Introduction

Cardiovascular disease (CVD) is a frequent cause of maternal morbidity and mortality, in both developing and developed countries.1,2,3,4,5,6 The prevalence of CVD in pregnant women is increasing owing to improved rates of survival among women with congenital heart disease and pregnancy at older ages in the Western world. Cardiac complications, including arrhythmias, heart failure, and thromboembolism, are seen in 10% of pregnant women with heart disease.4,6,7,8 The magnitude of the risk of maternal cardiac complications varies with the type and severity of the cardiac condition.9 Obstetric complications, including hypertension and pre-eclampsia, are also more prevalent in women with CVD than in healthy women.4,8,10,11 Many women with CVD need to take medication during pregnancy, either chronically or in the short term to treat a pregnancy-related complication.12,13 Common indications for medication during pregnancy in women with CVD are arrhythmias, heart failure, hypertension, and valvular disease (mitral stenosis or the presence of a mechanical valve prosthesis). On average, 32% of pregnant women with CVD use medication for their cardiac condition during pregnancy.14 β-Blockers are used by approximately two-thirds of these women.14 Other frequently used medications include anticoagulants, calcium-channel blockers, diuretics, and platelet aggregation inhibitors.4,14

The physiological changes of pregnancy affect the pharmacokinetic properties of medication. Optimal medical treatment of women with CVD requires an understanding of these changes to avoid overtreatment or undertreatment.15 Furthermore, the potential toxic effects of medication for the fetus need to be taken into account and might require changes in treatment. Patient compliance during pregnancy also requires special attention. Many women are reluctant to use prescribed medication during pregnancy because they fear that the fetus could be harmed. Low adherence to prescribed medication has been reported in 33% of pregnant women with CVD, on the basis of the eight-item Morisky Medication Adherence Scale.16 Women who believed that abstaining from prescribed medication is best for the fetus had a higher likelihood of being nonadherent to their medication regimens.16 However, in many cases, abstaining from prescribed medication harms not only the mother, but also the fetus. Therefore, the use of medication needs to be discussed thoroughly with the mother in a timely manner—before pregnancy when possible. Such dialogue will ensure that informed decisions can be made and that harm for both mother and fetus can be minimized (Box 1).

In this Review, the physiological changes of pregnancy and their effect on pharmacokinetics will be discussed, with particular focus on the implications for drugs used to treat CVD. The effects of such drugs on fetal health are outlined, together with the underlying mechanisms, and advice is provided for the use of these medications during pregnancy. Finally, information on the cardiovascular effects of medication used for obstetric indications is presented, to enable cardiologists to advise obstetricians on the use of these medications in patients with CVD.

Pharmacokinetics in pregnancy

During pregnancy, profound physiological changes occur that potentially change the absorption, distribution, metabolism, and excretion of drugs (Figure 1).15,17,18,19 These changes can lead to alterations in dose requirements. The pharmocokinetics of drugs in pregnancy is incompletely studied, for both practical and ethical reasons. Therefore, for many drugs, decisions about dosing during pregnancy should be made on the basis of general principles, taking into account both the physiological changes of pregnancy and data on pharmacokinetics (such as protein-binding, metabolism, and clearance) of specific drugs in nonpregnant women.

Figure 1
figure 1

Physiological changes in pregnancy that alter drug pharmacokinetics.

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Cardiovascular system

In the first weeks of pregnancy, plasma volume starts to increase owing to vasodilatation mediated by nitric oxide, as well as to water and sodium retention related to increased mineralocorticoid activity.15 Plasma volume peaks at 40–50% above baseline at ∼32 weeks of pregnancy.20 The increase in blood volume is accompanied by a rise in cardiac output, achieved by increases in both stroke volume and heart rate (Figure 2).21,22 By the end of the first trimester, 75% of the total increase in cardiac output has occurred, and a further rise happens during the peripartum period. The increase in blood flow is distributed mainly to the uterus (tenfold increase), the breasts (threefold increase), and the kidneys (up to 0.8-fold increase), whereas cerebral and hepatic blood flow remain virtually unchanged.23,24,25 The increase in cardiac output and vasodilatation result in decreases in systemic vascular resistance and blood pressure. Blood pressure rises again after the 20–24th week of pregnancy. This dip in blood pressure means that a temporary decrease in dosage of antihypertensive drugs might be required in patients with pre-existing hypertension.

Figure 2: Haemodynamic changes during pregnancy.22,23,126
figure 2

Abbreviations: ERPF, effective renal plasma flow; GFR, glomerular filtration rate.

