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

Management of Coronary Artery Disease and Arrhythmias

Annemien E. van den Bosch1, Titia P. E. Ruys1 and Jolien W. Roos-Hesselink 

(1)

Department of Cardiology, Thorax Center, Erasmus Medical Center, ’s-Gravendijkwal 230, Rotterdam, 3015 CE, The Netherlands

Jolien W. Roos-Hesselink

Email: j.roos@erasmusmc.nl

Abstract

Although coronary artery disease is seldom encountered in women of childbearing age (16–45 years of age), the consequences of coronary disease are considerable, especially in pregnant women. Acute coronary syndrome (ACS) occurring in pregnancy can have devastating effects on mother and child. ACS in pregnancy has other causes than in the non-pregnant state. In the review of Roth and Elkayam only 40 % of the cases (41 of 103 patients) were caused by coronary artery stenosis (Roth and Elkayam 2008). Other causes were thrombus (in 8 % of cases), coronary artery dissection (27 %) and vascular spasm (2 %); normal coronary arteries were found in 13 % of the patients (Roth and Elkayam 2008). Pregnancy has shown to increase the risk of ACS three- to fourfold (James et al. 2006). Between 1991 and 2000 the overall incidence of pregnancy related ACS was reported to be 2.7 per 100,000 deliveries (Ladner et al. 2005). A decade later James et al. published on risk factors for ACS during pregnancy and reported an incidence of 6.2 per 100,000 deliveries between 2000 and 2002 (James et al. 2006). The rising incidence can be explained in three ways: firstly improved diagnostic tests, especially troponin assessment, have resulted in more women with acute chest pain being diagnosed with ACS; secondly, an increase in known cardiovascular risk factors is seen in the pregnant population and finally, maternal age has increased in the Western World (Ventura et al. 2004). The most important risk factors for ACS during pregnancy are hypertension and maternal age (Cecchini et al. 2010). In addition to cardiovascular risk factors, a few obstetric risk factors for ACS during pregnancy have been discovered. The most important is multiparity; others include: a history of preeclampsia, post-partum haemorrhage, transfusions and post-partum infections (Ladner et al. 2005).

Introduction

Although coronary artery disease is seldom encountered in women of childbearing age (16–45 years of age), the consequences of coronary disease are considerable, especially in pregnant women. Acute coronary syndrome (ACS) occurring in pregnancy can have devastating effects on mother and child. ACS in pregnancy has other causes than in the non-pregnant state. In the review of Roth and Elkayam only 40 % of the cases (41 of 103 patients) were caused by coronary artery stenosis (Roth and Elkayam 2008). Other causes were thrombus (in 8 % of cases), coronary artery dissection (27 %) and vascular spasm (2 %); normal coronary arteries were found in 13 % of the patients (Roth and Elkayam 2008). Pregnancy has shown to increase the risk of ACS three- to fourfold (James et al. 2006). Between 1991 and 2000 the overall incidence of pregnancy related ACS was reported to be 2.7 per 100,000 deliveries (Ladner et al. 2005). A decade later James et al. published on risk factors for ACS during pregnancy and reported an incidence of 6.2 per 100,000 deliveries between 2000 and 2002 (James et al. 2006). The rising incidence can be explained in three ways: firstly improved diagnostic tests, especially troponin assessment, have resulted in more women with acute chest pain being diagnosed with ACS; secondly, an increase in known cardiovascular risk factors is seen in the pregnant population and finally, maternal age has increased in the Western World (Ventura et al. 2004). The most important risk factors for ACS during pregnancy are hypertension and maternal age (Cecchini et al. 2010). In addition to cardiovascular risk factors, a few obstetric risk factors for ACS during pregnancy have been discovered. The most important is multiparity; others include: a history of preeclampsia, post-partum haemorrhage, transfusions and post-partum infections (Ladner et al. 2005).

Adequate management of patients with coronary artery disease in pregnancy is of the utmost importance if survival rates are to improve.

