Continuing Education Activity

Peripartum cardiomyopathy (PPCM) is a rare cause of cardiomyopathy that occurs during late pregnancy or in the early postpartum period. It is characterized by significant left ventricular dysfunction and heart failure in the peripartum period occurring in the absence of other identifiable causes of heart failure. Left ventricular ejection fraction is almost always less than 45 percent, and the left ventricle may or may not be dilated. This activity describes the evaluation, diagnosis, and management of peripartum cardiomyopathy and stresses the role of team-based interprofessional care for affected patients.

Objectives:

• Outline the criteria for peripartum cardiomyopathy.
• Review the presentation of peripartum cardiomyopathy.
• Describe the management of peripartum cardiomyopathy.
• Explain how an interprofessional approach is imperative to the effective management of patients with peripartum cardiomyopathy.

Introduction

Peripartum cardiomyopathy (PPCM) is a rare cause of cardiomyopathy that occurs during late pregnancy or the early postpartum period. This condition can be life-threatening and is characterized by significant left ventricular dysfunction and heart failure. [1][2][3]

PPCM is not a precisely defined entity. In 2010, the European Society of Cardiology described PPCM as an idiopathic cardiomyopathy with the following characteristics:

• Development of heart failure toward the end of pregnancy or in the postpartum period.
• Absence of another identifiable cause of the heart failure.
• Left ventricular systolic dysfunction with a left ventricle (LV) ejection fraction nearly always less than 45 percent. The LV may or may not be dilated.

Etiology

The etiology behind PPCM is still unclear. Relation with eclampsia and hypertension during pregnancy has been found. Still, the underlying mechanism is unclear. Risk factors for PPCM are African descent, age, pregnancy-related hypertension disorders, multiparity, multiple gestations, obesity, chronic hypertension, and prolonged used of tocolytics. Several studies have been proposed various hypothetical mechanisms related to the development of PPCM.[4][5] This will be explained in the pathophysiology section.

Epidemiology

The incidence of PPCM is uncertain, perhaps due to the misdiagnosis of this identity. Despite this, the available information from multiple studies has shown that PPCM varies geographically. In the United States, the incidence has been reported to be as low as 1 case per 4,000 live births in comparison with the higher incidence in Nigeria of 1 case in every 100 live births. 

Women older than 25 years with a mean age of 30 years were found more likely to develop PPCM. Other important factors related to the presence of PPCM include hypertensive disorders associated with pregnancy, the presence of anemia, and African descent.

In the other hand, Hispanic women are the ethnicity with the least PCCM incidence. [6][7]

Pathophysiology

The etiology behind PPCM is still unclear but is likely multifactorial. In the literature, potential factors that may contribute to the etiology of PPCM have been evaluated.

Significant hemodynamic changes occur during pregnancy. There is an increase in preload secondary to the increase in red cell mass and blood volume. This also increases the cardiac output by 20% to 30% due to an increase in heart rate and stroke volume by 15% to 25%. All these changes present during the first and second trimester, the moment when the patient with structural heart disease will develop symptoms. Compared with PPCM, these symptoms develop during the peripartum. For this reason, it is not clear that hemodynamic stresses are the main reason for PPCM.[8][7]

Other etiologies such as myocarditis has been hypothesized due to the presence of viral genomes in biopsy of patients with PPCM as echovirus, Coxsackie, and parvovirus B19. A discrepancy amongst other studies exists, and for this reason, the specificity of this findings is poor, and further studies are necessary. 

Studies have improved our understanding of the etiology of PPCM as the role of a toxic hormonal environment that generates in late pregnancy and the relationship with genetic factors that can contribute to the development of PPCM.

Significant hormonal changes occur at the end of pregnancy. Prolactins levels increase during late pregnancy and in the puerperium stage. Several analysts have been studying the effect of prolactin metabolism in the mouse model of PPCM. One of these models had a knockout expression of STAT3; an enzyme was found in the myocardium of patients with end-stage heart failure secondary to PPCM. This enzyme protects the heart from reactive oxygen species that, when increased, generates by a mechanism not known the secretion of a peptidase known as cathepsin D that cleavage prolactin into an angiostatic N-terminal 16 kDA prolactin fragment that promotes apoptosis in endothelial cells and cardiomyocytes apoptosis.  

Genetic factors also have been implicated in the etiology of PPCM. Evidence of cluster of families with PPCM has been observed, and it is possible that the expression of the genes with the toxic environment during late pregnancy due to oxidative stress can increase the susceptibility of PPCM. Several studies have identified mutations in some patients with PPCM. 

A pro-inflammatory state might play a role in the development of PPCM. Increased levels of cytokines such as TNF-alpha and interleukin-6 have been found in patients with PPCM and heart failure.

