University of Groningen

Pregnancy in women with congenital heart diseaseKampman, Marlies Aleida Maria

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Citation for published version (APA):Kampman, M. A. M. (2016). Pregnancy in women with congenital heart disease: complications andmechanisms. [Groningen]: Rijksuniversiteit Groningen.

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Chapter 1Introduction

Introduction 11

1ePideMiology

Congenital heart defects (CHD) are the most common congenital defects in newborns, with

a birth prevalence of 9/1000 live births worldwide 1,2. Due to improved surgical and medical

treatment, the majority of these children survive until adulthood. This resulted in a large co-

hort of adult survivors, mostly still young and of child bearing age 3. It is important to realize

that these women are not cured and that pregnancy can have deleterious effects on cardiac

function and patient wellbeing since pregnancy requires major hemodynamic changes.

PhysiologiCAl ChAnges during norMAl PregnAnCy

Pregnancy induces profound changes in the cardiovascular system, in order to meet the

increased maternal and fetal metabolic demands. During normal pregnancy, cardiac output

increases 30-50% above baseline, starting in early pregnancy and continues to rise until

24 weeks gestation. This augmented cardiac output is maintained until term (figure 1) 4.

The increase in cardiac output results from an increase in preload (circulating volume), a

decrease in afterload (peripheral vascular resistance) and an increase in heart rate. During

labor, delivery and the post-partum period again profound changes in cardiac output occur,

because of pain, anxiety, uterine contraction and uterine involution 4-6.

The hemodynamic changes described result in progressive left ventricular remodeling. Left

ventricular end-diastolic and end-systolic dimensions increase during pregnancy, where ejec-

tion fraction remains unchanged 7,8. The myocardium becomes hypertrophic as gestation

advances and as a result of that, left ventricular mass increases. Despite the morphological

changes, diastolic function is not impaired during pregnancy and left ventricular diastolic

filling pressures remain unchanged 7,9. Studies describing right ventricular remodeling during

pregnancy are extremely scarce. The available data suggests that right ventricular systolic

function remains stable during pregnancy 10,11. Right ventricular diameter appears to increase

towards the third trimester of pregnancy 10.

Figure 1: Hemodynamic changes during pregnancy according to gestational week (modified from Rob-son et al. 4).

12 Chapter 1

PregnAnCy in woMen wiTh CongeniTAl heArT diseAse

Thirteen years of ZAHARA (Zwangerschap bij Aangeboren HARtAfwijkingen, pregnancy in

congenital heart disease) research provided valuable insights to the knowledge of pregnancy

in women with CHD and the research line evolved from epidemiology focused to more

fundamental research focusing on the underlying pathophysiological mechanism of compli-

cations.

The first ZAHARA study was conducted between 2002 and 2007 aiming to investigate

pregnancy outcome in women with CHD and to identify predictors of cardiac complications

during pregnancy retrospectively. Pregnancy in women with congenital heart disease ap-

peared to be associated with increased incidence of cardiovascular, obstetric and neonatal

complications 12-22. In approximately 7-13% (depending on the underlying heart disease) of

the pregnancies in women with CHD, cardiovascular complications occur, with heart failure

and arrhythmia being most frequently observed 14,23-25. Siu et al. developed the CARPREG

(Cardiac disease in pregnancy) risk score, in order to estimate the risk of cardiac complications

during pregnancy in women with cardiac disease 24. The CARPREG risk score underestimated

the risk of cardiac events in a cohort of women with solely CHD, which suggested that modi-

fications in the risk score were needed 26. The ZAHARA study resulted in the development

of a new risk estimation model for the occurrence of cardiovascular complications during

pregnancy in women with CHD, and also identified new predictors of adverse neonatal

outcome 23. The study resulted in the thesis that was defended by Wim Drenthen (2-7-2007).

