Cardiac function and cardiac events 1-year postpartum in women with congenital heart disease

Valvular and Congenital Heart Disease

Cardiac function and cardiac events 1-year postpartum in women with congenital heart disease Marlies A. M. Kampman, MD, a,b Ali Balci, MD, PhD, Msc, a,c Henk Groen, MD, PhD, d Arie P. J. van Dijk, MD, PhD, e Jolien W. Roos-Hesselink, MD, PhD, f Joost P. van Melle, MD, PhD, a Krystyna M. Sollie-Szarynska, MD, g Elly M. C. J. Wajon, MD, h Barbara J. M. Mulder, MD, PhD, i Dirk J. van Veldhuisen, MD, PhD, a and Petronella G. Pieper, MD, PhD a , on behalf of the ZAHARA II investigators Groningen, Utrecht, Zwolle, Nijmegen, Rotterdam, Enschede, and Amsterdam, the Netherlands

Background Pregnancy is increasingly common in women with congenital heart disease (CHD), but little is known about long-term cardiovascular outcome after pregnancy in these patients. We studied the incidence of cardiovascular events 1-year postpartum and compared cardiac function prepregnancy and 1-year postpartum in women with CHD. Methods From our national, prospective multicenter cohort study, 172 women were studied. Follow-up with clinical evaluation and echocardiography and NT-proBNP measurement were performed during pregnancy and 12 months postpartum. Cardiovascular events were defined as need for an urgent invasive cardiovascular procedure, heart failure, arrhythmia, thromboembolic events, myocardial infarction, cardiac arrest, cardiac death, endocarditis, and aortic dissection. Results

Cardiovascular events were observed after 11 pregnancies (6.4%). Women with cardiovascular events postpartum had significant higher NT-proBNP values at 20-week gestation (191 [137-288] vs 102.5 [57-167]; P = .049) and 1-year postpartum compared with women without cardiovascular events postpartum (306 [129-592] vs 105 [54-187] pg/mL; P = .014). Women with cardiovascular events during pregnancy were at higher risk for late cardiovascular events (HR 7.1; 95% CI 2.0-25.3; P = .003). In women with cardiovascular events during pregnancy, subpulmonary end-diastolic diameter had significantly increased 1-year postpartum (39.0 [36.0-48.0] to 44.0 [40.0-50.0]; P = .028). No other significant differences were found in cardiac function or size 1-year postpartum compared with preconception values.

Conclusions Cardiovascular events are relatively rare 1 year after pregnancy in women with CHD. Women with cardiovascular events during pregnancy are prone to develop cardiovascular events 1-year postpartum and have increased subpulmonary ventricular diameter compared with preconception values. (Am Heart J 2015;169:298-304.)

Women with congenital heart disease (CHD) are prone to develop cardiovascular complications during pregnancy. 1-4 Until now, research has mainly focused on From the aDepartment of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands, bThe Netherlands Heart Institute (ICIN), Utrecht, the Netherlands, cDepartment of Cardiology, Isala, Zwolle, the Netherlands, dDepartment of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands, eDepartment of Cardiology, Radboud University Medical Center, Nijmegen, the Netherlands, fDepartment of Cardiology, Erasmus Medical Center, University of Rotterdam, Rotterdam, the Netherlands, gDepartment of Gynaecology and Obstetrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands, hDepartment of Cardiology, Medical Spectrum Twente, Enschede, the Netherlands, and iDepartment of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. Submitted May 20, 2014; accepted November 9, 2014. Reprint requests: Dr P.G. Pieper, MD, PhD, Department of cardiology, University Medical Centre Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands. E-mail: [email protected] 0002-8703 © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2014.11.010

risk prediction of cardiovascular complications during pregnancy, and several prediction models have been developed. 1-4 However, limited data exist regarding the effects of pregnancy on maternal cardiac function and prognosis after pregnancy. Data from a small number of (mostly retrospective) studies have suggested that pregnancy may have an adverse effect on maternal cardiac outcome (with each subsequent pregnancy causing progression of cardiac dysfunction) and that women with adverse cardiac events during pregnancy are at increased risk for cardiac events N6 months after pregnancy. 5-12 Prospective research data are very limited and concern only small study populations. Therefore, a large prospective multicenter study was conducted to observe the incidence of cardiovascular complications in the first year postpartum and to compare cardiac function parameters prepregnancy and 1-year postpartum in women with CHD.

