Professional Documents
Culture Documents
SO CIETY O F
CARDIOLOGY
Review
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
1954
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.
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
Rossberg et al.
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
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
1956
(a)
(b)
Haemodynamic changes
Procoagulant activation
E2 (pg/ml)
3000
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.
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
Rossberg et al.
1957
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 (%)
IVF (n = 23,498)
Natural pregnancies (n =11,960)
0.08
0.06
0.04
0.02
P < 0.034
0
0
28
56
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).
1958
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
Rossberg et al.
1959
Outcome
All
pregnancies
(n 22)a
Congenital
lesions
(n 15)b
Acquired
arrhythmias
(n 7)c
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
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
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
1960
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.
15.
Funding
The author(s) received no nancial support for the research,
authorship and/or publication of this article.
References
16.
17.
1. Qin J, Liu X, Sheng X, et al. Assisted reproductive technology and the risk of pregnancy-related complications
and adverse pregnancy outcomes in singleton pregnancies: A meta-analysis of cohort studies. Fertil Steril
2016; 105: 7385.
2. Dayan N, Laskin CA, Spitzer K, et al. Pregnancy complications in women with heart disease conceiving with
fertility therapy. J Am Coll Cardiol 2014; 64: 18621864.
3. Thomopoulos C, Tsioufis C, Michalopoulou H, et al.
Assisted reproductive technology and pregnancy-related
hypertensive complications: A systematic review. J Hum
Hypertens 2013; 27: 148157.
4. Schmidt L, Sobotka T, Bentzen JG, et al. Demographic
and medical consequences of the postponement of parenthood. Hum Reprod Update 2012; 18: 2943.
5. Segev Y, Riskin-Mashiah S, Lavie O, et al. Assisted
reproductive technologies: Medical safety issues in the
older woman. J Womens Health (Larchmt) 2011; 20:
853861.
6. Stangl V, Schad J, Gossing G, et al. Maternal heart disease and pregnancy outcome: A single-centre experience.
Eur J Heart Fail 2008; 10: 855860.
7. Regitz-Zagrosek V, Blomstrom Lundqvist C, Borghi C,
et al. ESC Guidelines on the management of cardiovascular diseases during pregnancy: The Task Force on the
Management of Cardiovascular Diseases during
Pregnancy of the European Society of Cardiology
(ESC). Eur Heart J 2011; 32: 31473197.
8. Udell JA, Lu H and Redelmeier DA. Long-term cardiovascular risk in women prescribed fertility therapy. J Am
Coll Cardiol 2013; 62: 17041712.
9. Siu SC, Sermer M, Colman JM, et al. Prospective multicenter study of pregnancy outcomes in women with heart
disease. Circulation 2001; 104: 515521.
10. Uebing A, Steer PJ, Yentis SM, et al. Pregnancy and
congenital heart disease. BMJ 2006; 332: 401406.
11. Pritchard JA. Changes in the blood volume during pregnancy and delivery. Anesthesiology 1965; 26: 393399.
12. Rovinsky JJ and Jaffin H. Cardiovascular hemodynamics
in pregnancy. 3. Cardiac rate, stroke volume, total peripheral resistance, and central blood volume in multiple
18.
19.
20.
21.
22.
23.
24.
25.
26.
Rossberg et al.
1961
27. McDonald SD, Murphy K, Beyene J, et al. Perinatel outcomes of singleton pregnancies achieved by in vitro fertilization: A systematic review and meta-analysis. J Obstet
Gynaecol Can 2005; 27: 449459.
28. Pandey S, Shetty A, Hamilton M, et al. Obstetric and
perinatal outcomes in singleton pregnancies resulting
from IVF/ICSI: A systematic review and meta-analysis.
Hum Reprod Update 2012; 18: 485503.
29. Toshimitsu M, Nagamatsu T, Nagasaka T, et al. Increased
risk of pregnancy-induced hypertension and operative
delivery after conception induced by in vitro fertilization/
intracytoplasmic sperm injection in women aged 40 years
and older. Fertil Steril 2014; 102: 10651070.