A detailed knowledge of the normal physiological changes during pregnancy, labour and the postpartum period is essential for doctors looking after pregnant women with heart disease. The normal physiological changes of pregnancy alter the absorption, distribution and clearance of medications. There is a well-known increase in cardiac output and glomerular filtration rate during pregnancy, as well as a significantly increased volume of distribution for most drugs (Dawes and Chowienczyk 2001). The vast majority of oral medications also pass fairly freely through the placenta, thereby posing a potential risk to the developing fetus. Drugs used to treat coronary artery disease and arrhythmias fall into a few general categories including anticoagulants, cardiac glycosides, anti-anginals, angiotensin-converting enzyme inhibitors & angiotensin receptor-blockers. Some of these medications have more than one indication.

Preconception Counselling

Ideally all women of reproductive age with cardiac disease should undergo thorough evaluation before becoming pregnant. This evaluation should focus on identifying and quantifying the risk to the mother and her unborn child. During pre-pregnancy counselling life expectancy and ethical aspects of parenthood should also be discussed. Risk stratification is made to inform the patient of possible complications during pregnancy. Not only should the influence of pregnancy on the cardiac condition be considered, but the influence of the cardiac condition on the pregnancy outcome must also be discussed. These include the higher incidence of hypertension, preeclampsia, arrhythmias and thrombotic complications. Medication used for treatment during pregnancy is also of concern to the cardiologist, obstetrical care providers and patients. Many patients are under the mistaken belief that if they become pregnant they should stop their medications (Koren et al. 1998). Women and their care providers must weigh the risks and benefits of using each individual medication during pregnancy. In some instances, withholding the medication may be the best option, in others a ‘safer’ alternative medication(s) may be substituted, while in some cases continuation of the medication is advised, if necessary with dose adjustment. Preconception counselling for all women with coronary artery disease is therefore mandatory.

Medication for Coronary Artery Disease in Pregnancy

Beta-Blocking Agents

Beta-adrenergic receptor antagonists remain a cornerstone in the therapy of all stages of ischemic heart disease. Beta-blockade is standard therapy for effort angina, mixed effort and rest angina, and unstable angina. Beta blockers also decrease mortality in acute phase myocardial infarction and in the post infarct period. Today, a multitude of beta-blockers are available and can differ in their beta-1 and beta-2 receptor affinity, lipid solubility and intrinsic sympathomimetic activity. Beta-1 blockade reduces the oxygen demand of the heart by reducing the cardiac output by decreasing heart rate, while Beta-2 blockade causes constriction of airway smooth muscle and increases systemic vascular resistance (Magee 2001). Based on available human data, beta-blockers do not appear to be teratogenic. Beta-blockers cross the placenta and there has been some concern that they may cause neonatal bradycardia as well as transient hypoglycaemia and lower birth weight (Magee et al. 2001). In particular, Atenolol has been associated with intrauterine growth restriction (IUGR) (Butters et al. 1990). Reduced fetal growth is related to increased vascular resistance in the mother and fetus, and is a function of the length of drug exposure (von Dadelszen et al. 2000). The other beta-blockers are weakly associated with IUGR and have been used widely during pregnancy for various cardiac conditions.

Nitrate

In 1933 Sir Thomas Lewis held that the effect of amyl nitrite was probably due mainly to its powerful dilatation of the coronary vessels, rather than to its effect in lowering the blood pressure. As time went on, the important role of nitrate-induced venodilatation was recognized. This venous dilation causes a reduction in cardiac preload and (to a lesser degree) cardiac afterload. Nitroglycerin has been used for obstetrical reasons during pregnancy, such as preterm labour, with no adverse effects (Schleussner et al. 2003). Therefore, nitrates can safely be used during pregnancy, but hypotension may occur. The pre-eminent role for nitrates in pregnancy, however, is probably found in the pharmacologic management of congestive heart failure due to myocardial dysfunction (in conjunction with hydralazine), given the contraindication to the use of ACE inhibitors and ARBs prior to delivery. Nitroprusside is another nitrate option for acute afterload reduction (Shoemaker and Meyers 1984). This parenteral antihypertensive is very potent but poses the potential risk of cyanide accumulation and toxicity in the mother and the fetus following prolonged use.