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The increase in plasma volume is also accompanied by a decrease in serum albumin concentration, leading to a fall in serum colloid osmotic pressure. Consequently, the volume of distribution of drugs is increased, which will increase the dose requirement of hydrophilic drugs (such as atenolol). A decrease in albumin concentration increases the free levels of drugs that are highly protein-bound, such as digoxin. The dose requirement of protein-bound drugs can, therefore, be decreased in pregnancy. On the other hand, when a protein-bound drug is renally cleared, the increased renal clearance during pregnancy can increase dose requirement, as is the case with digoxin.15 Such opposite effects make correct dosing complex.

Lungs

Tidal volume and minute ventilation increase by 30–50% during pregnancy. The resulting partially compensated respiratory alkalosis might affect protein binding of some drugs.15 The magnitude and implications of this effect for drugs used in the treatment of CVD are unknown.

Kidneys

Renal blood flow increases up to 80% during pregnancy, with a peak at the end of the second trimester. The increase in glomerular filtration rate peaks at 50% around the end of the first trimester (Figure 2).17,23,26,27 Drugs that are cleared renally, therefore, can have a shortened half-life during pregnancy. Given that mechanisms other than renal clearance, such as absorption and protein binding, are also altered by pregnancy, the net effect differs between drugs. Drugs used in the treatment of CVD that are cleared renally include atenolol, dalteparin, digoxin, enoxaparin, furosemide, and sotalol. The dosage of dalteparin, enoxaparin, and sotalol needs to be increased during pregnancy.17 Furosemide is mainly cleared by renal excretion; however, a small study showed no changes in its half-life during pregnancy.28

Liver

Oxidative liver enzymes, including the 50 cytochrome P450 enzymes, affect the metabolism of many drugs. Six of these enzymes control the metabolism of 90% of all drugs, and the two enzymes that are most relevant in terms of medications for CVD are CYP2D6 and CYP3A4.29 Genetic polymorphisms account for differences in cytochrome P450 enzyme activity between individuals.18,29,30,31 During pregnancy, changes in these enzyme systems occur.

Metoprolol is metabolized through CYP2D6, the activity of which increases during pregnancy.18 In the third trimester, the maximum metoprolol concentration after oral administration is 12–55% lower than in the nonpregnant state.32 Therefore, an increase in metoprolol dose might be required during pregnancy.30 Genetic differences in CYP2D6 activity might further modify the availability of metoprolol during pregnancy. Data are scarce, however, and no information is available on metoprolol metabolism during the first and second trimesters. Hydralazine decreases the first-pass metabolism of metoprolol and, therefore, increases its plasma concentration.18 CYP3A4 activity is also increased during pregnancy, with effects on the metabolism of nifedipine. Oral clearance is increased and half-life and maximal concentration of nifedipine are decreased during pregnancy.18,33 Additionally, an increase in unbound nifedipine concentration occurs owing to decreased albumin concentration.18 These data suggest that an increased dose of nifedipine during pregnancy might be necessary. Diltiazem and verapamil are also metabolized through CYP3A4, and an increased dose requirement can be expected in pregnancy, but no data from pregnant women are available.18 The progesterone-dependent hepatic isoenzyme UGT1A1, which controls the metabolism of labetalol, is upregulated during pregnancy. Therefore, a requirement for an increase in labetalol dose might be expected in pregnant women, but no confirmatory data are available.18

Stomach and intestines

In early pregnancy, the nausea and vomiting experienced by some women inhibit drug absorption. Delayed gastric emptying, prolonged small bowel transit time, and gastrointestinal reflux also influence the bioavailability of drugs. A decrease in maximal serum concentration and an increase in the time to maximal serum concentration can both occur. The bioavailability of drugs can be further decreased by interaction with iron and antacids, which are frequently prescribed during pregnancy.15

Blood and vascular system

Pregnancy constitutes a hypercoagulative state owing to the increase in coagulation factors and fibrinogen, as well as to venous stasis caused by compression of the inferior vena cava by the enlarged uterus. The risk of venous thromboembolism is, therefore, increased during pregnancy. Hypercoagulation and altered pharmacokinetics of drugs during pregnancy can change the dose requirements for anticoagulants. Low-molecular-weight heparins (LMWHs) are cleared renally; an increase in dose requirement for dalteparin and enoxaparin in pregnancy women has been demonstrated.34,35 A similar increase in dose could, therefore, be expected for other LMWHs. The metabolism of vitamin K antagonists (VKAs; acenocoumarol, phenprocoumon, and warfarin) is largely determined by vitamin K epoxide reductase and CYP2C9. Genetic polymorphisms account for the difference in dose requirements of VKAs between patients.31,36,37,38 Increased activity of CYP2C9 in pregnancy can decrease the plasma concentration of these drugs and an increase in dose is often required. For women who need anticoagulant therapy for the prevention or treatment of venous thromboembolism, LMWHs are the preferred treatment as they are proven to be effective and safe for this indication with fewer fetal adverse effects than VKAs.19 Weekly assessment of anticoagulation effect is recommended in the ESC guidelines for the management of CVDs during pregnancy.19

