University of Groningen. Pregnancy in women with congenital heart disease Kampman, Marlies Aleida Maria

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1 University of Groningen Pregnancy in women with congenital heart disease Kampman, Marlies Aleida Maria IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2016 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Kampman, M. A. M. (2016). Pregnancy in women with congenital heart disease: Complications and mechanisms [Groningen]: Rijksuniversiteit Groningen Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 Chapter 2 N-terminal pro-b-type natriuretic peptide predicts cardiovascular complications in pregnant women with congenital heart disease Marlies A.M. Kampman Ali Balci Dirk J. van Veldhuisen Arie P.J. van Dijk Jolien W. Roos-Hesselink Krystyna M. Sollie-Szarynska Marieke Ludwig-Ruitenberg Joost P. van Melle Barbara J.M. Mulder Petronella G. Pieper on behalf of the ZAHARA II investigators 7 8 A European Heart Journal 2014;35:

3 22 Chapter 2 Abstract Aims In women with congenital heart disease (CHD), cardiovascular complications during pregnancy are common, but the risk assessment of these patients remains difficult. This study sought to determine the independent role of N-terminal pro B-type natriuretic peptide (NtproBNP) levels in addition to other parameters in predicting adverse cardiovascular events during pregnancy in women with CHD. Methods We conducted a national, prospective multicenter cohort study. Follow-up with clinical evaluation and echocardiography and Nt-proBNP measurement was performed at 20 week gestation. Results Adverse cardiovascular events occurred in 10.3% of 213 pregnancies. N-terminal pro B-type natriuretic peptide levels > 128 pg/ml at 20 weeks gestation, the presence of a mechanical valve and subpulmonary ventricular dysfunction before conception were independently associated with events (odds ratio (OR) 10.6 (p=0.039), OR 12.0 (p=0.016) and OR 4.2 (p=0.041), respectively). The negative predictive value of Nt-proBNP levels < 128 pg/ml was 96.9%. N-terminal pro B-type natriuretic peptide levels > 128 pg/ml at 20 weeks of gestation had an additional value in predicting the occurrence of adverse cardiovascular events on top of the other identified predictors (area under the curve 0.90 versus 0.78, p=0.035). Conclusions Increased Nt-proBNP levels at 20 weeks of gestation are an independent risk predictor of cardiovascular events during pregnancy in women with CHD. Key words: congenital heart disease, pregnancy, natriuretic peptides, right ventricular function.

4 Nt-proBNP in pregnant women with CHD 23 Introduction Nowadays, the majority of patients with congenital heart disease (CHD) reach childbearing age. Although many women with CHD experience uncomplicated pregnancies, a substantial sub-group suffers from cardiovascular, obstetric and offspring complications during pregnancy 1. Many predictors of complications have been identified and several prediction models have been developed, but the identification of women who will experience cardiovascular complications remains difficult 1-7. As the increased volume load during pregnancy is thought to play a central role in the pathogenesis of cardiovascular events, natriuretic peptides may be an important predictor of cardiovascular complications during pregnancy. B-type natriuretic peptide (BNP) and N-terminal pro B-type natriuretic peptide (Nt-proBNP) are well established predictors of adverse outcome in various cardiac diseases 8-11 and predict outcome in patients with heart failure independent of ejection fraction 12. Data on their role in risk evaluation for adverse pregnancy outcome are scarce. The only study considering BNP levels during pregnancy in women with congenital and acquired heart disease found a clear association between high BNP levels and cardiovascular events, but was not able to determine the role of BNP in predicting adverse cardiovascular events 13. The primary objectives of the ZAHARA II (Zwangerschap bij Aangeboren HARtAfwijkingen; Pregnancy in CHD) study are described previously 14. The aims of the present study were (i) to determine the independent role of Nt-proBNP levels during pregnancy in predicting the occurrence of cardiovascular complications during pregnancy in women with CHD; (ii) to identify other independent predictors of cardiovascular complications in pregnant women with CHD; and (iii) to describe the nature and incidence of cardiovascular complications during pregnancy in this population. 2 Methods Study design As reported in detail elsewhere, the ZAHARA II study is a prospective observational multicentre cohort study 14. All consecutive pregnant women with structural CHD, aged 18, presenting in one of the eight participating centres between March 2008 and August 2011, were eligible for enrolment. Miscarriages or pregnancies terminated before 20 weeks gestation were excluded. To determine normal Nt-proBNP levels during pregnancy, healthy pregnant women, without chronic medication use, were recruited from midwife practices in Groningen and Rotterdam, the Netherlands. Women with known illicit drug or alcohol abuse were excluded. The Research Ethics Committee of all participating centers approved the study protocol and all participating women gave written informed consent.

