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EURO PEAN

SO CIETY O F
CARDIOLOGY

Review

Pregnancy and cardiovascular risk:


A review focused on women with heart
disease undergoing fertility treatment

European Journal of Preventive


Cardiology
2016, Vol. 23(18) 19531961
! The European Society of
Cardiology 2016
Reprints and permissions:
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DOI: 10.1177/2047487316673143
ejpc.sagepub.com

Nora Rossberg1, Karl Stangl1,2 and Verena Stangl1,2

Abstract
A growing number of women with heart disease are considering pregnancy with the help of assisted reproductive
technology (ART). Although an ever-increasing amount of knowledge exists on pregnancy in both congenital and
acquired heart disease patients, little information is available on fertility treatments specifically in these women. This
review seeks to provide an overview of the existing data and explores areas in need of research in this field. Changes in
the hormonal environment seen in ART patients initially entail an increase then a decrease in blood pressure and
peripheral vascular resistance. A shift in the thromboticthrombolytic balance towards coagulation is observed.
Compared to normal pregnancy, ART-conceived pregnancies exhibit an increased adverse event rate for both the
mother and foetus, including a higher incidence of hypertensive disorders and an increase in thromboembolic events
during the first trimester. Ovarian hyperstimulation syndrome in particular can cause dramatic haemodynamic changes
and an increase in upper body thrombosis. Viewing these findings within the context of women with an underlying heart
disease reveals indications that maternal and neonatal complications after fertility treatments are higher. Pre-pregnancy
risk assessment is essential to identifying women with heart disease for whom ART may be dangerous and therefore
inappropriate.

Keywords
Fertility treatments, pregnancy, cardiovascular, thromboembolic
Received 6 June 2016; accepted 16 September 2016

Introduction
Over 200,000 children are conceived worldwide each
year with the help of assisted reproductive technologies
(ARTs).1 In the largest European countries (Germany,
France, the United Kingdom and Italy) 1.72.2% of
births are conceived through fertility treatments
(FTs).1 Today, there is a higher demand for these technologies,13 as well as a trend towards delayed childbearing over recent decades.2,4
Furthermore, with older maternal age at the time of
rst pregnancy, the risk of cardiovascular diseases
increases owing to the greater prevalence of risk factors
such as hypertension and diabetes.5 In addition, the
number of congenital heart disease patients who reach
childbearing age in good clinical condition rises continuously as advances in medical management and surgical techniques improve overall health and prognosis.6
As a result, these women are now able to consider

pregnancy.6 Today, an estimated 0.24% of pregnancies occur in women with acquired or congenital heart
diseases,7 hence the demand for FTs has increased in
this patient group.1,2
Sparse data are available concerning the risks
involved when ARTs are used in patients with a background of cardiovascular disease. However, since both
heart disease and FTs individually enhance the risk of
adverse events in pregnancy, additional information is
required in order to enable clinicians to advise their
1
Medizinische Klinik fur Kardiologie und Angiologie, Campus Mitte,
Charite Universitatsmedizin, Berlin, Germany
2
DZHK (German Centre for Cardiovascular Research), Berlin, Germany

Corresponding author:
Verena Stangl, Medizinische Klinik fur Kardiologie und Angiologie,
Campus Mitte, Charite Universitatsmedizin, Berlin Schumannstr. 20-21,
10117 Berlin, Germany.
Email: verena.stangl@charite.de

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European Journal of Preventive Cardiology 23(18)

patients adequately.8,9 The aim of this review is to summarise current data on the cardiovascular risks of FTs,
particularly in women with heart disease.

Physiological changes in pregnancy


In a normal singleton pregnancy, plasma volume and
cardiac output increase during the rst two trimesters;
by the end of the pregnancy, both will have reached
levels that are 3050% above the pre-pregnant
state.1012 First, stroke volume and, later in pregnancy,
heart rate increase to account for the marked elevation
of cardiac output.6,7 Furthermore, there is a drop in
blood pressure due to active vasodilatation and a
reduction in systemic vascular resistance.7 Kametas
and colleagues reported that, compared to women
with singleton pregnancies, women with twin pregnancies experienced a maternal cardiac output increase of
20%.13,14 In addition, there was a signicant decrease
in total vascular resistance and greater left ventricular
(LV) end-diastolic and end-systolic dimensions, LV
mass, fractional shortening and ejection fraction.14
Labour and the postpartum period also pose additional physiological challenges with uterine contractions,
expulsive eorts, pain, anxiety, blood loss and the process of uterine involution.7 Systolic blood pressure
increases by as much as 25% during contractions, while
cardiac output increases by 15% during early labour and
by up to 80% in the early postpartum period.7

