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Published: February 2014

Masters in Medicine
Cardio Review

Pregnancy and Heart Disease

Sahar Naderi

Russell Raymond

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Cardiovascular disease (CVD) complicates 1% to 4% of pregnancies,1 with congenital heart disease (CHD) being the most common preexisting condition and hypertension the most common acquired condition. The incidence of maternal CVD appears to be growing, likely due to increasing maternal age, cardiovascular risk factors (i.e., obesity, diabetes, and hypertension,) and lifespan of patients with CHD. Studies suggest that pregnancy-related mortality has also increased over the last several decades, with deaths attributable to CVD increasing over the same time period.2 Given the potential complications associated with maternal CVD, the ability to both counsel patients prior to pregnancy and appropriately manage patients during pregnancy is of vital importance. The complexity of these patients requires a multidisciplinary approach with the involvement of obstetricians, cardiologists, anesthesiologists, and internists who are experienced in caring for these patients.

Normal Physiologic Changes During Pregnancy

Major hemodynamic changes occur during pregnancy, labor and delivery, and the postpartum period (Table 1). These changes begin in the first 5 to 8 weeks of gestation and peak late in the second trimester. In patients with preexisting CVD, cardiac decompensation often coincides with this peak. Blood volume increases 40% to 50% during normal pregnancy and outweighs the increase in red blood cell mass, contributing to the fall in hemoglobin concentration otherwise known as anemia of pregnancy. Similarly, cardiac output rises 30% to 50% above baseline, peaking at the end of the second trimester and reaching a plateau until delivery. The increase in cardiac output is achieved by three factors: an increase in preload due to greater blood volume, reduced afterload due to a fall in systemic vascular resistance (SVR), and a rise in the maternal heart rate by 10 to 15 beats per minute. Stroke volume increases during the first and second trimesters but declines in the third trimester due to compression of the inferior vena cava by the uterus, at which point heart rate is the major factor in the increase in cardiac output. Blood pressure typically falls approximately 10 mm Hg below baseline by the end of the second trimester due to reduction in SVR and addition of new blood vessels in the uterus and placenta.

Table 1: Normal Hemodynamic Changes During Pregnancy
Hemodynamic Parameter Change During Normal Pregnancy Change During Labor and Delivery Change During Postpartum
Blood volume ↑ 40%-50% ↓ (autodiuresis)
Heart rate ↑ 10-15 beats/min
Cardiac output ↑ 30%-50% ↑ Additional 50%
Blood pressure ↓ 10mmHg
Stroke volume ↑ First and second trimesters; ↓ third trimester ↑ (300-500mL per contraction)
Systemic vascular resistance

It should be noted that pregnancy also induces a hypercoagulable state, due to an increase in clotting factors as well as stasis induced by the compression of the inferior vena cava by the uterus. This is likely an evolutionary means by which to protect against maternal hemorrhage, and in fact, the most hypercoagulable time is the peripartum period. Studies show that pregnant women are three to four times more likely to have arterial thromboembolism and four to five times more likely to have venous thromboembolism as compared with women who are not pregnant.3

Pregnancy is also characterized by a complex series of hormonal and metabolic changes that govern glucose regulation. Typically, a state of maternal insulin resistance develops during the second and third trimesters. Insulin resistance is a physiologic response that favors a shift in the glucose supply to the fetus. In normal women, this is countered by a steady increase in basal insulin secretion and a marked increase in insulin secretion immediately after a glucose load (first phase). In contrast, women with gestational diabetes exhibit impaired pancreatic β-cell secretory function and demonstrate a blunted first-phase insulin secretion response to glucose loading. The cardiovascular consequences of gestational diabetes can include macrosomia, shoulder dystocia, future development of maternal type 2 diabetes and an increased risk of obesity and type 2 diabetes in the offspring.

During labor and delivery, hemodynamic fluctuations can be profound. Each uterine contraction displaces 300 to 500 mL of blood into the general circulation. Stroke volume increases, with a resultant rise in cardiac output by an additional 50% with each contraction. Thus, cardiac output can potentially be 75% above baseline during labor and delivery. Mean arterial pressure also rises, in part due to maternal pain and anxiety. Blood loss during delivery (300-400 mL for a vaginal delivery and 500-800 mL for a cesarean section) can contribute to hemodynamic stress.

The hemodynamic changes during the postpartum state are equally dramatic. Relief of inferior vena caval compression results in an increase in venous return, which in turn augments cardiac output and causes a brisk autodiuresis. The hemodynamic changes return to the prepregnancy baseline within 2 to 4 weeks following vaginal delivery and 4 to 6 weeks following cesarean section.

These marked hemodynamic changes during pregnancy account for signs and symptoms during normal pregnancy that can mimic that of heart disease. Normal pregnancy is typically associated with fatigue, dyspnea, and decreased exercise capacity. Pregnant women usually have mild peripheral edema and jugular venous distension. Most pregnant women have audible physiologic systolic murmurs as a result of augmented blood flow. A physiologic third heart sound (S3), reflecting increased blood volume, can sometimes be auscultated. Abnormal signs and symptoms during pregnancy include exertional chest pain, paroxysmal nocturnal dyspnea, orthopnea, sustained atrial or ventricular arrhythmias, pulmonary edema, severe obstructive systolic murmurs, diastolic murmurs, and an S4 gallop.

A careful personal and family history should be obtained from the patient. Noninvasive cardiac testing may include an electrocardiogram, plasma brain natriuretic peptide (BNP) testing, and an echocardiogram. The electrocardiogram may reveal a leftward axis deviation, especially during the third trimester when the uterus pushes the diaphragm upward. Routine chest radiographs should be avoided, particularly in the first trimester. BNP levels are typically low during normal pregnancy (<20 pg/mL). Elevations in BNP are a useful guide in managing early cardiac dysfunction and the hypertensive disorders of pregnancy. Echocardiography is an invaluable tool for the diagnosis and evaluation of suspected cardiac disease in the pregnant patient. Normal changes attributable to pregnancy include increased left ventricular (LV) mass and dilatation.