30. Lamminpaa R, Vehvilainen-Julkunen K, Gissler M, et al.
Preeclampsia complicated by advanced maternal age: A
registry-based study on primiparous women in Finland
19972008. BMC Pregnancy Childbirth 2012; 12: 47.
31. Imudia AN, Awonuga AO, Doyle JO, et al. Peak serum
estradiol level during controlled ovarian hyperstimulation
is associated with increased risk of small for gestational
age and preeclampsia in singleton pregnancies after
in vitro fertilization. Fertil Steril 2012; 97: 13741379.
32. Dubey RK, Oparil S, Imthurn B, et al. Sex hormones and
hypertension. Cardiovasc Res 2002; 53: 688708.
33. Chasan-Taber L, Willett WC, Manson JE, et al.
Prospective study of oral contraceptives and hypertension
among women in the United States. Circulation 1996; 94:
483489.
34. Rova K, Passmark H and Lindqvist PG. Venous
thromboembolism in relation to in vitro fertilization: An
approach to determining the incidence and increase in
risk in successful cycles. Fertil Steril 2012; 97: 95100.
35. Hansen AT, Kesmodel US, Juul S, et al. Increased
venous thrombosis incidence in pregnancies after
in vitro fertilization. Hum Reprod 2014; 29: 611617.
36. Westerlund E, Antovic A, Hovatta O, et al. Changes in
von Willebrand factor and ADAMTS13 during IVF.
Blood Coagul Fibrinolysis Int J Haemost Thromb 2011;
22: 127131.
37. Royal College of Obstetricians and Gynaecologists. The
Management of Ovarian Hyperstimulation Syndrome.
Green-top Guideline No. 5. https://www.rcog.org.uk/glo
balassets/documents/guidelines/green-top-guidelines/gtg_
5_ohss.pdf (Accessed 2 April 2016).
38. Budev MM, Arroliga AC and Falcone T. Ovarian hyperstimulation syndrome. Crit Care Med 2005; 33:
S301S306.
39. Kumar P, Sait SF, Sharma A, et al. Ovarian hyperstimulation syndrome. J Hum Reprod Sci 2011; 4: 7075.
40. Mor YS and Schenker JG. Ovarian hyperstimulation syndrome and thrombotic events. Am J Reprod Immunol
2014; 72: 541548.
41. Calabro RS, Gervasi G, Leo A, et al. Neurovascular
complications of ovarian hyperstimulation syndrome
(OHSS): From pathophysiology to recent treatment
options. Recent Pat Endocr Metab Immune Drug Discov
2014; 8: 109116.
42. Stewart JA, Hamilton PJ and Murdoch AP.
Thromboembolic disease associated with ovarian stimulation and assisted conception techniques. Hum Reprod
1997; 12: 21672173.
43. Vloeberghs V, Peeraer K, Pexsters A, et al. Ovarian
hyperstimulation syndrome and complications of ART.
Best Pract Res Clin Obstet Gynaecol 2009; 23: 691709.
44. Farland LV, Grodstein F, Srouji SS, et al. Infertility, fertility treatment, and risk of hypertension. Fertil Steril
2015; 104: 391397.
45. Westerlund E, Brandt L, Hovatta O, et al. Incidence of
hypertension, stroke, coronary heart disease, and diabetes in women who have delivered after in vitro fertilization: A population-based cohort study from Sweden.
Fertil Steril 2014; 102: 10961102.
46. Wei J, Minissian M and Bairey Merz CN. Pregnancy
outcomes, reproductive history and cardiovascular disease risk in women: What do we know and what is
needed? Eur J Prev Cardiol. 9 August 2016. DOI:
10.1177/2047487316664148.
47. Heida KY, Koster MPH, Franx A, et al. Relationship
between recurrent miscarriage and early preterm delivery
and recurrent events in patients with manifest vascular
disease: The SMART study. Eur J Prev Cardiol 2016;
23: 486492.
48. Heida KY, Bots ML, de Groot CJM, et al.
Cardiovascular risk management after reproductive and
pregnancy-related disorders: A Dutch multidisciplinary
evidence-based guideline. Eur J Prev Cardiol. 18 July
2016. DOI: 10.1177/2047487316659573.
49. ESHRE Capri Workshop Group. Venous thromboembolism in women: A specific reproductive health risk.
Hum Reprod Update 2013; 19: 471482.
50. Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy:
Antithrombotic Therapy and Prevention of Thrombosis,
9th ed. American College of Chest Physicians EvidenceBased Clinical Practice Guidelines. Chest 2012; 141:
691S736S.