Cardiomyopathy in pregnancy

Cardiomyopathy in Pregnancy

1. What every clinician should know

Clinical features and incidence

The hemodynamic changes that accompany pregnancy place increased workload on the heart.

Prepartum

During pregnancy the following hemodynamic changes occur and peak at the beginning of the third trimester: intravascular volume increases by 1500-1600 ml; heart rate and stroke volume increase, resulting in a 30-50% increase in cardiac output above pre-pregnancy levels; and cardiac output goes up an additional 15% in twin gestations.

Intrapartum

During labor and delivery there are catecholamine-induced increases in heart rate and stroke volume due to the pain of labor, resulting in as much as a 30% increase in cardiac output in the first stage of labor, and as much as 50% in the second stage of labor.

Postpartum

Postpartum there is auto transfusion from the contracted uterus and increased blood return from the lower extremities resulting in (a) increased preload; (b) as much as an 80% increase in cardiac output; and (c) other physiologic changes, including loss of the low resistance placental circulation and increase in system vascular resistance or afterload and mobilization of dependent edema and interstitial fluid back into the central circulation, which also increases preload. These physiologic alterations explain why women with heart disease are most likely to experience decompensation in the third trimester, the intrapartum or postpartum periods.

The more common cardiomyopathies in pregnancy can be divided into dilated or hypertrophic (Figure 1 and Figure 2). The echocardiographic characteristics, physiology, and etiologies are different; however, symptoms at the time of initial presentation can be very similar. Dilated cardiomyopathy occurring at the end of pregnancy or within 5 months of delivery is most commonly peripartum cardiomyopathy. Other dilated cardiomyopathies that will be encountered less frequently by the obstetric provider include viral, alcohol-related and familial dilated cardiomyopathy. Hypertrophic cardiomyopathies are usually pre-existing and unrelated to pregnancy.

Figure 1.

Figure 2.

Dilated cardiomyopathy

Risk factors

Etiologies include genetic, long-standing uncontrolled hypertension, aortic stenosis, obesity and sleep apnea. Patients with either a dilated or hypertrophic cardiomyopathy may be at significant risk for decompensation and congestive heart failure, arrhythmias and rarely death during pregnancy, the intrapartum or postpartum periods depending upon systolic ejection fraction (dilated cardiomyopathies) or degree of diastolic dysfunction and left ventricular outflow obstruction (hypertrophic cardiomyopathies). Other rare forms of cardiomyopathy that the obstetric provider is much less likely to encounter are arrhythmogenic right ventricular cardiomyopathy, left ventricular non-compaction cardiomyopathy and restrictive cardiomyopathy.

It is extremely important that health-care providers delivering care to pregnant and recently pregnant women be aware of the condition of peripartum cardiomyopathy. Because this condition occurs in women without prior heart disease who may have had an uncomplicated pregnancy, the initial level of suspicion for significant pathology may be low. While fatigue, dyspnea and edema are common in the third trimester and postpartum it is important that these symptoms not be dismissed without a thorough assessment.

In women with dilated cardiomyopathy, there is reduced contractile reserve. The increase in intravascular volume that occurs in pregnancy can lead to an increase in end-diastolic and end-systolic dimensions of the ventricle, and pulmonary edema.

Hypertrophic cardiomyopathy

The hemodynamic changes of pregnancy are usually well-tolerated in women without moderate to severe ventricular outflow obstruction or septal hypertrophy and who are without symptoms prior to pregnancy. The increase in blood volume causes an increase in end-diastolic dimension of the left ventricle, which can be beneficial by lowering the outflow gradient. However, in patients with a severe left ventricular outflow obstruction, the gradient may worsen during pregnancy.

2. Diagnosis and differential diagnosis

Establishing the diagnosis

Women with complaints of shortness of breath, dyspnea on exertion, paroxysmal noctural dyspnea, orthopnea, chest pain, or syncope should be carefully evaluated. Classical symptoms of congestive heart failure and physical findings of tachycardia, tachypnea, rales in the lung bases and jugular venous distention make a diagnosis of cardiomyopathy or other heart disease likely. Other possible physical findings include an S3 gallop and a systolic murmur of mitral regurgitation if the valve annulus is dilated.

Some patients will also have pleural effusions detected by decreased breath sounds at the bases and dullness to percussion. Women with cardiomyopathy not due to a viral cause will be afebrile. Symptoms of cardiomyopathy may mimic asthma symptoms but the physical findings and chest x-ray will point to cardiomyopathy if there is pulmonary vascular congestion, effusions and cardiac enlargement. If the patient is in the last month of pregnancy or within 5 months of delivery and has no prior history of heart disease and an ejection fraction less than 45%, she has peripartum cardiomyopathy. The usual time of presentation for patients with peripartum cardiomyopathy is within days to a few weeks post delivery. Patients can present as late as five months postpartum but many of these will have had symptoms of varying duration before seeking help.

