Pregnancy and cardiovascular disease

Karishma P. Ramlakhan MD1, Mark R. Johnson MD PhD2 and Jolien W. Roos-Hesselink MD

PhD1*

1Department of Cardiology, Erasmus University Medical Center, Rotterdam, the Netherlands.

2Academic Department of Obstetrics and Gynaecology, Imperial College London, Chelsea

and Westminster Hospital, London, United Kingdom.

*e-mail: j.roos@erasmusmc.nl .

Abstract | Cardiovascular disease complicates 1-4% of pregnancies – more, when including

hypertension – and is the leading cause of maternal death. In women with known

cardiaccardiovascular pathology such as congenital heart disease, timely counselling is

possible and the outcome is relatively good. In contrast, maternal mortality is high in women

with acquired heart disease presenting during pregnancy (e.g. acute coronary syndrome or

aortic dissection). Worryingly, the prevalence of acquired cardiaccardiovascular disease is

rising as older maternal age, obesity, diabetes and hypertension become more common in the

pregnant population. Management of cardiaccardiovascular disease in pregnancy provides a

challenge due to the unique maternal physiology, characterised by profound changes to

multiple organ systems. The presence of the fetus compounds the situation as both the disease

and its management may affect it adversely. Equally, avoiding essential treatment because of

potential fetal harm risks a poor outcome for both mother and child. In this review, we

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examine how the physiological adaptations of pregnancy may impact women with heart

disease and, conversely, how heart disease may compromise the adaptations and their

intended purpose: the development and growth of the fetus. We further review current

knowledge on the cardiometabolic complications that can arise during pregnancy.

Introduction

The burden of pregnancy on the cardiovascular system can undemask previously undiagnosed

cardiovascular problems and induce de novo disease. Cardiovascular diseases are estimated to

complicate 1-4% of pregnancies globally; even more if hypertension, which complicates 10%

of pregnancies, is included in the definition.1,2 The burden of pregnancy on the cardiovascular

system can expose previously undiagnosed cardiac problems and induce de novo disease.In

developing countries, both prevalence and mortality rates are poorly reported, except for

hypertensive disorders, which are a known major cause for maternal mortality.3 In developed

countries, aAlthough cardiovascularac disease is relatively infrequent, cardiovascular

diseaseit is the leading cause of maternal mortality.4-6 The percentage of maternal deaths due

to cardiaccardiovascular causes has risen from 3% to 15% in the last thirty years in developed

countries and is expected to increase further.6 Several reasons for this can be identified. The

number of pregnancies in women >35 years old has steadily increased over the past decades,

as women are delaying childbearing as a lifestyle choice.7 Additionally, the limits of

childbearing age have been extended by assisted reproductive technology (ART).8 This has

increased the proportion of older pregnant women with more acquired comorbidities and

contributed to the higher rates of maternal morbidity, mortality and adverse obstetric

outcome.9 Secondly, the prevalence of cardiovascular risk factors such as chronic

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hypertension and diabetes in pregnant women is increasing10,11 primarily driven by higher

rates of obesity,12,13 but also reflecting the increasing maternal age. Although overall smoking

rates are declining, prevalence among young women is on the rise.14,15 Medical advances and

ART have enabled pregnancy in women with chronic medical conditions that would hitherto

have prevented them from becoming pregnant. Pregnancy in these diseases, such as Turner’s

syndrome, may also have a negative influence on cardiaccardiovascular health.16,17 Lastly,

improved surgical approaches and medical therapy for women with congenital heart disease

have resulted in more women reaching childbearing age and choosing to become pregnant.

Many have significant residual problems and even though successful operations have enabled

them to live without any functional limitations, the haemodynamic stress of pregnancy might

precipitate cardiaccardiovascular complications 18. In conclusion, cardiac cardiovascular

disease in pregnancy is a topic of increasing relevance and importance for a broad spectrum of

health care providers, including – but not limited to –both cardiologists, and obstetricians,

anaesthesiologists, midwives, internists and general practitioners. Particularly in acquired

disease, early diagnosis and appropriate management is essential to reduce maternal mortality.

In this review, we The first aim of this review is to provide a comprehensive report on

consider the impact of both the physiological changes duringof pregnancy, which forms the

basis for understanding pathological complications. and of the pathological complicationsThe

second aim is to review cardiovascular and cardiometabolic pathology, acquired or presenting

during pregnancy. This includes , including hypertensive disorders, gestational diabetes

mellitus (GDM), thromboembolic disorders, ischemic heart disease, (peripartum)

cardiomyopathy, endocarditis, aortic disease, arrhythmias and altered pharmacokinetics.

Management of pre-existing cardiaccardiovascular disease or cardiaccardiovascular

complications in the fetus will not be discussed. The majority of data on cardiovascular

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disease in pregnancy is from Western regions, which hinders a global understanding of the

impact of cardiovascular disease in pregnancy.

Physiology of pregnancy

Pregnancy affects nearly every maternal organ system. Understanding these adaptations is

crucial to allow pathology to be differentiated from physiology, to better anticipate

complications and to design a truly personalised approach. Figure 1 summarizes the most

important cardiovascular changes (FIG. 1).

Haemodynamics

The extensive adaptions of the maternal cardiovascular system initially create the capacity to

maintain adequate uteroplacental perfusion throughout pregnancy. By 8 weeks gestational age

(GA), systemic vascular resistance (SVR) has already fallen by 10-30% and will further

decrease to a nadir between 20 and 26 weeks of pregnancy.19-21 This results in a decline in

mean arterial pressure (MAP)22, which reverses from 26-28 weeks, reaching pre-pregnancy

values again at full term.20,22 Underlying mechanisms of peripheral vasodilatation include

increased vascular compliance, reduced response to vasoconstrictive agents such as

angiontensin II and increased vascular relaxing agents such as nitric oxide.23-26 The fall in

SVR reduces afterload and preload, which requires volume expansion to compensate. The

SVR drop activates the renin-angiotensin-aldosterone (RAAS) system, causing water and

sodium retention.23,24,26 Total volume expansion, mostly manifesting as plasma volume

increase (1100-1600 cc), can be up to 45% at term and is proportional to the growth of the

fetus.24,27 Correspondingly, a low resistance uteroplacental circulation is created, which, as the

fall in SVR gradually reverses, results in a progressive increase in blood flow to the placenta,

keeping pace with the increased requirements for fetal growth and development.

