Cardiovascular adverse events in pregnancy: A global perspective

Pregnant women with heart disease are vulnerable to many adverse cardiovascular events (AE). AEs during and after pregnancy continue to be important causes of maternal mortality and morbidity worldwide, with huge variations in burden in different countries and regions. These AEs are classified as having direct or indirect causes, depending on whether they are directly caused by pregnancy or due to some pre-existing disease and/or non-obstetric cause, respectively. The risks continue throughout pregnancy and even after childbirth. Apart from immediate complications during pregnancy, there is increasing evidence of a significant link between several events and the risk of cardiovascular disease (CVD) later in life. A significant number of pregnancy-related deaths caused by cardiovascular disease are preventable. This prevention can be realized through increasing awareness of cardiovascular AE in pregnancy, coupled with the application of strategies for prevention and treatment. Knowledge of the risks associated with CVD and pregnancy is of extreme importance in that regard. We discuss the global distribution of cardiovascular maternal mortality, adverse events during and after pregnancy, their predictors and risk stratification. In addition, we enumerate possible solutions, particularly the role of cardio-obstetric clinics.


INTRODUCTION
Pregnant women with heart disease have pronounced vulnerability to adverse cardiovascular events. Diagnosis and treatment of heart disease in pregnancy is difficult due to similarities between disease manifestations and normal physiological changes.
Cardiovascular adverse events (AEs), during and after pregnancy continue to be important causes of maternal mortality and morbidity worldwide, with huge variations in burden in different countries and regions. 1,2 These AEs are classified as having direct or indirect causes, depending on whether they are directly caused by pregnancy or due to some pre-existing disease and/or non-obstetric cause, respectively. [3][4][5] Cardiovascular disease is the single largest cause of indirect maternal mortality, 3,6 accounting for over 33% of pregnancy-related maternal deaths. [6][7][8][9][10][11] Additionally, maternal heart disease complicates up to 4% of pregnancies [12][13][14] and up to 16% of pregnancies in women with previous cardiac conditions, 13 with risk depending on the underlying cardiac condition. 13,[15][16][17] Over 50% of maternal deaths occur post-partum. 18 Late maternal mortality is defined as death more than 42 days (and up to one year) after child birth. 19 Importantly, the currently cited figures almost certainly constitute an underestimate. 19 It is estimated that up to 68% pregnancy-related deaths caused by cardiovascular conditions are preventable. 6,20 This can be achieved, through increasing awareness, coupled with applying strategies for prevention and treatment. Knowledge of the risks associated with CVD and pregnancy is of extreme importance in that regard.
We discuss the global distribution of cardiovascular maternal mortality, the adverse events during and after pregnancy, their predictors and risk stratification. In addition, we enumerate possible solutions, particularly the role of cardio-obstetric clinics.

Incidence and global distribution of maternal mortality
According to the World Health Organization (WHO) 21 and Global Burden of Disease (GBD), 1,2 in 2017 there were up to 295,000 maternal deaths globally, leading to an estimated global maternal mortality rate (MMR) of 211 per 100,000 live births.
In 2017, every day approximately 810 women died from preventable causes related to pregnancy and childbirth, with 94% of all maternal deaths occurring in low and middleincome countries (LMIC's). 22 Sub-Saharan Africa alone accounted for roughly two-thirds of the estimated global maternal deaths. 21 In Egypt the number of maternal deaths was 1,316 in 2017 with a MMR of 62 per 100,000 livebirths. 8,23 The regional distribution and pattern of maternal death reported by the GBD varies considerably around the world. [23][24][25] ( Figure 1).

Causes of maternal mortality and burden of disease
Up to 1990, direct causes accounted for over two-thirds of maternal mortality worldwide. There has been a significant decrease in overall maternal mortality over the years due to progressive drops in direct causes, however, the contribution of indirect and late maternal deaths, as well as maternal hypertensive disorders, has remained unchanged ( Figure 2). 1,2

Regional and national variation in incidence and causes of maternal mortality
According to the GBD, maternal mortality rate (MMR) varied from 1 to 496 per 100,000 live births (Figure 3) in 2017. 1,2 The alarmingly high incidence in MMR in some countries continues, with very few exceptions.
The regional incidence and cause of maternal mortality varies considerably from one country to another (Table 1). In addition, the representation of maternal hypertensive disorders, indirect maternal deaths as well as the reported late maternal mortality also differs across countries.

Details of adverse cardiovascular events Direct maternal adverse cardiovascular events
Hypertensive disorders of pregnancy. Chronic hypertension, gestational hypertension and preeclampsia 26 are important causes of maternal and perinatal morbidity and mortality, 9,[27][28][29][30][31] particularly toward the end of pregnancy ( Figure 4). Novel diagnostic methods and therapies have recently been reviewed. 32 Gestational hypertension is defined as new-onset hypertension arising after 20 weeks of gestation 33,34 and occurs in 10% of women. 35 It is associated with acute and chronic cardiovascular changes leading to an increased risk for hypertension throughout life, 36,37 and a 4-fold increased risk of future maternal cardiovascular events. [37][38][39][40] Indirect maternal adverse cardiovascular events Cardiovascular disease is the single largest cause of indirect maternal mortality. 3,6 Patients who experience complications during pregnancy may also be at higher risk of cardiac events later in life. 44

