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.

Physiological Changes & Pharmadynamics in Pregnancy

During normal pregnancy, major cardiac adaptation is required.^[9,10] The physiological changes in pregnancy are necessary to adapt to the needs of the growing fetus and placenta. With respect to the cardiovascular system, pregnancy represents an extensive stress test in which the boundaries of maternal cardiac adaptation is tested. There is an increase in plasma volume by up to 45% above nonpregnant values, which begins by the mid-first trimester and peaks at the late-second trimester.^[11,12] As a result, there is a mild increase in maternal left and right ventricular volumes, which is accompanied by an important increase of cardiac output by 30–50%, beginning from early pregnancy and being maintained throughout pregnancy.^[12] Figure 1 shows the hemodynamic changes during pregnancy.^[13] Moreover, this increase in intra- and extra-vascular volume creates a larger volume of distribution for drugs administrated during pregnancy, and nonpregnant dosing regimens may give subtherapeutic concentrations.^[14] The increased blood volume and cardiac output of pregnancy would led to severe hypertension; however, the hormone progesterone contributes to vasodilatation.^[15] This vasodilatation results in a decrease in systemic blood pressure. The drop in blood pressure may have disproportionate effects on perfusion in different vascular beds, which may be of direct relevance to uterine and choriodecidual perfusion in the placental bed. The mechanism of vasodilatation is disputed, but may depend on a variety of endothelinium-derived hyperpolarizing factor channels.^[16] Cardiac drugs intercepting and augmenting these mechanisms may have an effect on the vasculature. These physiological changes can unmask latent cardiac disease and/or the new onset of cardiac complications during pregnancy or peripartum.^[17]

(Enlarge Image)

Figure 1.

Hemodynamic changes in the normal pregnancy.
CO: Cardiac output; Hb: Haemoglobin concentration; HR: Heart rate; SV: Stroke volume; TPVR: Total peripheral vascular resistance.
Reproduced with permission from [13].

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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.