Calcium Channel Blockers

Calcium channel blockers act chiefly by vasodilatation and reduction of the peripheral vascular resistance and against coronary spasm. They remain among the most commonly used agents in the treatment of hypertension and angina. Calcium channel blockers are a heterogeneous group of drugs that can chemically be classified into dihydropyridines and nondihydropyridines. Dihydropyridines, such as nifedipine and amlodipine, act predominately on the vasculature leading to smooth muscle relaxation and vasodilation. Nondihyropyridine calcium channel blockers (verapamil and diltiazem) act primarily on the heart and are often used to treat arrhythmias in pregnancy. Both classes of calcium channel blockers produce direct arterial vasodilation by inhibiting the influx of calcium through channels in smooth muscle. Nifedipine is used frequently to treat hypertension in pregnancy, as well as preterm labor. There have been no teratogenic risks associated with the use of nifedipine in pregnancy (Magee et al. 1996; Brown et al. 2002; Papatsonis et al. 2001). Amlodipine has been used less frequently during pregnancy, with very limited published data. A recent small case series was reassuring and there have been no animal studies showing that it is teratogenic or harmful to the fetus; however, amlodipine is not the first choice in the treatment of coronary artery disease, until there are more published human data available (Wagner et al. 1990; Briggs and Yaffe 2007).

Statins

Blood lipids are no longer a cardiologic curiosity; they form an essential step in the assessment of coronary artery disease for both primary and secondary prevention. Statins are the most commonly used drugs and shown to be very effective in reducing LDL cholesterol while increasing HDL cholesterol. They are competitive inhibitors of HMG CoA reductase, which is the rate-limiting step in cholesterol biosynthesis. Although statins have been identified as potential teratogens on the basis of theoretical considerations and small animal series, the available evidence is far from conclusive. Epidemiological data collected to date suggest that statins are not major teratogens (Kazmin et al. 2007). Based on the limited available human data regarding the use of statins, however, these agents are not recommended for use in pregnancy (Taguchi et al. 2008). In particularly high-risk women (i.e. recent MI or uncontrolled hyperlipidemia), the use of statins during pregnancy might be considered on an individual basis.

Acetylsalicylic Acid

Acetylsalicylic acid (ASA) is an antiplatelet agent, which irreversibly acetylates cyclooxygenase and activity is not restored until new platelets are formed. It has been shown that ASA (<100 mg/day) can be used safely during pregnancy (Czeizel and Rockenbauer 2000). A recent meta-analysis found no overall increase in the risk of congenital anomalies if aspirin was used in the first trimester, but there was a small increase in the risk of fetal gastroschisis (Kozer et al. 2002). Other studies showed no increase in the risk of maternal or fetal bleeding, nor placental abruption, with the use of low-dose ASA during pregnancy (Coomarasamy et al. 2003; Rotchell et al. 1998).

Thienopyridine

Ticlopidine and clopidogrel are thienopyridine derivates that irreversibly inhibit the binding of ADP to its receptor on the platelets, thereby preventing the transformation of the glycoprotein IIb/IIIa receptor into its active form. Thienopyridine derivates are used in patients with acute coronary syndromes and in patients with stents from percutaneous coronary interventions. There is very limited data on the use of these agents in pregnancy, but published cases are generally reassuring and the drugs do not appear to be teratogenic in animal studies (Briggs and Yaffe 2007; Al-Aqeedi and Al-Nabti 2008). The benefits of using thienopyridine derivates in a given high-risk pregnant woman (i.e., recent myocardial infarction with coronary stent) are likely to outweigh the potential fetal risks. Therefore, thienopyridine in pregnancy might be considered in high-risk cases.

Glycoprotein IIb/IIIa Receptor Antagonists

Glycoprotein IIb/IIIa inhibitors are frequently used during percutaneous coronary intervention (angioplasty with or without intracoronary stent placement). They work by preventing platelet aggregation and thrombus formation. There is very limited experience with the use of Glycoprotein IIb/IIIa receptor antagonists in pregnancy. Only a few case reports are documented in which patients received IIb/IIIa receptor antagonists after coronary stenting for an acute coronary syndrome during pregnancy. In these cases, no complications or adverse fetal outcomes were noted (Chow et al. 1998). These agents might be considered for use in pregnancy in high-risk clinical circumstances, but, in general, should be avoided, especially shortly before delivery.