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The heart rate also rises, as low afterload stimulates the baroreceptors in the cardiopulmonary

and renal systems to activate the sympathetic nervous system. Catecholamine release is

triggered, increasing contractility and heart rate by 15-25% throughout pregnancy.20,28 These

changes increase stroke volume by 20-30%.20 Cardiac output (CO) rises with at least 30-50%

in the first two trimesters, but findings in the third trimester are conflicting. At 26-30 weeks

adaptation seems to be mostly completed, and afterwards CO is reported to either remain

stable, increase or decrease slightly according to varying studies.20,28-30 Anatomically, the

increase in preload and myocardial contractility manifests in larger left ventricular mass (24-

34%), increased relative wall thickness (10%) and a larger left atrial diameter (14%).20,28,31

In childbirth, many of the haemodynamic changes reach their peak. Pain, stress and the

physical exertion of bearing down lead to increases in blood pressure, heart rate and cardiac

output.20,29,32 Contractions further amplify this effect, as with each contraction, 300-500cc of

blood is returned from the uteroplacental to the systemic circulation. Immediately after

delivery, stroke volume and cardiac output rise due to the (now permanent) auto-transfusion

from the uteroplacental circulation and the removal of aortocaval compression.20

As demonstrated in figure 2, the pattern of these physiological changes is are hypothesized to

be linked to the timing of cardiovascular events during pregnancy (FIG. 2). In a worldwide

registry of pregnancies in women with cardiaccardiovascular disease, the Registry of

Pregnancy and Cardiac Disease (ROPAC), the timing of heart failure was examined. When

CO plateaus at 26-30 weeks, the incidence of heart failure peaks for the first time.33 The

second peak in both CO and heart failure occurs after delivery, after when the autotransfusion

of blood from the uteroplacental circulation creates an "overload" state. The defined peaks of

cardiac failure contrast with the gradual increase in the incidence of pre-eclampsia throughout

pregnancy (Fig. 2).34

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Haematology

Pregnancy is a hypercoagulable state, designed to limit blood loss during labour. The

concentration of all clotting factors, excluding factors XI and XIII, increases by up to 50%

throughout pregnancy. Fibrinolysis is inhibited and levels of anticoagulatory agents (such as

antithrombin III and protein S) decrease.35,36 This predisposes to thromboembolic

complications. Erythropoiesis is stimulated by placental hormones and increased renal oxygen

consumption due to increased glomerular filtration rate (GFR).37,38 However, red blood cell

count increases to a lesser extent than plasma volume does. The resulting physiological

haemodilution of pregnancy combined with iron deficiency may progress to anaemia.27 The

white cell count also increases, in particular during labour and in the early postpartum period.

It is important to differentiate this mild physiological leucocytosis from infection, which is

also prevalent in the same period. Platelet count often decreases, but usually remains within

normal range.37

Metabolism

Glucose metabolism adapts to promote fetal growth and in preparation of lactation. Maternal

fasting glucose levels drop throughout pregnancy because of fetal glucose uptake, higher

peripheral consumption and dilution due to volume expansion.39 From the second trimester

on, insulin production increases as insulin sensitivity is lowered through diabetogenic

hormones, such as human placental lactogen, cortisol, prolactin, growth hormone and

progesterone.39-41 Environmental and genetic factors contribute to the mother’s capacity to

compensate for the increased insulin resistance, and a failure of compensatory mechanisms

results in the development of GDM.

Respiratory

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High fetal, placental and uterine oxygen consumption, increased carbon dioxide production

and the respiratory stimulating effect of progesterone combine to cause hyperventilation.42 A

physiological compensated respiratory alkalosis can be found in arterial blood gas

measurements.43 The growing uterus elevates the diaphragm, which decreases functional

residual capacity by 20-30% at full term.43-45 Respiratory rate changes minimally or not at

all,42 but tidal volume increases due to high progesterone concentrations. This results in a 20-

50% increased minute ventilation.42,43

Renal

The changes in plasma volume and cardiac output amplify renal perfusion, prompting a 40-

50% higher GFR in the first trimester.23,26 Kidney volume increases by 30% and the collecting

system dilates, which predisposes for pyelonephritis and hydronephrosis.26,46,47 Additionally to

water and sodium retention through RAAS upregulation, proteinuria and albumin excretion is

increased.48

Gestational Hhypertensive disorders

Epidemiology

Hypertensive disorders complicate 10% of pregnancies and include chronic hypertension,

pregnancy-induced hypertension, (pre-)eclampsia and HELLP (haemolysis, elevated liver

enzymes and low platelets) syndrome.2,49,50 This spectrum accounts for 10-16% of maternal

mortality worldwide.51,52 The incidence of pre-eclampsia is 3.4% in the Western world53 and

although the mortality rate in the UK has fallen from 0.83 to 0.13 deaths per 100.000

maternities in the last decade, pre-eclampsia still carries a significant burden of disease both

in the short and longer term.4,5 Hypertensive disorders are estimated to cause 10-15% of

maternal deaths in Asia, 16-17% in Africa and 22% in Latin America and the Caribbean.54

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Pathophysiology

At the heart of the pathophysiology of hypertensive disorders of pregnancy is a complex

interaction between maternal and fetal factors that is not yet fully understood. The first

abnormalities can be observed in the first weeks of pregnancy, as abnormal placentation

(stage I) provokes systemic endothelial dysfunction (stage II). Despite this, symptoms

typically do not present until the 2nd or 3rd trimester.34,49 Figure 3 shows a suggested

multifactorial model of the pathogenesis (FIG. 3). In the first weeks of normal pregnancy

implantation, trophoblasts from the conceptus remodel the uterine spiral arteries to create a

low-vascular resistance.55 In pre-eclampsia, this process is suboptimal, resulting in a high-

resistance utero-placental circulation and, ultimately, placental ischemia.56 The resulting

placental hypo-perfusion drives the release of sFlt and sEng, which impair maternal VEGF,

PlGF and TGF function, resulting in systemic endothelial dysfunction, hypertension and

renal impairment.57-59 The typical symptoms of pre-eclampsia include headaches, visual

disturbances, nausea and/or vomiting, epigastric or right upper quadrant pain and peripheral

oedema, although their presence is not necessary for diagnosis.60,61 Pathophysiological

differences exist between early and late onset pre-eclampsia, expressed in contrasting

haemodynamic states: early onset pre-eclampsia is associated with reduced CO increase,

whereas greater CO increase can be observed in later pre-eclampsia.62 The difference may

relate to more severe placental dysfunction in early pre-eclampsia, leading to failure to induce

the physiological fall in SVR.

