Manual of Cardiovascular Medicine

I.INTRODUCTION. Cardiovascular disease (CVD) is the leading cause of death of women in the United States and most developed countries, accounting for 1 in every 4 female deaths. Despite aggressive campaigns by the American Heart Association (AHA) and other organizations, only 54% of the women surveyed in 2009 listed coronary heart disease (CHD) as a leading cause of death for women, and only 13% of the women surveyed identified CHD as a risk for them personally. Minority women are even less aware of their cardiovascular (CV) risk, which is higher than for age-matched white women.

Gender-related differences exist in the presentation and outcome of CVD. In a national registry of over 300,000 patients (40% women) admitted with acute myocardial infarction (MI) between 1994 and 1998, female patients were found to be older compared with males (approximately 72 years vs. 66 years, respectively). Women also had higher in-hospital mortality compared with men (17% vs. 12%). Risk of death is particularly high in younger women, more than twice that of men in the under-50 age group, and also in women who presented with ST-elevation myocardial infarction (STEMI). These differences highlight the need to better understand and treat CVD in women. This chapter summarizes current understanding of the gender-specific features of CVD and concludes with a discussion of pregnancy and CVD.

II.GENDER DIFFERENCES IN PATHOPHYSIOLOGY. There appear to be gender-based differences in the atherosclerotic process of men versus women. Women, in general, have more diffuse atherosclerosis with less plaque volume and luminal obstruction than males. The underlying mechanism of thrombosis also appears to differ, with thrombosis in women resulting from superficial erosion of intact atheroma versus frank plaque rupture in males. Vasoreactivity, thrombosis, and inflammation are influenced by a variety of hormones, present in varying quantities in men and women. Women have smaller coronary arteries than men and, interestingly, women taking androgens have much larger coronary arteries than their age-matched controls. It is well established that estrogen confers protection from coronary artery disease (CAD) in premenopausal women. The exact mechanisms by which this occurs are not fully understood; however, it is likely multifactorial, with estrogen signaling involved in regulation of vasomotor tone, inhibition of smooth muscle cell proliferation, and maintenance of favorable metabolic conditions, including regulation of obesity, hypertension (HTN), and lipid profile. Animal studies suggest estrogen decreases oxidative stress via upregulation of the production of prostacyclin PGI₂, a molecule known to retard the progression of atherosclerosis. Additionally, women have higher levels of fibrinogen and factor VII, which may contribute to sex-related differences in endothelial function and hemostasis. There exists a clinical syndrome of typical angina pectoris with transient abnormal electrocardiogram (ECG) and/or ischemic stress testing, associated with normal or nonobstructive epicardial coronary disease on left heart catheterization (LHC). This clinical scenario is more common in women than men and is putatively caused by microvascular coronary dysfunction (MCD). In MCD, the microvasculature fails to appropriately vasodilate in response to increased myocardial oxygen requirements, perhaps because of hormonal signaling. The relationship between MCD and clinical outcomes is unknown. There is no known treatment or risk factor modification for microvascular dysfunction.

Stress cardiomyopathy, also known as Takotsubo cardiomyopathy or “broken heart syndrome” is another CVD affecting predominantly postmenopausal women. Stress cardiomyopathy is diagnosed when patients, often in the setting of severe emotional distress or physical trauma, present with chest pain, anterior ST-elevations, abnormal cardiac biomarkers, and characteristic appearance of an akinetic, ballooning apex on echocardiography or left ventricular (LV) ventriculogram. Diagnosis is a process of exclusion, including angiography which often reveals normal coronary vessels. The etiology of stress cardiomyopathy is not fully elucidated, but is believed to result from catecholamine toxicity with excessive sympathetic stimulation of the basal segment of the heart. Microvascular dysfunction and/or coronary vasospasm may also contribute to the pathophysiology of stress-induced cardiomyopathy. The prognosis of stress cardiomyopathy is very good, with the majority of patients recovering full ventricular function within weeks to months.

III.GENDER DIFFERENCES IN RISK FACTORS

A.Diabetes mellitus. Diabetes affects more women than men after the age of 60. In the female patient, diabetes increases the rate of CAD by three to seven times. Comparatively, men with diabetes have only a two- to threefold increased risk of CAD. Type 2 diabetes is associated with other components of the metabolic syndrome, all of which increase risk for CAD. Diabetes is also associated with the development of heart failure, with or without preserved ejection fraction (EF).

B.Hypertension. Women over the age of 65 have higher rates of HTN than males, with more than 73% of women aged 65 to 74 years diagnosed with HTN. A woman’s risk of developing HTN increases if she is 20 lb or more overweight, has a family history of HTN, or is postmenopausal. Women with HTN have a higher risk of both CAD and congestive heart failure than men with HTN. This risk for CVD related to HTN rises steeply with age, although most studies show that treatment attenuates this risk.

C.Hyperlipidemia. Lipid fractions in women are affected by their menopausal status. Premenopausal women have lower low-density-lipoprotein cholesterol (LDL-C) levels and higher high-density-lipoprotein cholesterol (HDL-C) levels than age-matched men. As women age, LDL-C increases, HDL-C decreases, and triglycerides increase. Total cholesterol and LDL-C are less predictive in women, unlike HDL-C, which is inversely associated with the risk.

D.Cigarette smoking. This is the single most preventable risk factor. Smoking leads to more CVD deaths than any other risk factor, likely owing to its effects of increasing inflammation, thrombosis, and oxidation of LDL-C. Smoking also has an antiestrogen effect, inducing unfavorable changes in lipid levels. There is a sixfold to ninefold increased risk of MI in female smokers compared with age-matched nonsmokers; in fact, the risk from smoking is equivalent to the risk of weighing about 42 kg more than a nonsmoking woman. However, with smoking cessation, risk is cut in half after 1 year without smoking and eventually declines back to baseline nonsmoker’s risk.

E.Obesity and metabolic syndrome. More than 30% of American women are obese, and this number continues to climb. In women, obesity and body fat distribution (i.e., abdominal location) are independent risk factors for CAD. As shown by an examination of a cohort of 115,195 women from the Nurses’ Health Study, risk of death from CVD increased with increasing body mass index (BMI).

F.Estrogen/menopause. Postmenopausal women have more CVD risk factors, such as obesity, HTN, and hyperlipidemia, likely owing to the precipitous decline in estrogen levels. The predominant source of estrogen changes from estradiol in the premenopausal state to the much weaker hormone estrone (produced by the conversion of androgens in peripheral adipose tissue) during menopause. Animal studies have shown that estrogen can have favorable CV effects, reducing cellular hypertrophy, enhancing vessel wall elasticity, and providing antioxidant and anti-inflammatory actions.

As part of the Women’s Ischemia Syndrome Evaluation study results, endogenous estrogen deficiency in young women was shown to be a strong risk factor for CHD, with a 7.4-fold increased risk. Because of the protection from CAD afforded for premenopausal women, there was early enthusiasm for the use of hormone replacement therapy (HRT) to prevent CVD in postmenopausal women, sparked by data from observational studies. However, multiple randomized, placebo-controlled trials over recent years have shown evidence of increased risk for CVD with HRT, such that it is no longer recommended for primary or secondary prevention of CVD (see Section VI.F).

G.Physical inactivity. As women age, they become less physically active than their male counterparts. This contributes to weight gain and predisposes to the development of diabetes and HTN. In addition, with the cessation of estrogen production with menopause, there is increased abdominal fat deposition, further predisposing to CAD. There is a strong inverse association between the activity level and incidence of CV events (see Tables 40.1 and 40.2).

TABLE 40.1 Risk Classification of Cardiovascular Disease in Women
High Risk	At Risk	Optimal Risk
•Known CAD	•Subclinical atherosclerosis (e.g., coronary calcification, carotid plaque, or thickened intima media)	•Fasting blood glucose <100 mg/dL (untreated)
•Cerebrovascular disease	•Cigarette smoking	•Nonsmoker
•Peripheral arterial disease	•Poor diet	•Healthy (Dietary Approaches to Stop Hypertension [DASH]-like) diet
•End-stage renal or chronic kidney disease	•Physical inactivity	•Physical activity goal for adults <20 y of age: >150 min/wk moderate intensity, >75 min/wk vigorous intensity, or combination
•Diabetes	•Obesity (especially abdominal location)	•BMI < 25 kg/m²
•10-y Framingham global risk >10%	•Dyslipidemia (total cholesterol > 200 mg/dL, HDL-C < 50 mg/dL, or treated for dyslipidemia)	•Total cholesterol < 200 mg/dL (untreated)
	•HTN (SBP > 120 mm Hg, DBP > 80 mm Hg, treated HTN, or history of pregnancy-induced HTN)	•BP < 120/< 80 mm Hg (untreated)
	•Family history of premature CAD (<55 y in men, <65 y in women)
	•Metabolic syndrome or history of preeclampsia or gestational diabetes
	•Poor exercise capacity on exercise treadmill test and/or abnormal heart rate recovery after stopping exercise
	•Family history of premature CVD occurring in first-degree relatives in men <55 y of age or in women <65 y of age
	•Autoimmune diseases (e.g., SLE or RA)

BMI, body mass index; BP, blood pressure; CAD, coronary artery disease; CVD, cardiovascular disease; DBP, diastolic blood pressure; HDL-C, high-density-lipoprotein cholesterol; HTN, hypertension; RA, rheumatoid arthritis; SBP, systolic blood pressure; SLE, systemic lupus erythematosus.

