The efficacy of antenatal corticosteroids on neonatal preterm complications wanes beyond 7 days after treatment. The neurodevelopmental effects of longer treatment-to-birth intervals have not been adequately evaluated.
To study the impact of antenatal corticosteroid timing on survival without moderate or severe neurological disabilities at 5½ years.
Secondary analysis of the EPIPAGE-2 study, a national population-based cohort (France) that recruited neonates in 2011 and followed them up at 5½ years (results first reported in 2021). Participants were children born alive between 24+0 and 34+6 weeks, with a complete corticosteroid course, delivery more than 48 hours after the first injection, and neither limitation of care decided before birth nor severe congenital malformation. The study included 2613 children, 2427 alive at 5½ years; 71.9% (1739/2427) had a neurological assessment at this age; 1537 had a clinical examination (complete for 1532), and 202 were assessed with a postal questionnaire. Exposure was defined as the interval between the first injection of the last antenatal corticosteroid course and delivery in days, studied in 2 categories (day 3 (D3) to D7 and after D7), in 4 categories (D3-D7, D8-D14, D15-D21 and after D21), and continuously in days. The main outcome was survival at 5½ years without moderate/severe neurological disabilities, defined as moderate/severe cerebral palsy, or unilateral or bilateral blindness or deafness, or full-scale intelligence quotient two standard deviations below the mean. A multivariate analysis with a generalized estimated equation logistic regression model assessed the statistical association between the main outcomes and the interval from the first corticosteroid injection of the last course to birth. Multivariate analyses were adjusted for potential confounders, defined with a directed acyclic graph: gestational age in days, number of corticosteroid courses, multiple pregnancy, and cause of prematurity in five categories. As neurological follow-up was complete in only 63.2% cases (1532/2427), the analyses used imputed data.
Among 2613 children, 186 died between birth and 5½ years. Overall survival was 96.6% (95% confidence interval [CI], 95.9-97.0), and survival without moderate or severe neurological disabilities 86.0% (95% CI, 84.7-87.0). Survival without moderate or severe neurological disabilities was lower after D7 (85.0%) than during the D3-D7 interval (87.0%) (adjusted odds ratio, 0.70; 95% confidence interval, 0.54-0.89).
The association between an interval between antenatal corticosteroid administration and birth exceeding 7 days and a lower rate of survival without moderate or severe neurological disabilities among 5½-year-old children emphasizes the importance of better targeting women at risk of preterm delivery to optimize the timing and thus benefits of treatment.

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