Contemporary Management of Cardiomyopathy and Heart Failure in Pregnancy

Peripartum cardiomyopathy (PPCM) is a rare but serious cardiac complication of pregnancy and is diagnosed when new onset cardiomyopathy (defined as a left ventricular ejection fraction [LVEF] < 45%) develops toward the end of pregnancy or in the months following delivery [7]. It is a diagnosis of exclusion and considered when no other cause of cardiomyopathy is apparent. Several risk factors have been associated with PPCM and include African ancestry, older maternal age, hypertensive disorders of pregnancy, and multi-gestational pregnancies [8]. Of the various prognostic factors that have been studied, LVEF at the time of PPCM diagnosis is the most reliable predictor of adverse events or long-term recovery. The IPAC (Investigations of Pregnancy Associated Cardiomyopathy) study followed 100 women in North America with PPCM for 1 year after delivery and found that LVEF < 30% was associated with lower rates of myocardial recovery and an increased risk of adverse events [9]. Severe left ventricular (LV) systolic dysfunction at PPCM presentation has also been shown to be associated with the presence of a genetic variant causal for dilated cardiomyopathy (DCM) [10]. Additional predictors of worse outcome include LV dilation (LV end diastolic diameter > 6 cm), LV thrombus, right ventricular systolic dysfunction, obesity, and African ancestry [8]. Subgroup analyses of the IPAC cohort further demonstrated an association between baseline LVEF and LVEF at 1 year only in Black women and that Black race was independently associated with lower LVEF at 1 year.

Medical management of PPCM is similar to general HF management in pregnant women and includes guideline-directed medical therapy (GDMT), which is discussed later in this review. In addition, there are ongoing clinical trials of the use of bromocriptine, a dopamine agonist that inhibits the release of prolactin, in PPCM. In small studies of European and African participants, bromocriptine in addition to standard therapy was associated with a higher rate of LVEF recovery [11, 12], though no significant difference in overall rates of recovery was seen in subsequent trials [12, 13]. The 2018 European Society of Cardiology (ESC) guidelines include a weak recommendation (class IIb, level of evidence: B) for the use of bromocriptine in PPCM [5]. A randomized double-blind, placebo-controlled study (REBIRTH [Randomized Evaluation of Bromocriptine In Myocardial Recovery Therapy]) to investigate the effect of bromocriptine on myocardial recovery and clinical outcome in 200 women with PPCM in the United States and Canada is currently enrolling. Due to its association with thrombotic complications, therapeutic anticoagulation is recommended if bromocriptine is used. Women with a history of PPCM carry a risk of relapse with subsequent pregnancies, and dedicated counseling and monitoring are essential. The risks associated with a subsequent pregnancy depend primarily upon recovery of myocardial function, and the pre-pregnancy LVEF is the strongest predictor of outcomes.

Dilated cardiomyopathy (DCM) refers to a large group of heterogeneous myocardial disorders characterized by depressed LV systolic function and LV dilation [14]. DCM can be caused by different myocardial processes, including ischemic heart disease, inflammatory insults such as myocarditis, genetic cardiomyopathies, and direct cardiotoxins such as alcohol or chemotherapy. Up to half of all cases of DCM are considered idiopathic [15]. Women with underlying DCM who become pregnant are at the highest risk for adverse maternal or fetal outcomes in the setting of moderate to severe LV dysfunction (LVEF < 45%) or a poor functional class prior to pregnancy (New York Heart Association [NYHA] III/IV) [16]. The hemodynamic challenge of pregnancy, labor, and delivery may result in further LV dilation and clinical decompensation. Furthermore, women who become pregnant appropriately interrupt their use of evidence-based HF medications that are known to be teratogenic, such as angiotensin-converting enzyme (ACE) inhibitors, which could delay the remodeling benefits or result in worsening HF. The long-term impact of pregnancy in women with DCM remains unclear [17].

