Best Practice & Research Clinical Obstetrics and Gynaecology 29 (2015) 579e597

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Heart disease in pregnancy Dr Y. Emmanuel, MBChB, MRCP, DPhil, Dr S.A. Thorne, MD, MRCP * Adult Congenital Heart Disease Unit, Department of Cardiology, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK

Keywords: pregnancy heart disease

Cardiac disease is the leading cause of maternal mortality in the developed world. The majority of women with heart disease are able to successfully undergo pregnancy. However, in women with severely impaired ventricular function, severe left heart obstruction, pulmonary hypertension and aortopathy, such as Marfan syndrome, with significant aortic dilatation, pregnancy is associated with a significant risk, and these women should be counselled against pregnancy if there is no option for treatment that reduces risk. Although there are increasing numbers of women with congenital heart disease who are considering pregnancy, as a result of joint expert specialist cardiac and obstetric care, maternal mortality is low. Most of the observed mortality occurs in women with structurally normal hearts who were not known to have heart disease before their pregnancy. It is therefore important that those caring for pregnant women are aware of the risk factors for and presentation of cardiac conditions in pregnancy. We review the presentation and management of both congenital and acquired heart diseases in pregnancy. © 2015 Elsevier Ltd. All rights reserved.

Introduction In the developed world, good antenatal and obstetric care has greatly reduced maternal mortality due to obstetric causes, and cardiac disease has now emerged as the leading cause of maternal mortality [1,2] (Fig. 1). Of concern, the most recent ‘Saving Mothers’ Lives' report covering maternal * Corresponding author. Adult Congenital Heart Disease Unit, Department of Cardiology, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK. Tel.: þ44 121 371 4495; Fax: þ44 121 371 4496. E-mail addresses: [email protected] (Y. Emmanuel), [email protected] (S.A. Thorne). 1521-6934/© 2015 Elsevier Ltd. All rights reserved.


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Fig. 1. Causes of maternal mortality.

mortality in the UK shows that whilst overall maternal mortality in the UK is low and continues to fall, deaths due to cardiac disease have risen [1,2]. The most recent UK maternal mortality review for which details of cardiac deaths are available is for 2006e2008 [1]. The majority of deaths occurred in women with structurally normal hearts, many of whom were not known to have heart disease prior to pregnancy: their disease was revealed or precipitated by the hormonal and haemodynamic changes associated with pregnancy. Importantly, care was deemed to be substandard in >50% of the cardiac deaths, and in half of these cases better care may have resulted in a different outcome. The increase in cardiac mortality found between 2006 and 2008 is likely to be a reflection of the changing demographics of the overall obstetric population with increasing maternal age, obesity and smoking. All the women who died from ischaemic heart disease had at least one identifiable risk factor. The detailed review of the cases in the report identified the importance of having a low threshold for investigation and cardiological review of women who present with possible cardiac symptoms during pregnancy or the post-partum period; therefore, investigations should not be withheld because of pregnancy. Although the numbers of patients with congenital heart disease surviving into their childbearing years are continuing to increase, and many have complex conditions, the maternal mortality in these patients continues to fall, and it accounted for only three out of the 53 cardiac deaths over the report period 2006e2008. Patients with congenital heart disease are generally under regular cardiology follow-up, and the low mortality is a testament to good pre-pregnancy counselling and the importance of the multidisciplinary team in providing joint cardiac obstetric care. Haemodynamic and hormonal changes in pregnancy The increased haemodynamic demands of pregnancy are significant, and they start early: cardiac output rises by 50% by the middle of the second trimester, and it must be maintained throughout the rest of the pregnancy (Fig. 2) [3]. Any condition that limits the ability to increase cardiac output will result in pregnancy being poorly tolerated. During labour, cardiac output increases further due to increased heart rate from pain and anxiety, and uterine contractions returning blood to the venous system. Blood pressure and oxygen requirements also rise during contractions. Following delivery, uterine and placental auto-transfusion and release of caval compression result in a significant increase in the venous return. The changes associated with pregnancy can take several weeks to return to

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Fig. 2. Haemodynamic changes associated with pregnancy.

normal. Patients with impaired ventricular function therefore remain at risk for several weeks after delivery, and many cases of pregnancy-associated cardiomyopathy are not revealed until several weeks later. In addition to the circulatory changes, a variety of hormonal changes to facilitate tissue relaxation also occur. These changes may also contribute to the observed increased risk of aortic and coronary artery dissection during pregnancy and the post-partum period. Preconception counselling and risk assessment Patients with heart disease should be offered specialist joint cardiac and obstetric preconception assessment and counselling. This assessment should address both the maternal and foetal risks (Tables 1 and 2). Different scoring systems have been developed to assess the risk of adverse maternal outcomes during pregnancy. The factors consistently predictive of morbidity are pre-pregnancy poor ventricular function, arrhythmia or cardiac event, poor functional class (New York Heart Association (NYHA) class II or more) and left heart obstruction. Further, these risks are additive, as reflected in the Cardiac Disease in Pregnancy (CARPREG) scoring system [4] (Table 3). The ZAHARA investigators reviewed this in patients with congenital heart disease, and they identified additional predictors [5] (Table 3).