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Methods Patient selection The ZAHARA II study is a prospective multicenter cohort study, conducted between March 2008 and August 2011. All consecutive pregnant women with structural CHD, aged ≥18 years, and presenting in 1 of the 8 participating centers were eligible for enrollment. The methods and primary results have been described elsewhere. 13,14 Women again pregnant before the postpartum follow-up visit were excluded from determination of cardiac outcome, and only the first pregnancy during the study period was included in this article. Baseline characteristics, pregnancy data, and 1-year postpartum follow-up Prepregnancy baseline characteristics were collected from medical records during the first antepartum visit. Baseline data included maternal age, underlying congenital anomaly, prior interventions, previous cardiovascular events, medication use, New York Heart Association (NYHA) functional class, echocardiographic recordings, cardiopulmonary aerobic capacity test results (b2 years before conception), 12-lead electrocardiogram, laboratory results, comorbid conditions, and obstetric history. Patients visited the outpatient clinic at 20 and 32 weeks of gestation and 1-year postpartum for clinical evaluation (including NYHA class assessment), standardized echocardiograms (according to study protocol), 12-lead electrocardiogram, and NT-proBNP measurement. In addition, when possible, cardiopulmonary aerobic capacity testing was performed 1-year postpartum. All echocardiographic recordings were evaluated offline by 4 experienced cardiologists, blinded to the end points. Chamber quantification, valvular function, and systolic and diastolic ventricular function assessment were performed according to the current recommendations as previously described. 13 Cardiac function and cardiovascular events 1-year postpartum Cardiovascular events (N6 months after delivery) were assessed during the follow-up visit 1-year postpartum. Primary cardiovascular events as previously defined include any of the following: need for an urgent invasive cardiovascular procedure, heart failure (according to the guidelines of the European Society of Cardiology and documented by the attending physician) 15, new onset or symptomatic tachyarrhythmia or bradyarrhythmia requiring new or extended treatment, thromboembolic events, myocardial infarction, cardiac arrest, cardiac death, endocarditis, and aortic dissection. 13 Echocardiographic changes were defined as deterioration in size or function of subpulmonary or subaortic ventricle, new onset or aggravation of valve regurgitation, or stenosis ≥1 grade (mild to moderate or severe or moderate to severe).

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Statistical analysis For continuous data, means and SD or medians with interquartile range were calculated, depending on their distribution. Absolute numbers and percentages were presented for categorical data. The Student t test, MannWhitney U test, χ 2, or Fisher exact test was used for intergroup comparison as appropriate. For comparison of cardiac function parameters before and after pregnancy, paired Student t test or Wilcoxon signed rank test for related samples was used, depending on their distribution. For categorical data, McNemar test for related samples was used. Differences in the rates of late cardiac events were determined using log-rank tests. The current study concerns an analysis of the secondary outcomes of the ZAHARA II study, for which a formal power analysis was not performed. Statistical analysis was performed using STATA software package (version 11; College Station, TX). A 2-tailed P value b.05 was considered significant. The research ethics committee of all participating centers approved the study protocol, and all participating women gave written informed consent. This work is supported by a grant from the Netherlands Heart Foundation (2007B75).The authors are solely responsible for the design and conduct of this study, all study analyses and drafting and editing of the paper.

