Pediatrics · Medical Literature
Prenatal exposure to asthma medications and risk of neurodevelopmental disorders and educational difficulties: A systematic review and meta-analysis.
Abstract
Since asthma exacerbations during pregnancy risk maternal and fetal health, continued medication is important. However, some studies have reported adverse neurodevelopmental outcomes following prenatal exposure to asthma medication. Therefore, this systematic review aimed to collate the existing evidence on the associations between prenatal exposure to asthma medication and neurodevelopmental and educational outcomes. A systematic review was conducted in accordance with PRISMA guidelines and the PECO framework. PubMed, Medline and Embase databases were searched for studies investigating prenatal exposure to one or more asthma medication and neurodevelopmental or educational outcomes published, in English, between January 2003 and September 2024, and updated in November 2025. Studies of asthma medication used for other indications were excluded. Study quality was assessed using the Newcastle-Ottawa scale. Random-effects meta-analyses were conducted where appropriate and heterogeneity was evaluated using Cochran's Q and I2 tests. Of 16,824 studies identified by the initial search, seven were eligible for inclusion. All investigated beta-2-adrenergic agonists (B2AA), with one including B2AA as mono- and polytherapy-and one study also investigated inhaled corticosteroids (ICS) exposure. Two reported associations with autism spectrum disorder (ASD) and one with attention-deficit hyperactivity disorder (ADHD). An updated search identified one additional eligible study, which examined both ADHD and ASD, as well as other neurodevelopmental disorders. The included eight studies (n = 3,867,170 participants) comprised cohort (n = 5) and case-control (n = 3) designs and reported inconsistent results. Meta-analysis of three studies (n = 1,380,871) indicated significant associations with ASD for exposure to B2AA both preconception (aOR 1.34, 95% CI [1.19,1.52]) and during pregnancy (aOR 1.29, 95% CI [1.16,1.42]). Heterogeneity was low, with no evidence of significant publication bias. Limitations of the included studies comprised residual confounding and exposure misclassification. Additionally, studies included in the meta-analysis were few in number and did not adequately distinguish between medication effects and underlying maternal asthma. Meta-analysis suggested an association between prenatal exposure to B2AA and ASD. An association with ADHD, reported in a single study, requires corroboration. To date, based on our search strategy, no association has been reported with communication skills, motor skills, problem-solving and personal-social skills, or cerebral palsy.
Clinical relevance
Is prenatal exposure to asthma medications—primarily beta-2-adrenergic agonists (B2AA) and inhaled corticosteroids (ICS)—associated with neurodevelopmental disorders (e.g., ASD, ADHD) or educational difficulties in children? __SNAPSHOT__ {"studyDesign":"Systematic review with random-effects meta-analysis (PRISMA/PECO framework)","setting":"Multi-national; studies identified from PubMed, Medline, and Embase; literature search from January 2003 to September 2024, updated November 2025; authors affiliated with University of Glasgow, United Kingdom","sampleSize":"8 eligible studies included (n = 3,867,170 total participants across included studies); meta-analysis of ASD outcome restricted to 3 studies (n = 1,380,871)","population":"Children born to mothers who used asthma medications during or before pregnancy; comparison group: offspring of women who did not take any asthma medication during pregnancy","intervention":"Prenatal (and preconception) exposure to asthma medications, including SABA, LABA, LTRA, ICS, oral corticosteroids, theophylline, and mast cell stabilizers; the primary exposure investigated across included studies was B2AA (beta-2-adrenergic agonists)","comparator":"Offspring of mothers without prenatal asthma medication use (reference group definitions varied across included studies)","primaryOutcome":"Neurodevelopmental disorders (per ICD-11: intellectual disability, ASD, ADHD, developmental speech/language disorder, developmental learning disorder, developmental motor coordination disorder, stereotypic movement disorder, and cerebral palsy) and educational outcomes (academic attainment, school performance, special educational needs)","followUp":"Not reported (varied across included primary studies; up to childhood/school age implied by outcome types)","fundingSource":"Not explicitly reported in the abstract; full-text acknowledgments reference HDR UK (funded by UK Medical Research Council and other UK health agencies)—no industry funding identified"}
Key findings
Of 16,824 studies identified in the initial search, 8 met eligibility criteria after a search update in November 2025. All 8 included studies investigated B2AA exposure; one additionally examined ICS. Study designs comprised 5 cohort and 3 case-control studies, and results across the 8 studies were inconsistent. Two studies reported associations with ASD and one with ADHD in the original search; the updated search added one study that examined both ASD and ADHD as well as other neurodevelopmental disorders. Meta-analysis of 3 studies (n = 1,380,871) examining B2AA exposure and ASD yielded statistically significant pooled associations: preconception exposure aOR 1.34 (95% CI 1.19–1.52) and prenatal exposure aOR 1.29 (95% CI 1.16–1.42). Statistical heterogeneity across these 3 pooled studies was low, and no evidence of significant publication bias was detected. These pooled aORs represent approximately a 29–34% relative increase in the odds of ASD diagnosis; absolute risk differences and NNT/NNH cannot be calculated from the reported data (not reported). Evidence for an association with ADHD derives from a single study, which suggested the potential effect may be male-specific; this finding was not meta-analyzed and requires corroboration. No associations with other neurodevelopmental outcomes—including gross or fine motor skills, communication and problem-solving skills, or cerebral palsy—were identified in the existing literature. Data on ICS and educational outcomes were insufficient to support meta-analysis. Key limitations within the included studies include residual confounding by indication and disease severity, and exposure misclassification.