The use of angiotensin-converting enzyme inhibitors & angiotensin receptor-blockers and antigoagulants in pregnancy will be discussed in another chapter of this book.

Table 1 gives an overview of the most common used medication for coronary heart disease and recommendations in pregnancy. In summary, low dose aspirin, beta blockade and nitrates can be continued during pregnancy. The safety of clopidogrel is unknown. In individual cases with recent (drug eluting) stent placement, continuation should be considered. ACE inhibitors and ARBs are advised to stopped in all patients or in the pre-conception clinic or immediately when pregnancy is diagnosed. Generally, statins should be stopped, however, in an individual patient with very high cholesterol, continuation may be considered.

Table 1

Drugs for coronary heart disease in pregnancy

Drugs

FDA

Listed complications

Transfer to breast milk

Atenolol

D

Intrauterine growth restriction and premature birth

Yes

Other beta-blockers

C

Low birth weight, hypoglycemia, and bradycardia in the fetus

Yes

Acetylsalicylic acid (ASA)

B

Low-dose aspirin is safe (large database)

Yes, but well-tolerated

Calcium channel antagonists

C

Diltiazem: an increase in major birth defects has been reported

Yes

Clopidogrel

C

The benefits of using clopidogrel in some high-risk pregnancies may outweigh the potential fetal risk

Unknown

Nitrates

B

Careful titration is advised to avoid maternal hypotension

Unknown

Statins

X

Animal studies demonstrated increased skeletal abnormalities, fetal and neonatal mortality.

Unknown

Percutaneous Intervention (PCI) or Coronary Artery Bypass Surgery

There is only limited information available on PCI during pregnancy. However, pregnancy is not a contraindication for PCI and since PCI is the primary treatment for non-pregnant STEMI (ST Elevation Myocardial Infarction) patients, more and more cases of stenting during pregnancy are published. With PCI as a treatment modality during pregnancy, mortality from ACS has dropped. In the first review of Roth and Elkayam in 1996 only 2 % had PCI, whereas in their second review 40 % had a PCI, all with bare metal stenting (Roth and Elkayam 19962008). The preference for bare metal stenting is based on the requirement of dual anti-platelet treatment around the delivery and the lack of experience with this regime in pregnancy.

Since pregnant women are excluded from most clinical trials, no randomised controlled trials have been performed on thrombolytic therapy, PCI or CABG in the pregnancy. However, thrombotic therapy is considered to be relatively contraindicated in patient with ACS because of the risk of bleeding complications. In stroke, pulmonary embolism and mechanical heart valve thrombosis there is some clinical experience with several strategies such as tPA, urokinase and streptokinase. This medication does not cross the utero-placental barrier (Leonhardt et al. 2006). Maternal and fetal outcomes were favourable, but complications, such as maternal haemorrhage, fetal loss, abruptio placentae, preterm delivery and post partum haemorrhage have been reported in up to 10 % of cases with a maternal mortality rate of 1.2 % (Turrentine et al. 1995; Garvey et al. 1998).

Very limited data is available on coronary artery bypass grafting (CABG) during pregnancy and no conclusion concerning the safety of the mother and the unborn child can be made. In normal non-pregnant patients with ischemic heart disease CABG is used when multiple vessels or the left main coronary artery are involved (Nallamothu et al. 2005). In the case study of Roth and Elkayam ten patients were described who underwent CABG, of which seven were due to coronary artery dissection, in these cases one fetal death and one late maternal death were reported (Garvey et al. 1998; Roth and Elkayam 2008). If CABG is necessary for the management of the mother, it is advised to perform the CABG in the second trimester of pregnancy.

