Autism, Depression Tied to Prenatal Exposure to Maternal Infection

Michael Vlessides

March 18, 2019

Fetal exposure to maternal infection increases the long-term risk for neuropsychiatric diseases, new research suggests.

Longitudinal data from a multicenter study of more than 1.5 million Swedish children who were followed for up to 4 decades show that persons who had been exposed to any maternal infection in utero were at significantly increased risk of subsequently developing either autism or depression during their lifetime.

Interestingly, no such association was found with respect to the development of either bipolar disorder or psychosis.

"Parts of the fetal brain are really sensitive to inflammation that can occur with infection," corresponding author Kristina Adams Waldorf, MD, told Medscape Medical News. "And we've found that development of fetal brain is a fragile process, and infections can be harmful for the long-term mental health of the child, even decades after birth.

"So what happens to a fetus during life in the womb really sets up the child's brain for the rest of their life," added Adams Waldorf, of the University of Washington in Seattle.

The study was published online March 6 in JAMA Psychiatry.

Foundation for Suicide?

Previous research has shown that infections during pregnancy may lead to fetal brain injury, neurodevelopmental abnormalities, and an increased lifelong risk for certain psychiatric disorders in children.

"Although compelling," the authors write, "these studies have focused mainly on linking specific infections with a particular psychopathologic condition, with few exceptions, rather than determining a generalized effect of infection and inflammation during pregnancy on a broad spectrum of psychopathologic conditions."

As such, there are limited data on the association between maternal infection and subsequent risk of developing a broad spectrum of psychopathologic conditions during a person's lifetime.

The investigators hypothesized that fetal exposure to either maternal infection or associated inflammation would increase the child's future risk of developing a wide range of psychopathologic conditions, including autism spectrum disorder, bipolar disorder, depression, and psychosis.

They postulated that the magnitude of risk for the development of these conditions would differ according to the type and severity of maternal infection.

"I have a large research program studying infections in pregnancy along with preterm birth, so this was a natural extension of other work that we've done looking at the impact of Zika virus infection on the fetal brain," said Adams Waldorf.

The analysis used data from 1,791,520 Swedish persons (48.6% females) who were born between January 1, 1973, and December 31, 2014, and who were observed for up to 41 years using linked population-based registries (32,125,813 person-years). Infection and psychiatric diagnoses were determined using various hospitalization codes.

The investigators then performed a systematic literature review to determine Cox proportional hazards regression models for the risk for psychopathologic conditions. Acyclic graphs were developed from these models. The results were evaluated using probabilistic and simple bias analyses.

Using the acyclic graph framework, the investigators found that fetal exposure to any maternal infection increased the risk of the person's having an inpatient diagnosis of either autism (hazard ratio [HR], 1.79; 95% confidence interval [CI], 1.34 – 2.40) or depression (HR, 1.24; 95% CI, 1.08 – 1.42).

The effect estimates for autism and depression were similar following diagnosis of either severe maternal infection (autism: HR, 1.81; 95% CI, 1.18 – 2.78; depression: HR, 1.24; 95% CI, 0.88 – 1.73) or urinary tract infection (autism: HR, 1.89; 95% CI, 1.23 – 2.90; depression: HR, 1.30; 95% CI, 1.04 – 1.61).

Although the relationship between infection and depression was susceptible to bias, separate data from the Swedish Death Registry demonstrated an increased risk for suicide among people who were exposed to infection in utero. The analysis found no evidence of increased risk for bipolar disorder or psychosis, including schizophrenia, among these individuals.

These findings, which are consistent with those from previous epidemiologic and animal studies, "suggest that inflammation during gestation alters brain architecture or transcriptional programs," the investigators note.

What's more, the findings suggest a potential fetal origin for depression and suicide, which prompted the investigators to underscore the importance of avoiding infections during pregnancy.

"I think our findings push even harder on the point that we need to aggressively prevent infections in pregnancy, such as influenza," Adams Waldorf said. "I have patients who are worried about having an influenza vaccination because they think it might harm the fetus. In fact, the opposite is true. If that woman develops influenza, this can impact fetal brain development and have a harmful effect on the baby."

Ensuring a Lifetime of Mental Health

Commenting on the study for Medscape Medical News, David M. Aronoff, MD, of Vanderbilt University Medical Center, Nashville, Tennessee, agreed.

"This research provides more evidence to support efforts to prevent infections in pregnant women, which could have beneficial effects not only for the mother but also on her offspring, even beyond the immediate windows of childbirth and the neonatal period," said Aronoff, who was not involved in the study.

"Studies such as this large Swedish study compel ongoing efforts to develop vaccines to prevent common infections during pregnancy and to more rapidly identify and treat infections that occur despite preventive efforts."

Nardhy Gomez-Lopez, PhD, of Wayne State University, Detroit, Michigan, told Medscape Medical News that the findings also open the door to novel treatment options for the developing fetus.

"I found it interesting that Dr Waldorf's study raises the importance of focusing research on diagnosing the effects of maternal infection on the fetal brain in utero," she explained. "In collaboration with MRI experts, my group is investigating whether we can detect the adverse effects of maternal inflammation on the fetal brain, which would allow for the early identification of fetal brain injury and provide a window of opportunity for treating fetuses in utero."

For Adams Waldorf, ensuring optimal health for pregnant mothers is an important goal. "Suicide rates have risen very sharply in recent years, and we've struggled to understand why," she concluded. "Our study provides a first insight that an infection in pregnancy may increase risk of depression or suicide in the child, and this can have enormous repercussions in terms of economic costs to society.

"I think the better we take care of pregnant women, the better we can set up the child for a lifetime of good health and mental health."

The authors, Aronoff, and Gomez-Lopez have disclosed no relevant financial relationships.

JAMA Psychiatry. Published online March 6, 2019. Abstract

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