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REVIEWS

Use of medication for cardiovascular disease


during pregnancy
Petronella G. Pieper
Abstract | One-third of women with heart disease use medication for the treatment of cardiovascular disease
(CVD) during pregnancy. Increased plasma volume, renal clearance, and liver enzyme activity in pregnant
women change the pharmacokinetics of these drugs, often resulting in the need for an increased dose. Fetal
well-being is a major concern among pregnant women. Fortunately, many drugs used to treat CVD can be used
safely during pregnancy, with the exception of high-dose warfarin in the first trimester, angiotensin-converting-
enzyme inhibitors, angiotensin-receptor blockers, amiodarone, and spironolactone. A timely and thorough
discussion between the cardiologist and the pregnant patient about the potential benefits and adverse effects
of medication for CVD is important. Noncompliance with necessary treatment for cardiovascular disorders
endangers not only the mother, but also the fetus. This Review is an overview of the pharmacokinetic changes
in medications for CVD during pregnancy and the safety of these drugs for the fetus. The implications for
maternal treatment are discussed. The Review also includes a short section on the cardiovascular effects of
medication used for obstetric indications.
Pieper, P. G. Nat. Rev. Cardiol. 12, 718–729 (2015); published online 20 November 2015; doi:10.1038/nrcardio.2015.172

Introduction
Cardiovascular disease (CVD) is a frequent cause of understanding of these changes to avoid overtreatment
maternal morbidity and mortality, in both developing or undertreatment.15 Furthermore, the potential toxic
and developed countries.1–6 The prevalence of CVD in effects of medication for the fetus need to be taken into
pregnant women is increasing owing to improved rates of account and might require changes in treatment. Patient
survival among women with congenital heart disease and compliance during pregnancy also requires special atten-
pregnancy at older ages in the Western world. Cardiac tion. Many women are reluctant to use prescribed medi-
complications, including arrhythmias, heart failure, cation during pregnancy because they fear that the fetus
and thromboembolism, are seen in 10% of pregnant could be harmed. Low adherence to prescribed medica-
women with heart disease.4,6–8 The magnitude of the risk tion has been reported in 33% of pregnant women with
of maternal cardiac complications varies with the type CVD, on the basis of the eight-item Morisky Medication
and severity of the cardiac condition.9 Obstetric com- Adherence Scale.16 Women who believed that abstaining
plications, including hypertension and pre-eclampsia, from prescribed medication is best for the fetus had a
are also more prevalent in women with CVD than in higher likelihood of being nonadherent to their medi-
healthy women.4,8,10,11 Many women with CVD need to cation regimens.16 However, in many cases, abstaining
take medication during pregnancy, either chronically or from prescribed medication harms not only the mother,
in the short term to treat a pregnancy-related compli- but also the fetus. Therefore, the use of medication needs
cation.12,13 Common indications for medication during to be discussed thoroughly with the mother in a timely
pregnancy in women with CVD are arrhythmias, heart manner—before pregnancy when possible. Such dialogue
failure, hypertension, and valvular disease (mitral steno- will ensure that informed decisions can be made and
sis or the presence of a mechanical valve prosthesis). On that harm for both mother and fetus can be minimized
average, 32% of pregnant women with CVD use medi- (Box 1).
cation for their cardiac condition during pregnancy.14 In this Review, the physiological changes of pregnancy
β‑Blockers are used by approximately two-thirds of these and their effect on pharmacokinetics will be discussed,
women.14 Other frequently used medications include with particular focus on the implications for drugs used
anticoagulants, calcium-channel blockers, diuretics, and to treat CVD. The effects of such drugs on fetal health
platelet aggregation inhibitors.4,14 are outlined, together with the underlying mechanisms,
The physiological changes of pregnancy affect the and advice is provided for the use of these medications
Department of pharmacokinetic properties of medication. Optimal during pregnancy. Finally, information on the cardio­
Cardiology, University
Medical Centre medical treatment of women with CVD requires an vascular effects of medication used for obstetric indi-
Groningen, Hanzeplein cations is presented, to enable cardiologists to advise
1, 9700 RB Groningen,
Netherlands. Competing interests obstetricians on the use of these medications in patients
p.g.pieper@umcg.nl The author declares no competing interests. with CVD.

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Key points cardiac output and vasodilatation result in decreases


