Peripartum cardiomyopathy: Causes, diagnosis, and treatment
ABSTRACTPeripartum cardiomyopathy is a life-threatening condition of unknown cause that occurs in previously healthy women during the peripartum period. It is characterized by left ventricular dysfunction and symptoms of heart failure that can arise in the last trimester of pregnancy or up to 5 months after delivery. We review its possible causes and how to recognize and manage it.
KEY POINTS
- Heightened suspicion is important when a pregnant woman presents with signs of heart failure, because early diagnosis allows proven treatment to be started.
- Standard heart failure therapy should be started in postpartum patients with this disease, using available local protocols.
- Pregnant women should not receive angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or warfarin because of potential teratogenic effects.
- An initial left ventricular end-systolic dimension less than 5.5 cm, a left ventricular ejection fraction greater than 30%, and a low cardiac troponin level may predict a better outcome.
- Subsequent pregnancies carry a high risk of relapse, even in women who have fully recovered left ventricular function.
MANAGEMENT OF POSTPARTUM CARDIOMYOPATHY
Heart failure treatment during pregnancy
When considering tests or treatments in pregnancy, the welfare of the fetus is always considered along with that of the mother. Coordinated management with specialists (an obstetrician and maternal-fetal medicine team) is essential, with fetal heart monitoring.
Angiotensin-converting enzyme (ACE) inhibitors and ARBs are contraindicated in pregnancy because they can cause birth defects, although they are the main treatments for postpartum women with heart failure. The teratogenic effects occur particularly in the second and third trimester, with fetopathy characterized by fetal hypotension, oligohydramnios-anuria, and renal tubular dysplasia.51,52 However, a recent study suggested a risk of malformations even after firsttrimester exposure to ACE inhibitors.53
Digoxin, beta-blockers, loop diuretics, and drugs that reduce afterload such as hydralazine and nitrates have been proven to be safe and are the mainstays of medical therapy of heart failure during pregnancy.44 Beta-blockers have strong evidence of efficacy in patients with heart failure, but they have not been tested in peripartum cardiomyopathy. Nevertheless, beta-blockers have long been used in pregnant women with hypertension without any known adverse effects on the fetus, and patients taking these agents prior to diagnosis can continue to use them safely.46,54
Heart failure treatment postpartum
After delivery, the treatment is identical to that for nonpregnant women with dilated cardiomyopathy.
ACE inhibitors and ARBs. The target dose is one-half the maximum antihypertensive dose.
Diuretics are given for symptom relief.
Spironolactone or digoxin is used in patients who have New York Heart Association class III or IV symptoms. The goal with spironolactone is 25 mg/day after dosing of other drugs is maximized. The goal with digoxin is the lowest daily dose to obtain a detectable serum digoxin level, which should be kept at less than 1.0 ng/mL. In the Digitalis Investigation Group trial,55 serum digoxin levels of 0.5 to 0.8 ng/mL (0.6–1.0 nmol/L) were most beneficial, and levels of 1.1 to 1.5 ng/mL (1.4–1.9 nmol/L) were associated with an increase in deaths related to heart failure.
Beta-blockers are recommended for peripartum cardiomyopathy,44 as they improve symptoms, ejection fraction, and survival. Nonselective beta-blockers such as carvedilol (Coreg) and selective ones such as metoprolol succinate (Toprol XL) have shown benefit. The goal dosage is carvedilol 25 mg twice a day (50 mg twice a day for larger patients) or metoprolol succinate 100 mg once a day.
Anticoagulation treatment
During pregnancy, the risk of thromboembolic complications increases due to higher concentrations of coagulation factors II, VII, VIII, and X, and of plasma fibrinogen. The risk may persist up to 6 weeks postpartum.1 Cases of arterial, venous, and cardiac thrombosis have been reported in women with peripartum cardiomyopathy, and the risk may be related to the degree of chamber enlargement and systolic dysfunction and the presence of atrial fibrillation.56,57
Patients with evidence of systemic embolism, with severe left ventricular dysfunction or documented cardiac thrombosis, should receive anticoagulation.56–58 Anticoagulation should be continued until a return of normal left ventricular function is documented.
We await the results of the Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction trial, which should determine which drug will best prevent death or stroke in patients with ejection fractions of less than 35%.
Warfarin can cause spontaneous fetal cerebral hemorrhage in the second and third trimesters and therefore is generally contraindicated during pregnancy.59,60 However, guidelines from the American College of Cardiology and the American Heart Association on the management of patients with heart valve disease say that “warfarin is probably safe during the first 6 weeks of gestation, but there is a risk of embryopathy if the warfarin is taken between 6 and 12 weeks of gestation.”61 The guidelines also say warfarin is “relatively safe” during the second and third trimesters but must be stopped and switched to a heparin several weeks before delivery. Unfractionated heparin or low-molecular-weight heparin can be used during pregnancy. However, should warfarin be needed for any reason, we believe a cesarian section should be performed to reduce the risk to the infant.
Cardiac transplantation
Patients with severe heart failure despite maximal drug therapy need cardiac transplantation to survive and to improve their quality of life. However, fewer than 3,000 hearts are available for transplantation worldwide per year. Therefore, ventricular assist devices are indicated as a bridge to transplantation.62
Patients with symptomatic ventricular arrhythmias should be considered for defibrillator implantation.63
New treatments
Pentoxifylline improved outcomes, left ventricular function, and symptoms when added to conventional therapy in a small prospective study.64
Intravenous immunoglobulin improved the ejection fraction in several studies65,66 and also markedly reduced the levels of inflammatory cytokines, namely thioredoxin.67
Immunosuppressive therapy does not yet have a fully proven role, but it could be considered in patients with proven myocarditis. Given the various etiologic mechanisms of peripartum cardiomyopathy, it is unlikely that immunosuppression will help all patients. Furthermore, without a large randomized trial, treatment successes may merely reflect the natural course of the disease.
Investigators have emphasized the need to rule out viral infection before starting immunosuppressive treatment, as the treatment may activate a latent virus, with subsequent deterioration in myocardial function.28,68
Bromocriptine (Parlodel). Peripartum cardiomyopathy develops in mice bred to have a cardiomyocyte-specific deletion of stat3, leading to enhanced expression and activity of cardiac cathepsin D and promoting the formation of a 16-kD proaptotic form of prolactin.29 Therefore, drugs that inhibit prolactin secretion may represent a novel therapy for peripartum cardiomyopathy. Based on this concept, two patients with peripartum cardiomyopathy were treated with bromocriptine, an inhibitor of prolactin secretion, and they showed a good recovery.69 We require large prospective randomized controlled studies to prove the beneficial effect of blocking prolactin in patients with peripartum cardiomyopathy.
Other proposed therapies are calcium channel antagonists,70 statins,71 monoclonal antibodies,72 interferon beta,73 immunoadsorption, 74 therapeutic apheresis,75 and cardiomyoplasty.76
How long to treat?
Patients with peripartum cardiomyopathy who recover normal left ventricular function at rest or with low-dose dobutamine (Dobutrex) can be allowed to taper and then discontinue heart failure treatment in 6 to 12 months.46
