Background
Peripartum (postpartum) cardiomyopathy (PPCM) is the most common cardiomyopathy in pregnancy. [1] PPCM is defined as an idiopathic cardiomyopathy that presents with heart failure secondary to left ventricular (LV) systolic dysfunction toward the end of pregnancy or in the months after delivery, in the absence of any other cause of heart failure. [2, 3] PPCM is a diagnosis of exclusion, and the majority are diagnosed postpartum. Although the LV may not be dilated, the ejection fraction is nearly always reduced below 45%. [2, 3]
This definition specifically excludes women who develop LV dysfunction early in their pregnancy and explicitly notes that not all cases of PPCM present with LV dilatation. [4] Thus, it helps avoid misdiagnosis of other conditions that present with pulmonary edema in pregnancy, such as diastolic dysfunction from preeclampsia and other disorders (see Differential Diagnosis).
PPCM is more common in women older than 30 years, black women, multiparous women, women with preeclampsia or hypertension, and those who smoke or are malnourished. [3] The overlap between PPCM and preeclampsia is clinically important, as patients with preeclampsia can present with noncardiogenic edema and the coexistence of these two conditions highlights potential shared pathogenic mechanisms.
The severity of symptoms in patients with PPCM can be classified by the New York Heart Association (NYHA) system as follows:
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Class I: Disease with no symptoms
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Class II: Mild symptoms/effect on function or symptoms only with extreme exertion
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Class III: Symptoms with minimal exertion
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Class IV: Symptoms at rest
Etiopathophysiology
Although many potential mechanisms for peripartum (postpartum) cardiomyopathy (PPCM) exist, its exact cause remains unknown [3] but is likely to be multifactorial. The timing of presentation argues against the hemodynamic changes of pregnancy for causing PPCM, because such changes usually peak by 28 weeks' gestation. Furthermore, the timing highlights a potential hormonal pathogenesis given that hormonal changes, such as the production of prolactin, continue in late pregnancy. Relatively recent research has focused on the "vasculo-hormonal hypothesis" with soluble Fms-like tyrosine kinase 1 (sFlt1) and prolactin as molecules involved in the pathophysiology of PPCM. [5]
Prolactin
Increased reactive oxygen species lead to secretion of cathepsin D by a mechanism that is currently not well understood. Cathepsin cleaves prolactin into a 16kDa prolactin. [6] 16kDa Prolactin induces endothelial cells to package miR-146 into exosomes which are then taken up by cardiomyocytes. [7] 16kDA Prolactin is associated with endothelial and myocyte apotosis.
sFLT1
A murine model of PPCM has implicated the loss of vascular endothelial growth factor (VEGF) in the pathogenesis of PPCM. [8] sFlt1 is a molecule secreted by the placenta in late gestation, and in higher levels in preeclampsia and twin gestations. sFlt1 neutralizes VEGF, thereby reducing circulating VEGF which is thought to contribute to PPCM. [9]
Taken together, the increased production of prolactin and placental secretion of sFlt1 in late pregnancy could be toxic to both the vasculature and the cardiac myocytes. The shared role of sFlt1 in preeclampsia, twin pregnancies, and PPCM provides a biological rationale for the increased incidence of PPCM in patients with preeclampsia or twin gestations.
Other pathophysiologic mechanisms
Genetics
Critics argue that the recovery of left ventricular ejection fraction and the lack of recurrence in all subsequent pregnancies challenge the notion that PPCM is a solely genetically-mediated condition. However, a study that sequenced 43 genes with variants associated with dilated cardiomyopathy from 172 women with PPCM revealed 26 (15%) distinct, rare truncating variants in 8 genes among these women, with TTN (titan) truncating variants the most prevalent. [10] The prevalence of these truncating variants was significantly higher than that found in a reference population of 60,706 people (4.7%) but similar to those of patients with dilated cardiomyopathy (17%).
Myocarditis
The equal prevalence of myocardial inflammation [11] and viral genomes [12, 13] that has been noted in subjects and controls who underwent endomyocardial biopsy challenges the pathogenic role of myocarditis in PPCM.
