In Vitro Fertilization (IVF) and Prenatal Effects Independent of Genetics

Official title

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

Overview

This study examines how maternal stress during pregnancy affects infant brain and behavioral development, focusing on whether these effects are due to the prenatal environment or shared genes. By comparing IVF pregnancies using donor eggs/embryos (no shared genetics) with non-donor IVF pregnancies, the investigators aim to understand how stress influences the baby's development independent of genetic factors. Participants will complete questionnaires, provide blood samples, and take part in placenta and cord blood collection, fetal monitoring, and newborn brain activity assessments. Aim 1: The influence of maternal distress on perinatal neurobehavioral development. Hypotheses: Independent of IVF group status, higher maternal AL will be associated with higher 3rd trimester FHR reactivity, lower FHR variability, AND lower FHR-movement coupling Aim 2: Maternal distress affecting placenta gene methylation. Hypotheses: Independent of IVF group status, maternal AL will be associated with placenta differential DNA methylation in glucocorticoid-regulating genes (FKBP5 and HSD11B2), 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 pro-inflammatory genes

Detailed description

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.

Interventions

• Other Prenatal maternal psychosocial and biological assessment protocol
  This is not a therapeutic or experimental intervention. The data-collection protocol includes structured psychosocial questionnaires, physiological monitoring, maternal blood draws, placental and cord blood collection, and newborn physiological monitoring. These procedures are used to observe associations between maternal prenatal distress and infant outcomes. All participants undergo the same assessments; no clinical treatment or behavioral manipulation is delivered.

Primary outcome measures

• Change in fetal heart rate (FHR) [Time frame: At Pregnancy Session 2 (approximately 34-36 weeks of pregnancy)]
• Standard deviation of fetal heart rate [Time frame: At Pregnancy Session 2 (approximately 34-36 weeks of pregnancy)]
• Cross correlation of fetal movement and heart rate change [Time frame: At Pregnancy Session 2 (approximately 34-36 weeks of pregnancy)]
• Average percent DNA methylation of the FKBP5 gene in placental tissue [Time frame: At delivery (approximately 37-40 weeks)]
• Average percent DNA methylation of the HSD11B2 gene in placental tissue [Time frame: At delivery (approximately 37-40 weeks)]
• Relative expression of key pro-inflammatory markers in placental tissue [Time frame: At delivery (approximately 37-40 weeks)]

Eligibility criteria

Inclusion criteria

• Individuals at 18-28 gestational weeks with donor and homologous IVF pregnancies, ages 18-50.
• Participants must be patients receiving their perinatal health care through Columbia University Irving Medical Center's Department of OB/GYN and delivering at New York-Presbyterian Morgan Stanley Children's Hospital.
• Participants must be patients delivering at Columbia University Irving Medical Center's Department of OB/GYN and delivering at New York-Presbyterian Morgan Stanley Children's Hospital.
• Participants will include the offspring of patients receiving care and delivering at the above institutions.
• Enrollment Location(s): Columbia University Irving Medical Center's Department of OB/GYN, delivering at New York-Presbyterian Morgan Stanley Children's Hospital.

Exclusion criteria

• Identified addiction disorder
• Severe psychiatric condition (defined as symptoms that significantly impair daily functioning and are untreated or not effectively managed)
• Multiple fetal pregnancy
• Known chromosomal, genetic, or major fetal malformations (unlikely due to routine preimplantation genetic testing)
• Inflammatory conditions including rheumatoid arthritis, lupus, and multiple sclerosis
• Not planning to deliver at a CUIMC-affiliated hospital

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Observational model

Cohort

Study locations

United States · 1 center

• Columbia University Irving Medical Center/New York Presbyterian Hospital — New York

Identifiers

NCT: NCT07296107 · AAAV4123 · 1R01HD118949-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