• Anthony Walters, Christopher McKinlay, Philippa Middleton, Jane E Harding, and Caroline A Crowther.
• Liggins Institute, The University of Auckland, Auckland, New Zealand.
• Cochrane Db Syst Rev. 2022 Apr 4; 4 (4): CD003935CD003935.

BackgroundInfants born preterm (before 37 weeks' gestation) are at risk of respiratory distress syndrome (RDS) and need for respiratory support due to lung immaturity. One course of prenatal corticosteroids, administered to women at risk of preterm birth, reduces the risk of respiratory morbidity and improves survival of their infants, but these benefits do not extend beyond seven days. Repeat doses of prenatal corticosteroids have been used for women at ongoing risk of preterm birth more than seven days after their first course of corticosteroids, with improvements in respiratory outcomes, but uncertainty remains about any long-term benefits and harms. This is an update of a review last published in 2015.ObjectivesTo assess the effectiveness and safety, using the best available evidence, 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 with the primary aim of reducing fetal and neonatal mortality and morbidity.Search MethodsFor this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP), and reference lists of retrieved studies.Selection CriteriaRandomised controlled trials, including cluster-randomised trials, of women who had already received one course of corticosteroids seven or more days previously and were still at risk of preterm birth, randomised to further dose(s) or no repeat doses, with or without placebo. Quasi-randomised trials were excluded. Abstracts were accepted if they met specific criteria. All trials had to meet criteria for trustworthiness, including a search of the Retraction Watch database for retractions or expressions of concern about the trials or their publications.Data Collection And AnalysisWe used standard Cochrane Pregnancy and Childbirth methods. Two review authors independently selected trials, extracted data, and assessed trial quality and scientific integrity. We chose primary outcomes based on clinical importance as measures of effectiveness and safety, including serious outcomes, for the women and their fetuses/infants, infants in early childhood (age two to less than five years), the infant in mid- to late childhood (age five to less than 18 years) and the infant as an adult. We assessed risk of bias at the outcome level using the RoB 2 tool and assessed certainty of evidence using GRADE.Main ResultsWe included 11 trials (4895 women and 5975 babies). High-certainty evidence from these trials indicated that 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) of corticosteroids, compared with no repeat corticosteroid treatment, reduced the risk of their infants experiencing the primary infant outcome of RDS (risk ratio (RR) 0.82, 95% confidence interval (CI) 0.74 to 0.90; 3540 babies; number needed to treat for an additional beneficial outcome (NNTB) 16, 95% CI 11 to 29) and had little or no effect on chronic lung disease (RR 1.00, 95% CI 0.83 to 1.22; 5661 babies). Moderate-certainty evidence indicated that the composite of serious infant outcomes was probably reduced with repeat dose(s) of corticosteroids (RR 0.88, 95% CI 0.80 to 0.97; 9 trials, 5736 babies; NNTB 39, 95% CI 24 to 158), as was severe lung disease (RR 0.83, 95% CI 0.72 to 0.97; NNTB 45, 95% CI 27 to 256; 4955 babies). Moderate-certainty evidence could not exclude benefit or harm for fetal or neonatal or infant death less than one year of age (RR 0.95, 95% CI 0.73 to 1.24; 5849 babies), severe intraventricular haemorrhage (RR 1.13, 95% CI 0.69 to 1.86; 5066 babies) and necrotising enterocolitis (RR 0.84, 95% CI 0.59 to 1.22; 5736 babies).  In women, moderate-certainty evidence found little or no effect on the likelihood of a caesarean birth (RR 1.03, 95% CI 0.98 to 1.09; 4266 mothers). Benefit or harm could not be excluded for maternal death (RR 0.32, 95% 0.01 to 7.81; 437 women) and maternal sepsis (RR 1.13, 95% CI 0.93 to 1.39; 4666 mothers). The evidence was unclear for risk of adverse effects and discontinuation of therapy due to maternal adverse effects. No trials reported breastfeeding status at hospital discharge or risk of admission to the intensive care unit.  At early childhood follow-up, moderate- to high-certainty evidence identified little or no effect of exposure to repeat prenatal corticosteroids compared with no repeat corticosteroids for primary outcomes relating to neurodevelopment (neurodevelopmental impairment: RR 0.97, 95% CI 0.85 to 1.10; 3616 children), survival without neurodevelopmental impairment (RR 1.01, 95% CI 0.98 to 1.04; 3845 children) and survival without major neurodevelopmental impairment (RR 1.02, 95% CI 0.98 to 1.05; 1816 children). An increase or decrease in the risk of death since randomisation could not be excluded (RR 1.06, 95% CI 0.81 to 1.40; 5 trials, 4565 babies randomised). At mid-childhood follow-up, moderate-certainty evidence identified little or no effect of exposure to repeat prenatal corticosteroids compared with no repeat corticosteroids on survival free of neurocognitive impairment (RR 1.01, 95% CI 0.95 to 1.08; 963 children) or survival free of major neurocognitive impairment (RR 1.00, 95% CI 0.97 to 1.04; 2682 children). Benefit or harm could not be excluded for death since randomisation (RR 0.93, 95% CI 0.69 to 1.26; 2874 babies randomised) and any neurocognitive impairment (RR 0.96, 95% CI 0.72 to 1.29; 897 children). No trials reported data for follow-up into adolescence or adulthood.  Risk of bias across outcomes was generally low although there were some concerns of bias. For childhood follow-up, most outcomes had some concerns of risk of bias due to missing data from loss to follow-up.Authors' ConclusionsThe short-term benefits for babies included less respiratory distress and fewer serious health problems in the first few weeks after birth with repeat dose(s) of prenatal corticosteroids for women still at risk of preterm birth seven days or more after an initial course. The current available evidence reassuringly shows no significant harm for the women or child in early and mid-childhood, although no benefit. Further research is needed on the long-term benefits and risks for the baby into adulthood.Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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