Use and Impact of Cardiac Medication During Pregnancy

Annemien E van den Bosch; Titia PE Ruys; Jolien W Roos-Hesselink

Future Cardiol. 2015;11(1):89-100.

Medications for Cardiovascular Diseases in Pregnancy

Medication use for cardiovascular diseases during pregnancy is a concern to obstetricians, cardiologists, anesthetists, general practitioners and patients. Patients with or without cardiac disease think they can stop their medication when they become pregnant.^[20] Women and their doctors must discuss the risks and benefits of using medication during pregnancy. In some circumstances, the medication can be stopped or a 'safer' alternative medication(s) be substituted. Preconception counseling for women with cardiac diseases is therefore indicated.^[1]

Medications used for the treatment of cardiac diseases fall into a few general categories, including antihypertensives, antiarrhythmics, antianginal medications, antiplatelets therapies and anticoagulants. Some of these drugs have more indications. The different categories, including the pharmacokinetics, mechanisms of action, indications, safety and effectiveness of the medications in pregnancy, will be reviewed in the following sections.

Antihypertensive Medications

High blood pressure affects approximately 10% of all pregnancies and is the second most frequent cause of maternal death in low- and middle-income countries.^[23] The most serious form of pregnancy hypertension is pre-eclampsia, a progressive multisystem disorder only curable by delivery of the conceptus (fetus and placenta). To plan clinical management, knowledge of the spectrum of pregnancy hypertensions and their classifications is necessary. The 2013 European Society of Cardiology (ESC) Task Force on Hypertension advise that, despite a lack of evidence, early initiation of antihypertension treatment is recommended at a blood pressure ≥140/90 mmHg in pregnant women with gestational hypertension (with or without proteinuria), pre-existing hypertension with the superimposition of gestational hypertension or hypertension with asymptomatic organ damage or symptoms at any time during pregnancy.^[1,24]

In the initial assessment of patients with hypertension in pregnancy, two essential elements of management are: to treat any presenting emergency, including severe hypertension, stroke, hypovolemia from placental abruption and acute pulmonary edema; and to classify the hypertensive disorder in order to plan ongoing management. However, in most cases, women presenting with hypertension in pregnancy have no or minimal symptoms.^[17] The choices for the pharmacological treatment of hypertension in pregnancy are restricted to older and tested drugs and are based on the severity of blood pressure elevations. In the recent guidelines on hypertension, the recommendations to use methyldopa, labetalol and nifedipine (as the only calcium antagonists that have been sufficiently tested in pregnancy) is confirmed. β-blockers can cause fetal growth retardation (especially in early pregnancy) and diuretics should be used with caution. Methyldopa is the preferred first-line agent to lower maternal blood pressure.^[25] Labetalol is considered equally appropriate as a first-line agent and may be better tolerated than methyldopa. Several studies compared methyldopa and labetalol; in all but one, maternal tolerance was reported with either agent, but labetalol showed less tiredness, headache and hypotension. Table 1 shows the preferred drugs for the treatment of mild hypertension or the maintenance of antihypertensive effects after acute blood pressure lowering for severe hypertension. For acute blood pressure lowering in severe hypertension in pregnancy, the preferred medication is intravenous labetalol.^[26,27] The field of hypertension in pregnancy is rapidly expanding and new developments are expected.

Methyldopa is a centrally acting α-2 adrenergic agent prodrug that is converted to α-methylepinephrine, which replaces norepinephrine in adrenergic nerve terminals. There is extensive experience and data of methyldopa being used in pregnancy, including long-term follow-up of the children exposed during fetal life. Methyldopa is the first choice in the treatment of hypertension during pregnancy.^[28,29]

Labetalol is a nonselective β-blocker with α-1 receptor blocker activity. There have been reports of neonatal bradycardia, but these effects did not have clinical consequences.^[26] Labetalol is contraindicated in women with asthma or congestive cardiac failure.

