There is new evidence supporting the theory that children born of mothers who had inflammation during pregnancy have an elevated risk for developing a psychotic disorder by adulthood. The data suggests that inflammation during the first half of pregnancy has the greatest likelihood of having such an impact, weeks or months earlier than previous studies have indicated.

In recent years much attention has been focused on the degree to which adverse events occurring during the fetal period, when the brain is just coming into being and “wiring up,” may be causally related to the child’s risk for schizophrenia and other psychiatric illnesses, including autism spectrum disorder and bipolar disorder.

Among the adverse events affecting the mother during pregnancy that have been linked tentatively to schizophrenia in their offspring are extreme stress, undernutrition, and having an infectious disease. The new study, appearing in the journal Lancet Psychiatry, tells us more about inflammation, which can be the result of various causes. These range from bacterial and viral infections to irritations of the stomach, skin, lungs or joints—all of which can activate the maternal immune system.

The researchers analyzed a subset of serum samples collected from over 50,000 pregnant women between 1959 and 1965. Serum refers to the clear, fluid portion of blood that is not involved in clotting; the samples were stored at the National Institutes of Health at very low temperatures, preserving them for future study. Pregnant women who donated their serum were part of a large nationwide study called the National Collaborative Perinatal Project.

Senior author Tyrone Cannon, Ph.D., of Yale University, a 2006 BBRF Distinguished Investigator and 1997 Independent Investigator and member of the BBRF Scientific Council, with colleagues including first author Dana Allswede, M.S., also of Yale, considered data collected from women in the study’s Philadelphia cohort, which includes 9,236 surviving offspring of 6,753 pregnant women. Their focused sample consisted of 90 of these offspring who were later diagnosed with a psychotic disorder, as confirmed in medical records. For purposes of comparison, the sample also included 79 siblings of these offspring and 273 matched controls.

Dr. Cannon’s team specifically looked at levels of cytokines in the blood samples of the pregnant women who took part in the study and contributed multiple samples from the 7th week of gestation through birth. Cytokines are signaling proteins that are secreted by cells of the immune system, when, for instance, an infection or other cause of inflammation is present. Some cytokines promote inflammation and others act to reduce it. The study was interested in levels of pro-inflammatory cytokines in the mother’s serum.

Inflammation is one way in which elevated pro-inflammatory cytokines in the mother’s serum may perturb fetal brain development. As the researchers note, cytokines also have roles very early in the fetal period in the development and migration within the brain of newly born neural cells, as well as in processes related to the emergence of synapses, the points of connection between brain cells.

The team found that concentrations of three pro-inflammatory cytokines in particular were “significantly higher” in the maternal serum of offspring who later developed psychosis. This was judged in comparison with levels in the maternal serum of the matched controls. The differences were greatest in weeks 7 to 20 of pregnancy—with no difference noted in serum samples from the second half of pregnancy.

“This implicates an earlier time point in gestation than previously understood,” the team wrote. They added that the three inflammatory cytokines identified, called TNF-alpha, Interleukin 1-beta, and Interleukin 6, “are potent pro-inflammatory proteins that have a critical role in the initial response to infection and in initiating and sustaining inflammatory responses.”

The team reminds us that most women with inflammation during pregnancy give birth to children who do not go on to develop a psychotic disorder, or any other psychiatric illness. A major thrust of the research by Dr. Cannon’s team and others has to do with identifying factors that incrementally raise the chances of an adverse outcome. Knowing these factors opens the possibility of working specifically to minimize them in pregnant women. While some risk factors like genetic predisposition may be beyond the power of doctors to alter, others are within reach—such as minimizing infection or treating it promptly in women who do develop inflammation during pregnancy.