Hypertrophic cardiomyopathy (HCM) is diagnosed in the setting of asymmetric LV hypertrophy (> 15 mm) in the absence of another cause. Hypertrophy can be present with or without left ventricular outflow tract (LVOT) obstruction, which can become especially significant in pregnancy. During pregnancy, the increased plasma volume and stroke volume are well tolerated and can, in fact, lower a dynamic LVOT gradient. However, the tachycardia, decreased afterload, and increased LV contractility of pregnancy can worsen obstructive physiology [18]. Beta blockers, the first-line therapy for symptomatic obstructive HCM, are generally safe during pregnancy and should be continued in pregnant women with HCM. Any associated arrhythmias, such as atrial fibrillation, may be poorly tolerated, and non-pharmacologic interventions such as cardioversions can still be considered. Most women with HCM will experience pregnancy and labor with minimal risk [19]. As with other cardiomyopathies, peripartum risk is highest in those with advanced symptoms, severe LV systolic dysfunction, and severe LVOT obstruction [17]. The risk of experiencing an adverse cardiac event is proportional to the degree of symptoms and/or the degree of LVOT obstruction prior to pregnancy. Limited retrospective and observational data have shown that the incidence of maternal death in individuals with HCM was low at 0.2%, with a similarly low occurrence of neonatal death (0.2%) [20]. Family planning and pre-pregnancy counseling are especially important for women with HCM, as 40–60% of individuals have an identifiable genetic etiology of disease that is largely inherited in an autosomal dominant pattern. Pre-implantation genetic testing can be offered to individuals with HCM who are considering expanding their families. Women should also be prospectively counseled about the risks of future pregnancy [15].

Echocardiography remains the first-line imaging modality for the initial evaluation of pregnant women with suspected cardiovascular disease because of its availability, cost-effectiveness, and safety. Computed tomography and cardiac catheterization may be considered where indicated, but the risks of teratogenicity with ionizing radiation must be weighed, and shared decision making and informed consent must be obtained. If used, radiation must be kept ‘as low as reasonably achievable,’ and doses should be kept as low as possible (preferably < 50 mGy) [5]. Magnetic resonance imaging is advised if other noninvasive tests are not sufficient for definitive diagnosis and is preferred over ionizing-radiation-based imaging modalities [5]. Evidence regarding gadolinium-based contrast in pregnancy is controversial; its use should be avoided if possible, especially in the first trimester. Excretion of gadolinium-based agents into breast milk is limited, and breastfeeding after gadolinium administration is generally felt to be safe.

N-terminal pro–brain-type natriuretic peptide (NT-proBNP) levels can be elevated in normal pregnancy. The median NT-pro BNP level in normal pregnant woman is about twice that in non-pregnant women, rising early in pregnancy and remaining high throughout gestation [23, 24] until about 72 h after delivery [25]. The best use of NT-proBNP in pregnancy is in its negative predictive value. In one series, the negative predictive value of NT-proBNP < 128 pg/mL at 20 weeks’ gestation was 96.9% [26]. Adverse maternal cardiac events have been associated with high concentrations (> 128 pg/mL) [26], and NT-proBNP levels > 200 pg/mL should raise concern for HF and/or pre-eclampsia [27]. Cardiac troponin (cTn) assays using high-sensitivity methods can also provide a key role in the diagnosis of acute or chronic cardiac injury in pregnant women with cardiomyopathy, and in some cases may signal early cardiac injury prior to detection on imaging [28]. An elevated troponin level is never normal in pregnancy and should prompt further evaluation for myocardial injury [27, 29‐31]. The combined measurement of natriuretic peptides and cTn may provide complementary information in patients with cardiovascular diseases. Outside of obstetrics, prior meta-analyses have shown that individuals with no HF symptoms but who had elevated cTn levels are at greater risk for future cardiovascular events and also for progression to HF [32]. Furthermore, the combination of NT-proBNP with cTn improves risk stratification in non-ST elevation acute myocardial infarctions [33]. Further work is needed to further elucidate the complementary roles of cardiac biomarkers in pregnant populations.

Beta-adrenergic blocking agents are generally safe in pregnancy but may be associated with hypoglycemia and increased rates of fetal growth restriction [47, 48]. However, the overall magnitude of these neonatal complications is not thought to outweigh the maternal benefits of therapy. Beta blockers should be cautiously used in pregnancy. Beta-1-selective drugs such as metoprolol and bisoprolol are preferred [47], as they are less likely to affect uterine contraction and peripheral vasodilation and are associated with lower rates of fetal growth restriction [48]. Nonselective beta blockers such as atenolol have been associated with higher rates of fetal growth restriction and so are generally avoided in pregnancy [49]. Among the alpha/beta blockers, labetalol is the drug of choice for hypertension in pregnancy [50]. Data for carvedilol use in pregnancy are limited, though in a recently published small study with 13 patients with HF receiving this drug, there was no association with fetal growth restriction [48]. The use of metoprolol, bisoprolol, and labetalol in lactating women is generally considered safe. Beta blockers should be continued in patients on an existing beta-blocker therapy, cautiously started in those with new cardiomyopathies, and offered to HCM patients with signs of LVOT obstruction or arrhythmias.

Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-receptor blockers (ARBs) are teratogenic and contraindicated during pregnancy [46]. Renal or tubular dysplasia, renal failure, oligohydramnios, growth retardation, ossification disorders of the skull, lung hypoplasia, contractures, large joints, anemia, and intrauterine fetal death have been described. In a systematic review, 48% of 118 fetuses exposed to ACEi and 87% of fetuses exposed to ARBs had complications related to their use [46]. These risks also apply to the angiotensin-receptor neprilysin inhibitor (ARNI) since it contains an ARB. ACEi can be used during lactation; in particular, enalapril and captopril appear safe as long as fetal weight is monitored every 4 weeks. ARB use during lactation, however, is not well described, and their use postpartum is cautiously advised with breastfeeding [51].

Aldosterone antagonist use is not advised in pregnancy [46]. Spironolactone has been associated with feminization of developing male rats [52], raising concern about anti-androgenic effects during the first trimester. Eplerenone has been associated with post-implantation losses at the highest administered doses in rabbits [5], so caution is advised when used in pregnant humans. Both spironolactone and eplerenone may be used safely during breastfeeding.

There are limited data regarding the use of sodium glucose cotransporter 2 (SGLT2) inhibitors. Prior animal studies have suggested that that SGLT2 inhibition may affect fetal renal development and maturation [53], so their use is not recommended during pregnancy or with breastfeeding [45].

Loop diuretics can be safely used in pregnancy but can result in oligohydramnios and increase the risk of electrolyte imbalance in the fetus [46]. Diuretics have also been suggested to suppress lactation at high doses [54]. Given these important physiologic concerns, diuretic use should be judicious and mainly limited to patients with clinical signs of congestion. More data exist on the use of furosemide than torsemide, bumetanide, or metolazone in pregnancy, so the former is usually the first-line therapy [45].

Digoxin is generally used in pregnant women with persistent HF symptoms who are on beta blockers, nitrate/hydralazine, and diuretics. Digoxin crosses the placenta readily during later pregnancy, but no adverse maternal or fetal effects have been observed [46]. Digoxin intoxication has, however, been associated with miscarriage and fetal death [55, 56], so periodic drug monitoring is encouraged, especially given the altered pharmacokinetics in pregnancy.

The most widely used anticoagulants in pregnancy are vitamin K antagonists (VKAs), unfractionated heparin (UFH), and low molecular weight heparins (LMWH); timing and indication are key to their safety. VKAs such as warfarin cross the placenta and can result in embryopathy (limb defects and nasal hypoplasia) in a dose-dependent manner in 0.6–10% of cases when used in the first trimester [57, 58]. Warfarin also carries a 0.7–2% risk of fetopathy, such as ocular and central nervous system abnormalities and intracranial hemorrhage beyond the first trimester [57, 59], and so it is generally avoided throughout pregnancy. However, in high-risk scenarios such as the presence of prosthetic mechanical valves and LVADs, warfarin may be used throughout pregnancy at doses of less than 5 mg/day, though counseling is still required [5]. In general, LMWH are the preferred anticoagulant for use throughout pregnancy as they have not been associated with embryopathy or fetopathy [5]. Close monitoring of factor Xa levels is recommended when LMWH are used. Special consideration is needed regarding the use of anticoagulation around delivery given the importance of epidural anesthesia during labor and for uterine hemostasis after delivery [60]. LMWH should be switched to UFH at least 36 h before the induction of labor or cesarean delivery to minimize the bleeding risk during delivery [5]. Factor Xa inhibitors are considered when there is an allergy or adverse response to heparin [61]; however, data on their safe use in pregnancy are sparse. One study showed minor transplacental passage of fondaparinux [62], and more work is required to assess the risk of congenital malformations. Direct oral anticoagulants (DOACs) have been shown to be harmful to the fetus in animal studies, and data in humans are limited [46]. They should be avoided in pregnant patients. A systematic review of 137 pregnancies on rivaroxaban revealed a miscarriage rate of 23% (n = 31), elective terminations in 29% (n  = 39) of cases, and possible embryopathy in 2.2% (n  = 3) of cases [63]. Thrombolytics are considered to be relatively contraindicated and should only be used in high-risk patients with severe hypotension or shock [64]. Maternal hemorrhagic complications can occur with all regimens [59].

Pregnant women with advanced HF may require cardiac implantable electronic devices (CIEDs), including permanent pacemakers, implantable cardioverter-defibrillators (ICDs), and cardiac resynchronization therapy devices. Data on the use and safety of these devices in pregnancy are limited. In two small cohorts of pregnant women with CIEDs, the live birth rate was 70–95% [65, 66]. Between the two cohorts, three of 39 pregnancies were complicated by ventricular arrhythmias, and in two cases, women received appropriate ICD shocks.

