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Inherited CardiomyopathiesSpaendonck-Zwarts, Karin Yvon van

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Systematic review of pregnancy in women with inherited cardiomyopathies

8Sébastiaan P.J. Krul Jasper J. van der Smagt Maarten P. van den BergKrystyne M. SolliePetronella.G. PieperKarin.Y. van Spaendonck-Zwarts

European Journal of Heart Failure 2011; 13:584-594

Spaendonck.indd 177 21-01-14 09:00

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ABSTRACTPregnancy exposes women with inherited cardiomyopathies to increased risk for heart fail-ure and arrhythmias. In this paper, we review the clinical course and management of pregnant women with the following inherited cardiomyopathies: hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, left ventricular non-com-paction cardiomyopathy, and restrictive cardiomyopathy. We also discuss peripartum cardiomyopathy. Pregnancy is generally well tolerated in asymptomatic patients with inherited cardio myopathies. However, worsening of the clinical condition can occur during pregnancy, despite intensive medical treatment. If prior cardiac events, poor functional class (New York Heart Association class III or IV), or advanced left ventricular systolic dysfunction are present, the risk of maternal cardiac complications during pregnancy are markedly increased. The postpartum condition is generally no worse than the antepartum condition, but no long-term follow-up studies have been reported. Preconception evaluation and counselling are important aspects of managing women with inherited cardiomyopathies. Genetic counselling and DNA testing should be offered to all women following the diagnosis of an inherited cardiomyopathy.


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INTRODUCTIONIn the last two decades, there has been are increate in the understanding of the genetic and hereditary basis of cardiomyopathies. Inherited cardiomyopathies can present at a young age and these patients are therefore likely to experience numerous life events, including pregnancy. In this paper, we review the literature on the clinical course of inherited cardiomyopathies and their medical management during pregnancy, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), left ventricular non-compaction cardiomyopathy (LVNC), and restrictive cardiomyopathy (RCM) (Table 1). We also discuss the literature on peripartum cardiomyopathy (PPCM), a condition that affects women late in pregnancy or in the early puerperium (Table 1).

Chapter 8

Type of cardiomyopathy Search query used

HCM(hypertrophic cardiomyopathy OR hypertrophic obstructive cardiomyopathy OR HCM OR HOCM) AND (pregnancy OR peripartum OR puerperium OR pregnant)

DCM (dilated cardiomyopathy OR DCM) AND (pregnancy OR peripartum OR puerperium OR pregnant)

ARVC

(arrhythmogenic right ventricular dysplasia/cardiomyopathy OR arrhythmogenic right ventricular dysplasia OR arrhythmogenic right ventricular cardiomyopathy OR ARVD/C OR ARVD OR ARVC) AND (pregnancy OR peripartum OR puerperium OR pregnant)

LVNC(noncompaction OR non-compaction OR non compaction OR hypertrabeculation OR LVNC) AND (pregnancy OR peripartum OR puerperium OR pregnant)

RCM (restrictive cardiomyopathy OR RCM) AND (pregnancy OR peripartum OR puerperium OR pregnant)

PPCM (cardiomyopathy) AND (pregnancy OR peripartum OR puerperium OR pregnant)

Table 1: Search queries used in PubMed search

The search queries were performed on 4 October 2010 in PubMed (www.pubmed.org). Only articles written in English were selected.HCM= hypertrophic cardiomyopathy, DCM= dilated cardiomyopathy, ARVC/D= arrhythmogenic right ventricular cardiomyopathy/dysplasia, LVNC= left ventricular non-compaction cardiomyopathy, RCM= restrictive cardiomyopathy, PPCM= peripartum cardiomyopathy.