In addition to a careful history and physical exam, chest x-ray and measurement of oxygen saturation give important clues. The diagnosis is made with transthoracic echocardiography. Peripartum and other dilated cardiomyopathies are characterized by systolic dysfunction with an ejection fraction of less than 45%. Hypertrophic cardiomyopathies are characterized by a thickened ventricular septum and/or wall (15mm or greater), a normal ejection fraction, and left ventricular outflow obstruction at rest (20% of patients) or with exertion. These changes can progress to diastolic dysfunction, a stiff ventricle that does not fill well, and congestive heart failure.

Women with hypertrophic cardiomyopathy typically have been diagnosed prior to pregnancy. Many with genetic hypertrophic cardiomyopathy are asymptomatic. The findings of left ventricular hypertrophy on an electrocardiogram (EKG), a murmur of mitral insufficiency (holosystolic loudest at the apex with radiation into the axilla) or family history will have led to their diagnosis.

Hypertrophic cardiomyopathy may, however, first be detected during pregnancy or shortly after delivery when the heart cannot handle the hemodynamic changes. The more common symptoms are dyspnea on exertion, chest pain, palpatations or even syncope. Unfortunately the clinical presentation also includes sudden cardiac death due to arrhythmias, but this is rare. Physical findings include S4 gallop, prominent left ventricular impluse or lift, and brisk carotid upstroke. EKG abnormalities may include patterns of LVH, left atrial enlargement, prominent Q waves in inferior and lateral leads, and diffuse T-wave inversions.

In patients with congestive heart failure, chest x-ray will show signs of congestion, an enlarged cardiac silhouette and possibly pleural effusions (Figure 3). Oxygen saturation may be low or normal. B-type naturetic peptide will almost always be elevated (normal is less than 100 pg/ml) but is not necessary to make the diagnosis. The diagnosis is made by echocardiogram (Figure 4).

Figure 3.

Figure 4.

Often these patients are evaluated for a pulmonary embolus. Spiral chest CT will usually be normal in patients presenting acutely with cardiomyopathy; however, women with low ejection fractions due to dilated cardiomyopathy and patients with hypertrophic cardiomyopathy are at increased risk for thrombi and embolic disease.To make the diagnosis of peripartum cardiomyopathy, the patient must have heart failure within the last month of pregnancy or five months postpartum, an absence of prior heart disease, no other determinable causes, and a strict echocardiographic indication of left ventricular systolic dysfunction, which is an ejection fraction less than 45% and/or fractional shortening less than 30% or end-diastolic dimension greater than 2.7 cm/m^2.

Holter monitoring for arrhythmias may be a very useful adjunct, particularly in patients with symptoms of syncope or near syncope. Detailed electrophysiology studies may be necessary to determine advisability of implantable cardioverter defibrillator.

Hypertrophic cardiomyopathy is characterized by hypertrophy of the left ventricular wall or septum (15 mm or greater) with normal size (not dilated) left ventricular cavity, with a pattern of hypertrophy that is varied and may be concentric and symmetric, antero-septal, or purely apica. It is also charecterized by preserved systolic function with normal ejection fraction, and left ventricular outflow obstruction, present in about 20% of patients at rest and more with exertion, which is related to the degree of hypertrophy of the basal septum. Systolic anterior motion (SAM) of the mitral valve also causes obstruction of the left ventricle outflow tract and the murmur of mitral regurgitation. There may be evidence of diastolic dysfunction as determined by tissue Doppler. Diastolic dysfunction can precede left ventricular wall hypertrophy and outflow obstruction in some patients.

Cardiac catheterization is rarely indicated and is reserved mainly for those patients where there is concern for coronary artery disease. In patients with a history of peripartum cardiomyopathy who appear to have recovered left ventricular function, dobutamine stress testing has been shown to uncover subclinical reduced contractile reserve. This information may be useful in counseling these women about the risks of future pregnancies. HIV infection should be excluded. Biopsy of the endocardium/myocardium is a possible option in patients with a dilated cardiomyopathy to better define the etiology. However, the histopathology is not always conclusive and this approach is rarely necessary.

In patients with hypertrophic cardiomyopathy, underlying causes should be sought, including hypertension, aortic stenosis, alcohol abuse or medication toxicity. Evaluation by a geneticist may help to exclude causes associated with other genetic conditions as listed above. If no underlying cause is determined, the likely etiology is genetic hypertrophic cardiomyopathy. At least 14 genes and more than 900 individual mutations have been found to be associated with the phenotype. These genes code for various sarcomeric proteins, most commonly myosin heavy chain and myosin binding protein C. In about 40% of cases of hypertrophic cardiomyopathy a mutation within one of these genes can be detected.

About half of these mutations are familial and the other half are de novo. In familial cases the inheritance pattern is autosomal dominant. This is important for counseling women about the risk to offspring. Among patients with the same genotype, expression is variable. Evaluation includes a detailed 3-4 generation family history with attention to relatives with heart failure, hypertrophic cardiomyopathy, heart transplant, unexplained sudden death or arrhythmias, or unexplained thromboembolic disease. Genetic testing in asymptomatic individuals should not be performed outside of genetic consultation and formal genetic counseling, given the implications of detecting a mutation.

