UC Irvine

ABSTRACT OF DISSERTATIONInvestigating the Impact of Prenatal Exposure to Hypertensive Disorders of Pregnancy on Adolescent Neurodevelopment and Pubertal Maturation: A Study of Neuroimaging and Salivary Biological Measures. By Vida Bobela Fabiola Rebello Doctor of Philosophy in Public Health University of California, Irvine, 2023 The increasing prevalence of hypertensive disorders of pregnancy (HDP), including specific types of HDP like pregnancy-related hypertension (PR-HTN), preeclampsia, and eclampsia (P/E), pose significant health risks for pregnant individuals and their offspring. Although, prenatal HDP exposure has been reported to augment children’s sensitivity to adverse health outcomes, few studies have examined the long-term associations of prenatal exposure to HDP on neurodevelopment and hormone profiles beyond childhood. Adolescence is a critical period during which both the brain and the endocrine system undergo substantial development, representing a core risk period for when HDP-related differences may become discernable. Previous studies on the impact of HDP on adolescent health have primarily focused on discrete populations (e.g., clinical, low prevalence populations) exposed to a single type of HDP, predominantly preeclampsia. Moreover, these studies have been constrained by the lack of prospective follow-up and insufficient consideration of potential mediators. Elucidating the biophysiological mechanisms that demonstrate long-term postnatal alterations following prenatal exposure to HDP is needed. Therefore, the objective of this dissertation was to identify biological measures pertinent to psychopathology and metabolic risks influenced by HDP and to examine the role of HDP types in these relationships, utilizing the Developmental Origins of Health and Disease (DOHaD) framework. Data from the longitudinal Adolescent Brain Cognitive Development (ABCD) Study© was used, including approximately 11,888 adolescents aged 9-10 years at baseline. In Chapter 2, direct and indirect associations between HDP and cortical and subcortical brain structures were examined while accounting for the mediating role of intracranial volume in adolescents, using structural magnetic resonance imaging (sMRI) measures at two timepoints: baseline and year 2 follow-up. In chapter 3, diffusion weighted MRI (dMRI) measures were employed at two time points (baseline and Year 2 follow-up) to assess whether prenatal exposure to HDP contributes to white matter connectivity differences among the adolescents. In chapter 4, the influence of HDP on long-term endocrine development focusing in on androgen hormone profiles were investigated at three timepoints: baseline, year 1 follow-up and year 2 follow-up among the adolescents. HDP exposure was categorized as pregnancy-related hypertension (PR-HTN), preeclampsia/eclampsia (P/E), or unexposed (no HDP). Hierarchical mixed effects models were used to account for the multilevel data structure, and analyses were stratified by biological sex. In Chapter 1, findings demonstrate direct and indirect impact of prenatal exposure to HDP on the development of cortical and subcortical brain structure, identifying distinct variations in the impact of prenatal HDP exposure on neurodevelopment, with the observed associations being sex-dependent. Specifically, the unique consequences of the two distinct HDP types on brain structures differed between males and females. In chapter 2, further evidence is presented, illustrating that HDP exposure, particularly PR-HTN, is a significant predictor of alterations in white matter development. This association was observed exclusively among female adolescents, potentially because of the earlier onset of puberty-related initiation of myelination of white matter in females. Chapter 4 revealed distinct androgenic hormonal patterns in both males and female adolescents to the two types of HDP exposures. Collectively, this dissertation addresses the gap in our understanding of the unique ways in which PR-HTN and P/E influence adolescent neuroendocrine development. It underscores the importance of early monitoring and intervention for neurodevelopment and pubertal maturation to address potential pathological deviations that could lead to neuropsychiatric and metabolic disorders later in life. Additionally, this dissertation emphasizes the need to consider community-level hypertension in preconceptual health, as increased resources could benefit both the pregnant individuals and the child. Furthermore, it highlights the importance of accounting for prenatal HDP exposure when investigating adolescent neurodevelopment and pubertal maturation. Future research is warranted to elucidate the long-term disease outcomes associated with HDP.