Practice implications
This systematic review and meta-analysis synthesizes a very sparse evidence base (only 8 eligible studies from >16,000 screened) and establishes a statistically significant pooled association between prenatal and preconception B2AA exposure and ASD (aOR ~1.29–1.34). However, the review explicitly does not establish whether this association reflects a causal medication effect, confounding by indication (i.e., asthma itself driving the risk signal), or confounding by severity (women with more severe or uncontrolled asthma using more B2AA). The similar effect sizes observed for preconception and prenatal B2AA exposure—a pattern consistent with confounding by indication rather than a direct fetal drug effect—was noted by the authors as raising interpretive uncertainty. The ADHD signal rests on a single study and cannot be evaluated conclusively. Outcomes for which no association was found (motor development, communication, cerebral palsy) should be interpreted cautiously given the paucity of available primary literature rather than as definitive evidence of safety. Findings apply to populations of pregnant individuals with asthma using B2AA; populations using other asthma drug classes (ICS, LTRA, OCS) are inadequately represented in the included literature. This review was based on abstract and full-text data from published observational studies; no unpublished or registry data were synthesized. Clinicians should not alter prescribing of guideline-recommended asthma medications during pregnancy on the basis of these findings alone, as untreated or poorly controlled asthma carries independent and well-documented maternal and fetal risks. __LIMITATIONS__ Critically small evidence base: only 8 eligible studies from >16,800 screened, with ASD meta-analysis restricted to 3 studies—severely limiting precision and generalizability.,Confounding by indication: none of the included studies fully disentangled the effect of B2AA medication from the effect of underlying maternal asthma or asthma severity, which is itself associated with adverse offspring outcomes.,Confounding by severity: continuous B2AA use (>45 days per trimester) in some studies may proxy for severe or uncontrolled asthma rather than representing a medication-specific effect.,Exposure misclassification: most studies defined exposure via ATC classification codes from pharmacy/dispensing databases, which do not confirm actual drug ingestion or adherence.,None of the included studies reported whether B2AA was administered as monotherapy or in combination with controller therapies, precluding isolation of B2AA-specific effects.,Only 3 of 8 included studies adjusted for socioeconomic confounders (e.g., income).,Heterogeneous reference groups across studies (e.g., some compared to women without asthma; others to women with asthma not taking medication), limiting direct comparability.,No data on ICS, LABA, LTRA, OCS, theophylline, or mast cell stabilizers and neurodevelopmental outcomes; evidence gap is substantial.,No educational outcome data were meta-analyzable.,English-language restriction and search limited to 3 databases may have introduced selection bias.,Statistical significance of pooled results does not establish clinical causation; effect sizes (aOR ~1.29–1.34) may be partially or wholly attributable to residual confounding. __BOTTOM_LINE_CATEGORY__ low_certainty __BOTTOM_LINE__ This meta-analysis of 3 large observational studies found a statistically significant association between prenatal B2AA exposure and ASD (aOR 1.29–1.34), but the evidence base is very small and cannot exclude confounding by indication or severity as the primary driver of this signal. No conclusions can be drawn about other asthma drug classes or about ADHD, educational outcomes, or other neurodevelopmental disorders. Clinicians should continue prescribing guideline-recommended asthma therapies during pregnancy, as the risks of undertreated asthma are well-established; this review highlights the urgent need for large, confounder-adjusted pharmacoepidemiological studies that can separate medication effects from disease effects.