Beyond TORCH: A narrative review of the impact of antenatal and perinatal infections on the risk of disability.

Infections and inflammation during pregnancy or early life can alter child neurodevelopment and increase the risk for structural brain abnormalities and mental health disorders. There is strong evidence that TORCH infections (i.e., Treponema pallidum, Toxoplasma gondii, rubella virus, cytomegalovirus, herpes virus) alter fetal neurodevelopment across multiple developmental domains and contribute to motor and cognitive disabilities. However, the impact of a broader range of viral and bacterial infections on fetal development and disability is less well understood. We performed a literature review of human studies to identify gaps in the link between maternal infections, inflammation, and several neurodevelopmental domains. We found strong and moderate evidence respectively for a higher risk of motor and cognitive delays and disabilities in offspring exposed to a range of non-TORCH pathogens during fetal life. In contrast, there is little evidence for an increased risk of language and sensory disabilities. While guidelines for TORCH infection prevention during pregnancy are common, further consideration for prevention of non-TORCH infections during pregnancy for fetal neuroprotection may be warranted.

Disruption of myelin structure and oligodendrocyte maturation in a pigtail macaque model of congenital Zika infection.

Zika virus (ZikV) infection during pregnancy can cause congenital Zika syndrome (CZS) and neurodevelopmental delay in non-microcephalic infants, of which the pathogenesis remains poorly understood. We utilized an established pigtail macaque maternal-to-fetal ZikV infection/exposure model to study fetal brain pathophysiology of CZS manifesting from ZikV exposure in utero. We found prenatal ZikV exposure led to profound disruption of fetal myelin, with extensive downregulation in gene expression for key components of oligodendrocyte maturation and myelin production. Immunohistochemical analyses revealed marked decreases in myelin basic protein intensity and myelinated fiber density in ZikV-exposed animals. At the ultrastructural level, the myelin sheath in ZikV-exposed animals showed multi-focal decompaction consistent with perturbation or remodeling of previously formed myelin, occurring concomitant with dysregulation of oligodendrocyte gene expression and maturation. These findings define fetal neuropathological profiles of ZikV-linked brain injury underlying CZS resulting from ZikV exposure in utero. Because myelin is critical for cortical development, ZikV-related perturbations in oligodendrocyte function may have long-term consequences on childhood neurodevelopment, even in the absence of overt microcephaly.