Prenatal risk factors for severe cardiovascular diseases up to middle-age : a Nordic collaborative study

Background and objectives: Cardiovascular diseases (CVDs) are major causes of death and disability. However, the established traditional risk factors cannot explain a substantial proportion of CVD cases, prompting investigations into novel risk factors. A growing body of evidence underscores the potential role of suboptimal intrauterine conditions on the development of CVD. Nonetheless, our knowledge about the associations between factors contributing to an adverse intrauterine environment and the risk of developing CVD remains limited. The overall objective of this thesis is to enhance our comprehension of the potential role of prenatal risk factors in developing CVD later in life. More specifically, the thesis aims to study the following research questions: (1) Are negative birth outcomes such as preterm birth, being small (SGA) or large (LGA) for gestational age related to the atrial fibrillation risk later in life (Study I)? (2) Is maternal preeclampsia and its subtypes linked to increased risks of stroke and ischemic heart disease in the offspring (Study II)? (3) Is maternal polycystic ovary syndrome (PCOS) associated with the risks of overall CVD and its major subtypes in her offspring (Study III)? and (4) Is prenatal exposure to maternal severe stress related to the risk of heart failure later in life (Study IV)?

Methods: We performed four register-based prospective cohort studies, including all live singletons from Denmark (Study I: 1978-2016, Studies II-IV: 1973-2016) and Sweden (Studies I-IV: 1973-2014), and live births from a randomly selected 90% of all births in Finland Studies I and II; 1987-2014). The size of the study population was 8,012,433 in Study I, 8,475,819 in Study II, 6,839,703 in Study III, and 6,758,560 in Study IV. Information on birth outcomes, maternal and offspring's health and covariates were obtained through linkage to population-based socioeconomic and health registers. Each study participant was followed up until the earliest diagnosis of the CVD of interest, emigration, death, or end of follow-up (Denmark: December 31, 2016; Finland: December 31, 2014; Sweden: December 31, 2020), whichever occurred first. We examined the association between prenatal exposures (including preterm birth, SGA, LGA, maternal preeclampsia, PCOS, and severe stress) and CVD outcomes in offspring using multivariable Cox regression models. Furthermore, we used family- based study designs, i.e. sibling and cousin comparison analyses, to account for unmeasured familial genetic and environmental confounders. Additionally, we investigated the mediating roles of abnormal birth outcomes and congenital heart disease in case of some of the observed associations.

Results: In Study I, we found that being born preterm or LGA was linked to an increased risk of atrial fibrillation in both childhood and adulthood. The associations persisted in the sibling comparison analyses. In contrast, SGA was related to an increased atrial fibrillation risk in childhood but not in adulthood. In Study II, we found that individuals prenatally exposed to maternal preeclampsia had higher risks of stroke and ischemic heart disease than those unexposed, and that the associations were more pronounced in cases of severe than milder forms of preeclampsia. The associations of the severe forms of maternal preeclampsia with the offspring's risk of stroke remained in the sibling comparison analyses. In Study III, maternal PCOS was associated with elevated risks of overall CVD, hypertensive disease, stroke, and ischemic heart disease in the population analysis; most of these associations, except that observed in case of stroke, remained in the cousin comparison analysis. When investigating the interaction between maternal PCOS and its prevalent comorbidities, we found that individuals born to mothers with both PCOS and its common comorbid conditions, i.e. diabetes, hypertensive disease, or psychiatric disorders, had higher CVD risks than those born to mothers with only PCOS. In Study IV, we found that offspring exposed to maternal loss of a close family member the year prior to or during pregnancy did not have a higher risk of heart failure than those unexposed. However, the severe forms of maternal bereavement, specifically loss due to unnatural causes and loss of a child or partner, were linked to an increased risk of heart failure in the offspring.

When splitting follow-up for Studies I-IV at the age of 18, we found that the association between preterm birth and the risk of atrial fibrillation, maternal preeclampsia and the risk of stroke, and severe maternal stress and the risk of heart failure were stronger during childhood than during adulthood. In the mediation analyses, there was some evidence that the association between maternal PCOS and the risk of CVD in offspring was to a modest extent mediated by preterm birth, LGA, and congenital heart disease. In the case of the link between severe maternal stress and the risk of heart failure, we observed considerable contributions from congenital heart disease and preterm birth.

Conclusions: This thesis revealed associations of prenatal risk factors with increased risks of CVD up to early middle-age. Specifically, our findings suggest that preterm birth, SGA, and LGA were related to elevated risks of atrial fibrillation. Additionally, maternal preeclampsia, especially its severe types, was associated with elevated risks of stroke and ischemic heart disease in offspring, while maternal PCOS was associated with increased risks of overall CVD and its major types. Moreover, severe maternal stress was associated with an elevated risk of heart failure in offspring. If subsequent studies confirm our findings, early-life prevention and targeted intervention programs may be developed to inform health policies, eventually resulting in a reduced burden of CVD.

List of scientific papers

I. Yang F, Janszky I, Gissler M, Cnattingius S, Roos N, Miao MH, Yuan W, Li J, László KD. Preterm birth, small for gestational age, and large for gestational age and the risk of atrial fibrillation up to middle age. JAMA Pediatrics. 2023;177(6):599-607.
https://doi.org/10.1001/jamapediatrics.2023.0083

II. Yang F, Janszky I, Gissler M, Roos N, Wikström AK, Yu YF, Chen H, Bonamy AKE, Li J, László KD. Association of maternal preeclampsia with offspring risks of ischemic heart disease and stroke in Nordic countries. JAMA Network Open. 2022;5(11):e2242064.
https://doi.org/10.1001/jamanetworkopen.2022.42064

III. Yang F, Wang ZL, Sørensen HT, Janszky I, Gissler M, Yuan W, Miao MH, Roos N, Wikström AK, Li J, László KD. Risk of cardiovascular diseases in offspring of women with polycystic ovary syndrome: a binational cohort study. [Submitted]

IV. Yang F, Janszky I, Roos N, Li J, László KD. Severe maternal stress during pregnancy and the offspring's risk of heart failure in the first five decades of life: a binational cohort study. [Accepted]
https://doi.org/10.1001/jamanetworkopen.2023.49463