Nutritional factors
Lower levels of selenium or iron have been proposed as causative factors. Patients with PPCM, particularly in Nigeria, have been noted to have low selenium levels. [14]
Microchimerism
Microchimersium, with fetal-derived cells in the maternal circulation, has been hypothesized as potential contributing factor to the development of PPCM. [5, 15]
Patient History
Long-term survivors of malignancy who were treated with potentially cardiotoxic therapies are higher risk for PPCM than the general population. [16]
Epidemiology
United States statistics
Reports estimating the incidence of peripartum (postpartum) cardiomyopathy (PPCM) in the United States vary widely, ranging from 1 case per 1000-4000 live births. Approximately 75% of cases are diagnosed within the first postpartum month, and 45% present in the first week. [4]
International statistics
The prevalence is reported to be 1 case per 15,000 live births in Japan, 1 case per 1000 live births in South Africa, and 1 case per 350-400 live births in Haiti. [17] A high prevalence of 1 in 100 live births in Nigeria has historically been attributed to the tradition of ingesting kanwa (dried lake salt) while lying on heated mud beds twice a day for 40 days postpartum. More recent research suggests these practices are falling out of favor and the high incidence of PPCM may be attributable to genetic factors and poor nutrition in the region. [18]
Age- and race-related demographics
Although PPM can occur at any age, approximately 50% of cases occur in women older than 30 years. [19]
PPCM has been reported in White, Black, Chinese, Korean, and Japanese women. Case series indicate that many cases occur in Black women from the southern United States. A case control study in the United States found that, when compared to non–Black women, Black women had a 15.7-fold higher relative risk of PPCM. [20]
Prognosis
Reduced left ventricular ejection (LVEF) (< 30%) is single most important predictor of adverse outcomes. Other factors include LV dilatation, LV thrombus, RV systolic dysfunction, obesity, and Black race.
Mechanical support devices and transplantation
A study of 99 patients who received durable ventricular assist devices (VADs) between 2006 and 2012 reported better outcomes in patients with peripartum (postpartum) cardiomyopathy (PPCM) than for patients with other etiologies of cardiomyopathy. Approximately half of patients with VADs went on to have cardiac transplantation with only four of the patients having the VAD removed. Approximately 5% of transplants performed in women in the United States are in the context of PPCM. [5]
Mortality
In general, PPCM-related mortality ranges from less than 2% to 50%. [1] In-hospital mortality in the United States has been reported as 1.3%. Long-term mortality at 7-8 years has been reported as 11-16%. [5] Internationally, 6-month mortality has ranged from 2% in Germany to 12.6% in South Africa; 24-month data from Turkey reveal a 24% mortality. [3]
Left ventricular (LV) recovery
In the Investigations of Pregnancy Associated Cardiomyopathy (IPAC) study of 100 women in the United States, the majority (71%) improved their LVEF to above 50% by 6 months postpartum. [21] Approximately 13% of women had major events with persistent cardiomyopathy and an LVEF below 35%.
Predictors that suggest the LV will not recover include an initial LVEF below 30%, LV dilatation (LV end diastolic diameter [LVEDD] >60 mm) and black race. [21] In a Chinese study, both LVEF below 35% at presentation and an elevated B-type natriuretic peptide (BNP) level over 1860 pg/mL predicted persistent LV dysfunction. [22]
Black women in the United States have a worse prognosis, with lower rates of LV recovery and a higher incidence of mortality or transplantation. [23] Mortality is higher in South Africa (28% at 2 years) and Haiti (15% at 2 years).
