Graphical Abstract: Women suffering a pregnancy loss have a significantly higher risk of developing cardiovascular disease later in life. Identifying the unknown biological mechanism(s) behind this association can help us understand disease initiation and progression at an early stage to improve risk stratification and intervention. Image: Microsoft Word with colours added by EHJ.
Pregnancy loss, the spontaneous demise of a foetus before the 22nd gestational week, is the most common pregnancy complication occurring in every fourth pregnancy (~1.4 million/year in Europe). While ~60% of pregnancy losses have gross chromosomal abnormalities with abnormal amounts of chromosomal material which can explain the pregnancy loss, the remaining 40% are euploid with normal numbers of chromosomes. This raises an important question: what is not yet discovered in the population of euploid pregnancies? It could be that there are undiscovered lethal foetal variants or, more strikingly, a perfectly viable pregnancy is rejected due to maternal conditions. Due to the lack of foetal genetic investigation in pregnancy loss (lack of priority and good methods), we, and others, have investigated this problem by performing observational studies on the extreme case of pregnancy loss, namely recurrent pregnancy loss defined by consecutive pregnancy losses, since with each pregnancy loss, the risk of an euploid pregnancy increases. These studies all indicate that maternal conditions are involved in pregnancy loss such as lack of progesterone in early pregnancy or presence of thyroid autoimmunity.[2,3] At the molecular level, maternal immunity against male antigens has also been shown to play a role in women with repeated losses after the birth of a firstborn boy. Consequently, pregnancy loss and recurrent pregnancy loss is not just the loss of a foetus incompatible with life: it is a complex phenotype with many underlying risk factors.
Multiple studies have also investigated this complex phenotype as a risk factor for disease. Most notably, pregnancy loss and recurrent pregnancy loss are associated with a later occurrence of cardiovascular disease (Graphical Abstract), type 2 diabetes, and mental disorders.[5–7]
In this issue of the European Heart Journal, Wang et al. add to the bulk of evidence that pregnancy losses are associated with later cardiovascular disease. A significant contribution to the puzzle is that they found pregnancy terminations were not associated with later cardiovascular disease. This indicates that the interruption of pregnancy itself is not the aetiological mechanism behind cardiovascular disease but rather that the underlying pathophysiology of some pregnancy losses seems to lead to greater cardiovascular morbidity. Later cardiovascular disease was more frequent in women experiencing pregnancy loss before the age of 30 years and women experiencing more than one pregnancy loss, strongly suggesting that euploid pregnancy losses are the key to understand the association with cardiovascular disease. One very important question that has not been addressed thus far is whether pregnancy loss increases the risk of cardiovascular disease, independent of other cardiovascular disease risk factors such as type 2 diabetes, hypertension, and hypercholesterolaemia. In the present study, the authors tackled this by performing a mediation analysis and found that traditional risk factors mediated <10% of the hazard rate. Consequently, pregnancy loss is not just a proxy for cardiometabolic dysfunction.
Limiting reproductive events to females may also be detrimental to our understanding of basic biological phenomena potentially important for cardiovascular disease in men. The association between pregnancy loss and cardiovascular disease extends even beyond women; in a Danish study, first-degree relatives of women with recurrent pregnancy loss also had increased rates of cardiovascular disease. This highlights a point of significance; that the relationship may be due to common genetic risk factors. Another pathway for increased cardiovascular disease in men fathering a pregnancy loss is through sperm DNA fragmentation. Sperm DNA fragmentation is high in 40% of men in couples experiencing recurrent pregnancy loss. It has never been investigated whether sperm DNA fragmentation is associated with euploid or aneuploid pregnancy losses, although a fragile DNA would theoretically be more likely to result in an aneuploid loss. Sperm DNA fragmentation is associated with male health, including cardiovascular disease and diabetes.[10,11]
Identifying these components is critical to help us understand disease initiation and progression at a very early stage to improve risk stratification and actions. It is also, from a preventive point of view, interesting for clinicians and public health to take advantage of the favourable learning opportunity resulting from the strong desire to reproduce.
With the compiling of evidence of an association between pregnancy outcomes and later disease, it is relevant to ask why we still do not understand the underlying mechanisms. The reproductive life span is massively understudied for a range of different reasons including a strong perception that reproduction is a natural process not meant for interventions and that we should not pathologize women experiencing these unstoppable events. This is completely opposite to the academic and economic investments put into combatting nature when it comes to other medical conditions. Another, however linked, reason is the sex bias that has affected decades of biomedical and clinical research including cardiovascular research, with the vast majority of investigated persons being males. The apparent advantage of including individuals without a menstrual cycle and a pregnancy history now seems to be the missing link to understand women’s cardiovascular disease.
As recently strongly stated in a Lancet editorial, ‘For too long pregnancy loss has been minimized and often dismissed. The lack of medical progress should be shocking. Instead, there is a pervasive acceptance. Not all pregnancy losses could be avoided, but the insidious implication that pregnancy loss, like other women’s reproductive health issues, including menstrual pain and menopause, should be managed with minimal medical intervention is ideological, not evidence based.’
Hopefully, the coming years will be the era where we build on and supplement the epidemiological studies revealing associations of pregnancy loss and later disease with in-depth biological mechanistic studies acknowledging the complexity of having three involved individuals (father, mother, and foetus) in each event and taking advantages of the revolution in methodologies needed to disentangle the genetic and functional contributions to pregnancy loss.