Cardiac Drugs in Pregnancy (Current Cardiovascular Therapy), 2014th Ed.

Managing Heart Failure Pre- and Postpartum

Karen Sliwa1, 2   and Kemilembe B. Tibazarwa1, 2

(1)

Department of Medicine, Faculty of Health Sciences, Hatter Institute for Cardiovascular Research in Africa, Groote Schuur Hospital & University of Cape Town, Observatory, Cape Town, 7925, South Africa

(2)

Soweto Cardiovascular Research Unit, Chris Hani Baragwanath Hospital, University of the Witwatersrand, Johannesburg, South Africa

Karen Sliwa

Email: sliwa-hahnlek@mdh-africa.org

URL: http://www.hatter.uct.ac.za

Abstract

Heart failure is the final common pathway of a large spectrum of diseases which can occur in pregnancy or in the immediate postpartum period. The spectrum of cardiovascular diseases (CVD) leading to heart failure in pregnancy and postpartum is changing and differs between regions of the world.

General Considerations

Introduction

Heart failure is the final common pathway of a large spectrum of diseases which can occur in pregnancy or in the immediate postpartum period. The spectrum of cardiovascular diseases (CVD) leading to heart failure in pregnancy and postpartum is changing and differs between regions of the world (Regitz-Zagrosek et al. 2011).

In the western world, the risk of having heart failure due to CVD has increased due to the increasing age of first pregnancy and increasing prevalence of cardiovascular risk factors. In addition, management of congenital heart disease has substantially improved, resulting in an increased number of women with congenital heart disease planning to have children. However, some women with operated or not operated congenital heart disease are already in heart failure or develop heart failure while pregnant or in the postpartum period. In non-western countries, such as South Africa, rheumatic valvular disease dominates, comprising more than 50 % of all cardiac diseases in pregnancy presenting with heart failure (Nqayana et al. 2008; Soma-Pillay et al. 2008).

Cardiomyopathies often lead to cardiovascular complications in pregnancy. Women with previously diagnosed familial cardiomyopathy or peripartum cardiomyopathy have a serious risk of developing heart failure, leading to death in up to 30 % of cases. The aetiology of cardiomyopathies occurring in association with pregnancy is diverse – acquired as in peripartum cardiomyopathy (PPCM), genetic as in hypertrophic cardiomyopathy (HCM) or familial dilated cardiomyopathy (DCM).

This chapter will address counselling women who are at risk of developing heart failure or a known cardiomyopathy, general aspects of pharmacological and non-pharmacological management, as well as discuss novel data on the use of the dopamine D2-receptor antagonist, bromocriptine, in PPCM. The recommendations are based on the recently published European Society of Cardiology (ESC) Guidelines on the Management of Cardiovascular Disease During Pregnancy (Regitz-Zagrosek et al. 2011) and the ESC Guidelines for the Management of Grown-up Congenital Heart Disease (Baumgartner et al. 2010).

Management of Acute Heart Failure in Pregnancy

Heart failure in pregnant women with a pre-existing CVD can develop very rapidly and the guidelines for the management of acute heart failure include non-pharmacological and pharmacological intervention (Dickstein et al. 2008). Acute heart failure in pregnant women needs to be managed by a multi-disciplinary team of cardiologists, obstetricians, intensivists and anaesthesiologists. Any women presenting with shortness of breath in the post- partum period needs to be evaluated (Fig. 1, Table 1).

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Fig. 1

Evaluation of a breathless woman towards the end of pregnancy/early postpartum

Table 1

Pre-conception evaluation and risk assessment in a women with heart failure

Pre-conception evaluation and risk management

Thorough history of cardiac symptoms and physical examination 12-lead ECG

Baseline exercise tolerance and functional class

Baseline echocardiogram

Assessment of ventricular function (right and left)

Assessment of pulmonary artery pressure

Presence and degree of valvular dysfunction

Assessment of stability of cardiac hemodynamic status over time

Effective contraception until pregnancy desired

Adjust medications to prevent adverse fetal events

Genetics referral for patients with heritable cardiac lesion

If a patient is hypotensive, or needing inotropes despite optimal medical therapy, she should be transferred to a facility where intra-aortic balloon pump counterpulsation, ventricular assist devices, and transplant consult teams are available. Urgent delivery, irrespective of gestation, may need to be considered in women presenting or remaining in advanced heart failure with haemodynamic instability. As soon as the baby is delivered, and the patient is haemodynamically stable, standard therapy for heart failure can be applied.