5 24 Chapter 2 Baseline characteristics Medical records were used to collect baseline data at the first prenatal visit (at 20 weeks gestation). Baseline data included underlying congenital anomaly, prior interventions, cardiac sequelae, previous cardiac events, comorbidity and obstetric history. Data related to cardiac function prior to pregnancy (including data on New York Heart Association functional class, physical examination, medication use, laboratory values, echocardiographic and electrocardiographic registrations and modified WHO classification of pregnancy risk 7 ) were also recorded. During follow-up visits at 20 and 32 weeks of gestation, clinical evaluation, echocardiography, electrocardiography and 24 hour electrocardiographic registrations, as well as Nt-proBNP measurements were performed. Serum creatinine was measured in all patients to exclude renal dysfunction. Healthy pregnant women underwent identical evaluation. All echocardiographic recordings were evaluated offline in one of the participating centers by 4 experienced cardiologists, blinded to the endpoints. Chamber quantification, valvular function, systolic and diastolic ventricular function were assessed according to the current recommendations We defined values > 95 th percentile of the Nt-proBNP values in healthy women as elevated, since no generally accepted normal values for Nt-proBNP during pregnancy exist. In this paper, data of 20 week gestation are evaluated for their value in predicting the occurrence of cardiovascular complications during pregnancy. Cardiovascular events Cardiovascular events were recorded during pregnancy and up to 6 months post-partum. Primary cardiovascular events were defined as 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 19 ), new onset or symptomatic tachy- or brady arrhythmia requiring new or extended treatment, thromboembolic events, myocardial infarction, cardiac arrest, cardiac death, endocarditis and aortic dissection. New York Heart Association (NYHA) class deterioration 2 points during pregnancy or within the first six months post-partum was defined as a secondary cardiovascular event 14. Statistical analysis Descriptive statistics for categorical data were expressed in absolute numbers and percentages. Mean and standard deviations or median with interquartile ranges were presented for continuous variables, depending on their distribution. For intergroup comparisons, the Student s t-test, Mann-Whitney U test, Chi-square and Fisher s exact test were used as appropriate. Univariable logistic regression was performed to identify variables associated with the composite endpoint of primary cardiovascular events. The following preconception variables were assessed: disease complexity, modified WHO risk classification 6,7, the presence of a systemic right ventricle, NYHA functional class, maternal age, parity, body surface area,

6 Nt-proBNP in pregnant women with CHD 25 resting heart rate, the presence of sinus rhythm, mean arterial pressure, smoking, use of cardiac medication, prior cardiac events, valve regurgitation and stenosis, systemic ventricular size and function, left atrial volume index, subpulmonary ventricular size and function and Nt-proBNP levels. Systemic right ventricles were excluded from quantitative analysis of echocardiographic chamber function measurements only (tricuspid annular plane systolic excursion (TAPSE) and ventricular ejection fraction determination), since these measurements are invalid in systemic right ventricles. Because of the limited amount of endpoints, only the five variables most significantly associated with an increased incidence of the composite endpoint entered the multivariable model. Bootstrap selection methods were used to avoid an over-fit model. Two hundred bootstrap samples were selected and predictors selected in > 130 models (65%) were included in the final model. The final model was constructed by backward deletion of the least significant variable until all remaining variables were significantly associated with the endpoint. To identify the additional role of Nt-proBNP levels at 20 weeks gestation as a discriminator between patients at risk for complications, receiver operating curves (ROCs) of the initial multivariable model and the initial multivariable model plus Nt-proBNP at 20 weeks gestation were constructed and compared. Cardiovascular complications occurring before 20 weeks gestation and valve thrombosis were excluded from this analysis. Statistical analysis was performed using SPSS (IBM SPSS statistics, version 20.0, Chicago, IL, USA) and STATA software package (version 11, College Station, TX, USA). A two-tailed p-value < 0.05 was considered significant. 2 Results Baseline characteristics We identified 234 women who were potentially eligible for participation. Twenty-one women were excluded, because of miscarriage (n=11), serious protocol violation (n=6) and withdrawal of informed consent (n=4). A total of 213 pregnancies in 203 women were observed (209 singleton and 4 twin pregnancies). Maternal baseline characteristics are shown in table 1; underlying CHD is summarized in table 2. Results are reported per pregnancy. The majority of patients had a mildly or moderately increased risk of cardiovascular complications during pregnancy, as indicated by the modified WHO class. Most patients were in NYHA class I or II. The majority of the patients did not use any medication 6 months prior to pregnancy; two patients who were on ACE-inhibitors discontinued use before conception. Systemic ventricular ejection fraction < 45% was seen in 7.9% of the patients; 14.3% had systolic dysfunction of the subpulmonary ventricle.