Concern for an autoimmune response as a possible cause of PPCM has been described, especially because high levels of antibodies against certain cardiac tissue could be the cause autoimmune myocarditis as the etiology behind PPCM. The evidence supporting this theory is based on another theory that described changes in the immune system of the mother during pregnancy (immunosuppression) leading the mother's body exposed to antigens from the fetus that can cause generation of an immune response after pregnancy when the immune system recovers. 

Histopathology

In heart specimens found in the autopsy of women with a history of PPCM, appears to be pale, heavier and dilated. In the hearts with cardiac dysfunction, variable presence of mural thrombi has been found. Inside the heart, the valves look normal and the coronary vessels are patent most of the time unless know history of ischemia exists. Pericardial effusion is occasionally found. In the microscopic view of the heart, evidence of interstitial edema and cellular swelling, fibrosis, and hypertrophy is frequently found in the myocardium with often areas of abundant collection of eosinophils. 

Increased the number of glycogen and mitochondrias is commonly found in myocardial cells evaluated with electron microscopy.

History and Physical

PPCM will present after 36 weeks of gestation, and the majority of cases is seen in the first month after delivery. An earlier presentation can occur in patients with underlying cardiac comorbidities as valvular or ischemic cardiomyopathy.

Presentation of PPCM can vary depending on the degree of the disease at the moment of presentation. Symptoms related to heart failure and related to pregnancy are paroxysmal nocturnal dyspnea, pedal edema, orthopnea, and dyspnea on exertion. Other symptoms included a dry cough, palpitations, increase of abdominal girth, lightheadedness, and chest pain. 

Findings in the physical exam like jugular venous distentions, displaced apical impulse, third heart sound, and mitral regurgitation murmurs are common.

Evaluation

The diagnosis of PPCM requires a high index of suspicion based on the three clinical criteria because symptoms are similar to those related to physiopathologic changes secondary to pregnancy. PPCM is a diagnosis of exclusion, and detailed investigation is required to rule out other more common causes of cardiomyopathy. [1][9]

• Initial evaluation consists of routine blood work to evaluate for other causes of those symptoms such as anemia, electrolyte abnormalities, endocrine conditions as thyroid dysfunction, and renal or liver dysfunction. Elevation of brain natriuretic peptide (BNP) is commonly found elevated in patients with heart failure and patients with PPCM.
• Radiography of the chest can be part of the initial evaluation, showing cardiomegaly and/or pulmonary edema. These findings are nonspecific for PPCM but suggestive of heart failure. 
• Cardiovascular studies such as an electrocardiogram and echocardiogram are part of the initial evaluation.
• Electrocardiographic findings can be nonspecific. The common findings are sinus tachycardia, supraventricular tachycardia (including atrial fibrillation or flutter), and occasionally ventricular tachycardia. ST segment and T wave abnormalities have been reported but are nonspecific. Dilation of chambers by electrocardiogram can be present too. Despite this nonspecific findings, QRS prolongation of greater than 120 milliseconds is related to increased mortality in patients with PPCM. Echocardiography is the main study to evaluate the anatomy and functionality of the heart in patients with suspected PPCM. Evaluation of the left ventricular ejection fraction (LVEF) is key to rule out PPCM, as part of the criteria requires an LVEF less than 45%. Echocardiography also evaluates for other causes of heart failure such valvular diseases or any other structural abnormalities. Dilation of the ventricles and atriums can be present, and LV thrombus or atrial thrombosis can be found.

Further cardiovascular testing can be done with cardiac MRI; this modality can help to diagnose other causes of heart failure not related with PPCM and can determine the volume of the chambers and ventricular function in a more precise fashion than echocardiography. A further role of cardiac MRI in PPCM is to be determined.

Cardiac catheterization is only for selected patients. Left heart catheterization is indicated in patients with suspicion of ischemic cardiomyopathy. Right heart catheterization is less frequently used for the evaluation of PPCM. Echocardiographic parameters for chamber pressure can be used initially, and if further assessment is necessary or patient illness is severe and more accurate measurement is required, a right heart catheterization can help with these situations. 

Endomyocardial biopsy is not recommended and is mostly used to evaluate for infiltrative diseases that can be causing the failing heart. 

At the moment, there is a specific test for diagnosis of PPCM.

Treatment / Management

The initial medical management of PPCM is similar to other causes of heart failure with the special attention to how the condition can affect the pregnancy. Additional therapeutic considerations for this population may include arrhythmia management, anticoagulation therapy, mechanical support, and investigational therapies.[10][11][12]

As part of the goal of treatment for patients with PPCM, optimizing the preload or volume status is done through appropriate diuresis and keeping a balance of intra- and extravascular volume. Fluid restriction is fundamental to achieve this goal. Prepartum PCCM has special considerations for treatment due to side effects of medication that might cross the placenta and affect the fetus. As an example, use of diuretics during pregnancy should be done carefully and in very low doses as they may impair perfusion of the placenta and cause potential harm to the fetus. Both hydrochlorothiazide and furosemide are safe during pregnancy and lactation, with close monitoring for diuresis and at low doses. Insufficient data exist about potassium-sparing diuretics for PPCM during pregnancy.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are contraindicated during pregnancy due to the well known teratogenic effects if administrated during pregnancy. Both of these medications can be used after delivery, but breastfeeding is contraindicated.

