Gestational age at birth and risk of intellectual disability without a common genetic cause

Abstract

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. We therefore 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. 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 outcome-discordant siblings (n = 8034). Risk of intellectual disability 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_37weeks = 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_{43 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 cohort of matched siblings suggesting they were robust against confounding by shared familial traits. Risk of intellectual disability was greatest among children showing evidence of fetal growth restriction, especially when birth occurred before or after term. 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 are relevant to clinical practice concerning elective delivery around term and mitigation of risk in post-term children.

Keywords: Gestational age; Intellectual disability; Post-term birth; Regression splines; Siblings; Stockholm Youth Cohort.

Fig. 1

Selection of the study cohort

Fig. 2

Population-level association between gestational duration and risk of intellectual disability. Notes: The population-level association (N = 499,621) was estimated using a generalized estimating equations model with a logit link, and adjusted statistically for year of birth, child sex, parity, gestational hypertension or preeclampsia, gestational diabetes, birth weight for gestational age, maternal and paternal age, maternal and paternal psychiatric history, maternal and paternal country of birth, family disposable income quintile at birth, and parental educational attainment at birth. Those born at 40 weeks and 3 gestational days are the referent

Fig. 3

Within-family association between gestational duration and risk of intellectual disability. Notes: The within-family association (N = 8034) was estimated using a conditional likelihood logistic regression model, and adjusted statistically for year of birth, child sex, parity, gestational hypertension or preeclampsia, gestational diabetes, birth weight for gestational age, maternal and paternal age, family disposable income quintile at birth, and parental educational attainment at birth. Those born at 40 weeks and 3 gestational days are the referent.