By David W. Markham, M.D., MSc
A 29-year-old woman presents two weeks after delivery of her second child complaining of lower extremity edema and dyspnea on exertion. She had mild dyspnea at the end of her first pregnancy two years ago, but she has had an uneventful second pregnancy. She has no other medical problems. The patient has a faint third heart sound (S3) on cardiac exam, basilar rales on lung exam, and 2+ peripheral edema. An echocardiogram shows an Ejection Fraction (EF) of 35 percent. The patient is admitted for diuresis in the setting of peripartum cardiomyopathy (PPCM). A few months pass, and her EF is now over 55 percent and normalized. She is asymptomatic. The patient asks about possibly becoming pregnant again. In this brief review, I will discuss a few of the questions surrounding this case.
What is PPCM?
PPCM is an important and often under-recognized cardiac disease of pregnancy. It is rare in the United States and has varied incidence around the world. When the disease occurs, it affects the mother, the children and the local community, especially in poor parts of the world. PPCM has been defined as a heart failure syndrome occurring in the last month of pregnancy or within five months of delivery, but some cases may manifest outside this time frame (1).
In the United States, PPCM has a reported incidence of approximately 1 in 3000 births (2). Studies from Deschapelles, Haiti, report one of the highest incidence rates in the world at approximately 1 in 300 births (3-4). Worldwide, the estimated number of women with PPCM could be as high as 72,500 cases a year if 145,000,000 babies are born each year and if there is an approximate incidence of 1 in 2,000 in childbearing women.
A variety of risk factors have been identified for PPCM (See Table 1), including history of hypertension, multigravid state, prolonged tocolysis, obesity, smoking and low socioeconomic status (5–9). Regarding race/ethnicity, the incidence of PPCM seems to be highest in women with an African or African-American background (10). Genetic factors likely play a role in PPCM, but specific links are not yet understood.
The viral hypothesis of PPCM has been considered. Viral genomic material has been discovered in cardiac biopsy specimens from PPCM patients, but the incidence is not different than controls (11). Immune activation may also be important in PPCM. For instance, various autoantibodies are found in some PPCM patients (12). The presence of fetal cells in the motherâ€™s heart (microchimerism) also suggests a role for immune activation (13).
Micronutrient deficiency has also been proposed as a hypothesis because of the significant association of low socioeconomic status with PPCM. Hormonal imbalances are also a possible etiology in PPCM. Data in this area come from studies of the prolactin pathway (14-15). As such, bromocriptine, an inhibitor of prolactin, has been proposed as a treatment for PPCM, but the use of bromocriptine has not been widely accepted due to safety concerns and limited data. Another recently proposed mechanism involves abnormal angiogenesis (16). The variety of hypotheses regarding PPCM and supporting clinical data may suggest multiple pathways for development of the disease.
Distinguishing PPCM is often difficult because of the high prevalence of edema and dyspnea during normal pregnancy. Practitioners must have a high degree of suspicion and be prepared to perform screening echocardiography. PPCM often goes undiagnosed or misdiagnosed. The typical symptoms of heart failure (HF) are often present in PPCM patients: edema, orthopnea, paroxysmal nocturnal dyspnea, dyspnea of exertion, exercise intolerance, cough and chest pain.
On the physical exam, patients may have the usual array of HF signs: elevated jugular venous pulsations, pulmonary rales, displaced apical pulse or S3 on cardiac exam, ascites or peripheral edema. Echocardiography is the cornerstone of PPCM diagnosis, particularly to assess left ventricular EF (typically < 45 percent) (17). Cardiac magnetic resonance imaging (MRI) can also be useful in the evaluation of PPCM patients.
All guideline-based recommendations for HF of other etiologies apply to the management of PPCM. Patients with HF due to PPCM are often initially treated with intravenous diuretics and vasodilatory agents. Inotropes may be necessary in some patients. Following stabilization, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, diuretics and digoxin make up the standard regimen for PPCM patients. Also, other vasodilatory agents may be added to the chronic HF regimen in some persistently symptomatic patients such as isosorbide and hydralazine.
It is important to note that patients diagnosed during the antepartum period often require early delivery. Beta-blockers are often titrated upward to obtain target doses recommended from clinical trials. ACE inhibitors and angiotensin II receptor blockers (ARBs) are not recommended for pregnant women because of the risk of fetal renal abnormalities. Aldosterone receptor antagonists should be avoided in the antepartum period. Diuretics should be used, in all instances, at the lowest possible dose to maintain a euvolemic state.
High incidence rates of left ventricular (LV) thrombi have been reported in PPCM patients, and stroke rates seem to be increased (18). This risk is likely complicated by the hypercoagulable state of pregnancy. Patients with severely reduced ejection fraction (EF<35 percent) should be considered for anticoagulation. During pregnancy, unfractionated heparin (UFH) or low molecular weight heparin may be used since they do not cross the placenta. After delivery, heparin or warfarin may be used since they are not secreted in the breast milk.