Medication for CVD and fetal health

Teratogenicity

The long-held belief that the placenta protects the fetus from exposure to drugs taken by the mother was dispelled in the 1960s when thalidomide was found to have caused severe birth defects in thousands of children. Subsequently, all drugs were erroneously suspected to be potential teratogens. In reality, no more than about 30 drugs have been proven to be teratogenic in humans when used at therapeutic dose.39 Whether or not a drug is harmful to the fetus depends on the type of drug, the dose, and also the time of administration. Teratogenic effects are most commonly seen with exposure to the drug during the first trimester, with the exception of the first 2 weeks after conception. However, some drugs, such as angiotensin-converting-enzyme (ACE) inhibitors, exert harmful effects later in pregnancy. The adverse effect of a drug on the fetus is often apparent immediately after birth. However, some medications are associated with late adverse effects. Although not used to treat CVD, the most well-known example is diethyl-stilbestrol, which leads to infertility and an increased risk of vaginal and cervical cancer in women exposed to the drug in utero.40

The only data available on the teratogenicity of new drugs come from animal studies. A drug that is not teratogenic in animals is usually also safe in humans.39 However, a drug that is teratogenic in animals, particularly at a high dose, could be safe in therapeutic doses in humans. Unfortunately, information on adverse fetal effects is incomplete for many drugs.41 Information on teratogenic effects in humans is often initially found in case reports and can be difficult to interpret. When the drug is used widely, the occurrence of a congenital defect in a few cases might just represent the normal prevalence of that defect in the population. When use of the drug is uncommon, or the reported defects are rare and characteristic, the relationship between the drug and the defect can be more-easily established. Other sources of information on drug teratogenicity are epidemiological studies (usually retrospective cohort or case–control studies) and teratology services that are usually based on voluntary reporting. Methodological flaws (such as reporting bias and confounding) hamper the interpretation of these studies. In addition to drug teratogenicity, other risks to the fetus include unnecessary abortion owing to the unrealistic perception of fetal risk and avoidance by the mother of necessary therapy for CVD.39

FDA classification

Until 4 December 2014, the FDA classification (Box 2) was widely used to describe the fetal risk of drugs. This system comprised five classes: A (safest), B, C, D, and X (do not use).19 None of the drugs commonly used to treat CVD was classified as category A, around 25% were category B, approximately 50% category C, and the remainder category D or X. The FDA classification was criticized for several reasons.42,43 First, the majority of drugs were in category C, which meant that insufficient data exist to judge the safety of the drug in human pregnancy and, therefore, no guidance could be given. In such cases, to provide the (scarce) information that is available would be preferable to giving a classification that is not helpful. Second, the FDA classification was often too simple because the effects of the drugs in the first, second, and third trimesters of pregnancy were not differentiated. For example, warfarin was classified as category X mainly based on its teratogenic effects in the first trimester. This drug is, however, fairly safe in the second and third trimesters of pregnancy. Third, the classification seemed to be subjective; ACE inhibitors, which are associated with severe fetal abnormalities in all trimesters of human pregnancy, were categorized as category D, whereas statins, which have been shown to be teratogenic in animal studies but not in human studies, were categorized as category X.43 Fourth, the classification also gave a false sense of security. Clopidogrel, for example, is safe in animals during pregnancy and was categorized as category B despite the absence of data in humans. To address these concerns, on 4 December 2014, the FDA amended regulations on the pregnancy and lactation sections of drug labelling.44 The categories A, B, C, D, and X are no longer used and have been replaced by a narrative summary on the risk of each drug during pregnancy and lactation, together with a discussion of the available data to help health-care providers make decisions about medication and counselling of women.45 However, much of the available literature as well as current guidelines are still based on the old system.

Studies of pregnant women with CVD

In a large, retrospective study of 1,302 completed pregnancies among women with congenital heart disease, the use of medication for the cardiac condition was associated with adverse maternal (such as arrhythmias and heart failure) and neonatal (such as low birth weight and premature birth) events.4 Similar findings were reported in a population of women with tetralogy of Fallot.46 However, these associations were mainly related to medication use before pregnancy as well as the complex underlying disease and its sequelae, which in itself might have contributed to the poor outcomes. Medication use in 1,321 pregnancies among women with structural heart disease was reported in the Registry On Pregnancy And Cardiac disease (ROPAC).14 Medication was used during pregnancy by 32% of the women: β-blockers by 22%, antiarrhythmic drugs by 8%, and diuretics by 7%. ACE inhibitors were used by only 2.8% and statins by 0.5%. The use of medication was significantly associated with adverse fetal events (defined as death, premature birth, or low birth weight).14 The association remained significant after exclusion of anticoagulants and after correction for obstetric and cardiac parameters (including pre-eclampsia, smoking, heart failure, underlying disease, risk of pregnancy-related and cardiac complications). The rate of fetal malformations was similar in women who took medication and in those who did not. The use of β-blockers was associated with a reduction in birth weight of 100 g compared with women who did not use β-blockers. However, the magnitude of this reduction was dependent on the underlying disease—no effect, or a small effect, was observed in women taking β-blockers for hypertension or aortic disease, whereas a pronounced effect was evident in women with valvular disease. This finding indicates that the underlying disease in the mother, rather than the effect of the β-blocker, is likely to be associated with reduced birth weight. Intrauterine growth restriction and a fetus that is small for gestational age are widely recognized complications of maternal heart disease. A relationship between these outcomes and maternal medication use is sometimes, but not always, indicated.4,5,7,14,46,47