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Assessment of Risk in Patients with Preexisting Cardiac Disease

Maternal and Fetal Outcomes

It is advised that individuals with structural cardiac disease who have undergone surgical or catheter-based repair should not be considered "corrected," as some residual disease almost always remains and the responses to the physiology of pregnancy can be unpredictable. Whenever possible, women with known pre-existing cardiac lesions should receive preconception counseling. This should include contraceptive advice, quantification of maternal and fetal risks during pregnancy, and discussion of possible long-term morbidity and mortality after pregnancy. Unfortunately, many women with pre-existing heart disease are not aware of the risks of pregnancy. In one questionnaire-based study of 116 adult females with CHD, of which 55% had been pregnant at least once, 37% of respondents reported that they had never been informed that they were at increased risk for maternal cardiac complications during pregnancy.

The following conditions are generally considered contraindications to pregnancy: severe pulmonary hypertension of any etiology, severe fixed obstructive cardiac lesions, New York Heart Association (NYHA) class III-IV heart failure, left ventricular ejection fraction (LVEF) <40%, prior peripartum cardiomyopathy (PPCM), dilated unstable aorta of 40 to 45 mm or above, or severe cyanosis. The CARdiac disease in PREGnancy (CARPREG) risk score has been shown to predict the risk of adverse cardiac complications during pregnancy (Table 2). It is composed of four clinical features found to be predictive of maternal cardiac complications (Table 2).4,5 Each risk factor is assigned one point, and the maternal cardiac event rate associated with 0, 1, and >1 points is 5%, 27%, and 75% respectively. While the CARPREG study included both acquired and CHD, the more recent ZAHARA predictors were developed based on a population of CHD patients.6 The predictors included history of arrhythmia, baseline NYHA class III-IV, left heart obstruction, mechanical valve prosthesis, moderate-to-severe atrioventricular valve regurgitation, moderate-to-severe subpulmonary atrioventricular valve regurgitation, use of cardiac medication prior to pregnancy, and repaired or unrepaired cyanotic heart disease. Although such scores serve as an overall assessment of risk, pre-pregnancy counseling should be tailored according to specific cardiac lesions.

Table 2: Predictors of Maternal Risk for Cardiac Complications
Criteria Example Points*
Prior cardiac events Heart failure, transient ischemic attack, stroke before present pregnancy, arrhythmia (defined as symptomatic sustained tachyarrhythmia or bradyarrhythmia requiring treatment) 1
NYHA III/IV or cyanosis 1
Valvular and outflow tract obstruction Aortic valve area <1.5 cm2, mitral valve area <2 cm2, or left ventricular outflow tract peak gradient >30 mm Hg 1
Myocardial dysfunction LVEF <40% or restrictive cardiomyopathy or hypertrophic cardiomyopathy 1

LVEF, left ventricular ejection fraction; NYHA, New York Heart Association.

* Maternal cardiac event rate for 0, 1, and >1 points is 5%, 27%, and 75%, respectively.

Specific Congenital or Acquired Cardiac Lesions

Specific congenital or acquired cardiac lesions are classified as low, intermediate, or high risk during pregnancy (Box 1).

Box 1: Maternal Cardiac Lesions and Risk of Cardiac Complications During Pregnancy
Low Risk
Atrial septal defect
Ventricular septal defect
Patent ductus arteriosus
Asymptomatic aortic stenosis with low mean gradient (<50 mm Hg) and normal left ventricle function (EF >50%)
Aortic regurgitation with normal left ventricle function and NYHA functional class I or II
Mitral valve prolapse (isolated or with mild-to-moderate mitral regurgitation and normal left ventricle function)
Mitral regurgitation with normal left ventricle function and NYHA class I or II
Mild-to-moderate mitral stenosis (mitral valve area >1.5 cm2, mean gradient <5 mm Hg) without severe pulmonary hypertension
Mild/moderate pulmonary stenosis
Repaired acyanotic congenital heart disease without residual cardiac dysfunction
Intermediate Risk
Large left-to-right shunt
Coarctation of the aorta
Marfan syndrome with a normal aortic root
Moderate-to-severe mitral stenosis
Mild-to-moderate aortic stenosis
Severe pulmonary stenosis
High Risk
Eisenmenger's syndrome
Severe pulmonary hypertension
Complex cyanotic heart disease (tetralogy of Fallot, Ebstein’s anomaly, truncus arteriosus, transposition of the great arteries, tricuspid atresia)
Marfan syndrome with aortic root or valve involvement
Uncorrected severe aortic stenosis with or without symptoms
Uncorrected severe mitral stenosis with NYHA functional class II-IV symptoms
Aortic and/or mitral valve disease (stenosis or regurgitation) with moderate-to-severe left ventricle dysfunction (EF <40%)
NYHA class III-IV symptoms associated with valvular disease or cardiomyopathy of any etiology
History of prior peripartum cardiomyopathy

EF, ejection fraction; NYHA, New York Heart Association

Low-Risk Lesions

Atrial Septal Defect

Ostium secundum atrial septal defect (ASD), the most common congenital cardiac lesion encountered during pregnancy, is usually well tolerated. An uncorrected ASD does carry a small increased risk of paradoxical embolism, and therefore, deep vein thrombosis (DVT) prevention should be meticulous. With advancing maternal age (particularly >40 years), uncomplicated ASDs may be associated with a higher incidence of supraventricular arrhythmias (e.g., atrial fibrillation or atrial flutter). Although rare during the childbearing years, the presence of pulmonary hypertension substantially increases the risk of cardiac complications during pregnancy. A secundum ASD that has been repaired prior to pregnancy is not associated with any increased risk of cardiac complications. Device or operative repair of hemodynamically significant ASDs should be performed prior to conception. There is evidence that patients with secundum ASDs are at elevated risk of bacterial endocarditis. Holt-Oram syndrome, a rare heart–upper limb malformation complex that most commonly includes ASD, requires additional consideration given the potential for autosomal dominant transmission of the TBX5 gene defect to offspring.

Ventricular Septal Defect

Isolated ventricular septal defects (VSD) are low-risk lesions that are usually well tolerated during pregnancy. However, VSD accompanied by pulmonary hypertension and/or Eisenmenger syndrome carries a high risk for cardiac complications. VSD can occur in conjunction with other congenital cardiac lesions, including ASD, patent ductus arteriosus (PDA), mitral regurgitation, and transposition of the great arteries. The risk associated with a VSD repaired prior to the development of pulmonary hypertension is negligible.

Patent Ductus Arteriosus

The presence of a PDA during pregnancy is not associated with additional maternal risk, provided the shunt is small to moderate and the pulmonary artery pressures are normal. Percutaneous closure is now considered first-line therapy, and it is reasonable to close even asymptomatic small PDAs. Following repair of more significant PDAs, women are at no additional risk for complications during pregnancy.