in systemic vascular resistance and blood pressure. Blood
■■ The physiological changes of pregnancy result in changes to the
pressure rises again after the 20–24th week of pregnancy.
pharmacokinetics of many drugs used for the treatment of cardiovascular
disease, often necessitating an increase in dosage
This dip in blood pressure means that a temporary
■■ Avoiding necessary medication for fear of teratogenicity threatens both mother decrease in dosage of antihypertensive drugs might be
and fetus, and is often a worse option than accepting the small increase in required in patients with pre-existing hypertension.
fetal risk related to the medication The increase in plasma volume is also accompanied
■■ Most drugs for cardiovascular disease can be used safely during pregnancy; by a decrease in serum albumin concentration, leading
exceptions include high-dose warfarin during the first trimester, angiotensin- to a fall in serum colloid osmotic pressure. Consequently,
converting-enzyme inhibitors, angiotensin-receptor blockers, amiodarone, the volume of distribution of drugs is increased, which
and spironolactone
will increase the dose requirement of hydrophilic drugs
■■ Anticoagulation in pregnant women with mechanical heart valves is complex,
and these women need expert care in specialized centres throughout (such as atenolol). A decrease in albumin concentra-
their pregnancies tion increases the free levels of drugs that are highly
■■ Cardiologists should be able to advise obstetricians about the safe use protein-bound, such as digoxin. The dose requirement
of tocolytic and uterotonic drugs in patients with cardiovascular disease 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
Box 1 | Medication for heart disease during pregnancy during pregnancy can increase dose requirement, as
Pharmacokinetics is the case with digoxin.15 Such opposite effects make
■■ Is an increase or decrease in the dose of the drug correct dosing complex.
expected to be necessary?
■■ Should the effect of the drug be monitored?
Lungs
Teratogenicity and fetotoxicity Tidal volume and minute ventilation increase by 30–50%
■■ What is the cost:benefit ratio for mother and fetus?
during pregnancy. The resulting partially compensated
■■ Is discontinuation or replacement with another drug
necessary?
respiratory alkalosis might affect protein binding of some
drugs.15 The magnitude and implications of this effect
Patient compliance
■■ Might be reduced during pregnancy when women fear
for drugs used in the treatment of CVD are unknown.
harming the fetus by using medication
Kidneys
Renal blood flow increases up to 80% during preg-
Pharmacokinetics in pregnancy nancy, with a peak at the end of the second trimester.
During pregnancy, profound physiological changes The increase in glomerular filtration rate peaks at 50%
occur that potentially change the absorption, distribu- around the end of the first trimester (Figure 2).17,23,26,27
tion, metabolism, and excretion of drugs (Figure 1).15,17–19 Drugs that are cleared renally, therefore, can have a
These changes can lead to alterations in dose require- shortened half-life during pregnancy. Given that mech­
ments. The pharmocokinetics of drugs in pregnancy anisms other than renal clearance, such as absorption
is incompletely studied, for both practical and ethical and protein binding, are also altered by pregnancy, the
reasons. Therefore, for many drugs, decisions about net effect differs between drugs. Drugs used in the treat-
dosing during pregnancy should be made on the basis of ment of CVD that are cleared renally include atenolol,
general principles, taking into account both the physio­ dalteparin, digoxin, enoxaparin, furosemide, and sotalol.
logical changes of pregnancy and data on pharma­ The dosage of dalteparin, enoxaparin, and sotalol needs
cokinetics (such as protein-binding, metabolism, and to be increased during pregnancy.17 Furosemide is mainly
clearance) of specific drugs in nonpregnant women. cleared by renal excretion; however, a small study showed
no changes in its half-life during pregnancy.28
Cardiovascular system
In the first weeks of pregnancy, plasma volume starts Liver
to increase owing to vasodilatation mediated by nitric Oxidative liver enzymes, including the 50 cytochrome
oxide, as well as to water and sodium retention related P450 enzymes, affect the metabolism of many drugs.
to increased mineralocorticoid activity.15 Plasma volume Six of these enzymes control the metabolism of 90% of
peaks at 40–50% above baseline at ~32 weeks of preg- all drugs, and the two enzymes that are most relevant
nancy.20 The increase in blood volume is accompanied in terms of medications for CVD are CYP2D6 and
by a rise in cardiac output, achieved by increases in both CYP3A4.29 Genetic polymorphisms account for dif-
stroke volume and heart rate (Figure 2).21,22 By the end ferences in cytochrome P450 enzyme activity between
of the first trimester, 75% of the total increase in cardiac individuals.18,29–31 During pregnancy, changes in these
output has occurred, and a further rise happens during enzyme systems occur.
the peripartum period. The increase in blood flow is Metoprolol is metabolized through CYP2D6, the activ-
distributed mainly to the uterus (tenfold increase), the ity of which increases during pregnancy.18 In the third
breasts (threefold increase), and the kidneys (up to trimester, the maximum metoprolol concentration after
0.8‑fold increase), whereas cerebral and hepatic blood oral administration is 12–55% lower than in the non­
flow remain virtually unchanged.23–25 The increase in pregnant state.32 Therefore, an increase in metoprolol

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REVIEWS

through CYP3A4, and an increased dose requirement


can be expected in pregnancy, but no data from preg-
Cardiovascular system and blood Liver nant women are available.18 The progesterone-dependent
■ Increases in plasma volume, ■ Changes in oxidative hepatic isoenzyme UGT1A1, which controls the metab-
cardiac output, stroke volume, liver enzymes, such as
and heart rate cytochrome P450 olism of labetalol, is upregulated during pregnancy.
■ Decreases in serum albumin Therefore, a requirement for an increase in labetalol
concentration and serum colloid
osmotic pressure dose might be expected in pregnant women, but no
■ Increases in coagulation Lungs confirmatory data are available.18
factors and fibrinogen ■ Increase in tidal volume
■ Compression of the inferior and minute ventilation
vena cava by the uterus Stomach and intestines
Stomach and intestines In early pregnancy, the nausea and vomiting experienced
Kidneys ■ Nausea and vomiting by some women inhibit drug absorption. Delayed gastric
■ Increases in renal blood ■ Delayed gastric emptying
flow and glomerular ■ Prolonged small bowel emptying, prolonged small bowel transit time, and
filtration rate transit time gastro­intestinal reflux also influence the bioavailability
■ Gastrointestinal reflux
of drugs. A decrease in maximal serum concentration
and an increase in the time to maximal serum concentra-
tion can both occur. The bioavailability of drugs can be
further decreased by interaction with iron and antacids,
Figure 1 | Physiological changes in pregnancy that alter Nature
drug pharmacokinetics.
which are frequently prescribed during pregnancy.15
Reviews | Cardiology

Blood and vascular system


100 Pregnancy constitutes a hypercoagulative state owing
to the increase in coagulation factors and fibrinogen,
80 as well as to venous stasis caused by compression of the
inferior vena cava by the enlarged uterus. The risk of
70
venous thromboembolism is, therefore, increased during
pregnancy. Hypercoagulation and altered pharmaco­
60
kinetics of drugs during pregnancy can change the dose
Increase (%)