Pregnancy and heart disease


In western countries, the most frequent cardiovascular
diseases during pregnancy are congenital, making up
7582% of heart diseases in pregnancy.7 Of these,
shunt lesions are the most common.7 In contrast, in
non-western countries, rheumatic heart diseases with
associated valvular abnormalities represent the majority
(5689%) of cases.7 In general, hypertensive disorders are
the most predominant sources of complications during
pregnancy, while peripartum cardiomyopathy is the most
frequent source of severe adverse events in pregnancy.7

Risk stratification and counselling


Since pregnancy requires a complex set of adaptations
of the cardiovascular system, which may be particularly
demanding in the context of underlying heart disease,
preconception care and counselling for these women
is of fundamental importance. Before considering
the possibility of ART, the rst question to address is
whether, a pregnancy would be possible without posing
an inappropriate risk to the mother or the neonate. The
specic risk of multiple gestations is associated with a
further haemodynamic burden for the mother and must

be taken into account. Multiple pregnancies are frequent in ART usage: the incidence of twins in in vitro
fertilisation (IVF)-conceived pregnancies is approximately 27%.3
The extent to which women are able to cope with the
haemodynamic challenges imposed by pregnancy, particularly multiple pregnancies, depends on the nature,
severity and current status of the underlying heart condition.7 Despite the broad morphological and functional diversity of heart disease, only a few
parameters have been shown to be associated with complications in pregnancy: previous cardiac events (heart
failure, transient ischaemic attack or stroke before
pregnancy) or arrhythmia; poor functional New York
Heart Association (NYHA) class (>II) or cyanosis; LV
systolic dysfunction (ejection fraction <30%); left heart
obstruction; and pulmonary arterial hypertension.6,7,9
Data from the literature and from our own studies
show that maternal and neonatal event rates increase
in women who meet at least one of these criteria.6,7,9
Several risk assessment models have been developed for
estimating maternal and neonatal risk.7 Of these,
the modied World Health Organization (WHO) classication appears to be the most reliable score for the
prediction of maternal risk.7,1517 As shown in Table 1,
conditions in which pregnancy risk is signicantly elevated are summarized in WHO class III, and contraindications for pregnancy are summarized in WHO class
IV. As a matter of fact, FTs should not be performed
under these conditions. Maternal predictors of neonatal
adverse events are baseline NYHA class >II or cyanosis,
left heart obstruction, smoking during pregnancy, multiple gestation, use of oral anticoagulants during pregnancy and mechanical valve prostheses.7

Assisted reproductive technologies


ART refers to all FTs in which oocytes and sperm are
handled with the aim of achieving pregnancy, and
includes IVF, intracytoplasmic sperm injection (ICSI),
egg donation and surrogacy. For the purposes of this
review, we also include ovulation-induction therapies
without in vitro procedures, as there are important similarities in the medical and hormone treatments
employed.18
For both IVF and ICSI, the womans uterus and
hormonal environment are primed for oocyte retrieval
and endometrial implantation through the use of
exogenous hormones.18,19 In order to control the menstrual cycle and ovarian maturation, oral contraceptives or gonadotrophin-releasing hormone (GnRH)
analogues are given during the menstrual cycle before
the ART attempt.18 Gonadotrophins (luteinising hormone (LH) and follicle stimulating hormone (FSH)),
human menopausal gonadotrophins, human chorionic