Results During the study period, 213 pregnancies (209 singleton and 4 twin pregnancies) in 202 women were observed. Twenty-three women had a second pregnancy during the study period (12 before the postpartum follow-up visit), and 18 women did not return for follow-up. None of the women lost to follow-up died; these patients were all in modified World Health Organization (WHO) risk class 1 or 2, except 1 (modified WHO class 3). The final study included 172 pregnancies in 172 women. Maternal baseline characteristics and underlying CHD are shown in Table I. Mean age at conception was 28.9 years. Most patients were in NYHA functional class I or II and had a mildly or moderately increased risk of cardiovascular complications during pregnancy as indicated by the modified WHO risk class. 16 Most did not use cardiac medication before pregnancy, and the 2 patients who were on angiotensin-converting enzyme inhibitors discontinued the use because of its teratogenic effects. Systemic ventricular dysfunction (ejection fraction b45%) was present in 6.5% of the women, and subpulmonary ventricular dysfunction (tricuspid annular plane systolic excursion [TAPSE] b16 mm) was seen in 13.8%.

Cardiovascular events 1-year postpartum Cardiovascular events were seen after 11 pregnancies (6.4 %). The median follow-up time was 1.07 years (interquartile range 0.98-1.32 years).

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Table I. Maternal baseline characteristics (before pregnancy). n = 172 women n (%) Demographics and clinical data Maternal age at conception (y ± SD) Parity status 0 1 ≥2 Smoking before pregnancy NYHA class I II III Modified WHO class⁎ I II III IV Mechanical valve prosthesis Sustained symptomatic bradyarrhythmia or tachyarrhythmia requiring treatment Pacemaker Congestive heart failure Hypertension Cardiac medication ACE inhibitor β-blocker Calcium-channel blocker Anticoagulants Type of congenital lesion Left-sided lesions Aortic valve stenosis/bicuspid aortic valve Surgically repaired aortic coarctation Other† Right-sided lesions Tetralogy of Fallot after repair Pulmonary valve stenosis Ebstein anomaly Shunt lesions Ventricular septal defect Atrial septum defect Atrioventricular septal defect Abnormal pulmonary venous return Connective tissue disorder Marfan syndrome Loeyz-Dietz syndrome Complex CHD Complete transposition of the great arteries D-TGA with mustard or Senning D-TGA with arterial switch Congenital corrected TGA Single ventricle with Fontan physiology Other complex cyanotic heart disease‡ Echocardiographic parameters§ Systemic atrioventricular valve regurgitation‖ Pulmonary atrioventricular valve regurgitation‖ Pulmonary valve stenosis¶ Pulmonary valve regurgitation‖ Aortic valve stenosis¶ Aortic valve regurgitation‖ Systemic ventricular systolic dysfunction# Subpulmonary ventricular systolic dysfunction⁎⁎

28.9 (±4.3) 115 (66.9) 43 (25.0) 14 (8.1) 32 (18.6) 127 (73.8) 44 (25.6) 1 (0.6) 32 (18.6) 94 (54.7) 44 (25.6) 2 (1.2) 10 (5.8) 16 (9.3) 5 (2.9) 5 (2.9) 11 (6.4) 35 (20.4) 2 (1.2) 21 (12.2) 3 (1.7) 14 (8.1) 49 27 (15.7) 21 (12.2) 1 (0.6) 51 33 (19.2) 16 (9.3) 2 (1.2) 46 17 (9.9) 17 (9.9) 7 (4.1) 5 (2.9) 8 (4.7) 7 1 12 (7.0) 10 2 1 (0.6) 3 (1.7) 2 (1.2) 4 (2.7) 10 (6.9) 10 (7.6) 27 (19.9) 12 (8.3) 8 (5.4) 9 (6.5) 16 (13.8)

Table I (continued) n (%) Pregnancy outcome Primary cardiac event during pregnancy

18 (10.5)

Abbreviations: ACE, angiotensin-converting enzyme; TGA, transposition of great arteries. ⁎ Modified WHO class according to European Society of Cardiology guidelines.16 † Patient with cleft mitral valve. ‡ One patient with a corrected truncus arteriosus, type A; 1 patient with pulmonary valve atresia, atrial septum defect, and intact ventricular septum. § Missing data excluded from analysis. ‖ Moderate or severe regurgitation. ¶ Peak gradient ≥36 mm Hg. # Ejection fraction b45%. ⁎⁎ TAPSE b16 mm.