7 26 Chapter 2 Table 1. Maternal baseline characteristics (prior to pregnancy; N = 213 pregnancies) N (%) Demographics Maternal age at conception (years ± SD) 28.7 (± 4.4) Parity status Smoking prior to pregnancy NYHA class I II III Modified WHO class* I II III IV Past medical history Mechanical valve prosthesis Sustained symptomatic brady- or tachyarrhythmia requiring treatment Pacemaker Subacute bacterial endocarditis Congestive heart failure Cerebrovascular accident Hypertension Medication use prior to pregnancy None ACE-inhibitor Beta-blocker Calciumchannel blocker Digoxin Anticoagulants Echocardiographic parameters Systemic AV valve regurgitation Pulmonary AV valve regurgitation Pulmonary valve stenosis Pulmonary valve regurgitation Aortic valve stenosis Aortic valve regurgitation Systemic ventricular systolic dysfunction Subpulmonary ventricular systolic dysfunction** * Modified World Health Organisation class according to ESC guidelines.7 Moderate or severe regurgitation; peak gradient 36 mmhg; Ejection fraction < 45%; ** TAPSE < 16 mm.

8 Nt-proBNP in pregnant women with CHD 27 Cardiovascular events We observed primary cardiovascular events in 22 (10.3%) pregnancies (table 2). Six of these patients (27.3%) had a history of previous cardiovascular events. Five patients (22.7%) had > 1 cardiovascular event during pregnancy. Two patients (0.9%) required an urgent invasive procedure. One patient with compromised right ventricular function needed valve replacement two weeks post-partum because of mechanical valve thrombosis and a patient with a subvalvular aortic stenosis received a pacemaker because of a second degree atrioventricular block two months after pregnancy. Eight patients (3.8%) developed heart failure (including the patient with pacemaker implantation); seven of these patients (87.5%) developed heart failure during the third trimester or post-partum and one patient during the second trimester. Fourteen patients (6.6%) had arrhythmias, mainly supraventricular arrhythmias, occurring from the second trimester until the post-partum period. Four patients (1.9%) had thrombosis of their bileaflet mechanical valve; two during the first trimester, one during the 18 th week of pregnancy and one in the post-partum period. Three of these patients developed valve thrombosis while on low molecular weight heparin treatment. One patient (0.5%) developed a type B aortic dissection two weeks post-partum. No mortality, cardiac arrest, endocarditis or myocardial infarction occurred. Thirty-nine patients (18.3%) had a decline of 2 points in NYHA functional class during pregnancy or within 6 months post-partum compared with pre-pregnancy. 2 N-terminal pro-b-type natriuretic peptide during pregnancy N-terminal pro-b-type natriuretic peptide was available in 169 of 213 patients. Figure 1 shows the distribution of patients and cardiovascular complications by Nt-proBNP level. The 95 th percentile of the Nt-proBNP values at 20 weeks gestation in healthy women was 128 pg/ ml. Of the patients with cardiovascular complications, 82.4% had Nt-proBNP > 128 pg/ml Women with Nt-proBNP concentration < 100 pg/ml (77/169) had no cardiovascular complications. Patients with cardiovascular events had significantly higher Nt-proBNP at 20 weeks gestation compared with patients without events (173 ( ) vs. 100 ( ), p< 0.001). N-terminal pro-b-type natriuretic peptide levels >128 pg/ml at 20 weeks of gestation had a negative predictive value (NPV) of 96.9% for the occurrence of cardiovascular events after 20 weeks gestation; the positive predictive value (PPV) was 18.3%. The sensitivity of Nt-proBNP > 128 pg/ml was 81.3%; the specificity was 61.8%. There was no difference in Nt-proBNP levels between patients with heart failure compared to patients with arrhythmia and all women with elevated Nt-proBNP values had normal serum creatinine (48.7 ± 7.1 µmol/l). 8 patients had BMI > 30. Four of these patients had Nt-proBNP < 128 pg/ml, but none of the patients with BMI > 30 had cardiovascular events. The presence of a mechanical valve and subpulmonary ventricular dysfunction (tricuspid annular plane systolic excursion (TAPSE) < 16 mm) were identified as independent preconception predictors of primary cardiovascular events (table 3). In addition, an elevated Nt-proBNP