Beta-blockers can be used with caution during pregnancy (beta-1 selective agents are preferred) and are contraindicated during breastfeeding because this is excreted in the breastmilk. Carvedilol is a combined beta-blocker with an additional alpha-blockade effect that allows a decrease of the afterload and is effective in the treatment of PPCM.

Hydralazine, a vasodilator, is safe during pregnancy. A nitroglycerin drip can be used to manage afterload in the acute setting. Nitroprusside is contraindicated during pregnancy for concern of cyanide's toxicity. 

In very ill patients with hemodynamic instability, the use of inotropes might be necessary. Use of inotropes such as dobutamine, dopamine, and milrinone is restricted for this critical situation with close monitoring and with fast weaning off medication if possible.

Digoxin is another drug that can be used for the treatment of PPCM. It is safe during pregnancy and can be used when the ionotropic and chronotropic effect is necessary, especially in the setting of uncontrolled atrial fibrillation. 

Anticoagulation therapy in patients with PPCM is controversial. As a general recommendation, patients with PPCM without LV thrombus or atrial fibrillation should not be in anticoagulation. Patients with PPCM and atrial fibrillation and/or LV thrombus should be anticoagulated according to the guidelines for anticoagulation and the trimester of pregnancy. 

Decisions regarding the use of an implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy in patients with PPCM should consider the natural history of these diseases, including the potential for the recovery of ventricular function.

Use of mechanical circulatory support has been describing in patients with fulminant PPCM. Placement of left ventricular assistant device (LVAD) can be a bridge for transplant or recovery.

Experimental medications such as pentoxifylline, bromocriptine, IVIG, and immunosuppression are still under investigation, and nonspecific recommendations exist for these drugs. 

Differential Diagnosis

PPCM is a diagnosis of exclusion. Evaluation of other causes of heart failure is necessary. Valvular diseases before pregnancy or pre-existing cardiomyopathy can decompensate with the hemodynamic changes related to pregnancy, and further manifestation can be seen later in the pregnancy.

Prognosis

Recovery normally occurs three to six months postpartum but has been described until 48 months after delivery.

Good Prognosis Factors

Several factors are associated with good prognosis, these include:

• Small LV diastolic dimension (less than 5.5cm)
• LVEF greater than 30% to 35% and fractioning of shortening greater than 20% at the time of diagnosis.
• The absence of troponin elevation.
• The absence of LV thrombus.
• Non-African American ethnicity

Poor Prognosis Factors

The following factors may indicate a poor prognosis:

• QRS greater than 120 milliseconds 
• Delayed diagnosis
• High NYHA class
• Multiparity
• African descent

Recurrence of PPCM in subsequent pregnancies is elevated, and the patient should be advised against further pregnancies and monitored closely.

Complications

Maternal complications

• Thromboembolism
• Arrhythmias
• Progressive heart failure
• Misdiagnosis as pre-eclampsia

Fetal complications

• Fetal distress from hypoxia

Consultations

Anesthesiologist

Internist

High-risk obstetrician

Perinatologist

Deterrence and Patient Education

Patients should be educated on the potential for adverse effects during pregnancy. Most patients blame the doctor when the cardiomyopathy presents without any prior knowledge.

Enhancing Healthcare Team Outcomes

Peripartum cardiomyopathy is a rare but very serious disorder. The overall prognosis depends on the ejection fraction. About 50-70% of patients have gradual improvement in ventricular function and symptoms by 6 months. However, embolic events carry a mortality of 30%. For women who survive, a second pregnancy should not be undertaken if the ejection fraction is low. Prior to a second pregnancy, the female should be thoroughly worked up with an echo or a stress test. Even patients with a complete recovery should be warned that the condition can recur again. The timing of delivery and management require an interprofessional approach and individualization of the patient.  [13][14] (Level V)

The role of the obstetric nurse is critical. These patients need a thorough education on the subject so that they have realistic expectations. Most patients never consider that a pregnancy will be adversely affected, and when cardiomyopathy occurs, the patient and or the family usually blame the healthcare providers for lack of information. 

Over the years, many guidelines have become available on the diagnosis and management of peripartum cardiomyopathy. Thus, all healthcare workers who look after these patients must be well informed about the treatment. [15][16](Level V)

Outcomes

Women with a minimal decrease in ejection fraction tend to have a good prognosis, but those with a poor ejection fraction have a high risk of death. In addition, any female who requires an assist device tends to have adverse events and a low survival. A heart transplant is not always an option because of a lack of donors. In many cases, while the pregnant female may survive, the fetus may not. Given this morbid statistics, all healthcare workers should educate the patient and family about the disorder and its outcomes. [17][18] (level III)