Chair:
Lauren C. Shuffrey, PhD, Assistant Professor, Department of Child and Adolescent Psychiatry, NYU Grossman School of Medicine, New York, United States
Discussant:
Brie M. Reid, PhD, Assistant Professor, Department of Psychology Department of Health Sciences Center for Cognitive and Brain Health Northeastern University, Boston, United States
Presenters:
Michael K. Georgieff, MD, Executive Vice Chair & Martin Lenz Harrison Land Grant Professor, Division of Neonatology; Faculty, Department of Pediatrics; Director, Center for Neurobehavioral Development; Co-Director, Masonic Institute for the Developing Brain (MIDB); Faculty, Institute of Child Development; Faculty, Department of Obstetrics, Gynecology and Women’s Health (OBGYN); Preceptor & Steering Committee Member, Graduate Program in Neuroscience, University of Minnesota, Minneapolis, United States
Sarah M. Banker, PhD, Postdoctoral Research Fellow, Department of Child and Adolescent Psychiatry, NYU Langone Health, New York, United States
Kate Keenan, PhD, Professor of Psychiatry and Behavioral Neuroscience; Professor of Neuroscience Institute, Department of Psychiatry and Behavioral Neuroscience, University of Chicago, United States
Elinor L. Sullivan, PhD, Professor of Psychiatry, School of Medicine; Professor, Behavioral Neuroscience, School of Medicine, Departments of Psychiatry and Behavioral Neuroscience, Oregon Health & Science University, Center for Mental Health Innovation, Oregon Health & Science University, United States
Symposium Description:
Throughout pregnancy, the maternal body undergoes significant changes to support the developing fetus, including adaptations in immune and metabolic functions. In this symposium, we explore the intricate interplay between maternal inflammation and metabolic health, and their profound impacts on fetal brain development and infant outcomes. Our presentations will delve into the mechanisms by which maternal inflammation influences nutrient delivery, metabolic pathways, birth outcomes, and long-term neurodevelopment, providing a comprehensive understanding of these critical processes across species and time points. Dr. Michael K. Georgieff will discuss how maternal inflammation alters nutrient delivery and metabolism, particularly affecting the fetal brain, in both preclinical and human samples. He will also highlight the cellular pathways by which inflammation impacts long-term neurodevelopment. Sarah M. Banker will present findings from the NIH Environmental influences on Child Health Outcomes (ECHO) Program, examining inflammatory changes across pregnancy in a diverse human sample. She will additionally identify pro- and anti-inflammatory markers linked to adverse pregnancy outcomes and their potential role in neurobehavioral development. Dr. Kate Keenan will focus on systemic inflammation as a marker for cardiometabolic disease risk in Black women. She will present data on the predictive utility of C-reactive protein (CRP) levels during and after pregnancy for identifying individuals at risk for poor cardiometabolic health. Finally, Dr. Elinor L. Sullivan will explore the kynurenine (KYN) pathway as a mechanistic link between maternal adiposity and child negative affect. Her findings suggests that alterations in KYN metabolites during pregnancy are associated with increased child negative affectivity, highlighting potential biomarkers and targets for intervention. Dr. Brie Reid will serve as the symposium discussant, facilitating conversation on interactions between the immune and metabolic systems during pregnancy and their impact on birth and neurodevelopmental outcomes. Together, these presentations will provide a comprehensive overview of how maternal inflammation and metabolic health influence fetal and infant development across species and developmental time points. These findings hold promise for identifying biomarkers and informing interventions aimed at improving maternal and child outcomes.
List of abstracts and presenters:
MATERNAL INFLAMMATION AND FETAL BRAIN DEVELOPMENT, Michael K. Georgieff1,2, Brie M Reid3, Phu Tran1
1 Department of Pediatrics, University of Minnesota
2 Masonic Institute for the Developing Brain (MIDB), University of Minnesota
3 Northeastern University, in the departments of Psychology and Health Sciences and Public Health
Maternal nutritional substrate requirements increase substantially during pregnancy due to her own metabolic demands coupled with those of the placenta and the developing fetus. The developing human fetal brain has an extraordinarily high metabolic rate, accounting for 60% of the total body’s oxygen consumption. Thus, deficits or restrictions of nutrients that support oxidative metabolism, e.g., glucose, amino acids, fatty acids, iron, copper, thyroid (iodine) are a particular risk to the developing brain. Certain maternal gestational conditions (e.g., maternal hypertension, pre-eclampsia) directly restrict these nutrients due to placental vascular changes. However, little consideration has been given to how maternal inflammation, either due to infection or non-infectious causes (e.g., obesity; excessive weight gain) alters maternal-fetal nutrient delivery, metabolism and utilization, particularly by the fetal brain. Besides the direct toxic effect of pro-inflammatory cytokines on developing white and gray matter, studies in preclinical models and human infants indicate inflammation diverts amino acids toward gluconeogenesis rather than structural protein synthesis. It restricts maternal iron absorption and sequesters iron in the maternal reticulo-endothelial system, thus reducing maternal-fetal iron transport. Fetal iron deficiency induces a hypothyroid state that further restricts neuronal growth and development. These factors, while likely adaptive for survival of the maternal-fetal dyad, result in long-term risk to offspring neurobehavioral development. This presentation discusses the “two-way street” between stress/inflammation and nutrition in the maternal-fetal dyad with emphasis on the fundamental cellular pathways by which inflammation potentially negatively affects long-term neurodevelopment.
