Maternal oxidative stress during pregnancy associated with emotional and behavioural problems in early childhood: implications for foetal programming

Abstract

Childhood mental disorders, including emotional and behavioural problems (EBP) are increasingly prevalent. Higher maternal oxidative stress (OS) during pregnancy (_matOS_preg) is linked to offspring mental disorders. Environmental factors contribute to _matOS_preg. However, the role of _matOS_preg in childhood EBP is unclear. We investigated the associations between (i) _matOS_preg and offspring EBP; (ii) social and prenatal environmental factors and _matOS_preg; and (iii) social and prenatal factors and childhood EBP and evaluated whether _matOS_preg mediated these associations. Maternal urinary OS biomarkers, 8-hydroxyguanosine (8-OHGua; an oxidative RNA damage marker) and 8-hydroxy-2'-deoxyguanosine (8-OHdG; an oxidative DNA damage marker), at 36 weeks of pregnancy were quantified by liquid chromatography-mass spectrometry in a population-derived birth cohort, Barwon Infant Study (n = 1074 mother-infant pairs). Social and prenatal environmental factors were collected by mother-reported questionnaires. Offspring total EBP was measured by Child Behavior Checklist Total Problems T-scores at age two (n = 675) and Strengths and Difficulties Questionnaire Total Difficulties score at age four (n = 791). Prospective associations were examined by multivariable regression analyses adjusted for covariates. Mediation effects were evaluated using counterfactual-based mediation analysis. Higher maternal urinary 8-OHGua at 36 weeks (_mat8-OHGua_36w) was associated with greater offspring total EBP at age four (β = 0.38, 95% CI (0.07, 0.69), P = 0.02) and age two (β = 0.62, 95% CI (-0.06, 1.30), P = 0.07). Weaker evidence of association was detected for 8-OHdG. Five early-life factors were associated with both _mat8-OHGua_36w and childhood EBP (P-range < 0.001-0.05), including lower maternal education, socioeconomic disadvantage and prenatal tobacco smoking. These risk factor-childhood EBP associations were partly mediated by higher _mat8-OHGua_36w (P-range = 0.01-0.05). Higher _matOS_preg, particularly oxidant RNA damage, is associated with later offspring EBP. Effects of some social and prenatal lifestyle factors on childhood EBP were partly mediated by _matOS_preg. Future studies are warranted to further elucidate the role of early-life oxidant damage in childhood EBP.