50
requirements for anticoagulants. Low-molecular-weight
heparins (LMWHs) are cleared renally; an increase
40 in dose requirement for dalteparin and enoxaparin in
pregnancy women has been demonstrated.34,35 A similar
30 increase in dose could, therefore, be expected for other
ERPF
LMWHs. The metabolism of vitamin K antagonists
GFR
20
Cardiac output
(VKAs; acenocoumarol, phenprocoumon, and war­
Stroke volume farin) is largely determined by vitamin K epoxide reduc-
10 Heart rate tase and CYP2C9. Genetic polymorphisms account for
Plasma volume the difference in dose requirements of VKAs between
0
patients.31,36–38 Increased activity of CYP2C9 in preg-
0 4 8 12 16 20 24 28 32 36 40
nancy can decrease the plasma concentration of these
Weeks of pregnacy
drugs and an increase in dose is often required. For
Figure 2 | Haemodynamic changes during pregnancy.22,23,126Nature Reviews | Cardiology
Abbreviations: ERPF, women who need anticoagulant therapy for the preven-
effective renal plasma flow; GFR, glomerular filtration rate. tion or treatment of venous thromboembolism, LMWHs
are the preferred treatment as they are proven to be effec-
dose might be required during pregnancy.30 Genetic tive and safe for this indication with fewer fetal adverse
differences in CYP2D6 activity might further modify effects than VKAs.19 Weekly assessment of anticoagula-
the availability of metoprolol during pregnancy. Data tion effect is recommended in the ESC guidelines for the
are scarce, however, and no information is available on management of CVDs during pregnancy.19
metoprolol metabolism during the first and second tri-
mesters. Hydralazine decreases the first-pass metabolism Medication for CVD and fetal health
of metoprolol and, therefore, increases its plasma con- Teratogenicity
centration.18 CYP3A4 activity is also increased during The long-held belief that the placenta protects the fetus
pregnancy, with effects on the metabolism of nifedipine. from exposure to drugs taken by the mother was dis-
Oral clearance is increased and half-life and maximal pelled in the 1960s when thalidomide was found to have
concentration of nifedipine are decreased during preg- caused severe birth defects in thousands of children.
nancy.18,33 Additionally, an increase in unbound nifedi- Subsequently, all drugs were erroneously suspected to
pine concentration occurs owing to decreased albumin be potential teratogens. In reality, no more than about
concentration.18 These data suggest that an increased 30 drugs have been proven to be teratogenic in humans
dose of nifedipine during pregnancy might be neces- when used at therapeutic dose.39 Whether or not a drug
sary. Diltiazem and verapamil are also metabolized is harmful to the fetus depends on the type of drug, the

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dose, and also the time of administration. Teratogenic Box 2 | FDA classification of drugs in pregnancy*
effects are most commonly seen with exposure to the drug
Category A
during the first trimester, with the exception of the first
Well-controlled, adequate studies have not identified
2 weeks after conception. However, some drugs, such as any risks to the fetus in the first trimester of pregnancy,
angiotensin-converting-enzyme (ACE) inhibitors, exert and no evidence of risk is apparent in later trimesters
harmful effects later in pregnancy. The adverse effect of Category B
a drug on the fetus is often apparent immediately after Animal reproduction studies have not identified any
birth. However, some medications are associated with late risk to the fetus and well-controlled studies in pregnant
adverse effects. Although not used to treat CVD, the most women have not been performed; or animal studies
well-known example is diethyl-stilbestrol, which leads to showed an adverse effect that was not confirmed in
infertility and an increased risk of vaginal and cervical controlled studies in women
cancer in women exposed to the drug in utero.40 Category C
The only data available on the teratogenicity of new Animal reproduction studies have demonstrated an
adverse effect on the fetus and there are no adequate
drugs come from animal studies. A drug that is not
and well-controlled studies in humans, or no studies in
teratogenic in animals is usually also safe in humans.39 women or animals are available; drugs should be given
However, a drug that is teratogenic in animals, particu- only if potential benefits justify the potential risk to
larly at a high dose, could be safe in therapeutic doses the fetus
in humans. Unfortunately, information on adverse fetal Category D
effects is incomplete for many drugs.41 Information on Adverse reaction data from investigational or marketing
teratogenic effects in humans is often initially found in experience or studies in humans have identified an
case reports and can be difficult to interpret. When the adverse effect on the fetus, but potential benefits might
drug is used widely, the occurrence of a congenital defect warrant use of the drug in pregnant women despite
in a few cases might just represent the normal preva- the risks
lence of that defect in the population. When use of the Category X
Animals or human studies have shown the presence of
drug is uncommon, or the reported defects are rare and
fetal abnormalities and/or there is positive evidence
characteristic, the relationship between the drug and the
of human fetal risk based on adverse reaction data from
defect can be more-easily established. Other sources of investigational or marketing experience, and the risks
information on drug teratogenicity are epidemiological involved in use of the drug in pregnant women clearly
studies (usually retrospective cohort or case–control outweigh potential benefits
studies) and teratology services that are usually based *From 4 December 2014, the use of these categories was
on voluntary reporting. Methodological flaws (such as discontinued and replaced by a narrative summary on the risk of a
particular drug during pregnancy and lactation.44 These categories
reporting bias and confounding) hamper the interpreta- are, however, still widely used in the literature.
tion 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 of human pregnancy, were categorized as category D,
avoidance by the mother of necessary therapy for CVD.39 whereas statins, which have been shown to be terato-
genic in animal studies but not in human studies, were
FDA classification categorized as category X.43 Fourth, the classification also
Until 4 December 2014, the FDA classification (Box 2) gave a false sense of security. Clopidogrel, for example,
was widely used to describe the fetal risk of drugs. This is safe in animals during pregnancy and was categorized
system comprised five classes: A (safest), B, C, D, and as category B despite the absence of data in humans. To
X (do not use).19 None of the drugs commonly used to address these concerns, on 4 December 2014, the FDA
treat CVD was classified as category A, around 25% amended regulations on the pregnancy and lactation sec-
were category B, approximately 50% category C, and the tions of drug labelling.44 The categories A, B, C, D, and
remainder category D or X. The FDA classification was X are no longer used and have been replaced by a narra-
criticized for several reasons.42,43 First, the majority of tive summary on the risk of each drug during pregnancy
drugs were in category C, which meant that insufficient and lactation, together with a discussion of the available
data exist to judge the safety of the drug in human preg- data to help health-care providers make decisions about
nancy and, therefore, no guidance could be given. In such medication and counselling of women.45 However, much
cases, to provide the (scarce) information that is avail- of the available literature as well as current guidelines are
able would be preferable to giving a classification that still based on the old system.
is not helpful. Second, the FDA classification was often
too simple because the effects of the drugs in the first, Studies of pregnant women with CVD
second, and third trimesters of pregnancy were not dif- In a large, retrospective study of 1,302 completed preg-
ferentiated. For example, warfarin was classified as cat- nancies among women with congenital heart disease, the
egory X mainly based on its teratogenic effects in the first use of medication for the cardiac condition was associ­
trimester. This drug is, however, fairly safe in the second ated with adverse maternal (such as arrhythmias and
and third trimesters of pregnancy. Third, the classifica- heart failure) and neonatal (such as low birth weight and
tion seemed to be subjective; ACE inhibitors, which are premature birth) events.4 Similar findings were reported
associated with severe fetal abnormalities in all trimesters in a population of women with tetralogy of Fallot.46