Adapted from ACC/AHA guidelines 2011 update. Adapted from Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women—2011 update: a guideline from the American Heart Association. J Am Coll Cardiol. 2011;57(12):1404–1423. Copyright © 2011 American Heart Association, Inc. With permission.

TABLE 40.2 Evidence-Based Guidelines for Prevention of Heart Disease in Women
Lifestyle Interventions	Major Risk Factor Interventions	Preventive Drug Interventions
Class I Recommendations
Smoking cessation (B)	Maintain optimal BP (<120/80 mm Hg) with lifestyle modification (B)	ASA in high-risk women (known CAD, cerebrovascular disease, PAD, AAA, ESRD, CKD, diabetes, and 10-y Framingham risk >20%) (A)
Exercise: 150 min/wk of moderate intensity exercise (e.g., brisk walking), 75 min/wk of vigorous intensity exercise (e.g., running), or combination (B)	Pharmacotherapy for BP ≥ 140/90 mm Hg (≥130/80 mm Hg in CKD or diabetes). Thiazide should be initial agent unless compelling indications for β-blockers and/or ACE inhibitor/ARB exist (e.g., ACS/MI) (A)	Clopidogrel therapy for high-risk women intolerant of ASA (B)
Weight loss to BMI <25 kg/m² and waist circumference ≤35″ (B)	Control of lipids through lifestyle modification (LDL-C < 100 mg/dL, HDL-C > 50 mg/dL, triglycerides < 150 mg/dL, and non–HDL-C [total cholesterol—HDL-C] < 130 mg/dL) (B	β-Blockers for at least 1 y and up to 3 y in women after MI and ACS, with normal LV function. Use indefinitely if LV dysfunction present (A)
CV rehabilitation in those with recent ACS or PCI, angina, and recent CVA, PAD, or CHF (B)	Pharmacotherapy of lipids in those with CAD (A), diabetes, or 10-y absolute risk >20% (B) to goal LDL-C <100 mg/dL	ACE inhibitors in those after MI or with clinical CHF, LV dysfunction (LVEF ≤ 40%), or diabetes (A). If intolerant of ACE inhibitor, ARB can be substituted (B)
Diet counseling to promote intake of fruits and vegetables, whole grain and high-fiber foods, and fish at least two times per week. Limit consumption of saturated fat, cholesterol, alcohol, sodium, and trans-fatty acids (B)	Pharmacotherapy of lipids in those with LDL-C ≥130 mg/dL after lifestyle modification and presence of multiple risk factors (or if LDL-C ≥160 mg/dL in those with multiple risk factors, even if Framingham risk <10%) (B Pharmacotherapy of lipids in those with LDL-C ≥190 mg/dL regardless of other risk factors Maintain HbA1c <7% in diabetics (B)	Aldosterone blockade after MI in symptomatic women with LVEF ≤40% who are without renal dysfunction or hyperkalemia and who are already on an ACE inhibitor and β-blocker (B)
Class IIa Recommendations
	Goal LDL-C < 70 mg/dL is reasonable in the very high risk (known CAD + multiple major risk factors, severe and poorly controlled risk factors, or diabetes) (B)
Class IIb Recommendations
ω-3 fatty acid in the form of fish or capsule (e.g., EPA 1,800 mg/d) may be considered in women with hypercholesterolemia or hypertriglyceridemia for primary or secondary prevention (B)	Pharmacotherapy with niacin or fibrates when HDL-C is low or non–HDL-C is elevated in high-risk women (after LDL-C goal reached) (B)	Low-dose ASA therapy (81 mg daily or 100 mg on alternate days) in women ≥65 y if benefits outweigh risk of bleeding (B)

AAA, abdominal aortic aneurysm; ACE, angiotensin-converting enzyme; ACS, acute coronary syndrome; ARB, angiotensin II receptor blocker; ASA, aspirin; BMI, body mass index; BP, blood pressure; CAD, coronary artery disease; CHF, congestive heart failure; CKD, chronic kidney disease; CV, cerebrovascular; CVA, cerebrovascular accident; EPA, eicosapentaenoic acid; ESRD, end-stage renal disease; HbA1c, glycosylated hemoglobin; HDL-C, high-density-lipoprotein cholesterol; LDL-C, low-density-lipoprotein cholesterol; LV, left ventricular; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PAD, peripheral arterial disease; PCI, percutaneous coronary intervention.

H.Novel risk factors. Traditional risk factors are known to underestimate CHD risk in women. For this and other reasons, research has been focused on identifying other novel biomarkers that can better define a woman’s risk. Multiple biomarkers have been investigated (e.g., high-sensitivity C-reactive protein [hsCRP], brain natriuretic peptide, and fibrinogen), but the greatest promise appears to be with hsCRP. As part of the Women’s Health Study, over 27,000 healthy American women had their CRP and LDL-C levels measured. The women were then followed for a mean of 8 years for the occurrence of the primary end point (MI, ischemic stroke, coronary revascularization, or death from CVD). Although minimally correlated with each other, both CRP and LDL-C levels had strong linear relationships with CVD events, with CRP being the stronger predictor. Each biomarker tended to identify different high-risk groups, but better prognostic values were obtained when both were used together. Routine measurement of hsCRP is not currently recommended, but these data suggest hsCRP may add benefit to the risk assessment of women with intermediate CV risk.

IV.GENDER DIFFERENCES IN CLINICAL MANIFESTATIONS. CVD often manifests differently in women than men, potentially because of underlying differences in pathophysiology. This is particularly true for diabetic women. Women usually present at an older age and have more comorbidities than do men. As such, once the diagnosis of CAD is made, women are at higher risk for adverse outcomes.

A.Like men, women can present with typical symptoms of angina, such as substernal chest pain and dyspnea on exertion that is relieved by rest. These symptoms more often occur in older women, who present more similarly to men.

B.Women can also present with atypical chest pain; shortness of breath; neck, shoulder, or arm pain; diaphoresis; and nausea/vomiting.

C.Women are more likely to have subtle symptoms that require detailed history-taking to elicit, such as chest “pressure or tightness,” lightheadedness, palpitations, or fatigue. Women most often have symptoms that occur at rest, wake them from sleep, or occur in times of psychological stress.

D.Women more often present acutely without preexisting prodromes of symptoms or with sudden cardiac death.

V.GENDER DIFFERENCES IN ASSESSMENT

A.Exercise electrocardiography. Guidelines suggest that women at low risk for CAD are not candidates for diagnostic testing, whereas women who are intermediate to high risk capable of performing 5 metabolic equivalents or greater should undergo an exercise ECG. As with men, an abnormality is identified if there is ≥1 mm of ST-segment depression or elevation. Generally, exercise ECG has lower sensitivity and specificity than other modalities, and this is even more prominent in women (sensitivity and specificity of 31% to 71% and 66% to 88%, respectively). This difference is not well understood, but it has been attributed to several factors, including lower ECG voltage and more frequent resting ST and T-wave changes. In general, women are more likely than men to have a false positive stress test; however, a negative exercise stress test has a negative predictive value of ~80%.

B.Stress echocardiography (transthoracic echocardiography [TTE]). Stress TTE tends to have higher specificity and lower sensitivity than stress perfusion imaging, as wall motion abnormalities occur later than perfusion abnormalities. However, stress TTE has the advantages of eliminating radiation exposure, decreasing cost, and providing the ability to assess LV function and cardiac structures. It has been shown to be a cost-effective strategy for determining CV risk in patients at intermediate risk.

C.Stress myocardial perfusion scan. Because of the limited sensitivity and specificity of exercise ECG in women, other modalities are frequently employed to assess the risk of CAD. The most frequently used test is the single-photon emission computed tomography (SPECT) scan, a radionuclide-based technique. Because alterations in myocardial perfusion generally occur earlier than electrocardiographic changes or wall motion abnormalities, this test is more sensitive than exercise ECG or echocardiography for estimating risk in either gender. For those individuals unable to exercise or attain target heart rates, adenosine or dipyridamole can be used as a pharmacologic stress agent. To increase specificity, the higher energy isotopes (technetium 99m) are recommended in women to reduce the soft tissue attenuation artifacts (influenced by both breast tissue and obesity) that tend to occur anteriorly and laterally. Other limitations of SPECT can be critical in women. Because women have smaller hearts, the limitations in spatial resolution of SPECT can lead to small areas of hypoperfusion being missed.

D.Coronary angiography. Diagnostic coronary angiography is the gold standard for diagnosing CAD in both men and women. When evaluated by LHC, however, women more often have minimal to no obstructive CAD. For reasons not fully elucidated, women tend to experience vascular complications such as bleeding and renal failure related to diagnostic LHC more frequently than do men. The occurrence of a complication is thought to be related to older age at the time of presentation, smaller body size, smaller vessel size, and higher prevalence of diabetes. A radial approach to diagnostic and interventional coronary procedures leads to less bleeding complications than femoral catheterizations in both men and women and, when feasible, should be considered in women.