Recurrence with subsequent pregnancies
In a study of 34 patients (predominantly black women) with subsequent pregnancies after a diagnosis of PPCM, the risk of relapse was 56%. [24] The risk of recurrence was higher in those with persistent LV dysfunction than in those with a normalized LVEF, with a study of 191 subsequent pregnancies demonstrating a relapse in 48% of patients with persistent LV dysfunction and 27% of patients with a normalized LVEF. [25] The incidence of mortality in recurrent PPCM in patients with persistent LV dysfunction prior to pregnancy has been reported as 19% [25] to 25%. [24] The risk of premature delivery and threatened abortions is also higher in patients with persistent LV dysfunction. [25]
Although assessment with stress echocardiography to demonstrate contractile reserve has been studied, the clinical relevance of adequate LV augmentation in subsequent pregnancies is not clear. [26]
The 2018 European Society of Cardiology (ESC) guidelines on the management of cardiovascular diseases and pregnancy categorize PPCM with persistent LV dysfunction (LVEF < 50%) as modified World Health Organization level IV (mWHO IV), a category defined as high maternal risk in which pregnancy should be considered contraindicated. [3] Prior PPCM with a normalized LVEF is categorized as mWHO III, a category defined as moderate maternal risk in which close monthly surveillance and delivery at a specialized center is recommended. [3] Prophylactic bromocriptine at the time of delivery in subsequent pregnancies in patients with prior PPCM is an evolving area of study. [3, 24, 27, 28, 29, 30]
Complications
Maternal complications of peripartum (postpartum) cardiomyopathy (PPCM) may include the following:
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Hypoxia
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Thromboembolism: Small case series have reported the incidence to be as high as 50%, but they are limited by selection bias
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Progressive cardiac failure
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Arrhythmias
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Misinterpretation of hemodynamic data obtained from right-heart catheterization as a result of failure to consider the normal physiologic alterations of pregnancy (see Cardiac Catheterization and Invasive Hemodynamic Monitoring)
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Inadequate treatment or testing because of exaggerated concern about the effect on the fetus
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Misdiagnosis of preeclampsia: Patients with preeclampsia experience depletion of intravascular volume and should receive low doses of diuretics only when they have pulmonary edema
Fetal complications of PPCM may include the following:
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Distress due to maternal hypoxia
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Distress due to placental hypoperfusion as a result of poor cardiac output, maternal hypovolemia due to excessive diuresis, or hypotension from aggressive afterload reduction
Patient Education
The initial diagnosis of peripartum (postpartum) cardiomyopathy is most often unexpected. It is important to provide honest and clear advice about the potential for decompensation. Education should be provided about heart failure management including lifestyle modifications (salt and fluid restrictions), daily weights, the importance of medication compliance, and awareness of worrisome symptoms such as weight gain, worsening dyspnea, pedal edema, orthopnea, paroxysmal dyspnea, chest pain, palpitations, presyncope, or syncope.
Women should be advised to avoid conceiving until follow-up echocardiography has been performed to provide an informed discussion about the risks of subsequent pregnancies. Education should also include a discussion on the risks of recurrent decline in left ventricular ejection fraction, possible mortality, and potential fetal events in subsequent pregnancies, particularly in women with persistent left ventricular dysfunction.
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Peripartum (Postpartum) Cardiomyopathy (PPCM). This radiograph reveals noncardiogenic pulmonary edema in patient with preeclampsia, due to a capillary leak that can be a primary component of preeclampsia. Note the diffuse increase in lung markings without the cephalization or vascular redistribution seen in patients with pulmonary edema from systolic dysfunction. The patient had rapid clinical improvement after only 10 mg of intravenous furosemide.
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Peripartum (Postpartum) Cardiomyopathy (PPCM). Baseline (A) and follow-up (B) four-chamber view echocardiograms in a woman who developed cardiomyopathy 4 weeks after an elective cesarean delivery. Image A demonstrates a large thrombus (arrow) attached to the lateral wall of the left ventricle (LV) at baseline (A), which completely resolved after two months (B). The patient's younger sister also experienced peripartum cardiomyopathy. Courtesy of BioMed Central Ltd, Springer Nature (Meyer GP, Labidi S, Podewski E, et al. Bromocriptine treatment associated with recovery from peripartum cardiomyopathy in siblings: two case reports. J Med Case Rep. 2010 Mar 4;4:80. Online at https://jmedicalcasereports.biomedcentral.com/articles/10.1186/1752-1947-4-80).
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Peripartum (Postpartum) Cardiomyopathy (PPCM). These images were obtained in a young woman with peripartum cardiomyopathy and multiple left ventricular (LV) thrombi. (A) Apical five-chamber view on transthoracic echocardiography demonstrating a large layered echodense mass attached to the LV lateral wall consistent with thrombi. (B) Four-chamber view of a balanced steady-state free precession cardiac magnetic resonance imaging acquisition 4 days after anticoagulation with parenteral heparin demonstrating near resolution of the thrombus, leaving behind only the underlying muscular trabeculations on this view (arrows). RV = right ventricle. Courtesy of BioMed Central Ltd, Springer Nature (Altuwaijri WA, Kirkpatrick ID, Jassal DS, Soni A. Vanishing left ventricular thrombus in a woman with peripartum cardiomyopathy: a case report. BMC Res Notes. 2012 Oct 2;5:544. Online at https://bmcresnotes.biomedcentral.com/articles/10.1186/1756-0500-5-544).