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PHYSIOLOGICAL CHANGES DURING PREGNANCYMany pregnancy-related problems in women with cardiovascular disease are related to the physiological changes of the cardiovascular system. During pregnency, maternal blood volume increases by 40%, resulting in a 30-50% increase in cardiac output. The increase in cardiac out-put is achieved by a rise in stroke volume and, later in pregnancy, an increase in the heart rate of 10-15 beats per minute. Vasodilation occurs early in pregnancy due to hormonal influences, triggering the increase in plasma volume and cardiac output. In addition, remodelling of placental vessels in the second trimester results in a marked decrease in systemic vascular resistance accompanied by a lowering of the blood pressure by about 10 mm Hg. A rise in several blood coagulation factors and a decrease of fibrinolytic activity results in a hypercoagu-lable state. In labour, stroke volume is increased due to increased venous return resulting from uterine contractions. Finally, after delivery there is an increase in cardiac output depending on blood loss during labour and auto-transfusion directly after delivery as a result of uterus con-traction. All cardiovascular parameters gradually return to pre-pregnancy values a few weeks after delivery.1-3 All these haemodynamic changes combined with metabolic changes that occur during pregnancy can influence the pharmacokinetics and may necessistate dosage modifica-tions. During pregnancy drug absorption is usually decreased and renal elimination is increased, decreasing the total plasma concentration of the drug. Expansion of the blood volume leads to dilution and a decrease in blood proteins, resulting in higher concentrations of unbound drugs in the blood. Furthermore hepatic metabolization may increase or decrease depending on the isoenzyme involved4-6.

GENERAL MANAGEMENT BEFORE AND DURING PREGNANCY IN CARDIOMYOPATHIESThe following issues should be considered, ideally before pregnancy: the specific underlying cardiac disease and its severity (including the New York Heart Association (NYHA) functional class), effects of pregnancy on the disease, effects of the disease on the unborn child, medi-cation regime during pregnancy, the possibility of further palliative or corrective procedures, implantable cardioverter defibrillator (ICD) implantation, life expectancy and ability to care for a child, and the risk of heart disease in the offspring.7 These issues should be discussed with the woman and a plan for pregnancy management should be made, scheduling outpatient clinic visits at least once every trimester and more often in serious disease. Before focusing on specific cardiomyopathies, we will discuss several general therapeutic principles relevant for treating cardiomyopathies during pregnancy.

Heart FailureSymptoms such as dyspnoea and fatigue and signs such as fluid retention are common in pregnancy, but can mask heart failure. A thorough physical and echocardiographic exami-


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nation can aid in distinguishing the physiological and pathological changes. The treatment of heart failure during pregnancy is not essentially different to that for non-pregnant patients,8 although potential teratogenic effects of the medication may limit the therapeutic options (Table 2).9 Diuretics are relatively safe to use if salt restriction is not sufficient to reduce fluid overload; most experience has been gained with furosemide and hydrochlorothiazide. Care must be taken to avoid iatrogenic dehydration as it can cause placental hypoperfusion and oligohydramnion.10 Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor II blockers (ARBs) are contraindicated in pregnancy because of teratogenicity, neonatal anuric renal failure, and neonatal death.11 The use of spironolactone is not advised during pregnancy, since safety data are limited and its anti-androgen activity has caused feminisation in male animals.12 Hydralazine, with or without nitrates, is a safe alternative,13 but nitroprusside should be avoided because of the risk of neonatal cyanide poisoning.14 There is extensive experience with beta-blockers dur-ing pregnancy, especially with labetolol, propanolol, atenolol and metoprolol. Atenolol is asso-ciated with a higher incidence of foetal growth restriction compared with other beta-blockers and its use is not advised. Theoretically, selective cardiac beta-blockers are preferred because they seem to have fewer effects on peripheral vasodilatation and uterine tone, although scien-tific evidence is not available.15 Finally, digoxin is a safe treatment modality in pregnant patients with heart failure. It should be noted that the above considerations apply to systolic heart failure.