VI.GENDER DIFFERENCES IN THERAPIES. Most CVD in women, as in men, can be prevented if risk factor modification occurs early and aggressively. Until recently, most of the clinical trial data, on which the guidelines for prevention and treatment of both genders are based, were derived from trials conducted largely in men. This information had been extrapolated to women because gender-specific trial data were lacking. Because of this uncertainty, more recent clinical trials have offered insights into gender-specific results, allowing for evidence-based guidelines for disease prevention and treatment in women. However, with only a few exceptions, the guidelines are the same for both men and women. The gender-specific results are highlighted here; for a full discussion, please see appropriate sections of previous chapters.

A.Aspirin. Aspirin (ASA) is the principal antiplatelet agent in patients with CAD. Its benefit in secondary prevention, as well as in acute coronary syndrome (ACS), STEMI, and after revascularization (coronary artery bypass grafting or percutaneous coronary intervention [PCI]), is well known and discussed elsewhere. However, there are very few gender-specific data in these instances, so most recommendations are extrapolated from trials conducted largely in men.

The role of ASA in primary prevention of CAD in women is better defined. Early data suggested that ASA may be protective as primary prevention for future CVD events in women, as it is in men. However, as part of the Women’s Health Study, 39,876 healthy women older than age 45 were randomized to either ASA 100 mg on alternate days or placebo, and they were followed for the incidence of CV events (nonfatal MI, nonfatal stroke, or CV death) over 10 years. Despite a 24% reduction in ischemic stroke, ASA had no benefit over placebo in reducing MI or CV death. However, ASA did appear protective as primary prevention in those women aged 65 years or older, because it significantly decreased the risk of both MI and stroke in this age group. In 2016, the United States Preventive Services Task Force reported that low-dose ASA (≤100 mg/day) for primary prevention in both men and women showed the most significant positive benefit when initiated between age 40 and 69, with harm potentially exceeding benefit in people starting ASA after the age of 70. Harm may also outweigh benefits in men and women during the first 10 to 20 years of ASA use. Notably, there is an increased risk of bleeding for women taking daily ASA, highlighting the need for an individualized approach to the use of ASA as primary prevention in older women.

B.Thienopyridines. Thienopyridines, the most common of which is clopidogrel, have proven beneficial, when given with ASA, to reduce the rate of stent thrombosis after PCI. Clopidogrel has also shown benefit in secondary prevention of CAD, ACS, and STEMI (discussed in detail elsewhere). Few of the clinical trials using clopidogrel have given gender-specific data, but there are some data available for specific settings.

In the substudy of the Clopidogrel in Unstable angina to prevent Recurrent Events trial, in which the patients received PCI, 2,658 patients with non–ST-segment elevation ACS undergoing PCI were randomly assigned to ASA plus clopidogrel or placebo for 9 months. Of the study population, 30.2% were women. Clopidogrel plus ASA long-term therapy improved outcomes in those patients who received PCI. This was more significant in men, but a definite trend toward benefit in women was evident as well. Similar results were seen for women in the Clopidogrel for the Reduction of Events During Observation (CREDO) trial, where 29% of the 2,116 patients were women. The CREDO trial showed benefit of post-PCI therapy with ASA and clopidogrel out to 1 year of therapy, again with a trend toward benefit in women. CREDO trial also revealed, by subgroup analysis, equally beneficial effects of a loading dose of clopidogrel in men and women.

C.Statins. The primary prevention efficacy of statins in women is unclear because of underrepresentation of women in clinical trials; however, multiple studies suggest that women achieve equal, if not greater clinical benefit from statins than men. This is potentially due to underlying differences in atherogenesis between the sexes. The Cholesterol Treatment Trialists’ collaboration performed a meta-analysis of 27 statin trials where approximately one quarter of the patients were female. This meta-analysis showed that for equivalent reductions in LDL-C, men and women have similar relative risk reductions in vascular events. Furthermore, a post hoc subgroup analysis of the PROVE IT-TIMI 22 suggested that women may actually have greater risk reduction than men with lesser degrees of LDL-C reduction. In the Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin, multivariable analysis showed greater decreases in plaque volume for women compared to men, across both rosuvastatin and atorvastatin treatment groups.

D.Hormone replacement therapy. Despite beneficial evidence from previous observational studies which demonstrated decreased rates of CVD in postmenopausal women, data from randomized control trials have presented conflicting results In 2002, the Heart and Estrogen/progestin Replacement Study (HERS) reported an association between oral HRT and increased rates of coronary disease and stroke. In this study of secondary prevention, 2,763 postmenopausal women with CAD were randomized to either 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate or placebo daily. After an average 4-year follow-up, there was no significant difference in the primary outcome of nonfatal MI or CHD death between the groups. Of interest, however, was the fact that the greatest numbers of CV events were noted within the first year in the HRT group. Not surprisingly, the HRT group had a greater incidence of venous thromboembolism (VTE) and gallbladder disease.

Because of the high number of CV events in the first year, the investigators thought that the beneficial effects of HRT might be observed after time, because it appeared that HRT became more protective by 4 to 5 years of follow-up in the HERS population. With this in mind, the HERS II study followed 2,321 of the original HERS patients, the majority of whom stayed on their original treatment in an open-label format, for an average of 6.8 years. After the longer follow-up, there was still no difference in nonfatal MI or CHD death between the groups; however, there was an increased rate of stroke. These studies received significant publicity and led to a decrease in oral HRT prescriptions. These studies received criticism for enrolling patients with a mean age in the mid-60s, 10 years later than the average age of menopause. Subgroup analysis subsequently suggested that women started on HRT prior to age 60 may have a trend to decreased CV events.

To date, there have been nine primary prevention trials of HRT, which in a meta-analysis showed a significant association between oral HRT and increased incidence of stroke, pulmonary embolism, and VTE, but no significant association with all-cause mortality, death by CV cause, nonfatal MI, angina, or revascularization. A meta-analysis of the 10 secondary prevention trials published to date again showed a significant association between oral HRT and rates of VTE, but no association with all-cause mortality, death by CV cause, MI, angina, or revascularization. A subgroup analysis of these trials demonstrated an association with lower rates of all-cause mortality and CHD if oral HRT is started within 10 years of menopause or before 60 years of age.

Based on the 2011 American Heart Association Guideline for the Prevention of Cardiovascular Disease in Women, HRT should not be recommended for the primary or secondary prevention of CVD.

E.Lifestyle modification. The good news for women is that initiating lifestyle modifications can reduce CV risk by reducing the risk of developing diabetes. As part of the Diabetes Prevention Program Research Group, 3,234 patients (68% women) with impaired glucose tolerance were randomized to placebo, metformin (850 mg twice daily), or lifestyle modification (goal 7% weight loss and at least 150 minutes of physical activity per week). After almost 3 years of follow-up, the lifestyle modification group had a 58% reduction in the incidence of diabetes compared with 31% in the group with metformin. This translates to a decreased risk of CVD.

VII.EVIDENCE-BASED GUIDELINES FOR HEART DISEASE PREVENTION IN WOMEN. The American College of Cardiology (ACC)/AHA guidelines emphasize the importance of recognizing the wide-ranging spectrum of CV disease in women. In general, a woman aged 20 years or older is first classified as at high risk, at risk, or at optimal risk based on the criteria in Table 40.1. Several factors should be evaluated, such as medical history, lifestyle, family history of premature CAD, Framingham risk score, and other genetic conditions, before decision regarding the aggressiveness of preventive therapy is finalized.

The guidelines are grouped into three main areas: lifestyle interventions, major risk factor interventions, and preventive drug interventions. Table 40.2 lists the class I and class IIa recommendations for primary or secondary prevention of CVD in women. These guidelines are suggested as a starting point, with therapy tailored to the needs of each individual patient.

In general, it is suggested that the initial evaluation begin with a complete history, specifically eliciting symptoms of CVD, as well as a complete physical examination, with particular attention to blood pressure, BMI, and waist size. Laboratory evaluation should follow, including fasting lipids and glucose levels. During the evaluation, assessment of Framingham risk should be performed, as well as depression screening in those women with known CVD. All class I lifestyle interventions should be employed in all women, regardless of risk level.

If the woman is at high risk (established CAD, cerebrovascular disease, peripheral arterial disease, abdominal aortic aneurysm, diabetes, chronic kidney disease, or Framingham risk > 20%), the class I major risk factor and preventive drug interventions should be initiated (see Table 40.2). Consideration should also be given to some of the class II recommendations, particularly the LDL-C goal of <70 mg/dL.

There are some interventions that should not be considered under any circumstances. Table 40.3 lists those therapies that are contraindicated based on the results of recent clinical trials.

TABLE 40.3 Class III Interventions (Ineffective, Possibly Harmful in Cardiovascular Disease Prevention in Women)

Hormone replacement therapy or selective estrogen receptor modulators

Antioxidant vitamin supplementation (vitamin E, vitamin C, and β-carotene)

Folic acid with or without vitamin B₆ or B₁₂ (folic acid supplementation should be used in the childbearing years to prevent neural tube defects)

ASA in healthy women < 65 y

ASA, aspirin.

