Failing the stress test: Spiral artery pathology in pregnancy and the interplay with maternal cardiovascular health

Abstract

In part I of this thesis, we first aimed to elucidate factors leading to the actual ‘failing of the stress test of pregnancy’ by studying maternal spiral arteries and the uterine tissue underlying the placenta (i.e. the placental bed) in pregnancy complications. We produced comprehensive data indicating that impaired spiral artery remodeling is present in almost two thirds of women with fetal growth restriction (FGR) and/or preeclampsia (chapter 3). Impaired remodeling was often combined with absence of intramural trophoblast cells, although presence of interstitial trophoblast was abundant. This challenges the classic hypothesis that impaired spiral artery remodeling is the result of problems with invasiveness of the trophoblast cells. Next to remodeling problems, acute atherosis can be found in almost a third of women presenting with these pregnancy complications (chapter 3). These lesions appear to be associated with modifiable cardiovascular risk factors in the mother underlining the role of pre-existent maternal constitution (chapter 2). This is consistent with the concept of complicated pregnancy as a ‘stress test’ for future cardiovascular disease (CVD). Furthermore, we found that the baby is born earlier and relatively smaller when preeclampsia and/or FGR is associated with underlying impaired spiral artery remodeling (chapter 4). Studying vascular endothelial cells (ECs) from the placental bed at the transcriptional level, we found evidence of altered inflammation and endothelial dysfunction suggesting that maternal inflammatory predisposition is also at play in women who ‘fail the stress test’ (chapter 5). Moreover, placental function seems to be directly affected by the mothers health and constitution as we found evidence of histopathological lesions in mothers who were obese before getting pregnant (chapter 6). In part II, we aimed to elucidate some of the missing information regarding the development of cardiovascular disease (CVD) after have ‘failed the stress test’ previously (i.e. women with a history of preeclampsia). In other words, we investigated factors that may help to identify who is at increased risk, when cardiovascular damage develops and if timely screening and lifestyle interventions may be cost- beneficial and effective. To further specify who would have added benefit from screening and prevention, we performed a systematic review and meta-analysis and found that women who experienced preeclampsia in more than one pregnancy have an increased risk of CVD compared to women having preeclampsia once (chapter 7). To pinpoint when visible cardiovascular damage develops, we performed coronary computed tomography (CCT) in women with a history of preeclampsia. On average women with previous preeclampsia develop coronary artery calcification (CAC) 5 years earlier than women with uncomplicated obstetric history, around the age of 45 (chapter 8). Although research on effective prevention programs in these women is lacking, one may conclude that the recommended screening after the age of 50 is too late for women who experienced preeclampsia. Lastly, to identify when to screen and if we may be able to prevent it, we performed a model-based micro simulation study entailing data from the CCT study. We found that early (i.e. at 30 years) and regular screening in combination with lifestyle interventions reduce the risk of CVD in these women, are likely to improve quality of life and to be cost-effective (chapter 9).