Arrythmias
The altered cardiac anatomy during pregnancy can elicit new onset arrhythmia or prompt the recurrence of preexisting arrhythmias. 45,46 An increased incidence of cardiac arrhythmias has been reported during pregnancy 47 in patients with and without identifiable heart disease. Arrhythmias are responsible for complications in 67 per 100,000 pregnancies, 49 mainly in the form of atrial fibrillation (27 per 100,000 pregnancies) and supraventricular tachycardia (22 per 100,000 pregnancies). [48][49][50] Heart failure Heart failure (HF) remains the most common complication during pregnancy among all women with heart disease, regardless of the cardiac pathology. 42,51 Heart failure can occur during, or immediately after pregnancy ( Figure 5). Despite the poor prognosis associated with the diagnosis of HF during pregnancy, and the fact that prevalence of HF among pregnant women has increased over the years -particularly in the post-partum period, 52 data in the literature are scarce.
The incidence of PPCM varies markedly from 1-100 per 10,000 live births depending on the region. 59,61-63 PPCM has the highest mortality rate in pregnancy, with a worldwide mortality of 2.4%, 57 although it may be underdiagnosed. PPCM leads to substantial maternal and neonatal morbidity and mortality, with less than half of all cases recovering   full cardiac function 58,64-67 (Figure 7). Six-month mortality is around 6%, mainly due to heart failure. 58 Neonatal death is around 5%, although with marked regional variation. 63 Management follows the guidelines of HF. In non-responsive patients, other pharmacological agents -such as bromocriptine and prolactin-blocking therapy with dopamine D2 receptor agonists -have been tried with variable results. 68 Contributing factors to PPCM include genetic predisposition 69 as well as auto-immune responses. [70][71][72] Using such factors, all be it indirectly, to define phenoclusters 73 -it could be possible to identify novel therapeutic targets to guide personalized medicine in PPCM.
For a small proportion of patients with rapidly-progressive PPCM resistant to conventional therapy, the use of the current generation of left ventricular assist devices can give long-lasting ''cures'' in some patients (personal experience in Harefield and Aswan series). 74,75 Registries on the condition will provide fundamental data on predisposing factors, potential aetiologia and regional variations. 57,63,76,77 Mechanical valve thrombosis Even with the right care, the incidence of thromboembolism during pregnancy is estimated from 7-23% with half of these cases being mechanical valve thrombosis (MVT), 78 which is associated with 20% mortality. 79 Thrombosis is the most life-threatening complication for women with prosthetic heart valve, during pregnancy. 78,80 The chance of a successful uncomplicated pregnancy, which depends on the balance between the thrombotic and bleeding risks, is around 57%.

Acute coronary syndromes
The incidence of coronary artery disease (CAD) in women of childbearing age is unclear and varies between countries. 81,82 CAD, is a major cause of maternal death and accounts for over 20% of maternal cardiac deaths, 83 especially in the form of acute coronary syndromes (ACSs). 84 The estimated incidence of 6.2 per 100,000 deliveries 85-88 nearly 4 times higher than in non-pregnant women 89 and reflects the growing prevalence of cardiovascular risk factors in the pregnant population. 90

Risk stratification
Several tools have been developed to estimate morbidity and mortality risk in pregnant women with cardiac disease, such as CARPREG 13 and ZAHARA. 12 However, the best estimate of the risk of cardiovascular events during pregnancy in pre-existing heart disease is the WHO's 91 (Figure 8), as it integrates congenital and acquired heart disease. The risk of cardiac adverse events during pregnancy are significantly increased in mWHO IV compared to mWHO I (Figure 9).
Based on the modified WHO risk classification for milder conditions, where the risk of pregnancy is very low to moderate, the needed care might be limited to a few visits during pregnancy, while in case of high risk of complications, a more frequent followup schedule is recommended. Women in the highest risk group (WHO IV) should be advised against pregnancy. In case of pregnancy, strict monitoring is required. 92 More comparative studies should be performed in order to define the most accurate risk index for pregnant women with heart disease. 91,95 The role of comprehensive cardio-obstetric clinics The concept of multidisciplinary cardio-obstetric clinics ( Figure 10) has evolved and been applied in several countries, with extremely encouraging results [96][97][98][99][100][101][102][103][104][105][106][107][108][109][110][111][112][113][114] and excellent survival rates of mothers even with complex diseases, and their offspring. 24 However, the need for cardio-obstetric clinics remains un-met, with most programs to be found in developed countries and with only a few centers continuing follow-up long term. 24,101,102 Although these initiatives might be feasible in large metropolitan areas, smaller towns, rural communities and remote regions are completely neglected. There is an urgent need for action and worldwide implementation of cardio-obstetric clinics, strategically placed, in order to reach the majority of those in need.
Integrated, tailored and dynamic healthcare services responding to current state of disease burden and initiatives are essential. Cardio-obstetric care clinics (COcare) have been initiated in the metropolitan Aswan Heart Center as well as its rural branch in Ballana. 116

CONCLUSIONS
Preventable maternal cardiovascular adverse events continue to be a global problem with an unacceptably high burden of disease. This requires urgent concerted efforts