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However, these associations were mainly related to An important concern with the use of β-blockers in
medication use before pregnancy as well as the complex pregnancy is the association with fetal growth retardation.
underlying disease and its sequelae, which in itself might This outcome was demonstrated in the ROPAC and in
have contributed to the poor outcomes. Medication use other studies.14,47 In the Quebec registry,49 7,445 of 48,889
in 1,321 pregnancies among women with structural babies were small for gestational age, and maternal anti­
heart disease was reported in the Registry On Pregnancy hypertensive therapy was associated with being small for
And Cardiac disease (ROPAC).14 Medication was used gestational age after correction for confounding factors.
during pregnancy by 32% of the women: β‑blockers by This relationship was most significant for β1‑selective
22%, antiarrhythmic drugs by 8%, and diuretics by 7%. agents.49 Another report included 911,685 births from
ACE inhibitors were used by only 2.8% and statins by the Danish Fertility Database.50 Exposure to β‑blockers
0.5%. The use of medication was significantly associated was identified in 2,459 pregnancies and was associated
with adverse fetal events (defined as death, premature with being small for gestational age, preterm birth, and
birth, or low birth weight).14 The association remained perinatal mortality. Labetalol did not seem to be safer than
significant after exclusion of anticoagulants and after other β‑blockers.50 These two studies have the advantage
correction for obstetric and cardiac parameters (includ- of including large numbers of patients, but they were not
ing pre-eclampsia, smoking, heart failure, underlying randomized and confounding by indication cannot be
disease, risk of pregnancy-related and cardiac compli- ruled out. In a Cochrane review, the maternal and fetal
cations). The rate of fetal malformations was similar in effects of antihypertensive treatments were explored for
women who took medication and in those who did not. women with mild-to-moderate hyper­tension (systolic
The use of β‑blockers was associated with a reduction in blood pressure 140–169 mmHg, diastolic blood pres-
birth weight of 100 g compared with women who did not sure 90–109 mmHg) during pregnancy.51 This review
use β‑blockers. However, the magnitude of this reduction included 46 randomized trials involving 4,282 women.
was dependent on the underlying disease—no effect, or Antihypertensive drugs, including β‑blockers, had no
a small effect, was observed in women taking β‑blockers significant effects on fetal outcome (death, growth retard­
for hypertension or aortic disease, whereas a pronounced ation, or premature birth). For the mother, the benefit of
effect was evident in women with valvular disease. This the treatment was that the risk of severe hyper­tension
finding indicates that the under­lying disease in the was reduced, with β‑blockers being more effective in this
mother, rather than the effect of the β‑blocker, is likely respect than methyldopa. No differences in other maternal
to be associated with reduced birth weight. Intrauterine outcomes, including pre-eclampsia, were observed.51 In
growth restriction and a fetus that is small for gestational these studies, however, the focus was not on women with
age are widely recognized complications of maternal underlying CVD. The majority of patients had pregnancy-
heart disease. A relationship between these outcomes induced hypertension and were treated only in the second
and maternal medication use is sometimes, but not half of pregnancy. In a Danish study of 175 pregnant
always, indicated.4,5,7,14,46,47 women with heart disease, β‑blockers were independently
associated with being small for gestational age.52 Children
β-Blockers that were prenatally exposed to β-blockers were, on
According to the ROPAC, β‑blockers constitute two- average, 8.6% lighter at birth than babies who were not
thirds of all medication for CVD used during pregnancy.14 exposed. Interestingly, in a subgroup of 69 women without
β‑Blockers are used for the treatment of arrhythmias, structural heart disease, but with isolated tachyarrhyth-
hypertension (for example, in women with repaired mias, β-blockers were the only independent predictor of
coarctation), and aortic dilatation (for example, in women fetal growth restriction.52 Although this finding suggests
with Marfan syndrome). The possible adverse fetal that β-blockers affect fetal growth, the use of these drugs
effects of β‑blockers, therefore, warrant close attention could simply be an indirect marker of severe arrhythmias
in this Review. A meta-analysis was performed to explore and that these arrhythmias are associated with haemody-
whether β‑blockers are associated with birth defects.48 namic impairment that causes slow fetal growth. Although
A total of 12 studies that included women who used the data on the associ­ation between maternal β‑blocker
β‑blockers in the first trimester were taken into account. use and being small for gestational age are inconsistent,
No increased risk of all or major congenital abnormali- the effects that have been reported do not seem to be large
ties was found.48 However, organ-specific malformations enough to be of clinical importance and will not gener-
(cardiovascular defects, cleft palate or lip, and neural tube ally be a reason to withhold this medication when it is
defects) were more prevalent in the offspring of women ­considered beneficial to the mother.
treated with β-blockers. Causality was difficult to ascer- Maternal use of β‑blockers is associated with hypogly-
tain, because the indication for therapy was not always caemia, bradycardia, and hypotension in the neonate.53–56
known and the underlying disease can also be associated The risk of these manageable problems is higher in
with these abnormalities. In addition, recall bias might preterm newborns. 54,56 Neonates of mothers taking
have influenced the findings. On the basis of this meta- β‑blockers, therefore, need to be observed for these effects.
analysis, the use of β‑blockers during pregnancy does not Given the wide experience with labetalol and metoprolol
seem to increase the risk of congenital malformations during pregnancy, these are the preferred drugs for use in
substantially (although a slightly increased risk cannot pregnant women. Atenolol is not recommended for these
be ruled out). patients because it has been associated with birth defects.19

