While evidence increasingly indicates that the pre- and perinatal periods are crucial for lifelong health, little is known regarding fetal susceptibility during these periods, explains Benjamin J. S. al-Haddad, MD, MSc, PhD. While autism and schizophrenia development have been linked with infection during fetal life, whether more common psychiatric conditions, such as depression, might begin in utero remains unknown. “Psychiatric illness is responsible for an enormous burden of disease in both low-income and high-income countries,” says Dr. al-Haddad. “If it is possible to prevent even a small portion of these mental illnesses through infection prevention, this is important, low-hanging fruit.”


Assessing the Link

For a study published in JAMA Psychiatry, Dr. al-Haddad and colleagues sought to determine whether maternal infection during gestation increased risk of neuropsychiatric pathology in the fetus over the course of his or her lifetime. “We also wanted to know if there was a difference in risk based on the infection severity (severe infections versus urinary tract infections),” adds Dr. al-Haddad. “While other work has examined some of these questions, we used innovative methods and compared severe infections to urinary tract infection and used separate data from death registries to compare with depression data.”

Using data from Sweden, where they were able to follow children’s (and mother’s) medical records from before birth up to 41 years, the researchers derived infection and psychiatric diagnoses with codes from hospitalizations. Directed acyclic graphs were developed from a systematic literature review of more than 12,000 papers to determine Cox proportional hazards regression models for risk of psychopathologic conditions in the children. Results were evaluated using probabilistic and simple bias analyses. Exposures assessed among the nearly 1.8 million children—accounting for more than 32 million person-years—and their mothers were hospitalization during pregnancy with any maternal infection, severe maternal infection, and urinary tract infection, with the main outcomes of inpatient diagnosis of autism, depression, bipolar disorder, or psychosis among offspring.


Relationships Emerge

Given the directed acyclic graph framework assumptions embedded in the study, al-Haddad and colleagues found that fetal exposure to any maternal infection increased risk of an inpatient diagnosis of autism (hazard ratio [HR], 1.79; 95% CI, 1.34-2.40) or depression (HR, 1.24; 95%CI, 1.08-1.42) in the child (Table). No statistical differences were observed between severe infections (eg, sepsis, pneumonia, influenza, meningitis, chorioamnionitis, pyelonephritis) and urinary tract infections among mothers in terms of risk for depression or autism in children. While the relationship between maternal infection and depression among children was vulnerable to bias from loss to follow-up, separate data from the Swedish Death Registry mirrored this data, demonstrating increased risk of suicide among those exposed to pregnancy infection. Risk for bipolar disorder or psychosis among children was not found to be increased among those exposed to infection in utero.

“In many ways, the pregnancies with infection were quite different from those without infection,” says Dr. al-Haddad. “For example, infants exposed to gestational infection were smaller and more likely to have mothers who smoked or who had gestational diabetes. At baseline, these children are different. We use regression to attempt to control for these differences based on our causal model.”


The Importance of Maternal Vaccination

Studies are needed to determine if mild infections like urinary tract infections really can cause fetal brain damage through both different and replication studies, according to Dr. al-Haddad. “We also need to work on better understanding these mechanisms with basic laboratory work in animal models,” he adds. In the meantime—with the study findings suggesting that any infection during pregnancy appears to have the potential to cause subtle fetal brain damage—he stresses the importance of ensuring that women receive the influenza vaccine during pregnancy and avoid exposure to potential infection, which may help decrease the risk for psychiatric illness in their unborn child over the course of that child’s lifetime.