Did Mom's Immune System Affect Your Fetal Brain?
Researchers investigate the implications of a pregnant mother's immune system.
Posted June 12, 2018
Researchers have found that a more active immune system in a pregnant mother can negatively impact the brain of her developing fetus.
Previous epidemiological studies revealed a link between maternal inflammation (i.e. activation of mom’s immune system) and an increase in her child’s likelihood of developing a psychiatric disease, for instance schizophrenia or autism. 1 Research in other animal systems also suggested a link between immune response of a mother and negative cognitive consequences for her offspring. 2
Immune response was, for a long time, thought to specifically relate to infection and inflammation–indicating the infiltration of a virus or bacterial strain. As it turns out, infection is only one of the culprits underlying immune response—the constant influence of the immune system, in this case, on a growing fetus, is greater than was previously considered. 3
Researchers at Oregon Health & Science University sought to expand current knowledge in the field by performing a longitudinal study of the effects of maternal inflammation during pregnancy on the formation of neonatal neural networks and working memory at two years of age. 4 The research team, led by Marc D. Rudolph, used a multi-pronged approach: first assessing maternal immune activity by testing for marker interleukin-6, and then using a combination of functional magnetic resonance imaging of neonates and machine-learning methodologies to evaluate its relevance in the creation of neural networks. They then evaluated the working memory of those children at two years old.
Interleukin-6, or IL-6, is a cytokine that can be found throughout the fetal brain. Cytokines are markers of inflammation that have been shown to be important for various brain processes, including axon growth and the formation of synapses. 5 These properties make the study of cytokines and their receptors appealing, as they have the potential to affect the course of neurogenesis. Consequently, Rudolph et al. chose to use IL-6 as the indicator of systemic inflammation in the pregnant mothers they studied.
Functional magnetic resonance imaging (fMRI) was used to collect neonatal brain activity data to ultimately create a model that would allow the researchers to predict maternal IL-6 concentrations. fMRI is a technique used to detect blood flow and draw conclusions about neuronal activation. In other words, the assumption is that increased blood flow is an indicator of increased brain activity. They combined this technique with machine-learning methodologies to estimate the effect of maternal immune activity on the development of neural networks in offspring.
The research team then tested the working memory of these children at two years of age. Working memory falls under the broad category of “executive function.” Executive function relates to cognitive processes that support goal-directed behavior, and working memory more specifically requires the ability to hold on to information in order to process it (allowing for decision-making), and can start to be interrogated around two years of age. A functional working memory is critical at a young age because it sets the foundation for higher-order cognition later in life. 6
Based on IL-6 levels and FMRI results, Rudolph et al. found that functional connectivity within and between neonatal brain networks could be used to create a model for estimating a mother’s IL-6 concentrations throughout the course of her pregnancy and corresponded to brain regions that had previously been implicated in working memory.
They also found that IL-6 measurements over the course of pregnancy did in fact predict working memory—increased maternal systemic immune activation was significantly associated with a decreased working memory performance in the offspring. On average, IL-6 levels in the third trimester of pregnancy carried the strongest weight when predicting a child’s working memory at two years of age.
This research set a baseline for disassociating post- versus pre-natal influences on brain development. That knowledge has opened up the possibility of early intervention, and thereby better outcomes down the road.
 Buka, S. L. et al. Maternal infections and subsequent psychosis among o spring. Arch. Gen. Psychiatry 58, 1032–1037 (2001).
 Hava, G., Vered, L., Yael, M., Mordechai, H. & Mahoud, H. Alterations in behavior in adult o spring mice following maternal in ammation during pregnancy. Dev. Psychobiol. 48, 162–168 (2006).
 Knuesel, I. et al. Maternal immune activation and abnormal brain development across CNS disorders. Nat. Rev. Neurol. 10, 643–660 (2014).
 Rudolph MD, Graham AM, Feczko E, et al. Maternal IL-6 during pregnancy can be estimated from newborn brain connectivity and predicts future working memory in offspring. Nature Neuroscience. 2018:1-8.
 Deverman, B. E. & Patterson, P. H. Cytokines and CNS development. Neuron 64, 61–78 (2009).
 Beck, D. M., Schaefer, C., Pang, K. & Carlson, S. M. Executive function in preschool children: test-retest reliability. J. Cogn. Dev. 12, 169–193 (2011).