Maternal early-pregnancy body mass index-associated metabolomic component and mental and behavioral disorders in children

Abstract

Maternal pre-pregnancy obesity and/or higher body mass index (BMI) have been associated with neurodevelopmental and mental health adversities in children. While maternal metabolomic perturbations during pregnancy may underpin these associations, the existing evidence is limited to studying individual metabolites, not capturing metabolic variation specific to maternal BMI, and not accounting for the correlated nature of the metabolomic measures. By using multivariate supervised analytical methods, we first identified maternal early-pregnancy BMI-associated metabolomic component during pregnancy. We then examined whether this component was associated with mental and behavioral disorders in children, improved the prediction of the child outcomes over maternal BMI, and what proportion of the effect of maternal BMI on the child outcomes this component mediated. Early-pregnancy BMI of 425 mothers participating in the PREDO study was extracted from the national Medical Birth Register. During pregnancy, mothers donated up to three blood samples, from which a targeted panel of 68 metabolites were measured. Mental and behavioral disorders in children followed-up from birth until 8.4-12.8 years came from the Care Register for Health Care. Of the 68 metabolites averaged across the three sampling points, 43 associated significantly with maternal early-pregnancy BMI yielding a maternal early-pregnancy BMI-associated metabolomic component (total variance explained, 55.4%; predictive ability, 52.0%). This metabolomic component was significantly associated with higher hazard of any mental and behavioral disorder [HR 1.45, 95%CI(1.15, 1.84)] and relative risk of having a higher number of co-morbid disorders [RR 1.43, 95%CI(1.12, 1.69)] in children. It improved the goodness-of-model-fit over maternal BMI by 37.7-65.6%, and hence the predictive significance of the model, and mediated 60.8-75.8% of the effect of maternal BMI on the child outcomes. Maternal BMI-related metabolomic perturbations during pregnancy are associated with a higher risk of mental and behavioral disorders in children. These findings may allow identifying metabolomic targets for personalized interventions.

Fig. 1

Loadings of the 68 metabolites on the maternal early-pregnancy BMI-associated metabolomic component.

Fig. 2. Maternal BMI-associated metabolomic component and mental and behavioral disorders in children.

A Cumulative incidence of mental and behavioral disorders in the children of the mothers with the maternal early-pregnancy body mass index (BMI)-associated metabolomic component during pregnancy below and above the median; B Probability of the children to have a higher number of co-morbid mental and behavioral disorder diagnoses according to each standard deviation unit increase in the level of the maternal early-pregnancy BMI-associated metabolomic component.

Fig. 3. Mediation analysis.

A Maternal early-pregnancy BMI-associated metabolomic component showing mediation of 60.8% of the effect of maternal early-pregnancy BMI on any mental and behavioral disorder. B Maternal early-pregnancy BMI-associated metabolomic component showing mediation of 75.8% of the effect of maternal early-pregnancy BMI on co-morbidity of mental and behavioral disorders in children.