ArrhythmiasAll sorts of arrhythmias and conduction disturbances may occur during pregnancy. Pre-pregnancy arrhythmic events are predictive of a recurrence during pregnancy. As a general rule, treatment is only indicated in the case of more severe arrhythmias, which could possibly endanger both mother and child. In addition, the underlying haemodynamic derangement should be dealt with first. Most anti-arrhythmic medication (Table 2) is relatively safe in terms of potential side-effects on the foetus based on limited experience, but side-effects are documented for all the therapeutic agents.16 For treating supraventricular tachycardias (SVT), beta-blockers, digoxin and calcium-antagonists can be used. There is ample experience with beta-blockers, owing to their broad use in pregnancy. Digoxine, a drug with direct and indirect positive inotropic-, negative chronotropic-, and negative dromotropic characteristics, is supposed to be one of the safest agents of its kind in pregnancy and there is experience of its use in SVT.17 Calcium-antagonists are less attractive during pregnancy since their negative inotropic effects and a risk of possible atrio-ventricular -block by these drugs can endanger pregnant patients.17 Sotalol is not frequently used in pregnancy because of limited experience with it and its relatively easy passage through the placenta, although no adverse effects on pregnancy or the foetus have been reported. In the case of a ventricular tachycardia (VT), lidocaine is a safe option but of limited efficacy. Amiodarone is generally contraindicated and only advised in (therapy-resistant) acute, life-threatening arrhythmias, because of reported side-effects during long administration.16 Procainamide is a third, relatively safe, alternative and can be used to treat VT for a limited

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DrugsFDA safety classification

Comments

Heart failure

ACE inhibitorsC (1st trimester), D (2nd and 3rd trimesters)

Contra-indicated during pregnancy

Aldosterone inhibitors

Spironolactone C/DNot advised, limited data available on effects during pregnancy, reports of feminisation in male animals

ARBsC (1st trimester), D (2nd and 3rd trimesters)

Contra-indicated during pregnancy

Beta-blockers See below

Calcium-antagonists

Amlodipine CLimited data available on effects during pregnancy

Diuretics

Furosemide CRelatively safe, beware of iatrogenic dehydration

Hydrochlorothiazide BRelatively safe, beware of iatrogenic dehydration

Vasodilators

Hydralazine CLimited data available on effects during pregnancy

Isosorbide nitrate CLimited data available on effects during pregnancy

Nitroprusside CNot advised, limited data available on effects during pregnancy, risk of neonatal cyanide poisoning

Anti-arrhythmic

Dysopyramide CNot advised, limited data available on effects during pregnancy, can induce uterine contractions

Procainimide CRelatively safe, can be used for chronic treatment of VT

Lidocaine B Safe, but limited efficacy

Flecainide CProbably safe, but limited data available on effects during pregnancy

Propafenone CLimited data available on effects during pregnancy, avoid using in first trimester

Table 2: Food and Drug Administration safety classification of cardiovascular drugs during pregnancy


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Beta-blockers

Atenolol D Not advised, rather use other beta-blocker

Bisoprolol C Relatively safe

Carvedilol C Relatively safe

Metoprolol C Relatively safe

Labetalol C Relatively safe, ample experience

Propanolol C Relatively safe

Amiodarone DTeratogenic, use only in acute treatment of arrhythmias

Sotalol BLimited data available on effects during pregnancy, easy passage through placenta

Calcium-antagonists C

Diltiazem CLimited data available on effects during pregnancy, negative inotropic and possible risk of AV-block

Verapamil CRelatively safe, negative inotropic and possible risk of AV-block

Digoxin C Safe, first choice in SVTs

Adenosine CRelatively safe, limited data available on effects during pregnancy

Anti-coagulation

Acenocoumarol None*Only on indication (high thrombotic risk), avoid in first trimester due to teratogenic effect

Phenprocoumon None*Only on indication (high thrombotic risk), avoid in first trimester due to teratogenic effect

Warfarin DOnly on indication (high thrombotic risk), avoid in first trimester due to teratogenic effect

Heparine CRelatively safe, difficult to maintain appropriate anticoagulation

* No FDA classificationFDA= Food & Drug Administration (USA), ACE= angiotensin-converting enzyme, ARBs= angio-tensin receptor II blockers, VT= ventricular tachycardia, AV-block= atrio-ventricular nodal block, SVT= supraventricular tachycardia.FDA safety classification: A: Controlled studies show no risk; B: No evidence of risk in humans; C: Risk cannot be ruled out; D: Positive evidence of risk; X: Contraindicated in pregnancy.


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period of time.18 In treating arrhythmias, direct current cardioversion is a safe alternative in the acute phase of an arrhythmia.19 If indicated, ablation should be performed before conception but during pregnancy it is only indicated in otherwise untreatable, life-threatening arrhythmias; radiation exposure should be avoided in the first trimester of pregnancy.20, 21 Evidence of the safety ICD devices and ICD therapy is limited to a retrospective analysis of 44 patients,22 which suggested that there was no risk for the mother or foetus, and that pregnancy did not increase ICD-related complications or the number of ICD discharges in general.