Table 1 Maternal risk factors. Maternal risk factors Impaired ventricular function Aortopathy Previous arrhythmia Mechanical valve Pulmonary arterial hypertension Myocardial ischaemia Severe left heart obstruction


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Table 2 Foetal risks. Foetal risks Miscarriage/stillbirth Maternal cardiovascular state leading to placental hypoperfusion and/or cyanosis leading to foetal growth restriction and prematurity Teratogenicity The risk of bleeding due to maternal anticoagulation Inheritance risk Maternal cyanosis

Maternal risk may also be classified by lesions [6] (Table 4). Severe systemic ventricular impairment, previous peripartum cardiomyopathy with residual ventricular impairment, severe left heart obstruction, pulmonary arterial hypertension (PAH) of any cause and Marfan syndrome or other aortopathy with aorta >40 mm are associated with a significant risk of mortality, and women with these conditions should be advised that pregnancy would be associated with a high risk of morbidity and mortality. Any treatment to reduce pregnancy risk should be considered, and effective contraception should also be discussed as well as alternatives to pregnancy. Further evaluation to determine the haemodynamic significance of valvular lesions and ventricular function may be required, and cardiopulmonary exercise testing, exercise echocardiography, specialised cardiac imaging and cardiac catheterisation should be considered. Haemodynamically significant valve lesions may require intervention prior to pregnancy. Exercise echocardiography can refine risk stratification for some women with significant disease who wish to conceive, for example, the asymptomatic woman with severe aortic stenosis (valve area 1 cm2) and good ventricular function. Such a patient is likely to tolerate pregnancy well if she has a normal exercise capacity, normal blood pressure response to exercise, no exertional electrocardiographic (ECG) changes, the increase in Doppler-derived aortic valve gradient at peak exercise is 40 mm should be considered for prophylactic surgery, and care should be discussed with an aortic multidisciplinary team. It is important to remember that prophylactic aortic root replacement does not eliminate the risk of dissection in the descending aorta.

Table 3 Scoring systems of risk factors for poorer outcome of pregnancy. Predictors from CARPREG study

Predictors from ZAHARA studies

Systemic ventricular impairment (EF 50 mm Hg) Mechanical valve prosthesis Moderate/severe atrioventricular valve regurgitation (due to associated ventricular dysfunction) Unrepaired cyanotic heart disease Use of cardiac medication prior to pregnancy

Adapted from Siu et al. [4]. Score derived by assigning a point to the presence of each feature. Risk of maternal adverse event according to score: 0 ¼ 5%, 1 ¼ 27%, >1 ¼ 75%.

Class I (No detectable increase in maternal mortality and no or mild increase in morbidity)

Classes IIeIII Class II (Small increase in maternal mortality and moderate increase in morbidity)

Uncomplicated small or mild: Unoperated ASD Repaired tetralogy of Fallot  Pulmonary stenosis  VSD Most arrhythmias  PDA  Mitral valve prolapse

Successfully repaired simple lesions, e.g., Secundum ASD, VSD, PDA, Total anomalous pulmonary venous drainage

Class IV Class III (Extremely high risk of maternal (Significantly increased risk of maternal mortality or mortality or severe morbidity) severe morbidity)

Mild left ventricular impairment Hypertrophic cardiomyopathy

Mechanical valve Systemic right ventricle

Native or tissue valve disease not considered class IV Marfan syndrome (or other aortopathy, e.g., EDS type IV, LDS or FTAA) without aortic dilatation Repaired coarctation Heart transplantation

 CCTGA  TGA with Mustard or Senning repair Post-Fontan repair Cyanotic heart disease Other complex congenital heart disease Marfan syndrome with aorta 40e45 mm

Adapted from Thorne et al. [6]. LVEF, Left ventricular ejection fraction; NYHA, New York Heart Association class.

