A 29-year-old Caucasian woman presents to the emergency department 5 days post delivery with complaints of dyspnea and fatigue for 2 days. She reports it to be her first pregnancy, the course of which was complicated with gestational hypertension (HTN) (without other features of preeclampsia), and dependent bilateral pedal edema. She was treated with labetalol 200 mg by mouth twice a day for gestational HTN during her antepartum period. On physical examination, she was found to be dyspneic with respiratory rate of 25 breaths per minute and hypoxic with 80% saturation on room air. She was afebrile and had a blood pressure of 156/88 mm Hg and a pulse rate of 98 beats per minute. Her neck examination demonstrated a jugular venous distention of 17 cm water and grade 2+ pedal edema on both lower extremities. On systemic examination, lungs had diffuse bilateral inspiratory crackles; cardiac examination demonstrated regular heart rate with an S₃ summation gallop. No calf tenderness was observed and the rest of her physical examination was unremarkable.

Her laboratory investigation demonstrated urinalysis negative for protein. Cardiac enzymes, D-dimer, and thyroid function were within normal range and antinuclear antibodies were absent. The circulating levels of B-type natriuretic peptide (BNP) were 864 pg/mL. An electrocardiogram (ECG) showed a normal sinus rhythm with no conduction delays and no ectopy. Chest radiograph showed cardiomegaly with increased vascular congestion bilaterally (Figure 13-1). A computed tomography (CT) chest scan with contrast was negative for pulmonary embolism, but did show small bilateral pleural effusions and cardiomegaly. Subsequently an echocardiogram was obtained, which showed an ejection fraction (EF) of 35%.

At this point, the patient appears to have a new onset congestive heart failure (HF). The differential diagnosis to consider includes:

1. 
   

   Peripartum cardiomyopathy (PPCM)

   
   
2. 
   

   Cardiomyopathy including dilated, hypertrophic, or restrictive

   
   
3. 
   

   Myocardial infarction

   
   
4. 
   

   Pulmonary embolism (less likely given a negative CT scan)

   
   
5. 
   

   Other cardiomyopathies: Drug-induced (alcoholic or cocaine-induced, although our patient denies usage of both)

   
   
6. 
   

   Valvular heart disease (rheumatic mitral stenosis, aortic stenosis)

   
   
7. 
   

   Noncardiogenic pulmonary edema

   
   
8. 
   

   Primary pulmonary disease (asthma, chronic obstructive pulmonary disease, pulmonary fibrosis)

   
   
9. 
   

   Others, including: Arrhythmogenic right ventricular dysplasia; infiltrative cardiac disease; toxic or metabolic disorders.

The diagnosis of PPCM is often missed as the signs and symptoms of a normal pregnancy coincide with findings of HF. These findings include dyspnea, dizziness, orthopnea, and decreased exercise capacity. Patients often do not show any indication of the syndrome until after delivery. Elkayam et al¹ and Sliwa et al² showed that patients could manifest similar symptoms even before the last gestational month and hence represent a continuum in the spectrum of this disease. The diagnostic criteria for peripartum cardiomyopathy are as follows: development of cardiac failure in the last month of pregnancy or within 5 months of delivery; absence of an identifiable cause for the cardiac failure other than pregnancy; absence of recognizable heart disease before the last month of pregnancy; and left ventricular (LV) systolic dysfunction with left ventricular ejection fraction (LVEF) <45%, fractional shortening below 30%, or both.

The risk factors of PPCM include age >30 years;^1,3,4 African descent;¹ multiple pregnancy;¹ history of preeclampsia, eclampsia, or postpartum HTN;^5,6 maternal cocaine abuse;⁷ or long-term (>4 weeks) oral tocolytic therapy with beta adrenergic agonists such as terbutaline.⁸ The presenting history of patients with PPCM includes symptoms consistent with systolic dysfunction in nonpregnant patients.⁹ Dyspnea and tachycardia are the most common initial complaints in these patients.¹⁰ However, a new or rapid onset of the following symptoms requires prompt evaluation: cough, orthopnea, paroxysmal nocturnal dyspnea, chest pain, and nonspecific symptoms of fatigue, palpitations, hemoptysis, and abdominal pain. The physical examination findings may include hypoxia, tachypnea, tachycardia with a normal blood pressure, elevated jugular venous pressure, worsening bilateral peripheral pedal edema, cardiomegaly, pulmonary crackles, ascites, hepatomegaly, and thromboembolism. Cardiac examination is consistent with loud pulmonic component of the second heart sound, mitral or tricuspid regurgitation,¹¹ and often S₃ and/or S₄ summation gallop.