ThrombosisPatients with severe heart failure or arrhythmias require proper anti-coagulation, especially during pregnancy, since it induces a hypercoagulable state. Vitamin K antagonists are dangerous to foetal development in the first trimester and cause embryopathy (especially nasal hypoplasia, but sometimes more severe abnormalities) in about 6% of reported cases. They can also cause foetal bleeding. Embryopathy seems to be dose-dependent in several studies, and no embryo-pathy was described with a warfarin dose < 5 mg daily.23 Therapy with heparin, however, is difficult and exposes the mother to possible complications like thrombocytopenia and osteo-porosis. Furthermore, a problem with low-molecular-weight heparin or unfractionated heparin is the difficulty of maintaining an appropriate clinical level of anticoagulation and the subcutane-ous or intravenous administration of the drugs.24 There are therefore several anti-coagulation strategies available in the guidelines on antithrombotic therapy during pregnancy, depending on the underlying anti-coagulation indication.24

DeliveryA plan for delivery should be made by a multidisciplinary team and should be in place no later than the beginning of the third trimester. The timing and type of delivery should be deter-mined by a combination of obstetric and cardiological factors. During a caesarean delivery there is substantial blood loss, especially compared with a vaginal delivery, which is usually safe but this depends on the severity of clinical symptoms. Adequate pain management is im-portant to avoid sympathetic stimulation and increases in the haemodynamic load from pain and anxiety.25 Irrespective of the mode of delivery, the plan for delivery should include proper anaesthesiological care of the patient during labour. Spinal anaesthesia and epidural anaesthesia both incur the risk of haemodynamic instability, albeit more common with spinal anaesthesia, based on the accompanying pre-load and after-load reduction. These types of anaesthesia are relatively contra-indicated in patients with HCM with a left ventricular outflow tract obstruc-tion, because changes in pre-load and after-load influence the outflow tract gradient and left ventricular filling, which may result in acute deterioration of the patient’s condition.26 General anaesthesia or slow titration of epidural anaesthesia is, in specific situations, a safer way of haemodynamically controlling the patient. Invasive monitoring of the patient can be indicated depending on the patient’s clinical condition. Fluid supply should be performed carefully in all


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cases of cardiomyopathy to avoid cardiac decompensation with pulmonary oedema, especially after delivery when there is already an increase in blood volume.25

HYPERTROPHIC CARDIOMYOPATHY (HCM)With an estimated prevalence of 1:500, HCM is the most common type of cardiomyopathy. Familial occurrence is described to be around 90%, mainly with autosomal dominant inherit-ance (Table 3).27 HCM is characterized by hypertrophy of the left ventricle, sometimes resulting in dynamic obstruction of the outflow tract. The clinical course is highly variable between patients. Patients can present at all ages, while clinical presentation can range from asympto-matic to severe events, like heart failure or even sudden cardiac death (SCD).28 Important aspects in managing HCM are identifying those patients that have a high risk of SCD,29 treating arrhythmias and treating heart failure. Beta-blockers should be continued as they can provide a safe treatment for both the haemodynamic and anti-arrhythmic problems of pregnancy in these patients.9, 11 Potential dangers in HCM patients during labour are a reduced venous return because of the expulsive effort, acute blood loss, and an increased or new obstruction of the left ventricular outflow tract through increase in the contractile forces of the heart and tachy-cardia caused by physical stress.30 There are a few studies and numerous case reports on preg-nancy outcomes in women with HCM (Table 4); these show that the rate of maternal morbidity is mainly related to the NYHA functional class before pregnancy.31 Asymptomatic patients with HCM have a small risk of cardiac complications in pregnancy,11 whereas patients with a poor NYHA functional class prior to pregnancy have a higher risk of cardiac events during pregnancy. Clinical deterioration is more frequently seen in patients with outflow obstruction than those without obstruction.31, 32 Compared with a non-pregnant group of patients with HCM, cardiac complications occurred at similar rates, implying there was no effect on the clini-cal course of HCM during pregnancy,32 although further studies on the short- and long-term effects need to be performed. Deaths reported in pregnant patients with HCM concern high risk patients who were strongly advised against becoming pregnant.31 Vaginal delivery is uneventful in the majority of asymptomatic patients, despite possible haemodynamic complications during labour. Epidural anaesthesia may be useful in selected patients. Elective Caesarean section is only advised for obstetrical reasons, or for patients with decompensated heart failure or with symptomatic outflow obstruction.33, 34