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However, an argument also exists for β‑blockers


having a positive effect on fetal outcome. Right ventric-
ular 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.47,62–64 When the β‑blocker improves
cardiac output, for example in patients with mitral sten­
osis, the positive effects on the fetus through improved
cardiac function could outweigh the direct negative
effects of the β‑blocker (Figure 3).
a
Methyldopa
Methyldopa is an α2‑adrenergic agent that is widely used
to treat hypertension in pregnant patients. Methyldopa
b 3
is safe for the fetus, and is, therefore, a first-line drug
for the treatment of maternal hypertension during preg-
2
nancy.65–67 However, this agent is not always effective.
Other first-line drugs for hypertension are metoprolol
and labetalol (Box 3).
1

Anticoagulants
Effects on the fetus
Anticoagulation therapy can be indicated during preg-
nancy in women with atrial fibrillation, valvular heart
disease (particularly those with mechanical heart
valves), heart failure, pulmonary hypertension, con-
genital heart disease (for example, those with a Fontan
Figure 3 | Effects of cardiovascular medication on the fetus. Direct
Nature negative
Reviews | Cardiology
effects on fetal heart rate and cardiac output can occur (1), as well as a circulation), or venous thrombosis or pulmonary embo-
negative effect on uteroplacental blood flow (2). However, maternal cardiovascular lism. VKAs cross the placenta and are associated with
disease can also negatively influence fetal growth and development (3). When embryopathy, but only when the fetus is exposed to the
medication positively influences maternal cardiac performance (for example, drug during the first trimester of pregnancy.68–70 Effects
β‑blockers in mitral stenosis [a]), uteroplacental blood flow can be enhanced (b), on the fetus include developmental abnormalities of the
with benefits for the fetus. face, skeleton, and central nervous system, as well as
bleeding.69,70 The incidence of embryopathy with expo-
Mechanism of fetal adverse effects sure to VKAs in the first trimester is 6%, according to
Several mechanisms might underlie the potential nega- two reviews published in the early 2000s.68,71 A lower
tive effect of β‑blockers on fetal growth. Evidence from incidence has been reported in subsequent studies,
animal experiments shows that the direct effects of the possibly because the doses of the drugs have reduced
β‑blocker on fetal cardiac development and fetal heart over time.72–76
rate negatively influence outcome. 57,58 Additionally, Evidence is emerging that fetal risk associated with
β‑blockers might restrict fetal growth by reducing mater- VKAs is dose-dependent. In a systematic review pub-
nal cardiac output.47 The uteroplacental circulation is lished in 2014, an incidence of embryopathy of 0.9% in
characterized by the remodelling of spiral arteries into 494 pregnancies in which the mother took a daily war­
low resistance vessels by the invasion of trophoblasts, farin dose of <5 mg was reported.77 The risk of pregnancy
leaving these arteries without autoregulatory capacity and loss is also increased in women who take VKAs during
directly dependent on maternal cardiac output.59,60 The pregnancy,78 and is not limited to the first trimester. The
decrease in maternal cardiac output caused by a β‑blocker risk of pregnancy loss also seems to be dose-dependent,
could negatively affect uteroplacental circulation and thus with a mean incidence of 13.4% with low-dose (<5 mg)
restrict fetal growth. This outcome might, theoretically, be warfarin (which is similar to the rate of pregnancy loss
pronounced in women with CVD. These women might in healthy women) versus 33.0% in women who used an
already be unable to meet the increased demands for unreported or unlimited dose of warfarin. However, the
cardiac output in pregnancy and exposure to a β‑blocker rates differ between studies.77,79 Unfractionated heparin
could exacerbate the problem. Indeed, medication for and LMWH do not cross the placenta and are, there-
CVD (primarily β‑blockers) has been shown to be related fore, not associated with embryopathy. As might be
to impaired uteroplacental blood flow in women with expected, both VKAs and heparins are associated with an
congenital heart disease.8 Impaired uteroplacental blood increased risk of maternal bleeding.76,77,80–83 Intrauterine
flow, with high resistance in the placental vascular bed, haematoma increases the risk of pregnancy loss, early
is associated with fetal growth retardation and maternal delivery, and fetal growth retardation.84 Vaginal delivery
hypertensive disorders of pregnancy.8,61 is contrain­dicated in women taking VKAs because the

