Does administration of antenatal corticosteroids (ACS) to pregnant individuals at risk of preterm birth between 31+0 and 36+6 weeks of gestation affect the risk of cerebral palsy in the newborn?

Key Takeaway: Antenatal Corticosteroids and Cerebral Palsy Risk

This regression discontinuity study found no convincing evidence that antenatal corticosteroids administered at 34 weeks gestation affect the risk of cerebral palsy, though the estimates were imprecise and compatible with both benefits and harms.

Study Design and Context

This natural experiment leveraged a sharp policy discontinuity in Ontario, Canada, where guidelines recommended antenatal corticosteroids through 33+6 weeks but not at 34+0 weeks and beyond. The study examined 20,009 singleton livebirths between 31+0 and 36+6 weeks gestation to assess whether the abrupt drop in corticosteroid treatment at 34+0 weeks affected cerebral palsy rates.

• The study used a regression discontinuity design to estimate the effect of the treatment drop at 34+0 weeks on the composite outcome of death before age 2 or cerebral palsy 1.
• Cerebral palsy was defined using diagnostic codes through age five years, with correction for misclassification using external estimates of sensitivity and specificity 1.

Primary Findings

The risk ratio for death or cerebral palsy comparing just before versus just after 34+0 weeks was 0.98 (95% CI: 0.50 to 1.98), indicating no statistically significant difference.

• The crude risk of cerebral palsy was 6.2 per 1,000, and the misclassification-corrected risk was 5.6 per 1,000 1.
• While the overall risk of death or cerebral palsy declined with increasing gestational age at delivery, there was no abrupt change at the 34+0 week threshold where corticosteroid use dropped 1.
• Results remained consistent across sensitivity analyses using different outcome definitions (in-hospital newborn death or cerebral palsy, and cerebral palsy alone) 1.

Interpretation in Context of Current Guidelines

Despite this study's null findings, current SMFM guidelines strongly recommend antenatal corticosteroids for singleton pregnancies at 34+0 to 36+6 weeks who are at high risk of delivery within 7 days (GRADE 1A recommendation). 1

• The SMFM recommendation is based primarily on the ALPS trial, which demonstrated clear reductions in respiratory morbidity (RR 0.80 for need for respiratory support; RR 0.67 for severe respiratory complications) 1, 2, 3.
• The primary benefit of late preterm corticosteroids is prevention of respiratory complications, not cerebral palsy prevention. 1, 2, 3

Important Caveats About This Study

• The confidence intervals were wide (0.50 to 1.98), meaning the study cannot rule out either substantial benefit or harm from antenatal corticosteroids regarding cerebral palsy risk. 1
• The study was underpowered to detect clinically meaningful differences in cerebral palsy, which is a relatively rare outcome (approximately 5-6 per 1,000 in this population) 4.
• Cerebral palsy diagnosis at age 5 may miss some cases and the study relied on administrative diagnostic codes rather than standardized clinical assessments 1.

Reconciling with Broader Evidence

Previous research has shown conflicting results regarding antenatal corticosteroids and cerebral palsy:

• A 2001 case-control study found that maternal corticosteroid administration was associated with a reduced risk of cerebral palsy in extremely preterm infants (OR 0.4,95% CI 0.1 to 0.98) 5.
• A 2017 Cochrane overview found low-quality evidence suggesting a possible reduction in cerebral palsy with antenatal corticosteroids for accelerating fetal lung maturation (RR 0.60,95% CI 0.34 to 1.03) 6.
• The SMFM guidelines acknowledge that long-term neurodevelopmental effects of antenatal corticosteroids remain uncertain, with follow-up studies showing no increased risk of neurologic impairment but limited by small sample sizes 1.

Clinical Implications

Continue offering antenatal corticosteroids to eligible patients at 34+0 to 36+6 weeks based on proven respiratory benefits, while counseling that long-term neurodevelopmental risks remain uncertain. 1, 2, 3

• The decision to administer corticosteroids should be based on the well-established reduction in respiratory morbidity, not on uncertain effects on cerebral palsy 1, 2, 3.
• Patients must be counseled that while short-term respiratory benefits are clear, long-term neurodevelopmental outcomes including cerebral palsy risk remain incompletely understood (GRADE 1C recommendation) 1.
• Avoid corticosteroids in patients with pregestational diabetes mellitus due to increased risk of severe neonatal hypoglycemia (GRADE 1C recommendation). 1, 2, 3

Research Gaps Highlighted

This study underscores the critical need for adequately powered, long-term follow-up studies of antenatal corticosteroid interventions that can definitively assess neurodevelopmental outcomes including cerebral palsy 6, 7, 8. The wide confidence intervals in this natural experiment demonstrate that observational studies, even with sophisticated designs, may lack sufficient power to detect clinically important differences in rare outcomes like cerebral palsy.