Mitral Valve Prolapse

In isolation, mitral valve prolapse (MVP) rarely causes any difficulties during pregnancy. MVP is specifically stated as a low-risk condition for endocarditis in the American Heart Association 2007 guidelines and is not an indication for antibiotic prophylaxis at delivery.

Mitral Regurgitation

Chronic regurgitant lesions are generally well tolerated during pregnancy. In chronic mitral regurgitation, the physiologic reduction in SVR partially compensates for the additional volume overload generated by the regurgitant valve. However, the development of new atrial fibrillation or severe hypertension can disrupt this balance and precipitate hemodynamic deterioration. In contrast, acute mitral regurgitation (e.g., from rupture of chordae tendineae) is not well tolerated, leading to flash pulmonary edema and/or life-threatening cardiac decompensation. The most common causes of mitral regurgitation are rheumatic heart disease and myxomatous degeneration. Hypertrophic cardiomyopathy (HCM) and mitral annular dilatation secondary to dilated cardiomyopathy can also result in mitral regurgitation.

Women with pre-existing severe mitral regurgitation may develop heart failure symptoms during pregnancy, particularly during the third trimester. In general, these symptoms can be managed medically with judicious use of diuretics and afterload-reducing agents. Nitrates, hydralazine and dihydropyridine calcium channel-blocking agents can serve as relatively safe afterload-reducing agents in pregnant women. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) are strictly contraindicated during pregnancy. Women with severe symptomatic mitral regurgitation prior to pregnancy should consider operative repair prior to conception. Although repair is strongly preferred to valve replacement before pregnancy, the success of operative repair is dependent on suitable valve anatomy.

Aortic Regurgitation

Like chronic mitral regurgitation, chronic aortic regurgitation is generally well tolerated during pregnancy. In addition to the physiologic fall in SVR, the tachycardia of pregnancy shortens diastole and reduces the aortic regurgitant fraction. Marfan syndrome should be considered as an etiology, given the implications of aortic root instability during pregnancy. Aortic regurgitation is generally medically managed during pregnancy with diuretics and afterload reduction. Operative repair prior to pregnancy is feasible in certain patients, especially when the valve is anatomically bicuspid. However, the long-term durability of repair may be inferior to valve replacement. During pregnancy, surgical intervention for both mitral and aortic regurgitation is rarely undertaken and performed only for refractory heart failure.

Pulmonary Stenosis

As an isolated lesion, pulmonic stenosis is well tolerated during pregnancy. Severe, symptomatic pulmonary stenosis may be treated with percutaneous pulmonary valvuloplasty prior to conception. If necessary during pregnancy, percutaneous pulmonary valvuloplasty should be delayed until after the first trimester to avoid fetal radiation exposure during early development. Pulmonary stenosis frequently coexists with other congenital cardiac lesions that may cause cyanotic heart disease.

Moderate-Risk Lesions

Mitral Stenosis

Mitral stenosis in women of childbearing age is most often rheumatic in origin. Patients with moderate-to-severe mitral stenosis often experience hemodynamic deterioration during the third trimester or at the time of labor and delivery. The physiologic increase in blood volume and rise in heart rate lead to an elevation of left atrial pressure, resulting in pulmonary edema. Additional displacement of blood volume into the systemic circulation during contractions makes labor particularly hazardous.

The development of atrial fibrillation in the pregnant patient with mitral stenosis can result in rapid decompensation. Digoxin and beta blockers can be used to reduce heart rate and diuretics to gently reduce the blood volume and left atrial pressure. The development of atrial fibrillation increases the risk of stroke, necessitating the initiation of anticoagulation (see "Medication Guidelines During Pregnancy"). With hemodynamically unstable atrial fibrillation, electrocardioversion can be performed safely.

Mild mitral stenosis can often be managed with careful medical therapy. In contrast, patients with moderate-to-severe mitral stenosis should be referred to a cardiologist. Severe mitral stenosis is associated with a high likelihood of maternal complications (including pulmonary edema and arrhythmias) and/or fetal complications (including premature birth, low birth weight, respiratory distress, and fetal or neonatal death).3 Women with moderate-to-severe mitral stenosis require correction before conception, favoring percutaneous mitral balloon valvuloplasty over surgical repair/replacement. If severe mitral stenosis is discovered during pregnancy, medical therapy with diuretics and digoxin is preferred. If symptoms cannot be controlled with medical therapy, percutaneous valvuloplasty can be performed in the second or third trimester to prevent fetal radiation exposure during the first trimester. Treatment options for patients with mitral stenosis are summarized in Figure 1.

Most patients with mitral stenosis can undergo vaginal delivery. However, patients with symptoms of congestive heart failure or moderate-to-severe mitral stenosis may need close hemodynamic monitoring during labor and delivery and for several hours into the postpartum period. In these patients, epidural anesthesia is usually better tolerated hemodynamically than general anesthesia.

Aortic Stenosis

The most common etiology of aortic stenosis in women of childbearing age is a congenitally bicuspid valve. Mild-to-moderate aortic stenosis with preserved LV function usually is well tolerated during pregnancy. Severe aortic stenosis (aortic valve area <1.0 cm2, mean gradient >50 mm Hg), in contrast, is associated with a 10% risk of maternal morbidity (although maternal mortality is rare). Symptoms such as dyspnea, angina pectoris, or syncope usually become apparent late in the second trimester or early in the third trimester. Cardiac surgery is needed in approximately 40% of patients with severe aortic stenosis within 2.5 years of pregnancy.7

Women with known severe aortic stenosis should be referred to a cardiologist. Ideally, the patient should undergo correction of the valvular abnormality before conception. Treatment options include surgical valve repair, surgical valve replacement, or percutaneous balloon valvotomy but require a multidisciplinary approach to determine the appropriate treatment option. When severe symptomatic aortic stenosis is diagnosed during pregnancy, maximal medical therapy is preferred over intervention. However, if the patient has refractory symptoms and hemodynamic deterioration despite maximal medical therapy, percutaneous balloon valvotomy may be performed (Figure 2). Spinal and epidural anesthesia are discouraged during labor and delivery because of their vasodilatory effects. As with mitral stenosis, hemodynamic monitoring is recommended during labor and delivery.