IDENTIFYING INFLAMMATORY CHANGES ACROSS PREGNANCY AND THEIR LINKS TO ADVERSE PREGNANCY OUTCOMES, Sarah M. Banker1, Stephanie Giamberardino2, Akhgar Ghassabian3, Sarah Sinsel4, Christian Douglas4, Santiago Morales5, Christine Hockett6,7, Amy Elliott6,7, Lauren C. Shuffrey1
1 Department of Child and Adolescent Psychiatry, NYU Grossman School of Medicine
2 GenOmics and Translational Research Center, RTI International
3 Department of Pediatrics, NYU Grossman School of Medicine
4 Center for Clinical Research, RTI International
5 Department of Psychology, University of Southern California
6Avera Research Institute, Sioux Falls, SD, USA
7 Department of Pediatrics, University of South Dakota School of Medicine, Sioux Falls, SD
Over the course of pregnancy, the maternal immune system undergoes substantial changes to support and adapt to the development of a semi-allogenic fetus. Immune adaptations help balance the need to defend against pathogens while protecting the fetus from harmful immune responses. Nevertheless, a comprehensive understanding of inflammatory adaptations during pregnancy remains elusive, and it is still unclear how disruptions to these carefully timed immunological shifts may contribute to adverse outcomes. Utilizing data collected from the NIH Environmental influences on Child Health Outcomes (ECHO) Program, this presentation will provide a cross-sectional overview of inflammatory changes and associated outcomes in a diverse sample of over 1,200 pregnancies from 6 different pregnancy cohorts. The Olink Target-96 Inflammation Panel was used to analyze plasma samples collected at different points throughout pregnancy, ranging from 6 to 40 gestational weeks. Proteins whose expression levels show significant associations with gestational age will be highlighted, along with a discussion of how the structure of protein correlation networks evolve across pregnancy. The presentation will also explore the biological implications of these network changes. Finally, several pro- and anti-inflammatory markers identified as predictors of adverse pregnancy outcomes—such as gestational hypertension, gestational diabetes, and preterm birth—will be presented, offering insights into underlying mechanisms. We will also discuss the overlap between markers linked to adverse outcomes and those potentially mediating neurobehavioral development, highlighting shared pathways that may shape long-term child health under a developmental origins of health and disease framework.
SYSTEMIC INFLAMMATION DURING AND AFTER PREGNANCY AS A MARKER FOR CARDIOMETABOLIC DISEASE IN BLACK WOMEN, Kate Keenan1, Alison Hipwell2, Michele Levine2, Kelsey Magee2
1Department of Psychiatry and Behavioral Neuroscience, University of Chicago
2Department of Psychiatry, University of Pittsburgh
Pregnancy is an important window for identifying markers for poor cardiometabolic health (CMH) in the postpartum period and beyond. For Black women, the postpartum period is one characterized by increased health risks combined with decreased contact with health professionals. Thus, identifying prenatal markers of postpartum CMH health may inform targets for prevention efforts that improve Black women’s health. We examine the predictive utility of changes in systemic inflammation from pregnancy to postpartum as measured via serum levels of C-reactive protein (CRP) and biomarkers of cardiovascular health (glucose, insulin, triglycerides) at 6 months post-partum in a community sample of Black women enrolled in a substudy to the Pittsburgh Girls Study. Venous blood samples were collected during pregnancy, and at 2- and 6-months postpartum. CRP was determined turbidmetrically, glucose by EIA, insulin by RIA, and triglycerides by conventional enzymatic methods. For analytic purposes, CRP values were log10 transformed and clinically elevated levels of CMH biomarkers (e.g., glucose > 99 mg/dL) were used to define risk. CRP levels were higher during pregnancy and at 2 months postpartum for women with clinical elevated levels of glucose (F [1,58] = 10.68, p <.01) and triglycerides (F 1,58) = 4.06, p <.05) at 6 months postpartum, controlling for prenatal levels of glucose and triglycerides. Magnitude of change in CRP from pregnancy to 2 months postpartum differed between women with and without elevated insulin levels at 6 months postpartum (F [1,54] = 5.33, p = .025). CRP, a clinically available test, may be useful for identifying individuals during pregnancy -who merit increased surveillance to promote future CMH.
GESTATIONAL KYNURENINE METABOLITES MEDIATE EFFECTS OF PREGNANCY ADIPOSITY ON CHILD NEGATIVE AFFECT, Elinor L. Sullivan, Departments of Psychiatry and Behavioral Neuroscience, Oregon Health & Science University, Center for Mental Health Innovation, Oregon Health & Science University
Mounting evidence links increased maternal adiposity during pregnancy and offspring risk for mental health disorders. Yet the mechanisms underlying this association remain poorly understood, limiting our ability to design effective interventions. We hypothesize that alterations in the kynurenine system of the pregnant individual may help to explain this association. Participants were recruited during pregnancy with repeated assessments through 24 months postpartum. Maternal adiposity was assessed using air displacement plethysmography. Liquid chromatography tandem mass spectrometry was used to measure kynurenine system metabolites in maternal plasma. Child negative affect was assessed using maternal-report at 6, 12, and 24 months. Participants (N=305) included mothers and their children (70% non-Hispanic White, 50% female). The ratio of Picolinic to Quinolinic Acid (PA:QA) predicted child fear (β=-.16, 95%CI -.28 to -.04, p=.009) and sadness (β=-.14, 95%CI -.28 to .01, p=.03) at 6 months. PA:QA mediated the effect of pregnancy adiposity on child fear (β=.03, bootstrapped 95%CI .004-.07, p=.04) and sadness (β=.04, bootstrapped 95%CI .002-.07, p=.05). Similar associations were observed when children were 12 and 24 months old, suggesting enduring effects. This is the first evidence that alterations in the kynurenine system during pregnancy are associated with increased child negative affectivity, an early life risk factor for psychopathology. Results further suggest that these kynurenine metabolites are a mechanistic link between pregnancy adiposity and child negative affect. Picolinic and Quinolinic Acid during pregnancy may be novel biomarkers for offspring behavioral risk, and novel targets for intervention.