9 28 Chapter 2 Table 2. Distribution of cardiovascular events by primary type of congenital heart disease (N = 213 pregnancies). Maternal congenital lesion N % Pregnancies with primary cardiovascular events Cardiovascular events (N (%)) NICP HF AR TE Aortic dissection NYHA Left sided lesions 57 Aortic valve stenosis / Bicuspid aortic valve Surgically repaired Aortic coarctation Other* Right sided lesions 66 Tetralogy of Fallot after repair Pulmonary valve stenosis Ebstein s anomaly Shunt lesions 61 Ventricular septal defect Atrial septum secundum defect Atrioventricular septal defect Abnormal pulmonary venous return Connective tissue disorder Marfan syndrome Loeyz-Dietz syndrome 1 Complex CHD 20 Complete transposition of great arteries (TGA) D-TGA with Mustard or Senning D-TGA with arterial switch 2 0

10 Nt-proBNP in pregnant women with CHD 29 Table 2. Distribution of cardiovascular events by primary type of congenital heart disease (N = 213 pregnancies). (continued) Cardiovascular events (N (%)) NICP HF AR TE Aortic dissection NYHA Pregnancies with primary cardiovascular events Maternal congenital lesion N % Congenital corrected TGA 1 0 Single ventricle with Fontan physiology Other complex cyanotic heart disease Total (10.3) 2 (0.9) 8 (3.8) 14 (6.6) 4 (1.9) 1 (0.5) 39 (18.3) NICP need of invasive cardiovascular procedure; HF heart failure; AR arrhythmia; TE thrombo-embolic event; NYHA deterioration of 2 New York Heart Association (NYHA) functional classes during pregnancy or until 6 months post-partum. * 1 patient with a right sided aortic arch and 1 patient with a cleft mitral valve. 1 patient with a corrected truncus arteriosus, type A; 1 patient with pulmonary atresia, atrial septal defect and intact intraventricular septum. Secondary cardiovascular event. 2

11 30 Chapter Number of patients NT-proBNP (pg/ml) >400 A Patients with cardiovascular event (%) NT-proBNP (pg/ml) Figure 1: N-terminal pro-b-type natriuretic peptide (pg/ml) at 20 weeks of gestation in women with congenital heart disease. A: distribution of patients by N-terminal pro-b-type natriuretic peptide level; B: Percentage of cardiovascular events by N-terminal pro-b-type natriuretic peptide level. B Table 3. Maternal preconceptional predictors of cardiovascular events during pregnancy. OR 95% CI P-value Number of times selected # Univariate predictor preconception WHO class III or IV < Mechanical valve prosthesis < Subpulmonary ventricular dysfunction (TAPSE < 16 mm) Prior cardiovascular event 4, History of pacemaker implantation Right systemic ventricle Multivariable predictor preconception* Mechanical valve prosthesis Subpulmonary ventricular dysfunction (TAPSE < 16 mm) * Adjusted for preconception WHO risk class. # Explanation can be found in the statistical method section. level at 20 weeks gestation (> 128 pg/ml) was an independent predictor of cardiovascular events, OR 10.6 (95% CI , p=0.039) (adjusted for the preconception variables in the model, after exclusion of patients with complications before 20 weeks gestation only and considering only complications other than valve thrombosis). The area under the ROC increased from 0.78 to 0.90 (p=0.035) when Nt-proBNP at 20 weeks gestation was added to the multivariable model with the identified independent preconception predictors. The

