REVIEwS

Pregnancy and cardiovascular disease

Karishma P. Ramlakhan   1, Mark R. Johnson2 and Jolien W. Roos-​Hesselink   1 ✉
Abstract | Cardiovascular disease complicates 1–4% of pregnancies — with a higher prevalence
when including hypertensive disorders — and is the leading cause of maternal death. In women
with known cardiovascular pathology, such as congenital heart disease, timely counselling is
possible and the outcome is fairly good. By contrast, maternal mortality is high in women with
acquired heart disease that presents during pregnancy (such as acute coronary syndrome
or aortic dissection). Worryingly, the prevalence of acquired cardiovascular disease during
pregnancy is rising as older maternal age, obesity, diabetes mellitus and hypertension become
more common in the pregnant population. Management of cardiovascular disease in pregnancy
is challenging owing to the unique maternal physiology, characterized by profound changes to
multiple organ systems. The presence of the fetus compounds the situation because both the
cardiometabolic disease and its management might adversely affect the fetus. Equally, avoiding
essential treatment because of potential fetal harm risks a poor outcome for both mother and
child. In this Review, we examine how the physiological adaptations during pregnancy can
provoke cardiometabolic complications or exacerbate existing cardiometabolic disease and,
conversely, how cardiometabolic disease can compromise the adaptations to pregnancy
and their intended purpose: the development and growth of the fetus.

1
Department of Cardiology,
Erasmus University Medical
Center, Rotterdam,
Netherlands.
2
Academic Department of
Obstetrics and Gynaecology,
Imperial College London,
Chelsea and Westminster
Hospital, London, UK.
✉e-​mail: j.roos@
erasmusmc.nl
https://doi.org/10.1038/
s41569-020-0390-​z
The burden of pregnancy on the cardiovascular sys­
tem can reveal previously undiagnosed cardiovascu­
lar problems and induce de novo disease. Cardiovascular
diseases are estimated to complicate 1–4% of pregnan­
cies globally, with a higher prevalence if hypertension,
which complicates 10% of pregnancies, is included
in the definition1,2. In developing countries, both the
prevalence of cardiovascular disease and death rates
in pregnant women are poorly reported, except for
hypertensive disorders, which are a known major cause
of maternal death3. In developed countries, although
cardiovascular diseases are infrequent, they are the
leading cause of maternal mortality4–6. The percent­
age of maternal deaths from cardiovascular causes has
risen from 3% to 15% in the past 30 years in developed
countries, and is predicted to increase further6. Several
reasons for this increase can be identified. First, the
number of pregnancies in women aged >35 years has
steadily increased over the past three decades because
women are delaying childbearing as a lifestyle choice7.
Additionally, the limits of childbearing age have been
extended by assisted reproductive technology8. This
extension of childbearing age has increased the pro­
portion of older pregnant women with more acquired
comorbidities and has contributed to the higher rates
of maternal morbidity, death and adverse obstetric
outcome9. Second, the prevalence of cardiovascular
risk factors such as chronic hypertension and diabetes
mellitus in pregnant women is increasing10,11, primarily
driven by higher rates of obesity12,13 but also reflecting
the increasing maternal age. Although overall rates
of smoking are declining, the prevalence of smoking
among young women is rising 14,15. Third, medical
advances and assisted reproductive technology have
enabled pregnancy in women with chronic medical
conditions that would hitherto have prevented them
from becoming pregnant. Pregnancy in women with
these diseases, such as Turner syndrome, can also have
a negative influence on cardiovascular health16,17. Last,
improved surgical approaches and medical therapy for
women with congenital heart disease have resulted in
more women with these diseases reaching childbear­
ing age and choosing to become pregnant. Many of
these women have considerable residual problems and,
even though successful operations have enabled these
women to live without any functional limitations, the
haemodynamic stress of pregnancy might precipitate
cardiovascular complications18. In conclusion, cardio­
vascular disease in pregnancy is a topic of increasing
relevance and importance for a broad spectrum of
health care providers, including — but not limited
to — cardiologists, obstetricians, anaesthesiologists,
midwives, internists and general practitioners. Early
diagnosis and appropriate management are essential
to reduce maternal mortality, particularly in acquired
cardiovascular disease.

Nature Reviews | Cardiology

Reviews
Key points
• Cardiovascular disease complicates 1–4% of pregnancies — with a higher prevalence
when hypertensive disorders are included — and accounts for 16% of maternal
mortality, making cardiovascular diseases the leading cause of death in pregnant
women in developed countries.
• Advanced maternal age, obesity, hypertension, smoking and diabetes mellitus 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, place
a burden on the maternal cardiovascular system during pregnancy and can provoke
new-​onset or an exacerbation of existing cardiovascular disease.
• When prescribing medication, the altered pharmacokinetics during pregnancy
should be considered in addition to fetal safety, and regular serum measurements can
be beneficial because drug concentrations can change.
• During pregnancy, a high index of suspicion and a low threshold for investigation of
cardiometabolic diseases is warranted.
The first aim of this Review is to provide a com­
prehensive report on the physiological changes that
occur during pregnancy, which forms the basis for
understanding pathological complications. The sec­
ond aim is to review the cardiovascular and cardio­
metabolic pathologies that can present or be acquired
during pregnancy. These cardiometabolic diseases
include hypertensive disorders, gestational diabetes
mellitus, thromboembolic disorders, ischaemic heart
disease, (peripartum) cardiomyopathy, endocarditis,
aortic disease and arrhythmias. We also discuss the
altered pharmacokinetics in pregnancy. Management
of pre-​existing cardiovascular disease or cardiovascular
complications in the fetus is not discussed. The majority
of the available data on cardiovascular diseases in preg­
nancy are from Western regions, which hinders a global
understanding of the effects of cardiovascular disease
in pregnancy3.
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 personal­
ized approach. Figure 1 summarizes the most important
cardiovascular changes that occur during pregnancy.
Haemodynamics. The extensive adaptions of the mater­
nal cardiovascular system initially create the capacity to
maintain adequate uteroplacental perfusion throughout
pregnancy. By 8 weeks gestational age, maternal systemic
vascular resistance has already fallen by 10–30% and
will further decrease to a nadir between 20 weeks
and 26 weeks of pregnancy19–21. This decrease in systemic
vascular resistance results in a decline in mean arterial
pressure22, which reverses from 26–28 weeks, reaching
prepregnancy values at full term20,22. Underlying mech­
anisms of peripheral vasodilatation include increased
vascular compliance, reduced response to vasocon­
strictive agents such as angiotensin II, and increased
levels of vascular relaxing agents such as nitric oxide23–26.
The fall in systemic vascular resistance reduces cardiac
afterload and preload, which requires volume expan­
sion to compensate. The drop in systemic vascular
resistance activates the renin–angiotensin–aldosterone
system, causing water and sodium retention 23,24,26.
Total volume expansion, mostly manifesting as plasma
volume increase (with increases of 1,100–1,600 ml
compared with reference values), can be up to 45% at
term and is proportional to the growth of the fetus24,27.
Correspondingly, a low-​resistance uteroplacental circu­
lation is created, which, as the fall in systemic vascular
resistance gradually reverses, results in a progressive
increase in blood flow to the placenta, keeping pace
with the increased requirements for fetal growth and
development.
The heart rate also rises during pregnancy because
the low afterload stimulates the baroreceptors in the
cardiopulmonary and renal systems to activate the sym­
pathetic nervous system. Catecholamine release is trig­
gered, increasing contractility and heart rate by 15–25%
throughout pregnancy20,28. These changes increase stroke
volume by 20–30%20. Cardiac output rises by at least
30–50% in the first two trimesters, but findings in the
third trimester are conflicting20,28–30. At 26–30 weeks,
the adaptation of cardiac output seems to be mostly
completed and, thereafter, cardiac output is reported to
remain stable, increase or decrease slightly according
to different studies20,28–30. 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%)
compared with non-​pregnant women20,28,31.
In childbirth, many of the haemodynamic changes
reach their peak. Pain, stress and the physical exertion
of childbearing lead to increases in blood pressure,
heart rate and cardiac output20,29,32. Contractions fur­
ther amplify this effect because, with each contraction,
300–500 ml of blood is returned from the uteroplacen­
tal circulation to the systemic circulation. Immediately
after delivery, stroke volume and cardiac output rise as a
result of the (now permanent) autotransfusion from the
uteroplacental circulation and the removal of aortocaval
compression20.
The pattern of these physiological changes is hypoth­
esized to be linked to the timing of cardiovascular events
during pregnancy (Fig. 2). An analysis of the Registry
of Pregnancy and Cardiac Disease, a worldwide regis­
try of pregnancies in women with cardiovascular dis­
ease, showed that the incidence of heart failure peaks
for the first time when cardiac output plateaus at
26–30 weeks33. The second peak in both cardiac output
and the incidence of heart failure occurs after deliv­
ery, when the autotransfusion of blood from the uter­
oplacental circulation creates an ‘overload’ state. The
defined peaks of heart failure contrast with the gradual
increase in the incidence of pre-​eclampsia throughout
pregnancy34 (Fig. 2).
Haematology. Pregnancy is a hypercoagulable state,
designed to limit blood loss during labour. The con­
centration of all clotting factors, excluding factor XI
and factor XIII, increases by up to 50% throughout
pregnancy35,36. Fibrinolysis is inhibited, and the levels
of anticoagulant agents (such as antithrombin III and
protein  S) decrease 35,36. This hypercoagulable state
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 Reviews