For women with ICDs in place at the time of cesarean delivery, a magnet should be placed to prevent electric interference with electrocautery [39, 45]. Transcutaneous pads can be applied for added safety at the time of delivery. Data on ICD implantation in pregnant women with de novo systolic dysfunction is limited. In the case of primary prevention, implantation should be ideally deferred until after delivery, and after at least 3 months of GDMT if LV function remains depressed. If an ICD is indicated more expeditiously for secondary prevention, fluoroscopy during implantation should be minimized as much as possible. In some cases, a subcutaneous defibrillator may be necessary to avoid excessive fluoroscopy exposure [45]. The data on the benefit of a wearable cardioverter defibrillator (WCD) in the general population are controversial [67], and such data in pregnancy are sparse. In general, these devices should be considered for women with HF who do not meet the duration of time on GDMT required for primary prevention ICD implantation or in whom LVEF recovery is anticipated [45].

In cardiogenic shock, decision making regarding the use of inotropes and vasodilators in the pregnant patient should follow the same considerations as for the non-pregnant patient. If inotropic support is required during pregnancy, milrinone, dobutamine, dopamine, and levosimendan are generally considered safe. There is some concern about excessive vasodilation with milrinone in the setting of already decreased systemic vascular resistance in pregnancy [45], though this is not prohibitive. Dopamine may also reduce breastmilk production [68], though this is not rigorously established and does not limit its use. Possible adverse effects have been reported with dobutamine in patients with severe PPCM [69]. Unlike epinephrine (which is generally avoided in pregnancy), levosimendan, an inodilator and calcium sensitizer, is not known to increase myocardial oxygen demand, and is recommended by the ESC as the preferred inotrope for use in pregnant women with cardiogenic shock; however, this is not currently approved by the Food and Drug Administration (FDA) for use in the United States [70].

If vasodilator therapy is required, nitroglycerin is preferred over nitroprusside due to potential concerns related to toxic fetal cyanide levels in animal models exposed to nitroprusside [71], though this finding has not been replicated in humans. Calcium channel blockers such as intravenous nicardipine do not seem to pose a teratogenic risk to the fetus and are safe for use in pregnancy [72]. If continuous infusions are not needed, oral alternatives such as oral nitrates, methyldopa, and hydralazine are also safe for use in pregnancy and in the postpartum period [71].

Mechanical circulatory support (MCS) should be considered when severe heart failure persists despite maximal pharmacological support. Early initiation of MCS can mitigate the hemometabolic consequences of cardiogenic shock (CS) [73]. Data from the National Inpatient Sample have shown that pregnant women who developed CS and were treated with MCS within 6 days of the diagnosis of CS had lower mortality compared with those who were placed on MCS later [74]. However, there are no prospective studies investigating the optimal use of MCS in the peripartum period. Though the intraaortic balloon pump (IABP) only provides 0.5–1.0 L/min of cardiac output, it can be quickly and easily placed at the bedside and may not mandate anticoagulation [71]. IABPs have been successfully used for hemodynamic support in pregnant patients who have undergone surgery requiring cardiopulmonary bypass [75, 76] and during cesarean section prior to percutaneous coronary intervention or coronary bypass surgery [77]. IABP use has also been successful in patients with severe PPCM [78]. The Impella (Abiomed, Danvers, MA, USA) device can provide up to 5.0 L/min of cardiac output and has also successfully been used in cases of severe PPCM [79, 80] as well as in cardiac arrest in pregnancy [81, 82]. If additional hemodynamic support is required, extracorporeal membrane oxygenation (ECMO) may be considered and has been successfully used in pregnancy [81, 83]. However, as with Impella, ECMO carries both bleeding and thrombosis risks [8, 80], so both temporary MCS platforms require adherence to specialized anticoagulation protocols. Another unique challenge is that prolactin levels have been shown to increase in pregnant patients supported on ECMO, and elevated prolactin levels are associated with poor outcomes [84]. The ESC recommends the suppression of prolactin while on ECMO with doses of bromocriptine of up to 10 mg twice daily [70].