Epidemiology

Hypertensive disorders complicate 10% of pregnancies and include chronic hypertension,

pregnancy-induced hypertension, (pre-)eclampsia and HELLP (haemolysis, elevated liver

enzymes and low platelets) syndrome.2,49,50 This spectrum accounts for 10-16% of maternal

mortality worldwide.51,52 The incidence of pre-eclampsia is 3.4% in the Western world53 and

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although the mortality rate in the UK has fallen from 0.83 to 0.13 deaths per 100.000

maternities in the last decade, pre-eclampsia still carries a significant burden of disease both

in the short and longer term.4,5

Risk assessment and diagnosis

Risk factors are nulliparity, multiple pregnancy, prior pre-eclampsia, chronic hypertension,

diabetes, obesity, maternal age >35 and several chronic systemic diseases.61 Gestational

hypertension is defined as de novo hypertension (>140/90 mmHg) presenting after 20 weeks

GA.61 For pre-eclampsia, the traditional requirement of the presence of both hypertension and

proteinuria (>30 mg/mmol) has been replaced by more inclusive criteria. Pre-eclampsia is

now diagnosed as the combination of hypertension and proteinuria and/or fetal growth

restriction and/or biochemical or haematological abnormalities.63 These abnormalities may

culminate in HELLP syndrome in 25% of pre-eclampsia patients.63 In 2%, pre-eclampsia

progresses to eclampsia, an obstetric emergency characterized by tonic-clonic seizures.64

Management

High-risk patients as described above should receive low dose aspirin (150 mg/day) from 12

to 28 weeks GA.Low-dose aspirin prophylaxis is recommended in women at high risk of

preeclampsia and should be initiated between 12 weeks and 28 weeks of gestation (ideally

before 16 weeks and possibly before 12 weeks ) and continued daily until delivery.63,65,66 The

recommended daily dosage varies regionally, with guidelines from the American College of

Obstetricians and Gynecologists (ACOG) prescribing 81 mg and the European Society of

Cardiology (ESC) 100-150 mg.1,61, however, a meta-analysis suggest that doses >100mg are

more effective ().

When hypertension is diagnosed, a target diastolic BP of 85 mmHg (and systolic BP of 110-

140) should be aimed for, using the antihypertensive drugs of preference: oral methyldopa,

calcium channel blockers (e.g. nifedipine) or beta blockers (e.g. labetalol).63,67 Severe

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hypertension (≥>160/110mmHg) should be treated promptly in a clinical setting with

nifedipine, or intravenous labetalol or intravenous hydralazine, in combination with

magnesium sulphate for neuroprotection.63,64 Induction of labour is indicated at 37 weeks GA

or earlier based on disease severity, as delivery is considered the only cure.68 Nonetheless,

postpartum (pre-)eclampsia can occur up to six weeks after delivery.69 As demonstrated in

figure 4, the risk of developing cardiovascular disease in the future is increased for these

women, probably owing to common risk factors and developmental pathways (FIG. 4).70

Annual follow-up to evaluate blood pressure and cardiometabolic status is recommended.63

Gestational diabetes mellitus

Epidemiology

Gestational diabetes mellitus (GDM) is the most common metabolic disease of pregnancy,

with an overall prevalence of 6-13%. Geographic variation is large due to the impact of

genetic and environmental factors, with the highest prevalence found in the Middle East and

North Africa and the lowest in Europe.71 Associated adverse maternal outcome includes pre-

eclampsia, Caesarean section and post-partum haemorrhage. Adverse fetal outcome includes

macrosomia (large fetal birth weight) and consequently, obstetric complications like shoulder

dystocia and prematurity, and an increased risk of stillbirth.72,73 Long-term implications for the

child are impaired glucose metabolism, subsequent obesity and problems in

neurodevelopment (mental and psychomotor function).74-77

Pathophysiology

Placental hormones increase glucose production and insulin resistance, requiring

progressively higher insulin production from pancreatic beta cells. When the beta cells fail to

meet this demand a persistent hyperglycaemic state may develop.39,40 Genetic and

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environmental factors also play a significant role in the development of GDM.78,79 Women

who ultimately develop GDM demonstrate lower insulin sensitivity even before pregnancy.

This suggests pregnancy is a stress test for underlying subclinical metabolic dysfunction.80

Epidemiology

GDM is the most common metabolic disease of pregnancy, with an overall prevalence of 6-

13%. Geographic variation is large due to the impact of genetic and environmental factors.71

Associated adverse maternal outcome includes pre-eclampsia, Caesarean section and post-

partum haemorrhage. Adverse fetal outcome includes macrosomia (large fetal birth weight)

and consequently, obstetric complications like shoulder dystocia and prematurity, and an

increased risk of stillbirth.72,73 Long-term implications for the child are impaired glucose

metabolism, subsequent obesity and problems in neurodevelopment (mental and psychomotor

function).74-77

Diagnosis and risk assessment

Risk factors are maternal advanced age, obesity, GDM or macrosomia in a previous

pregnancy, diet and lifestyle factors and ethnicity.78,79 International guidelines disagree on

whether universal screening, such as in the US, or selective screening in women with risk

factors, such as in the UK, should be performed.81,82 Screening is ideally performed between

24-28 weeks and through oral glucose tolerance test (OGTT). The diagnosis GDM is

confirmed when plasma glucose levels are >5.6 mmol/l (fasting) or >7.8 mmol/l (after 2 hours

of 75 gram OGTT).83

Management

The management of GDM includes blood glucose monitoring and dietary advice; drug

therapy is introduced when diet alone fails to control glucose levels. InsulinMetformin is

preferrablepreferable, with insulin metformin and glibenclamide glyburide as alternative and

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inferior options, as both cross the placenta and are less successful in attaining maternal

glycemic control.81 Treatment lowers fetal birth weight and the rate of serious perinatal

complications: fetal death, shoulder dystocia, bone fracture and nerve palsy.84 Although

normal glucose metabolism is restored postpartum, life time risk of developing type 2

diabetes is increased at least sevenfold.76 Other risks include metabolic syndrome and

cardiovascular disease.85 After delivery, the glucose tolerance of all women with GDM should

be re-evaluated by a 75 gram OGTT at 4-12 weeks postpartum and every two years thereafter

in cases of normal glucose.Long-term follow-up is recommended, with diabetes screening at

the postpartum visit and every 1-3 years thereafter by the general practitioner.81