a Haemodynamic changes b Vascular changes

60 Normal artery • Fragmentation of
reticulum fibres
50 Internal • ↓ Levels of acid
40 elastic mucopolysaccharides
membrane • Straightening and
30
loss of configuration
20 Smooth of elastic fibres
Pregnancy
muscle cell • Oestrogen-induced
Change (%)
10
Elastic inhibition of elastin
0 and collagen
5 8 12 16 20 24 28 32 36 38 fibre
–10 deposition
Pregnancy duration (weeks) External • Progesterone-
–20
elastic induced acceleration
–30 membrane of non-collagenous
–40 Adventitia protein deposition
Cardiac output Media
Stroke volume Intima
Heart rate Higher risk
Systemic vascular resistance of dissection

c Haematological changes d Metabolic changes

150
Changes in blood composition GFR
• Increase in plasma volume 100 Insulin

Change (%)
and a more modest increase Haemodilution production
in haemoglobin level 50
• Mild leukocytosis during 0
labour and postpartum
10 20 30 40 Postpartum
• Mild decrease in blood –50
platelet count Pregnancy duration (weeks)

Hypercoagulability
• 50% increase in blood
coagulation factors
• Inhibition of fibrinolysis
• Inhibition of
anticoagulant agents
Drug clearance
• ↑ Renal drug clearance (owing to ↑ GFR),
High risk of with the potential to lead to
thrombosis subtherapeutic drug levels
Thrombus
• Hepatic drug clearance is inconsistent,
depending on the increased, decreased
or unchanged activity of the relevant
drug-metabolizing enzymes

Fig. 1 | Physiological changes in pregnancy. a | Haemodynamic changes. Cardiac output, stroke volume and heart rate
increase throughout pregnancy, whereas systemic vascular resistance decreases in the first two trimesters, with a gradual
reversal during the third trimester. Based on data from ref.155. b | Vascular changes. Pregnancy-​induced changes to the
aortic vessel wall include loss of corrugation of elastic fibres, fragmentation of reticulum fibres and diminished levels of acid
mucopolysaccharides101. Furthermore, oestrogen inhibits elastin and collagen deposition, and progesterone accelerates
non-​collagenous protein deposition in the aortic wall131, thereby increasing the risk of aortic dissection during pregnancy.
c | Haematological changes. Pregnancy is a hypercoagulable state, which predisposes the pregnant woman to thromboembolic
complications. The concentration of all clotting factors increases, excluding factor XI and factor XIII, whereas fibrinolysis and
serum levels of anticoagulant agents decrease. Red blood cell count increases to a lesser extent than the increase in plasma
volume, leading to physiological haemodilution during pregnancy. d | Metabolic changes. Placental diabetogenic hormones
increase maternal glucose production and insulin resistance to promote fetal growth, requiring progressively higher insulin
production from pancreatic β-​cells. When the β-​cells cannot meet this demand, a persistent hyperglycaemic state is
established, and gestational diabetes mellitus develops. Increases in plasma volume and cardiac output amplify renal
perfusion, causing an increase in glomerular filtration rate (GFR) and, correspondingly, renal drug clearance. Hepatic drug
clearance depends on changes in the metabolizing enzyme involved. Based on data from refs26,41.

predisposes the pregnant woman to thromboembolic
complications. Erythropoiesis is stimulated by placen­
tal hormones and increased renal oxygen consumption
as a result of an increased glomerular filtration rate
(GFR)37,38. However, the red blood cell count increases to
a lesser extent than plasma volume. The resulting physio­
logical haemodilution during pregnancy combined
with iron deficiency can progress to anaemia27. The
white cell count also increases in pregnancy, in particu­
lar during labour and in the early postpartum period.
Differentiating this mild physiological leukocytosis from
the presence of infection, which is also prevalent in the
same period, is important. Platelet count often decreases,
but usually remains within the normal range37.
Metabolism. Glucose metabolism adapts to promote
fetal growth and in preparation for lactation. Maternal
fasting glucose levels drop throughout pregnancy
because of fetal glucose uptake, higher peripheral con­
sumption and dilution caused by volume expansion39.
From the second trimester, insulin production increases
and insulin sensitivity decreases, mediated by hormones
with diabetogenic effects, such as human placental lac­
togen, cortisol, prolactin, growth hormone and proges­
terone39–41. Environmental and genetic factors contribute
to the capacity of the mother to compensate for the
increased insulin resistance, and a failure of compensa­
tory mechanisms results in the development of gestational
diabetes mellitus.