Pulmonary hypertension of any cause Severe systemic ventricular impairment e LVEF 45 mm

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Table 4 Classification of maternal risk by lesion.



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Many drugs have potential teratogenic effects, and therefore medication should also be reviewed prior to pregnancy (Table 5).

Table 5 Risks associated with cardiovascular drugs. Type of drug


Antiplatelet agents Aspirin (low dose) Aspirin (high dose) Clopidogrel Anticoagulants Warfarin Heparins Anti-arrhythmics

Beta blockers

Calcium channel blockers Flecainide and Propafenone Adenosine Amiodarone Atenolol



All others Furosemide Bumetanide Thiazides


Lipid-lowering agents

FDA class

Breast feeding

N but considered safe Considered D B X (except for mechanical valves, considered category D in this setting) C but human reports show no adverse effects C

Small amounts excreted


B (All have a risk of causing intrauterine growth restriction) C C C

Amiloride Spironolactone ACEI/ARB

Bendrofluazide C Hydrochlorothiazide D B C D

Hydralazine Nitrates Statins


No data Considered safe Considered safe Small amounts excreted, consider risks versus benefits, monitor for neonatal bradycardia As above Safe, short half-life Excreted in breast milk, not advised Small amounts excreted, consider risks versus benefits, monitor for neonatal bradycardia

Excreted but no adverse effects seen Excreted but adverse effects not expected As above

Excreted in breast milk, use with caution Captopril/Enalapril not associated with adverse effects Excreted but no adverse effects seen As above Not advised

FDA ¼ Food and Drug Administration. Category A ¼ No evidence of foetal harm during first trimester. Category B ¼ Animal studies show no foetal risk, no well-controlled human studies. Category C ¼ Adverse effects in animal studies, no well-controlled human studies. Category D ¼ Evidence in humans of adverse effects, consider risks versus maternal benefits. Category X ¼ Significant human adverse effects, use not advised. Category N ¼ Not classified. Adapted from FDA website.

Ventricular dysfunction Pregnancy places a prolonged stress on the cardiovascular system, and heart failure is an important cause of morbidity as well as mortality. With improvements in medical care, increasing numbers of women with impaired ventricular function are well enough to consider pregnancy. Ventricular impairment may be due to congenital heart disease, previous chemotherapy, cardiomyopathy or ischaemic heart disease. However, ventricular impairment often presents for the first time during pregnancy or the post-partum period because pregnancy either unmasks previously undiagnosed heart disease or precipitates peripartum cardiomyopathy. Breathlessness and mild peripheral oedema are common during pregnancy, but marked symptoms or signs should raise the suspicion of heart failure (Table 6), particularly in women with risk factors such as hypertension, obesity, diabetes,

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Table 6 Cardiovascular clinical examination signs in pregnancy. Normal symptoms and signs

Abnormal symptoms and signs

Breathlessness on exertion Palpitations due to atrial and ventricular ectopics Mild peripheral oedema Heart rate rise by 10e20 bpm Jugular venous pressure visible by up to þ2 cm Third heart sound Soft systolic murmur

Extreme breathlessness Marked peripheral oedema Pleural effusion Persistent tachycardia >100 bpm Jugular venous pressure >2 cm Fourth heart sound Diastolic murmur