Nifedipine is the only calcium channel blocker for which there is extensive experience in treating severe hypertension during pregnancy, as well as in preterm labor. No teratogenic risks have been described to be associated with the use of nifedipine in pregnancy.^[30–32] Side effects of oral nifedipine include headache and tachycardia. Theoretical fears of serious interactions with magnesium sulfate have not been realized in practice, and the simultaneous use of the two agents is acceptable, but must be used with caution.

Hydralazine is a direct vasodilator of arteriolar smooth muscle. It is best not to administer hydralazine in the presence of tachycardia (>120 bpm) or fixed cardiac output due to valvular disease. Side effects include tachycardia, headache and nausea.

Antiarrhythmic Medications

The majority of arrhythmias occurring during pregnancy are supraventricular and benign, but can be troublesome. The arrhythmias may have occurred before pregnancy or be the first presentation in a woman with structural heart disease.^[17] In the majority of patients, no previous history of heart disease is known, and experience of a new cardiac problem can give considerable anxiety.^[1] Reassurance and appropriate advice on what to do during symptomatic episodes of palpitations are usually all that are required. In the remaining cases, sensible use of antiarrhythmic drugs will lead to a safe and successful outcome.^[18]

The decision to treat a woman with arrhythmia depends on the frequency, duration and tolerability of the arrhythmia.^[33] It is a balance between the benefit (as the medication will reduce or terminate the arrhythmia) and the maternal and fetal side effects, especially during organogenesis, which is completed by the end of the first trimester for most organs.^[17] It is recommended to start with the smallest dose and regular monitor the clinical condition of the mother and child. In the acute phase, supraventricular arrhythmias can be corrected by vagal stimulation or, when not successful, intravenous adenosine. Electrical cardioversion is safe and can be used for any tachyarrhythmia with hemodynamic instability. However, appropriate data on the adverse effects on the fetus are not available for the majority of drugs for their use in pregnancy.^[1] For prophylaxis, digoxin and a selective β-blocker are the first-line drugs for supraventricular tachycardia.^[33] In the past, there has been concern regarding the effect of β‐blockers on intrauterine growth restriction.^[34] This effect is seen for all β-blockers, especially when the β-blockers are used during the time of conception and/or during the first trimester.^[35] When the benefit exceeds the risk (e.g., in patients with arrhythmias, mitral stenosis or thyrotoxicosis) β‐blockers should not be withheld. Amiodarone class III (a potassium-blocking agent) is known for its risk of fetal hypothyroidism, prematurity and growth retardation.^[36,37] Amiodarone should only be used when other medications or therapies have failed and the tachyarrhythmia causes hemodynamic instability. Calcium channel-blocking agents, such as verapamil and diltiazem, are considered to be relatively safe.^[30] It is important to recognize that therapeutic levels of medications are difficult to maintain during pregnancy because of the decrease of concentration of the drugs due to an increased volume of distribution and drug metabolism. This is especially true with the use of digoxin, where the levels may decrease by 50%. Therapeutic levels of digoxin must be regularly monitored and dose adjustments must be made during the whole pregnancy. This may explain why some women who were previously stable on their therapy develop arrhythmias during pregnancy. Table 2 lists the available antiarrhythmic drugs for specific arrhythmias and their complications during pregnancy.^[1]

Antianginal Medications

In the management of all stages of ischemic heart disease, β-adrenergic receptor antagonists remain the cornerstone of treatment. β-blockade is the standard therapy for effort angina, mixed effort and rest angina and unstable angina and decreases mortality in acute coronary syndrome and in the postinfarct period. Today, a multitude of β-blockers are available and can differ in their β-1 and β-2 receptor affinity, lipid solubility and intrinsic sympathomimetic activity.^[17] Based on available human data, β-blockers appear not to be teratogenic.^[34] However, there has been some concern, since β-blockers can cross the placenta and may cause neonatal bradycardia, as well as hypoglycemia. In the literature, a weak association with intrauterine growth restriction has been found for all β-blockers.^[35,47]