Nature Reviews | Cardiology

 Reviews

35 900 Pathophysiology. At the heart of the pathophysiology

Patients with heart failure (%)

Patients with hypertensive

Heart failure
30 Pre-eclampsia
800 of hypertensive disorders in pregnancy is a complex
n = 6,426 700
25 Gestational hypertension interaction between maternal and fetal factors that is

disorders (n)
600
20
not yet fully understood. The first abnormalities can be
500
observed in the first weeks of pregnancy, when abnor­
15 400
n = 173 300 mal placentation (stage I) provokes systemic endothelial
10 dysfunction (stage II). Despite this alteration, symp­
200
5 toms typically do not present until the second or third
n = 2,810 100
0 0 trimester34,49. Figure 3 shows a suggested multifactorial
model of the pathogenesis of pre-​eclampsia. In the first
2

10

we ery

we –4

we 8
13
1–

3–

–1

–1

–2

–2

–3

–3

–3

–4

PP 4–
PP k 1
7–

ek
PP eliv
11

15

19

23

27

31

35

39

ek
weeks of normal pregnancy implantation, trophoblasts

e
D
Pregnancy duration (weeks)
Fig. 2 | onset of cardiovascular events during pregnancy. The left-​hand y axis and
the blue line represent the percentage of women with heart failure at different stages of
pregnancy and postpartum (PP) in the Registry of Pregnancy and Cardiac disease, an
observational registry from 28 participating countries. The registry reported 173 patients
with heart failure among a total of 1,321 pregnancies in women with structural heart
disease. The right-​hand y axis and the red line represent the number of patients with
pre-​eclampsia, and the orange line represents the percentage of patients with gestational
hypertension in a nationwide observational perinatal database in Japan, reporting the
incidence of hypertensive disorders of pregnancy among women without chronic
hypertension. Based on data from refs33,34.
Respiratory system. High fetal, placental and uterine
oxygen consumption, increased carbon dioxide produc­
tion and the respiratory-​stimulating effect of progester­
one combine to cause hyperventilation42. A physiological
compensated respiratory alkalosis can be found in arte­
rial blood gas measurements43. The growing uterus
elevates the diaphragm, which decreases functional
residual capacity by 20–30% at full term43–45. Respiratory
rate changes minimally or not at all, but tidal volume
increases owing to high concentrations of progester­
one42. This elevation in tidal volume results in a 20–50%
increased minute ventilation42,43.
from the conceptus remodel the uterine spiral arteries to
create a low vascular resistance55. In pre-​eclampsia, this
process is suboptimal, resulting in a high-​resistance uter­
oplacental circulation and, ultimately, placental ischae­
mia56. The resulting placental hypoperfusion drives the
release of soluble fms-​like tyrosine kinase 1 (sFLT1; also
known as soluble VEGFR1) and soluble endoglobin
(sENG) by placental trophoblast cells, which impair the
function of maternal vascular endothelial growth factor,
placental growth factor and transforming growth
factor-​β, resulting in systemic endothelial dysfunction,
hypertension and renal impairment57–59. The typical
symptoms of pre-​eclampsia include headaches, visual
disturbances, nausea and/or vomiting, epigastric or right
upper quadrant pain and peripheral oedema, although
the presence of these symptoms is not necessary for
diagnosis60,61. Early-​onset and late-​onset pre-​eclampsia
have pathophysiological differences, expressed in con­
trasting haemodynamic states: early-​onset pre-​eclampsia
is associated with a smaller increase in cardiac output,
whereas a greater increase in cardiac output can be
observed in late-​onset pre-​eclampsia62. The difference
might relate to more severe placental dysfunction in
early pre-​eclampsia, leading to a failure to induce the
physiological fall in systemic vascular resistance.

Renal system. The changes in plasma volume and
car­diac output amplify renal perfusion, prompting a
40–50% higher GFR in the first trimester23,26. Kidney
volume increases by 30%, and the collecting system
dilates, which predisposes the pregnant woman to pye­
lonephritis and hydronephrosis26,46,47. In addition to
water and sodium retention through renin–angiotensin–
aldosterone system upregulation, proteinuria and
albumin excretion increase48.
Gestational hypertensive disorders
Epidemiology. Hypertensive disorders complicate
10% of pregnancies and include chronic hypertension,
pregnancy-​induced hypertension, (pre-)eclampsia and
HELLP syndrome (haemolysis, elevated liver enzymes
and low platelet count)2,49,50. This spectrum accounts for
10–16% of maternal mortality worldwide51,52. The inci­
dence of pre-​eclampsia is 3.4% in the Western world53
and, although the pre-​eclampsia-​related mortality in the
UK has fallen from 0.83 to 0.13 deaths per 100,000 mater­
nities in the past decade, pre-​eclampsia is still associated
with a substantial burden of disease in both the short term
and the long term4,5. Hypertensive disorders are estimated
to cause 10–15% of maternal deaths in Asia, 16–17% in
Africa and 22% in Latin America and the Caribbean54.
Diagnosis and risk assessment. Risk factors for gesta­
tional hypertensive disorders are nulliparity, multiple
pregnancy, previous pre-​eclampsia, chronic hyperten­
sion, diabetes, obesity, maternal age >35 years and several
chronic systemic diseases61. Gestational hypertension is
defined as de novo hypertension (systolic/diastolic blood
pressure >140/90 mmHg) presenting after 20 weeks
gestational age61. 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 abnormalities63. These abnormal­
ities might culminate in HELLP syndrome in 25% of
patients with pre-​eclampsia63. In 2% of the patients,
pre-​eclampsia progresses to eclampsia, an obstetric
emergency characterized by tonic–clonic seizures64.
Management. Low-​dose aspirin prophylaxis is reco­
mmended in women at high risk of pre-​e clampsia
and should be initiated before 16 weeks, and possibly
before 12 weeks, and continued daily until 36–37 weeks
of gestation63,65–67. The recommended daily dose varies
regionally, with guidelines from the American College of

