부산대학교 도서관

Congenital heart disease (CHD) refers to the collection of diseases involving a problem with the structure of the heart present at birth. CHDs are a significant cause of infant morbidity and mortality. The causes of CHD are largely unknown. Observational epidemiological studies have reported links between a wide range of maternal lifestyle factors during pregnancy and CHD in the offspring. However, the causal relevance of these is unclear. This PhD thesis explores relationships between maternal pregnancy exposures and offspring CHD by employing a range of epidemiological techniques using multiple independent data sources. Chapter 1 introduces CHDs, summarises the literature in relation to maternal pregnancy exposures and offspring CHD, puts forward the case for using pregnancy metabolomics and outlines epidemiological methods that could help improve causal inference. Chapter 2 describes cases of congenital anomalies and CHD in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. In Chapter 3, I used parental negative exposure control analyses to explore the effects of maternal pre- pregnancy body mass index (BMI), and pregnancy smoking and alcohol on offspring CHD. I found that maternal pregnancy smoking may increase offspring CHD risk via intrauterine mechanisms but did not find evidence to suggest maternal overweight or obesity increase risk. Results for alcohol were inconclusive. In Chapter 4, I used Mendelian randomisation (MR) to explore the effects of the same exposures studied in Chapter 3. I found no robust evidence of an effect for maternal BMI or smoking on offspring CHD using MR. Using a genetic risk score of drinks per week, there was some evidence of a potential causal effect for maternal alcohol intake on offspring CHD. In Chapter 5, I examined the relationship of maternal gestational mass spectrometry-derived metabolites with offspring CHD using multivariable regression and MR analyses. I found evidence that amino acid metabolism during pregnancy, androgenic steroid metabolites, and levels of succinylcarnitine could be important contributing factors to CHD. In Chapter 6, I explored the relationship of maternal gestational nuclear magnetic resonance-derived metabolic traits with offspring CHD. I replicated the findings for amino acids seen in Chapter 5 and found evidence of potential effects for some fatty acid and very low-density lipoprotein traits, albumin, and citrate. Chapter 7 provides an overview of the primary findings for analyses included in each chapter along with strengths and limitations. It then considers the public health and clinical implications of my findings and provides recommendations for future research.