DILATED CARDIOMYOPATHY (DCM)DCM is characterized by dilation and impaired contraction primarily of the left ventricle. Many causes for DCM have been identified, including ischemic heart disease, hypertension, infec-tious diseases (viral myocarditis), alcohol abuse, and medication toxicity.35 In around 50% of DCM cases, no causal mechanism can be discovered (idiopathic DCM).35 Its estimated preva-

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lence is 1:2500 with familial disease in 35% of the patients, mainly with autosomal dominant inheritance (Table 3).36 The presentation of DCM is typically with progressive heart failure, some-times necessitating heart transplantation. Other problems are arrhythmias, thromboembolism, and SCD. Only a few studies on the pregnancy outcomes of women with idiopathic DCM have been published (Table 4). Pregnancy in asymptomatic or mildly symptomatic patients seems to be associated with a low risk of adverse maternal events.37-39 Predictors of such events are moderate or severe left ventricular dysfunction and/or NYHA functional class III

Cardiomyopathy

Prevalence Familial disease

Known genes

Most frequently affected genes Frequency (%)

Yield DNA testing

HCM

1:500 90% >10 MYH7 (β-myosin heavy chain)MYBPC3 (myosin binding protein C) TNNT2 (cardiac troponin T) TNNI3 (cardiac troponin I) TPM1 (α-tropomyosin)

30–4030–40<5<5<5

65%

DCM

1:2500 35% >30 LMNA (lamin A/C)MYH7 (β-myosin heavy chain)TNNT2 (cardiac troponin T)

4–84–63

20%

ARVC/D

1:5000 50% >5 PKP2 (plakophilin-2)DSG2 (desmoglein-2)DSP (desmoplakin)

11–523–10<5

50%

LVNC

Unknown 60% >5 MYH7 (β-myosin heavy chain)MYBPC3 (myosin binding protein C) TNNT2 (cardiac troponin T)

2154

40%

RCM

Rare 30% >5 TNNI3 (cardiac troponin I) >50 60%

HCM= hypertrophic Cardiomyopathy, DCM= dilated Cardiomyopathy, ARVC= arrhythmogenic right ventricular cardiomyopathy, LVNC= left ventricular non compaction cardiomyopathy, RCM= restrictive cardiomyopathy.

Table 3: Genes involved in inherited cardiomyopathies and yield from DNA testing


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or IV. Foetal complication rate is also increased, depending on the presence of maternal and obstetric risk factors.37 In comparison with non-pregnant women with DCM, pregnant women with DCM experience more adverse events. This can probably be explained by a better medical treatment in non-pregnant patients (i.e. use of ACE inhibitors) and the increased haemody-namic challenge in pregnant patients.37

ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY (ARVC)ARVC is an inherited cardiomyopathy with a prevalence of 1:5000; it is familial in 50% of the cases and predominantly shows an autosomal dominant inheritance (Table 3). Despite the autosomal dominant inheritance, the male/female ratio is 3:1, suggesting a mild clinical expres-sion in the female sex. It is characterized by cardiomyocytes being replaced by fibrofatty tissue in mainly the right ventricle.40 This disruption of normal myocardium leads to electrical instability, causing arrhythmias, and to right heart failure.40 During pregnancy, anti-arrhythmic medication can be necessary to protect these patients from harmful episodes of arrhythmia.41 Eleven cases of pregnancy in patients with ARVC have been reported in the literature (Table 4). These suggest a favourable outcome in asymptomatic patients treated with optimal anti-arrhythmic medical therapy during pregnancy. In the third trimester of the pregnancy and after delivery, the occur-rence of arrhythmias seems to be increased, usually relating to rhythm disturbances known before pregnancy.42 These reports indicate the need for a thorough follow-up programme, particularly in the last trimester and after delivery, because of the possibly increased risk of disease manifestations. Together, there is little evidence that there is a serious risk of disease progression in asymptomatic patients. Furthermore, delivery, whether vaginal or by caesarean section, seems to be safe and uncomplicated. The additional risk of pregnancy in women with ARVC is unknown in patients with symptoms of ventricular arrhythmias or (right-sided) heart failure, but it is probably considerable. We would therefore advise patients with ventricular ar-rhythmias or (right-sided) heart failure not to become pregnant.