Thromboembolic disorders

Epidemiology

Venous thromboembolism (VTE) complicates 0.5-2.0 per 1.000 pregnancies and causes 1.1

deaths per 100.000 pregnancies.86-88 VTE includes deep-vein thrombosis (DVT), pulmonary

embolism and cerebral venous thrombosis. Postpartum incidence is up to 5 per 1000

pregnancies.88 DVT is three times more common than pulmonary embolism.87,88 In developing

countries, VTE causes 3% of maternal deaths, whereas in developed countries this proportion

is estimated to be 14%.54

Pathophysiology

Pregnancy is a hypercoagulable state due to an increase in clotting factors and a decrease in

anticoagulatory and fibrinolytic agents.35,36 Additionally, venous flow velocity is reduced

because of physiological vasodilation and vena cava compression by the gravid uterus.89

During pregnancy the risk of venous thromboembolism (VTE) is five-fold increased,

including deep-vein thrombosis (DVT), pulmonary embolism and cerebral venous

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thrombosis.88,90 This effect peaks in the puerperium and can be exacerbated by comorbidities,

periods of immobilization and interventions such as Caesarean section.

Epidemiology

VTE complicates 0.5-2.0 per 1.000 pregnancies and causes 1.1 deaths per 100.000

pregnancies.86-88 Postpartum incidence is up to 5 per 1000 pregnancies.88 DVT is three times

more common than pulmonary embolism.87,88

Diagnosis and risk assessment

Pregnancy-related risk factors for VTE are GDM, multiple pregnancies, nulliparity, Caesarean

section and pre-eclampsia.86,87 Assisted reproductive technologies are an increasingly relevant

risk factor, with ovarian hyperstimulation syndrome carrying a hundredfold greater risk of

VTE.91 General risk factors include previous VTE, obesity, smoking and thrombophilia (e.g.

factor V Leiden-mutation, deficiencies in protein S, C and antithrombin).86 Due to intra-

individual biological variation in D-dimer in pregnancy, repeated D-dimer measurements

should not be used in the evaluation of thromboembolic events during pregnancy.92

Management

Adequate prophylaxis for patients at risk is necessary.93 Direct oral anticoagulants cross the

placenta with teratogenic effects and should preferably not be used, especially in the first

trimester. Low molecular weight heparin (LMWH) does not cross the placenta and is the first

choice as prophylaxis or treatment in patients with VTE.94 When treating acute VTE during

pregnancy, initial dosage should be based on early pregnancy body weight and then corrected

by the measurement of peak and trough antifactor Xa activity.95 Special care, directed by

current guidelines, should be taken in the peripartum period for the precarious balance

between risk of bleeding and of recurrent VTE1.

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Acute coronary syndrome

Epidemiology

Acute coronary syndrome (ACS) is a major cause of maternal mortality in developed

countries, accounting for 20% of cardiovascular deaths.5 Incidence is 6 per 100.000 deliveries

and is increasing, which reflects the growing prevalence of cardiovascular risk factors in the

pregnant population. The case fatality rate is 5%.96 Data on developing countries is lacking.

Pathophysiology

Unlike inIn contrast to the general population, in pregnant women atherosclerosis is not the

most important cause of acute coronary syndrome (ACS) in pregnancy. Instead, sSpontaneous

coronary artery dissection (SCAD) leads is the most frequent cause (43%), whereas

atherosclerosis accounts for 27% of ACS. Other pathological mechanisms include clots (17%)

and spasms (2%). Normal coronary anatomy is found in 18% of women with ACS during

pregnancy97. The high frequency of SCAD may be due to pregnancy-induced changes in

vessel structure, along with the increased haemodynamic burden in late pregnancy (Fig. 1).98,99

ACS presents most frequently in the postpartum period, followed by the third trimester. The

left anterior descending artery or left main segment are most commonly affected and, with

multi-vessel disease beingis prevalent.97

Epidemiology

Acute coronary syndrome is a major cause of maternal mortality, accounting for 20% of

cardiac deaths.5 Incidence is 6 per 100.000 deliveries and is increasing, which reflects the

growing prevalence of cardiovascular risk factors in the pregnant population. The case fatality

rate is 5%.96

Diagnosis and risk assessment

Risk factors are obesity, age >35 years, smoking, diabetes, chronic hypertension and positive

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family history,5,96,97 but these risk factors are primarily related to atherosclerosis and may be

absent in conditions such as SCAD.97 SCAD may be associated with inherited aortopathy

fibromuscular dysplasia (FMD) or genetically-mediated vasculopathy.100,101 ACS can present

atypically in women and particularly in pregnancy. All complaints of chest pain, but also pain

in the neck, stomach, arms or dyspnoea on exertion should be taken seriously and promptly

assessed with electrocardiogram (ECG) and cardiac troponins tests. If performed at a pain-

free momentduring complaintsan episode of chest pain, a single normal ECG makes ischemia

unlikely, but consider serial ECGs if clinical suspicion persists.5

Management

When performing invasive diagnostic or treatment techniques, the high increased rate of

iatrogenic coronary dissection in this population needs to be considered.97 In ST elevation

myocardial infarction (STEMI), primary percutaneous intervention (PCI) using bare-metal

stents (BMS) is the first choice of treatment in the third trimester. BMS require a month of

dual antiplatelet therapy (DAPT), which allows for timely interruption during the peripartum

period to prevent bleeding complications. Although there is less experience with new-

generation drug-eluting stents during pregnancy and they necessitate at least 3 months of

DAPT, they can be used in the first two trimesters.102 Blind use of thrombolytic treatment is

not recommended, as a relatively large portion of women has normal coronary anatomy or

SCAD.97 In low-risk non-STEMI, non-invasive therapy can be considered. Fetal safety needs

to be considered when choosing pharmacological treatment, which is hindered by the lack of

evidence for many drugs. Angiotensin-converting enzyme (ACE) inhibitors and statins are

contra-indicated in pregnancy, although more recent data suggest that statins may be safe.103-

106 Anticoagulatory agents such as clopidogrel are not well investigated and although they

seem safe, their use should be limited. Antiplatelet therapy with low dose aspirin is

considered safe. Follow-up after SCAD should include imaging of all vessels from brain to