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1955

Table 1. Modified World Health Organization (WHO) classification of maternal cardiovascular risk.7
Conditions in which pregnancy risk is WHO class I
 Uncomplicated, minor or mild pulmonary stenosis; patent ductus arteriosus; mitral valve prolapse; successfully repaired
simple lesions (atrial or ventricular septal defect, patent ductus arteriosus and anomalous pulmonary venous drainage); isolated
atrial or ventricular ectopic beats
Conditions in which pregnancy risk is WHO class II
 Atrial or ventricular septal defect not treated by surgery; repaired tetralogy of Fallot; most arrhythmias
Conditions in which pregnancy risk is WHO class IIIII
 Mild left ventricular impairment; hypertrophic cardiomyopathy; native or tissue valvular heart disease not considered WHO
class I or IV; Marfan syndrome without aortic dilation; aorta <45 mm in aortic disease associated with bicuspid aortic valve
disease
Conditions in which pregnancy risk is WHO class III
 Mechanical valve; systemic right ventricle; Fontan circulation; cyanotic heart disease (unrepaired); other complex congenital
heart diseases; aortic dilation 4045 mm in Marfan syndrome; aortic dilation 4550 mm in aortic disease associated with bicuspid
aortic valve
Conditions in which pregnancy risk is WHO class IV
 Pulmonary arterial hypertension of any cause; severe systemic ventricular dysfunction (left ventricular ejection fraction
<30%, New York Heart Association class IIIIV); previous peripartum cardiomyopathy with any residual impairment of left
ventricular function; severe mitral stenosis; severe symptomatic aortic stenosis; Marfan syndrome with aorta dilated >45 mm;
aortic dilation >50 mm in aortic disease associated with bicuspid aortic valve; native severe coarctation
Risk class

Risk of pregnancy

I
II
III
IV






No detectable increased risk of maternal mortality and no/mild increase in morbidity


Small increased risk of maternal mortality or moderate increase in morbidity
Significantly increased risk of maternal mortality or severe morbidity
Extremely high risk of maternal mortality or severe morbidity; pregnancy contraindicated

gonadotrophin (hCG) or clomiphene citrate are then


applied in order to achieve follicle stimulation over
the rst 11.5 weeks of the cycle.18 Once the target follicle size and oestradiol level are reached, hCG is
administered in order to initiate ovulation, followed
by oocyte retrieval.18 After IVF and transfer of the
embryo into the uterus, oestrogen, progesterone or
hCG may be given in the luteal phase and up to the
end of the rst trimester in order to encourage implantation and endometrial development.18,19 The oestrogen
levels resulting from ovarian stimulation lie well above
normal physiological levels, although not as high as
those during pregnancy itself.20 However, the rate of
oestrogen rise is considerable: from 10-fold during the
down-regulation phase to 100-fold during the stimulation phase.21
All ARTs result in pronounced changes in endogenous hormone levels, with potential impact on several
components of the cardiovascular system; haemodynamic changes and eects on the coagulation
system are of particular importance in this context.
As shown in Figure 1(a), oestradiol suppression in
response to GnRH agonists is associated with an
increase in blood pressure and peripheral vascular
resistance.22 Conversely, an increase in oestradiol
levels during ovulation stimulation induces a decrease

in mean arterial pressure and peripheral vascular resistance, as well as an increase in cardiac output.22
Changes in hormone levels also aect the coagulation
cascade, inducing a shift in the thromboticthrombolytic equilibrium towards a coagulative state with
increases in von Willebrand factor, Factor VIII,
Factor V and brinogen and increased activated protein C resistance. This coincides with a decrease in antithrombin and protein C and S activity, as well as a
reduction in important brinolytic agents such as
tissue plasminogen activator (Figure 1(b)).18,23 In addition, thrombin generation and brin formation are
augmented in ART patients.23
In the majority of cases, these haemodynamic and
haemostatic changes have few clinical consequences.
However, in the context of complicating conditions
(such as ovarian hyperstimulation syndrome (OHSS))
or pre-existing cardiovascular diseases, they may
adversely impact patient outcome.

General pregnancy-related
complications of ARTs
Various studies have shown that pregnancies conceived
with ARTs, although generally safe and widespread,
face an increased risk of adverse outcomes when

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European Journal of Preventive Cardiology 23(18)

(a)

(b)

Haemodynamic changes

Procoagulant activation

E2 (pg/ml)

3000

von Willebrand Factor

2000
1000

Factor VIII

100

Peripheral vascular
Mean arterial
resistance (dyn./s.cm) pressure (mmHg)

Factor V

100
90

APC resistance
80

Fibrinogen

70
1700
1500
1300

Anti-thrombin

1100

Cardiac
output (L /min)