Coarctation of the Aorta

Coarctation of the aorta is a narrowing in the region of the ligamentum arteriosum, just distal to the origin of the left subclavian artery, usually presenting with resistant hypertension in childhood. Coarctation is well tolerated during pregnancy, although hypertension, heart failure, angina, and aortic dissection are possible complications. Coarctation can be associated with intracerebral aneurysms, which may rupture during pregnancy. Hypotension in vascular beds distal to the coarctation can compromise uteroplacental blood flow, resulting in intrauterine growth retardation. Coarctation of the aorta is often associated with a congenitally bicuspid aortic valve, which increases the risk of infective endocarditis. The aortic wall adjacent to an area of coarctation has histologic features of cystic medial necrosis, which renders it vulnerable to dissection. Thus, women who have previously undergone surgical repair of an aortic coarctation remain at risk for complications during pregnancy.

If at all possible, coarctation of the aorta should be corrected prior to pregnancy with standard surgical repair or balloon angioplasty with endovascular stent placement. Correction of coarctation during pregnancy is indicated in patients with severe uncontrollable hypertension, heart failure, or uterine hypoperfusion.

Marfan Syndrome

Marfan syndrome is a connective tissue disorder resulting from autosomal dominant mutations (i.e., 50% of offspring will inherit the disorder, regardless of gender) in the fibrillin gene. Thus, women with Marfan syndrome should receive genetic counseling well in advance of pregnancy. The clinical manifestations of Marfan syndrome include skeletal abnormalities, ectopia lentis, and cardiovascular abnormalities such as aortic root dilatation with or without aortic regurgitation, aortic dissection, and MVP. Marfan syndrome is a heterogeneous disorder with highly variable disease penetrance.

It is estimated that pregnancy in patients with Marfan syndrome carries a 1% risk of serious cardiac complications. This risk rises with increasing aortic root dimensions. Women with Marfan syndrome are more vulnerable to aortic dissection and/or rupture during pregnancy because of the additional weakness in the aortic wall imposed by hormonal changes. Interestingly, the occurrence of dissection appears to peak 3 to 20 days post-partum. It is thought that oxytocin stimulation during breast-feeding may activate the ERK pathway, which has been recently implicated in the pathophysiology of this condition. In addition, women with Marfan syndrome may be more prone to spontaneous abortion and preterm labor.

Screening echocardiography should be performed prior to pregnancy. Enlargement of the aortic root >4.5 cm is associated with maternal mortality as high as 10%. There is some evidence that pregnancy in women with Marfan syndrome may be relatively safe up to 4.5 cm. However, in women with an aortic diameter of 4.0 to 4.5 cm, pertinent risk factors for dissection (family history of dissection, rapid growth) and body surface area should be taken into account. The 2011 European Society of Cardiology guidelines strongly recommend pre-conception elective aortic root repair for aortic root aneurysms >4.5 cm and individualization of management for those that are 4.0 to 4.5 cm. The 2010 American College of Cardiology/American Heart Association guidelines state that it is "reasonable" to prophylactically replace the aortic root and ascending aorta when the diameter exceeds 4.0 cm. The aortic root should be measured by serial echocardiography throughout pregnancy, with progressive dilatation warranting termination of pregnancy and/or timely aortic repair or replacement.

Medical management involves the use of beta-blockers throughout pregnancy to reduce the risk of aortic rupture, careful control of blood pressure, and consideration of general anesthesia and cesarean section at the time of delivery to maximize hemodynamic control. Women with Marfan syndrome with no identifiable cardiac abnormalities have a low rate of complications and can usually tolerate a normal vaginal delivery. Spinal or epidural anesthesia is advised to minimize the pain and stress of labor.

High-Risk Lesions

The high-risk conditions listed in Box 1 are associated with increased maternal and fetal mortality, and pregnancy is not advised. If pregnancy should occur, the risk of maternal mortality and morbidity must be assessed on an individual basis. If deemed extremely high, consideration of medical termination of pregnancy is advised to safeguard the mother’s health. If the pregnancy is continued, patients are best managed with the assistance of a cardiologist and a maternal-fetal medicine specialist at a center with high-risk obstetrical facilities and a level three neonatal unit.

Eisenmenger Syndrome

The Eisenmenger syndrome is a consequence of uncorrected long-standing left-to-right shunting. Over time, pulmonary artery pressures approach and can exceed systemic pressures, resulting in cyanosis due to reversal of the shunt flow direction from right to left. Eisenmenger syndrome is a possible common endpoint of multiple congenital lesions, including ASD, VSD, and PDA. Maternal mortality in women with Eisenmenger syndrome ranges from 30% to 50%, with a 50% risk of fetal loss if the mother survives. Mortality is frequently caused by complications of thromboembolic disease. Decompensation occurs most frequently during the first week after delivery. Fetal risk due to maternal hypoxemia is substantial, with a high incidence of fetal loss, premature delivery, intrauterine growth retardation, and perinatal death.

Because of the considerable risk to both the mother and the fetus, pregnancy is contraindicated in women with Eisenmenger syndrome. If pregnancy should occur, therapeutic abortion is recommended. Women who choose to continue with pregnancy are advised to restrict physical activity, use continuous oxygen for at least the third trimester and consider use of pulmonary vasodilating drugs such as iloprost and prostacyclin. Anticoagulation is recommended during the third trimester and for 4 weeks after delivery. The most vulnerable period for the mother is labor and delivery and the first week postpartum. Vaginal delivery, facilitated by vacuum or low forceps extraction, is the delivery method of choice. Cesarean delivery is associated with a substantially higher mortality than the vaginal route. Anesthetic management includes central venous and arterial pressure monitoring, with maintenance of adequate SVR and intravenous volume and prevention of sudden increases in pulmonary vascular resistance.

