Systematic review and meta-analysis of MRI-based sex differences in the human fetal brain

Abstract

Sex differences in child neurobehavioral health suggest that male and female brains differ early in development. We took advantage of recent advances for in-utero magnetic resonance imaging (MRI) to conduct a pre-registered systematic review and meta-analysis of sex differences in brain structure and network connectivity of human fetuses. PubMed literature searching yielded 4,738 studies published between 2002 and 2025. All studies were screened by two independent reviewers and included if either structural or functional MRI was used to image brains of healthy human fetuses in utero and any results were reported stratified by sex. After title and abstract screening, 545 studies remained for full-text screening, resulting in 34 total studies meeting inclusion criteria. Analysis focused on 28 of these that reported sex-disaggregated data on the same measure across three or more independent samples. Pooled effect sizes revealed significantly larger male brains based on both linear measures (cerebral fronto-occipital and biparietal diameters and corpus callosum length) and global volumes (intracranial, total brain, lateral ventricle) by the start of the third trimester. Among 11 studies reporting brain growth trajectories, a majority reported faster growth in males. Among nine studies measuring functional connectivity using resting state functional MRI (rs-fMRI), six reported no significant sex differences and the others reported sporadic differences that were not replications. Together with large ultrasound studies, this review demonstrates larger brain size and faster brain growth in human males compared to females beginning in the second trimester, comparable to overall body size and other internal organ volumes. However, existing MRI and ultrasound research has not identified specific brain regions that differ disproportionately between male and female fetuses or any reliable sex differences in functional connectivity. Faster fetal growth in males, including the brain, does not readily explain neonatal male vulnerability and appears to be a product of genetic, rather than hormonal influences. These findings provide a reference for the emergence of brain sex differences later in development.