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Cardiomyopathies in Pregnancy

Joan Briller

What Is a Cardiomyopathy?

The cardiomyopathies are a diverse group of disorders characterized by structural abnormalities of the heart muscle, many of which have a genetic component. Abnormalities may be anatomic (dilatation, thickened, or stiff musculature), histologic (manifested by fiber disarray, fibrofatty dysplasia, or fibrosis) or functional (systolic or diastolic dysfunction). Nonischemic cardiomyopathies have several phenotypes that include dilated, hypertrophic, restrictive, arrhythmogenic right ventricular, and unclassified. Each of these types may have familial and non-familial forms [1–3]. Several classificatory schemes exist, but the most recently endorsed is the MOGE(S) system which incorporates morphofunctional phenotype (M), organ involved (O), genetic inheritance (G), etiologic annotation (E), and functional status [1–4]. Examples of major nonischemic cardiomyopathies are shown in Box 12.1.

Dilated cardiomyopathies (DCM) are characterized by left ventricular (LV) enlargement and impaired systolic function. Dilated cardiomyopathy commonly presents in the third and fourth decade of life, which underscores concerns during reproductive years [5]. Etiologies include genetic defects, infections, and toxins. For many, the underlying cause is unknown and labeled idiopathic [2]. Peripartum cardiomyopathy (PPCM) is a specific form of DCM which is associated with pregnancy and usually classified under the idiopathic group.

Hypertrophic cardiomyopathies (HCM) differ in that they are characterized by ventricular hypertrophy and pressure overload but may not result in systolic dysfunction [2].

Heart failure (HF), in contrast, is a clinical syndrome resulting from impaired LV ejection or filling [6]. HF may be secondary to other underlying pathology such as ischemic disease, hypertensive disease, congenital heart disease, or valvular heart disease in addition to the cardiomyopathies.

How Does Pregnancy Affect Cardiomyopathy?

Adaptation to the physiologic requirements of pregnancy can challenge women with CMP. Women with baseline reduced cardiac reserve may not be able to accommodate demands to increase cardiac output by 30%–50%. Pregnancy is a state of volume overload [7,8]. Increased volume load may exacerbate associated valve lesions such as mitral regurgitation or increased ventricular filling pressure precipitating overt HF. Pregnancy-related alterations in hemodynamic, hormonal, and autonomic systems lead to atrial and ventricular stretch, which may increase arrhythmia burden when combined with the normal increased heart rate during pregnancy [9]. Pregnancy-associated CMP complications and management strategies are shown in Table 12.1.

The precise frequency of cardiomyopathy during pregnancy is not known and varies with geographic location, population, and specific cardiomyopathy. The European Registry on Pregnancy and Heart Disease (ROPAC) enrolled 1321 women with structural heart disease from 2001–2011. Cardiomyopathy was present in 7% [10]. DCM was seen in 32%, PPCM in 25%, hypertrophic nonobstructive cardiomyopathy in 16%, hypertrophic obstructive cardiomyopathy in 11%, and 5% other forms [10]. HF was the most common cardiovascular event during pregnancy in ROPAC [11]. In the United States, DCM predominated, usually attributed to peripartum cardiomyopathy, followed by hypertrophic etiologies [12,13]. In a CARPREG II study of outcomes in 1938 pregnancies in women with heart disease, at least mild ventricular dysfunction was present 13.6% but not all were secondary to cardiomyopathy, as the most common cardiac diagnosis was congenital heart disease [14]. Pregnancy-associated HF hospitalizations represented 112 cases per 100,000 pregnancy hospitalizations in a National Inpatient Sample analysis from 2001–2011. Cardiomyopathy was the most common comorbidity responsible for 39.7% of HF hospitalizations antepartum, 70.8% of HF during delivery hospitalizations, and 34.5% of postpartum hospitalizations [15]. The reported incidence of PPCM in the United States is approximately 1:1000 to 1:4000 live births [16]. Analysis of the National Inpatient Sample database suggests an increasing PPCM frequency over time with incidence rising from 8.5 to 11.8 per 10,000 live births [17]. There is marked geographic variation with regard to incidence. PPCM is more common in the southern United States and has been reported to occur as frequently as 1:300 live births in Haiti and 1:100 live births in Nigeria [18,19].

