BACKGROUND AND PURPOSE:

• Räikkönen et al. (JAMA, 2020) investigated whether antenatal corticosteroid treatment is associated with mental and behavioral disorders in children born at term and preterm
• Gyamfi-Bannerman et al. (JAMA, 2020) provide a ‘Comment and Response’ that provides a review and highlight important clinical points (see below)

METHODS:

• Population retrospective cohort study
  • Data collected on deliveries ≥22 weeks and ≥500g
• Participants
  • All singleton live births in Finland surviving until 1 year (2006 through 2017)
• Exposures
  • Maternal antenatal corticosteroid treatment
  • Number and timing of treatments were not available in the database
• Finnish corticosteroid protocol
  • Betamethasone (12 mg) twice 24 hours apart
    • Until 2009: up to 34w0d
    • After 2009: Up to 34w6d and possibly later depending on clinical scenario
  • Repeat treatments
    • Until 2009: Not recommended
    • After 2009: 1 repeat course if risk of RDS high
• Within-sibpair comparison conducted to help address unmeasured familial confounding
  • Sibpairs discordant for treatment exposure were compared with sibpairs concordant for nonexposure
  • Multiple other potential confounders (e.g., maternal age, gestational age, mode of delivery, BMI etc.) were extracted from the database
• Primary outcome
  • Any childhood mental and behavioral disorder diagnosed in a specialized medical care setting

RESULTS:

• Total of 670,097 singleton births used in the analysis
  • Median length of follow-up: 5.8 (IQR 3.1-8.7) years
• Corticosteroid exposure and birth
  • Corticosteroid exposed children: 2.22% | 46.1% female
    • Born at term: 45.27%
    • Born preterm: 54.74%
  • Non-exposed children: 97.78% | 48.9% female
    • Born at term: 96.88%
    • Born preterm: 3.12%
• Eligible sibpairs: 241,621
  • Discordant for treatment exposure: 1.71%

Compared to non-exposure, exposure to corticosteroids was significantly associated with higher risk of any mental or behavioral disorder

• Entire cohort
  • Exposed: 12.01%
  • Non-exposed: 6.45%
  • Absolute difference 5.56% (95% CI, 5.04% to 6.19%)
  • Adjusted hazard ratio (HR) 1.33 (1.26 to 1.4)
• Term-born children
  • Exposed: 8.89%
  • Non-exposed: 6.31%
  • Absolute difference 2.58% (95% CI, 1.92% to 3.29%)
  • HR 1.47 (95% CI, 1.36 to 1.69)
• Term within-sibpair analysis
  • Exposure in sibling of discordant sibpair was associated with increased risk for mental and behavioral disorder
    • Exposed:6.56%
    • Unexposed: 4.17%
    • Absolute difference: 2.40% (95% CI, 1.67%-3.21%)
    • HR 1.38: (95% CI, 1.21-1.58)
• Preterm-born children
  • Cumulative incidence was significantly different but not the HR
    • Exposed: 14.59%
    • Non-exposed: 10.71%
    • Absolute difference 3.38% (95% CI, 2.95% to 4.87%)
    • HR 1.00 (95% CI, 0.92 to 1.09)

CONCLUSION:

• This study identified an association between antenatal exposure to corticosteroids for lung maturity and mental and behavioral disorders in offspring
• The authors acknowledge multiple limitations, including
  • The data reflecting association and not causation
  • The Finnish population is homogeneous and therefore results may not be generalizable to other populations
• The authors conclude

…exposure to maternal antenatal corticosteroid treatment was significantly associated with mental and behavioral disorders in children

These findings may help inform decisions about maternal antenatal corticosteroid treatment

Comment and Response from Gyamfi-Bannerman et al. (JAMA, 2020)

The authors, who were all involved with the MFMU RCTs related to corticosteroids use, point out significant limitations with this study, including  

• Study design
  • Observational study can only assess associations and not causation
• Absence of key data
  • Number of doses
  • Courses of corticosteroids
  • Gestational age  
  • Indication for corticosteroid administration | Critical as outcome may be related to indication and not medication especially when assessing neurodevelopment
  • Individual-level data on deaths after infancy | Neonatal death is impacted by corticosteroids
  • Gestational age not studied separately in this study | However, the authors also speculate regarding risk of use in the late preterm period
• Current evidence for corticosteroid use and outcomes
  • Long-term neurodevelopment after a single course of corticosteroids: Data from “well-conducted clinical trials in which patients were randomized” and “dosing and indication for administration were characterized precisely” have been reassuring
  • Late Preterm: Corticosteroids reduce RDS in late preterm neonates | Due to patient volume (late preterm neonates account for the majority of NICU admissions for respiratory disease) | Therefore, use of corticosteroids can prevent a significant proportion of bronchopulmonary dysplasia
• The authors of this ‘Comment and Response’ conclude

We do not agree that the study supports a reconsideration of the use of antenatal corticosteroids

We agree that clinical care would be improved by devising better ways to accurately select women who actually deliver in the week following administration, but this applies regardless of gestational age

We concur that perinatal trials should evolve to consistently include assessments of long-term outcome

Learn More – Primary Sources:

Associations Between Maternal Antenatal Corticosteroid Treatment and Mental and Behavioral Disorders in Children (Räikkönen et al. JAMA, 2020)

Maternal Antenatal Corticosteroid Treatment and Childhood Mental and Behavioral Disorders (Gyamfi–Bannerman et al. JAMA, 2020)

MFMU Network: Antenatal Betamethasone for Women at Risk for Late Preterm Delivery (NEJM, 2016)

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