Complex Cyanotic Congenital Heart Disease

Women born with cyanotic CHD are increasingly surviving to childbearing age. In general, pregnancy is not recommended for women with uncorrected lesions. Studies show that a low maternal oxygen saturation (<85%) correlates with a very low rate of live-born infants (12%). The most common cyanotic congenital defect, tetralogy of Fallot, is characterized by a VSD, pulmonic stenosis, right ventricular outflow tract obstruction, and an overriding aorta. Women with tetralogy of Fallot who have undergone successful repair in childhood may tolerate pregnancy, provided they have little or no residual right ventricular outflow tract gradient, no pulmonary hypertension, and preserved ventricular function. Genetic counseling and screening for the 22q11 deletion should be offered as its transmission is autosomal dominant. Ebstein anomaly, characterized by abnormal right ventricular function, apical displacement of the tricuspid valve septal leaflet, and tricuspid regurgitation, is often associated with the Wolf–Parkinson–White syndrome. Pregnancy can precipitate supraventricular arrhythmias that may rapidly conduct over the accessory pathway. Surgical correction reduces the maternal risk of pregnancy but does not reduce the risk of congenital anomalies in the fetus. Individuals with a single functional ventricle will often have a palliative version of the Fontan procedure during childhood. Heart failure, thromboembolism and atrial arrhythmias occur in 10% to 20% pregnant patients with this anomaly, and fetal loss can reach 50%. Experience with pregnancy in women with surgically corrected D-transposition of the great arteries, truncus arteriosus, or tricuspid atresia is limited. Women with congenitally corrected transposition (L-transposition) and no cyanosis, heart failure or conduction disease should tolerate pregnancy well. Pre-term delivery rates in these complex conditions range from 22% to 65%, and an elevated rate of premature rupture of membranes has been associated with Fontan patients and transposition.

Cardiomyopathy

Women with heart failure of any etiology and an ejection fraction (EF) <40% or NYHA class III-IV symptoms should be counseled to avoid pregnancy. PPCM and its implications for subsequent pregnancies are discussed further in the following section. HCM is associated with increased maternal morbidity and mortality. Although an increase in blood volume helps to reduce intracavitary or LV outflow tract gradients, tachycardia and a reduction in SVR can exacerbate outflow tract obstruction. Avoidance of volume depletion and the use of beta blockers if there is evidence of LV outflow tract obstruction and/or maximal wall thickness >15 mm helps to prevent hemodynamic deterioration in these patients. Vaginal delivery is usually well tolerated. Whenever possible, women should receive genetic counseling prior to conception, given the heritability of certain forms of HCM approaches 50%.

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Prepregnancy Cardiovascular Risk Factors

Birth rates for older women have increased over the last several decades. Older women have a higher prevalence of traditional cardiovascular risk factors (i.e., diabetes and chronic hypertension) and preexisting CVD than younger women. This has a profound impact on both the mother and the fetus. Risk factors, such as smoking, diabetes, hypertension, hyperlipidemia, and thrombophilia, are associated with increased risk of spontaneous abortion, maternal placental syndromes ([MPS] see next section), preterm labor or premature rupture of membranes, and acute arterial or venous thromboses during pregnancy. Furthermore, the presence of such risk factors also predicts future development of coronary artery disease, chronic hypertension, stroke, and peripheral arterial disease in the mother. Emerging risk factors for future CVD in women include maternal obesity and gestational diabetes. Maternal obesity is associated with increased risk of gestational hypertension, preeclampsia, gestational diabetes, and high fetal birth weight (>4,000 grams).8 Gestational diabetes can progress to type 2 diabetes, with the cumulative incidence increasing markedly in the first 5 years after pregnancy.9

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Acquired Cardiovascular Disorders During Pregnancy

Maternal Placental Syndromes

A group of disorders collectively known as maternal placental syndromes (MPS) have been associated with increased risk of maternal premature CVD. In CHAMPS (Controlled High-Risk Avonex Multiple Sclerosis Study),10 MPS were defined as the presence of preeclampsia, eclampsia, gestational hypertension, placental abruption, or placental infarction during pregnancy. MPS occurred in 7% of the 1.03 million women who were free from CVD before pregnancy. Interestingly, traditional cardiovascular risk factors were more prevalent in women with MPS as compared to women without MPS. Women with MPS were two times as likely to experience a hospital admission or revascularization procedure for coronary, cerebrovascular, or peripheral vascular disease compared to women without MPS. The growing body of evidence linking cardiovascular risk factors, MPS, and future CVD might indicate underlying vascular pathology that predates pregnancy and can manifest as MPS during pregnancy or chronic CVD later in life.

Hypertension in Pregnancy

Hypertensive disorders can complicate 12% to 22% of pregnancies and are a major cause of maternal morbidity and mortality. Hypertension during pregnancy is defined as a systolic pressure >140 mm Hg and/or a diastolic pressure >90 mm Hg. Hypertension during pregnancy is classified into three main categories: chronic hypertension, gestational hypertension, and preeclampsia with or without preexisting hypertension.

Chronic hypertension is defined as blood pressure >140/90 mm Hg that either precedes pregnancy or develops before 20 weeks gestation. Chronic hypertension usually also persists beyond 42 days postpartum. Women of childbearing age who take chronic antihypertensive medications should be counseled in regards to their safety well in advance of a potential pregnancy. Most notably, women who are treated with ACE inhibitors should be made aware of the potential teratogenic effects. Women with chronic hypertension have an increased risk of developing preeclampsia and should be made aware of the signs and symptoms of preeclampsia. Options for drug therapy during pregnancy are shown in Box 2. It should be noted that methyldopa alone has been studied in trials of treatment of hypertension during pregnancy.

Box 2: Drug Therapy of Hypertension in Pregnancy
First line
Alpha methyldopa (PO)
Labetolol (PO)
Second Line
Hydralazine (PO)
Nifedipine (PO)
Beta blockers (PO)
Contraindicated
Angiotensin-converting enzyme inhibitors (PO)
Angiotensin-receptor blockers (PO)
Aldosterone antagonists (PO)
Avoid
Thiazide diuretics
Severe Hypertensive Urgency or Emergency
Labetolol (IV)
Nitroglycerine (IV)
Nitroprusside (IV)*
Beta blockers (IV)
Nifedipine (PO)

* Avoid prolonged use given concern for fetal cyanide poisoning.

Gestational hypertension is defined as hypertension developing after 20 weeks gestation not associated with proteinuria or other features of preeclampsia that resolves by 42 days postpartum. This condition is also known as pregnancy-induced hypertension. Although it resolves after delivery, women with this condition may be at risk for developing hypertension or CVD in the future. Therefore, they should undergo physical examination and screening for traditional cardiovascular risk factors annually after pregnancy.

Preeclampsia occurs in 3% to 8% of pregnancies in the United States but increases in incidence in patients with preexisting hypertension. The classic clinical triad involves accelerating hypertension, proteinuria (>300 mg/day), and edema. Eclampsia is the development of grand mal seizures in a woman with preeclampsia. Symptoms usually begin in the third trimester and occur more frequently during the first pregnancy. BNP can be a useful marker in women with preeclampsia. During normal pregnancy, BNP remains low despite volume overload. In even mild preeclampsia, elevation of BNP can precede other laboratory abnormalities, such as platelet and liver function abnormalities. Although definitive treatment includes delivery of the baby, many women with preeclampsia require treatment with antihypertensive medications before delivery and for some period of time after. Typical antihypertensive medications used to treat preeclampsia include labetolol. The etiology of preeclampsia is still unclear. Both preeclampsia and eclampsia have been linked to future development of CVD. As with pregnancy-induced hypertension, women with these conditions should receive annual cardiovascular evaluation.