Familial dilated cardiomyopathy is diagnosed by family history and gene testing may be informative. Inheritance patterns include autosomal dominant and recessive, and X-linked. More than 20 familial dilated-cardiomyopathy-causing genes have been identified. As with hypertrophic cardiomyopathy, gene testing is recommended only in conjunction with formal genetic consultation and counseling.

Imaging studies

The most helpful imaging study in the setting of a patient suspected of having a cardiomyopathy is echocardiography. In obese patients, a transthoracic approach may be suboptimal. Imaging quality is improved in these patients with a transesophageal approach. MRI can also be helpful when visualization of the left ventricle is suboptimal with echocardiography, particularly in patients with hypertrophic cardiomyopathy.

Assessment for diastolic dysfunction is not obtained with standard 2D echocardiography. This requires tissue Doppler derived measurements. This is essential in patients with hypertrophic cardiomyopathy and helpful in patients with dilated cardiomyopathy. Request both 2D and Doppler with specific comment to evaluate for diastolic dysfunction when ordering an echocardiogram in a patient being evaluated for cardiomyopathy.

Other lab tests

Exercise stress testing may be helpful in evaluating functional capacity if this is unclear from the patient’s history. This is best performed before pregnancy. Functional capacity is an important predictor of cardiac events and ability to tolerate the physiologic demands of pregnancy. In patients with a history of peripartum cardiomyopathy who appear to have recovered left ventricular function, dobutamine stress testing has been shown to uncover subclinical reduced contractile reserve. This information may be useful in counseling these women about the risks of future pregnancies.Inflammatory cytokine levels have been reported to be increased in some case series of patients with peripartum cardiomyopathy but are not helpful in directing clinical care.

Other clinical manifestations that may aid in diagnosis

Unusual symptoms include nocturnal cough and profound fatigue. Patients may also present with near-syncope or syncope due to arrhythmias or significant left ventricular outflow track obstruction. It is not uncommon for patients with either hypertrophic or dilated cardiomyopathy to present with a chief complaint of chest pain. Symptoms can mimic pulmonary embolus.

Clinical manifestation of very low cardiac output include:

• Cool extremities

• Hypotension

• Low pulse pressure

• Mental status change

Patients presenting with these symptoms of very low cardiac output (cardiogenic shock) require inotropic agents to maintain perfusion of vital organs. Those who do not respond to medical management require ventricular assist devices or aortic counterpulsation balloon therapy and transplant. In patients with similar symptoms but a normal echocardiogram, other pathologies must be considered, including non-cardiogenic pulmonary edema and lung disease.

Women can develop non-cardiogenic pulmonary edema prenatally or postnatally due to fluid overload, low oncotic pressure, or as a complication of infection, tocolysis or preeclampsia. These women will have the same signs and symptoms as those with cardiomyopathy but will have a normal echocardiogram with normal ejection fraction and no evidence of ventricular hypertrophy or diastolic dysfunction.

The differential diagnosis of women presenting in the peripartum period or up to five months post delivery with symptoms of chest pain, dyspnea, orthopnea, paroxsymal noctural dyspnea, or fatigue includes pneumonia, pulmonary embolus, asthma, congenital heart diseases possibly not previously recognized, as detected on echocardiogram, and other acquired heart disease, including rheumatic or bacterial endocarditis with valvular dysfunction or coronary artery disease. Dilated cardiomyopathy, hypertrophic cardiomyopathy, and non-cardiogenic pulmonary edema or adult respiratory distress syndrome are others.

Non-cardiogenic pulmonary edema or adult respiratory distress syndrome can occur with fluid overload in the setting of pregnancy with reduced oncotic pressure. This can also be a complication of infections including pyelonephritis, sepsis and chorioamnionitis or as a complication of tocolysis or preeclampsia. These individuals will have a normal ejection fraction and otherwise normal echocardiogram.

The differential diagnosis for dilated cardiomyopathy include HIV infection, familial causes, toxins, including drugs and alcohol, Viral myocarditis, and peripartum cardiomyopathy. In women with no prior history of heart disease, peripartum cardiomyopathy would be the most likely cardiomyopathy to present in this time frame. Echocardiographic criteria for making this diagnosis are listed above.

Although less likely to be first diagnosed during or shortly after pregnancy, hypertrophic cardiomyopathy may be uncovered by physiologic changes, including increased intravascular volume and cardiac output that occur during pregnancy and postpartum. Differential diagnosis include hypertension, aortic stenosis, morbid obesity, sleep apnea, inborn error of metabolism, e.g., glycogen storage diseases, malformation syndromes with multiple organ system involvement, e.g. Noonan’s syndrome, neuromuscular disorders, the most common to be associated with hypertrophic cardiomyopathy is Friedreich ataxia. 55-70% of cases of unexplained left ventricular hypertrophic cardiomyopathy are due to gene mutations affecting the production of sarcomeric proteins.