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pelvis at least once to assess for FMD and other non-coronary arterial abnormalities, using

computed tomography angiography (CTA) or magnetic resonance angiography (MRA).101

(Peripartum) Cardiomyopathy

Epidemiology

The incidence of cardiomyopathies first presenting during pregnancy is not well studied,

except for peripartum cardiomyopathy (PPCM), which is unique to pregnancy. The incidence

of PPCM varies greatly between countries, as ethnicity is an impactful risk factor, ranging

from 1 per 100 pregnancies in Nigeria to 1 per 10.000 in Denmark.107,108 The worldwide

mortality rate is 2.4%.109 In a nation-wide study in the United States with an incidence of 10.3

per 10.000 live births and a mortality rate of 1.3%, cardiogenic shock as result of heart failure

occurred in 2.6% and cardiac arrest in 2.1%.110

Pathophysiology

Pregnancy can reveal previously asymptomatic cardiomyopathy, which may be congenital or

acquired. Increases in CO and blood volume, which make pregnancy as a “stress test” for the

cardiovascular system, can provoke complaints from dilated cardiomyopathy in particular.1,30

Peripartum cardiomyopathy (PPCM) is unique to pregnancy and diagnosed when no other

cause of heart failure can be identified.111 The A proposed pathophysiological pathway is a

pro-inflammatory state, where oxidative stress triggers the metabolism of prolactin to an anti-

angiogenic form, which causes myocardial and vascular damage.112 PPCM typically leads to

heart failure with impaired left ventricular ejection fraction (LVEF), occurring most

frequently late in pregnancy or postpartum.109,113 The resulting left ventricular failure can be

permanent and has high recurrence risk in the next pregnancy.111

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Epidemiology

PPCM is rare, but the consequences are far-reaching. The incidence also varies greatly

between countries, as ethnicity is an impactful risk factor. Described incidences range from 1

per 100 pregnancies in Nigeria, to 1 per 10.000 in Denmark.107,108The incidence is 10.3 per

10.000 live births and increasing, with a mortality rate of 1.3-2.4%.109 Cardiogenic shock as

result of heart failure occurs in 2.6% and cardiac arrest in 2.1%.110 The incidence also varies

greatly between countries, as ethnicity is an impactful risk factor. Described incidences range

from 1 per 100 pregnancies in Nigeria, to 1 per 10.000 in Denmark.

Diagnosis and risk assessment

The symptoms related to Ddeveloping heart failure as consequence of cardiomyopathy isare

easily dismissed as being part of the normal physiological adaptation to pregnancy. When

suspected, the diagnostic workup should include ECG, natriuretic peptides, echocardiography

and chest X-ray. Computed tomography (CT), coronary angiography or cardiac magnetic

resonance imaging (MRI), if available, may provide additional information depending on the

clinical presentation.113

For PPCM specific risk factors exist, includingRisk factors are African ethnicity, multiple

pregnancy, multiparity, advanced age, diabetes, smoking and pre-eclampsia.113 PPCM is a

diagnosis of exclusion and other possible diagnoses should first be explored.111 Developing

heart failure is easily dismissed as being part of the normal physiological adaptation to

pregnancy. When suspected, the diagnostic workup should include ECG, natriuretic peptides,

echocardiography and chest X-ray. Cardiac magnetic resonance imaging (MRI), computed

tomography (CT) or coronary angiography may provide additional information depending on

the clinical presentation.113

Management

Standard heart failure care should, when possible, be adapted to avoid fetotoxic drugs when

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possible, most notably angiontensin-converting-enzyme (ACE) inhibitors and angiotensin II

receptor blockers (ARBs). ESC guidelines recommend against early implantation of cardiac

assist devices, allowing time for improvement on medication.1 In patients with PPCM, Iin

addition to standard heart failure care, prolactin blockade through bromocriptine treatment has

been described shows promising results, in to improvinge mortality, morbidity and to

increaseincreasing the chance of full LV-recovery.,114,115 although the first placebo-controlled

trial to prove its efficacy is still ongoing. PPCM is rare, but the consequences are far-reaching.

One month after diagnosis, 87% of patients are still in clinical heart failure, 7% experience an

embolic event and 4% need an implantable device.109 Timely and multidisciplinary pre-

conception counselling is extremely important, as persistent LV dysfunction (LVEF <50-

55%) is a contra-indication for subsequent pregnancies.1

Endocarditis

Epidemiology

No good studies are available describing the incidence of endocarditis during pregnancy. Case

reports mostly involve women with congenital heart disease (overall incidence 0.1%) or

prosthetic heart valves (overall incidence 0.3-1.2%).116 However, reported maternal mortality

is very high (11-33%).117-120

Pathophysiology

There is no evidence of a different aetiology for endocarditis in pregnancy. Although

infection severity for some pathogens is increased through immunologic alterations by

pregnancy hormones, infection susceptibility is not convincingly increased.121

Epidemiology

No good studies are available describing the incidence of endocarditis during pregnancy. Case

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reports mostly involve women with congenital heart disease (overall incidence 0.1%) or

prosthetic heart valves (overall incidence 0.3-1.2%).116 However, reported maternal mortality

is very high (11-33%).117-120

Diagnosis and risk assessment

Risk groups are intravenous drug users, women with congenital or rheumatic heart disease

and women with cardiac prostheses.118 Prosthetic heart valves, particularly, carry a long-term

endocarditis risk. Non-valve-containing prostheses are only associated with increased risk in

the first six months after implementation, before endothelialisation is complete.122 The same

workup as for the general population applies, with a key role for obtaining blood cultures,

echocardiography and supplementary advanced imaging.116

Management

Current guidelines do not recommend prophylaxis for either vaginal or Caesarean delivery

even in high-risk groups1,116, but data is limited and the high mortality rates may justify

prophylaxis in selected patients. Antibiotic therapy should be based on culture and sensitivity

tests, as well as fetal safety. Considering the high mortality rate and potentially increased

infection severity, patients should be treated by a multidisciplinary team in an appropriate

centre.116,121

Aortic disease

Epidemiology

Aortic dissection occurs in only 0.4-0.55 per 100.000 pregnancies, but is nonetheless a major

cause of maternal cardiovascular death in developed countries due to the dramatically low

survival chances (prehospital mortality 53%, case fatality rate 60%).5,123,124 The ascending

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aorta is predominantly affected, accounting for 79% of dissections.125 Insufficient

epidemiological data from non-Western countries is available.