Delivery

Planning delivery should be the task of a multidisciplinary team consisting of at least an obstetrician, anaesthesiologist and cardiologist. The delivery should be postponed if possible for at least 2 or 3 weeks after ACS to allow adequate healing (Presbitero et al. 2009). The mode of delivery depends on the maternal hemodynamic situation and obstetric factors. Women with adequate cardiac output may tolerate induction of labour and vaginal delivery. Vaginal delivery can lead to fluctuations in blood pressure, especially if labour is prolonged. Assisted vaginal delivery (by vacuum or forceps extraction) is recommended in high-risk women to avoid excessive maternal efforts and prolonged labour (Roth and Elkayam 2008). Adequate pain relief is very important, but epidural anaesthesia is contraindicated when the patient is on antithrombotic or anticoagulant treatment. As an alternative, narcotic analgesia can be used to reduce anxiety and pain. Vaginal delivery with a shortened second stage of labour and adequate pain relief can be safe and is preferred to caesarean section, especially as blood loss is lower. However, caesarean section is the preferred mode of delivery in patients with cardiac instability. During caesarean delivery, the blood pressure can be controlled, stress and pain relieved and a stable environment created. However, caesarean section has been associated with a higher risk of venous thrombo-embolism, infection and peripartum haemorrhage. In some cases general anaesthesia will be necessary with some risk of complications (Deneux-Tharaux et al. 2006). In addition, blood loss during caesarean section has been shown to be about twice as high as during vaginal delivery.

Breastfeeding

The effects of breast-feeding on maternal cardiovascular function are caused by circulating hormones. High levels of oxytocin circulate through the body. In the study of Mezzacappa cardiac output during breastfeeding was found to be higher than in bottle-feeding mothers. They describe a decrease in heart rate and a slight increase in systolic blood pressure during the first minutes of breast-feeding (Mezzacappa et al. 2001). The fluctuations in blood pressure may be dangerous in severely symptomatic patients and bottle-feeding should be considered (Light et al. 2000).

Arrhythmias

Arrhythmias in pregnancy are common and may cause concern for the wellbeing of both the mother and child. The arrhythmias may be a recurrence of a previously diagnosed arrhythmia or the first presentation in a woman with known structural heart disease. In most cases, however, no previous history of heart disease is known, and the new occurrence of a cardiac problem can give rise to considerable anxiety. The majority of arrhythmias occurring during pregnancy are benign, and simply troublesome. Reassurance and advice about appropriate actions during symptomatic episodes are usually all that is required. In the remaining minority of cases, judicious use of antiarrhythmic drugs will lead to a safe and successful outcome for both mother and baby (Newstead-Angel and Gibson 2009). The major concern regarding the use of antiarrhythmic drugs is their potential adverse effects on the fetus. All antiarrhythmic drugs should be regarded as potentially toxic to the fetus.

Mechanism of Arrhythmia

The cardiovascular system undergoes significant changes in adaptation to pregnancy, including an increase in heart rate and cardiac output, reduced systemic resistance increased plasma catecholamine concentrations and adrenergic receptor sensitivity, atrial stretch and increased end-diastolic volumes due to intravascular volume expansion, as well as hormonal and emotional changes. A combination of these and the heightened visceral awareness experienced in pregnancy may lead a woman to seek advice on symptoms that are within the normal range and may otherwise have been ignored. Being pregnant is unlikely to generate a new arrhythmia, however, premature extra systolic beats are often seen during pregnancy.

Management of Specific Arrhythmias

Table 2 summaries the drug of choice for specific arrhythmias.

Table 2

Drugs for management of specific arrhythmias: to use or to avoid

Arrhythmia

Preferred medication

Avoid

Comments

Supraventricular tachycardia

Adenosine

Dispyramide

β-blockade is often effective at suppressing ventricular ectopy and arrhythmias. Lidocaine followed by proacainamide is suggested for sustained ventricular arrhythmias. In refractory cases, amiodarone or placement of an ICD may be considered

Metoprolol

Propafenone

Digoxine

 

Verapamil

 

Sotalol

 

Procainamide

 

Atrial fibrillation

Digoxine

Amiodarone

β-blockers, digoxin or verapamil may be used to slow the ventricular rate. Restoration of sinus rhythm is desirable (to avoid need for anticoagulation) and may be attempted with sotalol, procainamide, flecainide or electrical cardioversion.