3. Management

Severity of initial symptoms and degree of respiratory distress can vary greatly between patients. In the patient in respiratory distress or respiratory failure, the first task is to provide respiratory support that will correct hypoxemia. This requires delivery of high flow humidified oxygen or, in severe cases, intubation and ventilation. Aggressive diuresis should be started in these patients UNLESS they are known to have hypertrophic cardiomyopathy with a significant left ventricular outflow gradient (greater than 50 mm Hg), in which case reduction in preload with diuresis and reduction in afterload with drop in blood pressure will worsen the gradient and significantly reduce cardiac output. Sinus tachycardia needs to be controlled to allow adequate time for left ventricular filling with the use of intravenous beta blockers (IV propranolol 1-2 mg).

These measures should be instituted and the patient stabilized before she is sent to the radiology or cardiology suite for imaging studies. Planning for delivery in patients with a cardiomyopathy should involve obstetrics, cardiology and obstetric anesthesiology. Most patients can safely undergo labor and a vaginal delivery. Cesarean delivery can be reserved for standard obstetric indications. It is important to decrease the catecholamine release associated with pain of labor through the use of anesthesia/ analgesia. Careful fluid management with avoidance of sudden reduction in preload is particularly important in the patient with a hypertrophic cardiomyopathy.

In the acute setting of signs and symptoms of congestive heart failure/pulmonary edema, immediately institute respiratory support with high-flow humidified oxygen 10 liters by nasal cannula or 60% rebreathing mask. Monitor heart rate, blood pressure and pulse oximetry. In those patients without known preexisting hypertrophic cardiomyopathy, diuresis should also be instituted immediately with intravenous lasix, 40-80 mg. This can be repeated every 2 hours.

Urinary bladder catheterization is usually required in this setting for the patient and to monitor diuresis. Attention to electrolytes is critical to avoid cardiac complications of hypokalemia. Hypoxemia must be corrected before the patient is sent to the radiology or cardiology suite for imaging studies. Portable AP chest x-ray while these interventions are being initiated may be helpful in confirming clinical suspicions but therapy should not be withheld pending the results.

It is usually also possible to obtain a portable 2D echocardiogram if the patient is unstable. Oxygen saturation should be maintained at no less than 90%; this is equivalent to a PO₂ of approximately 60 mm Hg. If hypoxemia is not corrected with these measures quickly, consultation for intubation and ventilation should be requested. Positive end-expiratory pressure is almost always necessary if the patient requires intubation.

Pulmonary edema due to dilated cardiomyopathy, fluid overload or preeclampsia is more easily reversed than pulmonary edema from diastolic dysfunction and hypertrophic cardiomyopathy. In the setting of hypertrophic cardiomyopathy with moderate (50-100 mm Hg) or severe (greater than 100 mm Hg) left ventricular outflow gradient, diuresis will decrease preload and worsen the gradient. A drop in systemic vascular resistance in these patients can also worsen the gradient, leading to depressed cardiac output.

It is important to control heart rate. A rapid sinus tachycardia due to hypoxemia or catecholamine release results in inadequate time for the left ventricle to fill during diastole and reduces stroke volume. This is best achieved with carefully titrated IV propranolol. Atrial and ventricular arrhythmias must also be treated. These are not uncommon in the setting of either a dilated or hypertrophic cardiomyopathy and may have precipitated heart failure. Arrhythmias also carry a significant risk of thromboembolic complications.

A beta blocker should to initiated. (Carvediol, an alpha and beta blocker, is commonly used in patients with congestive heart failure.) If the patient is postpartum, an angiotensin converting enzyme (ACE) inhibitor should also be started. Oral diuretics are continued. Digoxin may be helpful. These patients are at increased risk for thrombo-emobolic events so careful consideration should be given to prophylactic anticoagulation with low molecular weight heparin, particularly in patients with an ejection fraction less than 35%. Patients with a mural thrombus, paroxysmal or sustained atrial fibrillation or flutter should receive therapeutic anticoagulation.

Antepartum management

Dilated cardiomyopathy

Medical therapies for congestive heart failure include beta blockers, which should be continued during pregnancy. Pindolol is considered one of the safest for use in pregnancy. Atenolol is associated with the greatest risk of intrauterine growth restriction. Metoprolol is acceptable and preferred if the patient is breast-feeding. Carvediol is also considered safe in pregnancy and has been shown in randomized trials to improve outcomes in patients with chronic congestive heart failure.

Angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) are also recommended. ACE inhibitors and ARBs are known teratogens associated with a 3-4 fold increased risk of cardiovascular and central nervous system malformations with first trimester exposure. Exposure after the first trimester carries risk of fetal anuric renal failure and even death. Skull hypoplasia has also been reported. The recommendation is therefore to discontinue these drugs in women planning pregnancy or as soon as pregnancy is diagnosed. Women must weigh the risk of discontinuing these drugs, which prolong survival, with the desire for pregnancy.

