Inflammation during pregnancy, often caused by stress, can result in the production of maternal proteins that may, through alterations in three key pathways in the fetal brain, lead to difficult temperament in children, scientists from the March of Dimes Prematurity Research Center (PRC) at Stanford found in a recent study.
While previous research has highlighted the role of pro-inflammatory cytokines, or proteins that promote inflammation (some cytokines are anti-inflammatory), during pregnancy in contributing to changes in the fetal brain that can lead to challenging temperament in preschool-aged children, the PRC researchers have begun to elucidate the biological pathways involved.
In a paper published earlier this year in the Journal of Child Psychology and Psychiatry, the PRC team detailed their use of a machine learning (ML) model to analyze over 1,000 proteins in blood samples of 89 women collected in their first trimester of pregnancy. As part of the study, these women also completed two questionnaires about their preschool-aged children with whom they were pregnant when the blood samples were obtained.
The investigators reported two primary findings.
First, inflammation-driven changes in a trio of processes that affect the fetal brain, namely those dealing with the immune system, the central nervous system, and associated cell signaling pathways, can contribute to difficult temperament in children aged 3 to 5 years. (Characteristics can include increased sadness, attention difficulties, trouble with impulse control, issues with sensory overload, and increased emotional reactivity).
Second, the work of maternal proteins related to stress account for about 10% of the differences among children in their temperament levels—representing a sizable influence on temperament.
“That means that [maternal stress] is one of several factors that influence child temperament,” said senior study author Dr. Ian Gotlib, a Stanford Medicine psychology professor and a leading scientific expert on the topic of mental health and depression in children, as well as brain development of babies exposed to maternal stress both before and during pregnancy. “It’s a significant finding, and highlights the importance of first trimester maternal health for fetal development.”
Inflammation can happen in the body as a result of fairly routine, everyday stress, Dr. Gotlib said, and isn’t limited to extreme or acute events. For example, inflammation could result from stress related to financial strains or lack of social support, he said.
Interestingly, some women seem to be more resilient to stress than others, and not all children born to moms who experience stress will develop difficult temperaments. Despite this, Dr. Gotlib maintains that, in general, “high levels of inflammation are not advantageous to development or health.”
And while more research is needed to uncover how inflammatory proteins impact emotional and behavioral characteristics in children, the pathways identified in the paper represent an important step forward.
“Proteins that promote inflammation can cross the placenta and affect prenatal brain development, said Dr. Jonas Miller, a University of Connecticut assistant professor of psychology who, alongside Stanford post-doctoral researcher Jessica Buthmann, was the paper’s first author.
“This includes early cell signaling and nervous system development processes such as cell migration, the formation of new neurons and synapses, elimination of synapses, and neuroinflammatory responses in the embryonic and fetal brain.”
“These prenatal alterations, early in pregnancy, may set the stage for long-lasting brain structure/function differences that continue after birth.”
Although in this study the researchers examined proteins only during the first trimester of pregnancy, Dr. Gotlib said it’s likely that stress-related inflammation affects fetal brain development in each trimester of pregnancy, albeit differently. He added that the team’s next step is to assess brain function of children whose moms were exposed to environmental toxins like air pollution and extreme heat during different trimesters of pregnancy.
As for this study, however, Dr. David Stevenson, a neonatologist who contributed to the research as the PRC’s principal investigator, echoed Dr. Gotlib’s statements that maternal stress during pregnancy is one of many contributing factors of difficult temperament in children – and that babies encounter a world of change out of the womb that can either heighten or dampen any predisposition stemming from their time in utero.
“Of course, the brain continues to develop after birth, so there are a number of ways that a child's behavior and temperament could be influenced—for better or worse,” he said.