advanced maternal age, multiparity, smoking, previous chemotherapy or human immunodeficiency virus (HIV) infection. The risk of major morbidity and mortality rises with the severity of ventricular dysfunction, and there is an unpredictable risk of a permanent deterioration in ventricular function. Thus, women with pre-existing moderate or severely impaired systemic ventricular function with an inability to increase cardiac output on stress testing should be advised that pregnancy is associated with a high risk of morbidity and mortality. If ventricular impairment is milder, then the main risk is of progressive permanent decline in function. Although treatment of heart failure should follow the same principles as in the non-pregnant state, drug therapy has to be modified. Cardioselective beta blockers (bisoprolol and metoprolol) can be used with appropriate monitoring of foetal growth. Hydralazine and oral nitrates may be used as vasodilator agents instead of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB). The latter are not recommended because of foetal toxicity, but they may be used in individual cases following specialist advice if the maternal benefits are considered to outweigh the foetal risks. Similarly, loop diuretics should be used instead of aldosterone antagonists unless the maternal benefits of spironolactone outweigh the foetal risk. Admission for bed rest and intravenous diuretics and anticoagulation should be considered if there is an evidence of overt heart failure and early delivery planned. Mechanical and inotropic support as a bridge to transplantation may be required. Peripartum cardiomyopathy Peripartum cardiomyopathy develops during the last trimester or the first 5 months post partum. The precise aetiology remains unclear, but pre-eclampsia, multiparity and advanced maternal age are consistently identified as risk factors [8]. Autoimmune processes and oxidative-stress-mediated cleavage of prolactin have been purported as possible underlying causes, and immunoglobulins and bromocriptine have been used as treatment, but their efficacy has not yet been established. Therefore, at present, medical therapy is the same as for other causes of heart failure. These patients also frequently develop intracardiac mural thrombus, which may embolise and so should be anticoagulated. Ventricular function may decline rapidly, and mortality is 15e30% [9]. If ventricular function remains impaired, a subsequent pregnancy carries a 44% risk of recurrence and a 19% risk of mortality [10]. Even if ventricular function recovers fully, a further pregnancy is associated with a 20% risk of recurrence. Hypertrophic cardiomyopathy If systolic ventricular function is preserved, pregnancy is generally well tolerated as the vasodilatory effects of pregnancy are beneficial in patients without significant left ventricular outflow obstruction [11]. However, atrial arrhythmias may occur as a result of increased atrial stretch and should be treated promptly as they are not well tolerated because of diastolic dysfunction. The incidence of ventricular arrhythmias and sudden cardiac death is not increased by pregnancy. Patients with significant outflow tract obstruction, a history of ventricular arrhythmias and severe hypertrophy are at an increased risk of


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decompensation. Beta blockers may be used to reduce outflow tract obstruction and in the management of arrhythmias. Patients with implantable defibrillators may undergo pregnancy provided that the ventricular arrhythmias are adequately controlled. The highest risk period is around the time of delivery and the first 48 h post partum as the rapid fluid shifts may precipitate heart failure and arrhythmias. Conditions that present with chest pain There should be a low threshold for early cardiology referral of pregnant patients with chest pain e the failure to do so has contributed significantly to cardiac death being the most common cause of maternal mortality. Aortopathies Aortic dissection is an important cause of maternal mortality [1]. The highest risk is during the last trimester and the early post-partum period. Care in five of the seven women who died in the most recent UK review was substandard due to inadequate investigation of chest pain. Whilst clinicians are likely to have a higher index of suspicion in patients with known aortopathy, only three of the women who died were known to have an aortopathy. Therefore, aortic dissection should be considered in any woman who presents with severe chest pain. Aortopathy may be due to inherited or connective tissue disorders such as Marfan syndrome, LoeyseDietz syndrome (LDS), EhlerseDanlos type IV or familial thoracic aortic aneurysm. These conditions often have an autosomal dominant inheritance pattern, and any woman with a family history of aortopathy or deaths during pregnancy or the post-partum period, or other features suggestive of a connective tissue disorder should be evaluated for aortopathy and offered specialist genetic assessment and preconception counselling. Aortic dilatation due to cystic medial necrosis also occurs in association with congenital heart disease notably coarctation of the aorta, bicuspid aortic valve and Turner syndrome. Marfan syndrome The risk of dissection increases with increasing aortic size; however, even patients with a normalsize aorta 40 mm may be associated with up to a 10% risk of dissection [13]. Elective pre-pregnancy prophylactic aortic surgery is recommended when the ascending aorta is >45 mm [14]. Surgery should also be considered for aortas between 40 and 45 mm if there is a family history of dissection or evidence of progressive dilatation. Beta blockers should be considered to limit the heart rate, prevent hypertension and reduce the shear stress on the aorta. A mid-trimester non-contrast magnetic resonance imaging (MRI) of the aorta is helpful to look for evidence of dilatation during pregnancy. Patients with a normalsize aorta may have a normal vaginal delivery. Patients with moderate aortic dilatation between 40 and 45 mm may have a vaginal delivery with a shortened second stage of labour. The recent guidelines suggest elective caesarean section delivery for patients with an ascending aorta >45 mm [14]: however, assisted vaginal delivery with good regional anaesthesia and forceps lift-out to avoid maternal strain is acceptable. Some patients have dural ectasia that may make epidural or spinal anaesthesia difficult or impossible. Apart from the risks of aortic dissection, there is an increased risk of uterine rupture. LoeyseDietz syndrome LDS was first reported in 2005, and it is associated with mutations in the transforming growth factor beta receptor genes (TGFRß) [15]. The vascular features include arterial tortuosity, aortic root and peripheral arterial aneurysms. The aortopathy is more aggressive than in Marfan syndrome, and recent guidelines have advocated a lower threshold of 40 mm for prophylactic aortic root replacement in patients with LDS [16]. There is also an increased risk of uterine rupture. EhlerseDanlos syndrome Type IV EhlerseDanlos syndrome is associated with aortic involvement as well as bleeding and poor wound healing. Due to the tissue fragility, patients are at a risk of aortic dissection even with a normalsize aorta. The risks of surgery are greater than for other forms of connective tissue disease, and