Dilated Cardiomyopathies

The prevalence of DCM in the United States is estimated at 36/100,000 population [6]. Etiology is diverse, ranging from familial cardiomyopathies which are felt to represent approximately 20%–35% of DCM to toxin exposure from substance abuse (e.g., alcohol, cocaine) to prior cancer therapy for childhood leukemia/lymphoma or breast cancer. Idiopathic DCM, which comprises about 50% of DCM, is diagnosed when detectable causes of cardiomyopathy other than genetic have been excluded [6]. Alcoholic cardiomyopathy, another leading cause of DCM, is diagnosed in the setting of heavy alcohol consumption for more than 10 years in the absence of another identified cause. Women represent approximately 14% of alcoholic cardiomyopathy [20]. Cancer patients receiving chemotherapy, especially anthracyclines, or chest radiation therapy are at risk of ventricular dysfunction. In a review of over 1800 survivors of childhood cancer, only 5.8% had overt LV dysfunction but over a third had reduced global longitudinal strain, a more subtle measure of ventricular dysfunction than ejection fraction, diastolic dysfunction, or both [21].

Pregnancy outcomes with DCM are based on a small cohort series [20,22–25]. Grewal examined outcomes in 36 pregnancies in 32 women with DCM. The majority (86%) had idiopathic DCM, the remainder chemotherapy induced. Thirty-nine percent of pregnancies were associated with at least one adverse maternal event. Moderate to severe LV dysfunction and poor functional status were the main determinants of adverse outcome. Neonatal events were also highest in women with increased cardiac risk factors. Sixteen-month event-free survival was worse in women who had a pregnancy than in women who did not [22].

Familial Dilated Cardiomyopathy

Family-based studies suggest a familial relationship in 20%–35% of patients diagnosed with DCM [26]. Most are transmitted as autosomal dominants, although all inheritance patterns are described. Genetic studies have identified mutations in more than 30 genes [26]. Estimated incidence is approximately 1:2500 [1]. Most patients will have an initial diagnosis of idiopathic cardiomyopathy. Diagnosis of familial DCM requires presence of LV dilatation and impaired systolic function in one or both ventricles in two or more closely related family members [27]. Mutation-specific genetic testing is recommended for family members when a DCM causative mutation is found in the index case even in the absence of symptoms [5]. Clinical manifestations of familial DCM are similar to other idiopathic DCM. General risks to be considered include progressive LV dysfunction which can be severe enough to require transplantation, arrhythmias including sudden cardiac death and, if pregnancy is pursued, transmission to offspring. Outcome data on pregnancy in women with familial DCM is extrapolated from a small cohort series of women with idiopathic DCM [20,22–25,28].

Peripartum Cardiomyopathy

PPCM is a form of DCM in association with pregnancy in the absence of structural heart disease or another explanation for DCM. Criteria for diagnosis include LV enlargement and dysfunction (typically an ejection fraction <45%) presenting toward the end of pregnancy or in the months post-delivery in a woman without previously known structural heart disease [16,29]. Diagnosis is confirmed by transthoracic echocardiography.

Risk factors for development of PPCM are well known. In the United States, the incidence is strikingly higher in African Americans [16]. Preeclampsia and hypertension (chronic or gestational), age greater than 30, multiple gestations, and higher gravidity and parity are other risk factors [16,30–33]. Current research suggests that an imbalance in angiogenic factors promotes PPCM in susceptible individuals. Both prolactin and soluble FMs-like tyrosine kinase (sFlt1) have been implicated in its development [34,35]. Several studies suggest familial clustering. Moreover, genetic evaluation of DNA in women with PPCM found truncating variants in 15%, many in the TTN gene which is important in cardiac muscle function similar to a DCM cohort. Presence of a TTN gene mutation correlated with lower ejection fractions at 1-year follow-up [36].

Maternal prognosis is variable but may be better than many other forms of cardiomyopathy [16,37,38]. Mortality is higher, presence of cardiac arrest or shock, and length of stay are significantly longer in patients with PPCM than normal pregnancy. PPCM deliveries were more likely to be by cesarean [33]. Factors suggesting worse prognosis include degree of LV dilatation, worse ejection fraction at presentation, associated RV dysfunction, abnormal cardiac biomarkers, family history of heart failure, and low cholesterol [39–43]. Outcomes are significantly worse in African Americans [39,44–46]. Most women improve in the first 6 months postpartum but delayed recovery has also been reported [38,39]. In the Investigations of Pregnancy-Associated Cardiomyopathy (IPAC) registry, 71% of women had recovered to an ejection fraction >50% by 1 year, mortality was 4%, advanced mechanical support was performed in 4%, and transplantation in 1%. There is a wide variation in published outcomes ranging from 2% in a German registry to 13% in a recent South African study [16,38]. Longer-term mortality is less well known [38].