Peripartum Cardiomyopathy

Peripartum cardiomyopathy (PPCM) is defined as new-onset idiopathic LV systolic dysfunction in the interval between the last month of pregnancy and the first 5 months postpartum. The incidence of PPCM in the United States is estimated to be 1 in 3,000 to 1 in 4,000 live births; the incidence appears to be highest in Africa and Haiti (occurring in 1 in 300 pregnancies). Risk factors include maternal age >30 years, obesity, multiparity, multiple fetuses, pre-eclampsia, eclampsia, chronic hypertension, African descent, low socioeconomic status or tocolytic therapy with beta-agonists. There does not appear to be a hereditary predisposition.

PPCM has long been regarded as a disease of unknown etiology, with possible triggers including viral infection and autoimmunity. Recent mouse models have demonstrated a role for a 16kDa protein derived from proteolytic cleavage of prolactin under oxidative stress.11 This derivative is cardiotoxic, anti-angiogenic, proapoptotic, proinflammatory, and is observed in higher levels in PPCM patients. Furthermore, small numbers of postpartum women with PPCM have shown favorable cardiac outcomes with bromocriptine, a dopamine receptor agonist that inhibits prolactin secretion.

Medical therapy for PPCM is similar to therapy for cardiomyopathy of other etiologies. Digoxin and diuretics may be used safely during pregnancy and while breastfeeding. Beta-blockers are generally safe, although there have been case reports of fetal bradycardia and growth retardation. ACE inhibitors and ARBs are strictly contraindicated throughout pregnancy. ACE inhibitor fetopathy includes oligohydramnios, intrauterine growth retardation, hypocalvaria, renal dysplasia, anuria, and death. Hydralazine is an effective afterload-reducing agent, although it is currently listed as a category C agent (adequate and well-controlled studies in pregnant patients are lacking and should be used only when the expected benefit outweighs the potential risk to the fetus). Spironolactone should also be avoided given its associated antiandrogenic effects. Anticoagulation should be considered. When medical therapy is not successful, women with PPCM may ultimately require advanced mechanical support or cardiac transplantation. Cardiac transplantation is required in about 4% of women with PPCM.

The prognosis of PPCM is variable. Approximately 50% of women completely recover normal heart size and function, usually within 6 months of delivery.12 The remainder either experience stable LV dysfunction or experience clinical deterioration. Mortality at 2 years is approximately 9% in the white population and 15% in the African American population. Women with PPCM who attempt a subsequent pregnancy face high risk of complications, including deterioration of LV function, symptomatic heart failure, and death. Given the recurrence risk of 30% to 50%, some experts counsel affected women against subsequent pregnancies.13 It should be noted that the majority of maternal deaths have occurred in women whose LV function remained abnormal prior to future pregnancies and LVEF at first PPCM diagnosis seems to be a major prognostic indicator. Therefore, an EF <25% at initial presentation and/or persistence of any degree of EF reduction at the time of consultation are considered definite contraindications to future pregnancy.

Coronary Artery Disease

Acute myocardial infarction (AMI) during pregnancy is rare, occurring in approximately 1 in 35,000 pregnancies. Independent predictors of AMI during pregnancy include chronic hypertension, hyperlipidemia, smoking, advanced maternal age, diabetes, and preeclampsia. Most myocardial infarctions occur during the third trimester and are most common in multiparous women over the age of 33. Coronary spasm, in situ coronary thrombosis, and spontaneous coronary artery dissection occur more often than classic obstructive atherosclerosis. Spontaneous coronary artery dissection is more common in pregnant than non-pregnant women and often effects the left main trunk or the left anterior descending artery. Dissections have been successfully treated medically, and if refractory to medical management, with coronary stenting or coronary artery bypass grafting. Maternal mortality is highest in the peripartum period. Maternal mortality after AMI is estimated at 5% to 7%, with improved survival since the advent of percutaneous coronary intervention.14

Medical therapy for AMI must be modified in the pregnant patient. Although thrombolytic agents increase the risk of maternal hemorrhage substantially (8%), their use is permitted in situations where cardiac catheterization facilities are not available. Low-dose aspirin, nitrates, and beta blockers are generally considered safe. Short-term heparin administration has not been associated with increased maternal or fetal adverse effects. ACE inhibitors and statins are contraindicated during pregnancy. Clopidogrel and glycoprotein IIb/IIIa receptor inhibitors have been used in individualized cases, but there is a paucity of safety data. Therefore, clopidogrel should be used for the shortest period of time possible, favoring bare metal stenting. Percutaneous coronary intervention with either balloon angioplasty or stenting has been successfully performed in pregnant patients with AMI.15 Studies suggest that the dose of radiation during percutaneous intervention do not reach levels that are harmful to the fetus, particularly if the procedure is performed greater than 12 weeks after conception. In general, a radial approach is preferred and care should be taken to shield the abdomen.

Arrhythmias in Pregnancy

Premature atrial or ventricular complexes are the most common arrhythmias during pregnancy. They are not associated with adverse maternal or fetal outcomes and do not require antiarrhythmic therapy.

Supraventricular tachyarrhythmia (SVT) is also common and often diagnosed with the aid of an event or Holter monitor. Patients with documented SVT should be instructed on the performance of vagal maneuvers. In addition, beta blockers, digoxin, or both can be useful in controlling the ventricular rate. Adenosine and direct-current cardioversion are both safe during pregnancy and can be used to treat SVT. If patients do not respond to rate control, antiarrhythmic agents such as sotalol, fleicanide, or propafenone can be used. Fleicanide and propafenone should be combined with an AV nodal blocking agent. Patients with SVT during pregnancy should be observed after delivery. If the frequency of SVT episodes decreases over several months after delivery, the arrhythmia can be managed medically. If SVT continues to occur frequently and with rapid rates, it may be best treated with electrophysiologic ablation.

