The impact of prenatal maternal infection and inflammation on human brain development and psychopathology during adolescence

PROJECT SUMMARY
Maternal immune activation (MIA) refers to the triggering of the maternal immune system during pregnancy by
infections or chronic conditions. This leads to a series of immunologic alterations in the fetus, which can have
an impact on brain development. Large-scale, population-based studies have implicated MIA in a number of
neuropsychiatric disorders, including autism spectrum disorders, bipolar disorder and schizophrenia. Moreover,
studies in rodents have consistently demonstrated that MIA during early phases of pregnancy leads to structural
and functional brain abnormalities and behavioral dysfunction in the offspring. In humans, recent imaging studies
reported similar effects of MIA on child brain structure and behavior. However, these studies were limited by
modest sample sizes and relatively short follow-up periods.
The overall aim of this study is to investigate the impact of maternal immune activation during pregnancy on
adolescent neurodevelopment. We will use the only cohort in the world, Generation R, with both sufficient sample
size and longitudinal follow-up to combine (i) detailed information on infection and inflammation during
pregnancy, with (ii) offspring brain imaging and (iii) behavioral and psychiatric outcomes. In aim 1a we will define
our exposure variable Maternal Immune Activation (MIA). We will use detailed trimester-specific information on
infections and determine the type of infection, as well as severity. We will measure a panel of well-known pro-
inflammatory markers (CRP, IL-1β, IL-6, IL-8, TNF-α) to calculate an inflammatory index of chronic low-grade
inflammation in serum at 13 and 20 weeks of gestation. In aim 1b we will investigate the association between
MIA, fetal growth and gestational age at birth. In aim 2, we will investigate the impact of MIA on offspring brain
structure and connectivity at age 14 years. To test the hypothesis that MIA leads to atypical cortical development,
we will include MRI measures available and ready to use for 3,757 adolescents. These include total brain, white
matter, cortical gray and subcortical volumes. In aim 3 we will determine whether MIA increases the risk for
cognitive deficits, behavioral impairments and psychopathology also at age 14 years.
This project will provide a comprehensive definition of maternal immune activation, including specific aspects of
infection such as type and timing, examine its effects on neurodevelopment, and elucidate putative mechanisms
for these effects in the largest birth cohort to date. Collectively, these outputs will suggest targets for prevention
and aid the efforts towards early identification of high-risk pregnancies.

Grant Number: 5R01MH124776-05
NIH Institute/Center: NIH
Principal Investigator: Veerle Bergink