6.0

Protein C activity

5.5
5.0

Protein S activity

4.5
4.0

TPA

time points

Figure 1. (a) Haemodynamic changes (modified from Manau et al.22) and (b) haemostatic consequences of ovarian stimulation in the
context of fertility treatments (APC (activated protein C), TPA (tissue plasminogen activator)).18,23 Time points in (a): 1: cycle
preceding in vitro fertilization (day 8); 2: pituitary ovarian suppression; 3: human chorionic gonadotrophin (hCG) ovulatory injection
(after ovarian follicular stimulation); 4: day 1 after hCG ovulatory dose; 5: day 7 after hCG ovulatory dose.

compared to those conceived spontaneously. Some of


these eects have been attributed to the higher incidence of twin pregnancies in ART conceptions.
However, even when controlling for this confounder,
the dierence remains signicant.1,2428 In a systematic
review of 50 cohort studies covering a total of 161,370
ART and 2,280,241 non-ART pregnancies, Qin et al.
calculated the following increased maternal risk
outcomes for the ART-conceived group: 30% for pregnancy-induced hypertension (PIH) and 31% for gestational diabetes mellitus.1 Strikingly, the risk for
placenta praevia was increased by 271% in the ARTconceived group. Other signicantly elevated obstetric
risk factors included an increase of 83% for placental
abruption, 111% for antepartum haemorrhage, 29%
for postpartum haemorrhage, 74% for polyhydramnios, 114% for oligohydramnios, 58% for caesarean
section, 71% for preterm birth (<37 weeks gestation),
112% for very preterm birth (<32 weeks gestation),
61% for low birth weight (<2500 g), 112% for
very low birth weight (<1500 g), 35% for small for gestational age, 64% for perinatal mortality and 37%
for congenital malformations.1 The reasons for
the increased adverse pregnancy outcomes with ARTs

remain unclear, and there is much debate about


whether the eects arise from the technologies themselves or the pre-existing risk prole of the infertile
population.1,24,28

Hypertension
Hypertensive disorders, which are observed in 810%
of pregnancies, account for the leading cause of obstetric complications.3 Although data are inconsistent, FTs
have been linked to PIH.1,3,29,30 In their systematic
review, Thomopoulos et al. analysed 47 studies and
found that ARTs, and IVF in particular, are associated
with an increased risk of gestational hypertension and
pre-eclampsia.3 Multiple pregnancies and advanced
maternal age further increase the risk of hypertensive
complications.3 However, even after adjustment
for these confounders, the ART-associated increased
risk of PIH and pre-eclampsia persists.3 The underlying
reasons for this are multifactorial. Several factors have
been implicated that induce subtle abnormalities in placental development in ART pregnancies.3 Such factors
include the procedure of transferring the embryo
through the cervix or the fact that the formation

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Thromboembolic events
Although the overall incidence of thromboembolic
events associated with FTs is low, reports of thrombosis have long accompanied reproductive technologies, particularly in the context of OHSS (see below).
As outlined earlier, ovarian stimulation induces a procoagulant state, especially due to the increased oestradiol levels and hCG that is used for the induction of
ovulation.20 Clinical studies show that ARTs are associated with an increased risk of venous thrombosis;
however, this is only the case for successful cycles.
IVF that does not result in pregnancy is evidently not
associated with increased venous thrombosis incidence.
A large register-based cohort study including 30,884
Danish women investigated the incidence of arterial
and venous thrombosis within the rst 6 and 12
months after IVF or ICSI. In order to isolate the eects
of the ARTs themselves, all thromboembolic events
occurring during pregnancy were excluded from the
analyses.20 The incidence rates were then compared to
a reference population using published estimates of the
frequency of thrombosis in Danish women of a similar
age. No signicant dierences in thromboembolic event
rates were found.20
In contrast, rates of venous thromboembolisms
during pregnancy appear to be higher in women
undergoing IVF (Figure 2 and Table 2). Thrombosis
complicates 0.10.3% of the stimulation cycles.34,35
Henriksson et al. performed a large cross-sectional
study of 23,498 women who had conceived by IVF
and 116,960 women who had conceived naturally;
both cohorts were matched based on calendar year of
delivery and maternal age (Figure 2 and Table 2). The
authors found signicantly higher rates of venous