LEFT VENTRICULAR NON-COMPACTION CARDIOMYOPATHY (LVNC)Left ventricular non-compaction cardiomyopathy (LVNC), also referred to as non-compaction cardiomyopathy (NCCM), is a cardiomyopathy43 characterized by a distinctive hypertrabeculated morphological appearance of the myocardium, with familial disease in up to 60% of patients, showing mainly autosomal dominant inheritance (Table 3).44 The exact prevalence of LVNC is unknown, but advanced imaging modalities and enhanced awareness of LVNC suggests it may not be a very rare cardiomyopathy. There is limited evidence in the literature about managing LVNC in general or during pregnancy (Table 4). Prognosis in LVNC depends on the clinical presentation: asymptomatic patients have a good prognosis, but patients presenting with heart failure (NYHA III/VI), sustained ventricular arrhythmias, or an enlarged left atrium have an

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Cardiomyopathy

StudyYear of publication Study type Study population Comments

HCM

Turner et al.30 1969 Prospective 9 HCM

12 pregnancies, 2 pregnancies terminated because of increasing complaints of AP, 1 patient admitted with complaints of dyspnoea. Vaginal delivery was well tolerated.

Oakley et al.34 1979 Retrospective 23 HCM

43 completed pregnancies, 10 patients developed complaints of dyspnoea, 2 developed or had worsening of AP complaints, no deaths.

Siu et al.8 2001 Prospective9 HCM (total study population 546)

1 event (VT), in 4 cases LVOT obstruction.

Autore et al.31 2002Prospective

40 HCM (morbidity)

100 mixed HCM and family (mortality)

15% (6/40) developed cardiac complications, 5 were symptomatic before pregnancy (p>0.01) and 3 had left ventricular obstruction (p>0.05), maternal mortality rate was 10 per 1000 live births, deaths were of high-risk patients advised against pregnancy.

Avila et al.66 2003 Prospective15 HCM (total study population 1000)

High complication rate in HCM (73%) consisting of congestive heart failure, AP, and AF.

Thaman et al.67 2003 Questionnaire 127 HCM

271 pregnancies, 28% (36/127) reported complaints, 83% (30/36) had subsequent pregnancies with 60% (18/30) reported complaints, 90% (32/36) were symptomatic before pregnancy. Two postnatal complications of PE with good resolution.

Avila et al.32 2007 Prospective

23 pregnant HCM patients (and 12 non-pregnant HCM)

Cardiac complications in 48% (11/23) pregnant patients versus 42% (5/12) non-pregnant patients. LVOT obstruction in 74% (17/23) of pregnant patients versus 42% (5/12) in non-pregnant patients.

Case Reports 19

Table 4: Studies on pregnancy outcome in women with specific types of cardiomyopathy


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DCM

Bernstein et al.38 2001 Retrospective8 DCM (compared with 23 PPCM)

50% IDCM, 1 case (LVEF of 16%) of complicated pregnancy resulting in termination. No significant changes in LVEF before/after pregnancy.

Siu et al.8 2001 Prospective23 DCM (total study population 546)

12 pregnancies with events including 1 death, not further specified, unknown if IDCM.

Avila et al.66 2003 Prospective18 IDCM (total study population 1000)

CM in general had complication and mortality rates of 30% and 10% respectively, 18 IDCM cases not specified; in general, worse outcome with lower ventricular function.

Grewal et al.37 2009 Prospective27 IDCM (total study population 32)

27 IDCM, including patients from Sui et al.8 39% (14/36) pregnancies complicated, event-free survival worse in pregnant patients (n=18) compared to non-pregnant patients (n=18).

