University of Oulu

Crowther, C. A., Middleton, P. F., Voysey, M., Askie, L., Zhang, S., … Martlow, T. K. (2019). Effects of repeat prenatal corticosteroids given to women at risk of preterm birth: An individual participant data meta-analysis. PLOS Medicine, 16(4), e1002771.

Effects of repeat prenatal corticosteroids given to women at risk of preterm birth : an individual participant data meta-analysis

Saved in:
Author: Crowther, Caroline A.1,2; Middleton, Philippa F.2,3; Voysey, Merryn4;
Organizations: 1Liggins Institute, University of Auckland, Auckland, New Zealand
2Robinson Research Institute, Discipline of Obstetrics and Gynaecology, School of Medicine, The University of Adelaide, Adelaide, Australia
3Healthy Mothers Babies and Children, South Australian Health and Medical Research Institute, Adelaide, Australia
4Nuffield Department of Primary Care Health Sciences and Department of Paediatrics, University of Oxford, Oxford , United Kingdom
5NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia
6Department of Family Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
7Department of Paediatrics and Obstetrics/Gynecology, University of Toronto, Toronto, Ontario, Canada
8Birmingham Clinical Trials Unit, Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom
9Division of Neonatology, Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
10Mednax Inc., Sunrise, Florida, United States of America
11Kalispell Regional Health Care, Kalispell, Montana, United States of America
12Department of Paediatrics, University of Oulu, Oulu, Finland
13John A Burns School of Medicine, University of Hawaii, Honolulu , Hawaii, United States of America
14epartment of Pediatrics, Oregon Health and Science University, Portland, Oregon, United States of America
15The Biostatistics Center, George Washington University, Washington, DC, United States of America
16Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Columbia University Medical Center, New York, New York, United States of America
17Department of Obstetrics and Gynaecology, The Royal Women’s Hospital, University of Melbourne, Melbourne, Australia
18Clinical Sciences, Murdoch Children’s Research Institute, Parkville, Victoria, Australia
19Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.9 MB)
Persistent link:
Language: English
Published: Public Library of Science, 2019
Publish Date: 2019-09-25


Background: Infants born preterm compared with infants born at term are at an increased risk of dying and of serious morbidities in early life, and those who survive have higher rates of neurological impairments. It remains unclear whether exposure to repeat courses of prenatal corticosteroids can reduce these risks. This individual participant data (IPD) meta-analysis (MA) assessed whether repeat prenatal corticosteroid treatment given to women at ongoing risk of preterm birth in order to benefit their infants is modified by participant or treatment factors.

Methods and findings: Trials were eligible for inclusion if they randomised women considered at risk of preterm birth who had already received an initial, single course of prenatal corticosteroid seven or more days previously and in which corticosteroids were compared with either placebo or no placebo. The primary outcomes for the infants were serious outcome, use of respiratory support, and birth weight z-scores; for the children, they were death or any neurosensory disability; and for the women, maternal sepsis. Studies were identified using the Cochrane Pregnancy and Childbirth search strategy. Date of last search was 20 January 2015. IPD were sought from investigators with eligible trials. Risk of bias was assessed using criteria from the Cochrane Collaboration. IPD were analysed using a one-stage approach.

Eleven trials, conducted between 2002 and 2010, were identified as eligible, with five trials being from the United States, two from Canada, and one each from Australia and New Zealand, Finland, India, and the United Kingdom. All 11 trials were included, with 4,857 women and 5,915 infants contributing data. The mean gestational age at trial entry for the trials was between 27.4 weeks and 30.2 weeks. There was no significant difference in the proportion of infants with a serious outcome (relative risk [RR] 0.92, 95% confidence interval [CI] 0.82 to 1.04, 5,893 infants, 11 trials, p = 0.33 for heterogeneity). There was a reduction in the use of respiratory support in infants exposed to repeat prenatal corticosteroids compared with infants not exposed (RR 0.91, 95% CI 0.85 to 0.97, 5,791 infants, 10 trials, p = 0.64 for heterogeneity). The number needed to treat (NNT) to benefit was 21 (95% CI 14 to 41) women/fetus to prevent one infant from needing respiratory support. Birth weight z-scores were lower in the repeat corticosteroid group (mean difference −0.12, 95%CI −0.18 to −0.06, 5,902 infants, 11 trials, p = 0.80 for heterogeneity). No statistically significant differences were seen for any of the primary outcomes for the child (death or any neurosensory disability) or for the woman (maternal sepsis). The treatment effect varied little by reason the woman was considered to be at risk of preterm birth, the number of fetuses in utero, the gestational age when first trial treatment course was given, or the time prior to birth that the last dose was given. Infants exposed to between 2–5 courses of repeat corticosteroids showed a reduction in both serious outcome and the use of respiratory support compared with infants exposed to only a single repeat course. However, increasing numbers of repeat courses of corticosteroids were associated with larger reductions in birth z-scores for weight, length, and head circumference. Not all trials could provide data for all of the prespecified subgroups, so this limited the power to detect differences because event rates are low for some important maternal, infant, and childhood outcomes.

Conclusions: In this study, we found that repeat prenatal corticosteroids given to women at ongoing risk of preterm birth after an initial course reduced the likelihood of their infant needing respiratory support after birth and led to neonatal benefits. Body size measures at birth were lower in infants exposed to repeat prenatal corticosteroids. Our findings suggest that to provide clinical benefit with the least effect on growth, the number of repeat treatment courses should be limited to a maximum of three and the total dose to between 24 mg and 48 mg.

see all

Series: PLoS medicine
ISSN: 1549-1277
ISSN-E: 1549-1676
ISSN-L: 1549-1277
Volume: 16
Issue: 4
Article number: e1002771
DOI: 10.1371/journal.pmed.1002771
Type of Publication: A1 Journal article – refereed
Field of Science: 3123 Gynaecology and paediatrics
Funding: The PRECISE IPD-MA was funded by a Project Grant (ID 1010711) from the Australian National Health and Medical Research Council (NHMRC;
Copyright information: © 2019 Crowther et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.