Pathophysiology

Aortic dimensions and compliance increase in normal pregnancy, which becomes more

marked with increasing parity.126,127 Loss of corrugation of elastic fibers, fragmentation of

reticulin fibers and diminished acid mucopolysaccharides can be observed in the aortic vessel

wall.99 Estrogen inhibits elastin and collagen deposition, while progesterone accelerates non-

collagenous protein deposition.128 The combination of changes in vascular function, structure

and increased haemodynamic stress increase the risk of aortic dissection.98,99 Dissection occurs

most frequently postpartum or near delivery, when cardiac output and blood volumes reach

their peak.28,29,32

Epidemiology

Aortic dissection occurs in only 0.4-0.55 per 100.000 pregnancies, but is nonetheless a major

cause of maternal cardiac death due to the dramatically low survival chances (prehospital

mortality 53%, case fatality rate 60%).5,123,124 The ascending aorta is predominantly affected,

accounting for 79% of dissections.125

Diagnosis and risk assessment

Risk factors are advanced age, hypertension, pre-eclampsia and most importantly, connective

tissue disorders (odds ratio 4960).129 These hereditary disorders include Marfan syndrome,

Loeys-Dietz syndrome, Turner syndrome, Ehlers-Danlos vascular type and other forms of

Hereditary Thoracic Aorta Disease (HTAD).124,129 Another risk factor is concomitant

congenital heart disease such as bicuspid aortic valve or aortic coarctation.124 A lack of

adequate investigation for chest pain can be identified in 71% of maternal deaths due to aortic

dissection.5 Dissection should always be considered when a patient suffers from acute chest or

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back pain requiring opiate analgesia, or presents in shock. Subsequently, aortic imaging

should be performed through CT, MRI or (transoesophageal) echocardiogram.

Management

For these high-risk patients, imaging of the aorta should ideally be performed pre-pregnancy,

with surgery if necessary. Aortic diameters should be regularly monitored during pregnancy

with ultrasound and/or MRI. When progressive dilatation is observed, surgical therapy can be

performed with the fetus in utero (if not viable) or immediately after Caesarean section (if

viable).130 In certain cases (such as uncomplicated type B aortic dissection), conservative

therapy can be considered, comprising of strict blood pressure control through beta-

blockers.131 Patients presenting with acute type A dissections need urgent surgery, with

concurrent Caesarean delivery in case of a viable fetus. Alarming aortic dilatation (>45mm in

Marfan syndrome, >50mm with other risk factors) is one of the few cardiac indications for

Caesarean section delivery.1

Arrhythmias

Epidemiology

Arrhythmias complicate 67 out of 100.000 pregnancies. Most frequent are atrial fibrillation

(AF) in 27 per 100.000 and supraventricular tachycardia (SVT) in 22 per 100.000.132 Despite

most arrhythmias being benign, they are associated with higher maternal mortality rates (odds

ratio 13 for AF, odds ratio 6 for SVT).132 SVT is the most frequent symptomatic arrhythmia

and occurs most commonly in late pregnancy.133,134 Ventricular arrhythmia are rare in

pregnancy and occur most frequently in women with pre-existing cardiovascular disease.135

Pathophysiology

The altered anatomy of pregnancy can elicit new-onset arrhythmia or prompt the recurrence

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of pre-existing arrhythmias. Increased intravascular volume loads create a higher preload and

induce atrial and ventricular stretch. Other contributing cardiaccardiovascular factors are the

physiological tachycardia and increased contractility. Shifts in catecholamine sensitivity,

increased sympathetic activity and hormonal changes can all further predispose to the

development arrhythmia.133,136 Ectopic activity is increased during pregnancy and complaints

of palpitations are common.133

Epidemiology

Arrhythmias complicate 67 out of 100.000 pregnancies. Most frequent are atrial fibrillation

(AF) in 27 per 100.000 and supraventricular tachycardia (SVT) in 22 per 100.000.132 Despite

most arrhythmias being benign, they are associated with higher maternal mortality rates (odds

ratio 13 for AF, odds ratio 6 for SVT).132 SVT is the most frequent symptomatic arrhythmia

and occurs most commonly in late pregnancy.133,134 Ventricular arrhythmia are rare in

pregnancy and occur most frequently in women with pre-existing cardiac disease.135

Diagnosis and risk assessment

Anatomical abnormalities and surgical scars increase the risk of arrhythmia in women with

congenital heart disease.137 Other risk factors are advanced age and ethnicity.132 ECG and

Holter monitoring should be performed as in the non-pregnant population.

Management

All antiarrhythmic drugs cross the placenta, although exact evidence on fetotoxicity is limited

for most agents. Considering the benign and non-sustained nature of most arrhythmias, drug

therapy might be avoided in pregnancy or at least postponed during the first trimester.

Therapy is indicated in cases of sustained SVT with comprised compromised

haemodynamics. Procainamide, adenosine, digoxin and beta-blockers are commonly used

drugs that are considered safe, although not without potential side effects (such as fetal

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growth restriction in beta-blockers).134,138,139 Occasionally intervention with electric

cardioversion, pacemaker implantation or catheter ablation is required, which should not be

delayed because of the pregnancy.140,141

Drugs

Over 90% of pregnant women use at least one medication during pregnancy, be it a

prescription or over-the-counter drug or herbal preparation. The average number of

medications per pregnancy is rising, with 50% of women in the general population taking

more than 4 different drugs.142 The changing characteristics of the pregnant population, such

as increasing maternal age and comorbidities, mean that this upward trend will likely

continue.9-11

The effect on the unborn child is an important consideration. Clinical trials in pregnant

women are rare due to ethical considerations, which has created a paucity of evidence on the

exact embryo- or fetotoxicity of drugs. For some drugs, teratogenicity or other harmful effects

are clear. For others, there is simply insufficient experience. This may make caregivers

apprehensive when prescribing medication and means that drugs may be inappropriately

avoided, discontinued or reduced in dose. Pharmacokinetics (the absorption, distribution,

metabolism and excretion of drugs) are altered in various and sometimes opposing ways

during pregnancy. Absorption may be affected by decreased gastrointestinal motility,

increased gastric pH and, typically in the first trimester, by nausea and vomiting.143

Distribution is altered through increased plasma volumes, shifts in body water and fat

composition and lower levels of drug-binding proteins such as albumin.24,144 It is important to

keep in mind that for drugs which are significantly protein bound, the free (bioactive) level

may be increased despite lower circulating levels. Metabolism, through hepatic enzymes,

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depends on the impact of pregnancy on their activity.145 Drug excretion can be expedited by

the progressive increase in cardiac output, leading to high glomerular filtration rates and

increased hepatic blood flow.23,26,28,29

Although the exact effect will vary for each drug due to these numerous factors, the

elimination route is the most important consideration. If elimination is through the kidneys,

drug concentrations will generally decline due to increased renal clearance and may even

reach sub-therapeutic levels. For these drugs (e.g. digoxin), increased dosage is necessary. If

eliminated through the liver, the net effect is more variable and drug concentrations may be

decreased, increased or unchanged.145 As pharmacokinetic effects increase with pregnancy

duration, regular serum concentration measurements may be necessary to ensure safe

therapeutic levels.