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therefore prophylactic aortic root replacement is not indicated. Pregnancy is associated with an increased risk of aortic dissection as well as uterine rupture, and therefore pregnancy is not advised in these patients [14]. Bicuspid aortic valve associated aortopathy Ascending aortic dilatation occurs in association with a bicuspid aortic valve. Although there is a risk of dissection, advanced aortopathy is uncommon in women of childbearing age. Pre-pregnancy root replacement should be considered when the aorta is >50 mm or >45 mm if concomitant aortic valve surgery is required. As with other forms of aortopathy, elective caesarean section delivery should be considered in patients with ascending aorta >45 mm. Turner's syndrome Pregnancy is possible in women with mosaic Turner syndrome or following assisted reproduction techniques. Patients with Turner syndrome have an increased incidence of bicuspid aortic valve and coarctation and the associated aortopathy. As women with Turner syndrome are of short stature, the aortic size should be indexed to the body surface area. Patients with aortic dilatation >25 mm/m2 have been found to have a 33% risk of aortic dissection in the absence of pregnancy [17], and they should be considered for prophylactic aortic root replacement. Coarctation of the aorta Normotensive patients with repaired coarctation and no aneurysm or residual coarctation tolerate pregnancy well, and they are at a low risk of dissection. MRI scan of the aorta should be performed as part of pre-pregnancy assessment [18,19]. Coarctation may not be detected until adulthood e sometimes during pregnancy; the diagnosis should be considered in any young hypertensive adult. Confirmation in the pregnant patient is with echo and MRI. Antenatal and delivery management needs to be individualised, and care should be in a centre with a specialist obstetric and congenital cardiology expertise. Coronary artery disease Coronary artery disease is an important cause of mortality accounting for up to 20% of maternal cardiac deaths in the most recent UK data [1]. Morbidity is more difficult to measure with data from the UK Obstetric Surveillance System (OSS) study reporting an incidence of 0.7 per 100,000 pregnancies, but this may be an underestimate as data are only collected up to 1 week post partum [20]. Older studies using a review of discharge coding data reported an incidence of 6.2 acute myocardial infarctions during pregnancy per 100,000 pregnancies [21]. In the UK data, all of the women who died had at least one risk factor for coronary artery disease. Spontaneous coronary artery dissection is also more common during the latter stages of pregnancy and post-partum period than in non-pregnant women. Patients who are known to have coronary artery disease prior to pregnancy should undergo complete cardiology review and risk stratification, and if there is inducible ischaemia, this should preferably be treated prior to pregnancy. ST elevation myocardial infarction Patients presenting with ST elevation myocardial infarction (STEMI) should be treated the same as the non-pregnant population, and they should undergo urgent coronary angiography ± primary percutaneous coronary intervention (PPCI). Angiography is particularly important in this population given the increased incidence of spontaneous coronary dissection. If coronary stenting is required, bare metal stents are preferred in order to minimise the requirement for long-term dual antiplatelet therapy [14]. Access should be performed via the radial route whenever possible with appropriate lead shielding and pelvic tilt. Aspirin and clopidogrel appear to be safe in pregnancy apart from an increased risk of haemorrhage around the time of delivery. There are no data in pregnancy on the safety of the commonly used peri-procedural anticoagulants such as glycoprotein IIb/IIIa inhibitors and bivalirudin, and their use is not recommended during pregnancy. Intravenous heparin should be used instead. Following the treatment of STEMI with a bare metal stent, dual antiplatelet therapy