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Obstetricians and Gynaecologists recommending 81 mg,
and the European Society of Cardiology (ESC) recom­
mending 100–150 mg (refs1,61), but a meta-​analysis
suggests that doses ≥100 mg are more effective66.
When hypertension is diagnosed, a target diastolic
blood pressure of 85 mmHg (and systolic blood pressure
of 110–140 mmHg) should be aimed for with the use of
the antihypertensive drugs of preference (for example,
oral methyldopa, calcium-​channel blockers (such as
nifedipine) or β-​blockers (such as labetalol))63,68. Severe
hypertension (≥160/110 mmHg) should be treated
promptly in a clinical setting with nifedipine, intrave­
nous labetalol or intravenous hydralazine, in combina­
tion with magnesium sulfate for neuroprotection63,64.
Induction of labour is indicated at 37 weeks gestational
age or earlier on the basis of disease severity, given that
delivery is considered the only cure for gestational
hypertensive disorders69. Nonetheless, postpartum (pre-)
eclampsia can occur up to 6 weeks after delivery70. The
risk of developing cardiovascular disease in the future
is increased for women who had gestational hyperten­
sive disorders, probably owing to shared risk factors and
developmental pathways71 (Fig. 4). Annual follow-​up to
evaluate blood pressure and cardiometabolic status is
recommended63.
Gestational diabetes mellitus
Epidemiology. Gestational diabetes mellitus is the most
common metabolic disease in pregnancy, with an overall
prevalence of 6–13%72. Geographical variation is large
owing to the influence of genetic and environmental
factors, with the highest prevalence found in the Middle
East and North Africa and the lowest in Europe 72.
Associated adverse maternal outcomes include pre-​
eclampsia, Caesarean section and postpartum haemor­
rhage. Adverse fetal outcomes include macrosomia (large
fetal birthweight) and, consequently, obstetric complica­
tions such as shoulder dystocia and prematurity, and an
increased risk of stillbirth73,74. Long-​term implications
for the child are impaired glucose metabolism, sub­
sequent obesity and problems in neurodevelopment
(mental and psychomotor function)75–78.
Pathophysiology. Placental hormones increase maternal
glucose production and insulin resistance, requiring
progressively higher insulin production from pancre­
atic β-​cells. When the β-​cells cannot meet this demand,
a persistent hyperglycaemic state can develop39,40. Genetic
and environmental factors also have an important role
in the development of gestational diabetes mellitus79,80.
Women who ultimately develop gestational diabetes mel­
litus have lower insulin sensitivity even before pregnancy.
This observation suggests that pregnancy is a stress test
for underlying subclinical metabolic dysfunction81.
Diagnosis and risk assessment. Risk factors for ges­
tational diabetes mellitus are maternal age >25 years,
obesity, gestational diabetes mellitus or macrosomia
in a previous pregnancy, dietary and lifestyle factors,
and ethnicity 79,80,82. International guidelines disa­
gree on whether universal screening (for example, in
US guidelines) or selective screening (for example,
Nature Reviews | Cardiology
Reviews
in UK guidelines) should be performed in women with
risk factors83,84. Screening is ideally performed between
24 weeks and 28 weeks of gestational age and with an
oral glucose tolerance test (OGTT). The diagnosis of
gestational diabetes mellitus is confirmed when plasma
glucose levels are >5.6 mmol/l (fasting) or >7.8 mmol/l
(after 2 h of a 75 ​g OGTT)85.
Management. The management of gestational diabetes
mellitus includes maternal blood glucose monitoring
and dietary advice; drug therapy is introduced when
diet alone is not sufficient to control glucose levels.
Therapy with insulin is preferable, with metformin and
glyburide therapies as alternative and inferior options
because both cross the placenta and are less successful
for attaining maternal glycaemic control83. Treatment for
gestational diabetes mellitus lowers fetal birthweight
and the rate of serious perinatal complications, such as
fetal death, shoulder dystocia, bone fracture and nerve
palsy86. Although normal maternal glucose metabolism
is restored postpartum, the lifetime risk of developing
type 2 diabetes mellitus in women with gestational dia­
betes mellitus is increased at least sevenfold compared
with women with a normoglycaemic pregnancy77. Other
risks that are increased in women with gestational dia­
betes mellitus include metabolic syndrome and cardio­
vascular disease87. After delivery, the glucose tolerance
of all women with gestational diabetes mellitus should
be re-​evaluated by a 75 ​g OGTT at 4–12 weeks postpar­
tum and every 2 years thereafter in patients with normal
glucose levels83.
Thromboembolic disorders
Epidemiology. Venous thromboembolism (VTE)
complicates 0.5–2.0 per 1,000 pregnancies and causes
1.1 deaths per 100,000 pregnancies88–90. VTE includes
deep-​vein thrombosis, pulmonary embolism and cer­
ebral venous thrombosis. The postpartum incidence
of VTE is up to 5 per 1,000 pregnancies90. Deep-​vein
thrombosis is three times more common than pulmo­
nary embolism89,90. VTE causes 3% of maternal deaths
in developing countries, whereas this proportion is
estimated to be 14% in developed countries54.
Pathophysiology. Pregnancy is a hypercoagulable state
owing to an increase in clotting factors and a decrease
in anticoagulant and fibrinolytic agents35,36. Additionally,
venous flow velocity is reduced because of physiological
vasodilatation and vena cava compression by the gravid
uterus91. The risk of VTE is increased fivefold during
pregnancy compared with non-​pregnant women90,92.
This effect peaks in the puerperium and can be exacer­
bated by comorbidities, periods of immobilization and
interventions such as Caesarean section.
Diagnosis and risk assessment. Pregnancy-​related risk
factors for VTE are gestational diabetes mellitus, multi­
ple pregnancies, nulliparity, Caesarean section and pre-​
eclampsia88,89. Assisted reproductive technologies are
an increasingly relevant risk factor, with women with
ovarian hyperstimulation syndrome having a 100-​fold
greater risk of VTE than the general population93.
Reviews

a Stage I Maternal factors

Placental circulation • Nulliparity Fetal factors Genetic factors
• Advanced age • Multiple gestation • Family history of
• Comorbidities (such as • Immunological pre-eclampsia
chronic hypertension, maladaptation to • Previous
diabetes and kidney disease) fetal HLA pre-eclampsia

Impaired spiral
artery remodelling

Normal pregnacy Pre-eclampsia

Uterus
Maternal

Myometrium
spiral artery
Placenta

Placenta
Chorionic
villi

Decidua
Umbilical

Umbilical
cord

artery

Placenta
Umbilical
vein

Systemic endothelial Placental ischaemia

dysfunction Abnormal placentation
and hypoxia

b Stage II
Maternal circulation

↑ Antiangiogenic ↓ Angiogenic Microthrombus Peripheral

factors growth factors formation vasoconstriction

Endothelium

sFLT1, PlGF,
sENG VEGF
IL-6, Platelet
Maternal blood vessel TNF

Pathological ↑ Release of Capillary

progression inflammatory cytokines leakage

Maternal complications
• Pre-eclampsia
• HELLP syndrome

Fetal complications Vascular system Kidneys Liver Brain

• Intrauterine growth restriction • Hypertension • Proteinuria • Right upper • Headache
• Fetal hypoxia • Peripheral oedema • Oliguria quadrant pain • Visual disturbances
• Preterm birth • Pulmonary oedema • Glomerular • Elevated levels • Nausea and vomiting
• Oligohydramnios • Haemolysis endotheliosis of liver enzymes • Cerebral oedema
• Placental abruption • Low platelet count • Coagulopathy • Seizures (eclampsia)
• Intrauterine fetal death

General risk factors for VTE include previous VTE, obe­
sity, smoking and thrombophilia (for example, factor V
Leiden mutation and deficiencies in protein S, protein C
and antithrombin)88. Owing to the intraindividual bio­
logical variation in d-​dimer levels in pregnancy, d-​dimer
measurements should not be used in the evaluation of
thromboembolic events during pregnancy94.
Management. Adequate prophylaxis for patients at risk
of VTE is necessary95. Non-​vitamin K antagonist oral
anticoagulants cross the placenta, have teratogenic
effects and should preferably not be used, especially
in the first trimester1. Low-​molecular-​weight hepa­
rin does not cross the placenta and is the first choice
as prophylaxis or treatment in patients with VTE96.

