Mid-Childhood Outcomes of Repeat Antenatal Corticosteroids: A Randomized Controlled Trial

Abstract

To assess if exposure to repeat dose(s) of antenatal corticosteroids has beneficial effects on neurodevelopment and general health in mid-childhood, at 6 to 8 years' corrected age. METHODS:Women at risk for very preterm birth, who had received a course of corticosteroids ≥7 days previously, were randomized to intramuscular betamethasone (11.4 mg Celestone Chronodose) or saline placebo, repeated weekly if risk of very preterm birth remained. Midchildhood assessments included neurocognitive function, behavior, growth, lung function, blood pressure, health-related quality of life, and health service utilization. The primary outcome was survival free of neurosensory disability. RESULTS:Of the 1059 eligible long-term survivors, 963 (91%) were included in the primary outcome; 479 (91%) in the repeat corticosteroid group and 484 (91%) in the placebo group. The rate of survival free of neurosensory disability was similar in both groups (78.3% repeat versus 77.3% placebo; risk ratio 1.00, 95% confidence interval, 0.94-1.08). Neurodevelopment, including cognitive function, and behavior, body size, blood pressure, spirometry, and health-related quality of life were similar in both groups, as was the use of health services. CONCLUSIONS:Treatment with repeat dose(s) of antenatal corticosteroids was associated with neither benefit nor harm in mid-childhood. Our finding of long-term safety supports the use of repeat dose(s) of antenatal corticosteroids, in view of the related neonatal benefits. For women at risk for preterm birth before 32 weeks' gestation, ≥7 days after an initial course of antenatal corticosteroids, clinicians could consider using a single injection of betamethasone, repeated weekly if risk remains.

Timing of antenatal corticosteroid administration and survival in extremely preterm infants: a national population‐based cohort study

“…37 Recent work indicate no harm at follow-up to school age in those exposed to repeat courses of ACS at 24-28 weeks and born later after on average 32 weeks of gestation. 38 Observational data from adolescence and young adult age also suggest long-term safety after exposure to repeat ACS. 39 Repeat or rescue doses of glucocorticoids may therefore be considered in women at continued risk of preterm birth 7 or more days after an initial course.…”

“…The latest Cochrane review concluded that repeat courses of corticosteroids were associated with a reduction in the incidence and severity of neonatal lung disease and a small reduction in size at birth . Recent work indicate no harm at follow‐up to school age in those exposed to repeat courses of ACS at 24–28 weeks and born later after on average 32 weeks of gestation . Observational data from adolescence and young adult age also suggest long‐term safety after exposure to repeat ACS .…”

Prenatal programming of stress responsiveness and behaviours: Progress and perspectives

“…59 These effects were not evident if prematurity was not factored out of the analysis, a finding consistent with another prospective trial (ACTORDS). 60 A Finnish birth cohort study revealed that prenatal exposure to a single course of sGC was associated with adverse mental health outcomes, including ADHD symptomology in childhood (8 years) and adolescence (16 years). 61 A recent study demonstrated in term born infants that prenatal exposure to a single course of sGC was associated with a reduced IQ in children (6-11 years of age).…”

Repeat doses of antenatal betamethasone and risk factors for cardiometabolic disease at early school age

“…McKinlay et al provides new evidence regarding some aspects of long‐term safety with the use of repeated courses of antenatal corticosteroids. The original aim of the ACTORDS study was to evaluate short‐term outcomes, and it has shown reduced neonatal morbidity after repeated courses of antenatal corticosteroids without an associated increase in neurologic disability at two years of corrected age or at mid‐childhood . In the context of cardiometabolic health, the associations between preterm birth and later hypertension, diabetes, stroke and even death from cardiovascular disease – boosted by animal data – have generated worries about glucocorticoid exposure in foetal life, especially if repeated.…”

“…The latest Cochrane review of 10 randomised trials comparing single and repeat courses of antenatal glucocorticoids for neonatal morbidity favours repeat courses. And although repeated courses have been associated with lower birthweight and small reductions in head circumference, data on long‐term safety outcomes are so far generally reassuring . According to ACOG present guidelines, a single rescue course of antenatal corticosteroids may be considered if the antecedent treatment was given more than two weeks prior, the gestational age is less than 32 weeks and the women are judged by the clinician to be likely to give birth within the next week.…”