Nitrates have been used for many years in patients with congestive heart failure, coronary artery disease and hypertension. Nitrates are vasodilators causing venous dilation, resulting in a reduced cardiac preload and afterload. There is a lot of experience with nitroglycerin being used for obstetrical conditions, such as preterm labor, and no adverse effects have been documented.^[48] Nitrates have also been prescribed for hypertension during pregnancy, with no documented adverse effects on the mother or fetus. There is an important role for nitrates in pregnancy in the management of ischemic and congestive heart failure due to myocardial dysfunction (in conjunction with hydralazine), given the contraindication to the use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (ARBs) prior to delivery.^[22]

Statins are recommended in patients with coronary artery disease and hypercholesterolemia because of their important reduction of LDL-cholesterol and increase of HDL-cholesterol. Statins inhibit HMG-CoA reductase, thereby suppressing cholesterol biosynthesis. In the literature, for patients without cardiovascular disease but with significant cardiovascular risk factors, statins are associated with significantly improved survival and decreased cardiovascular events.^[49] Although statins are widely used during pregnancy, they are considered to be potential teratogens, but the available evidence is not conclusive. However, the available epidemiological data suggest that statins are not major teratogens and, at present, statin are being investigated in animal and clinical studies for use in the treatment of pre-eclampsia.^[50] A study by Taguchi et al. described 64 pregnant women who have taking statins (vs controls) during pregnancy and found no difference in the occurrence of major congenital malformations.^[51] However, the available human and animal data for the use of statins are still very limited and further investigation is warranted. Statins are recommended for use in pregnancy.^[1] However, in high-risk women (e.g., after recent myocardial infarction), statins can be considered for reduction during pregnancy on an individual basis.

Antiplatelet Therapies

Secondary prevention after a cardiovascular event is the major indication for acetylsalicylic acid (ASA; aspirin) during pregnancy. A low dose of ASA (<100 mg/day) is acceptable during pregnancy.^[52] In recent studies, no overall increase in the risk of congenital malformation was found, even when aspirin was used in the first trimester. There was no increased bleeding risk for the mother and child or placental abortion when ASA was used during pregnancy. However, these studies did find a small increase in the risk of fetal gastroschisis.^[53–55] The use of high-dose aspirin by lactating women should be cautioned, as ASA might lead to an increased risk of Reye's syndrome in children. Although there is no evidence available regarding the dose–response relationship between aspirin and Reye's syndrome, the use of low-dose aspirin (<100 mg/day) can be considered on an individual basis.^[56]

Clopidogrel is an another antiplatelet agent that is often used in patients with acute coronary syndrome, cerebrovascular disease and in patients who have undergone a coronary stent implantation. There are limited data available on the use of clopidogrel during pregnancy. The few cases published in literature are generally reassuring and animal studies showed no teratogenic effects.^[57,58] Clopidogrel can be considered for use during pregnancy if the benefits outweigh the potential teratogenic effects in a given high-risk pregnant woman (i.e., recent myocardial infarction with coronary stenting).

Furthermore, there are very limited data available for the use of glycoprotein IIb/IIIa inhibitors during pregnancy. A few case reports have described patients who have received glycoprotein IIb/IIIa inhibitors after coronary stenting for acute coronary syndrome during pregnancy.^[58] There were no bleeding complications or adverse fetal outcomes found. Glycoprotein IIb/IIIa inhibitors might be considered for the use in pregnancy in appropriate clinical circumstances.^[59] However, the bleeding risks may be higher and may cause problems, especially around delivery.

Anticoagulants

Anticoagulants are frequently used in cardiac disease, including for the prevention of embolism in patients with atrial fibrillation or mechanical heart valves. Prescribing anticoagulants during pregnancy is difficult due to the risk of bleeding complications, as well as concerns regarding potential teratogenic effects on the developing fetus.^[1] In addition, the risks of developing thromboemboli are increased during pregnancy, due to the hypercoagulable state that exists throughout pregnancy.

Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) exert their effects by activating antithrombin. The difference between UFH and LMWH is the relative inhibitory activity against factor Xa and prothrombin. UFH and LMWH are well studied in pregnancy and do not cross the placenta. They both have excellent fetal safety profiles.^[1,60] However, the long-term use of UFH during pregnancy has considerable maternal side effects, including osteoporosis and heparin-induced thrombocytopenia. LMWH appears to have a reduced risk of these side effects.^[61] Pregnant women who use LMWH have a potential risk of paraspinal hematoma when regional anesthesia (epidural or spinal) is required, even in prophylactic doses of UFH or LMWH.^[18] Guidelines published by the American Society of Regional Anesthesia (ASRA) suggest "that patients should not be offered regional anesthesia for at least 10–12 h after the last prophylactic dose of LMWH was administered or for more than 24 h after the last dose of therapeutic-intensity LMWH".^[62] There are different management strategies available, such as: a planned induction of labor (near term) with discontinuation of the anticoagulant medication at least 24 h prior; or a switch of patients on LWMH over to UFH at approximately 36 weeks of gestation.^[63] One can also consider discontinuation of the prophylactic anticoagulation in the last weeks of pregnancy, accepting a small increased risk of thrombosis events.^[18,62]

Warfarin, acenocoumarol and phenprocoumon inhibit the hepatic formation of vitamin K-dependent coagulation proteins (prothombin and factors VII, IX and X). Vitamin K antagonists are known to cross the placenta freely and can induce coumarin embryopathy (nasal bone hypoplasia and chondrodysplasia punctata), probably in a dose-dependent manner. Coumarin embryopathy has been described to occur in 6–8% of fetuses, especially when coumarins are administrated at between 6 and 9 weeks of gestation.^[64,65] Later in pregnancy, vitamin K antagonist are associated with increased fetal bleeding complications leading to CNS abnormalities, risk of fetal death and miscarriage. Vitamin K antagonists are not recommended for use in pregnancy beyond exceptional cases of very high thromboembolic risk. Coumarins are generally restricted to only being used in women with high thrombotic risks that outweigh the risk of maternal and fetal side effects.^[18]

Danaparoid is a drug with a heparin-like action. No teratogenic effects were found in animal studies or in approximately 80 reported human cases.^[67] It can be used as an alternative to heparin.

Fondaparinux is a direct inhibitor of factor Xa. The Pregnancy and Thrombosis Working Group for the Treatment and Prevention of Venous Thromboembolism During Pregnancy recommends fondaparinux for the treatment of patients with heparin-induced thrombocytopenia during pregnancy.^[68] Fondaparinux does not appear to cross the placenta. Some case reports demonstrate that fondaparinuxs use during pregnancy is effective without adverse fetal effects.^[66]

Table 3 summarizes the different anticoagulation treatments for women with increased risk of thromboembolic events during pregnancy, based on de ESC guidelines of 2011.^[1]

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Next Section

Abstract and Introduction
Physiological Changes & Pharmadynamics in Pregnancy
Pharmacokinetics
Classification of Cardiovascular Drugs in Pregnancy
Medications for Cardiovascular Diseases in Pregnancy
Conclusion & Future Perspective
References
Sidebar

Table 1. Drugs for the treatment of mild hypertension or the maintenance of antihypertensive effects after acute blood pressure lowering for severe hypertension in pregnancy.
Preference	Preferred medication	Dosage	Contraindications^†
First choice	Methyldopa	0.750–4.0 g/day in three to four doses.	Severe liver disease, depression
		No evidence supports a loading dose.
Second choice	Labetalol	200–1200 mg/day in two to three doses	Any degree of heart block, asthma, congestive heart failure, bradycardia
	Nifedipine	30–120 mg/day	Hypotension, known hypersensitivity
	Hydralazine	50–300 mg/day in two to four doses	Known hypersensitivity, idiopathic systemic lupus erythematosus and related diseases

^†Only the most common contraindications are listed. For a complete overview, refer to the drug information of the pharmaceutical companies.