Table 1 gives on overview of commonly used cardiaccardiovascular drugs and the known

effects on mother and child (TAB. 1).

Delivery and postpartum

A delivery plan should be made during pregnancy for all women with cardiaccardiovascular

disease, preferably before 26 weeks gestation. A multidisciplinary approach is key, including,

but not limited to an obstetrician, cardiologist and anaesthesiologist. . Induction of labour is

recommended at the latest at 40 weeks gestational age, as this reduces maternal and fetal

complications.146 In a cohort of women with cardiaccardiovascular disease, planned Caesarean

section did not improve maternal outcome and was detrimental to fetal outcome.147 Vaginal

delivery is therefore advised in almost all patients, Caesarean section being reserved for

selected severe pathology (e.g. critical acute heart failure or pulmonary hypertension,

alarming aortic dilatation or spontaneous labour under oral anticoagulant use).1

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For induction of labour, cervical ripening balloons and misoprostol may be safely used. 148

Oxytocin infusion may be used for induction or failure to progress in labour. When

administrated as the commonly used 10 U intravenous bolus during delivery or Caesarean

section, tachycardia, hypotension and myocardial ischaemia has been reported.149 A slow and

low-dose administration (2 U in 10 minutes combined with 10 U at 12mU/min) is

recommended, as it reduces bleeding without causing adverse cardiovascular effects in

women with cardiovascular disease.150

Epidural analgesia for pain relief should be titrated slowly to avoid hypotension. Assisted

delivery may limit the burden of bearing down efforts on the maternal cardiovascular system.1

Due to the physiological pattern of haemodynamic changes, the incidence of most

cardiaccardiovascular problems in pregnancy peaks in the third trimester, but importantly also

in the postpartum period.5,33,88,97,109 The fluid shifts of the postpartum period precipitate

decompensation and heart failure.33 Therefore in-hospital observation for the first 24-48 hours

postpartum is indicated for women with moderate to complex heart disease, possibly longer

with increased complexity.1

Gaps in evidence

Large international registries like the ROPAC are important to acquire the necessary patient

numbers to describe the epidemiology of infrequent cardiaccardiovascular diseases. Most data

on the haemodynamic physiology of pregnancy stems from the 1950-1970’s, and there is

persisting uncertainty about the exact pattern of cardiac output during the third trimester and

delivery. In hypertensive disorders of pregnancy, it is still unclear whether drug therapy

compared to no therapy leads to better outcome in mild to moderate hypertension. Also, the

optimal timing of induction of labour for women with severe pre-eclampsia >34 weeks should

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be investigated. In VTE, randomized controlled trials (RCT) on optimal anticoagulant

regimens are necessary. In ACS, treatment options for SCAD are insufficiently studied, in

particular the outcomes of invasive versus non-invasive management. Recurrence risk in

subsequent pregnancies is also uncertain. Evidence for beta blocker therapy in women with

aortic dilatation or cardiomyopathy is unclear. Current therapy for PPCM is limited and

should be explored more. Prospective data and RCT’s are scarce to assess drug efficacy,

safety and optimal dosage during pregnancy. The (long-term) effects of many currently used

drugs are not well known. As ethical concerns will always play a role in clinical drug trials

during pregnancy, large prospective registries might fill this gap.

Conclusions

Cardiovascular disease during pregnancy is a growing problem that can have long-term

consequences for maternal and fetal health. It is the leading cause of maternal death. It seems

likely that the pregnant population of the future will have more significant comorbidities and

cardiovascular risk factors, consequently being at higher risk of cardiaccardiovascular

morbidity and mortality. More attention for healthy lifestyle is clearly needed.

The extensive haemodynamic, metabolic and hormonal adaptations during pregnancy pose a

significant physiological burden on the cardiovascular system. This makes women during

pregnancy and the postpartum period particularly vulnerable to the development of

cardiaccardiovascular disease, or for exacerbation of previously asymptomatic disease. The

altered physiology of pregnancy may mask symptoms of disease, hindering timely diagnosis.

A high index of suspicion is essential for early recognition, and diagnostic imaging during

pregnancy should be used when necessary. A multidisciplinary approach between

obstetricians, cardiologists, anaesthesiologists (and when appropriate, obstetric medicine

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specialists and neonatologists) is key to the successful management of these cases. A delivery

plan should be agreed by this team for every woman with cardiaccardiovascular disease

during pregnancy. Referral centres with specialized experience and facilities are optimal

places to treat these patients. This review also demonstrates the gaps in evidence, as

prospective data and randomized controlled trials on which to base management decisions are

lacking. A better evidence base is necessary, if we are to reduce the burden of

cardiaccardiovascular disease in pregnancy.

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Competing interests

The authors declare no competing interests.

Key points

While cardiaccardiovascular disease affects 1-4% of pregnancies, it accounts for 16%

of maternal mortality – making it the leading cause of death.

Advanced maternal age, obesity, hypertension, smoking and diabetes are all major

cardiovascular risk factors that are increasingly prevalent in the pregnant population.

Profound haemodynamic changes, such as a 50% increase in cardiac output, pose a

burden on the maternal cardiovascular system during pregnancy and can provoke new-

onset or an exacerbation of existing cardiaccardiovascular disease.

When prescribing medication, consider – in addition to fetal safety – that

pharmacokinetics are altered during pregnancy and regular serum measurements may

be beneficial, as drug concentrations can increase or decrease.

During pregnancy, in terms of cardiaccardiovascular disease, a high index of suspicion

and a low threshold for investigation is warranted.

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Figure legends

Fig. 1 | The physiology of pregnancy. A: Haemodynamic changes, adapted with permission

from REF. 149. Roos-Hesselink et al. (2009)151. B: Vascular changes. C: Haematologic

changes. D: Metabolic changes, adapted with permission from REF. 25from Odutayo et al.