Women with cardiovascular events 1-year postpartum had higher modified WHO risk classifications before pregnancy (P = .010). They had more often a mechanical valve prosthesis (27.3% vs 4.4%; P = .024) or a history of arrhythmia (36.4% vs 7.5%; P = .021). Women with cardiovascular events postpartum were more likely to use cardiac medication preconception (54.6% vs 18.0%; P = .010), in particular β-blockers (36.4% vs 10.6%; P = .031) and anticoagulation therapy (45.5% vs 5.6%; P = .001). No differences were observed in systemic or subpulmonary ventricular function before pregnancy (0.0% vs 6.9%; P = 1.00) (28.6% vs 12.8; P = .25). Table II shows the cardiovascular events postpartum and underlying cardiac lesions. Of the women with cardiovascular events postpartum, 63.6% had no history of cardiovascular events before pregnancy and 71.4% developed new arrhythmia. Women with cardiovascular events during pregnancy had a higher risk of cardiovascular events postpartum compared with women without cardiovascular events during pregnancy (HR 7.1; 95% CI 2.0-25.3; P = .003) (Figure). The nature of cardiovascular events postpartum was identical to the events during pregnancy in 50% of the cases. Multivariable regression analysis was not performed because of the low incidence of cardiovascular events after pregnancy.

NT-proBNP 1-year postpartum NT-proBNP values 1-year postpartum were available in 90 of 172 women and ranged between 5 and 1044 pg/mL. Median NT-proBNP values did not differ between 20 weeks of gestation and 1-year postpartum (106 [57.0171.2] vs 111.5 [57.0-196.0] pg/mL; P = .13). Women with cardiovascular events postpartum had significant higher NT-proBNP values at 20-week gestation and 1-year postpartum compared with women without cardiovascular events postpartum (191 [137-288] vs

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Table II. Characteristics of patients with cardiovascular events after pregnancy (n = 11) Patient no. Type of congenital lesion Corrective procedure 1 2 3 4

5 6

7

8

9

10

11

Aortic valve stenosis – Aortic arch atresia type A Correction with end-toside anastomosis Double inlet left Fontan ventricle—hypoplastic RV circulation Fontan Hypoplastic RV with circulation Ebstein anomaly and tricuspid valve stenosis Ebstein anomaly

Tricuspid valve plasty Tetralogy of Fallot Total correction with transannular patch Tetralogy of Fallot Total correction with transannular patch Bicuspid aortic valve Mechanical aortic valve prosthesis Bicuspid aortic valve Ross procedure, mechanical aortic valve, and mechanical pulmonary valve prosthesis Cleft mitral valve Mechanical mitral valve prosthesis Ventricular septal defect –

Figure

Cardiovascular event after pregnancy Heart failure Ventricular tachycardia Atrial flutter Atrial tachycardia Protein losing enteropathy Atrial fibrillation Atrial fibrillation Atrial tachycardia Symptomatic ventricular ectopia Atrial flutter

Atrial fibrillation Infective endocarditis

102.5 [57-167] [P = .049] and 306 [129-592] vs 105 [54187] pg/mL [P = .014], respectively). In addition, women with cardiovascular events during pregnancy had significantly higher NT-proBNP values 1-year postpartum compared with women without cardiovascular events during pregnancy (303.5 [124.5-458] vs 104.5 [54-183] pg/mL; P = .0077). NT-proBNP level b128 μg/mL at 20 weeks of gestation had a negative predictive value of 98.7% for the occurrence of cardiovascular events 1-year postpartum.