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(aspirin and clopidogrel) should be continued for at least 6 weeks, followed by long-term single antiplatelet treatment, which may be with aspirin to reduce the risk of haemorrhage at the time of delivery. If a drug-eluting stent is used, dual antiplatelet therapy should be continued for a minimum of 1 year to reduce the risk of acute stent thrombosis. However, there are data to suggest that for the newer generation of drug-eluting stents, the duration of dual antiplatelet therapy may be reduced to 3 months on an individualised basis [22]. If PPCI is not possible, then maternal health should take precedence and thrombolysis may be appropriate, accepting the consequent bleeding risks. Non-ST elevation myocardial infarction Care was deemed to be substandard due to failure to investigate chest pain and inadequate evaluation for ischaemia in 46% of women who died from ischaemic heart disease in the latest available UK mortality data [1]. The symptoms of ischaemia, such as epigastric discomfort, palpitation and breathlessness, may be attributed to pregnancy. There may also be a reluctance to investigate for ischaemia because of concerns about radiation exposure. However, simple tests including serial ECGs and serial serum Troponin (results are unaffected by pregnancy) are safe and easy to perform, and they should be done in all pregnant women presenting with possible ischaemic symptoms. Urgent cardiological review is mandatory if chest pain is suspicious of angina, if there are ECG changes or if troponin is elevated. There is no firm evidence to guide the management of non-ST elevation myocardial infarction (NSTEMI) during pregnancy; however, consensus agreement in the most recent European guidelines recommends that patients with high-risk features such as ongoing pain and adverse ECG features should undergo invasive angiography and stenting if required [14]. Medical therapy Low-dose aspirin and beta blockers are considered relatively safe. Limited data from case reports show that clopidogrel, a second-generation thienopyridine, is not associated with significant foetal risk [23]. If dual antiplatelet is required after coronary artery stenting, then clopidogrel with aspirin should be used for the shortest duration possible, and then aspirin should be continued alone. To date, there is only one case report on the use of the third-generation thienopyridine Prasugrel [24] and no data on Ticagrelor in pregnancy. ACEI inhibitors and statins have been associated with foetal toxicity [25], and they are not recommended during pregnancy. However, more recent reviews suggest that the risk associated with statins may be overestimated [26,27]. Valvular disease Native valvular disease Valvular disease may present for the first time during pregnancy. Stenotic lesions that limit the ability to increase cardiac output may not be well tolerated during pregnancy and delivery. Regurgitant lesions are generally better tolerated. Women with severe valve disease and who wish to consider pregnancy require careful multidisciplinary discussion and counselling. If valve repair is not possible and replacement is required, then several factors need to be considered when making an individualised decision between a tissue and mechanical prosthesis. Mechanical valves have longer durability, but they require full anticoagulation. Whilst tissue valves do not require anticoagulation, the lifespan of the prosthesis is limited, and women of childbearing age will usually require redo surgery. It is not clear whether pregnancy may accelerate degeneration of the valve, and therefore younger women may require a redo valve replacement before further pregnancies. For those with previous sternotomies, the risk of inevitable further surgery if a bioprosthesis is used must be weighed against the risk of warfarin anticoagulation for a mechanical valve particularly if further pregnancies are contemplated. Further, to achieve the advantages of durability of a mechanical prosthesis, good compliance with anticoagulation is necessary, and therefore patients who are poorly compliant with anticoagulation may be safer and achieve longer durability with a tissue valve.

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Aortic stenosis Aortic stenosis in women of childbearing age is usually due to congenital bicuspid aortic valve disease, and it is often known prior to pregnancy. It may be associated with aortopathy. It may also be a part of the Shone spectrum of left-sided obstructive lesions occurring at multiple levels. Therefore, complete evaluation to look for coarctation of the aorta, aortic hypoplasia or interruption, subaortic membranes, parachute mitral valve disease and supravalvular mitral membranes should be performed with both echocardiography and MRI or computerised tomography (CT) scanning of the aorta. Patients with symptomatic severe aortic stenosis or impaired performance on exercise testing should be considered for surgery whether or not they are considering pregnancy, and they should undergo valve replacement prior to pregnancy. Severe aortic stenosis with an aortic valve area of 1 cm2 was previously thought to have been a contraindication to pregnancy and vaginal delivery, but there is now increasing evidence that asymptomatic patients can have successful vaginal delivery (Table 7). Yap et al. reported that 11 of 12 women with severe aortic stenosis had a successful planned vaginal delivery, and only one woman was delivered by elective caesarean section [28]. Symptomatic patients and those with haemodynamic decompensation or aortic dilatation >45 mm should be delivered by caesarean section. Patients with aortic stenosis should be followed up closely during pregnancy, and diuretics and bed rest may be required if decompensation occurs, as may early delivery and emergency palliative balloon aortic valvotomy or surgical aortic valve replacement. The risk of recurrence in the foetus is slightly higher at around 10% with bicuspid aortic valve than with other non-chromosomal forms of congenital heart disease. Mitral stenosis Mitral stenosis is usually rheumatic and poorly tolerated in pregnancy, and it is the leading cardiac cause of maternal mortality in the developing world [29]. Although less common in developed countries, it is still seen in the UK, more often in recent immigrants or where there is social deprivation. Many women with mitral stenosis are unaware of the condition until the haemodynamic changes of pregnancy precipitate symptoms of breathlessness or pulmonary oedema or atrial fibrillation develops usually in the mid-second trimester. Significant mitral stenosis results in left atrial dilatation and an increased risk of atrial fibrillation. As pregnancy is already a hypercoagulable state, these patients are at an increased risk of developing intracardiac thrombus, and they should be anticoagulated with therapeutic low-molecular weight heparin (LMWH). Diuretics should be used to relieve congestion, and beta blockers should be used in patients with symptoms to preserve sinus rhythm and prolong diastolic left ventricular filling. Patients with severe mitral stenosis (valve area 25 mm Hg is associated with up to 50% risk of maternal mortality in pregnancy [38]. With targeted pulmonary vasodilator therapies such as inhaled

