Leveraging IVF to Identify Prenatal Effects Independent of Shared Maternal-Child Genes

To rigorously test the Developmental Origins of Health and Disease (DOHaD) research model, this project will leverage the spectacular scientific advancements of in vitro fertilization (IVF) and compare maternal prenatal distress effects between IVF donor oocyte/embryo and non-donor oocyte pregnancies. This will be the first study to use multidisciplinary (neurobehavioral, epigenetic, transcriptomic) methods with adoption-at-conception preg- nant individuals to determine whether prenatal programming can be detected independent of shared maternal- child genes. In a longitudinal study of 2nd trimester pregnant individuals (60 donor oocyte/embryo,120 non-donor oocyte), n=180 post attrition, protocol is: Zoom-based psychosocial questionnaires 26-28 weeks (Pregnancy Session 1); laboratory session for maternal EKG, blood pressure, blood draw (immune markers), psychosocial questionnaires, fetal neurobehavior 34-36 weeks (Pregnancy Session 2); collect placenta and cord blood (corti- sol); newborn EEG in hospital; medical record data; and, methods: placenta targeted/genome-wide methylation, gene expression, distress, Allostatic Load (AL): Test three aims, identifying, independent of IVF group sta- tus: Aim 1: the influence of maternal distress on perinatal neurobehavioral development. Hypotheses: Independent of IVF group status, higher maternal AL will be associated with (a) higher 3rd trimester FHR reactiv- ity, lower FHR variability, lower FHR-movement coupling and (b) newborn reduced high-frequency EEG power, greater frontal alpha asymmetry, and smaller P3 component of the ERP to novel auditory stimuli. Aim 2: maternal distress affecting placenta gene methylation. Hypotheses: Independent of IVF group status, maternal AL will be associated with placenta (a) differential DNA methylation in glucocorticoid-regulating genes (NRC31, FKBP5, HSD11B2), (b) epigenetic differences using a novel hypothesis-generating method that reduces testing burden and will improve our ability to detect high order regulatory processes across the genome. Aim 3: maternal experiences associated with unique placenta transcriptomic profiles. Hypotheses: Independent of IVF group status, maternal AL and well-being each will be associated with unique placenta gene expression in (a) pro-inflammatory genes, (b) transcriptome-wide co-regulated modules, and (c) (exploratory) causal pathways in placental biology and perinatal development using multi-omics integration. This proposal is significant because it will move DOHaD science forward, carefully testing a key gap in current knowledge, a genetic confound, and potentially producing findings (1) relevant to policy initiatives supporting pregnant individuals for two-generation impact, (2) validating to those in the U.S. having children via IVF — yearly over 2% of total U.S. births, over 10 million born so far worldwide, and (3), meaningful to all par- ents interested in the extent to which parenting, and its influence on children, begin before birth. Project Number: 1R01HD118949-01 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Catherine Monk (+1 co-PI) | Institution: COLUMBIA UNIVERSITY HEALTH SCIENCES, NEW YORK, NY | Award Amount: $719,141 | Activity Code: R01 | Study Section: Biobehavioral Mechanisms of Emotion, Stress and Health Study Section[MESH] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HD11894901