De novo atrial fibrillation and atrial flutter are rare during pregnancy, although women with a history of prepregnancy tachyarrhythmias have a high likelihood of recurrence during pregnancy. It is important that underlying conditions such as hyperthyroidism or structural heart disease be ruled out. Recurrent tachyarrhythmias during pregnancy are associated with an increased risk of adverse fetal complications, including premature birth, low birth weight, respiratory distress syndrome, and death.16 Management strategies for atrial fibrillation and flutter are similar to that of SVT. Direct-current cardioversion can be performed safely during any stage of pregnancy.

Ventricular tachycardia is rare during pregnancy, but when it arises, it most commonly originates from the right ventricular outflow tract with a left bundle morphology and inferior axis. Other etiologies include PPCM, long QT syndrome, thyrotoxicosis, or hyperemesis gravidarum. VT associated with structural heart disease is associated with a significant risk of death and should be promptly treated per ACLS guidelines. Most antiarrhythmic medications used to treat ventricular tachycardia are safe during pregnancy, although amiodarone is not recommended given fetotoxic effects (iodine component may cause neonatal goiter).

Patients with refractory tachycardia despite drug therapy can be considered for catheter ablation. If at all possible, ablation should be postponed until the second trimester and performed at an experienced center. Cardioverter-defibrillator implantation should be considered if necessary to protect the mother’s life. Bradyarrhythmias are uncommon during pregnancy, but if necessary, pacemaker support is recommended in complete heart block, symptomatic bradyarrhythmia, or hemodynamic deterioration.

Fetal Tachycardia

Fetal tachycardia complicates about 0.5% of all pregnancies and is a significant cause of fetal morbidity and mortality, including fetal congestive heart failure, hydrops fetalis, and fetal demise. Fetal tachycardias include SVT, atrial flutter, and ectopic atrial tachycardia. Fetal echocardiography, using M-mode and pulsed wave Doppler ultrasound, is extremely useful in diagnosing fetal arrhythmias.

Management depends on the fetal condition and gestational age. Therapy includes transplacental therapy, direct fetal therapy, or early delivery and neonatal therapy. Digoxin is the initial drug of choice for transplacental therapy and can be delivered via direct fetal injection. Other antiarrhythmic medications include flecainide and sotalol. These medications require maternal cardiac monitoring during administration. It is typically necessary to use higher doses of digoxin and other antiarrhythmic medications in pregnant women due to decreased plasma concentrations of drug caused by increased blood volume and higher glomerular filtration rates.

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Medication Guidelines During Pregnancy

Cardiovascular Drugs in Pregnancy

Commonly used cardiovascular drug classes and their potential adverse effects during pregnancy are shown in Table 3. For drugs used to treat hypertension, see Box 2.

Table 3: Cardiovascular Drugs Used During Pregnancy
Drug Use Potential Side Effects Safe During Pregnancy Safe During Breast-Feeding
Adenosine Arrhythmia None reported Yes No data
Beta blockers Hypertension arrhythmias, MI, ischemia, HCM, hyperthyroidism, mitral stenosis, Marfan syndrome, cardiomyopathy Fetal bradycardia, low birth weight, hypoglycemia, respiratory depression, prolonged labor Yes Yes
Digoxin Arrhythmia, CHF Low birth weight, prematurity Yes Yes
Diuretics Hypertension, CHF Reduced uteroplacental perfusion Yes Yes
Lidocaine Arrhythmia, anesthesia Neonatal CNS depression Yes Yes
Low-molecular-weight heparin Mechanical valve, hypercoagulable state, DVT, AF, Eisenmenger syndrome Hemorrhage, unclear effects on maternal bone mineral density Limited data Limited data
Nitrates Hypertension Fetal distress with maternal hypotension Yes No data
Procainamide Arrhythmia None reported Yes Yes
Unfractionated heparin Mechanical valve, hypercoagulable state, DVT, AF, Eisenmenger syndrome Maternal osteoporosis, hemorrhage, thrombocytopenia, thrombosis Yes Yes
Warfarin Mechanical valve, hypercoagulable state, DVT, AF, Eisenmenger syndrome Warfarin embryopathy, fetal CNS abnormalities, hemorrhage Yes, after week 12 of gestation Yes

AF, atrial fibrillation; CHF, congestive heart failure; CNS, central nervous system; DVT, deep vein thrombosis; HCM, hypertrophic cardiomyopathy; MI, myocardial infarction.

Adapted with permission from Elsevier (Elkayam U. Pregnancy and cardiovascular disease. In: Braunwald E, ed. Heart Disease. A Textbook of Cardiovascular Medicine. 6th ed. Philadelphia, PA: WB Saunders; 2001:2184). Copyright ©2001 Elsevier.

Antibiotic Prophylaxis

The American Heart Association no longer recommends antibiotic prophylaxis for the prevention of bacterial endocarditis during genitourinary procedures, including vaginal delivery and cesarean section.

Anticoagulation

Several conditions require the initiation or the maintenance of anticoagulation during pregnancy, including mechanical valves, certain prothrombotic conditions, history of venous thromboembolism, acute deep venous thrombosis or thromboembolism during pregnancy, antiphospholipid antibody syndrome, and atrial fibrillation. The three most common agents considered for use during pregnancy are unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and warfarin.

The Seventh American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy has recommended three potential strategies for anticoagulation during pregnancy (Figure 3).17 In women with venous thromboembolism, LMWH has become the anticoagulant of choice. In women with mechanical heart valves, data are more limited and there has been concern regarding the efficacy of heparin products with respect to preventing valve thrombosis. Studies suggest that oral anticoagulation with warfarin throughout pregnancy is the safest regimen for the mother. At the 36th week of gestation, UFH or LMWH should be started. If the patient is started on LMWH, this should be switched to intravenous UFH at least 36 hours before delivery, stopped 4 to 6 hours before deliver, and restarted 4 to 6 hours after delivery. Protamine can be used for reversal if necessary. If delivery begins while on oral anticoagulation, a cesarean delivery is indicated. INR reversal with vitamin K and fresh frozen plasma can be used if needed. There are data that warfarin doses greater than 5 mg daily pose the greatest risk to the fetus. For these patients, substitution of oral anticoagulant therapy with UFH or LMWH in weeks 6 to 12 decreases the risk. The patient must understand that while this decreases the risk of embryopathy (see below), it does increase the risk of valve thrombosis.

