Mother’s Inflammation May Affect Developing Brain

Researchers have long believed that exposure to inflammation in the womb increases the risk of neuropsychiatric disorders and other health problems in offspring.

Now recent studies of pregnant women and their children suggest that variations in levels of interleukin-6 (IL-6, a pro-inflammatory cytokine) during pregnancy may influence brain development and function in children.

“The results provide strong evidence linking maternal inflammation during pregnancy with newborn brain organization and future executive function,” Damien Fair, Ph.D., Claudia Buss, Ph.D., and colleagues wrote in Nature Neuroscience. Fair is an associate professor of behavioral neuroscience and psychiatry in the School of Medicine at Oregon Health and Science University (OHSU). Buss is a professor of medical psychology at Charité University Medicine and an associate professor in the Development, Health, and Disease Research Program at the University of California, Irvine.

While the studies do not directly address the development of psychiatric disorders, they do touch on processes with a connection to mental illness. For instance, networks used in working memory are disrupted in schizophrenia, and the work by Fair, Buss, and colleagues indicates that higher levels of IL-6 during pregnancy are associated with more negative effects on those systems in offspring.

The researchers took blood samples from 84 pregnant women at 12, 20, and 30 weeks of gestation and measured serum levels of IL-6.

When the newborns of these women were about four weeks old, they underwent resting state functional connectivity magnetic resonance imaging (MRI) brain scans. Two years later, the toddlers were given psychological tests designed to assess cognitive and emotional functioning.

“By examining brain function shortly after birth, we increase the capacity to distinguish between the influences of prenatal (such as maternal inflammation during pregnancy) and postnatal environmental factors on functional brain development,” wrote Buss, Fair, and lead author Marc D. Rudolph, now a Ph.D. candidate at the University of North Carolina at Chapel Hill.

The researchers focused on functional connections within or between 10 functional brain networks. After adjusting for possible confounders including gestational age at birth, age at MRI scan and at working memory assessment, and maternal age, they found the functional connectivity patterns of the infants differed as a function of the mother’s IL-6 levels during pregnancy. The authors also found that IL-6 levels during pregnancy were associated with poorer memory in toddlers.

“This work is a significant step forward because it fills in some of the blanks explaining just how inflammation in pregnancy affects the trajectories of brain development, especially as it affects certain neurocircuits and brain structures implicated in psychiatric illness,” said Alan S. Brown, M.D., M.P.H., a professor of psychiatry and epidemiology at Columbia University Medical Center and director of the Program in Birth Cohort Studies at the New York State Psychiatric Institute. Brown’s research has also focused on inflammation and psychiatric outcomes, but he was not involved with the current studies.

A second article, in Biological Psychiatry, examined the effects of maternal IL-6 on the brains of newborns. Greater IL-6 concentration during pregnancy was prospectively associated with larger right amygdala volume in the newborns, wrote lead author Alice Graham, Ph.D., a postdoctoral fellow at OHSU, and colleagues. “Larger newborn right amygdala volume and stronger left amygdala connectivity were in turn associated with lower impulse control at 24 months of age and mediated the association between higher maternal interleukin-6 concentrations and lower impulse control,” they wrote. Lower impulse control in toddlers has been linked with elevated risk for emotional and behavioral problems in childhood.

A third article, published in NeuroImage, showed that high maternal IL-6 levels were associated with changes in brain development that predicted poorer cognitive performance at 12 months of age. “[T]his study provides a clinically relevant basis for an improved understanding of the developmental origins of psychiatric disease, early identification of at-risk pregnancies, and thereby targets for the primary prevention of disease risk,” wrote lead author Jerod Rasmussen, Ph.D., a staff research associate at University of California, Irvine, and colleagues.

The researchers will continue to explore the effects of exposure to maternal inflammation on the children as they grow older.

“These participants will be examined and scanned again in childhood at about age 6,” Fair told Psychiatric News. He and his colleagues are also collecting a new cohort of mother-infant pairs that they plan to follow through development.

“We now have new funding to get a full complement of inflammatory cytokines and chemokines in this same sample to examine large-scale patterns of inflammatory responses during pregnancy and longer-term outcomes in the infants,” said Fair. The researchers are also looking at the interactions between immune- and stress-related biomarkers, given their known close relationship.

This area of research reflects a step forward in the integration of methodology and multiple disciplines, wrote Monica Rosenberg, Ph.D., a postdoctoral associate in the Department of Psychology at Yale University, in a commentary appearing in Nature Neuroscience.

Such research “highlight[s] the power of combining experimental and analytical techniques—bridging fields such as immunology, obstetrics, neuroscience, and psychology; testing model-informed hypotheses with data-driven approaches; pairing longitudinal, dyadic samples with predictive modeling methods—for understanding what shapes the developing brain and mind to make us who we are,” she wrote. ■

“Maternal IL-6 During Pregnancy Can Be Estimated From Newborn Brain Connectivity and Predicts Future Working Memory in Offspring” can be accessed here. “Maternal Systemic Interleukin-6 During Pregnancy Is Associated With Newborn Amygdala Phenotypes and Subsequent Behavior at 2 Years of Age” is available here. “Maternal Interleukin-6 Concentration During Pregnancy Is Associated With Variation in Frontolimbic White Matter and Cognitive Development in Early Life” is located here.