0.10
Pulmonary embolisms (%)

of the chorion initially occurs in vitro instead of within


the maternal environment.3 Alterations in oestradiol
levels31 as well as dierences in other hormonal or vasoactive factors may also play a role. Whereas endogenous oestrogen is postulated to decrease hypertension
risk,32 exogenous hormone treatment is associated
with an increase in blood pressure.33 IVF procedures
without the formation of a corpus luteum reveal a relative deciency of the hormone relaxin, which may negatively impact on vasodilation and lead to vascular
dysfunction.3 Furthermore, genetic and immune factors
in cases of gamete donation have been implicated.3
Underlying mechanisms may also involve aberrant activation of the reninangiotensin system.33 To date, there
have been no studies specically comparing the incidence of hypertensive complications in ART pregnancies in women with or without a pre-pregnancy
diagnosis of hypertension.3

IVF (n = 23,498)
Natural pregnancies (n =11,960)

0.08
0.06
0.04
0.02
P < 0.034
0
0

28

56

84 112 140 168 196 224 252 280 308 336

Days from start of the pregnancy

Figure 2. Pulmonary embolisms in pregnancy in relation to


in vitro fertilisation (IVF) compared to a non-IVF population. Data
from the Swedish Birth Registry (modified from Rova et al.34 and
Henriksson et al.21).

Table 2. Venous thromboembolic events (VTE) in pregnancy in


relation to in vitro fertilisation (IVF) compared to a non-IVF
population.
Incidence/1000
A

IVF
Non-IVF
95%
(n 19,194) (n 935,338) OR CI

VTE
Trimester 1
Trimester 2
Trimester 3
Unknown Trimester
Total antepartum
VTE postpartum

1.67
0.26
0.68
0.05
2.66
0.63

0.17
0.18
0.59
0.03
0.97
0.55

9.8
1.5
1.1
NA
2.7
1.2

6.7-14.3
0.6-3.6
0.7-2.0
2.1-3.6
0.6-2.0

Data from the Swedish Birth Registry (mod. Rova K et al., Henriksson P
et al.21,34).

thromboembolism over the entire course of pregnancy


(hazard ratio: 1.77; 95% condence interval: 1.412.23)
after IVF (4.2 per 1000 women) compared to matched
controls (2.5 per 1000 women).21 Although the absolute
risk was low, the rate of pulmonary embolism increased
approximately sevenfold during the rst trimester (two
to three additional cases per 10,000 pregnancies).21
Similarly, a more recent analysis from the Danish
National Cohort reported that pregnancies achieved
with ARTs were associated with a threefold increase
in venous thrombosis.35 Interestingly, Henriksson
et al. found the highest venous thromboembolism incidence in the rst trimester after IVF, whereas in naturally conceived pregnancies, the highest rates occurred in
the postpartum period.21 Multiple pregnancies do not
further increase the risk of rst-trimester venous

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European Journal of Preventive Cardiology 23(18)

thrombosis.34 The short interval between ART use and


thrombosis suggests that procedure-associated changes
may be of pathophysiological relevance. Pronounced
oestrogen increases during the stimulation phase have
been suggested to be a major underlying causal factor.36

Ovarian hyperstimulation syndrome


OHSS is an exaggerated response to the pharmaceutical
induction of ovulation and represents a severe complication of ART usage; it is associated with increased
morbidity and mortality. The incidence of OHSS
varies with the type of ART and is related to the
degree of ovarian stimulation.37 The British Royal
College of Obstetricians and Gynaecologists quotes
an incidence for mild OHSS of approximately one in
every three cycles of IVF, with moderate or severe
forms ranging from 3.1% to 8% of cycles.37 It is
most often associated with the use of gonadotrophins
and clomiphene for ovarian stimulation.18,38 The syndrome appears to be rare without the use of hCG and is
therefore evidently linked to this hormone, potentially
via stimulation of vascular endothelial growth factor
production,39 which functions as a vascular permeability factor and has been reported to play a key role in the
pathogenesis of OHSS.40