Warfarin crosses the placental barrier freely and can result in warfarin embryopathy (abnormalities of fetal bone and cartilage formation). The risk of warfarin embryopathy has been estimated at 4% to 10%, but is minimized when the daily dose is less than 5 mg. Although the highest risk period is during the first trimester (weeks 6-12), warfarin use during the second and third trimesters has been associated with fetal central nervous system abnormalities, such as optic atrophy, microencephaly, mental retardation, spasticity, and hypotonia. Warfarin’s anticoagulant effect is more potent for the fetus than the mother given the fetus has lower levels of vitamin K-dependent clotting factors. Warfarin can cause spontaneous abortion, prematurity, stillbirth, neonatal intracranial hemorrhage or retroplacental hematoma. Note that the package insert for warfarin states pregnancy as a contraindication to use. However, data show that for mechanical valves the risk of valve thrombosis is substantially less with warfarin versus UFH (3.9% vs. 9.2%).

UFH does not cross the placenta and is considered safer for the fetus. Its use, however, has been associated with maternal osteoporosis, hemorrhage, thrombocytopenia, thrombosis (HITT syndrome), and a high incidence of thromboembolic events with older-generation mechanical valves. UFH may be administered parenterally or subcutaneously throughout pregnancy; when used subcutaneously for anticoagulation of mechanical heart valves, the recommended starting dose is 17,500 to 20,000 units twice daily. The appropriate dose adjustment of UFH is based on an activated partial thromboplastin time (aPTT) of 2.0 to 3.0 times the control level. High doses of UFH are often required to achieve the goal aPTT due to the hypercoagulable state associated with pregnancy. Lower doses of UFH may be appropriate when using anticoagulation for the prevention of venous thromboembolism during pregnancy.

LMWH produces a more predictable anticoagulant response than UFH and is less likely to cause HITT. Its effect on maternal bone mineral density appears to be minimal. LMWH can be administered subcutaneously and dosed to achieve an anti-Xa level of 1.0 to 1.2 U/mL 4 to 6 hours after injection. Anti-Xa levels should be monitored on a weekly basis. There are data to support the use of LMWH in pregnant women with deep venous thrombosis, but data on the safety and efficacy of LMWH in pregnant patients with mechanical valve prostheses are limited. Experience with these agents is accruing.

Anticoagulation in the pregnant patient poses a unique challenge. In planned pregnancies, a careful discussion regarding the risks and benefits of warfarin, UFH, and LMWH are crucial in determining an appropriate anticoagulation strategy. Dosing regimens for warfarin, UFH, and LMWH may vary by diagnosis and detailed dosing guidelines have been published.14

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Summary

Heart disease during pregnancy encompasses a wide spectrum of disorders. Basic concepts to keep in mind include:

  • Blood volume and cardiac output rise during normal pregnancy, reaching a peak during the late second trimester.
  • Preexisting cardiac lesions should be evaluated for the degree of risk to both the mother and the fetus during pregnancy.
  • Contraindications to pregnancy include severe pulmonary hypertension or Eisenmenger’s syndrome, cardiomyopathy with NYHA class III or IV symptoms, history of peripartum cardiomyopathy, severe uncorrected valvular stenosis, unrepaired cyanotic congenital heart disease, and Marfan syndrome with an abnormal aorta.
  • Awareness of major cardiac drug classes contraindicated in pregnancy is important for the treatment of cardiovascular conditions during pregnancy.
  • Anticoagulation during pregnancy presents unique challenges stemming from maternal and fetal side effects of warfarin, unfractionated heparin, and LMWH.

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References

  1. Weiss BM, von Segesser LK, Alon E, Seifert B, Turina MI. Outcome of cardiovascular surgery and pregnancy: a systematic review of the period 1984-1996. Am J Obstet Gynecol 1998; 179:1643–1653.
  2. Berg CJ, Callaghan WM, Syverson C, Henderson Z. Pregnancy-related mortality in the United States, 1998 to 2005. Obstet Gynecol 2010; 116:1302–1309.
  3. James AH. Venous thromboembolism in pregnancy. Arterioscler Thromb Vasc Biol 2009; 29:326–331.
  4. Siu SC, Sermer M, Harrison DA, et al. Risk and predictors for pregnancy-related complications in women with heart disease. Circulation 1997; 96:2789–2794.
  5. Siu SC, Sermer M, Colman JM, et al; on behalf of the Cardiac Disease in Pregnancy (CARPREG) Investigators. Prospective multicenter study of pregnancy outcomes in women with heart disease. Circulation 2001; 104:515–521.
  6. Drenthen W, Boersma E, Balci A, et al; on behalf of the ZAHARA Investigators. Predictors of pregnancy complications in women with congenital heart disease [published online ahead of print June 28, 2010]. Eur Heart J 2010; 31:2124–2132. doi:10.1093/eurheartj/ehq200.
  7. Silversides CK, Colman JM, Sermer M, Farine D, Siu SC. Early and intermediate-term outcomes of pregnancy with congenital aortic stenosis. Am J Cardiol 2003; 91:1386–1389.
  8. Leddy MA, Power ML, Schulkin J. The impact of maternal obesity on maternal and fetal health. Rev Obstet Gynecol 2008; 1:170–178.
  9. Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes Care 2002; 25:1862–1868.
  10. Ray JG, Vermeulen MJ, Schull MJ, Redelmeier DA. Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study. Lancet 2005; 366:1797–1803.
  11. Hilfiker-Kleiner D, Kaminski K, Podewski E, et al. A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell 2007; 128:589–600.
  12. Elkayam U, Akhter MW, Singh H, et al. Pregnancy-associated cardiomyopathy: clinical characteristics and a comparison between early and late presentation. Circulation 2005; 111:2050–2055.
  13. Elkayam U, Tummala PP, Rao K, et al. Maternal and fetal outcomes of subsequent pregnancies in women with peripartum cardiomyopathy. N Engl J Med 2001; 344:1567–1571.
  14. James AH, Jamison MG, Biswas MS, Brancazio LR, Swamy GK, Myers ER. Acute myocardial infarction in pregnancy: a United States population-based study [published online ahead of print March 13, 2006]. Circulation 2006; 113:1564–1571. doi:10.1161/CIRCULATIONAHA.105.576751.
  15. Dwyer BK, Taylor L, Fuller A, Brummel C, Lyell DJ. Percutaneous transluminal coronary angioplasty and stent placement in pregnancy. Obstet Gynecol 2005; 106:1162–1164.
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  17. Bates SM, Greer IA, Hirsh J, Ginsberg JS. Use of antithrombotic agents during pregnancy: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126(suppl 3):627S–644S.

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