12 Nt-proBNP in pregnant women with CHD 31 absence of all three risk factors had a high NPV for the occurrence of cardiovascular events (94.3%) in the entire study population. The positive predictive value of the presence of all three predictors was 50.0% for the entire study population. In a selected population with none or one of the preconception predictors present, the NPV of Nt-proBNP levels < 128 pg/ ml is 100%; the PPV of Nt-proBNP > 128 pg/ml is poor with 10.0% and 33.3% respectively. We could not calculate PPV and NPV in selected patients with both preconception risk factors, due to the absence of low Nt-proBNP in these patients. 2 Discussion The main new finding of the present study is the identification of elevated Nt-proBNP levels at 20 weeks gestation as an independent predictor of cardiovascular events during pregnancy, in addition to the presence of a mechanical valve and subpulmonary ventricular dysfunction before conception. The absence of these predictors had a high NPV for the occurrence of events. Our study is the first to report on the role of Nt-proBNP to predict events during pregnancy in women with CHD. All women survived and cardiovascular events occurred in 10.3% of all pregnancies. This is in line with most previous studies 1-5,20,21. Differences in the prevalence of cardiovascular events probably reflect differences in study design and in the composition of the study populations. In the present study, arrhythmias and heart failure were the most frequently observed adverse events, as consistently described before 2,3,5, The presence of a mechanical valve and subpulmonary ventricular dysfunction before pregnancy were identified as independent predictors of cardiovascular events. Mechanical valves are known for their association with pregnancy complications, mainly valve thrombosis resulting in embolism, heart failure, re-operation and maternal death However, mechanical valves were only reported once before, in a previous study of our group, as an independent predictor and are not incorporated in the CARPREG prediction model 2,4. The risk of valve thrombosis depends strongly on anticoagulation regimen, monitoring and patient adherence, which must be taken into account. Therefore we did not include mechanical valve thrombosis in the analysis of the predictive value of Nt-proBNP for cardiovascular events. On the other hand, the risk of valve thrombosis may be higher in patients with ventricular dysfunction due to lower flow velocities, which may link elevated Nt-proBNP levels to valve thrombosis. Indeed, our only patient with valve thrombosis of a mechanical valve after 20 weeks gestation had compromised right ventricular function and elevated Nt-proBNP. The present study identified subpulmonary ventricular dysfunction as an independent predictor of events. Two previous studies did identify subpulmonary ventricular dysfunction as a predictor, but only in combination with other predictors 3,26. The cohort described here included a considerable amount of patients with tetralogy of Fallot and right sided obstruc-

13 32 Chapter 2 tive lesions, which could have contributed to identifying subpulmonary ventricular dysfunction as an independent risk factor. Tricuspid annular plane systolic excursion as a marker of RV function has been scarcely validated in patients with CHD, but the available evidence indicates that TAPSE is associated with RV function and symptoms in patients with CHD and pressure- or volume loaded right ventricles Even though it did not emerge as an independent predictor, the modified WHO class was highly associated with the occurrence of cardiovascular events in our study 7. This is in line with results of the European Registry on pregnancy and cardiac disease 21. The results reported here underline that the WHO class can be a useful tool in preconception risk assessment and counseling 7. The presence of a systemic right ventricle was also associated with cardiovascular complications in the univariable analysis, in line with previous literature in which the complication rate in these patients was high 2,30. An elevated Nt-proBNP level at 20 weeks gestation was an independent predictor of cardiovascular events during pregnancy in this study and had additional value in identifying patients at risk of cardiovascular events after 20 weeks gestation. The NPV of Nt-proBNP levels < 128 pg/ml at 20 weeks for the development of cardiovascular events is high. This is in line with the results of Tanous et al. for BNP, but they measured BNP only during the event in 3/8 cases and therefore could not calculate the value of BNP for prediction of events 13. N-terminal pro-b-type natriuretic peptide appears helpful in identifying women with low risk of cardiovascular events during pregnancy, since a low Nt-proBNP has a very high NPV even when one other pre-pregnancy predictor of events is present. As a consequence, less frequent follow up during the second and third trimester may be acceptable for women with low Nt-proBNP levels at 20 weeks. It should be kept in mind though, that positive and negative predictive values are strongly dependent on the prevalence of complications in a cohort of patients for a given sensitivity and specificity of a test (table 4). Table 4. Estimates of negative and positive predictive values depending on disease prevalence. Reference Prevalence of cardiovascular complications NPV* PPV* Kampman et al. (present study) 10.3% 96.9% 18.3% Drenthen et al (2) 7.6% 97.8% 14.9% Khairy et al (3) 19.4% 93.2% 33.9% *Sensitivity and specificity values presented in the results section were used for the calculations. Patients with cardiovascular events had significantly higher Nt-proBNP levels than women without cardiovascular events. This may suggest that women with CHD who develop cardiovascular complications do not have the required cardiac reserve to adapt to the hemodynamic changes of pregnancy. Compared to the values found in clinical overt heart failure, our cutoff value of Nt-proBNP > 128 pg/ml for predicting cardiovascular events is relatively low. Two recent reviews concern-