Metoprolol

 

Verapamil

 

Sotalol

 

Fleicainide

 

Ventricular tachycardia

Metoprolol

Amiodarone

β-blockade is often effective at suppressing ventricular ectopy and arrhythmias. Lidocaine followed by proacainamide is suggested for sustained ventricular arrhythmias.

Procainamide

 

Lidocaine

 

Supraventricular Tachycardia (SVT)

The drug of choice is partly dependent upon the SVT being treated. Atrioventricular nodal re-entry tachycardia (AVNRT) and atrioventricular re-entry tachycardia (AVRT) involving an accessory pathway can be terminated by vagal manoeuvres or if that fails, an intravenous bolus of adenosine can be administered until the desired response is achieved (Elkayam and Goodwin 1995). Intra-venous metoprolol is recommended if adenosine fails to terminate a tachycardia. Prophylactic antiarrhythmic medication should be used only if symptoms are intolerable or the arrhythmia causes haemodynamic instability. Digoxin or a selective beta-blocker (metoprolol) are the first-line drugs, followed by sotalol, or propafenone (Blomstrom-Lundqvist et al. 2003). AV nodal blocking agents should not be used in patients with manifest pre-excitation on resting ECG. Catheter ablation should be considered only in special cases if necessary during pregnancy.

Atrial Fibrillation and Flutter

Atrial fibrillation and flutter are uncommon in pregnancy and are most commonly associated with congenital or valvular heart disease as well as metabolic disturbances such as thyrotoxicosis or electrolyte imbalance. A rapid ventricular response to these arrhythmias can lead to serious haemodynamic consequences for both mother and fetus. Diagnosis and treatment of the underlying condition is therefore the first priority. Electrical cardioversion should be performed in the case of haemodynamic instability. In haemodynamically stable patients, pharmacological termination of the atrial or AF can be considered. Intravenous ibutilide or flecainide are usually effective, but experience during pregnancy is very limited (Kockova et al. 2007).

When rate control is recommended, the ventricular rate can be controlled with AV nodal blocking drugs including digoxin, beta-blockers and non-dihydropyridine calcium channel antagonist (verapamil, diltiazem) (Fuster et al. 2006). Prophylactic antiarrhythmic drugs (sotalol, flecainide or propafenone) may be considered in the cases of severe symptoms despite rate-controlling drugs. Flecainide and propafenone should be combined with AV nodal blocking agents. Mexiletine and amiodarone are contra-indicated in pregnancy with the exception of an acute setting or as last resort (European Society of Gynecology et al. 2011).

The recommendation in respect of anticoagulation in atrial fibrillation and flutter will be discussed in another chapter.

Ventricular Tachycardia (VT)

Life-threatening ventricular arrhythmias are uncommon during pregnancy. Rapid VT causes hypotension, reduced myocardial coronary perfusion and subendocardial ischaemia, an unstable situation that may degenerate into ventricular fibrillation. In healthy patients, idiopathic right ventricular tachycardia (VT) originating from the right ventricular outflow tract is the most frequent type in pregnancy and should be treated using either verapamil or beta-blocking agents. The drugs should be used as prophylaxis only if the VT is associated with severe symptoms or haemodynamic compromise (Nakagawa et al. 2004).

Ventricular tachycardia in the presence of structural heart disease is associated with a significant risk of sudden death and requires emergency treatment. For acute treatment of VT with haemodynamic instability, immediate cardioversion, which seems safe in all phases of pregnancy, is recommended. Prophylactic therapy with a cardioselective beta-blocker, such as metoprolol, may be effective (European Society of Gynecology et al. 2011). Sotalol or Class Ic antiarrhythmic drugs may be considered in the absence of structural heart disease.

Antiarrhythmic Drugs in Pregnancy

The decision to treat a woman depends upon the type of arrhythmia, frequency, duration and tolerability of the arrhythmia. It is a balance between the benefit of arrhythmia reduction or termination and the maternal and fetal side effects of any drug treatment. The greatest risk to the fetus is during organogenesis and this is complete by the end of the first trimester. The smallest recommended dose should be used initially and be accompanied by regular monitoring of the maternal and fetal condition. An overview of medications used in the treatment of arrhythmia, including their pharmacokinetics, mechanism of action, indications, safety and effectiveness in pregnancy is set out in Table 3.