Most diuretics can be continued with the exception of aldosterone inhibitors. There is a theoretical concern that diuretics will prevent the increase in intravascular volume that occurs in normal pregnancies. This risk must be weighed against the risk of decompensation and heart failure. Digoxin is considered safe in pregnancy.

Hypertrophic cardiomyopathy

Ideally, evaluation of functional status and echocardiographic features, including degree of diastolic dysfunction, left ventricular outflow gradient at rest and with valsalva, and thickness of the septum, are completed prior to pregnancy. Patients should be co-managed with a cardiologist who will be available at the time of hospitalization.

Asymptomatic patients do not require any medical therapy. Patients with symptoms are treated with a beta blocker (see discussion above regarding beta blockers in pregnancy). A calcium channel blocker (verapamil or amlodipine) may also be used. Patients with hypertrophic cardiomyopathy are sensitive to drops in preload; therefore, vasodilating agents (hydralazine) and diuretics should be avoided. ACE inhibitors and ARBs are contraindicated in pregnancy as discussed above.

In women on chronic anticoagulation with coumadin, it is important to switch to low molecular weight heparin. Ideally this is done prior to pregnancy. The risk of warfarin embryopathy with first trimester exposure is about 9%, and coumadin can have effects on fetal development throughout pregnancy.

Intrapartum management

Dilated cardiomyopathy

Consultation with cardiology and anesthesiology prior to labor, continuous EKG monitoring, and careful monitoring of blood pressure are recommended. An arterial line may be particularly helpful in morbidly obese patients in whom it is difficult to assess blood pressure by non-invasive means. Arterial lines are low risk for complications.

Right heart cath (central venous line with pulmonary wedge pressure monitor) carries risks and is rarely necessary except in those patients with very low ejection fractions or very high LV outflow gradients. Use will depend upon the relative stability of the patient. The patient should be maintained in the left lateral decubitus position to avoid compression of the vena cava.

Timing of delivery is based upon the patient’s response to medical management and hemodynamic status. In patients who are well-compensated, labor can be allowed to occur spontaneously and is preferable to a long induction with an unfavorable cervix. Patients who become refractory to medical management should be delivered. A recent state of the art paper in the Journal of the American College of Cardiology recommends vaginal delivery be attempted unless an obstetric contraindication is present. The risk to the patient is believed to be less with vaginal delivery than with cesarean delivery.

Epidural anesthesia is a requirement in those patients undergoing labor and vaginal delivery. The purpose is to blunt the hemodynamic stress that results from the response to the pain of labor. In the patient undergoing cesarean delivery, regional anesthesia, usually combined spinal-epidural, is preferred over general anesthesia. The vasodilatory effects of sympathetic blockade with regional anesthesia can be advantageous in patients with dilated cardiomyopathy. The reduction in blood pressure that can occur with regional anesthesia should be treated with vasoactive agents rather than with fluids.

Management of the second stage of labor should be individualized and depends upon the patient’s functional status. Those who are NYHA class I with relatively good function can be allowed to valsalva in the second stage. Those with reduced function as assessed by history of dyspnea, chest pain or other symptoms should have a passive assisted second stage.

Hypertrophic cardiomyopathy

Avoiding tachycardia is important in these patients to allow time for ventricular filling. This is achieved by using lumbar epidural for labor anesthesia to reduce the tachycardia associated with the pain of labor. It is important to avoid hypotension that can accompany sympathetic blockade with epidural anesthesia. Aggressive management of the third stage of labor to avoid excessive blood loss is recommended. Sinus tachycardia not due to blood loss can be treated with IV propranolol. This improves LV filling.

If hypotension develops, vasoactive agents with inotropic effects are contraindicated as they worsen the outflow track obstruction. Phenyephrine, a purely alpha-agonist, is preferred. These patients should have a passive assisted second stage of labor. Valsalva causes decreased preload and worsens the left ventricular outflow track gradient. Low dose diuretics can be used if pulmonary edema develops but overly aggressive diuresis should be avoided because of the sensitivity to reduced preload.

Postpartum management

Dilated cardiomyopathy

Pitocin should be given by dilute infusion and not by IV push to avoid hypotensive effects. These patients may be at greatest risk for decompensation and pulmonary edema during the early postpartum period due to increased preload accompanying delivery and contraction of the uterus. Continued close hemodynamic monitoring is therefore indicated for a minimum of 24 hours post delivery. Decompensation can also occur later, 3-7 days post delivery. Anemia due to blood loss should be corrected as it can lead to tachycardia. Prophylactic anticoagulation for at least 6 weeks post delivery is prudent, particularly in those patients with an ejection fraction less than 35%. Patients with evidence of a mural thrombus or paroxysmal or sustained atrial arrhythmias should receive therapeutic anticoagulation.

