Pregnancy: the underestimated condition

This editorial refers to ‘Pregnancy outcomes in women with cardiovascular disease: evolving trends over 10 years in the ESC Registry Of Pregnancy And Cardiac disease (ROPAC)’†, by J. Roos-Hesselink et al., on page 3848. Cardiovascular diseases (CVDs) are at present the most frequent cause of death in pregnant women in developed countries. In our societies, severe cardiovascular conditions—such as congenital heart disease, aortic diseases, valvular heart disease, heart failure, myocardial infarction, and thrombo-embolic complications—lead to complications in 1–4% of pregnancies.1–3 Moreover, up to 10% of pregnancies are complicated by hypertension, eclampsia, and pre-eclampsia. As stated in the recently published ESC guidelines,1 knowledge of the risks associated with CVDs during pregnancy and the management of risk in pregnant women who suffer from CVD is of crucial importance for better outcomes. Nevertheless, data on pregnancy-related heart disease in the ESC countries are limited. In fact, the number of risk conditions is increasing, probably due to better treatment of risk conditions. Women with congenital heart disease now reach the age of pregnancy in a relatively healthy state and consider options for pregnancy. Furthermore, women are acquiring risk factors such as diabetes, hypertension, and CVD, such as atherosclerosis, at younger ages, whereas the age for first pregnancies is increasing. This leads to a higher rate of pregnancies in women with CVD, or high-risk pregnancies. Unfortunately, knowledge of pregnancy complications is scarce and has a very inhomogeneous distribution in ESC member countries. One of the few reviews on the topic summarizes the the problem: ‘This is a crucial issue because the absence of good data on maternal mortality and morbidity undermines national and European capacity to monitor maternal health in Europe, and to permit comparisons between countries or surveillance of trends over time’.2 Prospective or randomized studies in pregnancy are frequently lacking, since there are ethical considerations against conducting randomized controlled studies in pregnancy. Therefore, guidelines are of greatest importance, but the database is small and recommendations in the present ESC guideline on the management of CVD in pregnancy mostly correspond to evidence level C.1 Therefore, registries are urgently needed to improve the state of knowledge.3–5 The Registry Of Pregnancy And Cardiac disease (ROPAC) of the ESC is by far the largest collection of data on pregnancy outcomes in women with heart disease in Europe and ESC-associated countries.5 , 6 From 2007 to 2018, almost 6000 pregnant women with a mean age of 29.5 years with heart disease were prospectively enrolled. It provided a number of important insights which are discussed by Roos-Hesselink et al. in this issue of the European Heart Journal.5 The authors learned about causes for maternal mortality and the very high mortality risk associated with pulmonary hypertension (9%) as well as the unexpectedly high prevalence of heart failure, which reached 11% in the registry. The most frequent risk conditions were congenital (57%) and valvular heart disease (29%). Caesarean section (44%), obstetric and foetal complications (17% and 21%, respectively) were frequent and call for better co-operation between gynaecologists and cardiologists. Pre-pregnancy heart failure or NYHA >II, systemic ejection fraction <40%, mWHO functional class 4, and anticoagulant use were the most important indicators of maternal events. The number of high-risk pregnancies (mWHO class IV) increased significantly over time, which was mainly driven by an increase in developing countries. Notwithstanding this increase, complication rates fell during the same period, suggesting that better treatment and counselling were effective. Regarding pre-pregnancy counselling, which is highly recommended in the new ESC guidelines, two issues became obvious: fewer than half of the women (43%) underwent systematic pre-pregnancy counselling; and the article clearly documents how large the impact of counselling is. Maternal mortality or heart failure during pregnancy was almost twice as high in women who had not undergone pre-conceptional counselling in comparison with those who were counselled. This is a very strong argument to build centres for pregnancy and pre-pregnancy heart teams in all ESC-associated countries that can be accessed by any woman, her family, or her doctor to be counselled on safe management (or avoidance) of pregnancy. This is just as requested in the new ESC guidelines.1 Registries such as ROPAC could test the efficiency of such management strategies at a nationwide and European level. Looking at these impressive results of the registry, it becomes evident that registries such as ROPAC or the European Surveillance of Congenital Anomalies (EUROCAT) network fill gaps in knowledge and will provide data for future guidelines.3 , 5 They can serve as a benchmark for advice to and management of pregnant women with heart disease world wide. At the European level, the ROPAC of the ESC is providing data not only on epidemiology and management, but also on drug exposure in pregnancy. Ideally, they should be even more complete. We could imagine that if participation in ROPAC was mandatory for all hospitals treating women with CVD in pregnancy, ROPAC would include comprehensive data on medications and long-term follow-up. Naturally, adequate reimbursement for provision of such data would be needed. A wealth of data would result, leading to better solutions in treatment and care. Knowledge