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iloprost or intravenous prostacyclin, there has been some improvement, but mortality still remains up to 33% [39]. Death is often sudden a few days after delivery, and it occurs due to the combination of an increase in systemic vascular resistance limiting cardiac output, thrombosis of distal pulmonary vessels and the increased venous return from uterine auto-transfusion during contractions and from placental auto-transfusion and release of caval compression after delivery. Patients with PAH should be counselled about the risks associated with pregnancy, and they should be offered effective progesterone-only-based contraception because of the risk of thrombosis [6]. The oral agent Bosentan also induces liver enzymes and reduces the efficacy of hormonal contraception, and it has been associated with serious birth defects if taken during early pregnancy. DepoProvera and the Mirena coil are unaffected, but the efficacy of Cerazette and Nexplanon may be reduced. Therefore, patients taking this are advised to use two effective forms of contraception. Whilst the use of pulmonary vasodilator therapy has been associated with improved maternal outcomes, these agents all have a significant associated risk of teratogenicity, and therefore pregnancy should still be discouraged. Patients with PAH who become pregnant should be offered termination. Patients who wish to continue with pregnancy should be managed in specialist pulmonary hypertension centres by a multidisciplinary team. As the numbers of patients with successful outcomes remain small, there is little literature to conclusively determine optimal management strategies, and therefore each patient requires individual assessment and management according to local specialist experience. The general principles of management are to deliver at around 35 weeks by caesarean section with monitoring in intensive care for 2 weeks following delivery. The risk of mortality remains increased for 6 weeks after delivery. Anticoagulation All anticoagulation regimes are associated with significant maternal and foetal risks. It is therefore important that the reason for anticoagulation, the risks associated with different pharmacological regimes and the practical requirements for compliance with monitoring are discussed to allow women to make an informed choice about what balance of risks she chooses to accept. Anticoagulation may be achieved using either warfarin or heparin. Warfarin crosses the placenta, and it can cause foetal bleeding including intracerebral haemorrhage and intrauterine death. Teratogenic effects have been reported in 5e12% of foetuses exposed to warfarin in the early stages of pregnancy [40]. Late foetal death and stillbirth also occur, possibly due to foetal intracerebral bleeding or placental bleeding. There have been case reviews suggesting that lower doses of warfarin (5 mg of warfarin. The risk of valve thrombosis in pregnancy on warfarin has been reported at 4% [41,42]. Heparin does not cross the placenta, and therefore it is not associated with foetal risk of bleeding or embryopathy, but foetal complications may still develop as a result of placental bleeding. Rates of maternal thromboembolic complications with unfractionated heparin have been found to be unacceptably high. LMWH has better bioavailability and more reliable plasma levels than unfractionated heparin infusion, and so this is the preferred form of heparin treatment. Whilst the measurement of anti-factor Xa levels is not normally required with LMWH treatment in the nonpregnant state, during pregnancy the metabolism and volume of distribution of the drug changes, and standard dosing by weight alone has been shown to result in subtherapeutic treatment. This is particularly important in patients at the highest risk of thromboembolism: those with mechanical valves. Thromboembolic complications in pregnant women on LMWH mostly occurred in women who did not have regular monitoring of anti-Xa levels and dose-adjusted treatment. The recent literature review by McLintock found that in eight of the nine mechanical valve thromboses in pregnant women taking LMWH, subtherapeutic doses and poor compliance or inadequate