Management of Chronic Heart Failure in Pregnancy

For treatment of chronic heart failure the pregnancy status of the patient is important. Patients can be peri- or postpartum. Women who present with heart failure during pregnancy require joint cardiac and obstetric care. Possible adverse effects on the fetus must be considered when prescribing drugs (Fig. 2; Tables 2 and 3).

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Fig. 2

Treatment of heart failure in women with peripartum cardiomyopathy or other cardiomyopathies according to stage of pregnancy

Table 2

Recommendations for the management of cardiomyopathies and heart failure in pregnancy

Recommendations

Level of evidence

CLASS I

Anticoagulation is recommended in patients with intracardiac thrombus detected by imaging or with evidence of systemic embolism.

A

Women with HF during pregnancy should be treated according to current guidelines for non-pregnant patients, respecting contraindications for some drugs in pregnancy

B

Women with DCM should be informed about the risk of deterioration of the condition during gestation and peripartum.

C

In patients with a past history or family history of sudden death close surveillance with prompt investigation is recommended if symptoms of palpitations or presyncope are reported

C

Therapeutic anticoagulation with LMWH or vitamin K antagonists according to stage of pregnancy is recommended for patients with atrial fibrillation.

C

CLASS IIa

Delivery should be performed with β-blocker protection in women with HCM.

C

β-blockers should be considered in all patients with HCM and more than mild LVOTO or maximal wall thickness >15 mm to prevent sudden pulmonary congestion

C

In HCM, cardioversion should be considered for persistent atrial fibrillation.

C

CLASS IIb

Due to high metabolic demands of lactation and breastfeeding, preventing lactation may be considered in PPCM.

C

CLASS III

Subsequent pregnancy is not recommended if LVEF does not normalize in women with PPCM.

C

Adapted from Regitz-Zagrosek et al. (2011)

DCM dilated cardiomyopathy, HCM hypertrophic cardiomyopathy, HF heart failure, LMWH low molecular weight heparin, LVEF left ventricular ejection fraction, LVOTO left ventricular outflow tract obstruction, PPCMperipartum cardiomyopathy

Level of evidence A: Data derived from multiple randomized clinical studies or meta-analysis

Level of evidence B: Data derived from single randomized clinical trial or large non-randomized studies

Level of evidence C: Consensus of opinion of experts and/or small studies, retrospective studies or registries

Table 3

Medical management of chronic heart failure in pregnancy according to U.SFood and Drug Administration (FDAclass

Medical management of chronic heart failure in pregnancy

Drug/class

Purpose

Comments

Diuretics

Furosemide

Generally reserved for treatment of pulmonary edema

Can result in uteroplacental hypoperfusion

Use of lowest possible dose

FDA class Ca

Digoxin

Not considered first-line therapy for heart failure in non-pregnant patients

Generally considered safe

Useful in treatment of persistent symptoms, despite standard therapy

No improvement in mortality

FDA class C

Vasodilators

Hydralazine

Commonly used oral antihypertensive agent in pregnancy

Demonstrated efficacy in hypertension

Risk of hypotension

Can be substituted for ACE inhibitor during pregnancy

Avoid large or precipitous decreases in blood pressure

FDA class C

Aldosterone antagonists

Spironolactone, epleronone

Prolong survival in selected heart failure patients

Not routinely used in pregnancy No data to support safety in pregnancy

FDA class D

Warfarin

Risk/benefit ratio needs to be discussed with the patient for treatment and prophylactic anticoagulation in severe left ventricular dysfunction

First trimester teratogenesis

Dosing is complicated in pregnancy

FDA class X (contraindicated)

ACE angiotensin converting enzyme, ARB angiotensin receptor blocker, IUGR intrauterine growth retardation, SVR systemic vascular resistance

aU.S. Food and Drug Administration (FDA) class: A (controlled studies show no risk), B (no evidence of human risk in controlled studies), C (risk cannot be ruled out), D (positive evidence of risk), X (contraindicated in pregnancy)

Heart failure should be treated according to guidelines on acute and chronic heart failure (Gheorghiade et al. 2010). The principal objectives in the management of heart failure are to make patients feel better, reduce hospitalisations (new and recurrent) and to prolong survival. Drugs such as diuretics and digoxin improve symptoms. Beta-blockers, ACE-inhibitors and aldosterone antagonists improve survival. It is now recognized that preventing HF hospitalisation is important for patients and healthcare systems.

Data on the use of medications in pregnancy are limited as pharmaceutical studies often exclude pregnant women due to fear of litigation if fetal effects occur. Evidence is therefore limited and for most medication only a ‘class C’ (Consensus of opinion of experts and/or small studies, retrospective studies or registries) (Regitz-Zagrosek et al. 2011) is available. Levels of evidence on the recommendations for the management of cardiomyopathies and heart failure in pregnancy is summarized in Tables 2 and 3. A number of drugs commonly used in the management of chronic heart failure are not recommended during pregnancy.

