuals and their families are high, as are the immediate and long-term monetary costs of these morbidities for parents and society [3–6].
Strategies to reduce the risk of neonatal respiratory disease for preterm birth continue to receive considerable attention [7–9]. A single course of prenatal corticosteroids compared with placebo has not been shown to be effective in babies who are born more than seven days after treatment . Specifically, there is insufficient evidence of a reduction in the incidence of respiratory distress syndrome or neonatal mortality [7, 10, 11] and birth weight is significantly reduced . This evidence led to the suggestion  and uptake into clinical practice within Australia  and other countries , with minimal formal assessment, of repeating the dose of prenatal corticosteroids in the 34% to 40% [7, 10] of women who remained at risk of preterm birth seven or more days after the initial course.
Observational studies, with their inherent risk of bias, have given conflicting results, some suggesting adverse effects of repeat corticosteroids on measures of foetal growth  and on delayed development in early childhood , whilst others have indicated a possible reduction in cerebral palsy . Given the need for better quality evidence about the benefits and harms of repeat prenatal corticosteroids, randomised clinical trials have now been reported [18–27].
A recent Cochrane systematic review of published aggregate data was unable to answer some important clinical questions which this individual participant data (IPD) meta-analysis will address .
Summary of the Cochrane systematic review of the aggregate data in 2011
It remains unclear whether repeat dose(s) of prenatal corticosteroids are beneficial. The most recent Cochrane systematic review that assesses the use of repeat prenatal corticosteroids for women at risk of preterm birth to prevent neonatal respiratory disease included ten trials (over 4,730 women and 5,650 babies) with low to moderate bias .
Five of the trials were conducted in the US [20, 21, 23, 26, 27]; one in each of Canada , India  and Finland ; one in Australia and New Zealand ; and one involved 20 countries .
Six trials [18, 19, 21–23, 26] gave repeat corticosteroids at seven day intervals if risk of preterm birth remained, one trial  at 14 day intervals and three trials [20, 25, 27] specifically targeted women for 'rescue therapy' (repeat doses only given when preterm birth was considered imminent).
There was diversity in the inclusion and exclusion criteria for the ten included trials, with wide variation in the reasons women were at risk of preterm birth (preterm labour, preterm prelabour rupture of the membranes, antepartum haemorrhage, pre-eclampsia, foetal growth restriction, cervical incompetence and multiple pregnancy); the gestational age women were eligible (from 24 to 34 weeks); and the time of treatment prior to expected preterm birth. All women received a single course of prenatal corticosteroids one week or more before trial entry. However, the type, amount and timing regimen for administration of the corticosteroid given before the trial varied between trials.
Treatment of women who remain at risk of preterm birth seven or more days after an initial course of prenatal corticosteroids with repeat dose(s), compared with no repeat corticosteroid treatment, reduced the risk of their infants being affected by the primary outcomes, respiratory distress syndrome (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.75 to 0.91; eight trials; 3,206 infants; numbers needed to treat (NNT) 17, 95% CI 11 to 32) and serious infant outcome (RR 0.84, 95% CI 0.75 to 0.94; seven trials; 5,094 infants; NNT 30, 95% CI 19 to 79).
Treatment with repeat dose(s) of corticosteroid was associated with a reduction in mean birth weight (mean difference -75.8 g, 95% CI -117.6 g to -34 g; nine trials; 5,626 infants). However, outcomes that adjusted birth weight for gestational age (birth weight Z-scores, birth weight multiples of the median and small for gestational age) did not differ between treatment groups.
At early childhood follow-up, no statistically significant differences were seen for infants exposed to repeat prenatal corticosteroids compared with unexposed infants for the primary outcomes, total deaths (RR 0.98, 95% CI 0.72 to 1.33; two trials; 3,250 infants), survival free of any disability (RR 1.00, 95% CI 0.97 to 1.04; two trials; 3,164 infants), survival free of major disability (RR 0.77, 95% CI 0.55 to 1.08; one trial; 999 infants), disability (RR 0.98, 95% CI 0.83 to 1.16; one trial; 999 infants) or serious outcome (RR 0.99, 95% CI 0.87 to 1.12; two trials; 3164 infants), or in the secondary outcome growth assessments .
For maximising benefit and minimising harm, many questions remain. How can the potentially important benefits observed be applied to individual women who have different reasons for, and levels of risk, of preterm birth? If repeat prenatal corticosteroids are to be recommended, what are the optimal gestational ages for administration, the optimal number of repeat treatments that should be given, and at what dose and timing? Individual participant meta-analysis of the data from the 11 trials now available may help to answer these questions.
Overcoming limitations: conducting an individual participant data meta-analysis
Analysis of thoroughly checked and updated data from individual participants in all the available randomised trials has been described as the gold standard in systematic reviews . Estimates of treatment effects are often different from those obtained from aggregate published data due to inclusion of additional or updated data. The methods and advantages of IPD review have been well described [30, 31].
An integral component of conducting an IPD meta-analysis is the formation of an international collaborative group of trialists where all researchers endorse the IPD protocol and provide data from their trials. This generates additional benefits that include more complete identification of trials and of trial details; compliance with standard definitions; provision of missing data on characteristics of trials, all women who were randomised and their babies, and outcomes; more balanced interpretation, endorsement and global dissemination of results; and better clarification and consensus on future research needed with the opportunity for on-going international collaborations .