Table 2. Drugs for the treatment of arrhythmias during pregnancy.
Condition	Approach	Drug	Safety classification^†	Listed complications	Breast feeding
AVNRT or AVRT	To restore sinus rhythm	Adenosine [38]	C	Pregnant women may respond to lower doses due to a reduction in adenosine deaminase	Safe due to short half-life
		β-blockers [39], metoprolol	C	IUGR, bradycardia, apnea, hypoglycemia, hyperbilirubinemia	Safe
	Prophylactic drugs	Digoxin [33]	C	Miscarriage and fetal death in toxicity	Safe
	First choice	β‐blockers [33], metoprolol	C	IUGR, bradycardia, apnea, hypoglycemia, hyperbilirubinemia	Safe
		Verapamil [40]	C	Rapid injection may cause maternal ↓ BP and fetal distress	Safe
	Second choice	Sotalol [37]	B	Transient fetal bradycardia	Avoid
		Flecainide [33]	C	Insufficient data, but no reported significant complications. Concerns over its proarrhythmic potential in the fetus have limited its use in the past	Unknown
		Propafenone (class IC) [41]	C	Insufficient data	Unknown
Atrial flutter and fibrillation	Rate controle	β-blockers [1,42]	C	IUGR, bradycardia, apnea, hypoglycemia, hyperbilirubinemia	Safe
		Digoxin [1]	C	Miscarriage and fetal death in toxicity	Safe
		Verapamil [30,43]	C	Rapid injection may cause maternal ↓ BP and fetal distress	Safe
	Prophylactic drugs	Sotalol [33]	B	Transient fetal bradycardia	Avoid
		Flecainide [42]	C	Insufficient data, but no reported significant complications. Concerns over its proarrhythmic potential in the fetus have limited its use in the past	Unknown
		Propafenone (class IC) [44]	C	Insufficient data	Unknown
	Avoid	Amiodarone [1]	D	Amiodarone should only be used when other therapies have failed and the tachyarrhythmia causes hemodynamic instability, and then at the lowest effective dose	Avoid
Ventricular tachycardia	Idiopathic RVOT tachycardia	β-blockers [1]	C	IUGR, bradycardia, apnea, hypoglycemia, hyperbilirubinemia	Safe
		Verapamil [45]	C	Rapid injection may cause maternal ↓ BP and fetal distress	Safe
	Acute treatment	Sotalol (iv.) [1]	B	Transient fetal bradycardia	Safe
		Procainamide [46]	C	Chronic use may be associated with lupus-like syndrome, gastrointestinal disturbance, hypotension and agranulocytosis. Fetal distress may occur in fetal toxicity	Avoid
		Amiodarone [1]	D	Amiodarone should only be used when other therapies have failed and the tachyarrhythmia causes hemodynamic instability, and then at the lowest effective dose	Avoid
	Prophylactic drugs	β-blockers [1], metoprolol	C	IUGR, bradycardia, apnea, hypoglycemia, hyperbilirubinemia	Safe
		Sotalol [1]	B	Transient fetal bradycardia	Safe

^†Safety classification according to the US FDA pregnancy risk classification.
↓: Decrease; AVNRT: Atrioventricular nodal re-entry tachycardia; AVRT: Atrioventricular re-entry tachycardia; BP: Blood pressure; IUGR: Intrauterine growth restriction; iv.: Intravenous; RVOT: Right ventricular outflow tract.