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◀ Fig. 3 | Pathogenesis and pathophysiology of pre-eclampsia. a | Stage I: maternal, fetal
and genetic factors contribute to the risk of developing pre-​eclampsia. Uterine spiral
artery remodelling, which normally occurs to create low-​resistance uteroplacental
perfusion, is impaired in pre-​eclamptic pregnancies and causes placental hypoxia in the
first weeks of gestation. b | Stage II: oxidative stress triggers the release of the placental
antiangiogenic factors soluble fms-​like tyrosine kinase 1 (sFLT1) and soluble endoglobin
(sENG), which inhibit placental growth factor (PlGF) and vascular endothelial growth
factor (VEGF) in the maternal circulation. These alterations lead to systemic endothelial
dysfunction in both placental and maternal circulation. Maternal symptoms are caused
by endothelial damage, release of inflammatory cytokines, such as IL-6 and tumour
necrosis factor (TNF), formation of microthrombi, capillary leak and peripheral
vasoconstriction. Symptoms of HELLP syndrome (haemolysis, elevated liver enzymes
and low platelet count) are highlighted by a darker pink background. Fetal complications
result from both abnormal placentation and maternal disease55–59.
When treating acute VTE during pregnancy, the ini­
tial dosage should be based on early pregnancy body
weight and then corrected by the measurement of peak
and trough antifactor Xa activity97. Special care, directed
by current guidelines, should be taken in the peripar­
tum period for the precarious balance between risk of
bleeding and risk of recurrent VTE1.
Acute coronary syndromes
Epidemiology. Acute coronary syndromes (ACSs) are a
major cause of maternal death in developed countries,
accounting for 20% of cardiovascular deaths5. The inci­
dence is 6 per 100,000 deliveries and is predicted to con­
tinue increasing, which reflects the growing prevalence
of cardiovascular risk factors in the pregnant population.
The case fatality rate is 5% in the pregnant population98.
Data from developing countries are not available.
Pathophysiology. Compared with the general popu­
lation, atherosclerosis is not the most important cause
of ACS in pregnant women. Instead, spontaneous coro­
nary artery dissection is the most frequent cause of ACS
(43%), whereas atherosclerosis accounts for 27% of
ACS99. Other pathological mechanisms of ACS in pre­
gnancy include clots (17%) and spasms (2%)99. Normal
coronary anatomy is found in 18% of women with ACS
during pregnancy99. The high frequency of sponta­
neous coronary artery dissection might be caused by
pregnancy-​induced changes in vessel structure, along
with the increased haemodynamic burden in late preg­
nancy100,101 (Fig. 1). ACS presents most frequently in the
postpartum period, with the second highest frequency
seen in the third trimester. The left anterior descending
coronary artery or the left main segment are the most
commonly affected vessels, and multivessel disease
is prevalent99.
Diagnosis and risk assessment. Risk factors for ACS in
pregnancy are obesity, age >35 years, smoking, diabetes,
chronic hypertension and a family history of ACS5,98,99,
but these risk factors are primarily related to atheroscle­
rosis and can be absent in conditions such as spontane­
ous coronary artery dissection99. Spontaneous coronary
artery dissection can be associated with fibromuscular
dysplasia or genetically mediated vasculopathy102,103.
ACS can present with atypical symptoms in women and
particularly in pregnancy. All complaints of chest pain,
but also pain in the neck, stomach, arms or dyspnoea
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on exertion, should be taken seriously and promptly
assessed with electrocardiogram (ECG) and cardiac
troponins tests. If performed during an episode of chest
pain, a single normal ECG makes a diagnosis of ischae­
mia unlikely, but serial ECGs should be considered if a
clinical suspicion of ACS persists5.
Management. When performing invasive diagnostic or
treatment techniques, the increased rate of iatrogenic
coronary dissection in the pregnant population needs
to be considered99. In ST-​segment elevation myocardial
infarction (STEMI), primary percutaneous coronary
intervention with bare-​metal stents is the first choice
of treatment in the third trimester. Use of bare-​metal
stents requires a month of dual antiplatelet therapy
(DAPT), which allows for timely interruption during
the peripartum period to prevent bleeding complica­
tions. Although less experience is available with new-​
generation drug-​eluting stents during pregnancy, and
the use of these stents necessitates ≥3 months of DAPT,
new-​generation drug-​eluting stents can be used in the
first two trimesters104. Blind use of thrombolytic treat­
ment is not recommended because a fairly large pro­
portion of women have normal coronary anatomy or
spontaneous coronary artery dissection99. In low-​risk
non-​STEMI, non-​invasive therapy can be considered.
Fetal safety needs to be considered when choosing phar­
macological treatment, which is hindered by the lack of
evidence for many drugs. Use of angiotensin-​converting
enzyme (ACE) inhibitors and statins is contraindicated
in pregnancy, although in the past two decades data have
suggested that statins might be safe105–108. Use of anti­
platelet agents such as clopidogrel during pregnancy is
not well investigated and, although these agents seem to
be safe, their use should be limited. Antiplatelet therapy
with low-​dose aspirin during pregnancy is considered
to be safe1. Follow-​up after spontaneous coronary artery
dissection should include imaging of all vessels from
brain to pelvis at least once with the use of CT angiog­
raphy or magnetic resonance angiography to assess for
fibromuscular dysplasia and other non-​coronary arterial
abnormalities103.
Cardiomyopathies
Epidemiology. The incidence of cardiomyopathies that
first present during pregnancy is not well studied except
for peripartum cardiomyopathy, which is unique to
pregnancy. The incidence of peripartum cardiomyopa­
thy varies greatly between countries because ethnicity is
an important risk factor, ranging from 1 per 100 preg­
nancies in Nigeria to 1 per 10,000 in Denmark109,110. The
worldwide mortality for peripartum cardiomyopathy
is 2.4%111. In a 2014 nationwide study in the USA, the
incidence of peripartum cardiomyopathy was 10.3 per
10,000 live births, and maternal mortality was 1.3%,
with a 2.6% rate of cardiogenic shock as a result of heart
failure and a 2.1% rate of cardiac arrest112.
Pathophysiology. Pregnancy can reveal previously
asymptomatic cardiomyopathy, which can be congen­
ital or acquired. Increases in cardiac output and blood
volume during pregnancy, which make pregnancy a
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Cardiovascular death 2.21
Chronic hypertension
3.70
Heart failure 3.62
Coronary heart disease 2.11
Stroke 1.71
Venous thromboembolism
1.79
Diabetes mellitus 2.37
Vascular dementia 3.46
End-stage renal disease 6.35
0 5 10 15
Relative risk (95% CI)
Fig. 4 | risk of cardiometabolic disease after pre-eclampsia. The graph shows the
relative risk of cardiometabolic disease in women with a history of pre-​eclampsia.
Data for cardiovascular death are adjusted for confounders and are from a meta-​analysis
of four studies with a total of 2,614,180 participants from Europe and the USA156.
Data for chronic hypertension are from a meta-​analysis of 13 studies with a total of
21,030 participants from Europe, Jordan, New Zealand and the USA157. Data for heart failure
are from a meta-​analysis of seven studies with a total of 2,764,824 participants from
Europe, Taiwan and the USA156. Data for coronary heart disease are from a meta-​analysis
of 10 studies with a total of 3,239,797 participants from Europe, Taiwan and the USA156.
Data for stroke are from a meta-​analysis of seven studies with a total of 4,906,182
participants from Europe, Taiwan and the USA156. Data for venous thromboembolism
are from a meta-​analysis of three studies with a total of 427 ,693 participants from
Canada, the UK and the USA157. Data for diabetes mellitus include type 1 and type 2
and are adjusted for confounders; data are from a meta-​analysis of 10 studies with a
total of 1,235,567 participants from Canada, Europe, Hong Kong, Taiwan and the USA158.
Data for vascular dementia are hazard ratios and are from a nationwide register cohort
study in Denmark with 1,178,005 participants159. Data for end-​stage renal disease are
from a meta-​analysis of two studies with a total of 1,035,484 participants from Norway
and Taiwan160.
‘stress test’ for the cardiovascular system, can provoke
complaints, in particular for dilated cardiomyopathy1,30.
Peripartum cardiomyopathy is diagnosed when no other
cause of heart failure can be identified113. A proposed
pathophysiological pathway of peripartum cardiomy­
opathy is a pro-​inflammatory state, in which oxidative
stress triggers the metabolism of prolactin to an antian­
giogenic form that causes myocardial and vascular
damage114. Peripartum cardiomyopathy typically leads
to heart failure with impaired left ventricular ejection
fraction (LVEF), most frequently occurring late in
pregnancy or postpartum111,115. The resulting left ven­
tricular failure can be permanent and has a high risk of
recurrence in the next pregnancy113.
Diagnosis and risk assessment. The symptoms related to
developing heart failure are easily dismissed as being part
of the normal physiological adaptation to pregnancy.
When suspected, the diagnostic work-​up for heart fail­
ure should include ECG, measurement of natriuretic
peptide levels, echocardiography and chest radiography.
CT, coronary angiography or cardiac MRI, if available,
can provide additional information, depending on the
clinical presentation115. Peripartum cardiomyopathy has
specific risk factors, including African ancestry, multiple
pregnancies, multiparity, advanced age, diabetes, smok­
ing and pre-​eclampsia115. Peripartum cardiomyopathy is
a diagnosis of exclusion, and other possible diagnoses
should first be explored113.
Management. Standard care for heart failure should be
adapted to avoid the use of drugs with toxic effects on
the fetus when possible, most notably ACE inhibitors
and angiotensin II receptor blockers1. The ESC guide­
lines recommend against early implantation of cardiac
assist devices, allowing time for improvement with med­
ication1. In patients with peripartum cardiomyopathy,
in addition to standard care for heart failure, prolac­
tin blockade through bromocriptine treatment shows
promising results. Bromocriptine therapy has been
suggested to reduce morbidity and mortality in patients
with peripartum cardiomyopathy and to increase the
likelihood of full left ventricular recovery116,117, although
the first placebo-​controlled trial to assess its efficacy is
still ongoing118. Peripartum cardiomyopathy is rare, but
the consequences are far-​reaching. One month after
diagnosis, 87% of patients are still in clinical heart fail­
ure, 7% experience an embolic event and 4% need a
cardiac implantable device111. Timely and multidiscipli­
nary counselling before conception is extremely impor­
tant, given that persistent left ventricular dysfunction
(LVEF <50–55%) is a contraindication for subsequent
pregnancies1.
Endocarditis
Epidemiology. The incidence of endocarditis during
pregnancy is not well studied. Case reports mostly
involve women with congenital heart disease (over­
all incidence, 0.1%) or prosthetic heart valves (overall
incidence, 0.3–1.2%)119. However, reported maternal
endocarditis-​related mortality is very high (11–33%)120–123.
Pathophysiology. No evidence suggests a different aetio­
logy for endocarditis in pregnancy. Infection severity for
some pathogens is increased in pregnant women com­
pared with the general population, through immuno­
logical alterations induced by pregnancy hormones124.
However, infection susceptibility has not been con­
vincingly shown to be increased in pregnant women
compared with the general population124.
Diagnosis and risk assessment. Among pregnant women,
groups at high risk of endocarditis include intravenous
drug users, those with congenital or rheumatic heart
disease and those with cardiac prostheses121. Prosthetic
heart valves are particularly associated with a long-​term
risk of endocarditis119. Non-​valve-​containing prosthe­
ses are associated with an increased risk of endocarditis
only in the first 6 months after prosthesis implantation,
before prosthesis endothelialization is complete125. The
same diagnostic work-​up as for the general population
applies for pregnant women, with an essential role for
performing blood cultures, echocardiography and
supplementary advanced imaging119.
Management. Current guidelines do not recommend
prophylaxis for either vaginal or Caesarean delivery,