β-Blockers

According to the ROPAC, β-blockers constitute two-thirds of all medication for CVD used during pregnancy.14 β-Blockers are used for the treatment of arrhythmias, hypertension (for example, in women with repaired coarctation), and aortic dilatation (for example, in women with Marfan syndrome). The possible adverse fetal effects of β-blockers, therefore, warrant close attention in this Review. A meta-analysis was performed to explore whether β-blockers are associated with birth defects.48 A total of 12 studies that included women who used β-blockers in the first trimester were taken into account. No increased risk of all or major congenital abnormalities was found.48 However, organ-specific malformations (cardiovascular defects, cleft palate or lip, and neural tube defects) were more prevalent in the offspring of women treated with β-blockers. Causality was difficult to ascertain, because the indication for therapy was not always known and the underlying disease can also be associated with these abnormalities. In addition, recall bias might have influenced the findings. On the basis of this meta-analysis, the use of β-blockers during pregnancy does not seem to increase the risk of congenital malformations substantially (although a slightly increased risk cannot be ruled out).

An important concern with the use of β-blockers in pregnancy is the association with fetal growth retardation. This outcome was demonstrated in the ROPAC and in other studies.14,47 In the Quebec registry,49 7,445 of 48,889 babies were small for gestational age, and maternal antihypertensive therapy was associated with being small for gestational age after correction for confounding factors. This relationship was most significant for β1-selective agents.49 Another report included 911,685 births from the Danish Fertility Database.50 Exposure to β-blockers was identified in 2,459 pregnancies and was associated with being small for gestational age, preterm birth, and perinatal mortality. Labetalol did not seem to be safer than other β-blockers.50 These two studies have the advantage of including large numbers of patients, but they were not randomized and confounding by indication cannot be ruled out. In a Cochrane review, the maternal and fetal effects of antihypertensive treatments were explored for women with mild-to-moderate hypertension (systolic blood pressure 140–169 mmHg, diastolic blood pressure 90–109 mmHg) during pregnancy.51 This review included 46 randomized trials involving 4,282 women. Antihypertensive drugs, including β-blockers, had no significant effects on fetal outcome (death, growth retardation, or premature birth). For the mother, the benefit of the treatment was that the risk of severe hypertension was reduced, with β-blockers being more effective in this respect than methyldopa. No differences in other maternal outcomes, including pre-eclampsia, were observed.51 In these studies, however, the focus was not on women with underlying CVD. The majority of patients had pregnancy-induced hypertension and were treated only in the second half of pregnancy. In a Danish study of 175 pregnant women with heart disease, β-blockers were independently associated with being small for gestational age.52 Children that were prenatally exposed to β-blockers were, on average, 8.6% lighter at birth than babies who were not exposed. Interestingly, in a subgroup of 69 women without structural heart disease, but with isolated tachyarrhythmias, β-blockers were the only independent predictor of fetal growth restriction.52 Although this finding suggests that β-blockers affect fetal growth, the use of these drugs could simply be an indirect marker of severe arrhythmias and that these arrhythmias are associated with haemodynamic impairment that causes slow fetal growth. Although the data on the association between maternal β-blocker use and being small for gestational age are inconsistent, the effects that have been reported do not seem to be large enough to be of clinical importance and will not generally be a reason to withhold this medication when it is considered beneficial to the mother.