Cardiac function and aerobic exercise capacity 1-year postpartum Table III provides an overview of NYHA functional class, cardiac function parameters, and aerobic exercise capacity parameters before and 1 year after pregnancy. New York Heart Association class did not change significantly, although 2 women experienced NYHA functional class deterioration (≥2 functional class) postpartum (1.2%). In 5 women (33.3%) with NYHA class deterioration (≥2 functional classes) during pregnancy, NYHA class 1-year postpartum did not completely recover.

Freedom from late cardiovascular events after pregnancy in women with cardiac events during pregnancy (red line) and women without cardiac events during pregnancy (blue line).

In 1-year postpartum, no significant differences were seen in NYHA functional class, systemic ventricular enddiastolic diameter, systemic ventricular ejection fraction, and subpulmonary ventricular end-diastolic diameter or function. Valvular function had not changed. Aerobic exercise capacity testing before pregnancy was available in 18.6% of the patients, and no differences were observed postpartum. In patients with systemic right ventricles (RV), systolic function of the systemic RV (qualitative assessment) remained unchanged; the diameter of the systemic RV increased (34.0 mm [31.038.0] vs 36.5 mm [31.0-41.0] [P = .035]). Women with cardiovascular events during pregnancy had significantly larger subpulmonary ventricular enddiastolic diameter (apical 4-chamber view) postpartum compared with prepregnancy (39.0 [36.0-48.0] vs 44.0 [40.0-50.0] mm; P = .028; mean difference −4.8 mm [95% CI −9.1 to −0.61]). This could not be attributed to an increased incidence of right-sided valve insufficiency or tetralogy of Fallot in this group. In addition, women with cardiovascular events during pregnancy had significantly more often aggravation of aortic valve regurgitation 1-year postpartum (P = .046). The clinical and echocardiographic data of the patients with subpulmonary ventricular dilation are summarized in Table IV.

Discussion The present study shows that the incidence of cardiovascular events in the first year postpartum is relatively low and that most patients go through pregnancy without permanent damage to their cardiac function. Women with cardiovascular complications during pregnancy are at

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Table III. Comparison of cardiac function parameters preconception and 1-year postpartum 1Y n General parameters NYHA class NYHA class I NYHA class II NYHA class III NYHA class IV

Preconception

Postpartum

127 (73.8%) 44 (25.6%) 1 (0.6%) 0 (0.0%)

128 (74.9%) 39 (22.8%) 3 (1.8%) 1 (0.6%)

171

Mean difference P

95% CI

.96

Systemic ventricular size, mass, and systolic function⁎ Systolic ventricular end-diastolic diameter (mm) Systemic ventricular mass/BSA (g/m 2) Systemic ventricular ejection fraction

137 100 131

46.0 (43.0-49.0) 72.9 (62.0-86.8) 57.1 ± 8.7

47.0 (44.0-50.0) 70.9 (58.9-87.9) 56 ± 9.9

.62 .59 .27

−0.46 (−1.2 to 0.31) 0.75 (−3.6 to 5.1) 1.1 (−0.98 to 3.1)

Systemic ventricular diastolic function⁎ Left atrial volume (mL) E/A ratio Mean E' (septal lateral) (cm/s)† E/E'

111 72 24 20

95.3 (71.6-119.6) 1.7 (1.4-2.1) 9.6 (8.4-11.5) 10.6 (8.1-12.8)

101.9 (77.3-129.4) 1.5 (1.4-1.9) 10.2 (8.8-12.1) 8.8 (6.8-10.9)

.17 .23 .63 .06

−5.0 −0.07 0.30 0.98

Right ventricular size and function⁎ Right ventricular end-diastolic diameter (mm) TAPSE (mm) RV S' (cm/s)‡

107 100 28

38.0 (33.0-44.0) 21.0 ± 5.3 8.2 (7.0-9.8)

36.0 (32.0-42.0) 21.2 ± 5.3 8.9 (7.0-10.8)

.47 .95 .68

Valvular function Systemic atrioventricular valve regurgitation§ Pulmonary atrioventricular valve regurgitation§ Pulmonary valve regurgitation§ Pulmonary valve stenosis‖ Aortic valve regurgitation§ Aortic valve stenosis‖