VIII.HEART DISEASE AND PREGNANCY

A.Introduction. Maternal cardiac disease is a major risk factor for nonobstetric mortality and morbidity in pregnant women. Substantial progress in the management of congenital heart disease has occurred over recent decades, so the majority of females born with heart defects now survive into their reproductive years. Advances in obstetrics have also enabled pregnancy in older mothers in whom HTN and acquired heart disease are more prevalent and can pose challenges for the pregnancy. Rheumatic heart disease is less common than in the past, but is still encountered, especially in immigrant populations in the United States, and may manifest clinically for the first time in pregnancy. Cardiac disease has significant bearing on both maternal and fetal outcomes, and it is therefore essential that cardiologists and internists have a working knowledge of the impact of pregnancy on various cardiac diseases on pregnancy and can tailor management appropriately. In most cases, the presence of maternal heart disease does not preclude successful pregnancy, although thorough discussion and planning regarding risks and management strategies should begin prior to conception whenever possible.

B.Normal physiologic changes during pregnancy. A series of cardiocirculatory changes occur in pregnancy and peripartum. These changes usually begin during the early first trimester (5 to 8 weeks), peak in the late second trimester, and tend to plateau thereafter until the postpartum period. This second trimester peak in hemodynamic adaptations tends to correlate with the onset of clinical manifestations of cardiac complications during pregnancy.

1.The increase in blood volume during pregnancy is attributed to estrogen-mediated stimulation of the renin–aldosterone system, leading to salt and water retention. The plasma volume expansion varies from 20% to 100% and averages around 50%. The relatively greater increase in plasma volume as compared with red blood cell mass leads to the physiologic anemia of pregnancy, which usually manifests around 30 weeks.

2.Cardiac output, stroke volume, and heart rate. Table 40.4 summarizes the changes in heart rate, stroke volume, and cardiac output. The cardiac output is estimated to increase by approximately 30% to 50% above baseline. The increase is attributed to higher preload as a result of increased blood volume, decreased systemic vascular resistance, and an increase in maternal heart rate by 10 to 15 beats/min. During the third trimester, stroke volume and cardiac output are dependent on body position and increase in the lateral position (particularly left lateral) and decline in the supine position because of compression of the inferior vena cava by the gravid uterus.

TABLE 40.4 Normal Hemodynamic Changes during Pregnancy and Postpartum Period
Changes during Different Phases of Pregnancy
Hemodynamic Parameter	First Trimester	Second Trimester	Third Trimester	Labor and Delivery	Postpartum
Heart rate	↑5%–10%	↑10%–15%	↑15%–20%	↑20%–30%	↓
Stroke volume	↑5%–30%	↑30%–40%	↓20%–30%	↑300–500 mL with each contraction	↓
Cardiac output	↑5%–30%	↑30%–40%	↑>40%	↑50%	Initial ↑ then ↓
Systolic BP	↔ to ↓	↓	↔ to ↑	↑	Baseline
Diastolic BP	↔ to ↓	↓	↓ to ↔	↑	Baseline
Systemic vascular resistance	↓10%–30%	↓30%–40%	↓30%–40%	↑	Baseline

BP, blood pressure.

3.Blood pressure and systemic vascular resistance. The decline in systemic vascular resistance causes blood pressure to begin to fall in the first trimester and reach a nadir of about 10 mm Hg below baseline by the end of the second trimester. The addition of low-resistance vessels in the uteroplacental bed also contributes to the decrease in afterload.

4.The pulse pressure widens due to the greater fall in diastolic blood pressure than in systolic pressure. As many as 11% of women develop the uterocaval syndrome of pregnancy, with a significant and symptomatic drop in blood pressure when lying supine because of vena caval compression. Weakening of the vascular walls of the medium and large muscular arteries occurs because of estrogen-mediated decreased collagen deposition and the effects of circulating elastase and relaxin. This makes pregnant women more susceptible to aortic dissection, especially in individuals with abnormally weak aortic tissue such as in Marfan syndrome.

5.A hypercoagulable state with decreased protein S, increased stasis, and venous HTN is also observed.

6.Hemodynamic changes during labor and delivery. Each uterine contraction displaces 300 to 500 mL of blood into maternal circulation (autotransfusion). Cardiac output increases approximately 75% during contractions because of an increase in stroke volume and heart rate. Blood pressure and oxygen consumption also rise. The magnitude of these changes is influenced by the mode of delivery and the method of anesthesia.

7.Hemodynamic changes postpartum. Despite blood loss during delivery (averaging 300 to 400 mL for vaginal delivery and 500 to 800 mL for cesarean section), there is a temporary increase in effective venous return because of autotransfusion and relief of caval compression. This may lead to an increase in stroke volume and cardiac output, resulting in augmentation in renal blood flow and a brisk diuresis. In women with preexisting cardiac disease, these rapid hemodynamic shifts may cause profound clinical deterioration. The hemodynamic changes associated with pregnancy usually persist for a few weeks postpartum and it may take up to 12 to 24 weeks for the parameters to return to their prepregnancy baseline.

C.Cardiovascular evaluation in pregnancy

1.History. Fatigue, dyspnea, ankle swelling, and reduced exertional capacity are common in normal pregnancy and can mimic cardiac disease. Chest pain, orthopnea, or paroxysmal nocturnal dyspnea may represent cardiac pathology.

2.Physical examination. Table 40.5 highlights the important cardiac findings in normal pregnancy. Signs of jugular venous distention, displaced point of maximal impulse, and peripheral edema are common in normal pregnancy. Normal auscultatory findings in pregnancy include exaggerated physiologic splitting of S₂, a physiologic S₃, a physiologic systolic murmur in the pulmonic area, and the continuous murmurs of “mammary soufflé” or a cervical venous hum. Examination findings that are not physiologic include an S₄, a loud systolic murmur, a purely diastolic murmur, and fixed splitting of S₂ or pulmonary crackles.

TABLE 40.5 Findings in Normal Pregnancy

Symptoms

Fatigue

Dyspnea

Palpitations

Reduced exercise tolerance

Orthopnea

Lower extremity edema

Physical examination

Hyperventilation

Lower extremity edema

Distended neck veins with prominent a- and v-waves and brisk x and y descents

Increased heart rate and wide pulse pressure

Upward and leftward deviation of point of maximal impulse

“Flow” murmurs (pulmonic and aortic)

Mammary soufflé (left sternal border, continuous murmur)

Increased first heart sound and exaggerated splitting of second heart sound

Third heart sound

Electrocardiographic findings

Sinus tachycardia

Leftward axis deviation

Increased R/S ratio in leads V₁ and V₂

Repolarization changes

Echocardiographic findings

Increased LV diastolic dimension

Increased LV wall thickness

Mild increase in contractility

Moderate increase in size of right atrium, right ventricle, and left atrium

Functional pulmonary, tricuspid, and mitral regurgitation

Small pericardial effusion

LV, left ventricular.

3.Noninvasive testing with echocardiography is considered safe in pregnancy, and findings are as given in Table 40.5. Chest radiography should be performed only when absolutely necessary and with shielding of the pelvic area with protective lead. Magnetic resonance imaging is sometimes used for the diagnosis of cardiac disorders; its safety profile in pregnancy is unknown, and it should be avoided if possible.

4.Invasive testing with pulmonary artery catheterization (without fluoroscopy) can be utilized during pregnancy, labor, delivery, and the postpartum period for invasive monitoring and can be very useful for patients with hemodynamic complications. Cardiac catheterization during pregnancy is rarely needed, except in the setting of acute MI or to permit balloon valvuloplasty. Fluoroscopy and cine time should be minimized and direct radiation to the fetus avoided. Vascular access from the arm rather than the leg is preferred whenever feasible.

D.Risk assessment and general principles of management. One of the most important steps in managing a woman with heart disease considering pregnancy is to establish the level of maternal and fetal risk. This involves a multidisciplinary approach, with preconception counseling, contraception advice, and discussion of potential maternal and fetal acute and long-term morbidity and mortality. Baseline functional class, severity of cardiac disease, LV function, and pulmonary pressures should guide the risk assessment. Table 40.6 delineates a stepwise approach for management of women with preexisting cardiac disease, and Table 40.7 lists high-risk predictors. Maternal New York Heart Association (NYHA) class II symptoms or higher, LVEF <40%, or left-sided obstruction are factors known to be predictive of neonatal complications, including premature birth, intrauterine growth restriction, respiratory distress syndrome, and death. In certain conditions such as cyanotic congenital heart disease, Eisenmenger syndrome, or severe pulmonary HTN, pregnancy should be strongly discouraged, as patients with these conditions do not tolerate the hemodynamic changes of pregnancy. Formal risk prediction scores include Cardiac Disease in Pregnancy, which is composed of four clinical features (prior arrhythmia or cardiac event, NYHA functional class >II or cyanosis, left heart obstruction, systemic LV dysfunction with LVEF <40%) with maternal cardiac event rates of 5%, 27%, and 75% for 0, 1, and >1 of the features, respectively, and the more recent ZAHARA predictors derived from a large population of congenital heart disease patients.