Haemodynamic consequences
The loss of control of ovarian stimulation leads to
ovarian enlargement and a uid shift from the intravascular to the extravascular compartment as a result of
increased capillary permeability, as induced by ovarian
secretion of vasoactive substances. This leads to intravascular volume depletion along with ascites, oedema,
hydrothorax and hydropericardium.38,39 The haemodynamic changes in OHSS are characterised by intravascular hypovolaemia, hypotension and decreased
central venous pressure. Subsequent marked stimulation of the reninangiotensin system and the sympathetic nervous system, as well as increased levels of
antidiuretic hormone (ADH) and endothelin, are part
of the generalised homeostatic/haemodynamic response
in order to maintain circulatory function.41
Consequently, patients with OHSS exhibit hyperdynamic circulation characterised by arterial hypotension,
tachycardia, high cardiac output and low peripheral
resistance. In addition, renal sympathetic overactivity
and increased ADH and aldosterone levels promote
sodium and water retention and thereby contribute to
the formation of oedema and ascites.22 It is suggested
that circulatory dysfunction occurs to some degree in
all patients undergoing IVF, even those who are asymptomatic, and that OHSS is the extreme end of a spectrum of changes.22

Thromboembolic complications in OHSS


OHSS is associated with increased thromboembolic
risk.18 The rates of venous thromboembolism in
OHSS are reportedly between 0.8% and 2.4%.34
Compared to women conceiving naturally, pregnancies
with fresh IVF cycles complicated by OHSS are at a
100-fold increased risk of venous thrombosis in the rst
trimester.34
The underlying pathophysiology of OHSS-mediated
thromboembolism has not yet been completely elucidated, but a combination of hyperviscosity, haemoconcentration, hypovolaemia, activation of the coagulation
cascade and excess release of vasoactive cytokines from
stimulated, often polyfollicular ovaries has been implicated.39,41 Notably, venous thromboembolic events in
ART usage and OHSS have a tendency to occur in
unusual sites, including the upper limbs and cerebral
and cardiac vasculature.34,37,38 Reviewing published
cases, Stewart et al. found a rate of 60% of localisations
occurring in the arm, neck and head veins. This gure is
far above the reported 4% in the general population, in
which upper-limb thrombosis is comparatively infrequent.42 Thrombosis at these sites cannot be explained
by reduced venous drainage associated with pregnancy,
with the result that such data highlight the idea of a
hypercoagulable state with underlying haematological
changes.42 In addition to venous thrombosis, arterial
thromboembolism has also been reported in OHSS,
albeit more rarely.43

Implications for women


with heart disease
Risks of ART-induced pregnancy
in cardiovascular diseases
There are scarce data available with regards to ART
usage in women with pre-existing heart disease. Most of
this information is retrieved from case reports or small
studies. Recently, Dayan et al.2 reported the frequencies of pregnancy complications in women with cardiovascular disease who conceive with FTs (Table 3).
Although these data are generated from a small retrospective study (22 pregnancies and n 20 women) and
involve a variety of congenital and acquired cardiac
diseases, the authors found that 73% of pregnancies
were associated with at least one complication. OHSS
occurred in 18% of the patients with heart disease,
which is signicantly higher than rates observed in
healthy women. Both maternal cardiac (27% versus
20%) and neonatal complications (45% versus 20%)
were more frequent in pregnant women with heart disease who conceived with ARTs than those in previous
cohorts with heart disease and natural conception.9
Adverse maternal cardiac outcomes consisted of two

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Table 3. Complications in women with heart disease conceiving


with fertility treatment (modified from Dayan et al.2).

Outcome

All
pregnancies
(n 22)a

Congenital
lesions
(n 15)b

Acquired
arrhythmias
(n 7)c

ART outcome (%)


OHSS
Thrombosis
Cardiac outcome
Maternal death
Arrhythmia
CHF

4 (18)
4
0
6 (26)
0
2
4

4 (27)
4
0
4 (27)
0
1
3

0
0
0
2 (29)
0
1
1

Mean age 37  4 years, 64% nulliparity, 9% multiples.