even in groups at high risk of endocarditis1,119, but few
data are available and the high maternal mortality asso­
ciated with endocarditis might justify prophylaxis in
selected patients. Antibiotic therapy should be based
on culture and sensitivity tests as well as fetal safety.
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Considering the high maternal mortality and potentially
increased infection severity in pregnant women, these
patients should be treated by a multidisciplinary team
in an appropriate centre119,124.
Aortic disease
Epidemiology. Aortic dissection occurs in only 0.40–0.55
per 100,000 pregnancies but is nonetheless a major cause
of maternal cardiovascular-​related death in developed
countries, owing to the dramatically low likelihood of
survival (prehospital mortality is 53% and the case fatal­
ity rate is 60%)5,126,127. In pregnant women, the ascending
aorta is predominantly affected, accounting for 79% of
dissections128. Epidemiological data from non-​Western
countries are scarce.
Pathophysiology. Aortic dimensions and compliance
increase in normal pregnancy, which becomes more
marked with increasing parity129,130. Loss of corrugation
of elastic fibres, fragmentation of reticulum fibres and
diminished levels of acid mucopolysaccharides can be
observed in the aortic vessel wall of pregnant women101.
Oestrogen inhibits elastin and collagen deposition,
and progesterone accelerates non-​collagenous protein
deposition in the aortic wall131. The combination of
changes in vascular function and structure and the
increased haemodynamic stress increases the risk of
aortic dissection in pregnant women100,101 (Fig. 1). Dissec­
tion occurs most frequently postpartum or near deliv­
ery, when cardiac output and blood volumes reach their
peak28,29,32.
Diagnosis and risk assessment. Risk factors for aortic dis­
section are advanced age, hypertension, pre-​eclampsia
and, most importantly, connective tissue disorders
(OR  4,960) 132. These hereditary connective  disor­
ders include Marfan syndrome, Loeys–Dietz syndrome,
Turner syndrome, vascular Ehlers–Danlos  synd­
rome and other forms of hereditary thoracic aortic dis­
ease127,132. Another risk factor for aortic dissection is the
presence of congenital heart disease such as bicuspid
aortic valve or aortic coarctation127. A lack of adequate
investigation for chest pain can be identified in 71%
of maternal deaths caused by aortic dissection5. The
presence of aortic dissection should always be consid­
ered when a patient has acute chest pain or back pain
requiring opiate analgesia or when the patient presents
in shock. Subsequently, aortic imaging should be per­
formed with the use of CT, MRI or (transoesophageal)
echocardiography.
Management. For women at high risk of aortic dissec­
tion, imaging of the aorta should ideally be performed
before pregnancy, with subsequent surgery if neces­
sary. Aortic diameters should be regularly monitored
during pregnancy with the use of ultrasonography
and/or MRI. When progressive aortic dilatation is obser­
ved, surgical therapy can be performed with the fetus
in utero (if the fetus is not viable) or immediately after
Caesarean section (if the fetus is viable)133. In certain
cases (such as uncomplicated type B aortic dissection),
conservative therapy can be considered, comprising
Nature Reviews | Cardiology
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strict blood-​pressure control with β-​blocker therapy134.
Patients presenting with acute type A aortic dissec­
tions need urgent surgery, with concurrent Caesarean
delivery if the fetus is viable. Alarming aortic dilatation
(>45 mm in Marfan syndrome and >50 mm with other
risk factors) is one of the few cardiac indications for
Caesarean section delivery1.
Arrhythmias
Epidemiology. Arrhythmias complicate 67 per 100,000
pregnancies135. The most frequent arrhythmias are atrial
fibrillation (which occurs in 27 per 100,000 pregnan­
cies) and supraventricular tachycardia (which occurs in
22 per 100,000 pregnancies)135. Supraventricular tach­
ycardia is the most frequent symptomatic arrhythmia
in pregnancy and occurs most commonly in late preg­
nancy136,137. Despite the observation that most arrhyth­
mias associated with pregnancy are benign, they are
associated with high maternal mortality (OR 13 for
atrial fibrillation and OR 6 for supraventricular tachy­
cardia)135. Ventricular arrhythmias are rare in pregnancy
and occur most frequently in women with pre-​existing
cardiovascular disease138.
Pathophysiology. The altered anatomy of pregnancy
can elicit new-​onset arrhythmia or prompt the recur­
rence of pre-​existing arrhythmias. Increased intravas­
cular volume loads create a higher cardiac preload and
induce atrial and ventricular stretch. Other contributing
cardiovascular factors are the physiological tachycardia
and increased contractility that occur in pregnancy28,139.
Shifts in catecholamine sensitivity, increased sympa­
thetic activity and hormonal changes during preg­
nancy can all further predispose pregnant women to
develop arrhythmia136,139. The occurrence of ectopic
beats increases during pregnancy, and complaints of
palpitations are common136.
Diagnosis and risk assessment. Cardiac anatomical
abnormalities and surgical scars increase the risk of
arrhythmia in women with congenital heart disease140.
Other risk factors for arrhythmias are advanced age and
African ancestry135. ECG and Holter monitoring should
be performed as in the non-​pregnant population if
arrhythmia is suspected.
Management. All the available antiarrhythmic drugs
cross the placenta, although detailed evidence on toxic
effects on the fetus is limited for most agents. Con­
sidering the benign and non-​sustained nature of most
arrhythmias associated with pregnancy, drug therapy
might be avoided during pregnancy or at least post­
poned during the first trimester. Antiarrhythmic therapy
is indicated in women with sustained supraventricu­
lar tachycardia with compromised haemodynamics1.
Procainamide, adenosine, digoxin and β-​blockers
are considered safe, although with potential adverse
effects (such as fetal growth restriction with β-​blocker
therapy)137,141,142. Occasionally, electrical cardiover­
sion, pacemaker implantation or catheter ablation is
required, which should not be delayed because of the
pregnancy143,144.
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Medication during pregnancy
More than 90% of pregnant women use at least one
medication during pregnancy, including prescription
or over-​the-​counter drugs or herbal preparations. The
average number of medications used per pregnancy is
rising, with 50% of women in the general population
taking more than four different drugs145. The chang­
ing characteristics of the pregnant population, such as
increasing maternal age and comorbidities, mean that
this upward trend is likely to continue9–11.
The effect of these medications on the unborn child
is an important consideration. Clinical trials in pregnant
women are rare owing to ethical considerations, which
has created a paucity of evidence on the toxic effects of
drugs on the embryo and fetus. For some drugs, tera­
togenicity or other harmful effects are clear. For other
drugs, insufficient experience is available. This lack of
data might make caregivers apprehensive when pre­
scribing medication to pregnant women and means
that drugs might be inappropriately avoided, discontin­
ued or reduced in dose. Pharmacokinetics (the absorp­
tion, distribution, metabolism and excretion of drugs)
are altered in various and sometimes opposing ways
during pregnancy. Drug absorption can be affected by
decreased gastrointestinal motility, increased gastric pH
and, typically in the first trimester, by nausea and vom­
iting146. Drug distribution is altered through increased
plasma volumes, shifts in body water and fat compo­
sition and lower levels of drug-​binding proteins such
as albumin24,147. Importantly, for drugs that are mostly
protein-​bound, the free (bioactive) drug levels might be
increased despite lower circulating levels. Drug metab­
olism through hepatic enzymes depends on the effect
of pregnancy on the activity of each of these enzymes,
which is inconsistent148. Drug excretion can be expedited
by the progressive increase in cardiac output during
pregnancy, leading to high GFRs and increased hepatic
blood flow26,28,29,149.
Although the exact effect of pregnancy on drug phar­
macokinetics differs for each drug because of the numer­
ous factors involved, the elimination route is the most
important consideration. If drug elimination occurs
through the kidneys (such as for digoxin), drug con­
centrations will generally decline in pregnancy owing
to increased renal clearance and might even reach sub­
therapeutic levels. For these drugs, increased dosage is
necessary during pregnancy. If the drug is eliminated
through the liver, the net effect in pregnancy is more
inconsistent, and drug concentrations can be decreased,
increased or unchanged depending on the changes in
the metabolizing enzyme involved148. Given that the
effects on drug pharmacokinetics increase with preg­
nancy duration, regular measurements of drug concen­
trations in the serum might be necessary to ensure safe
and therapeutic levels. Table 1 provides an overview of
commonly used cardiovascular drugs and the known
effects on mother and child.
Delivery and postpartum
A delivery plan should be made during pregnancy for
all women with cardiovascular disease, preferably before
26 weeks of gestation. A multidisciplinary approach is
crucial, including the participation of, but not limited
to, an obstetrician, cardiologist and anaesthesiologist.
Induction of labour is recommended at 40 weeks of ges­
tation at the latest, because this approach reduces mater­
nal and fetal complications150. In a cohort of women with
cardiovascular disease, planned Caesarean section did
not improve maternal outcome and was detrimental to
fetal outcome151. Therefore, vaginal delivery is advised
in almost all patients, and Caesarean section should
be reserved for selected women with severe pathology
(for example, critical acute heart failure or pulmonary
hypertension, alarming aortic dilatation or spontaneous
labour during oral anticoagulant use)1.
For induction of labour, cervical ripening balloons
and misoprostol can be safely used152. Oxytocin infusion
can be used for induction or with failure to progress in
labour. Tachycardia, hypotension and myocardial ischae­
mia have been reported when oxytocin is administered
as the commonly used 10 U intravenous bolus directly
after delivery or Caesarean section153. Therefore, a slow
and low-​dose administration of oxytocin (2 U in 10 min
combined with 10 U at 12 mU/min) is recommended,
because this dosage reduces the risk of bleeding without
causing adverse cardiovascular effects in women with
cardiovascular disease154.
Epidural analgesia for pain relief should be titrated
slowly to avoid hypotension in women with cardiovas­
cular disease. Assisted delivery can limit the burden of
bearing down efforts on the maternal cardiovascular
system1. Owing to the physiological pattern of haemo­
dynamic changes, the incidence of most cardiovascular
problems in pregnancy peaks in the third trimester but,
importantly, also in the postpartum period5,33,90,99,111. The
shifts in body fluid during the postpartum period can
precipitate decompensation and heart failure in women
with cardiovascular disease33. Therefore, in-​hospital
observation for the first 24–48 h postpartum is indicated
for women with moderate-​to-​complex heart disease,
possibly longer with increased heart disease complexity1.
Gaps in evidence
Large international registries, such as the Registry of
Pregnancy and Cardiac Disease, are important to
acquire the necessary patient numbers to describe the
epidemiology of infrequent cardiovascular diseases.
Most data on the haemodynamic physiology of preg­
nancy stems from 1950–1980, and uncertainty persists
about the exact pattern of cardiac output during the
third trimester and delivery. In hypertensive disorders
of pregnancy, whether drug therapy compared with no
therapy leads to better outcomes in women with mild-​
to-​moderate hypertension is still unclear. Also, the
optimal timing of induction of labour in women with
severe pre-​eclampsia at >34 weeks of gestation should
be investigated. In VTE, randomized controlled trials on
optimal anticoagulant regimens are necessary. In ACS,
treatment options for spontaneous coronary artery dis­
section are insufficiently studied, in particular the out­
comes of invasive versus non-​invasive management.
Recurrence of the risk of spontaneous coronary artery
dissection in subsequent pregnancies is also uncertain.
Evidence for β-​blocker therapy in women with aortic
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 Reviews

