Profound hemodynamic alterations occur during pregnancy, labor and delivery, and in the post-partum period (Table 1). These changes begin during the first five to eight weeks of pregnancy and reach their peak late in the second trimester. Hemodynamic deterioration may become clinically manifest in the diseased heart at this time.

Blood volume increases 40 to 50 percent during normal pregnancy, in part due to estrogen-mediated activation of the renin-aldosterone axis. The rise in blood volume is greater than the increase in red blood cell mass, contributing to the fall in hemoglobin concentration (eg, the "anemia of pregnancy").

Cardiac output rises 30 to 50 percent above baseline. It peaks by the end of the second trimester, after which it reaches a plateau until delivery. The change in cardiac output is mediated by 1) increased preload due to the rise in blood volume, 2) reduced afterload due to a fall in systemic vascular resistance, 3) 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 caval compression by the gravid uterus. The direct effect of pregnancy on cardiac contractility is controversial.

Blood pressure typically falls, usually reaching a nadir of 10 mm Hg below baseline by the end of the second trimester. The decline in blood pressure is mediated by a fall in systemic vascular resistance induced by hormonal changes and by the addition of a low-resistance circuit through the uteroplacental bed.

During labor and delivery, hemodynamic fluctuations can be profound. Each uterine contraction results in the displacement of 300 to 500 ml of blood into the general circulation. Stroke volume increases, with a resultant rise in cardiac output by an additional 50 percent with each contraction. Mean systemic pressure also rises, in part due to maternal pain and anxiety. Blood loss during delivery (300 to 400 ml for a vaginal delivery and 500 to 800 ml for a cesarian section) can further compromise the hemodynamic state.

The hemodynamic changes during the post-partum state are mainly due to relief of vena caval compression after delivery. The resultant increase in venous return augments cardiac output and causes a brisk diuresis. The hemodynamic changes return to the pre-pregnant baseline within 3 to 4 weeks following delivery.

The marked hemodynamic changes associated with pregnancy explain the characteristic signs and symptoms that occur in the pregnant patient. Normal pregnancy is often associated with fatigue, dyspnea, and decreased exercise capacity. Pregnant women usually have peripheral edema and jugular venous distension. Most pregnant women have audible physiologic systolic murmurs, created by augmented blood flow. A physiologic third heart sound (S3), reflecting the volume overloaded state, can often be appreciated.

During normal pregnancy, noninvasive testing of the heart may include an electrocardiogram, a chest radiograph, and an echocardiogram. The electrocardiogram may reveal a leftward shift of the electrical axis, especially during the third trimester when the diaphragm is pushed upwards by the uterus. Routine chest radiographs should be avoided, especially in the first trimester. Echocardiography is an invaluable tool for diagnosis and evaluation of suspected cardiac disease in the pregnant patient. Normal changes attributable to pregnancy include increased left ventricular mass and dimensions.

Maternal and Fetal Outcomes:

Whenever possible, women with preexisting cardiac lesions should receive preconception counseling, including a discussion of contraception, maternal and fetal risks during pregnancy, and potential long-term maternal morbidity and mortality. The New York Heart Association functional class is often used as a predictor of outcome. Women with NYHA class III and IV face a mortality rate upwards of 7% and a morbidity rate of over 30%. These women should be strongly cautioned against pregnancy. In a study of 252 completed pregnancies in women with cardiac disease, five factors were found to be predictive of maternal cardiac complications (Table 2).¹ An updated risk index composed of the following four risk factors was shown to accurately predict a woman's chance of having adverse cardiac or neonatal complications: 1) a prior cardiac event, 2) cyanosis or poor functional class, 3) left heart obstruction, and 4) systemic ventricular dysfunction.²

Specific congenital or acquired cardiac lesions can be classified as low, intermediate, or high risk (Table 3).³

Low Risk Lesions:

Young women with uncomplicated secundum-type atrial septal defect (ASD) or isolated ventricular septal defect (VSD) usually tolerate pregnancy well. Patent ductus arteriosus (PDA) is not associated with additional maternal risk for cardiac complications if the shunt is small to moderate and if pulmonary artery pressures are normal. Antibiotic prophylaxis prior to labor and delivery is recommended for VSD and PDA (except in patients who are > 6 months after repair); it is not required for ASD.