TABLE 40.6 Basic Management Principles for Pregnant Women with Valvular Heart Disease

Risk Assessment

Preconception

Thorough history of cardiac symptoms and arrhythmias

Baseline exercise tolerance and functional class

Baseline ECG and echocardiography with ventricular function and pulmonary pressures

Detailed discussion with the patient about the potential risks to self and fetus

During Pregnancy

Follow-up evaluation at least once per trimester

Close monitoring of new symptoms or change in functional class

Serial echocardiography for development of any new symptoms or signs

Treatment

Preconception

Effective and safe contraception until pregnancy is desired

Consider valve repair or replacement, correction of anomaly prior to conception if pregnancy poses significant risk of worsening clinical status

Adjust medications to prevent adverse fetal side effects

During pregnancy

Minimize medication use to only those absolutely required and discontinue or replace medications contraindicated in pregnancy

If symptoms worsen and if indicated, consider correction of anomaly or valve repair or replacement

Labor and delivery

Invasive monitoring as needed

Cesarean section for obstetric indication

Monitor for decompensated heart failure and pulmonary edema and treat accordingly

Postpartum

Adjust and optimize medications

Consider correction of anomaly or valve repair or replacement if indicated

Treat postpartum anemia

Counseling and contraception for future pregnancies

ECG, electrocardiogram.

Adapted from Stout KK, Otto CM. Pregnancy in women with valvular heart disease. Heart. 2007;93(5):552–558, with permission from BMJ Publishing Group Ltd.

TABLE 40.7 Risk Predictors of Adverse Maternal and Fetal Outcomes

Prior cardiac events or medication

Prior arrhythmia

NYHA class II or higher, or cyanosis

EF < 40%

Pulmonary HTN (pulmonary artery systolic pressure > 50% systemic pressure)

Severe AS (valve area < 1.5 cm², Doppler jet velocity > 4 m/s)

Symptomatic or severe MS

Severe aortic or mitral regurgitation with NYHA class III or IV symptoms

Hypertrophic obstructive cardiomyopathy

Maternal anticoagulation

AS, aortic stenosis; EF, ejection fraction; HTN, hypertension; MS, mitral stenosis; NYHA, New York Heart Association.

Management of the pregnant patient with heart disease is a team effort involving the patient, her primary care physician, high-risk obstetric team, and cardiologist. Prophylactic intervention for cardiac lesions that significantly increase the risk of pregnancy should be performed before pregnancy when appropriate and feasible. Most patients with relatively low-risk cardiac conditions are successfully managed throughout pregnancy, labor, and delivery with conservative medical measures designed to optimize intravascular volume and systemic loading conditions. As with all pregnancies, medications should be used judiciously and only when absolutely required. Drugs that are contraindicated in pregnancy should be discontinued before conception if pregnancy is contemplated. Specific conditions and their management in pregnancy are described later. The list, although extensive, is not complete, as a detailed description of every condition is beyond the scope of this chapter.

E.Pregnancy in women with congenital heart disease. In general, patients with noncyanotic congenital heart disease have better outcomes with pregnancy compared with patients with cyanotic disease. Where applicable, patients should be made aware of the potential inheritability of the congenital disease.

1.Antibiotics. The 2007 AHA endocarditis guidelines recommend against the use of prophylactic antibiotics for vaginal delivery for any patient with congenital heart disease, unless she has incompletely repaired disease, completely repaired disease using prosthetic materials within the past 6 months, or unrepaired cyanotic congenital heart disease. The 2008 ACC/AHA guidelines on the management of adults with congenital heart disease suggest it is reasonable to consider antibiotics at the time of membrane rupture prior to vaginal delivery for patients with prosthetic cardiac material or unrepaired/palliated cyanotic defects.

2.Specific conditions and pregnancy

a.Atrial septal defect (ASD) and patent foramen ovale (PFO). Isolated ASD or PFO is usually well tolerated in pregnancy and considered low risk in general. Paradoxical pulmonary embolism during pregnancy has been reported. Ideally, an ASD with a significant shunt (>1.5:1) should be corrected prior to pregnancy. Secundum ASD that is repaired prior to pregnancy is not associated with an increased risk of complications.

b.Ventricular septal defect (VSD). Isolated VSD without pulmonary HTN is usually well tolerated during pregnancy, and correction of VSD prior to pregnancy and before development of pulmonary HTN eliminates the risk. In pregnant patients with VSD and pulmonary HTN, a drop in blood pressure during or after delivery can result in transient shunt reversal. This may be prevented by close monitoring of blood pressure, volume replacement, and the use of vasopressors, if necessary. VSD is commonly inheritable.

c.Patent ductus arteriosus without pulmonary HTN usually has a favorable outcome. In patients with pulmonary HTN, the management principles are similar to those with VSD.

d.Coarctation of aorta (COA). Coarctation, although usually associated with favorable outcomes, has been associated with severe HTN, congestive heart failure, or aortic dissection during pregnancy. There is an association with congenitally bicuspid aortic valves (AVs). It is also associated with circle of Willis aneurysms, and cerebral hemorrhage from rupture of an aneurysm during pregnancy is possible. Limiting physical activity and controlling blood pressure may prevent complications such as cerebral hemorrhage and dissection. β-Blockers are usually the antihypertensive drugs of choice, although care should be taken not to lower the blood pressure excessively because this may compromise uteroplacental circulation. COA with evidence of systemic HTN, heart failure, or a peak gradient >20 mm Hg should be corrected prior to pregnancy, although this does not alleviate the risk for dissection. Correction of COA during pregnancy is indicated in patients with severe uncontrollable HTN or heart failure and may be performed percutaneously.

e.Congenital aortic stenosis (AS). A congenitally bicuspid AV is one of the most common causes of AS. These patients should be screened for other cardiac malformations including COA. The details of management are described later in Section VIII.F.2.

f.Pulmonic stenosis. Isolated pulmonic stenosis is usually well tolerated in pregnancy. It should be corrected prior to pregnancy if severe (peak gradient > 60 mm Hg). Percutaneous balloon valvotomy during pregnancy may be required in patients with severe right ventricular failure.

g.Ebstein anomaly. Noncyanotic Ebstein anomaly is usually well tolerated. Cyanotic patients are at very high risk for maternal heart failure and fetal prematurity or death. During labor and delivery, care should be taken to prevent a drop in blood pressure, and close hemodynamic monitoring is required along with rest, oxygen, and blood gas monitoring. It is sometimes associated with Wolff–Parkinson–White syndrome, and pregnancy may precipitate supraventricular arrhythmias.

h.Tetralogy of Fallot (TOF). Women with TOF who have undergone successful repair during childhood with little or no residual outflow tract gradient, no pulmonary HTN, and preserved ventricular function usually tolerate pregnancy well. In women with uncorrected or only partially corrected TOF, increased blood volume during pregnancy with increased venous return and decreased systemic vascular resistance may result in right to left shunt and cyanosis. A similar process may also occur with a fall in blood pressure during labor and delivery. The outcome of pregnancy is very poor for both mother and fetus once cyanosis occurs. It is also associated with high rates of premature labor, spontaneous abortion, and fetal growth restriction. The risk of a cardiac defect in the neonate ranges from 3% to 17%; genetic counseling and screening for the 22q11 deletion should be offered to women with TOF. Patients with residual lesions after partial correction such as pulmonic regurgitation, right ventricular outflow obstruction, and right ventricular dysfunction are at risk for heart failure and arrhythmia during pregnancy. Poor prognostic signs include maternal hematocrit above 60%, arterial oxygen saturation below 80%, right ventricular HTN, and syncopal episodes.

i.Eisenmenger syndrome. Pregnancy in women with Eisenmenger syndrome is associated with a very high maternal mortality in the range of 30% to 50%, with a 50% risk of fetal loss if the mother survives. Maternal death occurs mostly between the first few days to first few weeks following delivery because of rapid hemodynamic deterioration. Therefore, patients with Eisenmenger syndrome should be strongly discouraged against pregnancy. Early therapeutic abortion may be considered given the danger to the mother. If pregnancy is continued, close monitoring is necessary. Restricted physical activity, continuous oxygen use for at least the third trimester, and consideration of pulmonary vasodilators are recommended. Because of increased incidence of thromboembolism, anticoagulant therapy is recommended, starting from the third trimester until 4 weeks postpartum. An attempt to shorten the second stage of labor by the use of forceps or vacuum should be made; cesarean delivery is associated with significantly higher mortality.

F.Valvular heart disease and pregnancy. Lesions generally associated with high maternal and/or fetal risks include symptomatic mitral stenosis (MS), severe AS (with or without symptoms), mitral regurgitation (MR)or aortic regurgitation with NYHA class III and IV symptoms, valvular disease with severe pulmonary HTN or LV dysfunction, mechanical prosthetic valve requiring anticoagulation, Marfan syndrome, and hypertrophic cardiomyopathy (HCM). Lesions generally associated with low maternal or fetal risk include asymptomatic AS with normal ventricular function, mitral valve prolapse, mild MS, and MR or aortic regurgitation associated with NYHA functional class I or II symptoms.

1.Mitral stenosis. MS is one of the most common rheumatic valvular lesions seen in pregnancy and is poorly tolerated. The physiologic changes in pregnancy with increased blood volume and heart rate can lead to an increased pressure gradient across the valve and decreased filling time, respectively. This leads to increases in left atrial pressure and ensuing symptoms of pulmonary edema with dyspnea, orthopnea, and paroxysmal nocturnal dyspnea. Occurrence of atrial fibrillation with a rapid ventricular rate often causes further clinical deterioration. Patients with moderate to severe MS are more susceptible to these hemodynamic disturbances. The rapid increase in venous return during labor and delivery may cause significant decompensation and requires close monitoring.