Hypertrophic cardiomyopathy

The same recommendations as outlined for intrapartum management also apply to the postpartum period for patients with hypertrophic cardiomyopathy. These patients should be observed carefully for deterioration during the first few days postpartum. Therapeutic anticoagulation should be continued in those patients with sustained or paroxysmal atrial arrhythmias. Prophylactic anticoagulation should be considered in all other patients.

For women with either a dilated or hypertrophic cardiomyopathy, consultation with cardiology to determine the advisability of an implantable cardioverter defibrillator is recommended. For patients with peripartum cardiomyopathy, IV immune globulin therapy has not been shown to be of benefit. There is recent interest in treatment acutely with bromocriptine, a dopamine D2 receptor agonist, based upon studies suggesting a role of the 16-kDa subform of prolactin in the pathomechanism for the development of PPCM.

A small randomized pilot study of standard treatment plus bromocriptine versus standard treatment alone in 20 women showed promising results. Only one woman in the bromocriptine group (10%) compared with 8 (80%) in the control group experienced the composite outcome of death, NYHA functional class III/IV, or LV ejection fraction less than 35% at 6 months, p = 0.006. However, according to the Cochrane review these results are not sufficient to provide clear evidence of benefit because of the small sample size.

4. Complications

Counseling regarding pregnancy in women with a cardiomyopathy

Risk stratification is helpful as discussed above. Factors that place women at high risk for unfavorable outcomes include:

• New York Heart Association Function Class greater than II.

• Left ventricular ejections fraction less than 40% currently.

• Ejection fraction less than 25% at the time of initial diagnosis.

• Significant left ventricular outflow track obstruction (a gradient greater than or equal to 50 mm Hg).

• History of paroxysmal or sustained arrhythmias or arrest.

• Prior episode(s) of congestive heart failure.

In patients with one, and certainly those with more than one of these risk factors, the risk of pregnancy is prohibitive and these women should be counseled to avoid pregnancy. Retrospective case series indicate that among women with a dilated cardiomyopathy, those with peripartum cardiomyopathy have a worse prognosis and greater risk of further deterioration in cardiac function with subsequent pregnancythan women with dilated cardiomyopathy of other etiologies.

Specific patient populations

Patients with severe dilated cardiomyopathy (ejection fraction < 20%) who have an unplanned pregnancy and do not want to terminate

This is an extremely high risk situation. These patients should be delivered when they become refractory to medical management and otherwise in the mid third trimester (32-34 weeks). They typically require prolonged hospitalization. Plans for perimortem cesarean delivery should be in place if the fetus is of a viable gestational age. The intrapartum and postpartum period are particularly high risk and delivery should occur in a center with availability of ventricular assist devices, aortic balloon assists and even cardiac transplantation. If a pregnant patient’s implanted cardioverter defibrillator fires, case reports indicate no adverse fetal effects.

Families with a history of hypertrophic cardiomyopathy who request prenatal diagnosis or genetic testing of asymptomatic family members

A family pedigree is necessary to estimate the risk to the fetus. About 50% of cases are de novo mutations so if a sibling is affected but the parents are not, the risk to the fetus is small. If a parent is affected the risk to the fetus is 50%. Prenatal genetic testing can be performed but only if the specific disease-causing mutation in an affected family member has previously been identified.

DNA testing can be done on tissue obtained by chorionic villus sampling or on amniocytes obtained by amniocentesis. Testing should not be performed outside of formal genetic counseling. There is no direct correlation between genotype and severity of disease or age of onset. Knowing a child carries the mutation may have benefit but also carries possible social, educational and career implications.

Preimplantation genetic diagnosis (PGD) may be available for families in which the mutation has been identified. Only very rarely will left ventricular hypertrophy of the fetal heart be detected by prenatal fetal echocardiography because the time of onset is usually after age 12 years. Similar concerns apply to familial dilated cardiomyopathy. Genotype does not predict phenotype. The mode of inheritance includes autosomal dominant, autosomal recessive and X-linked.

Medications

Risk to the fetus from drugs used to treat cardiomyopathy

Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) should be discontinued as soon as pregnancy is diagnosed because of their teratogenic potential, which extends across all trimesters. Beta blockers should be continued because of the beneficial effect for the mother, although this class of drugs is associated with an increased risk of intrauterine growth restriction.

Atenolol appears to have the greatest risk so use of metoprolol, pindolol, carvedilo or propranolol may be preferable. Aldosterone antagonists are not recommended in pregnancy but other diuretics can be continued. There is concern about lack of the normal plasma volume expansion during pregnancy in women on diuretics but this risk is small compared to the risk of decompensating heart failure. Digoxin is considered safe in pregnancy. There is also published data supporting the safety of hydralazine and amlodipine in pregnancy.

Contraceptive choices post-delivery

For women who have decided not to pursue future pregnancies and are in a stable relationship with a consenting partner, vasectomy is preferable; otherwise tubal ligation is an excellent choice if she is a safe surgical candidate. Estrogen-containing hormonal contraceptives, including pills and vaginal rings, are contraindicated in women with cardiomyopathy because of the risk of thromboembolic events.

