The fetal origins of mental illness

Abstract

The impact of infections and inflammation during pregnancy on the developing fetal brain remains incompletely defined, with important clinical and research gaps. Although the classic infectious TORCH pathogens (ie, Toxoplasma gondii, rubella virus, cytomegalovirus [CMV], herpes simplex virus) are known to be directly teratogenic, emerging evidence suggests that these infections represent the most extreme end of a much larger spectrum of injury. We present the accumulating evidence that prenatal exposure to a wide variety of viral and bacterial infections-or simply inflammation-may subtly alter fetal brain development, leading to neuropsychiatric consequences for the child later in life. The link between influenza infections in pregnant women and an increased risk for development of schizophrenia in their children was first described more than 30 years ago. Since then, evidence suggests that a range of infections during pregnancy may also increase risk for autism spectrum disorder and depression in the child. Subsequent studies in animal models demonstrated that both pregnancy infections and inflammation can result in direct injury to neurons and neural progenitor cells or indirect injury through activation of microglia and astrocytes, which can trigger cytokine production and oxidative stress. Infectious exposures can also alter placental serotonin production, which can perturb neurotransmitter signaling in the developing brain. Clinically, detection of these subtle injuries to the fetal brain is difficult. As the neuropsychiatric impact of perinatal infections or inflammation may not be known for decades after birth, our construct for defining teratogenic infections in pregnancy (eg, TORCH) based on congenital anomalies is insufficient to capture the full adverse impact on the child. We discuss the clinical implications of this body of evidence and how we might place greater emphasis on prevention of prenatal infections. For example, increasing uptake of the seasonal influenza vaccine is a key strategy to reduce perinatal infections and the risk for fetal brain injury. An important research gap exists in understanding how antibiotic therapy during pregnancy affects the fetal inflammatory load and how to avoid inflammation-mediated injury to the fetal brain. In summary, we discuss the current evidence and mechanisms linking infections and inflammation with the increased lifelong risk of neuropsychiatric disorders in the child, and how we might improve prenatal care to protect the fetal brain.

Keywords: TORCH; autism; brain; depression; fetus; infection; inflammation; influenza virus; microglia; neuronal injury; pregnancy; schizophrenia; seasonality of birth hypothesis; urinary tract infection.

Figure 1.

Factors linking perinatal infections with mild and severe fetal brain injury. Several factors are thought to influence the severity and extent of a maternal infection leading to mild or severe fetal brain injury. Mild fetal brain injuries may not be detected clinically at birth and may only manifest later in life as a neurodevelopmental or neuropsychiatric disorder.

Figure 2.

Photomicrographs of the placenta and fetal or neonatal brain infected with CMV. In the placenta (A), there is hyperplasia of fetal macrophages (Hofbauer cells) and infiltration with lymphocytes and plasma cells. Inclusions are shown, which are pathognomonic for CMV infection. (B) In the brainstem of a 4 month-old infant born at 26 weeks gestation with a prenatal CMV infection, a microglial nodule (within the white circle) is shown with most cells reflecting lymphocytes, activated microglia and reactive astrocytes. (C) In the white matter of a 25-day old neonate born at 24 weeks gestation with a CMV prenatal infection, a focus of remote necrosis and dystrophic mineralization (refractile dark purple deposits) is shown. (D) In the fetal brain of a 23-week fetus, the acute phase of a CMV infection is shown with a hypercellular focus containing a mixture of activated microglial cells, reactive astrocytes, and a presumed neuron with pathognomonic CMV cytoplasmic and nuclear inclusions. A measurement bar representing 100 um is shown in panel C, which is applicable to all panels.

Figure 3.

Perinatal infections, placental immune response and cellular targets in the fetal brain. A spectrum of maternal infections induced by viruses, bacteria and parasites have been implicated in the development of placental pathology and fetal brain injury. Infiltration of the placenta by immune cells, notably maternal CD8+ T cells and plasma cells, has been strongly linked to fetal brain injury. Neutrophilic infiltration of the placenta is classically associated with bacterial infections, like Group B Streptococcus, which can cause meningitis and fetal brain injury. The cellular response in the fetal brain typically associated with perinatal infectious or inflammatory injury reflects activation of microglia and astrocytes with neuronal loss and oligodendrocyte dysfunction. The pathogens listed are associated with fetal brain injury and in some instances with development of mental illness in the child.