of drug treatment in pregnancy is so scarce since industry often avoids comments on the use of drugs and medical products during pregnancy, just declaring that no experiences exist. However, providers of drugs and devices that could be used in pregnant women should be responsible to a greater degree—they could contribute to such registries to provide some data on their products. A number of open questions, of which only a few examples are listed here, have been assembled in the ESC guidelines.1 They could be answered by larger registries that include medications in a more systematic manner. (i) The impact of fertility treatment on pregnancy complications and maternal outcomes that remains currently unknown, could be tested. (ii) In women with mechanical valve prostheses, more comprehensive data could be generated on different anticoagulation regimens. There are unresolved questions concerning low molecular weight heparin, including optimal anti-Xa levels, the importance of peak vs. pre-dose levels, the best time intervals for anti-Xa monitoring, and the duration of use (first trimester or throughout pregnancy).1 (iii) In women with coronary artery disease, the required delay of a subsequent pregnancy following myocardial infarcion is unknown. Furthermore, optimal management and follow-up of patients with coronary artery dissections in pregnancy is an important clinical problem. This includes decisions for interventional therapy as well as counselling on the recurrence risk for repeated pregnancies. (iv) For acute heart failure in the context of pregnancy, there are almost no evidence-based treatments. More research is clearly needed. A registry for PPCM already exists and could be harmonized with a larger CVD in pregnancy registry, focusing on the potential for recovery and the risks of subsequent pregnancies.7 (v) In hypertension, it is still unclear whether mild to moderate hypertension in pregnancy should be pharmacologically treated. (vi) Data based on prospective randomized clinical trials in pregnant women to assess drug efficacy and safety are very limited. Burning questions are related, for example, to antiplatelet agents used after percutaneous coronary intervention in pregnancy or antiarrhythmic drugs and interventions, or the use of bromocriptine in heart failure. Answers will stay limited in some areas due to accepted ethical limitations. However, greater efforts can be made to answer open questions on treatment by prospective registries. Whereas there is considerable progress in short-term management of pregnancy complications, the long-term consequences of complicated pregnancies are presently largely underestimated. We know that women and men differ in the pathophysiology and presentation of CVD, and may need different treatment.8–10 We also know that the health of fathers is affected by pregnancies, but we do not have good hypotheses as to how this happens. We know that the health of the mother is associated with her hormonal state and gynaecological history, including pregnancy, but the mechanistic understanding is limited.11 We presently know that women affected by eclampsia or pre-eclampsia as well as women with gestational diabetes carry a major risk of developing diabetes or CVD later in life (Figure 1).12 This can happen tens of years after pregnancy, after the menopause. Therefore, systematic control later in life of women with pregnancy complications is required. However, most national health survey programmes presently do not offer systematic control to these women after the menopause. In addition, the mechanisms whereby this may happen are largely unknown. Some metabolites involved in short-term changes have been recently identified, but studies on the long-term mechanisms are lacking. We assume that they may be due to epigenetic changes induced during pregnancy, but proof is needed.13 Therefore, structured basic research programmes and specific studies in these areas are mandatory. During pregnancy epigenetic modifications may arise in the mother that lead to long term changes in her cardiovascular system and to CVD post menopause. Environmental conditions may induce fetal programming and affect development of CV and metabolic disease in the child and later adult. Probably equally importantly, pregnancy leads to long-lasting changes that will determine the development of diseases in the child (Figure 1). The effects of hunger as well as of psychological stress of the mother during pregnancy on the unborn have now been documented in large studies. Only a few mechanisms that determine foetal programming have been clarified. The effects of psychological stress on cortisol metabolism have been shown and connected to specific DNA methylation patterns.14 Epigenetic changes in metabolic genes and their effects on CVD in later life have been identified in the Rotterdam heart study and similar studies.15 Similar effects of overnutrition or malnutrition are suspected but need to be carefully investigated. Effects of air pollution during pregnancy on CVD development in the unborn also need to be studied. Stress of the unborn can also be caused by underperfusion, by malfunction of the placenta, and by reduced oxygen supply, and we may reasonably assume that this may play a role if the mother is affected by CVD, by hypertension, or by diabetes. Whether this leads to epigenetic changes that play a role later in life needs further investigation. Calls that specifically address these topics as well as prospectively set and well planned registries offer the possibility to approach these questions. The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.