Table 3. Anticoagulation treatments for women with increased risk of thromboembolic events during pregnancy.
Condition		Medication strategies	Comments
Mechanical valves^†	First choice	OACs throughout the pregnancy under strict INR control	Especially useful for mitral valve mechanic prosthesis or older-generation prosthetic cardiac valves (in all positions). This is the safest regime for the mother.
			Data suggest that the risk of abortion and embryopathy is very low in patients taking ≤5 mg per day
		† Discontinuation of OACs and a switch to UFH or LMWH at between 6 and 12 weeks of gestation	† Aortic valve prosthesis (new-generation valves)
		† For the second and third trimester, convert to OACs	† LMWH and UFH under strict dose control and supervision. LMWH twice daily with dose adjustment to weight and anti-factor Xa levels (levels between 0.8 and 1.2 U/ml)
		† At 36 weeks of gestation, convert to LMWH until delivery
	Second choice	LMWH/UFH throughout pregnancy under strict monitoring
Venous thromboembolism	Pophylactic	LMWH – prophylactic dose	For high-risk patients: the prophylactic dose of LMWH is half of the therapeutic dose, weight adjusted, applied twice a day
	Acute treatment	LMWH – therapeutic dose	LMWH should be adjusted for bodyweight in a twice-daily regime
AF		LMWH – therapeutic dose	For patients with AF duration <48 h and no thromboembolic risk factors, heparin or LMWH (therapeutic dose) may be considered per cardioversion
Cardiomyopathy with low EF and atrial arrhythmias and/or ventricular thrombi		LMWH – therapeutic dose	The first choice is LMWH; OACs can be used according to the stage of pregnancy

^†Note that valve and ventricular dysfunction, but also type and position of valve(s) as well as the history of valve thrombosis should be taken into account.
AF: Atrial fibrillation; EF: Ejection fraction; LMWH: Low-molecular-weight heparin; OAC: Oral anticoagulant; UFH: Unfractional heparin.
Data taken from [1].

Box 1. US FDA pregnancy risk classification.
*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 trimesters 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 trimesters) *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*

Sidebar

Executive Summary

Improvement in the diagnosis and treatment of congenital heart disease has increased the number of women reaching reproductive age. There is also a growing number of women who wants to get pregnant who have acquired heart disease due to the increasing age of first pregnancy and the increasing prevalence of cardiovascular risk factors.
Cardiovascular disease is the most frequently encountered cause of maternal death during pregnancy in the western world and an increase in maternal mortality due to cardiac causes has been observed.
Normal pregnancy induces and requires major cardiac adaptations, which are necessary to adapt to the needs of the growing fetus and placenta. These include an increase in blood volume by 40% and an accompanied increase of cardiac output by 30–50%.
The normal physiological changes of pregnancy alter the absorption, distribution, metabolism and clearance of medications.
Women and their care providers must weigh the risks and benefits of using each individual medication during pregnancy.
High blood pressure affects approximately 10% of all pregnancies and is the second most frequent cause of maternal death in low- and middle-income countries. There is a lack of evidence that early initiation of antihypertension treatments should be recommended at a blood pressure ≥140/90 mmHg in pregnant women with gestational hypertension (with or without proteinuria), pre-existing hypertension with the superimposition of gestational hypertension or hypertension with asymptomatic organ damage or symptoms at any time during pregnancy. The use of methyldopa, labetalol and nifedipine is recommended.
The majority of arrhythmias occurring during pregnancy are supraventricular and benign. The decision to treat a woman depends upon the frequency, duration and tolerability of the arrhythmia. For prophylaxis, digoxin and a selective β-blockers are the first-line drugs for supraventricular tachycardi. Amiodarone should only be used when other medications or therapies have failed and the tachyarrhythmia causes hemodynamic instability.
In the management of all stages of ischemic heart disease, β-adrenergic receptor antagonists remain the cornerstone of treatment. There is an important role for nitrates in pregnancy for the management of ischemic and congestive heart failure due to myocardial dysfunction (in conjunction with hydralazine), given the contraindication to the use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (ARBs).
A low dose of acetylsalicylic acid (<100 mg/day) is acceptable during pregnancy. The benefits of using other antiplatelet agents in a given high-risk pregnant woman (i.e., recent myocardial infarction with coronary stenting) are likely to outweigh the potential fetal risks. Anticoagulants are used for a variety of clinical reasons, including the treatment or prophylaxis of venous thromboembolism, as well as the prevention of systemic embolism in patients with atrial fibrillation or mechanical heart valves. Opting to use anticoagulants in pregnancy is difficult due to the risk of bleeding complications, as well as concerns regarding the potential teratogenic effects of anticoagulants on the developing fetus.