140 138 128 124 140 136

4 (2.9%) 10 (7.3%) 26 (20.3%) 10 (8.1%) 7 (5.0%) 11 (8.0%)

4 (2.9%) 11 (7.9%) 30 (22.4%) 7 (5.7%) 8 (5.7%) 11 (8.0%)

.53 .21 .43 .70 .44 .46

Aerobic exercise capacity VO2 max (mL/kg per minute) Anaerobic threshold (mL/kg per minute)

16 13

26.9 ± 5.7 15.8 (14.0-17.0)

25.4 ± 5.1 15.5 (12.3-18.7)

.64 .40

(−12.2 to 2.3) (−0.23 to 0.092) (−0.88 to 1.5) (−0.092 to 2.0)

0.81 (−0.67 to 2.3) 0.03 (−0.96 to 1.02) 0.11 (−0.81 to 1.03)

0.78 (−2.7 to 4.7) 0.67 (−1.6 to 2.9)

Abbreviations: BSA, body surface area; VO2 max, oxygen consumption per unit time. ⁎ Excluding systemic RVs. † Early diastolic tissue Doppler velocity of systemic ventricular annular ring. ‡ Systolic tissue Doppler velocity of subpulmonary ventricular annular ring. § Moderate or severe regurgitation. ‖ Peak gradient ≥36 mm Hg.

higher risk for developing cardiovascular complications 1-year postpartum and are prone to dilatation of the subpulmonary ventricle 1-year postpartum. In this study, the incidence of cardiovascular events 1-year postpartum was 6.4%. This incidence is lower than previously reported in a large retrospective study by Balint et al 8 (12%). This is probably due to differences in study population, study design, and follow-up duration. Most of the cardiovascular events postpartum were atrial arrhythmias. In the general CHD population, the overall 20-year risk of developing atrial arrhythmia is 7% in a 20-year-old CHD patient. 17 It is not clear if pregnancy as such or the number of pregnancies influences this risk. Women with cardiovascular events during pregnancy have higher risk of developing cardiovascular events 1year postpartum. This finding is consistent with Balint et al 8 .

Probably, these women have limited cardiac reserve, and the hemodynamic requirements of pregnancy cannot be met, which results in complications such as cardiac failure and arrhythmia. This is reflected by high NTproBNP levels during pregnancy (which was identified before as predictor of cardiovascular events during pregnancy) 18 and similarly by the higher NT-proBNP levels after pregnancy in women with cardiovascular events during pregnancy or in the first year postpartum. The current study shows that cardiac function and chamber dimensions did not change after pregnancy compared with prepregnancy and that valve dysfunction did not aggravate. However, in women with cardiovascular events during pregnancy, subpulmonary ventricular dilatation was seen 1-year postpartum. This could not be attributed to an increased incidence of patients with tetralogy of Fallot or right-sided valve insufficiency in this

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Table IV. Clinical and echocardiographic characteristics of women with an increase in subpulmonary ventricular diameters 1-year postpartum and cardiovascular events during pregnancy (n = 10/18) NYHA functional class

Patient no. 1 2 3 4 5 6 7 8

9 10

Diagnosis—corrective surgery ToF—repaired ToF—repaired pAVSD—repaired pAVSD—repaired PS—valvulotomy PA—intact ventricular septum—repaired Aortic arch atresia type A—repaired Bicuspid aortic valve—Ross procedure. Severe aortic and pulmonary valve insufficiency: 2× mechanical valve prosthesis Sinus venosus defect—repaired Cleft mitral valve—mechanical valve prosthesis

RV diameter (mm)

Tricuspid Pulmonary Pulmonary valve 1-Year 1-Year valve valve regurgitation⁎ stenosis⁎ regurgitation⁎ Preconception postpartum Preconception postpartum Severe Moderate Absent Absent Severe Severe Absent Absent