Duration of therapy for PPCM patients is controversial, and there is currently no consensus. If a patientâ€™s left ventricular (LV) function normalizes, some practitioners recommend continuing guideline-based HF therapy for at least one year. One study has demonstrated, however, that some patients may have deterioration months or even years after diagnosis if medications are stopped (19-20). Similar results have been noted in the Haitian PPCM population (personal communication from Albert Schweitzer Hospital, Haiti). If the LV function remains depressed, drug therapy should be continued indefinitely.
It is important to note that short- and long-term outcomes in patients with PPCM are better than other types of non-ischemic cardiomyopathies. PPCM patients have a high rate of LV recovery. Overall, the risk of death is low, but some patients do progress to refractory HF and need cardiac mechanical support or cardiac transplantation (21-22).
What About Subsequent Pregnancy After PPCM?
Studies of subsequent pregnancy after PPCM consistently show higher risk in unrecovered (abnormal LVEF) vs. recovered (normal LVEF) patients. The risk of decreased LV function during a subsequent pregnancy for a recovered patient is 20-30 percent. The risk of decreased LV function during a subsequent pregnancy for an unrecovered patient is 50 percent. The risk of death with subsequent pregnancy in recovered vs. unrecovered patients is approximately 0-5 percent vs. 15-20 percent (23-24).
Some studies suggest that a stress echocardiography test (dobutamine or exercise) may be helpful in risk stratification (20). Patients who have a normal stress echocardiography result seem to have a favorable prognosis, while an abnormal result may suggest a higher risk with subsequent pregnancy. For PPCM patients who elect to have subsequent pregnancies, our practice has been to perform frequent echocardiography â€“ as often as every 4-6 weeks â€“ during pregnancy and after delivery.
Back to the Patient
In the case presented at the beginning of this article, the decision to become pregnant again is complicated and is not without some risk. It is perhaps favorable that this patient had complete recovery of LV function and is asymptomatic, but if she becomes pregnant again she will require close monitoring and follow up.
- Pearson Gd, V.J.R.S. and et al., Peripartum cardiomyopathy: National heart, lung, and blood institute and office of rare diseases (national institutes of health) workshop recommendations and review. JAMA, 2000. 283(9): p. 1183-1188.
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- Fett, J.D., et al., Peripartum cardiomyopathy in the hospital Albert Schweitzer district of Haiti. American journal of obstetrics and gynecology, 2002. 186(5): p. 1005-1010.
- Fett, J.D., et al., Five-year prospective study of the incidence and prognosis of peripartum cardiomyopathy at a single institution. Mayo Clin Proc, 2005. 80(12): p. 1602-6.
- Lampert, M.B., et al., Peripartum heart failure associated with prolonged tocolytic therapy. Am J Obstet Gynecol, 1993. 168(2): p. 493-5.
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- Gentry, M.B., et al., African-American Women Have a Higher Risk for Developing Peripartum Cardiomyopathy. Journal of the American College of Cardiology, 2010. 55(7): p. 654-659.
- Bultmann, B.D., et al., High prevalence of viral genomes and inflammation in peripartum cardiomyopathy. Am J Obstet Gynecol, 2005. 193(2): p. 363-5.
- Warraich, R.S., et al., Impact of pregnancy-related heart failure on humoral immunity: clinical relevance of G3-subclass immunoglobulins in peripartum cardiomyopathy. Am Heart J, 2005. 150(2): p. 263-9.
- Kara, R.J., et al., Fetal cells traffic to injured maternal myocardium and undergo cardiac differentiation. Circ Res, 2012. 110(1): p. 82-93.
- Hilfiker-Kleiner, D., et al., A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell, 2007. 128(3): p. 589-600.
- Sliwa, K., et al., Evaluation of bromocriptine in the treatment of acute severe peripartum cardiomyopathy: a proof-of-concept pilot study. Circulation, 2010. 121(13): p. 1465-73.
- Patten, I.S., et al., Cardiac angiogenic imbalance leads to peripartum cardiomyopathy. Nature, 2012. 485(7398): p. 333-8.
- Elkayam, U., et al., Pregnancy-associated cardiomyopathy: clinical characteristics and a comparison between early and late presentation. Circulation, 2005. 111(16): p. 2050-5.
- Napporn, A.G., et al., [Intraventricular thrombosis complicating peri-partum idiopathic myocardiopathy]. Ann Cardiol Angeiol (Paris), 2000. 49(5): p. 309-14.
- Amos, A.M., W.A. Jaber, and S.D. Russell, Improved outcomes in peripartum cardiomyopathy with contemporary. Am Heart J, 2006. 152(3): p. 509-13.
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- Rasmusson, K., et al., Long-Term Outcomes in Patients With Peripartum Cardiomyopathy and No Recovery of Ventricular Function. Journal of cardiac failure, 2010. 16(8): p. S97.
- Zimmerman, H., et al., Treatment of peripartum cardiomyopathy with mechanical assist devices and cardiac transplantation. Ann Thorac Surg, 2010. 89(4): p. 1211-7.
- O’Connell, J.B., et al., Peripartum cardiomyopathy: clinical, hemodynamic, histologic and prognostic characteristics. J Am Coll Cardiol, 1986. 8(1): p. 52-6.
- Elkayam, U., et al., Maternal and fetal outcomes of subsequent pregnancies in women with peripartum cardiomyopathy. N Engl J Med, 2001. 344(21): p. 1567-71.