Association of Short Antenatal Corticosteroid Administration-to-Birth Intervals With Survival and Morbidity Among Very Preterm Infants

Abstract

; for the Effective Perinatal Intensive Care in Europe (EPICE) Research Group 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.

Maternal Betamethasone for Prevention of Respiratory Distress Syndrome in Neonates: Population Pharmacokinetic and Pharmacodynamic Approach

“…35,36 The authors also point out that the effectiveness could be of limited duration as it has been shown in very premature human lung explants that maturational signals from ACT are reversible if steroids are removed. 36,37 This was also reported in a clinical study published by Norman et al, 38 showing that for all evaluated outcomes, the risk reduction associated with ACT was transient. Both mortality and severe neonatal brain injury rates increased when delay between administration and delivery exceeded 1 week.…”

European Consensus Guidelines on the Management of Respiratory Distress Syndrome – 2019 Update

“…The optimal treatment to delivery interval is more than 24 h and less than 7 days after the start of steroid treatment; beyond 14 days, benefits are diminished. Beneficial effects of the first dose of antenatal steroid start within a few hours, so advanced dilatation should not be a reason to refrain from therapy and the same may hold for MgSO 4 [27]. There is still debate as to whether steroids should be repeated 1 or 2 weeks after the first course for women with threatened preterm labour.…”

All the right moves: why in utero transfer is both important for the baby and difficult to achieve and new strategies for change

“…The administrative burden and pathway variation of in utero transfer risk compromising the quality of clinical care. Antenatal corticosteroid administration is likely to have optimal impact on reducing neonatal mortality and respiratory distress syndrome if given between 24 hours and 7 days of delivery 34,35 . In the context of in utero transfer, it is common for the first dose to be delayed until the mother reaches the receiving unit and for steroid courses to be incomplete because of communication failures 19 .…”

“…It is well recognised that the transfer of babies in the early neonatal period is a frightening and stressful experience for parents 35 . The loss of familiarity and separation from their vulnerable child at a critical stage when bonds are being established represent a disruption in their parenthood, which can impair the health and development of the infant 37 .…”