Maternal influenza infection during pregnancy impacts postnatal brain development in the rhesus monkey

Abstract

Background: Maternal infection with influenza and other pathogens during pregnancy has been associated with increased risk for schizophrenia and neurodevelopmental disorders. In rodent studies, maternal inflammatory responses to influenza affect fetal brain development. However, to verify the relevance of these findings to humans, research is needed in a primate species with more advanced prenatal corticogenesis.

Methods: Twelve pregnant rhesus monkeys were infected with influenza, A/Sydney/5/97 (H3N2), 1 month before term (early third trimester) and compared with 7 control pregnancies. Nasal swabs and blood samples confirmed viral shedding and immune activation. Structural magnetic resonance imaging was conducted at 1 year; behavioral development and cortisol reactivity were also assessed.

Results: Maternal infections were mild and self-limiting. At birth, maternally derived influenza-specific immunoglobulin G was present in the neonate, but there was no evidence of direct viral exposure. Birth weight and gestation length were not affected, nor were infant neuromotor, behavioral, and endocrine responses. However, magnetic resonance imaging analyses revealed significant reductions in cortical gray matter in flu-exposed animals. Regional analyses indicated the largest gray matter reductions occurred bilaterally in cingulate and parietal areas; white matter was also reduced significantly in the parietal lobe.

Conclusions: Influenza infection during pregnancy affects neural development in the monkey, reducing gray matter throughout most of the cortex and decreasing white matter in parietal cortex. These brain alterations are likely to be permanent, given that they were still present at the monkey-equivalent of older childhood and thus might increase the likelihood of later behavioral pathology.

Figure 1

Illustration of the parcellation of cortical areas used for regional analysis of gray matter and white matter volumes in infant monkeys from control and influenza virus-exposed pregnancies.

Figure 2

Local and systemic measures confirming infection with influenza virus. (A) Viral shedding confirmed by nasal swabs from flu-exposed mothers. (B) Systemic reaction evident by increased neopterin levels at 3–7 days after exposure to influenza. (C) Significant correlation between the levels of flu-specific antibody (immunoglobulin G [IgG] class) found in virus-exposed mothers and their neonates at 2–3 days after birth.

Figure 3

To illustrate the magnitude of the cortical effects of prenatal infection, Figure 3 portrays how much smaller the gray matter volumes were in monkeys from flu-exposed pregnancies relative to controls. Regional reductions ranging from 4–7% reached statistical significance (*p < .05), with more modest decrements evident in the posterior cortex, including occipital lobe and the temporal-limbic area.