For aiding in an early diagnosis of PPCM, Fett¹² suggested a screening tool consisting of 6 clinical categories that were scored based on their symptom severity from 0 to 2 and comprised of orthopnea, dyspnea, unexplained cough, lower extremity swelling, excessive weight gain, and palpitations (Table 13-1).

DIAGNOSTIC WORKUP

The diagnostic workup of these individuals includes blood tests such as complete blood count, serum electrolytes, lipid profile, liver function chemistries, thyroid profile, cardiac enzymes, antineutrophil antibody, and viral serology as a baseline (although none of these are specific for diagnosing PPCM). Additional diagnostic tools include 12-lead ECG, chest x-ray, and echocardiogram for assessment of HF.

Cardiac Protein Assays

Cardiac biomarkers such as cardiac troponins, BNP, and N-terminal proBNP (NT-proBNP), although nonspecific, are useful for initial assessment in patients with HF. In the postpartum period, Forster et al¹³ demonstrated a significant elevation of NT-proBNP in patients with PPCM compared with healthy postpartum controls. Elevation of cardiac troponin T (≥0.04 ng/mL) within 2 weeks of PPCM onset has been shown to be a predictor of LV systolic dysfunction (sensitivity 55% and specificity 91%).¹⁴

Electrocardiogram

No specific ECG findings have been associated with PPCM. However, an ECG is useful in ruling out myocardial ischemia as an etiology of systolic dysfunction. The most common abnormalities noted on ECG are LV hypertrophy and ST-T wave changes. Although less frequently, other ECG findings notable with PPCM include arrhythmias such as atrial fibrillation, atrial flutter, and ventricular tachycardia; prolonged PR interval; and bundle branch block,¹⁵ but these changes are highly nonspecific. There has also been a case report on unmasking of inherited long QT interval via dyselectrolytemia and structural changes due to PPCM.¹⁶

Echocardiogram

Echocardiography is an essential tool in these patients as it not only aids in making the diagnosis of PPCM but also helps assess the degree of cardiac dysfunction. Some common findings seen include dilatation of LV cavity with moderate to severely reduced EF mitral and/or tricuspid regurgitation, right ventricle (RV) and/or biatrial dilatation, increased pulmonary artery pressures, and, in severe cases, LV thrombus (Figures 13-2 and 13-3).^2,9-11

A majority of women have a full recovery of their cardiac function over a time period ranging from 6 months to 48 months. However, it has been suggested that even after normalization of LV function after pregnancy, patients might continue to have decreased contractile reserves as demonstrated by a reduced rate-corrected velocity of fiber shortening on dobutamine stress echocardiogram.¹⁷ A study by Fett et al¹⁸ identified markers of persistent LV dysfunction and poor prognosis¹⁹ on echocardiogram as LV end-diastolic diameter of 6 cm or more and M mode fractional shortening of 20% or less. In another study by Karaye,²⁰ a higher prevalence of RV dysfunction was noted in patients with PPCM, as measured by a reduction in tricuspid annular plane systolic excursion (TAPSE) ≤14 mm (54.6% vs 37.1%, respectively, p = 0.05). Novel echocardiographic techniques such as strain, strain rate, and speckle tracking have not yet been adequately explored in PPCM patients.

The follow-up and monitoring of disease progression has been suggested to be done by serial echocardiograms at regular intervals including at the time of discharge, 6 weeks, 6 months, and annually subsequently until normalization of LV function.²

Cardiac Magnetic Resonance Imaging

The modality of choice for assessment of myocardial fibrosis is cardiac magnetic resonance imaging (MRI).²¹ Cardiac MRI has been shown to be helpful in prognostication of patients with HF based on presence or absence of late gadolinium enhancement.²² In patients with PPCM, cardiac MRI has been demonstrated to have a more accurate assessment of chamber volume and ventricular function, LV thrombus, and myocardial fibrosis compared with echocardiography (Figure 13-4).²³ Additionally, cardiac MRI is able to distinguish between inflammatory and noninflammatory cardiomyopathy on the basis of late gadolinium enhancement in these patients and also helps to delineate PPCM from other cardiomyopathies such as ischemic heart disease or Takotsubo cardiomyopathy or infiltrative diseases such as hemochromatosis or amyloidosis. The identification of myocarditis-like PPCM from the gadolinium enhancement patterns may help direct therapy with intravenous immunoglobulins (IVIGs) and other immunosuppressive therapies.²⁴

However, gadolinium contrast has been shown to have teratogenic effects in pregnancy and according to the American College of Radiology, gadolinium should be avoided during pregnancy.²⁵ Given the limited data for use of MRI with gadolinium contrast in the diagnosis and further management of PPCM and its teratogenic effects in pregnancy, it is not yet an approved diagnostic modality of choice in this patient population.

