Study Probes Risk Factors for ADHD in Children

A group of scientists, including two with ties to March of Dimes, have published research illuminating the risk relationship between neurodevelopmental disorders (NDD) in children and prenatal exposure to maternal immune activations (fever, placental inflammation) as well as preterm birth.

While the senior authors’ previous research has shown that maternal immune activations increase risk for NDD, it was unknown which of the two — fever or placental inflammation — carried the most risk, and whether risk increased when a mother had both. Another unknown was what role preterm birth played in the mix.

The paper, recently published in the Journal of Autism and Developmental Disorders (JADD), had multiple findings. First, the paper affirmed previous findings that when a mother’s immune system is activated during pregnancy — such as through fever or placental inflammation — her child has a higher likelihood of developing ADHD and other neurodevelopmental conditions. Second, it found that placental inflammation appears to be a stronger predictor of risk than fever, highlighting the importance of the in-utero environment. Third, the highest risk was seen when both fever and placental inflammation occurred together. And finally, the team found that preterm birth further increases risk, and when it occurs alongside maternal immune activation, the combined effect is greater than the sum of each factor alone.

The findings suggest that preterm birth sits directly on the biological pathway between maternal immune activation and neurodevelopmental disorders; a master influencer that raises NDD risk. They also point to the value of preventing and managing placental inflammation and reducing preterm birth in hopes of lowering NDD risk in offspring.

“We have known for a long time that preterm birth raises risk for NDD, and after this study, we know that part of the link between maternal immune activation and ADHD may be explained by preterm birth acting as an intermediate step, affecting early brain development,” said senior study author Dr. Xiaobin Wang, director of the Center on the Early Life Origins of Disease at Johns Hopkins Bloomberg School of Public Health and a longtime March of Dimes research grantee.

“Now, this study opens the door to investigating the exact mechanisms by which preterm birth and maternal immune activations raise NDD risk.”

Dr. Wang said the results were in line with her hypothesis. First, it made sense that the single greatest maternal immune activation risk to NDD was placental inflammation, which in this case was characterized by placental pathology findings under the microscope. That’s because unlike fever, which can result from a common cold and whose effects are harder to isolate in research, placental inflammation occurs right next to the fetus at the fetal-placental interface, carrying potential for more direct fetal exposure. It also makes sense, she said, that fever and placental inflammation show the highest risk for NDD, as their combined presence could “reflect more severe/prolonged inflammation…which could increase preterm birth risk and intensify fetal inflammatory exposure,” which is tied to NDD.

Still, Dr. Wang cautioned there was a lot left to uncover on the topic, and that the presence of either fever, placental inflammation, or preterm birth — or all three together — in pregnant women did not fully explain the occurrence of all NDD cases, nor did it neatly predict which children would be diagnosed with NDD.

“To put in context,” she said, “these are risk markers and pathway clues, not deterministic causes.”

The study, which was first authored by University of Pittsburgh PhD student Alexandra Starr, was funded by the Health Resources and Services Administration’s Maternal and Child Health Bureau, which is a federal agency. Dr. Wang led a multi-disciplinary team of scientists, including previous March of Dimes grantee Dr. Xiumei Hong, to complete the research. This included analysis of two previous studies Dr. Wang senior authored on the topic.

One was a 2017 paper that found maternal fever to raise the risk of autism in offspring. The second was a 2019 paper that found women with placental inflammatory lesions who delivered preterm were more likely to have children with ADHD than women who gave birth preterm without the lesions.

Both those papers, as well as the new JADD paper, were based on the Boston Birth Cohort, which was created in 1998 with help from March of Dimes. The cohort counts biological, clinical and epidemiological data from about 8,700 mother-newborn pairs and represents “one of the largest and longest-running birth cohorts in the U.S.,” said Dr. Wang.