Table 3

Drugs for arrhythmias in pregnancy

Drugs

FDA

Listed complications

Transfer to breast milk

Adenosine

C

Pregnant women may respond to lower doses due to a reduction in adenosine deaminase

No

Atropine

C

Insufficient data

Yes, small amount

Amiodarone (Class III)

D

If prolonged use; fetal hypo‐ and hyperthyroidism, goitre, IUGR, prematurity

Yes, avoid during breast feeding

Beta‐blockers

C

IUGR, bradycardia, apnoea, hypoglycaemia, hyperbilirubinaemia

Yes

Digoxin

C

Miscarriage and fetal death in toxicity

Yes, small amount

Calcium channel antagonists

C

Skeletal abnormalities, IUGR, fetal death

Unknown

Verapamil: rapid injection may cause maternal ↓ BP and fetal distress.

Disopyramide (Class IA)

C

Premature uterine contractions

Yes

Flecainide (Class IC)

C

Insufficient data but no reported significant complications. Concerns over its pro‐arrhythmic potential in fetus have limited its use in past

Yes

Lidocaine (Class IB)

C

Fetal distress may occur in fetal toxicity

Yes

Quinidine (Class IA)

C

Rarely, mild uterine contractions, premature labour, neonatal thrombocytopenia,fetal VIIIn damage

Yes

Procainamide (Class IA)

C

Chronic use may be associated with lupus‐like syndrome, gastrointestinal disturbance, hypotension, agranulocytosis

Yes

Propafenone (Class IC)

C

Insufficient data

Unknown

Mexiletine (Class IB)

C

Fetal bradycardia

Yes

Sotalol (Class III)

B

Transient fetal bradycardia an hypoglycemia

Yes

BP blood pressure, IUGR intrauterine growth restriction, SVT supraventricular tachyarrhythmia

Beta-Blockers

Metoprolol is a common choice for treating tachyarrhythmias and available pregnancy data are reassuring. Propranolol also has good safety data regarding its use in pregnancy, but is a non-selective beta-blocking agent and offers no clear advantage over metoprolol for most cardiac indications.

Calcium Channel Blockers

The nondihydropyridine calcium channel blockers (verapamil and diltiazem) slow conduction through the AV node and increase the refractory period of nodal tissue. Verapamil and diltiazem are similar in their electrophysiological properties and are used to treat arrhythmias in pregnancy. There is very limited published data regarding their safety and effectiveness. Verapamil in pregnancy has more published experience and does not appear to pose a significant teratogenic risk (Magee et al. 1996).

Sotalol

Sotalol is a class III anti-arrhythmic and combines beta-blockade with potassium channel blockade, causing prolongation of the refractory period of atrial, AV nodal, bypass tract and ventricular tissue. It is known that sotalol crosses the placenta. Limited published data do not show a teratogenic risk. As with other beta-blockers, some data have shown a risk of reduced placental weight and/or IUGR (O’Hare et al. 1980; Wagner et al. 1990). As Sotalol can also prolong the QT interval of the mother, posing a risk of proarrhythmia (mainly torsades de pointes), this medication should be restricted to use in cases where there is clearly a need for an antiarrhythmic agent (i.e., significant ventricular arrhythmias or recurrent atrial fibrillation) and where the maternal benefits are likely to outweigh these risks.

Amiodarone

Amiodarone is a unique “wide-spectrum” antiarrhythmic agent, chiefly class III, but also with powerful class I activity and ancillary class II an IV activity. It is a very potent antiarrhythmic drug in the general cardiac population, but its use in pregnancy is problematic. Amiodarone is associated with an increased risk of prematurity, fetal bradycardia and fetal/neonatal hypothyroidism (given its high iodine content). There have been congenital abnormalities reported in neonates exposed in the first trimester (Joglar and Page 1999; James 2001). It also poses a small risk of maternal proarrhythmia due to prolonged QT syndrome. Amiodarone is, therefore, only recommended for use in pregnancy in the setting of life-threatening conditions where other agents have failed.