Palojoki et al.68 2010 Case Series 5 DCM

Lamin A/C- DCM carriers, pre-pregnancy 2 patients with conduction disorder, 2 with palpitations, no disease progression during pregnancy, 1 complication caused by PE.

Case Reports 10

ARVC

Bauce et al.42 2005 Case series 6 ARVC

All on ADD. Pregnancy well tolerated no complaints of heart failure. In last trimester and puerperium, 2 patients had palpitations and 1 VT required ICD implantation.

Case Reports 5

LVNC

Case Reports 7

RCM

Avila et al.66 2003 Prospective1 RCM (total study population 1000)

Not described

Case Reports 0

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unfavourable prognosis.45, 46 There is no specific treatment for LVNC and its treatment should be extrapolated from experience with other cardiomyopathies and the problems encountered during pregnancy.47 LVNC in itself has an increased risk for thromboembolic events48 and pregnancy may be assumed to enhance this risk by inducing hypercoagulability. This increased risk of thromboembolic events warrants adequate anti-coagulation therapy during pregnancy, although proper evidence is lacking. Eight cases of LVNC during pregnancy have been described in the literature (Table 4). These cases show severe presentations during pregnancy, although a publication bias cannot be ruled out.

RESTRICTIVE CARDIOMYOPATHY (RCM)Restrictive cardiomyopathy (RCM) is a rare, inherited cardiomyopathy with an impaired ventricu-lar filling with restrictive physiology, normal (or near normal) systolic function, and a poor prognosis.49 There is little clinical data available to guide clinicians in managing patients with RCM, let alone pregnant patients. In the absence of any recommendations in the medical literature, management of these patients should focus on controlling the physiological factors (blood pressure, heart rate, blood volume, and myocardial ischemia) that are known to exert important effects on ventricular relaxation.50 Due to the severe clinical course of RCM in many (non-pregnant) patients and their poor prognosis in general, combined with the paucity of evidence on the clinical course of pregnancy in RCM, we would strongly advise symptomatic patients with RCM not to become pregnant.

PERIPARTUM CARDIOMYOPATHY (PPCM)During the course of pregnancy, the haemodynamic and cardiovascular changes can trigger overt disease in the setting of subclinical DCM. In contrast to this, PPCM develops de novo during pregnancy. It is an idiopathic cardiomyopathy presenting with heart failure secondary to left ventricular systolic dysfunction towards the end of pregnancy or in the first few months following delivery where no other cause of heart failure can be found. It is a diagnosis of exclusion. The clinical presentation often resembles DCM; however, the left ventricle may not be dilated.51 The precise aetiology of PPCM is unknown, but several pregnancy-associated pathophysiological mechanisms and risk factors have been reported to be involved.

This table was compiled from the results of our search query (Table 1) in PubMed. Articles with <5 patients are mentioned with the case reports. A full list of case reports is available from the authors.HCM= hypertrophic cardiomyopathy, AP= angina pectoris, AF= atrial fibrillation, CM= cardiomyopathy, VT= ventricular tachycardia, LVOT= left ventricular outflow tract, ICD= implantable cardioverter defibril-lator, NYHA= new york heart association, DCM= dilated cardiomyopathy, PE= pulmonary embolism, IDCM= idiopathic dilated cardiomyopathy, LVEF= left ventricular ejection fraction, ARVC= arrhythmo-genic right ventricular cardiomyopathy, ADD= anti-arrhythmic drugs, LVNC= left ventricular non compac-tion cardiomyopathy, PPCM= peripartum cardiomyopathy, RCM= restrictive cardiomyopathy.


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Familial occurrence of PPCM and joint occurrence of PPCM and DCM have been reported, suggesting that genetic factors also play a role.52 Indeed, recent studies have indicated that PPCM may also occur in the context of familial or genetically determined DCM.53, 54 The standard treatment consists of optimal supportive therapy for congestive heart failure, with attention to the timing and mode of delivery when it occurs prenatally. In 23-54% of patients who develop PPCM, normalisation of the left ventricular function occurs. The process of normalisation usually takes 3-24 months.55, 56 If the left ventricular ejection fraction is below 25%, the chances of restoration are reduced. In subsequent pregnancies, patients with a persistent left ventricular dysfunction of <50% will progress more often (44-46%) towards heart failure compared with women with a restored left ventricular function (17-21%). Additionally, patients with a persistent left ventricular dysfunction have a higher frequency of premature deliveries, more therapeutic abortions, and a high mortality (up to 19%) during a subsequent pregnancy.57-62

