Prenatal exposure to beta-2-adrenergic agonists was associated with autism spectrum disorder in offspring, but researchers cautioned that the available evidence could not determine whether the association reflected a treatment effect or confounding by indication or severity.
The systematic review and meta-analysis included 8 observational studies involving nearly 3.9 million participants from Denmark, Finland, Sweden, Japan, and the United States. Five studies were cohort studies and 3 were case-control studies. Most used national registry or administrative data, and all were limited to singleton births. No eligible studies evaluated educational outcomes.
The primary meta-analysis focused on beta-2-adrenergic agonist exposure and autism spectrum disorder. Three studies involving about 1.4 million participants were suitable for pooling. In pooled analyses, prenatal exposure was associated with an adjusted pooled effect estimate of 1.29 for autism spectrum disorder. Preconception exposure was associated with an adjusted pooled effect estimate of 1.34. Associations were also observed for each trimester, with broadly similar estimates across exposure windows.
The researchers noted that the pooled analysis combined odds ratios and incidence rate ratios because autism spectrum disorder was considered a rare outcome. The underlying studies also used different comparator groups, including offspring with no beta-2-adrenergic agonist exposure, no asthma medication exposure, asthma without medication exposure, or no maternal asthma and no asthma medication exposure.
Evidence for other neurodevelopmental outcomes was more limited. One Danish cohort study reported an association between prenatal beta-2-adrenergic agonist exposure and attention-deficit/hyperactivity disorder, with findings suggesting any association may have been specific to boys; however, confidence intervals overlapped, limiting evidence of a sex-specific difference. A Finnish cohort study evaluating asthma medication exposure more broadly reported associations with attention-deficit/hyperactivity disorder, autism spectrum disorder, motor developmental disorder, learning disabilities, language-developmental disorder, mixed developmental disorder, and intellectual disability. Studies evaluating communication skills, motor skills, problem-solving abilities, personal-social skills, and cerebral palsy generally did not find statistically significant associations.
Several studies attempted to account for maternal asthma through adjustment or subgroup analyses, but the evidence was mixed. In analyses restricted to mothers with confirmed asthma, associations between beta-2-adrenergic agonist exposure and autism spectrum disorder or attention-deficit/hyperactivity disorder generally were not statistically significant. However, 1 study found that adjustment for maternal asthma did not substantially change results, and a third-trimester association remained statistically significant after adjustment. The researchers said the overall pattern raised concern that the observed associations may reflect confounding by indication, meaning the reason for treatment, or confounding by asthma severity rather than treatment itself.
One study also found that second-trimester exposure lasting at least 45 days was associated with autism spectrum disorder, whereas shorter exposure was not. However, the researchers noted that the confidence intervals overlapped, limiting evidence of a meaningful duration-response pattern.
The review had several limitations. Most studies relied on prescription or registry data and generally lacked information on adherence, dose, duration, route of administration, and asthma severity. The available data did not adequately distinguish short-acting from long-acting beta-2-adrenergic agonists or clarify whether beta-2 agonists were used alone or with controller therapies. Although heterogeneity appeared low and no publication bias was detected, the researchers cautioned that these tests were underpowered because only 3 studies were included in the meta-analysis. All included studies were conducted in high-income countries, which may limit generalizability.
The authors noted that Global Initiative for Asthma guidance recommends continuing asthma medication during pregnancy because exacerbations can pose risks to maternal and fetal health.
Disclosures: The study was affiliated with Health Data Research UK and supported in part by a British Council-funded PhD program. The funders had no role in the study design, conduct, analysis, manuscript preparation, or publication decision. The researchers reported no competing interests.
Source: PLOS Medicine