Endomyocardial Biopsy

There is no clear role of endomyocardial biopsy in establishing the diagnosis of PPCM. For diagnosis of dilated cardiomyopathy, its role is controversial^26-28 except in patients with a strong clinical suspicion of myocarditis (Figure 13-5) or no improvement after 2 weeks of optimal medical therapy for HF, especially if malignant ventricular arrhythmias are present and the diagnosis of giant cell myocarditis is being considered. The disadvantages of the procedure include its invasive nature, availability, complication rates, and nonspecific pathologic findings (edema, inflammation, hypertrophy, and fibrosis).²⁸

Treatment of PPCM in pregnant women is analogous to the management of HF with a few exceptions, which are described below in the relevant subsections (Figure 13-6). The overall management comprises nonpharmacological, medical, complementary/alternative therapy, and experimental therapies.

NONPHARMACOLOGICAL

The nonpharmacological therapy involves lifestyle modification. This entails low-salt diet to <1.5 g/day, fluid restriction in patients with volume overload, daily monitoring of weight, and optimum blood pressure control. These measures form the main pillars in the management of PPCM presenting as HF.³ Physical activity should not be restricted unless limited by disease severity.²⁹

MEDICAL MANAGEMENT

The medical therapy should always be tailored to choose drugs safe in pregnancy and lactation for avoiding maternal and fetal morbidity.

Diuretics

The most commonly used diuretics in patients with HF are loop diuretics, for example, furosemide, which reduces preload and improves pulmonary vascular congestion and peripheral edema. Furosemide has been shown to be a category C drug during pregnancy (animal reproduction studies show an adverse effect on the fetus with absence of well-controlled studies in human beings, but the potential benefits may warrant use of the drug in pregnant women despite risks). While administering in pregnancy, it is essential to closely monitor the patient’s volume status, as diuretic-induced dehydration can cause adverse fetal outcomes with oligohydroamnios, decreased uterine perfusion, and subsequent worsening of maternal metabolic acidosis.³⁰ During lactation, although furosemide has been shown to be excreted in breast milk, no case of furosemide toxicity in infants has been reported to date.³¹ Other diuretic agents that can be used are thiazide diuretics and potassium-sparing diuretics. Thiazide diuretics have been labeled category B (animal reproduction studies failed to show a risk to the fetus, and insufficient data on usage in pregnant women; or animal studies have shown an adverse effect, but current data in pregnant women failed to demonstrate a risk to the fetus in any trimester) and potassium-sparing diuretics have been labeled category D (positive evidence of human fetal risk from studies in human beings). Thiazide diuretics have been deemed safe to administer during pregnancy and lactation. However, due to the teratogenic effects of potassium-sparing diuretics (such as spironolactone), their role and use in PPCM is controversial.³¹ During lactation, canrenone, an active metabolite of spironolactone, is minimally secreted in breast milk and is of likely no clinical significance. Hence, spironolactone has currently been approved by the American Academy of Pediatrics for management of HF in the postpartum period.³²

Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers

Angiotensin-converting enzyme (ACE) inhibitors and Angiotensin II receptor blockers (ARBs) form the cornerstone of therapy in patients with HF in the general population. However, they have been shown to be highly teratogenic both during pregnancy and lactation periods. Their teratogenic effects range from oligohydroamnios, intrauterine growth retardation, limb contractures, patent ductus arteriosus, hypocalvaria, fetal renal failure, and fetal death.³³ Due to these severe effects, these agents have been contraindicated during pregnancy in patients with PPCM.^34-36 However, enalapril and captopril have been deemed to be safe to administer during the lactation period by the American Academy of Pediatrics.

Other Afterload Reducing Agents

Other agents include digoxin, nitrates, and hydralazine. Digoxin has been shown to be relatively safe in both pregnancy and lactation when its levels are within therapeutic range between 0.5 and 0.8 ng/mL.^37,38 Digoxin levels between 1.1 and 1.5 ng/mL have been shown to be associated with increased mortality as demonstrated in the Digitalis Investigation Group Trial.³⁹ Both nitrates and hydralazine are classified as category C drugs, but they are considered relatively safe during pregnancy and serve as an effective combination for afterload reduction.^2,11