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 OR24 weeks = 14.54 [95% CI 11.46–18.44]), lessening with advancing gestational age toward term (aOR32 weeks = 3.59 [3.22–4.01]; aOR37 weeks = 1.50 [1.38–1.63]); aOR38 weeks = 1.26 [1.16–1.37]; aOR39 weeks = 1.10 [1.04–1.17]) and increasing with advancing gestational age post-term (aOR42 weeks = 1.16 [1.08–1.25]; aOR43 weeks = 1.41 [1.21–1.64]; aOR44 weeks = 1.71 [1.34–2.18]; aOR45 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.Electronic supplementary materialThe online version of this article (10.1007/s10654-017-0340-1) contains supplementary material, which is available to authorized users.

Risk of intellectual disability in children born appropriate-for-gestational-age at term or post-term: impact of birth weight for gestational age and gestational age

“…The risk of intellectual disability increases exponentially as gestational age decreases in preterm children [11,12]. A similar trend of increasing risk by decreasing gestational age was recently shown in children born at term (37-41 weeks), whereas a trend of increasing risk by increasing gestational age was observed in children born post-term (≥ 42 weeks) [12]. The same study also suggested a joint impact of term or postterm birth and SGA versus term birth and AGA.…”

“…Preterm birth (< 37 gestational weeks) is another known risk factor for cognitive deficits [10]. The risk of intellectual disability increases exponentially as gestational age decreases in preterm children [11,12]. A similar trend of increasing risk by decreasing gestational age was recently shown in children born at term (37-41 weeks), whereas a trend of increasing risk by increasing gestational age was observed in children born post-term (≥ 42 weeks) [12].…”

Does Birth Trigger Cell Death in the Developing Brain?

“…Changes in the overall magnitude of neonatal cell death may lead to long-term changes in neuron number, as shown for effects of birth mode in mice (Castillo-Ruiz et al, 2018b). Because naturally-occurring cell death in the human brain is ongoing at birth (Lossi et al, 1998;Abrahám et al, 2001;Lavezzi et al, 2006;Abitz et al, 2007), it is possible that some of the reported effects of birth timing on child development (El Marroun et al, 2012;Abel et al, 2017;Heuvelman et al, 2018) are related to alterations in cell death, or a dissociation of cell death from other neurodevelopmental events…”

Recent advances in the genetics of preterm birth

“…However, globally, complications related to preterm birth remain a major cause of neonatal and under‐5 mortality (Liu et al., ). Preterm individuals also are at substantially higher risk of impairments affecting multiple organ systems (Haraldsdottir et al., ; Huang, Lin, Wang, Su, & Lin, ; Parkinson, Hyde, Gale, Santhakumaran, & Modi, ), including potentially disabling neurological and neuropsychiatric disorders (Agrawal, Rao, Bulsara, & Patole, ; Franz et al., ; Heuvelman et al., ; Nosarti et al., ; Sutton & Darmstadt, ). This highlights the importance of determining the mechanisms behind preterm birth and how these mechanisms might relate to the difficulties faced later in life.…”

“…The former is where labor is induced or a Caesarean section is performed because of medical risks or complications, the latter where onset of labor occurs spontaneously prior to 37 weeks gestation. However, this distinction fails to take into impairments affecting multiple organ systems (Haraldsdottir et al, 2018;Huang, Lin, Wang, Su, & Lin, 2018;Parkinson, Hyde, Gale, Santhakumaran, & Modi, 2013), including potentially disabling neurological and neuropsychiatric disorders (Agrawal, Rao, Bulsara, & Patole, 2018;Franz et al, 2018;Heuvelman et al, 2018;Nosarti et al, 2012;Sutton & Darmstadt, 2013). This highlights the importance of determining the mechanisms behind preterm birth and how these mechanisms might relate to the difficulties faced later in life.…”