Gestational age at birth and risk of intellectual disability without a common genetic cause: findings from the Stockholm Youth Cohort

Background Preterm birth is linked to intellectual disability and there is evidence to suggest post-term birth may also incur risk. However, these associations have not yet been investigated in the absence of common genetic causes of intellectual disability (where risk associated with late delivery may be preventable) or with methods allowing stronger causal inference from non-experimental data. We aimed to examine risk of intellectual disability without a common genetic cause across the entire range of gestation, using a matched-sibling design to account for unmeasured confounding by shared familial factors.

Methods and Findings We conducted a population-based retrospective study using data from the Stockholm Youth Cohort (n=499,621) and examined associations in a nested cohort of matched siblings (n=8,034). Children born at non-optimal gestational duration (before/after 40 weeks 3 days) were at greater risk of intellectual disability. Risk was greatest among those born extremely early (adjusted OR_{24 weeks}=14.54 [95% CI 11.46–18.44]), lessening with advancing gestational age toward term (aOR_{32 weeks}=3.59 [3.22–4.01]; aOR_{37 weeks}=1.50 [1.38–1.63]); aOR_{38 weeks}=1.26 [1.16-1.37]; aOR₃₉ weeks=1.10 [1.04-1.17]) and increasing with advancing gestational age post-term (aOR_{42 weeks}=1.16 [1.08–1.25]; aOR_{42 weeks}=1.41 [1.21–1.64]; aOR_{44 weeks}=1.71 [1.34–2.18]; aOR_{45 weeks}=2.07 [1.47–2.92]). Associations persisted in a nested cohort of matched outcome-discordant siblings suggesting they were robust against confounding from shared genetic or environmental traits, although there may have been residual confounding by unobserved non-shared characteristics. Risk of intellectual disability was greatest among children showing evidence of fetal growth restriction, especially when birth occurred before or after term.

Conclusions Birth at non-optimal gestational duration may be linked causally with greater risk of intellectual disability. The mechanisms underlying these associations need to be elucidated as they will be relevant to clinical practice concerning elective delivery within the term period and the mitigation of risk in children who are born post-term.