Management depends upon the severity of stenosis, symptoms, and time of diagnosis. If MS is diagnosed prior to pregnancy, patients with severe MS (valve area < 1 cm²) or moderate symptomatic stenosis should be offered percutaneous mitral balloon valvuloplasty (PMBV) or valve repair if PMBV is not feasible, before pregnancy. In patients with moderate asymptomatic stenosis, careful assessment of symptoms and exercise tolerance testing can help guide the decision for prepregnancy intervention. In patients with mild MS (valve area > 1.5 cm²), pregnancy is usually tolerated with a favorable outcome. Optimal management of an already pregnant patient with MS is aimed at reducing heart rate and left atrial pressure. β-Blockers are the drug of choice, and selective β1-adrenergic drugs are preferred over nonselective β-blockers to avoid β2-adrenergic–mediated uterine relaxation. In patients with atrial fibrillation, digoxin may also be used for ventricular rate control. Electrical cardioversion can be performed safely during pregnancy if the hemodynamic status warrants restoration of sinus rhythm. Left atrial pressure may be controlled by salt restriction and very judicious use of diuretics (excessive use can lead to reduced uteroplacental perfusion). In patients with symptoms and signs of clinical deterioration despite optimal medical therapy, PMBV may be necessary during pregnancy. This should be avoided in the first trimester if possible and proper abdominal and pelvic shielding must be used. Echocardiographic guidance by an experienced operator can limit radiation exposure. In cases with severe MS refractory to medical therapy and not amenable to PMBV, mitral valve repair or replacement may be considered. Cardiopulmonary bypass during pregnancy carries a risk of fetal demise and should be performed with normothermic perfusion and high flow volumes with the mother in the lateral decubitus position to maximize placental perfusion.

Most patients with MS can safely undergo vaginal delivery. Patients with symptomatic moderate and severe MS should have hemodynamic monitoring and optimization guided by pulmonary artery catheterization during labor and delivery and in the immediate postpartum period (12 to 24 hours) when relief of uterocaval obstruction can cause increased venous return and pulmonary edema. Epidural anesthesia is usually better tolerated than general anesthesia, and cesarean section is generally performed for obstetric indications only.

2.Mitral regurgitation. The most common cause of MR during pregnancy is either rheumatic heart disease or mitral valve prolapse. MR is usually well tolerated in pregnancy because the fall in systemic vascular resistance leads to decreased LV afterload. Symptomatic decompensation may occur due to atrial fibrillation or HTN. Asymptomatic patients are managed conservatively without any therapy, whereas patients with decompensated heart failure are treated with diuretics and digoxin. In the peripartum period, increased venous return and systemic vascular resistance sometimes lead to decompensation requiring diuretics and afterload reduction. Angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) are contraindicated during pregnancy because of their teratogenic effect. Hydralazine may be used in patients with MR and HTN for afterload reduction. Acute MR because of ruptured chordae is rare in pregnancy and is usually not well tolerated. It may require intra-aortic balloon pump placement and emergent surgery.

3.Aortic stenosis. The most common etiology for AS in childbearing age is a congenitally bicuspid valve. Rheumatic AS is less common, but may occur in conjunction with MS. Mild-to-moderate AS with preserved LV function is usually well tolerated during pregnancy. Severe AS (i.e., AV area < 1.0 cm² and mean gradient > 40 mm Hg) significantly increases the risk during pregnancy and may lead to significant hemodynamic deterioration, heart failure, and premature delivery. Patients with severe AS should therefore be counseled against pregnancy or undergo surgery prior to conception. Symptoms such as chest pain, syncope, or dyspnea usually present late in the second trimester or early in the third trimester. Patients with bicuspid AV and aortic root dilation, especially those with COA, are at increased risk for spontaneous aortic dissection.

When severe symptomatic AS is diagnosed during pregnancy, PABV should be performed before labor and delivery. Although PABV may reduce the risk of decompensation in patients with severe AS, it has limited durability and only suffices as a temporizing measure until the patient can safely undergo AV replacement. Aortic insufficiency (AI) that occurs as a postprocedural complication of PABV is usually well tolerated during labor and delivery.

Close invasive hemodynamic monitoring, as in patients with MS, may be required. Spinal anesthesia and epidural anesthesia are discouraged during labor and delivery because of their vasodilatory effects.

4.Aortic regurgitation/aortic insufficiency. AI is generally well tolerated in pregnancy because of the combination of reduced systemic vascular resistance and shortened diastole with the rise in heart rate. In a young woman, AI may be due to a congenitally bicuspid valve, an infective endocarditis, an autoimmune disorder (e.g., rheumatoid arthritis), or a dilated aortic annulus. Marfan syndrome should always be excluded because of its implications regarding aortic root stability. In symptomatic patients with decompensated heart failure, diuretics, digoxin, and hydralazine may be used for afterload reduction.

5.Hypertrophic cardiomyopathy. Most asymptomatic patients with HCM have a favorable outcome during pregnancy. The overall morbidity and mortality with HCM and pregnancy is, however, still higher than that in the general population. Symptoms such as chest pain, palpitations, worsening dyspnea, and syncope may occur and are more common in women who were symptomatic prior to pregnancy. Various arrhythmias, including supraventricular tachycardias, atrial fibrillation with hemodynamic deterioration and fetal distress, and ventricular fibrillation, have also been reported. There is an increased risk of fetal prematurity. Women should receive genetic counseling before conception whenever possible; the risk of inheriting the disease may approach 50% in certain familial forms of HCM.

Basic tenets of management in the pregnant HCM patient include maintenance of adequate intravascular volume to maintain appropriate LV end diastolic volume, as well as avoidance of tachycardia, both of which decrease LV outflow tract gradients. Blood loss, volume depletion, and vasodilators should be avoided. β-Blockers are usually the drug of choice for symptomatic patients. Patients with a history of syncope, life-threatening arrhythmias, or a family history of sudden cardiac death should be considered for prophylactic implantable defibrillators prior to pregnancy because of the potential arrhythmogenic effect of pregnancy.

Vaginal delivery is considered safe, but tocolytics with β-adrenergic properties and prostaglandins should be avoided. Epidural anesthesia is used with caution because of the peripheral vasodilatory effect, and excessive blood loss should be promptly repleted with fluids or blood transfusion. The brisk diuresis immediately postpartum may lead to a rapid decrease in intravascular volume and, therefore, a symptomatic increase in outflow tract gradient. This can be avoided by gentle intravenous (IV) hydration decreasing over 24 to 48 hours postpartum.

6.Prosthetic heart valves. The selection of an appropriate prosthetic valve in a woman of childbearing age is controversial. Where possible, the patient’s own valve should be conserved or repaired. When valve replacement is necessary, bioprosthetic and homograft valves are safer for mother and child, although their use is associated with an increased risk of degeneration in younger people, which may also be accelerated by pregnancy. In pregnant patients with well-functioning bioprosthetic valves, the management is similar to that of patients with native valves. Patients should be made aware of the possibility of valve degeneration and should be monitored for signs and symptoms of this.

Pregnancy should be discouraged in patients with mechanical heart valves, because mechanical valves, and their anticoagulation requirement, confer increased maternal mortality, morbidity, and fetal loss. In pregnant patients with mechanical heart valves, management of anticoagulation is challenging. Pregnancy is a thrombogenic state, and thrombosis has been reported in up to 10% to 15% of patients with mechanical prosthetic valves during pregnancy. The incidence is particularly high in patients with older generation valves (Björk-Shiley and Starr-Edwards) in the mitral position, but complications and deaths have also been reported in newer generation valves in the aortic position. The management of anticoagulation during pregnancy is discussed in detail in a separate section of this chapter.

G.Other cardiovascular diseases and pregnancy

1.Hypertensive disorders in pregnancy. Hypertensive disorders complicate 8% to 10% of pregnancies and are a major cause of maternal and perinatal morbidity and mortality. Hypertensive disorders can be broadly classified into chronic HTN, gestational HTN, and the preeclampsia–eclampsia spectrum.

a.Chronic HTN is defined as blood pressure of 140/90 mm Hg or greater before pregnancy, before 20 weeks of gestation, or persisting beyond postpartum day 42. It is associated with increased maternal and fetal morbidity and elevates the risk of preeclampsia development. Blood pressure treatment is aimed at minimizing maternal end-organ damage (such as LV hypertrophy, renal failure, or intracerebral hemorrhage), balanced against concerns that excessive pressure lowering may negatively impact fetal growth. The threshold for initiating drug therapy is controversial, and differing recommendations are offered by the various international society guidelines.

b.Gestational HTN is defined as HTN induced by pregnancy and diagnosed after 20 weeks of gestation and usually resolving within 42 days postpartum. Gestational HTN may portend the development of future primary HTN and CVD, but is otherwise usually associated with good maternal and fetal outcomes.