14 Nt-proBNP in pregnant women with CHD 33 ing natriuretic peptides in patients with CHD describe relatively low Nt-proBNP values in asymptomatic patients, although values are higher than in healthy controls 31,32. Most of the patients described here were asymptomatic before pregnancy and had good cardiac function, explaining the relatively low Nt-proBNP values in our study. Although Nt-proBNP levels are relatively low, they have meaning in predicting cardiovascular events. The results of the present study are in line with previous studies in non-pregnant patients with CHD, which reported that relatively low levels of natriuretic peptides are associated with adverse outcome, ventricular dysfunction and exercise capacity Giannakoulas et al. found elevated BNP levels (> 78 pg/ml) to be strongly associated with mortality and Nt-proBNP is known to be a marker for early detection of right ventricular dysfunction in patients with right heart disease 11,33,35. Although the prognostic role of natriuretic peptides in patients with heart failure is studied extensively, its value in patients with CHD is still understudied. Large prospective studies are missing and additional research on this topic is clearly warranted. In our study, a considerable amount of patients without cardiovascular events did have elevated Nt-proBNP levels at 20 weeks gestation, which was reflected by low PPV. Comparable results were found by Tanous et al. for BNP levels 13. Exercise increases BNP values in patients with tetralogy of Fallot, which is associated with impaired contractile reserve of the right ventricle 34. Since pregnancy can be considered a stress test due to its hemodynamic changes, the elevated NT-pro-BNP levels in our population with CHD may indicate subclinical compromised cardiac function even in patients who have an uneventful pregnancy. To observe a possible relation with deterioration after pregnancy, long term follow up is necessary. 2 Strengths and limitations This relatively large prospective study is the first study evaluating the role of Nt-proBNP to predict cardiovascular events during pregnancy in women with CHD. Because all women with structural CHD were eligible for inclusion, our cohort was heterogeneous. Individual diseases may be underrepresented. Because of the design of our protocol (inclusion < 20 weeks gestation) pre-pregnancy data were collected retrospectively and missing data were inevitable. N-terminal pro-b-type natriuretic peptide values were scarcely available prior to pregnancy; therefore comparison with pre-pregnancy data was not possible. The exclusion of systemic right ventricles from quantitative analysis of chamber function measurements must be kept in mind when interpreting the reported results. Since NPV and PPV are strongly dependent on prevalence of cardiovascular complications, caution is warranted when extrapolating these results to other populations.

15 34 Chapter 2 Because of the limited amount of cardiovascular events, we could not correct for all the known independent predictors. Therefore, the presented results should be interpreted with caution and additional studies are required. The limited number of events prevented a separate analysis with heart failure as the only endpoint. Conclusions Women with CHD are prone to cardiovascular events during pregnancy. Increased Nt-proBNP levels at 20 weeks gestation are an independent predictor of adverse cardiovascular events during pregnancy in women with CHD and have additional value in predicting the risk of adverse cardiovascular events during pregnancy on top of preconception predictors. Normal levels of Nt-proBNP have a high NPV for adverse maternal cardiovascular events and determination of Nt-proBNP levels during pregnancy can therefore be helpful in clinical evaluation and follow-up of a pregnant woman with CHD. Further study is recommended to establish the role of Nt-proBNP values in subgroups with specific cardiac lesions. Acknowledgements The authors thank Dr. J.P.M. Hamer for his contribution in evaluating the echocardiograms. Funding This work is supported by a grant from The Netherlands Heart Foundation (2007B75). D.J.V. is a clinically established investigator of The Netherlands Heart Foundation (D97.015). Conflicts of interest D.J.V. has received Board Membership Fees from Amgen, BG Medicine, Biocontrol, Johnson & Johnson, Novartis, Sorbent and Vifor.