Angiotensin Converting Enzyme (ACE) inhibitors, Angiotensin Receptor Blockers (ARBs), and renin inhibitors are contraindicated because of fetotoxicity (Cooper et al. 2006; Bullo et al. 2012).

A recent systemic review by Bullo et al. in Hypertension (Bullo et al. 2012) reported on the use of ACE-inhibitors and ARBs from a total of 72 reports. Thirty-seven articles on 118 well-documented cases described the prenatal exposure to ACE-inhibitors and 35 articles on 68 cases described the use of ARBs. Overall, 52 % of the newborns exposed to ACE-inhibitors and 13 % of the newborns exposed to ARBs did not exhibit any complications (p < 0.0001). Neonatal complications were more frequent following exposure to ARBs and included renal failure, oligohydramnions, death, arterial hypertension, intrauterine growth retardation, respiratory distress syndrome, pulmonary hypoplasia, limb defects and persistent patent ductus arteriosus. Fetal adverse effects by both drugs had relevant neonatal and long-term complications. The outcome was poorer following exposure to ARBs versus ACE-inhibitors. The authors rightly concluded that relevant complications are regularly described, indicating that awareness of the deleterious effects of prenatal exposure to drugs inhibiting the renin-angiotensin system should be improved.

For symptomatic relief, and to reduce afterload, hydralazine and nitrates can be used instead of ACE inhibitors/ARBs for afterload reduction. Diuretics should only be used if pulmonary congestion is present since they may decrease blood flow to the placenta. Furosemide and hydrochlorothiazide are most frequently used.

For symptomatic relief, managing tachycardia and improving long-term outcome, beta-blockers can be considered, carefully weighing up the benefit for the mother versus the possible impaired outcome for the fetus and newborn baby. Data on beta-blocker use in pregnancy are limited and conflicting. However, a recently published survey from a Danish birth cohort (Meidahl Petersen et al. 2012), comprising all births in Denmark between 1995 and 2008, explored the effect of beta-blockers on pregnancy outcomes. The authors identified 2,459 pregnancies exposed to beta-blockers. Interestingly, Danish pharmacies are required by law to register all redeemed prescriptions and, therefore, this study included data on exposure to beta-blockers based on information on prescriptions paid for and not only prescribed by the physician. The authors defined being born small for gestational age as having a birth weight below the 10th percentile for the corresponding gestational week. Preterm birth was defined as born before the 37th gestational week. Beta-blocker exposure during pregnancy was found to be associated with increased risk of small for gestational age (SGA) fetuses (adjusted OR 1.97, 95 % CI 1.75–2.23), preterm birth (adjusted OR 2.26, 95 % ci 2.03–2.52) and an increased perinatal mortality (adjusted OR 1.89, 95 % CI 1.25–2.84). The authors found similar risks irrespective of type of beta-blocker used. However, the study has a major limitation in the way that the authors could not adjust for the treatment indication and severity of the maternal disease, nor were they able to rule out confounding factors. Maternal disease could also possibly explain the findings.

Newborns of mothers who needed to be on beta-blockers while pregnant should be supervised for 24–48 h after delivery to exclude hypoglycaemia, bradycardia, and respiratory depression.

Another medication that has been shown to improve long-term survival in patients with heart failure, aldosterone antagonists, should be avoided (Mirshahi et al. 2002). Animal studies suggest that the blockade of mineralocorticoid hormone provokes teratogenesis in rat embryos. Spironolactone can also be associated with antiandrogenic effects in the first trimester. Data for eplerenone are lacking.

Digoxin can be used safely in pregnancy and can be considered to reduce heart rate. In acute heart failure dopamine and levosimendan can be used if inotropic drugs are needed.

Care should be taken with anticoagulation therapy in the immediate phase after delivery but, once the bleeding has stopped, it should be considered in patients with a very low contractility of the heart and, therefore, a very low ejection fraction (<30 %) because peripheral embolism, including cerebral embolism and ventricular thrombi, are frequent in patients with severely impaired systolic function. This is in part due to increased procoagulant activity in the peripartum phase (Brenner 2004).

Anticoagulation is clearly recommended in patients with documented intracardiac thrombus detected by imaging or evidence of systemic embolism (Dickstein et al. 2008), as well as in patients with paroxysmal or persistent atrial fibrillation. Low molecular weight heparin (LMWH) or vitamin K antagonists are recommended according to the stage of pregnancy to prevent stroke (see chapter “Anticoagulation in Pregnancy” by Prof. Vera Regitz-Zagrosek). When LMWH is used, anti-Xa levels should be monitored.

