Mikael Norman1, Aurelie Piedvache2, Klaus Børch3, Lene Drasbek Huusom4, Anna-Karin Edstedt Bonamy5, Elizabeth A Howell6, Pierre-Henri Jarreau7, Rolf F Maier8, Ole Pryds3, Liis Toome9, Heili Varendi10, Tom Weber4, Emilija Wilson1, Arno Van Heijst11, Marina Cuttini12, Jan Mazela13, Henrique Barros14, Patrick Van Reempts15, Elizabeth S Draper16, Jennifer Zeitlin2. 1. Division of Pediatrics, Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden2Department of Neonatal Medicine, Karolinska University Hospital, Stockholm, Sweden. 2. INSERM 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. 3. Department of Neonatology, Hvidovre University Hospital, Hvidovre, Denmark. 4. Department of Obstetrics, Hvidovre University Hospital, Hvidovre, Denmark. 5. Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden7Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden. 6. Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York9Department of Obstetrics, Gynecology, and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, New York. 7. University Paris Descartes and Department of Neonatal Medicine and Intensive Care Unit of Port-Royal, Cochin University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France. 8. Children's Hospital, University Hospital, Philipp University of Marburg, Marburg, Germany. 9. Tallinn Children's Hospital, Tallinn, Estonia13University of Tartu, Tartu, Estonia. 10. Tartu University Hospital, University of Tartu, Tartu, Estonia. 11. Department of Neonatology, Radboud University Medical Center, Nijmegen, the Netherlands. 12. Research Unit of Perinatal Epidemiology, Clinical Care and Management Innovation Research Area, Bambino Gesù Children's Hospital, Rome, Italy. 13. Department of Neonatology, Poznan University of Medical Sciences, Poznan, Poland. 14. Epidemiology Research Unit, Institute of Public Health, University of Porto, Porto, Portugal. 15. Department of Neonatology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium20Study Centre for Perinatal Epidemiology Flanders, Brussels, Belgium. 16. Department of Health Sciences, University of Leicester, Leicester, England.
Abstract
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.
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.
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Authors: Matthew A Rysavy; Edward F Bell; Jay D Iams; Waldemar A Carlo; Lei Li; Brian M Mercer; Susan R Hintz; Barbara J Stoll; Betty R Vohr; Seetha Shankaran; Michele C Walsh; Jane E Brumbaugh; Tarah T Colaizy; Abhik Das; Rosemary D Higgins Journal: J Pediatr Date: 2019-02-06 Impact factor: 4.406
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