Peripartum cardiomyopathy is a unique type of heart failure that develops during the final month of pregnancy and up to 5 months postpartum. To be given a diagnosis of peripartum cardiomyopathy, patients must have symptom onset during the peripartum period and no symptoms before the final month of pregnancy, an ejection fraction less than 45%, and no other identifiable etiologies of cardiomyopathy. Pregnant women older than 30 with hypertension or preeclampsia have an increased risk of developing peripartum cardiomyopathy.¹ Incidence in the United States is around 1 per 3189 births, but the incidence is much greater in Nigeria (1 per 100 births) and Haiti (1 per 299 births).²

Several factors may contribute to the development of peripartum cardiomyopathy, including viral infections, autoimmune response, malnutrition, hormonal changes, and a genetic predisposition. The predominant theory, however, describes cardiomyocyte damage inflicted by the 16-kDa byproduct of prolactin degradation.³ Oxidative stress during pregnancy increases the activity of cathepsin D, which cleaves prolactin to a 16-kDa byproduct of prolactin. This is more common in patients with risk factors for developing this condition, such as increased age and uncontrolled hypertension. The 16-kDa derivative promotes inflammation, inhibits angiogenesis, impairs cardiomyocyte metabolism, and causes cardiomyocyte apoptosis. The net effect is ventricular systolic and diastolic dysfunction.³

Up to 30% of patients with peripartum cardiomyopathy recover ventricular systolic function with appropriate treatment.^4,5 Usual therapy mirrors treatment for systolic heart failure and includes angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), β-blockers, aldosterone antagonists, and loop diuretics. Preference is given to initiation of medications with no or minimal concentrations in breast milk, such as metoprolol succinate and enalapril.⁴ However, prepartum onset prohibits optimal treatment because of the teratogenic effects of ACE inhibitors, ARBs, and aldosterone antagonists.⁴ Despite optimal postpartum treatment, the mortality rate is around 10% within 2 years and 11% within 3 years of diagnosis, and about 7% of patients eventually require durable mechanical circulatory support or heart transplantation. Furthermore, the 3-year mortality rate increases to 29% for women of African descent.² Therefore, alternative therapies to prevent worsening heart failure and promote recovery of ventricular function are a priority for investigations.

Bromocriptine, a dopamine D₂ receptor agonist, suppresses prolactin secretion and may play a unique role in peripartum cardiomyopathy therapy by preventing degradation of prolactin to the 16-kDa derivative that causes cardiomyocyte damage.⁵ A prospective, open-label trial of 20 patients with an ejection fraction of 35% or less having a diagnosis of peripartum cardiomyopathy randomized patients to standard heart failure therapy (carvedilol, enalapril, and furosemide) with or without bromocriptine 2.5 mg orally twice daily for 2 weeks, then 2.5 mg orally daily for 6 weeks.⁶ At baseline, 50% of patients had New York Heart Association (NYHA) class II symptoms, and 50% had NYHA class III or IV symptoms. Bromocriptine significantly improved NYHA functional class (p=0.008), recovery of ejection fraction (p=0.012), and death at 6 months (p=0.006). Nine of 10 patients who received bromocriptine achieved an ejection fraction of 35% or greater and NYHA functional class I compared with no patients who received standard therapy. Infant development was not adversely affected with bromocriptine therapy, despite the inability to breastfeed, but the study was underpowered to assess this end point because growth data were only available for 13 of 21 infants.⁶

Another trial randomized 63 patients with peripartum cardiomyopathy and an ejection fraction of 35% or less to short- or long-term bromocriptine therapy. Patients in both groups received standard heart failure treatment with a β-blocker, ACE inhibitor or ARB, aldosterone antagonist, and loop diuretic. Short-term bromocriptine therapy consisted of 2.5 mg orally daily for 1 week, and long-term bromocriptine therapy consisted of 5 mg orally twice daily for 2 weeks, followed by 2.5 mg orally daily for 6 weeks.⁷ The study was not placebo controlled because this was considered unethical according to previous investigations. Patients were around 34 years of age, were 98.4% white, and had an average BMI of 28 kg/m². At baseline, 12.7% of patients had NYHA class II symptoms, 30.2% had NYHA class III symptoms, and 55.6% had NYHA class IV symptoms. Short- and long-term bromocriptine therapies were comparable at 6 months, with similar improvements in ejection fraction of 50% or more (about 70% of patients in the long-term group vs. 50% in the short-term group) and the composite of heart failure hospitalizations, heart transplantation, and all-cause mortality (p=0.651). Two venous thromboembolic events and one peripheral artery occlusion were documented during the study. This study was not adequately powered to determine a difference between the treatment groups.⁷ Therefore, the optimal dose and duration of bromocriptine therapy remain undetermined and require further investigation.

There are several limitations to current evidence and barriers to implementation of bromocriptine as a routine treatment of peripartum cardiomyopathy. Patients cannot breastfeed while taking bromocriptine because the drug suppresses prolactin secretion.⁵ This may disproportionately affect patients in underdeveloped countries where access to infant formula may be limited, which is especially a concern because these countries have a greater incidence of this condition. Bromocriptine may also increase the risk of venous thromboembolic and vascular events, and anticoagulation may be required to prevent such sequelae.⁴ Furthermore, despite the dramatic results of the investigations, bromocriptine has only shown a benefit in improving heart failure symptoms in small samples of patients.^6,7 Thus, larger studies are required to determine whether bromocriptine has a clinical benefit in peripartum cardiomyopathy.

Peripartum cardiomyopathy is a severe medical condition with a high mortality rate, despite appropriate treatment.² Bromocriptine, in addition to standard heart failure medications, may improve heart failure symptoms and facilitate recovery of ventricular function.⁸ Before bromocriptine can be recommended for routine treatment of peripartum cardiomyopathy, trials should be adequately powered to ensure the safety and efficacy of this novel intervention.

References:

1. Arany Z, Elkayam U. Peripartum cardiomyopathy. Circulation 2016;133:1397-409.

2. Harper MA, Meyer RE, Berg CJ. Peripartum cardiomyopathy: population-based birth prevalence and 7-year mortality. Obstet Gynecol 2012;120:1013-9.

3. Hilfiker-Kleiner D, Kaminski K, Podewski E, et al. A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell 2007;128:589-600.

4. Hilfiker-Kleiner D, Struman I, Hoch M, et al. 16-kDa and bromocriptine in postpartum cardiomyopathy. Curr Heart Fail Rep 2012;9:174-82.

5. Laliberte B, Reed BN, Ather A, et al. Safe and effective use of pharmacologic and device therapy for peripartum cardiomyopathy. Pharmacotherapy 2016;36:955-70.

6. Sliwa K, Blauwet L, Tibazarwa K, et al. Evaluation of bromocriptine in the treatment of acute severe peripartum cardiomyopathy: a proof of concept pilot study. Circulation 2010;121:1465-76.

7. Hilfiker-Kleiner D, Haghikia A, Berliner D, et al. Bromocriptine for the treatment of peripartum cardiomyopathy: a multicentre randomized study. Eur Heart J 2017;38:2671-9.

8. Hilfiker-Kleiner D, Haghikia A, Nonhoff J, et al. Peripartum cardiomyopathy: current management and future perspectives. Eur Heart J 2015;36:1090-7.