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Box 3 | Medication for hypertension during pregnancy19 thromboses. Valve thrombosis has, however, also been
reported with adequate peak anti‑Xa levels.82 Evidence
■■ Angiotensin-converting-enzyme inhibitors, angiotensin-
receptor blockers, and renin inhibitors are
exists that trough anti‑Xa levels might be subtherapeutic
contraindicated throughout pregnancy in pregnant women, even when peak anti‑Xa levels are
■■ Labetalol, methyldopa, and metoprolol are the first-line adequate.34,92 Dosing according to both trough and peak
antihypertensive drugs levels of anti‑Xa has been recommended by some experts,
■■ Nifedipine and other calcium-channel blockers are with target levels of ≥0.6 IU/ml (trough) and ≤1.5 IU/ml
second-line antihypertensive drugs (peak).92,93 However, these levels differ from those rec-
■■ Diuretics are not recommended ommended in the guidelines, which recommend dosing
■■ Newborn babies that were exposed to β‑blockers in utero
according to peak levels only.19,88. Determining whether
need to be observed for hypoglycaemia and bradycardia
dosing according to trough and peak levels of anti‑Xa is
effective in the prevention of valve thrombosis with an
resulting anti­coagulation effects on the fetus increase the acceptably low rate of bleeding should be the objective of
risk of cranial haemorrhage during the birth.19 further research. LMWH seems to be associated with a
lower rate of fetal loss than VKAs (0–10%).78,90,93
Venous thrombosis and pulmonary embolism Few data exist on the rate of valve thrombosis when
For women who experience venous thrombosis or pul- LMWH with anti‑Xa level monitoring is used in the
monary embolism during pregnancy, a therapeutic dose first trimester and VKAs thereafter, and no randomized
of LMWH is the treatment of choice. 19 The efficacy studies have been conducted. Only 56 cases were identi-
and safety of this class of drugs during pregnancy was fied from the literature, among which the rate of valve
demonstrated in a review of 174 patients.85 The risk of thrombosis was 3.6%.91 When unfractionated heparin
recurrence of venous thromboembolism was only 1.15%, was used during the first trimester instead of LMWH, the
‘significant’ bleeding (defined as >500 ml blood loss) reported rate of valve thrombosis was higher at 9.5%.71
occurred in 1.72% of women.85,86 Given that LMWHs are On the basis of the low risk of VKAs to the fetus in the
cleared renally, an increased dose requirement during second and third trimesters of pregnancy, and the high
pregnancy is expected. Dalteparin and enoxaparin risk of valve thrombosis with unfractionated heparin or
should be dosed twice daily in pregnant women, with a LMWH throughout pregnancy, the advice in both the
target peak anti-factor‑Xa (anti‑Xa) level of 0.6–1.2 IU/ AHA/ACC88 and ESC19 guidelines is to use VKAs in the
ml.19,87 Women who are at high risk of venous thrombosis second and third trimester in all women with mechani-
and pulmonary embolism during pregnancy (according cal valves, despite the increased risk of pregnancy loss.
to criteria defined by the Royal College of Obstetricians During the first trimester, both guidelines recommend
and Gynaecologists) should use a prophylactic dose using low-dose VKAs (<2 mg acenocoumarol, <3 mg
LMWH (50 IU/kg body mass dalteparin or 0.5 IU/kg phenprocoumon, or <5 mg warfarin daily) with close
body mass of enoxaparin twice daily).19 This dosing strat- monitoring of international normalized ratio), or dose-
egy seemed to be safe and effective in a review of 2,603 adjusted LMWH or unfractionated heparin when the
pregnancies.85 The ESC guidelines state that anti‑Xa level woman would otherwise need a high dose of VKAs.19,88
monitoring is “reasonable” in pregnant women treated Peak anti‑Xa levels during LMWH therapy should be
for venous thrombosis and pulmonary embolism. 19 monitored weekly, with a target of 0.8–1.2 IU/ml at
Such monitoring is not considered necessary for the 4–6 h after the dose. Unfractionated heparin therapy
prophylactic dose. should be given as continuous infusion, aiming for an
activated partial thromboplastin time of >2 times the
Mechanical valve prostheses control value.19,88 In addition, the AHA/ACC guidelines88
Importantly, pregnant women with mechanical heart contain a recommendation to add aspirin in the second
valves should be managed by experts in tertiary and third trimester.
centres19,88 Among this patient population, the avail-
able (mostly retrospective) data indicate that the inci- Other oral anticoagulants
dence of valve thrombosis is lower with VKAs than with Other oral anticoagulants, such as dabigatran and rivar-
unfractionated heparin or LMWH. For VKAs, the risk oxaban, have been shown to be harmful to the fetus
of thrombo­embolic complications varies between 0% in animal studies, and data in humans are not avail-
and 4%.71,72,74,75,77,79 The data for unfractionated heparin able. These drugs should not, therefore, be used in
are limited, with the rate of maternal thromboembo- pregnancy.19,94–96
lism reported to be 9–33%.71 LMWHs are also associ-
ated with high rates of valve thrombosis, especially when Calcium-channel blockers
anti‑Xa level monitoring is not performed.89 Among Calcium-channel blockers do not seem to be associated
111 women who took LMWH throughout pregnancy, with an increased incidence of congenital anomalies in
with anti‑Xa level monitoring and dose adjustment humans.97–100 However, in one study, an increased risk
according to peak anti‑Xa levels, the rate of mechani- of neonatal seizures with calcium-channel blockers was
cal valve thrombosis was 9%.19,82,83,90,91 Low compliance reported.99 Diltiazem, however, has been demonstrated
with medication and target anti‑Xa levels that were to be teratogenic (causing skeletal abnormalities) in
too low probably contributed to the majority of valve animals and, although little data on its safety in humans

