In Utero Exposure to Immune Molecules May Affect Neurocognitive Development
Tuesday, April 24, 2018
New IRP-led research has revealed a link between children’s cognitive abilities at age 7 and the levels of certain immune molecules they were exposed to in utero.
In the midst of the 1957 Asian flu pandemic, doctors and researchers were understandably focused on treating patients and developing ways to contain the outbreak. It wasn’t until 30 years later that scientists began reporting that women who were pregnant when they caught the virus were more likely to have children who would later be diagnosed with schizophrenia.1 While that relationship remains controversial,2 numerous studies have since linked activation of a pregnant woman’s immune system with an increased risk that her child will develop certain psychiatric disorders, including not just schizophrenia but also autism spectrum disorder and major depressive disorder.3 A new IRP study has now expanded on this work by showing that exposure to higher levels of two immune system molecules in utero can noticeably alter the neurological and cognitive development of young children.4
Factors from infections to stress to genetics all play a role in how active a person’s immune system is, and a more vigorous immune system releases greater amounts of chemicals called cytokines that can ramp up or tamp down inflammation. When a woman is pregnant, these molecules affect not just her own body but also that of her unborn child. Some cytokines can even pass through the blood-brain barrier and exert direct effects on the developing brain, which may explain the link between a mother’s immune response and her child’s future risk of developing a psychiatric illness.
“That link is very concerning because psychiatric disorders can have a substantial impact on functioning as well as longevity,” says IRP investigator Stephen E. Gilman, Sc.D., the study’s senior author. “Therefore, we wanted to know if the activity of a mother’s immune system can also affect cognitive development more generally before a major psychiatric disorder emerges.”
Dr. Gilman’s team relied on data collected during the Collaborative Perinatal Project (CPP), an NIH study that ran from the late 1950s through the 1970s. Among its many sources of data, the CPP took blood samples from pregnant mothers throughout their pregnancies and gave standardized tests to their children to assess their cognitive and neurological development. The IRP researchers determined the concentrations of five cytokines in those blood samples and looked for associations between those measurements and several neurocognitive evaluations the women’s children completed at age 7. The ability to assess cytokine levels at multiple time points during pregnancy was a particular strength of the new study, according to Dr. Gilman.
“Many studies have looked at immune markers at a single snapshot in time, but that approach misses critical variation over time,” he says. “We really need to know how these markers vary during the course of pregnancy in order to fully understand how immune activity is related to offspring development.”
Gilman’s team found that the children of women who had higher levels of a cytokine called tumor necrosis factor alpha (TNF-alpha) during their second and third trimesters scored lower on IQ tests and assessments of visual and motor skills at age 7 compared to children whose mothers had lower levels of TNF-alpha during that period of pregnancy. On the other hand, pregnant women with higher levels of the cytokine interleukin-8 (IL-8) had children who would go on to perform better on tests of sensory and motor function.
Overall, the findings support the idea that a pregnant woman’s level of immune system activity can affect her child’s neurocognitive development. Moreover, both TNF-alpha and IL-8 are ‘pro-inflammatory’ cytokines that increase inflammation, yet they appear to have opposite effects on children’s future cognitive abilities, hinting that different cytokines have diverse effects on the developing brain.
In addition to teasing out how particular cytokines influence a fetus’ growing brain, Dr. Gilman plans to examine levels of a wider array of cytokines in pregnant women to create a more detailed picture of how the molecules affect neurocognitive development. He also hopes that future studies will eventually allow clinicians to identify patterns of immune response during pregnancy that might portend a higher risk for psychiatric disorders or slowed neurocognitive development in children. This could potentially inform the development of interventions to optimize health even before an individual is born.
“We’re still learning a lot,” Dr. Gilman says. “Continuing to pursue this immune-inflammation hypothesis will help us understand the physiology of pregnancy and how that might influence child development and long-term health.”
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 Adult schizophrenia following prenatal exposure to an influenza epidemic. Mednick SA, Machon RA, Huttunen MO, Bonett D. Arc Gen Psychiatry. 1988 Feb;45(2): 189-192.
 Schizophrenia and 1957 Pandemic of Influenza: Meta-analysis. Selten J, Frissen A, Lensvelt-Mulders G, Morgan VA. Schizophr Bull. 2010 Mar; 36(2): 219-228.
 Prenatal immune programming of the sex-dependent risk for major depression. Gilman SE, Cherkerzian S, Buka SL, Hahn J, Homig M, Goldstein JM. Transl Psychiatry. 2016 May 31; 6(5):e822. doi: 10.1038/tp.2016.91.
 Gestational cytokine concentrations and neurocognitive development at 7 years. Ghassabian A, Albert PS, Hornig M, Yeung E, Cherkerzian S, Goldstein RB, Buka SL, Goldstein JM, Gilman SE. Transl Psychiatry. 2018 Mar 13;8(1):64. doi: 10.1038/s41398-018-0112-z.