Table 1 | Commonly used cardiovascular drug classes and their safety during pregnancy and lactation
drug class indication Frequently used Former Fda Safety during pregnancy Safety during
drugs risk class lactation
Angiotensin II receptor Hypertension, Losartan, valsartan D Contraindicated owing to Incompatible
blockers heart failure teratogenicity and fetal death
Angiotensin-​converting Hypertension, Enalapril, lisinopril, D Contraindicated owing to Enalapril and captopril
enzyme inhibitors heart failure, perindopril teratogenicity and fetal death are compatible,
ischaemic heart but potential risk of
disease neonatal hypotension
Antiarrhythmic drugs Arrhythmias Adenosine, C Adenosine, lidocaine and sotalol are Adenosine
amiodarone, probably safe, but potential risk of fetal and lidocaine
flecainide, lidocaine, bradycardia; amiodarone and flecainide are preferable;
sotalol are fetotoxic (fetal thyroid insufficiency; amiodarone is
teratogenic effects in animals) incompatible
Antiplatelet drugs Ischaemic Aspirin, clopidogrel B Aspirin is considered safe; clopidogrel Aspirin is compatible;
heart disease, is probably safe (on the basis of animal clopidogrel transfers
pre-​eclampsia studies) but duration should be limited to breast milk, safety
prevention unknown
β-​blockers Hypertension, Atenolol, bisoprolol, C Probably safe, but potential risk of fetal Compatible;
arrhythmias, labetalol, metoprolol, intrauterine growth restriction and propranolol and
ischaemic heart propranolol bradycardia; atenolol is contraindicated metoprolol are
disease owing to teratogenicity preferable
Calcium-​channel Hypertension, Diltiazem, nicardipine, C Probably safe, but potential risk of Compatible
blockers angina, nifedipine, verapamil maternal hypotension and fetal
arrhythmias, hypoxia, especially in sublingual or
tocolysis intravenous administration; diltiazem
is associated with teratogenicity
Cardiac glycosides Arrhythmias, Digoxin C Considered safe, digoxin is the Compatible
heart failure preferred drug for arrhythmias,
but beware of increased dosage
requirements and monitor serum
levels of the drug
Central α-​adrenergic Hypertension Methyldopa B Preferred drug for hypertension in Compatible
receptor agonist pregnancy
Diuretics Hypertension, Furosemide, B (thiazide) Probably safe, but potential risk of Compatible
heart failure hydrochlorothiazide and C (loop hypovolaemia and oligohydramnios;
diuretics) start at low doses
Heparins Anticoagulation Low-​molecular-​weight B Considered safe, but potential risk Compatible
heparin, unfractionated of bleeding; carefully consider dose
heparin timing, in particular around delivery
and analgesia or anaesthesia
Nitrates Angina, heart Glyceryl trinitrate C Risk of maternal hypotension and fetal Safety unknown
failure hypoxia
Non-​vitamin K Anticoagulation Apixaban, dabigatran, – Contraindicated owing to Incompatible
antagonist oral rivaroxaban teratogenicity in animal studies and
anticoagulants risk of bleeding
Statins Lipid lowering, Atorvastatin, X Currently contraindicated owing Safety unknown
cardiovascular simvastatin to fetal teratogenicity; however,
disease evidence for this risk is insufficient
prevention
Vitamin K antagonists Anticoagulation Acenocoumarol, D Associated with embryopathy and Compatible
phenprocoumon, risk of bleeding (in particular around
warfarin delivery and analgesia or anaesthesia)
Information based on the 2018 ESC guidelines for the management of cardiovascular diseases during pregnancy1. The formerly used FDA risk classification of
A–X has been replaced with the Pregnancy and Lactation Labelling Rule (PLLR), but the A–X classification is still prevalent and well known; therefore, both risk
classifications are reported here (the PLLR is provided in the last two columns). The categories of risk to the fetus are: A, safe — adequate and well-​controlled
studies show no risk to the fetus; B, likely to be safe — animal studies show no risk to the fetus but no adequate human studies are available; C, risk to the fetus is
possible — animal studies show increased risk to the fetus but no adequate human studies are available; use only if potential benefits outweigh the potential risk;
D, risk to the fetus has been proved in human studies — use only if potential benefits outweigh the potential risk; X, contraindicated — risk to the fetus has been
proved and evidently outweighs any potential benefits.