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© 2015 Macmillan Publishers Limited. All rights reserved
REVIEWS

exist, the use of this drug in pregnancy is not recom- Box 4 | Medication for arrhythmias during pregnancy19
mended.19 In the mother, calcium-channel blockers have
Supraventricular tachycardia
a tocolytic effect and can cause maternal hypotension and ■■ For acute conversion of paroxysmal supraventricular
placental hypoperfusion. Verapamil is considered to be tachycardia, intravenous adenosine is the first-line
fairly safe during pregnancy and is recommended in the treatment; intravenous metoprolol or propranolol can
ESC guidelines19 as a second-line drug (after β‑blockers) also be used
for rate control in atrial fibrillation and for treatment of ■■ For long-term management of chronic supraventricular
idio­pathic sustained ventricular tachycardia in pregnant tachycardia, digoxin, metoprolol, and propranolol
are the first-line drugs; if these medications are not
women. However, the potential for fetal atrioventricular
effective, flecainide or sotalol can be used
block and bradycardia cannot be excluded. ■■ Oral verapamil can be used for rate control of
supraventricular tachycardia if other agents have not
ACE inhibitors and ARBs been effective
ACE inhibitors and angiotensin-receptor block- ■■ Procainamide or propafenone can be used if all other
ers (ARBs) are teratogenic and are contraindicated agents prove to be ineffective
throughout pregnancy.19 Renal failure, anuria, skull and Ventricular tachycardia
lung hypo­plasia, craniofacial deformation, and death ■■ Electrical cardioversion is the first choice of therapy
in the fetus have been described.101–103 In the ROPAC, for sustained ventricular tachycardia
fetal anomalies associated with the use of ACE inhibi- ■■ Intravenous procainamide or sotalol are
alternative treatments for sustained monomorphic
tors or ARBs occurred in 8% of pregnancies, which was
ventricular tachycardia when the patent is
more often than with any other type of drug, despite haemodynamically stable
ACE inhibitors or ARBs usually being used only for a ■■ β-Blockers or verapamil (first-line agents) or flecainide,
short period of time.14 In a systematic review, 48% of 118 propafenone, or sotalol (second-line agents) can be
fetuses exposed to ACE inhibitors and 87% of fetuses used in long-term management
exposed to ARBs had complications related to the use of ■■ Amiodarone should be reserved for the treatment of
these medications.101 Congenital anomalies occur after arrhythmias that are life-threatening and resistant to
other therapies
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 Statins
No evidence for teratogenicity of statins was found
Antiarrhythmic agents in a review published in 2012, but a harmful effect of
Amiodarone has been reported to cause transient neo­ these drugs could not be ruled out mainly because the
natal hypothyroidism in 17% of exposed fetuses. 104 studies included were small.107 In a prospective case–
Mild neurological abnormalities (mainly nonverbal control study of 249 fetuses exposed to statins, the rate
learning disabilities) were also described in this study. of birth defects did not differ significantly between
Amiodarone should, therefore, be reserved for life- cases and controls.108 In ROPAC,14 only six fetuses had
threatening arrhythmias that do not respond to other been exposed to statins, one of these babies died and the
therapies.19,104,105 Adenosine and procainamide are not others did not have abnormalities. The available evidence
teratogenic and can be used safely during pregnancy. indicates that the risk of using statins during pregnancy
Flecainide has been used during pregnancy to treat both is low, but the lack of available data means that these
maternal and fetal arrhythmias with no teratogenic drugs cannot be concluded to be completely safe.
effects reported. However, no controlled studies are
available and caution with the use of this drug is advised. Diuretics and aldosterone antagonists
The ESC guidelines19 state that flecainide can be used for Bumetanide, furosemide, and hydrochlorothiazide do not
the treatment of maternal supraventricular tachycardia, seem to be teratogenic, but these drugs can result in oligo-
although β‑blockers and digoxin are the preferred choice. hydramnios (a deficiency of amniotic fluid) and increase
Other indications for flecainide in pregnancy are mater- the risk of electrolyte imbalance in the fetus.19 In preg-
nal atrial tachycardia and cardioversion of atrial flutter nancy, bumetanide, furosemide, and hydrochlorothiazide
or fibrillation.19 Flecainide is preferred over propafenone, are not advised for the treatment of hypertension, but can
because less is known about the safety of propafenone in be used for the treatment of heart failure.19 Spironolactone
pregnancy than for flecainide.19 Disopyramide is not has been associated with feminization of male rats, and
terato­genic, but can cause uterine contractions and is not therefore advised in humans during pregnancy.109
should, therefore, be used with caution. 53 No rand- Given that eplerenone has not been associated with
omized, controlled studies of sotalol during pregnancy adverse effects during pregnancy in animal studies, this
have been conducted. Sotalol might be associated with drug is likely to be a better choice for use in pregnant
growth retardation owing to its β‑blocking effect, as is women than spironolactone. However, no data on the use
the case for other β‑blockers,106 but no other harmful of these drugs in human pregnancy exist and, therefore,
effects on the fetus have been reported. This drug can, eplerenone should be used in pregnant women with heart
therefore, be used during pregnancy when necessary. The failure only when treatment with other diuretics (such as
use of antiarrhythmic medication during pregnancy is furosemide) is ineffective.19 The treatment of women with
summarized in Box 4. heart failure during pregnancy is summarized in Box 5.