Estrogen-containing hormonal contraceptives may be considered in women with completely recovered peripartum cardiomyopathy or hypertrophic cardiomyopathy without arrhythmias. Intrauterine devices are safe; however, women on chronic anticoagulation may experience heavier menses with an IUD. Progesterone-only contraception does have some cardiac effects but the benefits of preventing an unplanned or unadvised pregnancy outweigh the risks. Barrier methods are also safe and can be effective if used properly.

Tocolytics for preterm labor

Because of the cardio-depressive effects of magnesium and tachycardia associated with beta agonists, these drugs are best avoided in these patients. It would be reasonable to consider nifedipine in patients at extremely low gestational age for a short period of time (24-48 hours) as long as the nifedipine does not induce hypotension.

5. Prognosis and outcome

Peripartum cardiomyopathy (PPCM)

Ejection fraction (EF) at the time of initial diagnosis is the strongest predictor of prognosis. Those with an EF less than or equal to 20% are less likely to experience improved left ventricular function than those with an EF greater than or equal to 30%. Among women with an EF less than 25% the rate of developing end stage heart failure and need for transplant is as high as 55-60%. If the index EF is above 25%, the rate of end stage heart failure is extremely low. Most women who experience improvement will do so within six months of diagnosis but improvement can continue for up to two years in some women. Mortality from peripartum cardiomyopathy with current management is in the range of 10 to 16% overall; however, the rate is higher among women with EF less than 25% and NYHA functional class III or IV.

Subsequent pregnancies are associated with significant risk of further reduction in LV function in those patients without full recovery. Approximately 45% will experience symptoms of congestive heart failure and the mortality rate is about 20%. Subsequent pregnancies pose a lesser risk to those with complete recovery of LV function; however, 15-20% will experience at least a 20% reduction in ejection fraction and 20-25% will experience symptoms of congestive heart failure. However, mortality in this group is very low. Women with an ejection fraction less than 25% at baseline at the time of initial diagnosis should be strongly counseled against future pregnancies, even if their LV function has improved. This group is very high risk for cardiac events and adverse maternal outcomes.

Hypertrophic cardiomyopathy

Most women with hypertrophic cardiomyopathy who have no or only mild symptoms will tolerate pregnancy well. However those with moderate (50-100 mm Hg gradient) or severe (greater than 100 mm Hg gradient) left ventricular outflow obstruction are at high risk to develop congestive heart failure during pregnancy. The higher the gradient, the greater the risk. Other potential cardiac events include atrial fibrillation or atrial flutter, and ventricular tachycardia or fibrillation. Women with symptoms prior to pregnancy are more likely to experience adverse cardiac events during pregnancy.

Major risk factors for sudden death include:

• severe left ventricular outflow obstruction.

• documented episodes of sustained ventricular tachycardia.

• prior out-of-hospital arrest.

• a strong family history of sudden death due to hypertrophic cardiomyopathy.

Minor risk factors for sudden death include:

• septal hypertrophy greater than 3 cm.

• unsustained ventricular tachycardia on Holter monitor (3 beats in a row).

• drop in blood pressure with exercise.

Pregnancy does not hasten progression of hypertrophic cardiomyopathy, i.e. function after the postpartum period is unchanged from that before pregnancy. (This is not the case with peripartum cardiomyopathy.) Comparative case series suggest the incidence of cardiac events is no different in pregnant compared with non-pregnant individuals. If the patient has a genetic hypertrophic cardiomyopathy, genetic counseling is recommended as discussed above. The risk that the offspring will be affected may be as high as 50%.

6. What is the evidence for specific management and treatment recommendations?

Habli, M, O’Brien, T, Nowack, E. “Peripartum cardiomyopathy: prognostic factors for long-term maternal outcomes”. Am J Obstet Gynecol. vol. 199. 2008. pp. 415-9. (This case series of 70 patients with peripartum cardiomyopathy describes the prognostic value of ejection fraction at the time of diagnosis and subsequent pregnancy on long-term outcomes.)

Elkayam, U, Tummala, PP, Rao, K. “Maternal and fetal outcomes of subsequent pregnancies in women with peripartum cardiomyopathy”. N Eng J Med. vol. 344. 2001. pp. 1567-71. (This case series of 44 women with peripartum cardiomyopathy describes outcomes of subsequent pregnancies stratified by whether or not return to normal ejection fraction occurred between pregnancies.)

Elkayam, U, Akhter, MW, Singh, H, Khan, S. “Pregnancy-associated cardiomyopathy: Clinical characteristics and a comparison between early and late presentation”. Circulation. vol. 111. 2005. pp. 2050-5. (Description of the clinical characteristics of 100 women with classic PPCM and 23 with dilated cardiomyopathy diagnosed early in pregnancy.)