c.Preeclampsia occurs in 2% to 5% of all pregnancies, 10% of first pregnancies, and 20% to 25% of women with chronic HTN. It can be diagnosed with a systolic blood pressure above 140 or diastolic blood pressure of 90 and proteinuria exceeding 300 mg per 24-hour urine collection (or >30 mg/mmol in a spot urine sample), or an increase in proteinuria or loss of blood pressure control in a woman with chronic HTN. Symptoms supporting a diagnosis of preeclampsia include headache, blurred vision, abdominal pain, and shortness of breath. Onset is usually in the third trimester with rapid resolution after delivery, although postpartum cases are reported. Eclampsia is the development of grand mal seizures in a woman with preeclampsia. When preeclampsia is accompanied by poor prognostic features such as severe HTN, HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), placental abruption, cerebral hemorrhage, pulmonary edema, or renal failure, the fetus must be delivered immediately, usually with rapid normalization of blood pressure. Table 40.8 lists different drug therapies used to treat HTN in pregnancy. IV labetalol is the drug of choice for acute hypertensive urgency or emergency in pregnancy. Hydralazine may also be used as a vasodilator. Sodium nitroprusside is usually avoided, especially in later stages of pregnancy, because of concern for fetal cyanide toxicity if used for more than 4 hours and should be used only as a last resort in cases where emergent control of blood pressure is required. Methyldopa, labetalol, and nifedipine are the most commonly used oral antihypertensive agents during pregnancy, although there is a paucity of evidence for optimal blood pressure targets or drug choices. It is generally agreed that systolic blood pressures of 150 to 160 mm Hg and/or diastolic blood pressures of 100 mm Hg and above should be treated.

TABLE 40.8 Drug Therapy for Hypertension in Pregnancy
	Drugs for Hypertensive Urgency and Emergencies
Drug	Mechanism of Action	Dosing	Comments
Labetalol	α–β-Adrenergic blocker	20–80 mg IV q10–20 min (up to 300 mg)	Well tolerated; avoid in patients with severe asthma because of potential bronchoconstrictive effects; widely used; scant safety data
Hydralazine	Vasodilator	5–10 mg IV q15–30 min	Efficacious and safe during pregnancy and lactation
Sodium nitroprusside	Arterial-veno dilator	0.5–5.0 µg/kg/min	Concern for fetal thiocyanate toxicity
Drugs for Long-Term Treatment of Hypertension
Methyldopa	Central α₂-agonists	250 mg tid up to 4 g/d	May not be as effective in control of severe HTN; childhood safety data up to 7 y of age
Labetalol	α–β-Adrenergic blocker	200–2,400 mg/d in two to three divided doses	Well tolerated; avoid in patients with severe asthma because of potential bronchoconstrictive effects; widely used; scant safety data
Nifedipine	Calcium channel blocker	Once daily sustained release dosing up to 120 mg/d	Short-acting nifedipine may precipitate severe hypotension and should be avoided; hypotension also possible with sustained release

HTN, hypertension.

Adapted from Elkayam U. Pregnancy and cardiovascular disease. In: Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. 7th ed. Philadelphia, PA: Elsevier Saunders; 2005:1965–1982. Copyright © 2005 Elsevier. With permission.

2.Aortic dissection. Aortic dissection during pregnancy has been reported in women with Marfan syndrome, systemic HTN, COA, Turner syndrome, and cocaine use. It occurs most commonly in the third trimester and the peripartum period. Transesophageal echocardiography is the key diagnostic tool, and a β-blocker is the preferred medication for management during pregnancy.

3.Coronary artery disease. MI during pregnancy is rare, occurring in 1 in 16,129 deliveries in the United States between 2000 and 2002. The possibility of MI should always be entertained in a pregnant or immediately postpartum woman, especially if her symptoms and ECG are suspicious for coronary ischemia. Most MIs occur during the third trimester in older women who have had multiple prior pregnancies. Coronary spasm, in situ coronary thrombosis, and coronary dissection are more frequently the underlying precipitants of MI than classic obstructive atherosclerosis. Acute MI may be the initial clinical manifestation of an underlying hypercoagulable state, such as the antiphospholipid antibody syndrome. The diagnosis and management of acute MI in the pregnant patient should follow the guidelines established for the general population.

Medical therapy for acute MI must be modified in the pregnant patient. Thrombolytic agents increase the risk of maternal hemorrhage substantially (8%). Low-dose ASA, β-blockers, and nitrates are considered relatively safe. Short-term heparin administration has not been associated with increased maternal or fetal adverse effects. ACE-Is, ARBs, and statins are contraindicated during pregnancy; there is no established safety data for clopidogrel, ticagrelor, or glycoprotein IIb/IIIa inhibitors. Coronary angiography should be performed only when emergent angioplasty or coronary artery bypass grafting is anticipated.

4.Arrhythmias. Premature atrial complexes and premature ventricular complexes are the most frequent rhythm disturbances of pregnancy and are not associated with adverse maternal or fetal outcomes. No antiarrhythmic drug therapy is warranted.

a.Atrial fibrillation and atrial flutter are rare during pregnancy. Current ACC/AHA guidelines for management are detailed in Table 40.9. Rate control may be achieved with digoxin and β-blockers. Direct current cardioversion may be performed safely during any stage of pregnancy. Anticoagulation is recommended for chronic atrial fibrillation in the setting of underlying structural heart disease.

TABLE 40.9 ACC/AHA Guidelines for Management of Atrial Fibrillation in Pregnancy

Class I (Benefits >>> Risk) Procedure/Treatment Should Be Performed/Administered

Digoxin, a β-blocker, or a nondihydropyridine calcium channel antagonist is recommended to control the rate of ventricular response in pregnant patients with AF

Direct current cardioversion is recommended in pregnant patients who become hemodynamically unstable because of AF

Protection against thromboembolism is recommended throughout pregnancy for all patients with AF (except for those with lone AF and/or low thromboembolic risk). Therapy (anticoagulant or ASA) should be chosen according to the stage of pregnancy

ACC, American College of Cardiology; AF, atrial fibrillation; AHA, American Heart Association; ASA, aspirin.

b.Atrioventricular nodal reentrant tachycardia is the most common supraventricular arrhythmia in pregnant and nonpregnant women. It can lead to hemodynamic deterioration in women with underlying heart disease owing to rapid rates. Adenosine may be administered safely to the pregnant patient for both diagnostic and therapeutic purposes.

c.Ventricular tachycardia (VT) is rare during pregnancy. It may, however, be the presenting manifestation of peripartum cardiomyopathy (PPCM). VT has also been associated with thyrotoxicosis and hyperemesis gravidarum. Most antiarrhythmic medications used to treat VT are safe during pregnancy, except for amiodarone, which should be used with extreme caution and only for arrhythmias not responding to other medications, because it may lead to neonatal hypothyroidism.

5.Peripartum cardiomyopathy. This is defined as the development of idiopathic LV systolic dysfunction in the last month of pregnancy or within 5 months of delivery, in the absence of any identifiable or preexisting cause of heart failure. The incidence of PPCM in the United States is estimated to be 1 in 3,000 to 4,000 live births and is more common in women older than 30 years. The following risk factors for PPCM have been proposed: multiparity, history of preeclampsia, eclampsia, or postpartum HTN, African descent, low socioeconomic status, or tocolytic therapy with β-agonists. Symptoms include fatigue, dyspnea on exertion, orthopnea, nonspecific chest pain, peripheral edema, and abdominal discomfort and distention. PPCM has long been considered an idiopathic disease; however, recent studies suggest vascular dysfunction, hormonal insults, and underlying genetics may contribute to its pathogenesis. Standard management of pregnant patients presenting with decompensated heart failure includes oxygen, diuretics, digoxin, and vasodilators. ACE-Is and ARBs are absolutely contraindicated in pregnancy but should be commenced postpartum.

The prognosis after development of PPCM is variable. Approximately 70% of women completely recover normal heart size and function, usually within 6 months of delivery. The remainder either experience stable LV dysfunction or continue to experience clinical deterioration. Patients with severe cardiac dysfunction and decompensation should be evaluated for cardiac transplantation or mechanical support after pregnancy. Estimated maternal mortality ranges from 10% to 20%. Women with PPCM and persistent LV dysfunction or whose LVEF was below 25% at initial presentation are at very high risk for complications, including death, in a subsequent gestation.

6.Primary pulmonary hypertension. This is associated with very high maternal mortality (30% to 40%) and poor fetal outcomes. Worsening of symptoms occurs in the second and third trimesters, and death is usually from right ventricular failure or arrhythmias. Pregnancy should be strongly discouraged in patients with this diagnosis, and early therapeutic abortion should be considered for those who become pregnant. Anticoagulation throughout gestation, or at least during the third trimester, is recommended. Close hemodynamic monitoring during labor, delivery, and the early postpartum period is advised, and oxygen plus pulmonary vasodilators may be used.

7.Pregnancy after cardiac transplantation. Pregnancy after cardiac transplantation is considered high risk for the mother and fetus. Maternal morbidity is increased from HTN, preeclampsia, renal failure, premature rupture of membranes, and infection. Fetal growth restriction and preterm labor are also a concern, along with potential adverse fetal effects of immunosuppressive medications. One study examined the outcomes of 47 pregnancies in 35 transplant recipients. There was no increase in maternal mortality in this study, but increased maternal morbidity, premature deliveries, and fetal growth restriction were observed.