Maternal use of β-blockers is associated with hypoglycaemia, bradycardia, and hypotension in the neonate.53,54,55,56 The risk of these manageable problems is higher in preterm newborns.54,56 Neonates of mothers taking β-blockers, therefore, need to be observed for these effects. Given the wide experience with labetalol and metoprolol during pregnancy, these are the preferred drugs for use in pregnant women. Atenolol is not recommended for these patients because it has been associated with birth defects.19

Mechanism of fetal adverse effects

Several mechanisms might underlie the potential negative effect of β-blockers on fetal growth. Evidence from animal experiments shows that the direct effects of the β-blocker on fetal cardiac development and fetal heart rate negatively influence outcome.57,58 Additionally, β-blockers might restrict fetal growth by reducing maternal cardiac output.47 The uteroplacental circulation is characterized by the remodelling of spiral arteries into low resistance vessels by the invasion of trophoblasts, leaving these arteries without autoregulatory capacity and directly dependent on maternal cardiac output.59,60 The decrease in maternal cardiac output caused by a β-blocker could negatively affect uteroplacental circulation and thus restrict fetal growth. This outcome might, theoretically, be pronounced in women with CVD. These women might already be unable to meet the increased demands for cardiac output in pregnancy and exposure to a β-blocker could exacerbate the problem. Indeed, medication for CVD (primarily β-blockers) has been shown to be related to impaired uteroplacental blood flow in women with congenital heart disease.8 Impaired uteroplacental blood flow, with high resistance in the placental vascular bed, is associated with fetal growth retardation and maternal hypertensive disorders of pregnancy.8,61

However, an argument also exists for β-blockers having a positive effect on fetal outcome. Right ventricular dysfunction and valvular regurgitation have been shown to be related to uteroplacental flow impairment and fetal growth restriction in patients with congenital heart disease.8 Cardiac output might also be related to uteroplacental flow.47,62,63,64 When the β-blocker improves cardiac output, for example in patients with mitral stenosis, the positive effects on the fetus through improved cardiac function could outweigh the direct negative effects of the β-blocker (Figure 3).

Figure 3: Effects of cardiovascular medication on the fetus.
figure 3

Direct negative effects on fetal heart rate and cardiac output can occur (1), as well as a negative effect on uteroplacental blood flow (2). However, maternal cardiovascular disease can also negatively influence fetal growth and development (3). When medication positively influences maternal cardiac performance (for example, β-blockers in mitral stenosis [a]), uteroplacental blood flow can be enhanced (b), with benefits for the fetus.

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Methyldopa

Methyldopa is an α2-adrenergic agent that is widely used to treat hypertension in pregnant patients. Methyldopa is safe for the fetus, and is, therefore, a first-line drug for the treatment of maternal hypertension during pregnancy.65,66,67 However, this agent is not always effective. Other first-line drugs for hypertension are metoprolol and labetalol (Box 3).

Anticoagulants

Effects on the fetus

Anticoagulation therapy can be indicated during pregnancy in women with atrial fibrillation, valvular heart disease (particularly those with mechanical heart valves), heart failure, pulmonary hypertension, congenital heart disease (for example, those with a Fontan circulation), or venous thrombosis or pulmonary embolism. VKAs cross the placenta and are associated with embryopathy, but only when the fetus is exposed to the drug during the first trimester of pregnancy.68,69,70 Effects on the fetus include developmental abnormalities of the face, skeleton, and central nervous system, as well as bleeding.69,70 The incidence of embryopathy with exposure to VKAs in the first trimester is 6%, according to two reviews published in the early 2000s.68,71 A lower incidence has been reported in subsequent studies, possibly because the doses of the drugs have reduced over time.72,73,74,75,76

Evidence is emerging that fetal risk associated with VKAs is dose-dependent. In a systematic review published in 2014, an incidence of embryopathy of 0.9% in 494 pregnancies in which the mother took a daily warfarin dose of <5 mg was reported.77 The risk of pregnancy loss is also increased in women who take VKAs during pregnancy,78 and is not limited to the first trimester. The risk of pregnancy loss also seems to be dose-dependent, with a mean incidence of 13.4% with low-dose (<5 mg) warfarin (which is similar to the rate of pregnancy loss in healthy women) versus 33.0% in women who used an unreported or unlimited dose of warfarin. However, the rates differ between studies.77,79 Unfractionated heparin and LMWH do not cross the placenta and are, therefore, not associated with embryopathy. As might be expected, both VKAs and heparins are associated with an increased risk of maternal bleeding.76,77,80,81,82,83 Intrauterine haematoma increases the risk of pregnancy loss, early delivery, and fetal growth retardation.84 Vaginal delivery is contraindicated in women taking VKAs because the resulting anticoagulation effects on the fetus increase the risk of cranial haemorrhage during the birth.19

Venous thrombosis and pulmonary embolism

For women who experience venous thrombosis or pulmonary embolism during pregnancy, a therapeutic dose of LMWH is the treatment of choice.19 The efficacy and safety of this class of drugs during pregnancy was demonstrated in a review of 174 patients.85 The risk of recurrence of venous thromboembolism was only 1.15%, 'significant' bleeding (defined as >500 ml blood loss) occurred in 1.72% of women.85,86 Given that LMWHs are cleared renally, an increased dose requirement during pregnancy is expected. Dalteparin and enoxaparin should be dosed twice daily in pregnant women, with a target peak anti-factor-Xa (anti-Xa) level of 0.6–1.2 IU/ml.19,87 Women who are at high risk of venous thrombosis and pulmonary embolism during pregnancy (according to criteria defined by the Royal College of Obstetricians and Gynaecologists) should use a prophylactic dose LMWH (50 IU/kg body mass dalteparin or 0.5 IU/kg body mass of enoxaparin twice daily).19 This dosing strategy seemed to be safe and effective in a review of 2,603 pregnancies.85 The ESC guidelines state that anti-Xa level monitoring is “reasonable” in pregnant women treated for venous thrombosis and pulmonary embolism.19 Such monitoring is not considered necessary for the prophylactic dose.