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monitoring were factors [40]. It is important to counsel women that compliance with both twicedaily injections and weekly blood-test monitoring is essential to minimise the risks of subtherapeutic anticoagulation and maternal thromboembolic complications. Peak levels measured 3e4 h post dose should be maintained between 1.0 and 1.4 iU/L. Some also advocate measurement of trough levels. The risk of maternal thromboembolic complications is lower with warfarin but at the expense of an increased foetal risk of complications. For most indications for anticoagulation during pregnancy, LMWH is the preferred method. However, the risk of developing mechanical valve thrombosis and the morbidity (and mortality) is higher, so warfarin may be considered. Three anticoagulation strategies have been proposed (Table 8), and management should be decided following discussion of these risks and benefits on an individual basis. Low-dose aspirin has been shown to be beneficial in reducing the risk of thrombus with no increased foetal risk, and it is therefore recommended for all women requiring anticoagulation. Peripartum period Warfarin crosses the placenta resulting in an anticoagulated foetus, and therefore patients taking warfarin should be switched to LMWH after 36 weeks. Delivery, either by induction of labour or by caesarean section, should be planned in order to minimise the risk of bleeding. One management regime for the peripartum period is outlined in Fig. 3 [40]. Delivery planning Most women with heart disease are able to have a normal vaginal delivery. Some with more complex conditions may require closer monitoring and delivery in a particular centre, and therefore delivery may need to be planned for geographical reasons, as is the case for patients with anticoagulation and those requiring elective caesarean section. During the later stages of pregnancy, it is helpful to consider a delivery plan. Factors to consider include the mode and timing of delivery, the management of anaesthesia and anticoagulation and whether cardiac electrophysiological device support is required. Post-partum There are several issues to consider in the post-partum period. The haemodynamic changes take several weeks to resolve, and therefore heart failure may not present until after delivery. Those at the highest risk should be under observation in the hospital for at least 48 h. Early cardiology follow-up is also important for patients with impaired ventricular function and those with valvular disease, which may have deteriorated with pregnancy. Cardiac medications, anticoagulation and contraception should also be reviewed prior to discharge. Table 8 Possible anticoagulation strategies. Possible anticoagulation strategies for women with mechanical prosthetic valves Warfarin throughout until 36 weeks, then monitored LMWH  Most effective at preventing thromboembolic complications

 5e12% risk of embryopathy (not dose related)  Risk of late foetal loss LMWH first trimester and after 36 weeks, Warfarin second trimester and third trimester until 36 weeks  Risk of late foetal loss when on warfarin  Efficacy of warfarin in the prevention of thromboembolic complications  Avoids warfarin exposure during first trimester LMWH throughout  Avoids foetal exposure to warfarin  Higher risk of thromboembolic complications  Frequent monitoring required for dose adjustment LMWH, Low molecular weight heparin. Adapted from McLintock et al. [40].

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Fig. 3. Proposed plan for the management of anticoagulation in the peripartum period.

Conclusion Cardiac disease is the leading cause of maternal mortality. Most of the mortality occurs in women who are not known to have cardiac disease. There should be a low threshold for investigation of chest pain. Most women with heart disease, however, are able to have a pregnancy successfully, and indeed they should not be unnecessarily discouraged. Adverse outcomes can often be avoided with a specialist multidisciplinary team management. Conflict of interest The authors confirm that there are no conflicts of interest.

Practice points  Any woman who develops severe chest pain during pregnancy or early in the post-partum period should be investigated to exclude aortic dissection, pulmonary embolism or myocardial infarction.  Any woman who develops symptoms that could be due to cardiac ischaemia should have this excluded with serial ECG and troponin assessment.  All women with heart disease who are considering pregnancy should be referred for specialist expert joint cardiac and obstetric pre-pregnancy counselling and assessment.  Women with severe ventricular impairment, residual ventricular impairment following previous peripartum cardiomyopathy, severe left-heart obstruction, Marfan syndrome with aortic dilatation >45 mm or pulmonary arterial hypertension should be advised that pregnancy is associated with a significant risk of mortality.  Women with mechanical prosthetic heart valves should have expert counselling about the management of anticoagulation in pregnancy, and they should have meticulous monitoring during pregnancy.


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Research agenda  Further work is needed to investigate the aetiology of peripartum cardiomyopathy. This will enable the development of targeted therapies.  Advances in the management of pulmonary arterial hypertension may improve the prognosis for patients who become pregnant, but this remains to be established.  The increased burden of cardiovascular disease in women of childbearing age means that increased resources are required in order to provide appropriate specialist care during pregnancy. Further work to identify and evaluate efficient models of care will be helpful to plan future service delivery.

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Heart disease in pregnancy.

Cardiac disease is the leading cause of maternal mortality in the developed world. The majority of women with heart disease are able to successfully u...
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