H.Medication considerations in pregnancy

1.Cardiovascular drugs. The most commonly used CV drug classes and their potential adverse effects during pregnancy are shown in Table 40.10.

TABLE 40.10 Cardiovascular Drugs and Pregnancy
Drug	Indication	FDA Category	Potential Maternal or Fetal Side Effects
Adenosine	Arrhythmia	C	Limited data on use
Amiodarone	Arrhythmia	D	Hyper/hypothyroidism, congenital goiter, IUGR, neurologic effects
ACE-I/ARB	HTN	D	Contraindicated, IUGR, oligohydramnios, renal failure, fetal death
ASA	CAD	C in the first and second trimesters D in third trimester	IUGR, bleeding in mother and neonate, fetal death
β-Blockers	Arrhythmia, HTN, MI, HOCM, hyperthyroidism, Marfan syndrome, MS	C/D	Fetal bradycardia, hypoglycemia, IUGR (atenolol is category D and should be avoided due to greatest IUGR concerns)
Calcium channel blockers	HTN	C	Maternal hypotension causing fetal distress reported, potential tocolytic effects
Digoxin	Arrhythmia, heart failure	C	Possible low birth weight, prematurity, but generally considered safe
Dofetilide	Atrial fibrillation	C	Possibly teratogenic in animal studies
Diuretics (thiazides)	HTN	B	Hypovolemia and reduced uteroplacental blood flow
Flecainide	Arrhythmia	C	Fetal death; limited data
Hydralazine	HTN, heart failure	C	Possible hypospadias, neonatal thrombocytopenia, neonatal lupus-like syndrome
Lidocaine	Arrhythmia	B	Neonatal CNS depression
Methyldopa	HTN	B	Longest safety record, avoid in women with potential for depression
Nitrates	HTN	B/C (product specific)	Maternal hypotension causing fetal distress reported
Procainamide	Arrhythmia	C	No adverse effects reported in third trimester
Propafenone	Arrhythmia	C	Limited data
Quinidine	Arrhythmia	C	Neonatal thrombocytopenia, mild oxytocic effect
Sodium nitroprusside	HTN, aortic dissection	C	Fetal thiocyanate toxicity, but data are limited
Sotalol	Arrhythmia	B	Fetal bradycardia; IUGR

FDA category: A, controlled studies show no risk; B, no evidence of risk in humans; C, risk cannot be ruled out; D, positive evidence of risk

ACE-I, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blocker; ASA, aspirin; CAD, coronary artery disease; CNS, central nervous system; FDA, Food and Drug Administration; HOCM, hypertrophic obstructive cardiomyopathy; HTN, hypertension; MS, mitral stenosis; IUGR, intrauterine growth restriction; MI, myocardial infarction.

2.Anticoagulation during pregnancy. Conditions requiring anticoagulation during pregnancy include mechanical prosthetic heart valves, chronic atrial fibrillation, acute VTE, Eisenmenger syndrome, antiphospholipid antibody syndrome, and inherited deficiencies predisposing to thromboembolism (e.g., prothrombin gene mutation and factor V Leiden deficiency).

The three most common agents considered for use during pregnancy are unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and warfarin. The Ninth Edition of the American College of Chest Physician’s evidence-based clinical practice guidelines on antithrombotic therapy and prevention of thrombosis recommend LMWH for the prevention and treatment of venothromboembolism in pregnant women. Avoidance of warfarin, oral direct thrombin and anti-Xa inhibitors (1C) is advised. For women with mechanical heart valves, warfarin is recommended in the first trimester if the daily dose is <5 mg and for all patients in the second and third trimesters. For women with mechanical valves and daily dose of warfarin >5 mg, LMWH twice daily with anti-Xa levels for monitoring or a continuous infusion of UFH with a partial thromboplastin time (PTT) ≥ twice the control is recommended during the first trimester. The ACC/AHA guidelines for selection of anticoagulation regimen in pregnant patients with mechanical prosthetic valves, updated in 2014, are presented in Table 40.11. Ultimately, the choice of anticoagulation regimens depends on the preferences of the patient and physician after consideration of the maternal and fetal risks associated with the use of each drug.

TABLE 40.11 ACC/AHA Guidelines for Selection of Anticoagulation Regimen in Pregnant Patients with Mechanical Prosthetic Valves
Class I (Benefits >>> Risk): Procedure/Treatment Should Be Performed/Administered	Level of Evidence
All pregnant patients with mechanical prosthetic valves must receive continuous therapeutic anticoagulation with frequent monitoring	B
In women with mechanical prosthetic valves, warfarin is the recommended anticoagulant in the second and third trimesters	B
Pregnant women with mechanical valves should receive their care at a tertiary care center with a dedicated valve team	C
Women requiring long-term warfarin therapy who are attempting to become pregnant should receive prepregnancy counseling from a cardiologist knowledgeable in management of valvular heart disease	C
In pregnant women with mechanical valves who require less than 5 mg of warfarin a day to achieve a therapeutic INR, warfarin may be continued during the first trimester if a full discussion of risks and benefits occurs	C
In pregnant patients with mechanical prosthetic valves who receive dose-adjusted UFH, the aPTT should be at least twice the control	C
In pregnant patients with mechanical prosthetic valves, the mother should be hospitalized prior to planned delivery with initiation of continuous IV UFH and discontinuation of warfarin	C
In patients with mechanical or bioprosthetic valves, it is reasonable to give low-dose ASA (75–100 mg/d) in the second and third trimesters of pregnancy in addition to anticoagulation with warfarin or heparin	C
Class IIa (Benefits >> Risk): It Is Reasonable to Perform Procedure/Administer Treatment
In patients with mechanical prosthetic valves, it is reasonable to avoid warfarin between weeks 6 and 12 of gestation owing to the high risk of fetal defects	C
In patients with mechanical prosthetic valves, it is reasonable to resume UFH 4–6 h after delivery and begin oral warfarin in the absence of significant bleeding	C
Class III (Risk ≥ Benefits): Procedure/Treatment Should Not Be Performed/Administered
LMWH should not be administered to pregnant patients with mechanical prosthetic valves unless anti-Xa levels are monitored 4–6 h after administration	B

Level of evidence: A, multiple population risk strata evaluated; B, limited population risk strata evaluated; C, very limited population risk strata evaluated.

aPTT, activated partial thromboplastin time; ASA, aspirin; INR, international normalized ratio; IV, intravenous; LMWH, low-molecular-weight heparin; UFH, unfractionated heparin.

Adapted from Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(22):e57–e185.

a.Warfarin. Warfarin freely crosses the placental barrier and can adversely affect fetal development. It has been associated with a high incidence of spontaneous abortion, prematurity, still birth, and fetal bleeding. The incidence of warfarin embryopathy (fetal bone and cartilage formation abnormalities) has been estimated at 4% to 10%; the risk is highest when warfarin is administered during the 6th through the 12th week of gestation. The risks are dose dependent, and women maintained on a daily dose of <5 mg daily have the lowest risks. When administered during the second and third trimesters, warfarin has been associated with fetal central nervous system abnormalities, such as optic atrophy, microencephaly, intellectual disability, spasticity, and hypotonia. Warfarin’s anticoagulant effects are more potent in the fetus than in the mother because of lower fetal levels of the vitamin K–dependent clotting factors and can cause neonatal intracranial hemorrhage or a retroplacental hematoma. Warfarin is considered safe during breastfeeding. Women taking warfarin prior to pregnancy should be counseled regarding the risks and benefits of warfarin.

b.Unfractionated heparin. UFH does not cross the placenta and, unlike warfarin, does not have the teratogenic effects and is, therefore, considered safer. It is, however, associated with maternal osteoporosis, hemorrhage, thrombocytopenia, or thrombosis (heparin-induced thrombocytopenia with thrombosis [HITT] syndrome), and a high incidence of thromboembolic events with older generation mechanical valves. UFH may be administered parenterally or subcutaneously throughout pregnancy. Subcutaneous (SC) heparin use in patients with mechanical valve carries a 33% risk of valve thrombosis, compared to <4% when warfarin is used throughout pregnancy. The appropriate dose of UFH is based on an activated PTT (aPTT) of at least two times the control level. High doses of UFH are often required to achieve the goal aPTT because of the hypercoagulable state associated with pregnancy.

c.Low-molecular-weight heparin. The use of LMWH during pregnancy remains controversial, because it has not been adequately studied. Its advantages over UFH include a more predictable anticoagulant response and lower incidences of HITT and osteoporosis. It does not cross the placenta, and it may be safer to the fetus even though data in this regard are limited. A twice-daily dosing schedule should be used. During pregnancy, the volume of distribution for LMWH changes, and it is essential to monitor anti-Xa levels. The 4-hour-postdose target anti-Xa level varies between 0.7 to 1.2 and 1.0 to 1.2 U/mL depending on the guidelines followed; the manufacturer’s specific target range should also be consulted. Although LMWH is the drug of choice for prophylaxis and treatment of deep venous thrombosis in pregnancy, the safety and efficacy of LMWH in pregnant patients with mechanical valves remain controversial.

ACKNOWLEDGMENTS: The authors acknowledge the contributions of Drs. Kellan Ashley, Arti Choure, Jun-Yang Lou, and Amanda Vest for contributions to this chapter in an earlier edition.

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