Prenatal Predictors of Postnatal Outcome in Pulmonary Atresia with Intact Ventricular Septum: A Multicenter Study

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1 Fetal Heart Society Concept Research Proposal Date: 10/20/15 Main Study Prenatal Predictors of Postnatal Outcome in Pulmonary Atresia with Intact Ventricular Septum: A Multicenter Study Shaji C. Menon, MD; Whitnee Hogan, MD; Nelangi Pinto, MD, Thomas Miller, MD, Michael D. Puchalski, MD Division of Pediatric Cardiology, University of Utah, Salt Lake City, UT, USA Specific Aims: Specific Aim 1: To identify fetal echocardiographic anatomic and physiologic features that will predict post-natal outcomes in PA/IVS Hypothesis: Fetal echocardiographic anatomic features and measurements, as well as functional and physiologic parameters will successfully predict the eventual post-natal circulation and survival in patients with PA/IVS. Specific Aim 2: Evaluate the longitudinal pre-natal growth of cardiac structures in biventricular vs. single ventricle group. Background: Hypothesis: Longitudinal pre-natal growth of cardiac chambers, great arteries, and ratio of right to left heart structures in the biventricular group will be higher than the single or one-half ventricle groups. Pulmonary atresia with an intact ventricular septum (PA/IVS) is characterized by a broad range in the degree of hypoplasia of the right ventricle (RV), tricuspid valve (TV) and RV outflow tract (RVOT), as well as variable degrees of right ventricle to coronary artery connections (1). Usually the cavity of the right ventricle (RV) is hypoplastic and hypertrophied and the RV pressure is supra-systemic. Postnatal series have demonstrated that coronary anatomic features and RV and TV sizes guide management strategy, which ultimately results in a univentricular, one-andhalf ventricle or biventricular circulation (2-5). In the current era, PA/IVS is increasingly being diagnosed during fetal life. However, the wide variability and diversity in the morphological features of PA/IVS makes the pre-natal counseling of parents extremely challenging due to poor prediction of post-natal treatment plan and outcomes. Previous single center studies have addressed the fetal cardiac morphological and hemodynamic features that may predict postnatal outcome in PA/IVS (6-9). However, there is lack of large scale multicenter studies evaluating the appropriate anatomic and hemodynamic fetal echocardiographic criteria for

2 prediction of postnatal outcomes in PA/IVS. The objective of this multicenter study is to evaluate fetal anatomic and physiologic features that will predict postnatal outcomes in PA/IVS. Brief Approach: 1. Study design a. Methods: i. Aim 1: We will estimate the sensitivity and specificity of fetal measurements (z-scores) of the ventricles, atrio-ventriclular valves, great arteries, ratios of right and left heart structures, atrio-ventricular valve inflow and outflow Doppler and semi-quantitative estimates of partite nature of the RV, degree of tricuspid valve regurgitation and extent of coronary artery sinusoids in predicting postnatal outcomes (single ventricle, one-and-a-half ventricle or biventricular repair) and survival. ii. Aim 2: The difference in fetal measurements (z-scores) of the ventricles, atrio-ventriclular valves, great arteries, and ratios of right to left heart structures obtained from the first and last fetal echocardiogram and growth will be evaluated by the change or lack of change in z-score. Rate of growth in the biventricular group will be compared to the single and one and half ventricle group. b. Echocardiography: i. Pre-natal: We will obtain the first (22 ± 4 weeks) and last fetal echocardiograms from collaborating centers ii. Post-natal: We will obtain the first complete post-natal echocardiograms from collaborating centers c. Statistical analysis: i. Categorical Variables will be compared between biventricular and nonbiventricular group using chi-square or Fisher exact test. For comparing quantitative variables we will use Student t-test or Mann-Whitney nonparametric testing. ROC curves will be constructed to access the sensitivity and specificity of various cardiac measurements and composite score for predicting post-natal outcomes. 2. Study population a. Inclusion criteria: All cases of PA/IVS diagnosed by fetal echocardiogram and confirmed by post-natal echocardiogram will be included in the study b. Exclusion criteria: We will collect frequency distribution data regarding number and reason for termination of pregnancy, and number and type of fetal cardiac interventions. However, the following patients will be excluded from fetal echocardiographic measurements for prediction of future outcomes 1) Prenatal cardiac interventions 2) Termination of pregnancy 3. Time period to be studied: 2005 to present 4. Independent/Intervention variables: see attached Appendix 1 5. Outcomes/Dependent variables: a. Outcomes: Post-natal outcome (single ventricle, one-and-a-half ventricle, biventricular repair) and survival 6. Timeline