Breastfeeding

Some ACE inhibitors (benazepril, captopril, enalapril) have been sufficiently tested in breastfeeding women and use by the mother is safe for the baby (Regitz-Zagrosek et al. 2011; Beardmore et al. 2002). Weight monitoring of the child during the first 4 weeks is essential as an indicator of kidney dysfunction. A recent small prospective randomized pilot study supports the hypothesis that the addition of bromocriptine, which terminates lactation via inhibition of prolactin, in addition to standard heart failure therapy, has beneficial effects on ventricular function and clinical outcome in women with acute severe PPCM (Sliwa et al. 2010a). In addition, due to high metabolic demands of lactation and breastfeeding, preventing lactation may be considered.

Pre-conceptual Counselling for Women with Structural Heart Disease Receiving Medications

Women with any form of cardiomyopathy or heart failure should be informed about the risk of deterioration of the condition during gestation and peripartum (see below). They should be counselled based on individual risk stratification. Any pregnancy in patients with poor systolic function, such as a left ventricular systolic function (LVEF) <40 %, is a predictor of high risk and close monitoring in a tertiary centre should be advised. If LVEF is <20 %, maternal mortality is very high and termination of the pregnancy should be considered (Regitz-Zagrosek et al. 2011; Sliwa et al. 2010b). Women with mildly impaired systolic function wishing to fall pregnant and accepting the increased risk of maternal and fetal morbidity and mortality need to receive advice on medication that needs to be replaced (such as aldosterone antagonists, ACE-inhibitors and warfarin) due to documented teratogenic effects, prior to falling pregnant. They need to be referred and managed by a multi-disciplinary team of cardiologists, obstetricians and intensivists and carefully monitored throughout the pregnancy.

Pharmacological Management of Specific Cardiomyopathies in Pregnancy

Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is defined by the presence of a dilated left ventricle, impaired systolic function and, often, typical symptoms of heart failure. The condition can be of unknown etiology or have a familial predisposition due to genetic changes. Differentiation from PPCM is often difficult and can sometimes only be achieved retrospectively. If not known before conception, the condition is most often unmasked during the first or second trimester when the haemodynamic load is increased. A family history of DCM speaks in favour of the DCM diagnosis and against PPCM. Pregnancy outcome of women with a classical DCM in pregnancy describe marked deterioration during pregnancy and a poor outcome (Grewal et al. 2009). A pregnancy in patients with a DCMO with poor systolic function, such as a left ventricular systolic function (LVEF) <40 %, is considered to be a predictor of high risk. If LVEF is <20 %, maternal mortality is very high and termination of the pregnancy should be considered (Regitz-Zagrosek et al. 2011; Sliwa et al. 2010b).

Secondary cardiomyopathies such as infiltrative or toxic cardiomyopathies, arrhythmogenic right ventricular cardiomyopathy and other rare forms can also develop symptoms in pregnancy. At present data on continued use of beta-blocker therapy in patients with previously known DCM is scarce. Data from the ongoing ROPAC study by the European Cardiac Society via the EuroObs-program (www.escardio.org) (Roos-Hesselink et al. 2013) will hopefully provide data on maternal and fetal outcome of women receiving beta-blocker therapy throughout their pregnancy.

Peripartum Cardiomyopathy

Peripartum cardiomyopathy (PPCM) is a life-threatening heart disease developing towards the end of pregnancy or in the months following delivery, in previously healthy women (Sliwa et al. 2010b). It is a diagnosis of exclusion when no other cause of heart failure is found. The LV may not be dilated, but the EF is nearly always reduced below 45 %. PPCM is the major cause of pregnancy-induced heart failure and is associated with high morbidity and mortality.

The true incidence of PPCM is unknown as clinical presentation varies. Current estimates range from 1:299 (Haiti), 1:1,000 (South Africa) to 1:3,186 (USA) pregnancies (Blauwet et al. 2013). No data exists on the frequency of the disease in Europe. Pathophysiology still remains unclear, with multiple factors likely to contribute to and to drive progression. Predisposing factors seem to be multiparity, family history, ethnicity, twin pregnancy and either advanced age of mothers or teenage pregnancy. Nevertheless, decisive advances have been achieved in understanding some underlying molecular cascades deregulated in PPCM (Sliwa et al. 2006a; Hilfiker-Kleiner et al. 2007a). The aetiology of PPCM is uncertain but inflammation and autoimmune processes may play a role (Sliwa et al. 2006b). Novel data on circulating microparticles released from cellular membranes during cell activity may be a diagnositic marker of disease (Walenta et al. 2012). PPCM is suspected to be the consequence of an unbalanced oxidative stress leading to proteolytic cleavage of the lactating hormone, prolactin, into a potent angiostatic factor and into pro-apoptotic fragments (Hilfiker-Kleiner et al. 2007a). Prolactin (PRL) can have opposing effects on angiogenesis, depending on proteolytic processing of the potentially pro-angiogenic full-length 23-kDa PRL into the antiangiogenic 16-kDa PRL. The role of 16-kDa PRL and the inhibition by the dopamine D2-receptor antagonist bromocriptine in animal models and human studies have recently been reviewed by Hilfiker-Kleiner et al. (2012).