Neonatal outcomes in PPCM are also worse. Babies were born earlier, smaller, more likely to be small for gestational age, and APGAR scores were lower [47]. In the EURObservational Research Programme (EORP), the neonatal death rate was 3.1% [48].

Should PPCM Patients Receive Bromocriptine?

Bromocriptine stimulates hypothalamic dopaminergic receptors inhibiting prolactin production suggesting a potential role in therapy [49]. A randomized trial in 20 South African women showed improved ventricular recovery as proof in concept [50]. A nonrandomized German registry found bromocriptine use twice as common in women with recovered function, although advanced HF interventions were similar regardless of bromocriptine use [42]. Further interest has been stimulated by a multicenter trial in 63 women with ejection fractions less than 35% who were randomized to 1 week versus 8 weeks of bromocriptine, finding a nonsignificant trend toward greater recovery in the 8-week therapy group, but both groups improved. No women required advanced interventions, right ventricular function improved, and there were no deaths at 6 months [51,52]. A major limitation to the study was lack of a placebo arm. Small numbers of patients, the validity of comparing outcomes in the German study to historical controls in the IPAC registry which had a large number of African Americans known to have worse outcomes, concerns about hypertensive or thrombotic complications with bromocriptine, and loss of the ability to lactate have dampened enthusiasm for use in the United States in the absence of a larger placebo-controlled trial [16,53]. European guidelines have recommended consideration of bromocriptine in addition to guideline directed medical therapy [54]. If bromocriptine is used for treatment, anticoagulation is recommended [51]. Although approved for other indications, bromocriptine is not FDA approved in the United States for treatment of PPCM at the time of writing.

Do We Need to Anticoagulate Women with PPCM?

Thromboembolic complications in patients with DCM are estimated at 1%–3% per year and correlate with the degree of LV dysfunction, presence of atrial fibrillation, or presence of thrombus during cardiac imaging [6]. Thromboembolic complications in PPCM are considerably higher: 6.6% and 6.8% in a National Inpatient Sample and in EORP [17,48]. Other studies noted thrombi in more than 20% of patients with PPCM [55]. Precise recommendations for anticoagulation are based on expert opinion and vary but generally recommend anticoagulation for those with significant LV dysfunction (ranging from 30%–40%) at least until the thrombophilia of pregnancy has resolved in the absence of another indication [5,16,48,54,56,57].

Should a Woman with a Diagnosis of PPCM Breastfeed?

Controversy exists about safety of breastfeeding with PPCM. Breastfeeding prolongs postpartum prolactin elevation. Since prolactin has been proposed in the pathogenesis of PPCM, there are fears this will worsen likelihood of recovery. Additional concerns include hemodynamic requirements of breastfeeding and transfer of HF medications to the infant in breast milk. Fifteen percent of women in the IPAC registry breastfed without observed differences in myocardial recovery despite elevated prolactin levels [39]. A retrospective internet survey noted improved recovery in the two-thirds of women who breastfed [58]. However, it is unknown if there was a selection bias for breastfeeding in healthier women or those with better EFs. In another observational study of recurrent pregnancies in women with PPCM, a high percentage of women lactated and there were similar rates of recurrence in those who did or did not breastfeed [59]. Nevertheless, current ESC guidelines discourage breastfeeding for women with the most severe HF (NYHA class III/IV) [54].

What Is the Risk of PPCM Recurrence with a Subsequent Pregnancy?

Many women with PPCM desire another child. Recurrence risk estimations are derived from retrospective analysis of women with subsequent pregnancies. These typically divide women into those with recovered function in comparison with continued LV dysfunction. In the largest study, deterioration was seen in 21% of gravidas with recovered function in comparison with 44% of those with persistent dysfunction [60]. Similar results are noted in other publications and a meta-analysis [59,61–63]. Some women may have subnormal cardiac reserve even in the setting of improved function. Additional risk stratification might be considered using dobutamine or exercise stress prior to proceeding [63,64]. Most believe full recovery is associated with improved outcomes and lower mortality with a subsequent pregnancy, but all patients have a risk of deterioration [38,59,61]. Fett developed a simple periodic self-assessment tool validated on PPCM patients helpful in identifying women who would relapse, shown in Table 12.2. Elevated scores should prompt additional evaluation with biomarkers or transthoracic echocardiography. All women with PPCM had scores greater than 5 and controls less than 4 [65,66].

Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is characterized by LV hypertrophy in the absence of another explanatory cardiac or systemic disease [67]. The hypertrophy is often asymmetric with wall thickness >15 mm, but multiple patterns of hypertrophy have been described [67]. Many patients have a normal life expectancy and unremarkable clinical course. However, a subset develop HF related to outflow tract obstruction, diastolic dysfunction, myocardial ischemia, and mitral regurgitation. A small percentage develop systolic HF. Arrhythmia risks include atrial fibrillation, ventricular tachycardia, and sudden cardiac death.

HCM is the most common genetic cardiac disease with estimated prevalence as high as 1:200 using the newest techniques such as cardiac magnetic resonance and genetic testing [68]. HCM is typically caused by mutations in sarcomere genes that encode components of the myocardial contraction. Inheritance is in an autosomal dominant pattern in the vast majority with variable expression and age-related penetrance. Over 1500 mutations in 11 genes have been described as of 2015 [69]. HCM is estimated to be present in about 1:1000 pregnancies [54].

Diagnosis is usually made by a combination of ECG and echocardiography, with increasing use of cardiac magnetic resonance imaging since late gadolinium enhancement provides additional information about myocardial fiber disarray, fibrosis, and sudden death risk [67,70].

Symptomatic patients may present with fatigue, dyspnea, chest pain, palpitations, pre-syncope, or syncope. LV hypertrophy often occurs at the expense of cavity size, reducing stroke volume. Left ventricular outflow obstruction may be dynamic and worsen with exercise or reduced systemic vascular resistance of pregnancy; however, this may be offset by the increased volume of pregnancy. Left atrial enlargement or increased filling pressure can worsen mitral regurgitation and exacerbating arrhythmias such as atrial fibrillation. Despite this, many women with HCM often tolerate pregnancy well [28]. With contemporary management, mortality is very low (0.5% or less) [71,72]. Major adverse cardiac events were present in 23%–29% [71,72], including arrhythmias (atrial and ventricular) or HF usually occurring in the third trimester or postpartum. Issues to be addressed with pregnancy include genetic counseling about risk of transmission, medication adjustment, risk of arrhythmia or sudden death, and development of HF.

Rare Cardiomyopathies

Arrhythmogenic Right Ventricular Cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC/D), sometimes called arrhythmogenic RV dysplasia, is a rare inherited cardiomyopathy transmitted as an autosomal dominant disorder characterized by fibro-fatty tissue replacement in the right ventricle leading to right ventricular dilatation and dysfunction. The left ventricle is also frequently involved. Disruption of normal myocardium increases electrical instability, so arrhythmias are a prominent problem [73]. Prevalence is estimated to be 1:2000 to 1:5000 [73]. ARVC/D is an important cause of sudden cardiac death [1]. Diagnosis is based on echocardiogram or CMR. Information on outcomes during pregnancy is limited. In a single-center French study of 60 pregnancies in 23 women, major adverse cardiovascular events were rare: two (3%) sustained arrhythmias, neither during delivery or postpartum (3%) but no HF exacerbations. Beta-blocker therapy was common (16.7%) and associated with lower birth weights. Preterm delivery and cesarean rates were low, but premature sudden death was seen in five children before age 25 (10%) [74].

Left Ventricular Noncompaction

Left ventricular noncompaction (LVNC) is an uncharacterized type of cardiomyopathy that results in a distinctive spongy appearance of the myocardium due to increased trabeculations and deep myocardial recesses that communicate with the LV cavity increasing the risk for thromboembolism particularly in pregnancy. Diagnosis is made by echocardiography, cardiac magnetic resonance imaging, or occasionally LV angiography. Clinical manifestations of LVNC include HF (systolic or diastolic), atrial and ventricular arrhythmias, thromboembolic cerebral vascular events, and sudden cardiac death [75]. There are only a few case series of women with LVNC and pregnancy. There are no specific therapies, and general guidelines for management of CMP during pregnancy should be followed with the caveat that patients with LVNC have increased thromboembolic risk which may be enhanced with pregnancy [5,28].

Restrictive Cardiomyopathy

Restrictive cardiomyopathies are characterized by the presence of “restrictive filling pattern in the presence of normal or reduced diastolic volumes, normal or reduced systolic volumes, and normal wall thickness” and may represent various pathologies rather than a distinct entity [2]. Primary restrictive cardiomyopathy may be inherited due to genetic mutations in cardiac proteins, such as troponin, or non-inherited, such as in infiltrative disorders including hemochromatosis, amyloidosis, or sarcoid or radiation exposure [2]. There are only rare case reports of pregnancy outcomes with restrictive cardiomyopathy [76–78]. Some recommend that pregnancy be avoided in symptomatic patients [28].

Pregnancy Care for Women with Cardiomyopathy (Box 12.2)

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