The first ZAHARA study, as well as other reports, revealed that especially placenta-related

complications are more frequently observed in women with CHD (ie. hypertensive disor-

ders of pregnancy and fetal growth restriction) 12-14,27. The ZAHARA II study was primarily

designed to shed light on a possible underlying mechanism for the increased incidence. In

patients with chronic heart failure, worsening cardiac function is associated with dysfunction

of other organs 28,29 and a similar mechanism might be present during pregnancy, during

which cardiac dysfunction hampers placental development and function leading to adverse

pregnancy outcome. We postulated that maternal cardiac dysfunction is responsible for

abnormal placental development and placental dysfunction. In pregnant women without

underlying heart disease, inadequate adaption of the uteroplacental circulation is responsible

for several obstetric and offspring complications. The pathophysiological mechanism is poor

trophoblast invasion of the spiral arteries during the placentation process 30, causing failure

of the placental-bed arteries to transform from high to low-resistance vessels. Uteroplacental

flow investigations (resistance and pulsatility indices of the uterine artery and umbilical

artery) provide insight in the placentation process and are commonly used as screening tool

to predict the future development of pre-eclampsia, fetal growth restriction, still birth and

placental abruption 31,32. In ZAHARA II we investigated the effect of impaired cardiac function

Introduction 13

1on the uteroplacental circulation and its relationship with the occurrence of adverse obstetric

and offspring outcome 33.

The ZAHARA II study was conducted between March 2008 and August 2011. This study also

provided the opportunity to validate the ZAHARA prediction model and to compare it with

the other risk prediction models used. It turned out to perform better in a population with

CHD compared to the CARPREG risk score 34. These findings, as well as the study design of

ZAHARA II were described in the thesis of Ali Balci, defended at 5-9-2012.

The increased volume load is thought to play an important role in the pathogenesis of the

cardiovascular complications and therefore natriuretic peptides (B-type natriuretic peptide

(BNP) and amino terminal proBNP (Nt-proBNP)) may be an important predictor of cardio-

vascular events. Natriuretic peptides are well established predictors of adverse outcome in

various cardiac diseases and predict outcome independent of ejection fraction 35-39. Data on

the predictive role for cardiac event during pregnancy in women with CHD are scarce. Tanous

et al. reported a clear association between high BNP values and cardiovascular events during

pregnancy, but could not determine the role of BNP in predicting adverse cardiovascular

events 40. Natriuretic peptides can provide a valuable tool for the clinicians caring for these

patients in order to identify high risk patients, needing close follow up. The prospective

nature of ZAHARA II allowed a comparison of Nt-proBNP between women with CHD and

healthy controls. In addition, the role of Nt-proBNP in predicting cardiovascular events during

pregnancy could be assessed.

In women with congenital heart disease the progressive cardiac remodeling during preg-

nancy might have serious repercussions for cardiac function after pregnancy, and therefore

might influence their prognosis. Longitudinal data on cardiac remodeling during and after

pregnancy in women with CHD is scarce and most of the available research focuses on left

ventricular parameters. Data examining longitudinal changes in right ventricular parameters

have never been reported in pregnant women with CHD. Several studies indicate that

pregnancy can be associated with permanent deterioration in cardiac function and impaired

event-free survival 41-47. The secondary objective of ZAHARA II was to investigate the inci-

dence of permanent post-partum cardiovascular deterioration in women with CHD, since

data is scarce and existing reports mainly describe small retrospective study populations.

14 Chapter 1

AiMs of The Thesis

In this thesis we describe the incidence of cardiovascular complications and we report new

predictors for cardiovascular complications during and after pregnancy, furthermore we assess

the impact of pregnancy on cardiac function and remodeling. Finally, we investigate whether

cardiac dysfunction plays a role in the pathogenesis of obstetric and neonatal complications.

In part I of this thesis, we focus on the cardiovascular complications during and after preg-

nancy and we assess the impact of pregnancy on cardiac function and remodeling. In chapter

2 the independent role of Nt-proBNP levels during pregnancy in women with CHD in predict-

ing the occurrence of cardiovascular events will be assessed. Chapter 3 will focus on cardiac

adaption during pregnancy in women with CHD compared to healthy pregnant women. The

incidence of cardiovascular complications one year post-partum will be described and cardiac

function parameters pre-pregnancy and one year post-partum will be compared in chapter 4.

In part II of this thesis we investigate the role of cardiac dysfunction in the pathogenesis of

obstetric and neonatal complications. Chapter 5 describes the main outcomes of the ZA-

HARA II study, which assesses the differences in uteroplacental Doppler flow (UDF) patterns

as well as the differences in outcome in pregnant women with CHD and healthy pregnant

women. The relationship between cardiac dysfunction and uteroplacental Doppler flow pat-

terns will be investigated. Chapter 6 will focus on pregnancy outcome and complications in

women with Tetralogy of Fallot. The outcome of the ZAHARA II study will be verified in a

homogeneous population. The final chapter of this thesis, chapter 7, reviews the literature

systematically in order to investigate all existing evidence for a link between maternal cardiac

function, abnormal uteroplacental flow and poor perinatal outcome in women with and

without known cardiac disease.