16 Nt-proBNP in pregnant women with CHD 35 References 1. Drenthen W, Pieper PG, Roos-Hesselink JW, van Lottum WA, Voors AA, Mulder BJ, van Dijk AP, Vliegen HW, Yap SC, Moons P, Ebels T, van Veldhuisen DJ, ZAHARA Investigators. Outcome of pregnancy in women with congenital heart disease: a literature review. J Am Coll Cardiol 2007; 49: Drenthen W, Boersma E, Balci A, Moons P, Roos-Hesselink JW, Mulder BJ, Vliegen HW, van Dijk AP, Voors AA, Yap SC, van Veldhuisen DJ, Pieper PG, ZAHARA Investigators. Predictors of pregnancy complications in women with congenital heart disease. Eur Heart J 2010; 31: Khairy P, Ouyang DW, Fernandes SM, Lee-Parritz A, Economy KE, Landzberg MJ. Pregnancy outcomes in women with congenital heart disease. Circulation 2006; 113: Siu SC, Sermer M, Colman JM, Alvarez AN, Mercier LA, Morton BC, Kells CM, Bergin ML, Kiess MC, Marcotte F, Taylor DA, Gordon EP, Spears JC, Tam JW, Amankwah KS, Smallhorn JF, Farine D, Sorensen S, Cardiac Disease in Pregnancy (CARPREG) Investigators. Prospective multicenter study of pregnancy outcomes in women with heart disease. Circulation 2001; 104: Jastrow N, Meyer P, Khairy P, Mercier LA, Dore A, Marcotte F, Leduc L. Prediction of complications in pregnant women with cardiac diseases referred to a tertiary center. Int J Cardiol 2011; 151: Thorne S, MacGregor A, Nelson-Piercy C. Risks of contraception and pregnancy in heart disease. Heart 2006; 92: Regitz-Zagrosek V, Blomstrom Lundqvist C, Borghi C, Cifkova R, Ferreira R, Foidart JM, Gibbs JS, Gohlke-Baerwolf C, Gorenek B, Iung B, Kirby M, Maas AH, Morais J, Nihoyannopoulos P, Pieper PG, Presbitero P, Roos-Hesselink JW, Schaufelberger M, Seeland U, Torracca L, ESC Committee for Practice Guidelines, Bax J, Auricchio A, Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Knuuti J, Kolh P, McDonagh T, Moulin C, Poldermans D, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Torbicki A, Vahanian A, Windecker S, 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: 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; 352: Linssen GC, Bakker SJ, Voors AA, Gansevoort RT, Hillege HL, de Jong PE, van Veldhuisen DJ, Gans RO, de Zeeuw D. N-terminal pro-b-type natriuretic peptide is an independent predictor of cardiovascular morbidity and mortality in the general population. Eur Heart J 2010; 31: Omland T, Persson A, Ng L, O Brien R, Karlsson T, Herlitz J, Hartford M, Caidahl K. N-terminal pro-b-type natriuretic peptide and long-term mortality in acute coronary syndromes. Circulation 2002; 106: Kirk V, Bay M, Parner J, Krogsgaard K, Herzog TM, Boesgaard S, Hassager C, Nielsen OW, Aldershvile J, Nielsen H. 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; 6: van Veldhuisen DJ, Linssen GC, Jaarsma T, van Gilst WH, Hoes AW, Tijssen JG, Paulus WJ, Voors AA, Hillege HL. B-type natriuretic Peptide and prognosis in heart failure patients with preserved and reduced ejection fraction. J Am Coll Cardiol 2013; 61:

17 36 Chapter Tanous D, Siu SC, Mason J, Greutmann M, Wald RM, Parker JD, Sermer M, Colman JM, Silversides CK. B-type natriuretic peptide in pregnant women with heart disease. J Am Coll Cardiol 2010; 56: Balci A, Sollie KM, Mulder BJ, de Laat MW, Roos-Hesselink JW, van Dijk AP, Wajon EM, Vliegen HW, Drenthen W, Hillege HL, Aarnoudse JG, van Veldhuisen DJ, Pieper PG. 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; 161: e Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ, Chamber Quantification Writing Group, American Society of Echocardiography s Guidelines and Standards Committee, European Association of Echocardiography. Recommendations for chamber quantification: a report from the American Society of Echocardiography s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005; 18: Baumgartner H, Hung J, Bermejo J, Chambers JB, Evangelista A, Griffin BP, Iung B, Otto CM, Pellikka PA, Quinones M, American Society of Echocardiography, European Association of Echocardiography. Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice. J Am Soc Echocardiogr 2009; 22: 1-23; quiz Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, Waggoner AD, Flachskampf FA, Pellikka PA, Evangelista A. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. J Am Soc Echocardiogr 2009; 22: Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran K, Solomon SD, Louie EK, Schiller NB. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr 2010; 23: ; quiz Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P, Poole-Wilson PA, Stromberg A, van Veldhuisen DJ, Atar D, Hoes AW, Keren A, Mebazaa A, Nieminen M, Priori SG, Swedberg K, ESC Committee for Practice Guidelines (CPG). ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J 2008; 29: Stangl V, Schad J, Gossing G, Borges A, Baumann G, Stangl K. Maternal heart disease and pregnancy outcome: a single-centre experience. Eur J Heart Fail 2008; 10: Roos-Hesselink JW, Ruys TP, Stein JI, Thilen U, Webb GD, Niwa K, Kaemmerer H, Baumgartner H, Budts W, Maggioni AP, Tavazzi L, Taha N, Johnson MR, Hall R, on behalf of the ROPAC Investigators. Outcome of pregnancy in patients with structural or ischaemic heart disease: results of a registry of the European Society of Cardiology. Eur Heart J 2012; 22. Siu SC, Colman JM, Sorensen S, Smallhorn JF, Farine D, Amankwah KS, Spears JC, Sermer M. Adverse neonatal and cardiac outcomes are more common in pregnant women with cardiac disease. Circulation 2002; 105: Pieper PG, Balci A, Van Dijk AP. Pregnancy in women with prosthetic heart valves. Neth Heart J 2008; 16:

