Inflammation in pregnant mothers may be linked to their children’s brain organization after birth and their working memory two years later, according to a longitudinal study by German and U.S. researchers.

Neonates’ functional connectivity patterns predicted the degree to which their mother experienced inflammation while pregnant, and systemic maternal inflammation during pregnancy — reflected in interleukin-6 ( IL-6) levels — predicted these children’s performance on a memory game at age two, reported Claudia Buss, PhD, of the Charité University Medicine Berlin in Germany and colleagues in Nature Neuroscience.

“This study shows in very clear terms how the immune system can impact offspring brain development and behavior,” said co-author Damien Fair, PhD, of Oregon Health and Science University in Portland.

“The study establishes a missing link between inflammation in pregnant women and the way the entire newborn brain is organized into networks,” Fair told MedPage Today. “It showed that higher levels of cytokine interleukin-6 during pregnancy were associated with reduced working memory capacity in the child, as far out as the age of 2.”

Previous work has suggested that maternal inflammation may be linked to fetal neurodevelopment. “Notably, it appears that maternal inflammation itself, rather than infection or injury per se, increases risks for developmental disorders,” observed Monica Rosenberg, PhD, of Yale University, in an accompanying editorial. In mice, giving pregnant females a protein that stimulated immune responses was enough to cause autism spectrum-like and schizophrenia-like behaviors in offspring, she noted.

But while epidemiology and animal work have indicated that inflammation during may alter offspring’s brain function and behavior, “methodological constraints have limited our ability to directly observe these relationships in humans,” she added.

The researchers found that the functional connectivity patterns of newborn babies differed as a function of their mother’s IL-6 levels during pregnancy, reliably enough to use a neonate’s functional connectivity pattern to predict its mother’s IL-6 level. The researchers created an artificial intelligence model to predict a mother’s inflammatory response during pregnancy based on her baby’s brain connectivity patterns and found that the predicted levels were more strongly related to true maternal IL-6 values than would be expected by chance.

They also used the mothers’ IL-6 levels during the first, second, and third trimesters of pregnancy to predict children’s scores on a memory task and found that higher maternal IL-6 levels reliably predicted poorer memory, with maternal IL-6 concentrations measured latest in pregnancy being most predictive.

Maternal age, gestational age, and age at MRI scan were not correlated with maternal IL-6 concentrations or working memory at age 2.

The researchers provide “unique evidence that what we experience before we are born is related to neural and cognitive processes fundamental to our life outcomes,” noted Rosenberg. “Although, as they emphasize, their findings do not prove causal relationships (it’s unclear, for example, whether other factors, such as genetic variants, could explain these associations) or show whether the relationship between maternal IL-6 and behavior is specific to working memory or whether it generalizes to other aspects of executive function, such as impulse control, measured in the same dataset, they support epidemiological and preclinical evidence that maternal inflammation during pregnancy influences offspring neurodevelopment,” she wrote.

The researchers noted several limitations to their study: their sample was not representative of high-risk populations, and neonatal brain connectivity was assessed during sleep, not when babies were awake. Other pre- and postnatal environmental conditions may have affected the trajectories of brain development, they added.

“Future work should focus on questions about how diet and other environmental factors interact to influence changes to the immune system before and after birth,” Fair observed.

“These factors of our everyday lives are modifiable. It will be just as important as research that studies the subsequent effects of inflammation on brain function and cognition in newborns to determine if simple societal changes can help improve long-term outcomes in our children.”