Mild Moderate Absent Absent Absent Mild Absent Absent

Absent Mild Mild Absent Absent Moderate Mild Severe

II II II I I I II II

I II II I I II II III

53 36 31 39 49 40 48 36

66 37 44 46 54 45 50 50

Absent Absent

Mild Absent

Mild Absent

II I

I II

40 28

44 40

Abbreviations: ToF, tetralogy of Fallot; pAVSD, partial atrioventricular septal defect; PS, pulmonary valve stenosis; PA, pulmonary valve atresia. ⁎ Valve dysfunction preconception.

group. This is, partly, in contrast to the findings Uebing et al 5, where this effect was attributable to patients with tetralogy of Fallot. Interestingly and in line with results of Uebing et al 5, we found no association between subpulmonary ventricular dilatation and presence of pulmonary valve insufficiency. The increasing number of studies describing subpulmonary ventricular dilatation after pregnancy in women with tetralogy of Fallot 11,19 and the identification of subpulmonary ventricular dysfunction (TAPSE b16 mm) as a predictor of cardiovascular events during pregnancy suggest that the subpulmonary ventricle may be vulnerable for consequences of the physiologic volume overload of pregnancy. 18 The finding that tetralogy of Fallot patients with more severe disease needing medication are prone for complications during pregnancy is also in line with these findings. 20 Data on pregnancyrelated changes in subpulmonary ventricular function and dimension in healthy women are scarce, which makes interpretation of subpulmonary ventricular changes after pregnancy in women with CHD difficult. 21 As is known from a small study in healthy women, the subpulmonary ventricular volume increases far more during pregnancy than the systemic ventricle. 22 This physiologic dilatation may be aggravated in women with CHD because of abnormal myoarchitecture, damage from prior surgery, and preexistent volume or pressure overload, leading to persistent subpulmonary ventricle dilatation. 23 The clinical implications of the findings presented here are not completely clear yet. Nevertheless, the observations made in this study are important in counseling

women in their wish to pursue pregnancy. The present study indicates that women with CHD should have regular check-ups after pregnancy. This is particularly important for women with cardiovascular events during pregnancy because they appear to be prone for late cardiovascular events and subpulmonary ventricular dilatation.

Strengths and limitations This is the first large prospective study concerning cardiac function after pregnancy in women with CHD. Because of our protocol design (inclusion before 20 weeks of gestation) missing data were inevitable because prepregnancy data were collected retrospectively. Especially prepregnancy aerobic exercise capacity tests were only limited available. Because of the limited number of cardiovascular events late after pregnancy, it was not feasible to perform multivariable Cox regression models to investigate independent predictors of late cardiovascular events and cardiac function deterioration. Because this was an analysis of the secondary outcomes of the ZAHARA II study, it should be regarded as exploratory, and potentially relevant results may have failed to reach significance. Because all women with structural CHD were eligible for inclusion, our cohort is heterogeneous. Some individual lesions, in particular some high-risk lesions, are underrepresented, which may partly be the result of well-organized pregnancy counseling in the Netherlands. These limitations should be kept in mind, when extrapolating the findings, and the results should be interpreted with caution.

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Conclusion and clinical implications In this cohort, most women with CHD go through pregnancy without permanent damage to their cardiac function. Women with CHD who experience cardiovascular events during pregnancy or have high modified WHO risk classification were prone to develop cardiovascular events after pregnancy. In addition, an increase in subpulmonary ventricular diameter postpartum was seen in women with cardiovascular events during pregnancy. These findings indicate that regular followup after pregnancy, especially of women with cardiovascular events during pregnancy, is important. Large, lesion-specific, prospective studies are warranted to investigate the long-term effect of pregnancy on cardiac function and prognosis. This information is needed for effective counseling of patients regarding their wish to pursue pregnancy. In addition, to make advances in research concerning risk stratification and prognosis for women with CHD contemplating pregnancy, consequent guideline-based preconception evaluation is clearly warranted. 16

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