3 a. We anticipate 6-8 months for data collection, and 4 months for analysis and dissemination of results. Appendix 1 Measurements The following measurements and observations will be made on fetal echocardiograms: 1) Maximal ventricular dimensions: maximal length, width of RV and LV will be measured in end-diastole. 2) Atrio-ventricular valves: Maximal diameter of AV valve in diastole in apical 4 chamber view 3) Semilunar valves: Maximal diameter of aortic and pulmonary valve annulus in systole 4) Great arteries: Maximal diameter of main pulmonary artery, branch pulmonary arteries and ascending aorta in systole 5) Duration of tricuspid and mitral valve inflow expressed as ratio of cardiac cycle length 6) Semi quantitative estimation of degree of tricuspid valve regurgitation (none, mild, moderate (regurgitation reaching mid right atrium), severe (holosystolic regurgitation reaching the wall of right atrium). TR gradient 7) Semi quantitative estimation of degree of coronary sinusoids (none, few, large). Flow direction of the sinusoids by color and pulse Doppler. 8) Measure ductus arteriosus at aortic insertion and color Doppler flow direction 9) Venous Doppler characteristics/measurements 10) Umbilical artery Doppler 11) MCA Doppler 12) Pericardial, pleural effusions Calculations 1) Ratios of right to left heart structures ( RV/LV length, RV/LV width, TV/MV ratio, pulmonary annulus/aortic annulus ratio) 2) UA and MCA Doppler (UA Resistance Index, UA Pulsatility Index, MCA Resistance Index, MCA Pulsatility Index, Cerebroplacental Ratio) Post-natal and clinical outcome data 1) Demographic data: Race, birth weight, birth length, gender, gestational age, APGAR score, chromosomal defects, extra-cardiac defects 2) Post-natal findings, management and outcome: echocardiographic data, cardiac catheterization findings and interventions, type and timing of intervention and surgical repair, outcome of surgical management, length of ICU stay length of hospital stay, final disposition and future plans. We will also collect data on cardiac transplantation, mortality and cause of death

4 Data variables collected: First fetal echo and last fetal echo (collected at core lab) Date of study Apical 4 chamber view Degree of RV hypoplasia: Mild: tripartite RV Moderate: bipartite RV Severe: unipartite RV Type of pulmonary atresia membranous vs. muscular Maximal length of RV in end-diastole (mm) Maximal width of RV in end-diastole (mm) Maximal length of LV in end-diastole (mm) Maximal width of LV in end-diastole (mm) Diameter of tricuspid valve in diastole (mm) Diameter of mitral valve in diastole (mm) Any Plane Diameter of pulmonary valve annulus in systole(mm) Diameter of aortic valve valve annulus in systole(mm) Diameter of pulmonary artery (mm) Diameter of right pulmonary artery (mm) Diameter of left pulmonary artery (mm) Diameter of ascending aorta (mm) Estimation of degree of tricuspid valve regurgitation (none, mild, moderate, severe) Estimation of degree of coronary sinusoids (none, few, large). TR gradient mmhg Ductus arteriosus diameter mm UA Doppler peak velocity cm/s UA Doppler minimum velocity cm/s UA Doppler mean velocity cm/s MCA Doppler peak velocity cm/s