Introduction 15

1referenCes

1. European Surveillance of Congenital Anomalies (EUROCAT) Working Group. 2011; Available at:

http://www.eurocat-network.eu/accessprevalencedata/prevalencetables. Accessed 03/14, 2012.

2. van der Linde D, Konings EE, Slager MA, Witsenburg M, Helbing WA, Takkenberg JJ, et al. Birth

prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am

Coll Cardiol 2011 Nov 15; 58(21): 2241-2247.

3. Marelli AJ, Mackie AS, Ionescu-Ittu R, Rahme E, Pilote L. Congenital heart disease in the general

population: changing prevalence and age distribution. Circulation 2007 Jan 16; 115(2): 163-172.

4. Robson SC, Hunter S, Boys RJ, Dunlop W. Serial study of factors influencing changes in cardiac

output during human pregnancy. Am J Physiol 1989 Apr; 256(4 Pt 2): H1060-5.

5. Robson SC, Dunlop W, Boys RJ, Hunter S. Cardiac output during labour. Br Med J (Clin Res Ed)

1987 Nov 7; 295(6607): 1169-1172.

6. Robson SC, Dunlop W, Hunter S. Haemodynamic changes during the early puerperium. Br Med

J (Clin Res Ed) 1987 Apr 25; 294(6579): 1065.

7. Estensen ME, Beitnes JO, Grindheim G, Aaberge L, Smiseth OA, Henriksen T, et al. Altered

maternal left ventricular contractility and function during normal pregnancy. Ultrasound Obstet

Gynecol 2013 Jun; 41(6): 659-666.

8. Savu O, Jurcut R, Giusca S, van Mieghem T, Gussi I, Popescu BA, et al. Morphological and func-

tional adaptation of the maternal heart during pregnancy. Circ Cardiovasc Imaging 2012 May 1;

5(3): 289-297.

9. Fok WY, Chan LY, Wong JT, Yu CM, Lau TK. Left ventricular diastolic function during normal

pregnancy: assessment by spectral tissue Doppler imaging. Ultrasound Obstet Gynecol 2006

Nov; 28(6): 789-793.

10. Ducas RA, Elliott JE, Melnyk SF, Premecz S, daSilva M, Cleverley K, et al. Cardiovascular magnetic

resonance in pregnancy: insights from the cardiac hemodynamic imaging and remodeling in

pregnancy (CHIRP) study. J Cardiovasc Magn Reson 2014 Jan 3; 16(1): 1-429X-16-1.

11. Vogt M, Muller J, Kuhn A, Elmenhorst J, Muhlbauer F, Oberhoffer A. Cardiac Adaptation of the

Maternal Heart During Pregnancy: A Color-Coded Tissue Doppler Imaging Study - Feasibility,

Reproducibility and Course during Pregnancy. Ultraschall Med 2014 Apr 11.

12. Drenthen W, Pieper PG, Ploeg M, Voors AA, Roos-Hesselink JW, Mulder BJ, et al. Risk of compli-

cations during pregnancy after Senning or Mustard (atrial) repair of complete transposition of the

great arteries. Eur Heart J 2005 Dec; 26(23): 2588-2595.

13. Drenthen W, Pieper PG, Roos-Hesselink JW, van Lottum WA, Voors AA, Mulder BJ, et al. Preg-

nancy and delivery in women after Fontan palliation. Heart 2006 Sep; 92(9): 1290-1294.

14. Drenthen W, Pieper PG, Roos-Hesselink JW, van Lottum WA, Voors AA, Mulder BJ, et al. Outcome

of pregnancy in women with congenital heart disease: a literature review. J Am Coll Cardiol 2007

Jun 19; 49(24): 2303-2311.

15. Drenthen W, Pieper PG, Roos-Hesselink JW, Schmidt AC, Mulder BJ, van Dijk AP, et al. Non-

cardiac complications during pregnancy in women with isolated congenital pulmonary valvar

stenosis. Heart 2006 Dec; 92(12): 1838-1843.

16. Drenthen W, Pieper PG, Roos-Hesselink JW, Zoon N, Voors AA, Mulder BJ, et al. Fertility, preg-

nancy, and delivery after biventricular repair for pulmonary atresia with an intact ventricular

septum. Am J Cardiol 2006 Jul 15; 98(2): 259-261.