dilatation or cardiomyopathy is unclear. Current therapy
for peripartum cardiomyopathy is limited and should be
explored further. Prospective data and randomized con­
trolled trials to assess drug efficacy, safety and optimal
dosage during pregnancy are scarce. The (long-​term)
effects for the mother and child of many currently used
drugs are not well known. Given that ethical concerns
will always be present in clinical drug trials during
pregnancy, large prospective registries might fill this
knowledge gap.

Nature Reviews | Cardiology

Reviews

Conclusions mask symptoms of disease, hindering a timely diagnosis.

Cardiovascular disease during pregnancy is a growing
problem that can have long-​term consequences for
maternal and fetal health. Cardiovascular disease is the
leading cause of maternal death. The pregnant popu­
lation of the future is likely to have more comorbidities
and cardiovascular risk factors, and will consequently
be at higher risk of cardiovascular morbidity and mor­
tality than the current pregnant population. Therefore,
more attention to promote a healthy lifestyle is clearly
needed.
The extensive haemodynamic, metabolic and hor­
monal adaptations during pregnancy pose an impor­
tant physiological burden on the cardiovascular system.
This burden makes women during pregnancy and the
postpartum period particularly vulnerable to the devel­
opment of cardiovascular disease or to the exacerbation
of previously asymptomatic cardiovascular disease.
In addition, the altered physiology of pregnancy can
A high index of suspicion is essential for early recog­
nition of cardiovascular complications, and diagnostic
imaging during pregnancy should be used when nec­
essary. A multidisciplinary approach including obste­
tricians, cardiologists, anaesthesiologists (and, when
appropriate, obstetric medicine specialists and neona­
tologists) is essential for the successful management of
these complications. A delivery plan should be agreed
by this team for every woman with cardiovascular dis­
ease during pregnancy. Referral centres with special­
ized experience and facilities are optimal places to treat
these patients. This Review also highlights the gaps in
evidence because prospective data and randomized con­
trolled trials on which to base management decisions are
lacking. A better evidence base is necessary to reduce the
burden of cardiovascular disease in pregnancy.
Published online xx xx xxxx

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Author contributions
All authors contributed equally to all aspects of the article.
Competing interests
The authors declare no competing interests.
Peer review information
Nature Reviews Cardiology thanks R. Cífková, P. Presbitero
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