Twenty-year outcomes after repeat doses of antenatal corticosteroids prior to 32 weeks' gestation: Follow-up of a randomised clinical trial.

Background: For women who have received a course of antenatal corticosteroids ≥7 days prior and have ongoing risk of preterm birth within the next 7 days, repeat dose(s) of corticosteroids up to 32 weeks' gestation have been shown to reduce neonatal respiratory distress syndrome and serious health problems in the neonatal period but not other neonatal morbidities such as chronic lung disease, death, severe intraventricular haemorrhage or necrotising enterocolitis. Repeat antenatal corticosteroids were not associated with either benefit or harms in mid-childhood. However, this may have been too early to evaluate potential adverse effects on respiratory and other long-term outcomes. We aimed to assess if exposure to repeat dose(s) of antenatal corticosteroids administered to pregnant women up to 32 weeks' gestation has beneficial or harmful effects on respiratory and general health of the offspring in adulthood.

Methods and findings: We assessed the adult offspring of New Zealand participants in the Australasian Collaborative Trial of Repeat Doses of Corticosteroids for the Prevention of Neonatal Respiratory Disease (ACTORDS), a multicentre, placebo-controlled trial where women at risk of preterm birth within the next week, 7 or more days after having received a single course of corticosteroids were randomised to a repeat dose of intramuscular betamethasone or placebo, that could be repeated weekly if at ongoing preterm birth risk. Follow-up at 20 years included a health questionnaire and consent to access administrative data sources. The primary outcome was any asthma diagnosis. Secondary outcomes included neurodevelopmental, cardiovascular, mental and general health, functional difficulties and social outcomes. Of 352 infants born to 290 maternal trial participants, we assessed 214 (61%; 96 (45%) female) at mean (standard deviation) age 20.5 (1.5) years. The rate of any asthma diagnosis was similar in both groups (58/107 (54%) repeat bethamethasone versus 50/107 (47%) placebo; risk ratio adjusted for gestational age at trial entry, multiplicity and birth centre 1.13, 95% confidence interval, 0.87, 1.46). Differences between the groups for the secondary outcomes were generally small and confidence intervals included the possibility of no difference between groups.

Conclusions: In this follow-up of a randomised clinical trial, our data suggest neither major harm nor benefit for the offspring in early adulthood following exposure to repeat dose(s) of antenatal corticosteroids compared with a single course prior to 32 weeks' gestation. Smaller effects cannot be excluded and follow-up of adult offspring from other trials of repeat antenatal corticosteroids is recommended.

Trial registration: International Standard Randomized Controlled Trial, number ISRCTN48656428.