16 Chapter 1

17. Drenthen W, Pieper PG, Zoon N, Roos-Hesselink JW, Voors AA, Mulder BJ, et al. Pregnancy after

biventricular repair for pulmonary atresia with ventricular septal defect. Am J Cardiol 2006 Jul 15;

98(2): 262-266.

18. Yap SC, Drenthen W, Meijboom FJ, Moons P, Mulder BJ, Vliegen HW, et al. Comparison of

pregnancy outcomes in women with repaired versus unrepaired atrial septal defect. BJOG 2009

Nov; 116(12): 1593-1601.

19. Yap SC, Drenthen W, Pieper PG, Moons P, Mulder BJ, Klieverik LM, et al. Outcome of pregnancy

in women after pulmonary autograft valve replacement for congenital aortic valve disease. J

Heart Valve Dis 2007 Jul; 16(4): 398-403.

20. Yap SC, Drenthen W, Pieper PG, Moons P, Mulder BJ, Vliegen HW, et al. Pregnancy outcome

in women with repaired versus unrepaired isolated ventricular septal defect. BJOG 2010 May;

117(6): 683-689.

21. Yap SC, Drenthen W, Pieper PG, Moons P, Mulder BJ, Mostert B, et al. Risk of complications

during pregnancy in women with congenital aortic stenosis. Int J Cardiol 2008 May 23; 126(2):

240-246.

22. Balci A, Drenthen W, Mulder BJ, Roos-Hesselink JW, Voors AA, Vliegen HW, et al. Pregnancy

in women with corrected tetralogy of Fallot: Occurrence and predictors of adverse events. Am

Heart J 2011 Feb; 161(2): 307-313.

23. Drenthen W, Boersma E, Balci A, Moons P, Roos-Hesselink JW, Mulder BJ, et al. Predictors of

pregnancy complications in women with congenital heart disease. Eur Heart J 2010 Sep; 31(17):

2124-2132.

24. Siu SC, Sermer M, Colman JM, Alvarez AN, Mercier LA, Morton BC, et al. Prospective multicenter

study of pregnancy outcomes in women with heart disease. Circulation 2001 Jul 31; 104(5):

515-521.

25. Roos-Hesselink JW, Ruys TP, Stein JI, Thilen U, Webb GD, Niwa K, et al. Outcome of pregnancy in

patients with structural or ischaemic heart disease: results of a registry of the European Society

of Cardiology. Eur Heart J 2013 Mar; 34(9): 657-665.

26. Khairy P, Ouyang DW, Fernandes SM, Lee-Parritz A, Economy KE, Landzberg MJ. Pregnancy

outcomes in women with congenital heart disease. Circulation 2006 Jan 31; 113(4): 517-524.

27. Siu SC, Colman JM, Sorensen S, Smallhorn JF, Farine D, Amankwah KS, et al. Adverse neonatal

and cardiac outcomes are more common in pregnant women with cardiac disease. Circulation

2002 May 7; 105(18): 2179-2184.

28. Damman K, van Deursen VM, Navis G, Voors AA, van Veldhuisen DJ, Hillege HL. Increased central

venous pressure is associated with impaired renal function and mortality in a broad spectrum of

patients with cardiovascular disease. J Am Coll Cardiol 2009 Feb 17; 53(7): 582-588.

29. van Deursen VM, Damman K, Hillege HL, van Beek AP, van Veldhuisen DJ, Voors AA. Abnormal

liver function in relation to hemodynamic profile in heart failure patients. J Card Fail 2010 Jan;

16(1): 84-90.

30. Prefumo F, Sebire NJ, Thilaganathan B. Decreased endovascular trophoblast invasion in first

trimester pregnancies with high-resistance uterine artery Doppler indices. Hum Reprod 2004 Jan;

19(1): 206-209.

31. Cnossen JS, Morris RK, ter Riet G, Mol BW, van der Post JA, Coomarasamy A, et al. Use of uterine

artery Doppler ultrasonography to predict pre-eclampsia and intrauterine growth restriction: a

systematic review and bivariable meta-analysis. CMAJ 2008 Mar 11; 178(6): 701-711.

32. Harrington K, Cooper D, Lees C, Hecher K, Campbell S. Doppler ultrasound of the uterine

arteries: the importance of bilateral notching in the prediction of pre-eclampsia, placental abrup-

Introduction 17

1tion or delivery of a small-for-gestational-age baby. Ultrasound Obstet Gynecol 1996 Mar; 7(3):

182-188.

