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Original Investigation
July 2017

Association of Short Antenatal Corticosteroid Administration-to-Birth Intervals With Survival and Morbidity Among Very Preterm InfantsResults From the EPICE Cohort

Author Affiliations
  • 1Division of Pediatrics, Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden
  • 2Department of Neonatal Medicine, Karolinska University Hospital, Stockholm, Sweden
  • 3INSERM Joint Research Unit 1153, Obstetrical, Perinatal, and Pediatric Epidemiology Research Team (Epopé), Center for Epidemiology and Statistics Sorbonne Paris Cité, University Hospital Department Risks in Pregnancy, Paris Descartes University, Paris, France
  • 4Department of Neonatology, Hvidovre University Hospital, Hvidovre, Denmark
  • 5Department of Obstetrics, Hvidovre University Hospital, Hvidovre, Denmark
  • 6Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
  • 7Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
  • 8Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York
  • 9Department of Obstetrics, Gynecology, and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, New York
  • 10University Paris Descartes and Department of Neonatal Medicine and Intensive Care Unit of Port-Royal, Cochin University Hospital, Assistance Publique–Hôpitaux de Paris, Paris, France
  • 11Children’s Hospital, University Hospital, Philipp University of Marburg, Marburg, Germany
  • 12Tallinn Children’s Hospital, Tallinn, Estonia
  • 13University of Tartu, Tartu, Estonia
  • 14Tartu University Hospital, University of Tartu, Tartu, Estonia
  • 15Department of Neonatology, Radboud University Medical Center, Nijmegen, the Netherlands
  • 16Research Unit of Perinatal Epidemiology, Clinical Care and Management Innovation Research Area, Bambino Gesù Children’s Hospital, Rome, Italy
  • 17Department of Neonatology, Poznan University of Medical Sciences, Poznan, Poland
  • 18Epidemiology Research Unit, Institute of Public Health, University of Porto, Porto, Portugal
  • 19Department of Neonatology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium
  • 20Study Centre for Perinatal Epidemiology Flanders, Brussels, Belgium
  • 21Department of Health Sciences, University of Leicester, Leicester, England
JAMA Pediatr. 2017;171(7):678-686. doi:10.1001/jamapediatrics.2017.0602
Key Points

Question  What is the shortest administration-to-birth interval of antenatal corticosteroids that promotes survival and decreases neonatal morbidity in very preterm infants?

Findings  In a population-based cohort of 4594 European infants born before 32 weeks’ gestation, we found that in-hospital mortality was significantly reduced when antenatal corticosteroids had been administered only a few hours prior to delivery.

Meaning  Encouraging administration of antenatal corticosteroids when delivery is very imminent could result in substantial survival and health gains for very preterm infants.


Importance  Administration-to-birth intervals of antenatal corticosteroids (ANS) vary. The significance of this variation is unclear. Specifically, to our knowledge, the shortest effective administration-to-birth interval is unknown.

Objective  To explore the associations between ANS administration-to-birth interval and survival and morbidity among very preterm infants.

Design, Setting, and Participants  The Effective Perinatal Intensive Care in Europe (EPICE) study, a population-based prospective cohort study, gathered data from 19 regions in 11 European countries in 2011 and 2012 on 4594 singleton infants with gestational ages between 24 and 31 weeks, without severe anomalies and unexposed to repeated courses of ANS. Data were analyzed November 2016.

Exposure  Time from first injection of ANS to delivery in hours and days.

Main Outcomes and Measures  Three outcomes were studied: in-hospital mortality; a composite of mortality or severe neonatal morbidity, defined as an intraventricular hemorrhage grade of 3 or greater, cystic periventricular leukomalacia, surgical necrotizing enterocolitis, or stage 3 or greater retinopathy of prematurity; and severe neonatal brain injury, defined as an intraventricular hemorrhage grade of 3 or greater or cystic periventricular leukomalacia.

Results  Of the 4594 infants included in the cohort, 2496 infants (54.3%) were boys, and the mean (SD) gestational age was 28.5 (2.2) weeks and mean (SD) birth weight was 1213 (400) g. Mortality for the 662 infants (14.4%) unexposed to ANS was 20.6% (136 of 661). Administration of ANS was associated with an immediate and rapid decline in mortality, reaching a plateau with more than 50% risk reduction after an administration-to-birth interval of 18 to 36 hours. A similar pattern for timing was seen for the composite mortality or morbidity outcome, whereas a significant risk reduction of severe neonatal brain injury was associated with longer administration-to-birth intervals (greater than 48 hours). For all outcomes, the risk reduction associated with ANS was transient, with increasing mortality and risk for severe neonatal brain injury associated with administration-to-birth intervals exceeding 1 week. Under the assumption of a causal relationship between timing of ANS and mortality, a simulation of ANS administered 3 hours before delivery to infants who did not receive ANS showed that their estimated decline in mortality would be 26%.

Conclusions and Relevance  Antenatal corticosteroids may be effective even if given only hours before delivery. Therefore, the infants of pregnant women at risk of imminent preterm delivery may benefit from its use.