Symptoms and signs are often typical for heart failure but, due to the special physiological situation of pregnancy and post-partum, a broad spectrum of symptoms is reported in PPCM patients. PPCM should be suspected in all women with a delayed return to the pre-pregnancy state. Frequently patients present with acute heart failure. Complex ventricular arrhythmias and sudden cardiac arrest are also described.

Recent case reports have indicated that the addition of bromocriptine to standard heart failure therapy may be beneficial in patients with acute onset PPCM (Hilfiker-Kleiner et al. 2007b). A proof-of-concept pilot study of PPCM patients with severely reduced LVEF, diagnosed within 1 month of delivery, showed a marked improvement in systolic function and reduced mortality in patients treated with bromocriptine 2.5 mg twice daily for 2 weeks, followed by 2.5 mg daily for 4 weeks, compared with patients receiving standard care with ACE-inhibitors and beta-blockers only. A larger randomized study is currently underway in order to confirm the previously reported beneficial effects of bromocriptine during the acute phase of PPCM and to assess whether these effects are enhanced by chronic bromocriptine therapy. PPCM patients are particularly vulnerable to thrombotic and thromboembolic complications due to pregnancy-induced hypercoagulability which begins during pregnancy, is heightened during labor and delivery, and persists up to several months postpartum. These patients not only have an increased risk of deep vein thrombosis and pulmonary embolism, they also have an increased risk for developing intracardiac thrombus, even if their systolic function is only moderately decreased (Sliwa et al. 2006b). Anticoagulation is not recommended for all PPCM patients but should be considered in patients with an LVEF <35 %. Case-reports associate bromocriptine in postpartum women with an increased risk for thrombotic events such as myocardial infarction (Hopp et al. 1996), which resulted in the drug being advocated as an agent to suppress/stop lactation in the United States. However, it is widely used in many Western European countries, Africa and Asia for this purpose and other indications, such as the treatment of Parkinson’s disease. Recent studies suggest beneficial effect of bromocriptine being used in the therapy of adult patients with diabetes mellitus type 2 to diminish fasting glucose, improve glucose tolerance and being associated with reduction in cardiovascular morbidity (Gaziano et al. 2010). We feel that women with PPCM in general and, in particular, poor systolic function, should be considered for anticoagulation if INR monitoring can be offered, even if they are not receiving bromocriptine.

Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a common genetic disorder. The disease is frequently diagnosed for the first time in pregnancy by echocardiography. The most common substrates for complications are diastolic dysfunction due to the hypertrophied non-compliant myocardium, severe left ventricular outflow tract obstruction (LVOTO) and arrhythmias. Patients can present with symptoms that are typical for heart failure, with pulmonary congestion due to the increased end-diastolic pressure or syncope during physical activity. Echocardiography is the diagnostic tool of choice.

Women with HCM usually tolerate pregnancy well (Autore et al. 2002). Patients with a high risk clinical profile before pregnancy, i.e. having had a history of syncope or symptoms of heart failure, are at higher risk and need specialized obstetric care (Regitz-Zagrosek et al. 2011). Low risk cases may have a spontaneous labour and vaginal delivery.

Pharmacological management depends on symptoms and signs. Beta-blockers should be considered in patients with more than mild LVOTO and/or maximal wall thickness of >15 mm to prevent sudden pulmonary congestion during exertion or emotional stress (Spirito and Autore 2006). Beta-blockers should be used for rate control in AF and to suppress ventricular arrhythmias. Verapamil can be used as a second choice when beta-blockers are not tolerated but could cause AV block in the fetus. Cardioversion should be considered for persistent arrhythmia. Therapeutic anticoagulation with LMWH or vitamin K antagonists, according to stage of pregnancy, is recommended for those with paroxysmal or persistent AF. Patients with a past history or family history of sudden death need close surveillance with prompt investigation if symptoms of palpitations or pre-syncope are reported (Regitz-Zagrosek et al. 2011).

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