GENETIC COUNSELLINGWhen an inheritable cardiomyopathy is diagnosed, we recommend referring the index patient to a specialised cardiogenetic outpatient clinic. DNA analysis can be helpful in confirming a diagnosis, which is especially useful in borderline cases. However, because of marked genetic heterogeneity in cardiomyopathies, an underlying mutation cannot always be identified (Table 3, Figure 1). In HCM, LVNC, and RCM, mutations are mainly identified in genes encoding sarco-meric proteins. In DCM, mutations are mainly identified in genes encoding cytoskeleton proteins, but also in genes encoding sarcomeric proteins. In ARVC, mutations are mainly found in genes encoding desmosomal proteins. The yield of DNA analysis varies between the different types of cardiomyopathies (Table 3).63 Genotype-phenotype relations are emerging but do not usually alter clinical practice. Individual information about prognosis based solely on genotype is not possible in most cases. In addition, there is no data available on the influence of different geno-types on the course of pregnancy. The clinical relevance of the DNA analysis for the pregnant patient is therefore low and clinical management is mainly guided by the presenting phenotype. The role for DNA analysis in inherited cardiomyopathies is consequently mainly to identify other family members at risk, especially since most inherited cardiomyopathies have an auto-somal dominant inheritance.63 Cascade genetic screening can help to identify family members at risk and those without a disease-causing mutation. In asymptomatic family members with a mutation, repeated cardiological screening should be offered, whereas family members without a mutation can be discharged from follow-up. When no underlying mutation can be found in the index patient, it is important to advise all first-degree family members to adhere to repeated cardiological screening. In most cases we recommend starting this cardiological screening at the age of ten years. However, the family history or the specific mutation may warrant a more intensive and earlier screening in some families with a severe phenotype and early disease onset.In addition, all index patients should be offered genetic counselling with respect to the in-

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Figure 1: Genetic heterogeneity and overlap in genes causing inherited cardiomyopathies.Adapted from Van Spaendonck-Zwarts et al.63. *DES is mentioned twice in this figure. HCM, hyper-trophic cardiomyopathy; DCM, dilated cardiomyopathy; ARVC, arrhythmogenic right ventricular cardio-myopathy; LVNC, left ventricular non-compaction cardiomyopathy; RCM, restrictive cardiomyopathy; DES, desmin.


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creased risk of a cardiomyopathy in their offspring.64, 65 When the underlying mutation for inherited cardiomyopathy is known, prenatal screening or pre-implantation genetic diagnostics are possible. These are not routinely performed due to the variable disease expression, the fact that disease manifestation usually occurs later in life (generally well after the age of ten years), and the fact that there are treatment modalities available.

CONCLUSIONSPregnancy exposes patients with inherited cardiomyopathies to certain risks, like arrhythmias and heart failure. Pregnancy is generally well tolerated in asymptomatic patients and is mostly not accompanied by a worsening of the clinical condition postpartum compared to prepartum, but there are exceptions and an adverse clinical course cannot always be avoided despite intensive medical treatment. The chance of maternal cardiac complications increases in the presence of prior cardiac events, poor functional class (NYHA III or IV), severe left ventricular systolic dysfunction, and left outflow tract obstruction in the case of HCM. Early consultation when contemplating pregnancy is an important aspect of managing women with cardiomyopathy. Most of the recommendations on the subject of pregnancy in inherited cardiomyopathies are based on expert opinions, on small observational studies, or on case reports. In the light of this limited data, further evidence is necessary to offer these patients optimal care during pregnancy. We recommend close monitoring by a multidisciplinary team before, during, and in the months after pregnancy. In addition, genetic counselling, DNA testing and cardiological screening of first-degree family members should be initiated on diagnosis of an inherited cardiomyopathy.

Acknowledgements We thank Peter van Tintelen, MD, PhD, clinical geneticist, for critically reading the manu-script and Jackie Senior, editor, for editing the manuscript, both of the Department of Genetics, UMCG, Groningen, the Netherlands.

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