Mitral Regurgitation
Chronic mitral regurgitation most commonly is the result of rheumatic heart disease or myxomatous degeneration and usually is well tolerated during pregnancy. However, new onset atrial fibrillation or severe hypertension can precipitate hemodynamic deterioration. Acute mitral regurgitation (eg, from rupture of chordae tendineae) may produce flash pulmonary edema and life-threatening cardiac decompensation. Women with severe mitral regurgitation prior to pregnancy are advised to undergo operative repair prior to conception. Mitral valve prolapse in isolation rarely causes any difficulties during pregnancy.

Aortic Regurgitation
Aortic regurgitation may be encountered in women with rheumatic heart disease, a congenitally bicuspid or deformed aortic valve, infective endocarditis, or connective tissue disease. Aortic regurgitation generally is well tolerated during pregnancy. Ideally, women with severe aortic regurgitation should undergo operative repair prior to conception. Women with bicuspid aortic valves, with or without aortic regurgitation, are at increased risk for aortic dissection and should be followed carefully for signs and symptoms of this complication.

Congestive heart failure from either mitral or aortic regurgitation can be treated with digoxin, diuretics, and vasodilators such as hydralazine. Angiotensin converting enzyme inhibitors are teratogenic and therefore contraindicated. Beta blockers are generally safe during pregnancy, although fetal bradycardia and growth retardation has been reported.⁴ Antibiotic prophylaxis is recommended for both AR and MR during labor and delivery.

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 and/or during 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 may result in rapid decompensation. Digoxin and beta-blockers can reduce heart rate, and diuretics may be used to reduce blood volume and left atrial pressure. With atrial fibrillation and hemodynamic deterioration, electrocardioversion can be performed safely and promptly. The development of atrial fibrillation increases the risk of stroke, necessitating the initiation of anticoagulation.

Mild mitral stenosis often can be managed with careful medical therapy during pregnancy. In contrast, patients with moderate to severe mitral stenosis should be referred to a cardiologist. These women may require correction via operative repair/replacement or percutaneous mitral balloon valvotomy prior to conception or during pregnancy.

Most patients with mitral stenosis can undergo vaginal delivery. However, patients with symptoms of congestive heart failure or moderate to severe mitral stenosis should undergo hemodynamic monitoring with a Swan Ganz catheter during labor, delivery, and for several hours into the post-partum period. In these patients, epidural anesthesia is usually better tolerated hemodynamically than general anesthesia during labor and delivery. Antibiotic prophylaxis is recommended during labor and delivery.

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 left ventricular function usually is well tolerated during pregnancy. Severe aortic stenosis (aortic valve area < 0.7 cm², mean gradient > 50 mm Hg), in contrast, markedly increases the risk of pregnancy. Symptoms such as dyspnea, angina pectoris, or syncope usually become apparent late in the second trimester or early in the third trimester.

Women with known severe aortic stenosis should be referred to a cardiologist. Ideally, they should undergo correction of the valvular abnormality prior to conception. When severe symptomatic aortic stenosis is diagnosed during pregnancy, percutaneous aortic balloon valvuloplasty should be performed prior to labor and delivery. Spinal and epidural anesthesia are discouraged during labor and delivery because of their vasodilatory effects. As with mitral stenosis, hemodynamic monitoring with a pulmonary arterial catheter and antibiotic prophylaxis are recommended during labor and delivery.

High Risk Lesions:

The high-risk conditions listed in Table 3 ³ are associated with increased maternal and fetal mortality. Pregnancy is not advised. If pregnancy should occur, therapeutic abortion is advised. These patients are best managed with the assistance of a cardiologist.