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REVIEWS

Box 5 | Medication for heart failure during pregnancy19 inhibitors, during pregnancy and these drugs should
■■ Hydralazine and nitrates can be used instead be used only when absolutely necessary.19,86 The treat-
of angiotensin-converting-enzyme inhibitors and ment of ischaemic heart disease during pregnancy is
angiotensin-receptor blockers s­ummarized in Box 6.
■■ Dopamine can be used for positive inotropy
■■ β-Blockers can be used (as recommended for Medication for obstetric indications
nonpregnant women) Patients with CVD often need medication for obstetric
■■ Diuretics can be used for clinical signs of heart failure
reasons, for example the prevention of premature labour
■■ Spironolactone should be avoided
or postpartum haemorrhage. As these medications can
have cardiovascular adverse effects, cardiologists need to
Digoxin be able to provide advice on their appropriate use.
Digoxin is not teratogenic in humans. Digoxin intoxica-
tion has, however, been associated with miscarriage and Tocolytic agents
fetal death.53,110,111 As discussed earlier, the dose require- Nifedipine is a calcium-channel blocker that is frequently
ment for digoxin can decrease during pregnancy because used as a tocolytic agent to halt uterine contractions and
of the decrease in albumin concentration, but increased prevent premature labour.120 A high dose of nifedipine (up
renal clearance usually prevails and leads to an increased to 110 mg per day) is often used, which is associated with
dose being required. Dosing of this drug should not be hypotension. This therapy is, therefore, not suitable for
based on measurement of the blood level of digoxin women with obstructive left-sided lesions, such as aortic
because digoxin-like substances present in the pregnant stenosis or hypertrophic cardiomyo­pathy. Nifedipine
woman can produce an inaccurate test result.53 Dosing is also contraindicated in women with Eisenmenger
should be based on the clinical effect (for example, heart syndrome because it increases the right-to-left shunt.
rate in atrial fibrillation). β2‑Adrenergic receptor agonists, such as ritodrine, have
severe adverse effects, including tachycardia and chest
Dopamine pain, and are contraindicated in patients with CVD.
Dopamine is used as an inotropic drug in patients with The NSAID indomethacin is sometimes used in early
severe heart failure. Experience with this drug in preg- preterm labour and can be used in patients with CVD
nant women is limited. When necessary, dopamine can when other tocolytic agents are not effective. Atosiban,
be used according to the ESC guidelines.19 an oxytocin-receptor antagonist, has no reported cardiac
adverse effects and is advised as a first-line tocolytic agent
Platelet aggregation inhibitors in women with CVD.120
The use of aspirin (dose unspecified) in the first trimes-
ter of pregnancy has been associated with a possible Postpartum haemorrhage prevention
increased risk (twofold to threefold) of gastroschisis.112,113 At the beginning of the third trimester, a delivery manage-
In addition, aspirin use (dose unspecified) throughout ment plan for women with CVD should be constructed
pregnancy has been associated with premature closure by a multidisciplinary team. This plan must state explic-
of the ductus arteriosus.114–116 The antiplatelet proper- itly which drugs can be used to prevent and treat post-
ties of aspirin might also increase the risk of fetal bleed- partum haemorrhage. Oxytocin is frequently used as a
ing risk (including intracranial bleeding). However, the routine medication to cause contraction of the uterus after
data are controversial and generally reassuring,117,118 delivery. This drug can cause vasodilatation, leading to
particularly for low-dose aspirin (up to 100 mg daily),116 severe hypotension and reflex tachycardia, and has also
which is widely used during pregnancy for prevention been associated with coronary vasoconstriction.121–123
of premature birth and pre-clampsia. Low-dose aspirin A bolus injection of 5–10 IU oxytocin should not be used
seems to be safe throughout pregnancy.114 in patients with CVD. Small bolus injections of 0.1–1.0 IU,
Clopidogrel has been shown to be safe during preg- or a continuous infusion, are safe. Ergometrine, an
nancy in animal studies, but experience in humans α‑adrenergic receptor agonist, can cause coronary vaso­
is limited and caution with this drug is advised. 119 spasm, pulmonary vasoconstriction, and hypertension
Insufficient data exist on other platelet aggregation and should be avoided in most pregnant women with
inhibitors, such as ticagrelor and glycoprotein IIb/IIIa 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
Box 6 | Anti-ischaemic drugs used during pregnancy19 in pregnant women with CVD.119 Misoprostol, a prosta-
■■ β-Blockers are the first-line anti-ischaemic drugs
glandin E1 analogue, has fewer adverse cardiovas­cular
■■ Calcium-channel blockers and nitrates can also effects than carboprost and ergometrine and is, there-
be used fore, a preferred drug for the prevention of p­ostpartum
■■ Statins are associated with a low risk of congenital haemorrhage in addition to oxytocin.
malformations and should be avoided if possible
■■ Low-dose aspirin is the first choice of antiplatelet agent Conclusions
■■ Clopidogrel can be considered, but other antiplatelet The number of pregnant women with CVD is increas-
agents are not recommended
ing, and one-third of these patients use medication

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

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