Whitehead, SJ, Berg, CJ, Chang, J. “Pregnancy-related mortality due to cardiomyopathy; United States 1991-1997”. Obstet Gynecol. vol. 102. 2003. pp. 1326-31. (Reports the trend in pregnancy-related mortality ratios due to cardiomyopathy in the United States.)

Pearson, G, Veille, JC, Rahimtoola, S. “Peripartum cardiomyopathy; National Heart, Lung, and Blood Institute and Office of Rare Diseases (National Institutes of Health) workshop recommendations and review”. JAMA. vol. 283. 2000. pp. 1183-8. (This workshop stressed the importance of using strict diagnostic criteria for PPCM, including echocardiographic evidence of reduced LV systolic function.)

Packer, M, Bristow, MR, Cohn, JN. “The effect of carvedilol on morbidity and mortality in patients with chronic heart failure”. N Eng J Med. vol. 334. 1996. pp. 1349-55. (Randomized control trial of carvedilol versus placebo demonstrated a significant reduction in risk of death [65%] as well as the risk of hospitalization for cardiovascular events in patients with heart failure who were receiving treatment with digoxin, diuretics and angiotensin-converting-enzyme inhibitors.)

Lampert, M, Weinert, L, Hibbard, J, Korcarz, C, Lindheimer, M. “Contractile reserve in patients with peripartum cardiomyopathy and recovered left ventricular function”. Am J Obstet Gynecol. vol. 176. 1997. pp. 189-95. (Demonstrated that a portion of women who appear to have recovered normal LV function after PPCM will still have reduced contractile reserve as demonstrated by response to low dose dobutamine infusion.)

Sliwa, K, Blauwet, L, Tibazarwa, K. “Evaluation of bromocriptine in the treatment of acute severe peripartum cardiomyopathy: a proof-of-concept pilot study”. Circulation. vol. 121. 2010. pp. 1465-73. (Small [N=20] randomized trial of bromocriptine in addition to standard therapy versus standard therapy alone in the acute phase of PPCM.)

(An excellent source for genetic cardiomyopathies, either dilated or hypertrophic. It includes reviews, a listing of laboratories that offer testing and resources for patients.)

Stergiopoulos, K, Shiang, E, Bench, T. “Pregnancy in patients with pre-existing cardiomyopathies”. J Am Coll Cardiol. vol. 58. 2011. pp. 337-50.

Murali, S, Baldissert, MR. “Peripartum cardiomyopathy”. Crit Care Med. vol. 33. 2005. pp. S340-6.

Ro, A, Frishman, WH. “Peripartum cardiomyopathy”. Cardiology in Review. vol. 14. 2006. pp. 35-42.

Yamac, H, Bultmann, I, Sliwa, K, Hilfiker-Kleiner, D. “Prolactin: a new therapeutic target in peripartum cardiomyopathy”. Heart. vol. 96. 2010. pp. 1352-7.

Krul, SPJ, van der Smagt, JJ, van den Berg, MP. “Systematic review of pregnancy in women with inherited cardiomyopathies”. Eur J Heart Failure. vol. 13. 2011. pp. 584-594.

Spirito, P, Autore, C. “Management of hypertrophic cardiomyopathy”. BMJ. vol. 332. 2006. pp. 1251-5.

Matthews, T, Dickinson, JE. “Considerations for delivery in pregnancies complicated by maternal hypertrophic obstructive cardiomyopathy”. Aust and N Zeal J Obstet Gynecol. vol. 45. 2005. pp. 526-08.

Ware, JS, Li, J, Mazaika, E. “Shared genetic predisposition in peripartum and dilated cardiomyopathies”. N Engl J Med. vol. 374. 2016. pp. 233-41. (Truncating variants (most prevalent being TTN) were identified in 15% of 172 women with PPCM. This was similar to findings to individuals with idiopathic dilated cardiomyopathy. The presence of TTN truncating variants was significantly correlated with lower ejection fraction at one year follow-up.)

McNamara, DM, Elkayam, U, Alharethi, R. “Clinical outcomes for peripartum cardiomyopathy in North America: Results of the IPAC study”. J Am Coll Cardiol. vol. 66. 2015. pp. 905-14. (Prospective follow-up of 100 women with PPCM for 1 year. 13% experienced major events including death, transplant, or left ventricular assist device or had persistent severe cardiomyopathy with ejection fraction < 35%. No subjects with both a baseline LVEF < 30% and a left ventricular end diastolic dimension > 6.0 cm recovered by 1 year.)

Harper, MA, Meyer, RE, Berg, CJ. “Peripartum cardiomyopathy: population-based birth prevalence and 7-year mortality”. Obstet Gynel. vol. 120. 2012. pp. 1013-9. (State-based population study with a birth prevalence of 1 case in every 2,772 live births and 7-year mortality of 16%. Black, non-Hispanic women had a 4-fold higher prevalence and mortality when compared to white women. Women over 35 had the highest prevalence.)

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