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 pregnant individuals to determine whether prenatal programming can be detected independent of shared maternal-child genes.

Decades of prospective DOHaD research with birthing individuals and their genetic children, including reports from our group, support the prenatal programming hypothesis that pregnant individuals' mental health affects the next generation's. Seminal, population-based studies using parent reports, such as the Avon Longitudinal Study of Parents and Children (ALSPAC), showed pregnant women in the top 15% for anxiety symptoms had children with nearly twice the risk of mental health disorders across ages 4-13 after controlling for confounders including postpartum depression. In our work and others' using objective assessments, maternal prenatal distress associated with higher 3rd trimester fetal heart rate (FHR) reactivity, from EEG in newborns lower high- frequency power and greater frontal asymmetry (itself associated with adult depression), and decrements in NIH ToolBox executive functioning and motor skills at 4-8 years old. However, for each of these findings, shared maternal-child genes cannot be ruled out. Animal models - in which the genetic background and stress exposure can be manipulated - show prenatal stress leads to anxious and depressed behavioral phenotypes independent of genetic inheritance, though limitations in the applicability to humans include: stressors' ecological validity, differences in gestational biology, and developmental timing. Genetically-informed studies, including those with donor IVF participants, show mixed evidence for prenatal distress effects. However, designs are frequently retrospective, including in IVF research, such that medical confounds also are not well controlled. Mechanistic approaches, such as our work and others' work focused on the placenta, a gestational organ at the maternal-fetal interface, show maternal distress associated with epigenetic regulation of placenta glucocorticoid and pro-inflammatory genes and child outcomes; to date, no study using IVF to circumvent genetic confounding has included mechanistic approaches. Finally, most DOHaD science concerns maternal distress effects; to advance prenatal programming research and enhance its relevance for clinical interventions, maternal social connection and other aspects of well-being also should be examined. Our study will address these design limitations and aim to identify maternal prenatal distress effects 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 24-28 weeks (Pregnancy Session 1); laboratory session for maternal EKG, blood pressure, blood draw (immune markers), psychosocial questionnaires, fetal neurobehavior 34-38 weeks (Pregnancy Session 2); collect placenta and cord blood (cortisol); 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 status.