For pregnant patients with persistent LV systolic dysfunction, durable MCS may be an option as a bridge to recovery, a bridge to heart transplantation, or as destination therapy. In one of the largest observational studies on this topic, an Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) analysis identified 99 women with PPCM who underwent surgically implanted left, right, or biventricular assist devices between June 2006 and March 2012 and compared their outcomes with those who did not have PPCM. Women with PPCM had improved survival, with a 2-year survival of 83%. Recovery occurred at a frequency of 6% and 2% in the PPCM and non-PPCM groups, respectively. Adverse event rates were similar in patients with and without PPCM except for higher cardiac arrhythmias and respiratory failure in the non-PPCM group in the first 3 months post-implant [85].

For women with pre-existing durable MCS devices, pregnancy is contraindicated, given the risk of worsening biventricular failure from volume expansion, increased thrombotic risk, teratogenicity of HF medications, complications associated with anticoagulation, and risk of RV failure related to impingement of the enlarging uterus on LVAD components. Nevertheless, unplanned pregnancies still occur, and successful births have been reported [45]. As hemodynamics evolve during pregnancy and postpartum, changes in LVAD speed may be required to provide increased cardiac output and maintain optimal unloading conditions [45]. At delivery, invasive hemodynamic monitoring should be considered. Vaginal delivery is the generally preferred mode of delivery; however, if cesarean delivery is needed, there should be careful coordination with LVAD experts on device and hemodynamic management. With respect to anticoagulation, there are no specific guideline recommendations for patients with LVAD in pregnancy. Extrapolating the recommendations used for the management of prosthetic mechanical valves, patients on less than 5 mg/day of warfarin are maintained on this throughout pregnancy for international normalized ratio (INR) goal 2–3, though patients need to be counseled on the risk of warfarin embryopathy [86]. Patients requiring doses larger than 5 mg/day before pregnancy (and those who, after counseling, decline the use of any warfarin during pregnancy) should be transitioned to LMWH during the first trimester, with close monitoring of anti-Xa levels. Pregnancy in patients supported by durable LVADs requires early involvement of a multidisciplinary cardio-obstetrics team in a center with LVAD expertise [45].

The majority of data on heart transplantation in pregnant women comes from the PPCM literature. Many women with PPCM have LVEF recovery, but a small subset develop persistently severe cardiomyopathy requiring advanced therapy. In the IPAC study, 72% of women achieved LVEF ≥ 50% by 1 year postpartum, whereas 13% had a persistent LVEF < 30% and required LVAD or underwent cardiac transplantation at 1 year [9]. Heart transplantation may be the superior treatment option for those with significant RV dysfunction, malignant arrhythmias, a desire for future pregnancy (although generally not encouraged), or contraindications to anticoagulation. Importantly, the higher incidence of allograft rejection and lower allograft survival in patients with PPCM are potential risks that must be expectantly managed [87]. Once transplanted, patients with a history of PPCM have poorer survival outcomes compared with all transplant recipients. A review of data from 485 patients with PPCM transplanted between 1987 and 2010 demonstrated both a higher incidence of allograft rejection within the first year post-transplant and higher rate of mortality. It is posited that the poor outcomes in the PPCM population were partly related to their demographics: younger age, female sex, history of pregnancy, and increased pre-transplant panel reactive antibodies that may predispose to higher allograft rejection rates [87]. Black race was also an independent risk factor for worse post-transplant survival, although that has changed somewhat in recent years [88].

There are several unique considerations for heart transplant recipients considering pregnancy. To ensure the stability of graft function and immunosuppression regimens, pregnancy is discouraged in the first year after the transplant [89, 90]. Contraception counseling and planning should be discussed early given the possible rapid return of fertility after transplantation [91]. Contraindications to pregnancy in the post-transplant population include reduced graft function, non-adherence, donor-specific antibodies, significant allograft vasculopathy, poorly controlled hypertension, diabetes, renal dysfunction, and active infection [89]. In patients with a history of antibody-mediated rejection, pregnancy may not be advisable given the risk for sensitization from the fetus [89]. Allograft assessment should include echocardiography, evaluation for cardiac allograft vasculopathy, and checking for donor-specific antibodies [89]. Post-transplantation outcomes including rejection, graft survival, and age-adjusted survival are worse in patients with PPCM compared with other recipients [87]; and this should be considered as part of the pre-conception risk assessment and counseling in that population. If conception is being considered, immunosuppression regimens should be adjusted to minimize the risk for fetal injury. Calcineurin inhibitors and corticosteroids are typically considered safe [89]. Mycophenolate mofetil and mycophenolic acid are teratogenic and are discontinued at least 6 weeks prior to conception or as soon as pregnancy is confirmed if otherwise unplanned [89]. Data on mammalian target of rapamycin (mTOR) inhibitors are limited, and they should be discontinued prior to conception but may be continued on a case-by-case basis [89].