Mechanical valve prostheses

Importantly, pregnant women with mechanical heart valves should be managed by experts in tertiary centres19,88 Among this patient population, the available (mostly retrospective) data indicate that the incidence of valve thrombosis is lower with VKAs than with unfractionated heparin or LMWH. For VKAs, the risk of thromboembolic complications varies between 0% and 4%.71,72,74,75,77,79 The data for unfractionated heparin are limited, with the rate of maternal thromboembolism reported to be 9–33%.71 LMWHs are also associated with high rates of valve thrombosis, especially when anti-Xa level monitoring is not performed.89 Among 111 women who took LMWH throughout pregnancy, with anti-Xa level monitoring and dose adjustment according to peak anti-Xa levels, the rate of mechanical valve thrombosis was 9%.19,82,83,90,91 Low compliance with medication and target anti-Xa levels that were too low probably contributed to the majority of valve thromboses. Valve thrombosis has, however, also been reported with adequate peak anti-Xa levels.82 Evidence exists that trough anti-Xa levels might be subtherapeutic in pregnant women, even when peak anti-Xa levels are adequate.34,92 Dosing according to both trough and peak levels of anti-Xa has been recommended by some experts, with target levels of ≥0.6 IU/ml (trough) and ≤1.5 IU/ml (peak).92,93 However, these levels differ from those recommended in the guidelines, which recommend dosing according to peak levels only.19,88. Determining whether dosing according to trough and peak levels of anti-Xa is effective in the prevention of valve thrombosis with an acceptably low rate of bleeding should be the objective of further research. LMWH seems to be associated with a lower rate of fetal loss than VKAs (0–10%).78,90,93

Few data exist on the rate of valve thrombosis when LMWH with anti-Xa level monitoring is used in the first trimester and VKAs thereafter, and no randomized studies have been conducted. Only 56 cases were identified from the literature, among which the rate of valve thrombosis was 3.6%.91 When unfractionated heparin was used during the first trimester instead of LMWH, the reported rate of valve thrombosis was higher at 9.5%.71 On the basis of the low risk of VKAs to the fetus in the second and third trimesters of pregnancy, and the high risk of valve thrombosis with unfractionated heparin or LMWH throughout pregnancy, the advice in both the AHA/ACC88 and ESC19 guidelines is to use VKAs in the second and third trimester in all women with mechanical valves, despite the increased risk of pregnancy loss. During the first trimester, both guidelines recommend using low-dose VKAs (<2 mg acenocoumarol, <3 mg phenprocoumon, or <5 mg warfarin daily) with close monitoring of international normalized ratio), or dose-adjusted LMWH or unfractionated heparin when the woman would otherwise need a high dose of VKAs.19,88 Peak anti-Xa levels during LMWH therapy should be monitored weekly, with a target of 0.8–1.2 IU/ml at 4–6 h after the dose. Unfractionated heparin therapy should be given as continuous infusion, aiming for an activated partial thromboplastin time of >2 times the control value.19,88 In addition, the AHA/ACC guidelines88 contain a recommendation to add aspirin in the second and third trimester.

Other oral anticoagulants

Other oral anticoagulants, such as dabigatran and rivaroxaban, have been shown to be harmful to the fetus in animal studies, and data in humans are not available. These drugs should not, therefore, be used in pregnancy.19,94,95,96

Calcium-channel blockers

Calcium-channel blockers do not seem to be associated with an increased incidence of congenital anomalies in humans.97,98,99,100 However, in one study, an increased risk of neonatal seizures with calcium-channel blockers was reported.99 Diltiazem, however, has been demonstrated to be teratogenic (causing skeletal abnormalities) in animals and, although little data on its safety in humans exist, the use of this drug in pregnancy is not recommended.19 In the mother, calcium-channel blockers have a tocolytic effect and can cause maternal hypotension and placental hypoperfusion. Verapamil is considered to be fairly safe during pregnancy and is recommended in the ESC guidelines19 as a second-line drug (after β-blockers) for rate control in atrial fibrillation and for treatment of idiopathic sustained ventricular tachycardia in pregnant women. However, the potential for fetal atrioventricular block and bradycardia cannot be excluded.