(2012)26 and REF. 40. Marcinkevage et al. (2011)41. CO = cardiac output, GFR = glomerular

filtration rate, HR = heart rate, SV = stroke volume, SVR = systemic vascular resistance.

Fig. 2 | Onset of cardiovascular events during pregnancy. Left Y-axis (blue): number of

patients with heart failure, (%). Adapted with permission from REF. 32Ruys et al. (2014)33.

Right Y-axis (red): number of patients with pre-eclampsia (red) and gestational hypertension

(orange), (%). Adapted with permission from Shiozaki et al. (2013)REF. 33.34. GH =

gestational hypertension, HF = heart failure, PE = pre-eclampsia.

Fig. 3 | Pathogenesis and pathophysiology of pre-eclampsia. Stage I: maternal, fetal and

genetic factors contribute to the risk of developing pre-eclampsia. Uterine spiral artery

remodelling, which normally serves to create a low-resistance uteroplacental perfusion, is

impaired in pre-eclamptic pregnancies and causes placental hypoxia in the first weeks of

gestation. Oxidative stress releases the placental antiangiogenic factors soluble fms-like

tyrosine kinase receptor-1 (sFlt-1) and soluble endoglobin (sEng), which inhibit placental

growth factor (PlGF) and vascular endothelial growth factor (VEGF). Stage II: Systemic

endothelial dysfunction follows in both placental and maternal circulation. Maternal

symptoms arise through endothelial damage, release of inflammatory cytokines, such as

interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α), formation of microthrombi,

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capillary leak and peripheral vasoconstriction. Symptoms of HELLP syndrome displayed in

red. Fetal complications result from both abnormal placentation and maternal disease.55-59

Fig. 4 | Future risk of cardiovascular disease after pre-eclampsia. Data displayed as meta-

analytic relative risk with 95% confidence interval. Vascular dementia is displayed as hazard

ratio, instead of as relative risk. Diabetes mellitus included type 1 and 2.152-156

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Table 1 | Commonly used cardiaccardiovascular drug classes and their safety during pregnancy and lactation.

Drug class Indication Frequently used drugs

Former FDA risk class

Safety during pregnancy Breastfeeding

Angiotensin II receptor blockers

Hypertension, heart failure

Losartan, valsartan

D Contraindicated due to teratogenicity and fetal death.

Incompatible.

Angiontensin converting enzyme inhibitors

Hypertension, heart failure, ischemic heart disease

Enalapril, lisinopril, perindopril

D Contraindicated due to teratogenicity and fetal death.

Enalapril are captopril are compatible. Beware of neonatal hypotension.

Antiarrhythmic drugs

Arrhythmias Amiodarone, sotalol, lidocaine, adenosine, flecainide

C Adenosine, lidocaine and sotalol are probably safe. Beware of fetal bradycardia. Amiodarone and flecainide are fetotoxic (fetal thyroid insufficiency; teratogenic effects in animals).

Adenosine and lidocaine are preferable. Amiodarone is incompatible.

Antiplatelet drugs Ischemic heart disease, pre-eclampsia prevention

Aspirin, clopidogrel

B Aspirin is considered safe. Clopidogrel is probably safe (animal studies), but limit duration.

Aspirin is compatible. Clopidogrel transfers to breast milk, safety unknown.

Beta blockers Hypertension, arrhythmias, ischemic heart disease

Labetalol, metoprolol, bisprolol, propranolol, atenolol

C Probably safe. Beware of fetal intra-uterine growth restriction and bradycardia. Atenolol is contraindicated due to teratogenicity.

Compatible. Propranolol and metoprolol are preferable.

Calcium channel blockers

Hypertension, angina, arrhythmias, tocolysis

Nifedipine, nicardipine, verapamil, diltiazem

C Probably safe. Beware of maternal hypotension and fetal hypoxia, especially in sublingual or intravenous administration. Diltiazem is associated with teratogenicity.

Compatible.

Cardiac glycosides

Arrhythmias, heart failure

Digoxin C Considered safe, preferred drug for arrhythmias. Beware of increased dosage requirements, monitor serum levels.

Compatible.

Central alpha-agonist

Hypertension Methyldopa B Preferred drug for hypertension in pregnancy.

Compatible.

Direct oral anticoagulants

Anticoagulation Apixaban, rivaroxaban,

- Contraindicated due to teratogenicity in animal

Incompatible.

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dabigatran studies and bleeding risks.Diuretics Hypertension,

heart failureFurosemide, hydrochloro-thiazide

B (thiazide)C (loop)

Probably safe. Beware of hypovolemia and oligohydramnios, start in low doses.

Compatible.

Heparins Anticoagulation Low-molecular-weight-heparin, unfractioned heparin

B Considered safe. Beware of bleeding risk, and carefully consider dose timing in particular around delivery and analgesia or anaesthesia.

Compatible.

Nitrates Angina, heart failure

Glyceryl trinitrate

C Beware of maternal hypotension and fetal hypoxia.

Safety unknown.

Statins Lipid lowering, CVD prevention

Simvastatin, atorvastatin

X Currently contraindicated due to fetal teratogenicity, however, recent reports provide insufficient evidence for this.

Safety unknown.

Vitamin K antagonists

Anticoagulation Acenocoumarol, fenprocoumon, warfarin

D Associated with embryopathy and bleeding risk (in particular around delivery and analgesia or anaesthesia).

Compatible.

Adapted from the 2018 European Society of Cardiology (ESC) Guidelines for the

management of cardiovascular diseases during pregnancy.1 FDA = United States Food &

Drug Administration. CVD = cardiovascular disease. The formerly used risk classification of

A – X has been replaced with the Pregnancy and Lactation Labelling Rule (PLLR), but is still

prevalent and well-known. For this reason both former risk class and PLLR have been

reported here. The categories of fetal risk are:

A: Safe. Adequate and well-controlled studies show no fetal risk.

B: Likely to be safe. Animal studies show no fetal risk, but no adequate human studies are

available.

C: Fetal risk possible. Animal studies show increased fetal risk, but no adequate human

studies are available. Use only if potential benefits outweigh potential risk.

D: Fetal risk proven in human studies; use only if potential benefits outweigh potential risk.

X: Contraindicated. Fetal risk proven and evidently outweighs any potential benefits.

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