One repaired atrial septal defect (ASD), one situs inversus/repaired
ASD, one aortic coarctation, three tetralogies of Fallot, one bicuspid
aortic valve with dilation of the aorta, one bioprosthetic aortic valve,
one Kartagener syndrome, two pulmonary stenoses post-valvotomy
with residual pulmonary regurgitation and four hypertrophic
cardiomyopathies.
c
One mitral valve prolapse with severe mitral regurgitation (MR), two
mitral valve prolapses with MR and biventricular systolic dysfunction, one
coronary artery disease, two supraventricular and ventricular
tachycardia.
ART: assisted reproductive technology; OHSS: ovarian hyperstimulation
syndrome; CHF: congestive heart failure.
b

cases of arrhythmia and four of congestive heart failure. Foetal and neonatal outcomes included one neonatal death, seven preterm deliveries, one case of
respiratory distress, two small for gestational age and
one intracranial haemorrhage. The authors noted that
the pathophysiological mechanisms behind these
adverse obstetric events may be linked to suboptimal
endometrial function and impaired utero-placental
perfusion.2

Long-term cardiovascular risk of FTs


Another crucial point is the long-term risk associated
with ART usage. Does the potentially increased physiological stress of FTs worsen womens cardiac prognosis
postpartum, even years after the birth of her child?
It has been suggested that endothelial dysfunction,
prothrombotic eects and metabolic syndromes
(associated with gestational diabetes mellitus and
hypertension) could represent potential mechanisms
by which detrimental downstream health eects may
occur in women after ART usage.8 Literature reports
are inconclusive. Udell et al. conducted a cohort study
of women who had given birth in Ontario, Canada,
between 1993 and 2010.8 They analysed dierences in
cardiovascular events between women who had used
FTs in the 2 years before giving birth and those who
had not. Cardiac events included death, nonfatal coronary ischaemia, stroke, transient ischaemic attack,

thromboembolism and heart failure. The study revealed


that at a median follow-up of 9.7 years post-delivery,
women who had used FTs (n 6979) had fewer cardiovascular events than those who had not
(n 1,186,753).8 More specically studying hypertension, the Nurses Health Study II, involving 116,430
women, reported that the incidence of hypertension is
not higher among women who had previously undergone FT.44 In contrast, a Swedish study by Westerlund
et al. found higher rates of hypertension among 23,498
women who had undergone IVF compared with
116,960 individually matched mothers from the
Medical Birth Register.45 One explanation for this
could be a baseline dierence in incidence or risk factors for hypertension among the sub-fertile population.45 Studies specically focusing on cohorts of
women with pre-existing heart disease are lacking.
Pregnancy represents a stress test on a womans physiology and may therefore act as an early warning
mechanism by unmasking underlying cardiovascular
issues.4648 There is some evidence that reproductive
and pregnancy-associated disorders, including those
aecting fertility such as polycystic ovary syndrome
and premature ovarian insuciency, could be useful
indicators for future cardiovascular disease.46,48
However, more research is needed in order to evaluate
which obstetric events are meaningful markers that a
woman is at increased risk of developing cardiovascular
risk later in life and how best to act on them.46,48

Conclusions
ART usage is associated with a small but signicantly
increased risk of PIH and venous thromboembolism.
As a specic and potentially serious complication of
ART usage, OHSS may result in haemodynamic and
procoagulant burden. Multiple gestations occur more
frequently in ART usage and may contribute to additional circulatory challenge. Although increasing
amounts of data exist on the risks of pregnancy with
heart disease, little information is available specically
on FT in such women. There are indications that ART
usage poses an additional hazard to the pregnancy risk
for cardiac patients; however, further research is
required in order to determine the magnitude of this
eect. Risk stratication and counselling are important
for women with heart disease considering ART usage.
The WHO classication is a valuable tool for this purpose, and FTs should not be performed in women fullling WHO class III and IV critieria.7,1517 With
regards to the increased thromboembolic risk during
or after ART usage, it is important to identify highrisk women for whom thromboembolic prophylaxis
with stockings and heparin should be considered, particularly if OHSS occurs.49,50

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European Journal of Preventive Cardiology 23(18)

Author contribution
NR and VS contributed to the conception and design of the
work. NR and VS performed the literature research. NR and
VS drafted the manuscript. KS critically revised the manuscript. All gave nal approval and agree to be accountable for
all aspects of work ensuring integrity and accuracy.

13.

14.

Declaration of conflicting interests


The author(s) declared no potential conicts of interest with
respect to the research, authorship and/or publication of this
article.

15.

Funding
The author(s) received no nancial support for the research,
authorship and/or publication of this article.

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