ACE inhibitors and ARBs

ACE inhibitors and angiotensin-receptor blockers (ARBs) are teratogenic and are contraindicated throughout pregnancy.19 Renal failure, anuria, skull and lung hypoplasia, craniofacial deformation, and death in the fetus have been described.101,102,103 In the ROPAC, fetal anomalies associated with the use of ACE inhibitors or ARBs occurred in 8% of pregnancies, which was more often than with any other type of drug, despite ACE inhibitors or ARBs usually being used only for a short period of time.14 In a systematic review, 48% of 118 fetuses exposed to ACE inhibitors and 87% of fetuses exposed to ARBs had complications related to the use of these medications.101 Congenital anomalies occur after exposure to these drugs during all three trimesters,101,102 although the incidence of birth defects is lowest with exposure during the first trimester.101

Antiarrhythmic agents

Amiodarone has been reported to cause transient neonatal hypothyroidism in 17% of exposed fetuses.104 Mild neurological abnormalities (mainly nonverbal learning disabilities) were also described in this study. Amiodarone should, therefore, be reserved for life-threatening arrhythmias that do not respond to other therapies.19,104,105 Adenosine and procainamide are not teratogenic and can be used safely during pregnancy. Flecainide has been used during pregnancy to treat both maternal and fetal arrhythmias with no teratogenic effects reported. However, no controlled studies are available and caution with the use of this drug is advised. The ESC guidelines19 state that flecainide can be used for the treatment of maternal supraventricular tachycardia, although β-blockers and digoxin are the preferred choice. Other indications for flecainide in pregnancy are maternal atrial tachycardia and cardioversion of atrial flutter or fibrillation.19 Flecainide is preferred over propafenone, because less is known about the safety of propafenone in pregnancy than for flecainide.19 Disopyramide is not teratogenic, but can cause uterine contractions and should, therefore, be used with caution.53 No randomized, controlled studies of sotalol during pregnancy have been conducted. Sotalol might be associated with growth retardation owing to its β-blocking effect, as is the case for other β-blockers,106 but no other harmful effects on the fetus have been reported. This drug can, therefore, be used during pregnancy when necessary. The use of antiarrhythmic medication during pregnancy is summarized in Box 4.

Statins

No evidence for teratogenicity of statins was found in a review published in 2012, but a harmful effect of these drugs could not be ruled out mainly because the studies included were small.107 In a prospective case–control study of 249 fetuses exposed to statins, the rate of birth defects did not differ significantly between cases and controls.108 In ROPAC,14 only six fetuses had been exposed to statins, one of these babies died and the others did not have abnormalities. The available evidence indicates that the risk of using statins during pregnancy is low, but the lack of available data means that these drugs cannot be concluded to be completely safe.

Diuretics and aldosterone antagonists

Bumetanide, furosemide, and hydrochlorothiazide do not seem to be teratogenic, but these drugs can result in oligohydramnios (a deficiency of amniotic fluid) and increase the risk of electrolyte imbalance in the fetus.19 In pregnancy, bumetanide, furosemide, and hydrochlorothiazide are not advised for the treatment of hypertension, but can be used for the treatment of heart failure.19 Spironolactone has been associated with feminization of male rats, and is not therefore advised in humans during pregnancy.109 Given that eplerenone has not been associated with adverse effects during pregnancy in animal studies, this drug is likely to be a better choice for use in pregnant women than spironolactone. However, no data on the use of these drugs in human pregnancy exist and, therefore, eplerenone should be used in pregnant women with heart failure only when treatment with other diuretics (such as furosemide) is ineffective.19 The treatment of women with heart failure during pregnancy is summarized in Box 5.

Digoxin

Digoxin is not teratogenic in humans. Digoxin intoxication has, however, been associated with miscarriage and fetal death.53,110,111 As discussed earlier, the dose requirement for digoxin can decrease during pregnancy because of the decrease in albumin concentration, but increased renal clearance usually prevails and leads to an increased dose being required. Dosing of this drug should not be based on measurement of the blood level of digoxin because digoxin-like substances present in the pregnant woman can produce an inaccurate test result.53 Dosing should be based on the clinical effect (for example, heart rate in atrial fibrillation).

