Prenatal growth in humans and postnatal brain maturation into late adolescence

Abstract

Prenatal life encompasses a critical phase of human brain development, but neurodevelopmental consequences of normative differences in prenatal growth among full-term pregnancies remain largely uncharted. Here, we combine the power of a within-monozygotic twin study design with longitudinal neuroimaging methods that parse dissociable components of structural brain development between ages 3 and 30 y, to show that subtle variations of the in utero environment, as indexed by mild birth weight (BW) variation within monozygotic pairs, are accompanied by statistically significant (i) differences in postnatal intelligence quotient (IQ) and (ii) alterations of brain anatomy that persist at least into late adolescence. Greater BW within the normal range confers a sustained and generalized increase in brain volume, which in the cortical sheet, is specifically driven by altered surface area rather than cortical thickness. Surface area is maximally sensitive to BW variation within cortical regions implicated in the biology of several mental disorders, the risk for which is modified by normative BW variation. We complement this near-experimental test of prenatal environmental influences on human brain development by replicating anatomical findings in dizygotic twins and unrelated singletons. Thus, using over 1,000 brain scans, across three independent samples, we link subtle differences in prenatal growth, within ranges seen among the majority of human pregnancies, to protracted surface area alterations, that preferentially impact later-maturing associative cortices important for higher cognition. By mapping the sensitivity of postnatal human brain development to prenatal influences, our findings underline the potency of in utero life in shaping postnatal outcomes of neuroscientific and public health importance.

Fig. 1.

Vertex maps showing the relationship between BW variation within MZ twin-pairs and postnatal differences in cortical surface area. Associations between BW and vertex-level measures of surface area (SA) are shown as t-statistic maps after application of a FDR correction for multiple comparisons with q (the expected proportion of falsely rejected null hypotheses) set at 5%. As shown in the color bar, “warmer” colors indicate a more statistically significant positive association between BW and SA.

Fig. 2.

Whisker plot showing standardized coefficients (and 95% coefficient confidence intervals) for the age-invariant main effect of BW variation on CV, CT, and cortical SA within each of the three groups examined in this study. Note that changes in CV and SA for changes in BW are both similar to each other within each group as well as across groups.