Procainamide

Procainamide is a class Ia antiarrhythmic drug. It prolongs the action potential and the effective refractory period. It may be effective for both atrial and ventricular arrhythmias. Procainamide is often well tolerated and useful in the management of maternal and fetal arrhythmias. It may be administered orally, or intravenously in the management of an acute arrhythmia (James 2001; Joglar and Page 1999). Long-term use of procainamide can result in a lupus-like syndrome but it is well-tolerated for short-term use with a favourable adverse effect profile. Dose adjustments may be needed over the course of pregnancy.

Adenosine

Adenosine is very effective in the treatment of acute supraventricular tachycardia as it causes a transient conduction block in the atrioventricular node. It has been used safely and effectively in the acute treatment of supraventricular tachyarrhythmias during pregnancy with no significant adverse effects on the fetus (Kanai et al. 1996; Elkayam and Goodwin 1995). Minor maternal adverse effects include transient bradycardia and dyspnoea. It can also induce bronchospasm and is, therefore, not recommended in patients with asthma.

Digoxin

Digoxin has a long and safe history for use during pregnancy. Its main actions are through vagal-mediated slowing and blockade of atrioventricular conduction, as well as a mild prokinetic effect on the heart. Digoxin freely crosses the placenta and has been used for the treatment of fetal arrhythmias. The main issue with the use of digoxin in pregnancy is its effectiveness. The digoxin levels may decrease by 50 % during pregnancy due to increased renal clearance and an increase in dose is often required. In addition, levels must be monitored and dose adjustments made, particularly in patients with renal insufficiency. Digoxin will continue to have a role in the treatment of maternal and fetal arrhythmias as well as an adjunctive role in heart failure in pregnancy.

Table 2 gives an overview of the most commonly used medication for coronary heart disease and recommendations for use during pregnancy.

DC Cardioversion

DC cardioversion is safe in all stages of pregnancy; because the amount of current reaching the fetus is small. There is a small risk of inducing a fetal arrhythmia. The fetus needs to be carefully monitored during the cardioversion procedure.

Implantable Cardioverter-Defibrillators

The presence of an implantable cardioverter-defibrillators (ICD) is not itself a contraindication to future pregnancy and women with ICDs have had successful pregnancies with good fetal outcomes. Treatment with an ICD should also be considered during pregnancy to protect the mother’s life in those at high risk of sudden cardiac death (European Society of Gynecology et al. 2011). One study reported a series of 44 pregnant women with an ICD implant in situ and found no increase in either device or treatment complications during pregnancy, nor any increase in the number of shocks the women received compared to preconception (Natale et al. 1997). In addition to standard ICD management, after each therapy, fetal monitoring is advised.

Conclusion

Pregnancy may unmask latent cardiac disease or may lead to a new onset of maternal cardiovascular disease or arrhythmias. Morbidity and mortality due to coronary artery disease in pregnancy appears to have increased during the last 30 years. Women with known ischemic heart disease or a history of arrhythmias with or without underlying heart disease need careful preconception counselling, as well as multidisciplinary management during pregnancy. Medication for coronary artery disease or arrhythmias in pregnancy is of concern to both care providers and patients. The ever-expanding pool of cardiac medication and devices needs careful monitoring during pregnancy and regular updating. Caution is required in respect of utility and risks when interventions are used during pregnancy.

US FDA Risk Classification in Pregnancy

The US Department of Health and Human Service have published this classification. (Source: Drug information for the Heath Care Professional; USDPI Vol 1, Micromedex 23rd edn. 01.01.2003). The classification consists of category A (safest) to X (known danger – do not use). The following categories are used for drugs during pregnancy and breastfeeding.

Category A: controlled studies show no risk

Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester, there is no evidence of a risk in later trimester and, therefore, the possibility of fetal harm appears remote

Category B: no evidence of risk in humans

Either animal reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimester)

Category C: risk cannot be ruled out

Either studies in animals have revealed adverse effects on the fetus (teratogenic) or appropriate animal data are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus

Category D: positive evidence of risk

There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective). There will be an appropriate statement in the ‘warnings’ section of the labeling

Category X: contraindicated in pregnancy

Studies in animals or human beings have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience, or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may be pregnant

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