Peripartum Cardiomyopathy:

Peripartum cardiomyopathy (PPCM) is defined as the development of idiopathic left ventricular systolic dysfunction (demonstrated by echocardiography) in the interval between the last month of pregnancy up to the first five months post-partum in women without preexisting cardiac dysfunction. The incidence of PPCM in the United States is estimated to be 1 in 3000 to 1 in 4000 live births. The exact etiology of PPCM is unknown, although viral myocarditis has been proposed as a possible cause (Figure 1).⁵

Women who develop PPCM rarely have symptoms before 36 weeks gestation. In contrast, women with preexisting cardiac dysfunction usually experience cardiac deterioration during the end of the second trimester. Typical signs and symptoms include fatigue, dyspnea on exertion, orthopnea, non-specific chest pain, peripheral edema, and abdominal discomfort and distension.

Medical therapy for PPCM is similar to therapy for cardiomyopathies of other etiologies. Digoxin, diuretics, and hydralazine may be used safely during pregnancy and while breastfeeding. Beta-blockers may improve left ventricular function and are considered safe during pregnancy, although there have been case reports of fetal bradycardia and growth retardation. ACE inhibitors are contraindicated. Given the hypercoagulable state associated with pregnancy, anticoagulation can be considered in select patients with severe left ventricular dilatation and dysfunction. As with other etiologies of dilated cardiomyopathy, when conventional medical therapy is not successful, women with PPCM may be candidates for cardiac transplantation postpartum.

The prognosis after development of PPCM is variable. Fifty to sixty percent of women completely recover normal heart size and function, usually within 6 months of delivery. The remainder either experience persistent stable left ventricular dysfunction or continue to experience clinical deterioration. Maternal mortality estimates range from 10 to 50 percent. Women with PPCM and persistent left ventricular dysfunction who attempt subsequent pregnancy face a high risk of maternal morbidity and mortality.⁶ These women should be counseled against subsequent pregnancies.

Hypertension in Pregnancy:

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

Chronic hypertension is a blood pressure > 140/90 mm Hg present prior to pregnancy, before the 20th week of gestation, or persisting beyond the 42^nd post-partum day. Drug therapy for diastolic blood pressure > 110 mm Hg has been shown to reduce the risk of stroke and cardiovascular complications. Options for drug therapy are shown in Table 4.⁷

Gestational hypertension is hypertension that a) develops in the latter part of pregnancy, b) is not associated with proteinuria or other features of preeclampsia, and c) resolves by 12 weeks post-partum. This condition may portend the development of chronic hypertension in the future, but otherwise is associated with good maternal and fetal outcomes.

Preeclampsia occurs in 3 to 8 percent of pregnancies in the United States. Primagravid women under the age of 20 years are at the highest risk for development of this disorder. The classic clinical triad involves gradual onset of hypertension, proteinuria (>300 mg/24 hours), and edema. Symptoms usually begin in the third trimester and resolve with delivery. The etiology of preeclampsia is still unclear. Eclampsia is the development of grand mal seizures in a woman with preeclampsia.

Untreated preeclampsia is a risk to both the fetus and the mother. When preeclampsia is accompanied by risk factors including seizures, severe hypertension, HELLP syndrome [hemolysis, elevated liver enzymes, low platelets], placental abruption, cerebral hemorrhage, pulmonary edema, renal failure, or liver failure, the fetus must be delivered immediately. Antihypertensive agents are usually initiated after the diastolic blood pressure exceeds 105 mm Hg and the systolic pressure is greater than 160 to 180 mm Hg. Hydralazine, labetolol, and methyldopa are first line agents in the treatment of hypertension in pregnant women. Calcium channel blockers, such as amlodipine or diltiazem, are also used. Hypertension due to preeclampsia typically improves within a few days of delivery and should return to baseline by 12 weeks following delivery.

Coronary Artery Disease:

Acute myocardial infarction during pregnancy is rare, occurring in 0.01 percent of pregnancies. Most myocardial infarctions occur during the third trimester in women over age 33 who have had multiple prior pregnancies. Coronary spasm, in situ coronary thrombosis, and coronary dissection occur more frequently than classic obstructive atherosclerosis. The diagnosis and management of acute myocardial infarction in the pregnant patient should follow the guidelines established for the general population.