5 MCA Doppler minimum velocity cm/s MCA Doppler mean velocity cm/s Pericardial effusion? Pleural effusion? Post-natal data Echo study date Tricuspid annulus diameter (mm) Degree of RV hypoplasia Mild: tripartite RV Moderate: bipartite RV Severe: unipartite RV Type of pulmonary atresia (membranous vs. muscular) MPA diameter (mm) RPA diameter (mm) LPA diameter (mm) Estimation of degree of coronary sinusoids (none, few, large). Cardiac catheterization date RV dependent coronary circulation (yes vs.no) Coronary ostila atresia (yes vs.no) Perforation and balloon dilation of pulmonary valve (yes vs. no) Hospitalization Admission to NICU, CICU, PICU Surgery yes/no Date of surgery Type of surgery: BT shunt, RVOT reconstruction, both Date of ICU discharge Date of hospital discharge Final disposition Date of last follow up Tricuspid valve repair/replacement (yes vs.no) Date of tricuspid valve repair/replacement 2 ventricle (yes vs. no) Single ventricle (yes vs.no) One and half ventricle (yes vs.no) Date of Glenn Date of Fontan Cardiac transplantation (yes vs.no) Listed for transplant (yes vs.no) Date of cardiac transplantation Reason for cardiac transplantation Mortality (yes vs.no)

6 Date of death Cause of death: open field Autopsy findings (if available) Calculations: Maximal area of RV in end-diastole (mm) Maximal area of LV in end-diastole (mm) RV/LV length RV/LV width RV/LV area Tricuspid valve/mitral valve Pulmonary valve/aortic valve MPA z-score RPA z-score LPA z-score UA Resistance Index (RI) UA Pulsatility Index (PI) MCA Resistance Index (RI) MCA Pulsatility Index (PI) Cerebroplacental Ratio (CPR)

7 Measurements of LV and RV dimensions from four-chamber view References 1. Drighil A, Aljufan M, Slimi A, Yamani S, Mathewson J, AlFadly F. Echocardiographic determinants of successful balloon dilation in pulmonary atresia with intact ventricular septum. Eur J Echocardiogr Mar;11(2): Tworetzky W, McElhinney DB, Marx GR, Benson CB, Brusseau R, Morash D, et al. In utero valvuloplasty for pulmonary atresia with hypoplastic right ventricle: techniques and outcomes. Pediatrics Sep;124(3):e Ovaert C, Qureshi SA, Rosenthal E, Baker EJ, Tynan M. Growth of the right ventricle after successful transcatheter pulmonary valvotomy in neonates and infants with pulmonary atresia and intact ventricular septum. J Thorac Cardiovasc Surg May;115(5): Peterson RE, Levi DS, Williams RJ, Lai WW, Sklansky MS, Drant S. Echocardiographic predictors of outcome in fetuses with pulmonary atresia with intact ventricular septum. J Am Soc Echocardiogr Nov;19(11): Ashburn DA, Blackstone EH, Wells WJ, Jonas RA, Pigula FA, Manning PB, et al. Determinants of mortality and type of repair in neonates with pulmonary atresia and intact ventricular septum. J Thorac Cardiovasc Surg Apr;127(4):1000-7; discussion Lowenthal A, Lemley B, Kipps AK, Brook MM, Moon-Grady AJ. Prenatal tricuspid valve size as a predictor of postnatal outcome in patients with severe pulmonary stenosis or pulmonary atresia with intact ventricular septum. Fetal Diagn Ther. 2014;35(2): 101-7

8 7. Salvin JW, McElhinney DB, Colan SD, Gauvreau K, del Nido PJ, Jenkins KJ, et al. Fetal tricuspid valve size and growth as predictors of outcome in pulmonary atresia with intact ventricular septum. Pediatrics Aug;118(2):e Roman KS, Fouron JC, Nii M, Smallhorn JF, Chaturvedi R, Jaeggi ET. Determinants of outcome in fetal pulmonary valve stenosis or atresia with intact ventricular septum. Am J Cardiol Mar 1;99(5): Gardiner HM. In-utero intervention for severe congenital heart disease. Best Pract Res Clin Obstet Gynaecol Feb;22(1):49-61.