Objective:

To evaluate the association between prenatal exposure to beta-2-adrenergic agonists and the risk of autism spectrum disorder (ASD) in offspring.

Approach:

• Study Design: Systematic review and meta-analysis of 8 observational studies involving nearly 3.9 million participants from Denmark, Finland, Sweden, Japan, and the United States.
• Study Types: Five cohort studies and three case-control studies, primarily using national registry or administrative data, limited to singleton births.
• Primary Analysis: Focused on beta-2-adrenergic agonist exposure and ASD, with pooled analyses from three studies involving about 1.4 million participants.

Key Findings:

• Prenatal exposure to beta-2-adrenergic agonists was associated with an adjusted pooled effect estimate of 1.29 for ASD.
• Preconception exposure had an adjusted pooled effect estimate of 1.34.
• Associations were observed across all trimesters with similar estimates.
• Evidence for other neurodevelopmental outcomes was limited, with some associations noted for attention-deficit/hyperactivity disorder (ADHD).
• Adjustment for maternal asthma showed mixed results, with some studies finding no significant associations.
• No eligible studies evaluated educational outcomes.

Interpretation:

The observed associations may reflect confounding by indication or asthma severity rather than a direct treatment effect.

Limitations:

• Most studies relied on prescription or registry data lacking details on adherence, dose, duration, and asthma severity.
• Inability to distinguish between short-acting and long-acting beta-2-adrenergic agonists.
• All studies conducted in high-income countries, limiting generalizability.
• No eligible studies evaluated educational outcomes.

Conclusion:

The findings raise concerns about the potential risks of beta-2-adrenergic agonist exposure during pregnancy, but further research is needed to clarify these associations.

Sources:

• PLOS Medicine