Robust sex differences in functional brain connectivity are present in utero

Sex-based differences in brain structure and function are observable throughout development and are thought to contribute to differences in behavior, cognition, and the presentation of neurodevelopmental disorders. Using multiple support vector machine (SVM) models as a data-driven approach to assess sex differences, we sought to identify regions exhibiting sex-dependent differences in functional connectivity and determine whether they were robust and sufficiently reliable to classify sex even prior to birth. To accomplish this, we used a sample of 110 human fetal resting state fMRI scans from 95 fetuses, performed between 19 and 40 gestational weeks. Functional brain connectivity patterns classified fetal sex with 73% accuracy. Across SVM models, we identified features (functional connections) that reliably differentiated fetal sex. Highly consistent predictors included connections in the somatomotor and frontal areas alongside the hippocampus, cerebellum, and basal ganglia. Moreover, high consistency features also implicated a greater magnitude of cross-region connections in females, while male weighted features were predominately within anatomically bounded regions. Our findings indicate that these differences, which have been observed later in childhood, are present and reliably detectable even before birth. These results show that sex differences arise before birth in a manner that is consistent and reliable enough to be highly identifiable.