18 Nt-proBNP in pregnant women with CHD Sadler L, McCowan L, White H, Stewart A, Bracken M, North R. Pregnancy outcomes and cardiac complications in women with mechanical, bioprosthetic and homograft valves. BJOG 2000; 107: Elkayam U, Bitar F. Valvular heart disease and pregnancy: part II: prosthetic valves. J Am Coll Cardiol 2005; 46: Greutmann M, Von Klemperer K, Brooks R, Peebles D, O Brien P, Walker F. Pregnancy outcome in women with congenital heart disease and residual haemodynamic lesions of the right ventricular outflow tract. Eur Heart J 2010; 31: Koestenberger M, Nagel B, Avian A, Ravekes W, Sorantin E, Cvirn G, Beran E, Halb V, Gamillscheg A. Systolic right ventricular function in children and young adults with pulmonary artery hypertension secondary to congenital heart disease and tetralogy of Fallot: tricuspid annular plane systolic excursion (TAPSE) and magnetic resonance imaging data. Congenit Heart Dis 2012; 7: Koestenberger M, Nagel B, Ravekes W, Everett AD, Stueger HP, Heinzl B, Sorantin E, Cvirn G, Fritsch P, Gamillscheg A. Systolic right ventricular function in pediatric and adolescent patients with tetralogy of Fallot: echocardiography versus magnetic resonance imaging. J Am Soc Echocardiogr 2011; 24: Fang F, Henein MY, Yu CM, Li W, Kaya MG, Coats AJ, Lam YY. Right ventricular long-axis response to different chronic loading conditions: Its relevance to clinical symptoms. Int J Cardiol 2012; 30. Drenthen W, Pieper PG, Ploeg M, Voors AA, Roos-Hesselink JW, Mulder BJ, Vliegen HW, Sollie KM, Ebels T, van Veldhuisen DJ, ZAHARA Investigators. Risk of complications during pregnancy after Senning or Mustard (atrial) repair of complete transposition of the great arteries. Eur Heart J 2005; 26: Eindhoven JA, van den Bosch AE, Boersma E, Roos-Hesselink JW. The usefulness of brain natriuretic peptide in simple congenital heart disease - a systematic review. Cardiol Young 2012; : Eindhoven JA, van den Bosch AE, Jansen PR, Boersma E, Roos-Hesselink JW. The usefulness of brain natriuretic peptide in complex congenital heart disease: a systematic review. J Am Coll Cardiol 2012; 60: Giannakoulas G, Dimopoulos K, Bolger AP, Tay EL, Inuzuka R, Bedard E, Davos C, Swan L, Gatzoulis MA. Usefulness of natriuretic Peptide levels to predict mortality in adults with congenital heart disease. Am J Cardiol 2010; 105: Ishii H, Harada K, Toyono M, Tamura M, Takada G. Usefulness of exercise-induced changes in plasma levels of brain natriuretic peptide in predicting right ventricular contractile reserve after repair of tetralogy of Fallot. Am J Cardiol 2005; 95: Lemmer J, Heise G, Rentzsch A, Boettler P, Kuehne T, Dubowy KO, Peters B, Lemmer B, Hager A, Stiller B, German Competence Network for Congenital Heart Defects. Right ventricular function in grown-up patients after correction of congenital right heart disease. Clin Res Cardiol 2011; 100: Eindhoven JA, van den Bosch AE, Ruys TP, Opic P, Cuypers JA, McGhie JS, Witsenburg M, Boersma E, Roos-Hesselink JW. N-terminal probrain Natriuretic Peptide and its Relation with Cardiac Function in Adult Patients with Congenital Heart Disease. J Am Coll Cardiol 2013; Sep 24; 62(13):

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