Medical therapy for acute myocardial infarction must be modified in the pregnant patient. Thrombolytic agents increase the risk of maternal hemorrhage substantially to 8%. Low dose aspirin and nitrates are considered safe. Beta-blockers generally are safe. Short-term heparin administration has not been associated with increased maternal or fetal adverse effects. Angiotensin-converting enzyme (ACE) inhibitors and statins are contraindicated during pregnancy. Hydralazine and nitrates may be used as substitutes for ACE inhibitors.

Arrhythmias in Pregnancy:

Premature atrial and/or ventricular complexes are not associated with adverse maternal or fetal outcomes and do not require antiarrhythmic therapy. Atrial fibrillation and atrial flutter are rare during pregnancy. Rate control can be safely achieved with digoxin and beta-blockers. Electrical cardioversion can be performed safely during any stage of pregnancy. Other arrhythmias should be managed with the assistance of a cardiologist.

Cardiovascular Drugs in Pregnancy:

The most commonly used cardiovascular drug classes and their potential adverse effects during pregnancy are shown in Table 5.⁷

Anticoagulation:

Several conditions require the initiation or the maintenance of anticoagulation during pregnancy (Table 6). The three most common agents considered for use during pregnancy are unfractionated heparin (UH), low molecular weight heparin (LMWH), and warfarin. The Sixth American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy has recommended three potential strategies for anticoagulation during pregnancy (Figure 2).⁸ While all three strategies can be utilized, the majority of practitioners use heparin during the first trimester and after the 35^th week and warfarin during the second trimester and the initial part of the third trimester. Nevertheless, the choice of anticoagulation regimens depends on the preferences of the patient and physician after consideration of the maternal and fetal risks associated with each drug.

Warfarin freely crosses the placental barrier and can harm the fetus. Warfarin is safe during breastfeeding. The incidence of warfarin embryopathy (abnormalities of fetal bone and cartilage formation) has been estimated at 4 to 10 percent; the risk is highest when warfarin is administered during the 6^th through the 12^th weeks of gestation. When administered during the second and third trimesters, warfarin has been associated with fetal central nervous system abnormalities. However, recent data suggest that the risk of warfarin embryopathy is low in patients who take < 5 mg of warfarin per day.⁹

Unfractionated heparin (UH) does not cross the placenta and is considered safer for the fetus. Its use, however, has been associated with maternal osteoporosis, hemorrhage, thrombocytopenia and/or thrombosis (HITT syndrome), and a high incidence of thromboembolic events with older generation mechanical valves. UH may be administered intravenously or subcutaneously throughout pregnancy; when used subcutaneously, the recommended starting dose is 10,000 units twice daily. The appropriate dose adjustment of UH is based on an activated partial thromboplastin time (aPTT) of 2.0 to 3.0 times the control level. High doses of UH are often required to achieve the goal aPTT due to the hypercoagulable state associated with pregnancy. Parenteral infusions should be stopped 4 hours before cesarean sections. UH can be reversed with protamine sulfate.

Low molecular weight heparin (LMWH) produces a more predictable anticoagulant response than UH and is less likely to cause HITT. Its effect on maternal bone mineral density is unclear. LMWH can be administered subcutaneously without regular laboratory monitoring. While there are data to support the use of LMWH in pregnant women with deep venous thrombosis,¹⁰ data on the safety and efficacy of LMWH in pregnant patients with mechanical valve prostheses are limited to a small number of cases. Experience with these agents is accruing.

In summary, anticoagulation in the pregnant patient can be difficult because of the risk profile associated with each drug regimen. In planned pregnancies, a careful discussion about the risks and benefits of warfarin, UH, and LMWH will help the patient and physican choose an anticoagulation strategy. Unplanned pregnancies are often diagnosed part way through the first trimester. It is advisable to stop warfarin when the pregnancy is discovered and to use UH or LMWH at least until after the 12^th week.

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