Dopamine

Dopamine is used as an inotropic drug in patients with severe heart failure. Experience with this drug in pregnant women is limited. When necessary, dopamine can be used according to the ESC guidelines.19

Platelet aggregation inhibitors

The use of aspirin (dose unspecified) in the first trimester of pregnancy has been associated with a possible increased risk (twofold to threefold) of gastroschisis.112,113 In addition, aspirin use (dose unspecified) throughout pregnancy has been associated with premature closure of the ductus arteriosus.114,115,116 The antiplatelet properties of aspirin might also increase the risk of fetal bleeding risk (including intracranial bleeding). However, the data are controversial and generally reassuring,117,118 particularly for low-dose aspirin (up to 100 mg daily),116 which is widely used during pregnancy for prevention of premature birth and pre-clampsia. Low-dose aspirin seems to be safe throughout pregnancy.114

Clopidogrel has been shown to be safe during pregnancy in animal studies, but experience in humans is limited and caution with this drug is advised.119 Insufficient data exist on other platelet aggregation inhibitors, such as ticagrelor and glycoprotein IIb/IIIa inhibitors, during pregnancy and these drugs should be used only when absolutely necessary.19,86 The treatment of ischaemic heart disease during pregnancy is summarized in Box 6.

Medication for obstetric indications

Patients with CVD often need medication for obstetric reasons, for example the prevention of premature labour or postpartum haemorrhage. As these medications can have cardiovascular adverse effects, cardiologists need to be able to provide advice on their appropriate use.

Tocolytic agents

Nifedipine is a calcium-channel blocker that is frequently used as a tocolytic agent to halt uterine contractions and prevent premature labour.120 A high dose of nifedipine (up to 110 mg per day) is often used, which is associated with hypotension. This therapy is, therefore, not suitable for women with obstructive left-sided lesions, such as aortic stenosis or hypertrophic cardiomyopathy. Nifedipine is also contraindicated in women with Eisenmenger syndrome because it increases the right-to-left shunt. β2-Adrenergic receptor agonists, such as ritodrine, have severe adverse effects, including tachycardia and chest pain, and are contraindicated in patients with CVD. The NSAID indomethacin is sometimes used in early preterm labour and can be used in patients with CVD when other tocolytic agents are not effective. Atosiban, an oxytocin-receptor antagonist, has no reported cardiac adverse effects and is advised as a first-line tocolytic agent in women with CVD.120

Postpartum haemorrhage prevention

At the beginning of the third trimester, a delivery management plan for women with CVD should be constructed by a multidisciplinary team. This plan must state explicitly which drugs can be used to prevent and treat postpartum haemorrhage. Oxytocin is frequently used as a routine medication to cause contraction of the uterus after delivery. This drug can cause vasodilatation, leading to severe hypotension and reflex tachycardia, and has also been associated with coronary vasoconstriction.121,122,123 A bolus injection of 5–10 IU oxytocin should not be used in patients with CVD. Small bolus injections of 0.1–1.0 IU, or a continuous infusion, are safe. Ergometrine, an α-adrenergic receptor agonist, can cause coronary vasospasm, pulmonary vasoconstriction, and hypertension and should be avoided in most pregnant women with CVD or pulmonary hypertension.121,124,125 Carboprost is a smooth-muscle contractor, which can cause hypotension and pulmonary oedema, and this drug should not be used in pregnant women with CVD.119 Misoprostol, a prostaglandin E1 analogue, has fewer adverse cardiovascular effects than carboprost and ergometrine and is, therefore, a preferred drug for the prevention of postpartum haemorrhage in addition to oxytocin.

Conclusions

The number of pregnant women with CVD is increasing, and one-third of these patients use medication for their cardiovascular condition during pregnancy. Increases in blood volume and renal clearance, as well as changes in hepatic metabolism and coagulation, alter the pharmacokinetics and dose requirements of many drugs. When a woman needs medication during pregnancy, the benefit and harm of the drug to both mother and fetus need to be carefully evaluated and discussed. A small number of drugs used to treat CVD are associated with congenital anomalies in the fetus. These include high-dose warfarin during the first trimester, ACE inhibitors and ARBs, amiodarone, and spironolactone. Most other drugs for CVD are considered to be safe for the fetus, but often little or no safety data are available on which to base prescribing decisions. Importantly, pregnant women need to understand that not taking medication can lead to worsening cardiac status and thus harm to both mother and fetus. Cardiologists who manage women with CVD must have knowledge of the cardiovascular effects of medication used for obstetric indications, and be able to advise the obstetrician on their use in these patients. For many medications used to treat CVD, the data on safety and efficacy during pregnancy are insufficient. In the future, systematic reviews and meta-analyses on specific drugs will be helpful to expand our knowledge. Worldwide registries, such as the ROPAC, will also be helpful to increase our understanding of the effects of various medications. The use of drugs for CVD in pregnant women is often incidental and, therefore, large randomized trials or even systematic cohort studies are unlikely to be possible. However, because β-blockers are widely used by women with heart disease, for some indications (such as aortic dilatation and hypertension) a randomized trial might be a possibility. Such studies could enable the benefit for the mother to be assessed against the risk of harm (especially growth retardation) to the fetus. Another important area for research is the search for a safe and effective anticoagulation regimen for women with mechanical heart valves.