Parental asthma and risk of autism spectrum disorder in offspring: A population and family-based case-control study

Abstract

Background: Associations between parental asthma and prenatal exposure to asthma medications with offspring autism spectrum disorder (ASD) have been reported. However, the associations might be confounded by unmeasured (genetic and shared environmental) familial factors.

Objective: We investigated the association between (a) maternal/paternal asthma and offspring ASD, and (b) prenatal exposures to β2-agonists, other asthma medications and offspring ASD using cases and controls selected from the population as well as biological relatives with different degrees of relatedness.

Methods: We included all children (N = 1 579 263) born in Sweden 1992-2007. A nested case-control design was used to compare 22 894 ASD cases identified from the National Patient Register to (a) 228 940 age-, county- and sex-matched controls randomly selected from the population, (b) their eligible full-siblings (n = 1267), (c) half-siblings (n = 1323), (d) full-cousins (n = 11 477) and (e) half-cousins (n = 3337). Conditional logistic regression was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) for ASD in children differentially exposed to parental asthma or prenatal asthma medications.

Results: Maternal asthma was associated with increased risk of offspring ASD (OR 1.43, 95% CI 1.38-1.49); there was a weaker association for paternal asthma (OR 1.17, 95% CI 1.11-1.23). The risk of offspring ASD in mothers with asthma showed similar estimates when adjusting for shared familial factors among paternal half-siblings (OR 1.20, 95% CI 0.80-1.81), full-cousins (OR 1.28, 95% CI 1.16-1.41) and half-cousins (OR 1.30, 95% CI 1.10-1.54), albeit with wider confidence intervals. Prenatal exposure to asthma medications among subjects whose mothers had asthma was not associated with subsequent ASD.

Conclusions and clinical relevance: In this large observational study, parental asthma was associated with slightly elevated risk of ASD in offspring. More specifically, the increased risk by maternal asthma did not seem to be confounded by familial factors. There was no evidence of an association between asthma medications during pregnancy and offspring ASD.

Keywords: asthma; autism spectrum disorder; confounding; medications during pregnancy; nested case-control.

Figure 1

Overall representation of the study populations. The eligibility criteria of being at risk at the age when the case was diagnosed holds for all controls. Matching on sex and <5 years of age difference holds for all controls in panel (C)

Figure 2

Adjusted odds ratios (OR) and 95% confidence intervals (CI) of offspring autism spectrum disorders (ASD) by parental asthma when comparing cases with unrelated controls, half‐cousin, full‐cousin, and maternal/paternal half‐sibling controls nested in the birth cohort. Panels (A and B) show the estimates for maternal asthma and paternal asthma separately, after adjusting for parity, maternal smoking during pregnancy and civil status at year of child birth, country of birth and age at child birth for mothers and fathers, highest education between parents, and maternal body mass index at first antenatal visit. The asterisks were used to indicate statistically significant associations