33. Balci A, Sollie KM, Mulder BJ, de Laat MW, Roos-Hesselink JW, van Dijk AP, et al. Associations

between cardiovascular parameters and uteroplacental Doppler (blood) flow patterns during

pregnancy in women with congenital heart disease: Rationale and design of the Zwangerschap

bij Aangeboren Hartafwijking (ZAHARA) II study. Am Heart J 2011 Feb; 161(2): 269-275.e1.

34. Balci A, Sollie-Szarynska KM, van der Bijl AG, Ruys TP, Mulder BJ, Roos-Hesselink JW, et al.

Prospective validation and assessment of cardiovascular and offspring risk models for pregnant

women with congenital heart disease. Heart 2014 Sep; 100(17): 1373-1381.

35. van Veldhuisen DJ, Linssen GC, Jaarsma T, van Gilst WH, Hoes AW, Tijssen JG, et al. B-type

natriuretic Peptide and prognosis in heart failure patients with preserved and reduced ejection

fraction. J Am Coll Cardiol 2013 Apr 9; 61(14): 1498-1506.

36. Kirk V, Bay M, Parner J, Krogsgaard K, Herzog TM, Boesgaard S, et al. N-terminal proBNP and

mortality in hospitalised patients with heart failure and preserved vs. reduced systolic function:

data from the prospective Copenhagen Hospital Heart Failure Study (CHHF). Eur J Heart Fail 2004

Mar 15; 6(3): 335-341.

37. Kragelund C, Gronning B, Kober L, Hildebrandt P, Steffensen R. N-terminal pro-B-type natriuretic

peptide and long-term mortality in stable coronary heart disease. N Engl J Med 2005 Feb 17;

352(7): 666-675.

38. Linssen GC, Bakker SJ, Voors AA, Gansevoort RT, Hillege HL, de Jong PE, et al. N-terminal pro-B-

type natriuretic peptide is an independent predictor of cardiovascular morbidity and mortality in

the general population. Eur Heart J 2010 Jan; 31(1): 120-127.

39. Omland T, Persson A, Ng L, O’Brien R, Karlsson T, Herlitz J, et al. N-terminal pro-B-type natriuretic

peptide and long-term mortality in acute coronary syndromes. Circulation 2002 Dec 3; 106(23):

2913-2918.

40. Tanous D, Siu SC, Mason J, Greutmann M, Wald RM, Parker JD, et al. B-type natriuretic peptide

in pregnant women with heart disease. J Am Coll Cardiol 2010 Oct 5; 56(15): 1247-1253.

41. Uebing A, Arvanitis P, Li W, Diller GP, Babu-Narayan SV, Okonko D, et al. Effect of pregnancy on

clinical status and ventricular function in women with heart disease. Int J Cardiol 2010 Feb 18;

139(1): 50-59.

42. Guedes A, Mercier LA, Leduc L, Berube L, Marcotte F, Dore A. Impact of pregnancy on the

systemic right ventricle after a Mustard operation for transposition of the great arteries. J Am Coll

Cardiol 2004 Jul 21; 44(2): 433-437.

43. Balint OH, Siu SC, Mason J, Grewal J, Wald R, Oechslin EN, et al. Cardiac outcomes after preg-

nancy in women with congenital heart disease. Heart 2010 Oct; 96(20): 1656-1661.

44. Silversides CK, Colman JM, Sermer M, Farine D, Siu SC. Early and intermediate-term outcomes

of pregnancy with congenital aortic stenosis. Am J Cardiol 2003 Jun 1; 91(11): 1386-1389.

45. Tzemos N, Silversides CK, Colman JM, Therrien J, Webb GD, Mason J, et al. Late cardiac out-

comes after pregnancy in women with congenital aortic stenosis. Am Heart J 2009 Mar; 157(3):

474-480.

46. Zentner D, Wheeler M, Grigg L. Does pregnancy contribute to systemic right ventricular dysfunc-

tion in adults with an atrial switch operation? Heart Lung Circ 2012 Aug; 21(8): 433-438.

47. Kamiya CA, Iwamiya T, Neki R, Katsuragi S, Kawasaki K, Miyoshi T, et al. Outcome of pregnancy

and effects on the right heart in women with repaired tetralogy of fallot. Circ J 2012; 76(4):

957-963.

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Part iComplications