Prenatal care coordination, racial and socioeconomic inequities, and pre- and post-operative outcomes in hypoplastic left heart syndrome.

OBJECTIVE: We sought to identify associations between prenatal care coordination (PNC) and outcomes in hypoplastic left heart syndrome (HLHS). STUDY DESIGN: We hypothesized that suboptimal PNC is associated with worse pre-operative status. HLHS patients from 2016 through 2019 were identified using a multicenter registry. Optimal PNC was defined as (1) a completed interdisciplinary conference and (2) closed-loop communication with the obstetric team. Associations between PNC and outcomes were identified. RESULTS: Of 1441 patients, 1242 (86%) had prenatal diagnosis. Among those with a prenatal diagnosis, PNC was achieved in only 845 (68%). Suboptimal PNC was associated with adverse events (50% vs 40%, p < 0.001), inotrope need (19% vs 13%, p = 0.007), mechanical ventilation (22% vs 16%, p = 0.016), and parenteral feeding (60% vs 46%, p < 0.001). African-American race and non-commercial insurance were associated with a lower likelihood of optimal PNC (p = 0.006 and p < 0.001, respectively). CONCLUSION: Improving PNC and overcoming racial and socioeconomic barriers are important targets to improve HLHS perinatal care.

Effect of In utero Non-steroidal anti-inflammatory drug therapy for severe ebstein anomaly or tricuspid valve dysplasia (NSAID therapy for fetal ebstein anomaly)

Abstract: Ebstein anomaly (EA) and tricuspid valve dysplasia (TVD) are rare congenital malformations associated with nearly 50% mortality when diagnosed in utero. The diseases often produce severe tricuspid regurgitation (TR) in the fetus and in some cases, pulmonary regurgitation (PR) and circular shunting ensue. Since the ductus arteriosus (DA) plays a critical role in the circular shunt and may be constricted by transplacental non-steroidal anti-inflammatory drugs (NSAIDs), we sought to assess the effect of NSAIDs on fetuses with EA/TVD. We reviewed mothers of singleton fetuses with EA/TVD and PR, indicative of circular shunting, who were offered NSAIDs at multiple centers from 2010-2018. Initial dosing consisted of indomethacin, followed by ibuprofen in most cases. Twenty-one patients at 10 centers were offered therapy 4 at a median gestational age (GA) of 30.0 weeks (range: 20.9-34.9). Most (15/21=71%) mothers received NSAIDs, and 12/15 (80%) achieved DA constriction after a median of 2.0 days (1.0-6.0). All fetuses with DA constriction had improved PR; 92% had improved Doppler patterns. Median GA at pregnancy outcome was 36.1 weeks (30.7-39.0) in fetuses with DA constriction vs. 33 weeks (23.3-37.3) in fetuses who did not receive NSAIDs or achieve DA constriction (p=0.040). Eleven of 12 patients (92%) with DA constriction survived to live-birth, whereas 4/9 patients (44%) who did not receive NSAIDs or achieve DA constriction survived (p=0.046). In conclusion, our findings demonstrate the proof of concept that NSAIDs mitigate circular shunt physiology by DA constriction and improve PR among fetuses with severe EA/TVD. Although the early results are encouraging, further investigation is necessary to determine safety and efficacy.

Late gestation predictors of a postnatal biventricular circulation after fetal aortic valvuloplasty.

OBJECTIVES: Fetal aortic valvuloplasty (FAV) for severe aortic stenosis (AS) has shown promise in averting progression to hypoplastic left heart syndrome. After FAV, predicting which fetuses will achieve a biventricular (BiV) circulation after birth remains challenging. Identifying predictors of postnatal circulation on late gestation echocardiography will improve parental counseling. METHODS: Liveborn patients who underwent FAV and had late gestation echocardiography available were included (2000-2017, n = 96). Multivariable logistic regression and classification and regression tree analysis were utilized to identify independent predictors of BiV circulation. RESULTS: Among 96 fetuses, 50 (52.1%) had BiV circulation at the time of neonatal discharge. In multivariable analysis, independent predictors of biventricular circulation included left ventricular (LV) long axis z-score (OR 3.2, 95% CI 1.8-5.7, p < 0.001), LV ejection fraction (OR 1.3, 95% CI 1.0-1.8, p = 0.023), anterograde aortic arch flow (OR 5.0, 95% CI 1.2-20.4, p = 0.024), and bidirectional or right-to-left foramen ovale flow (OR 4.6, 95% CI 1.4-15.8, p = 0.015). CONCLUSION: Several anatomic and physiologic parameters in late gestation were found to be independent predictors of BiV circulation after FAV. Identifying these predictors adds to our understanding of LV growth and hemodynamics after FAV and may improve parental counseling.

Effect of In Utero Non-Steroidal Anti-Inflammatory Drug Therapy for Severe Ebstein Anomaly or Tricuspid Valve Dysplasia (NSAID Therapy for Fetal Ebstein anomaly).

Ebstein anomaly (EA) and tricuspid valve dysplasia (TVD) are rare congenital malformations associated with nearly 50% mortality when diagnosed in utero. The diseases often produce severe tricuspid regurgitation (TR) in the fetus and in some cases, pulmonary regurgitation (PR) and circular shunting ensue. Since the ductus arteriosus (DA) plays a critical role in the circular shunt and may be constricted by transplacental nonsteroidal anti-inflammatory drugs (NSAIDs), we sought to assess the effect of NSAIDs on fetuses with EA/TVD. We reviewed mothers of singleton fetuses with EA/TVD and PR, indicative of circular shunting, who were offered NSAIDs at multiple centers from 2010 to 2018. Initial dosing consisted of indomethacin, followed by ibuprofen in most cases. Twenty-one patients at 10 centers were offered therapy at a median gestational age (GA) of 30.0 weeks (range: 20.9 to 34.9). Most (15/21 = 71%) mothers received NSAIDs, and 12 of 15 (80%) achieved DA constriction after a median of 2.0 days (1.0 to 6.0). All fetuses with DA constriction had improved PR; 92% had improved Doppler patterns. Median GA at pregnancy outcome (live-birth or fetal demise) was 36.1 weeks (30.7 to 39.0) in fetuses with DA constriction versus 33 weeks (23.3 to 37.3) in fetuses who did not receive NSAIDs or achieve DA constriction (p = 0.040). Eleven of 12 patients (92%) with DA constriction survived to live-birth, whereas 4 of 9 patients (44%) who did not receive NSAIDs or achieve DA constriction survived (p = 0.046). In conclusion, our findings demonstrate the proof of concept that NSAIDs mitigate circular shunt physiology by DA constriction and improve PR among fetuses with severe EA/TVD. Although the early results are encouraging, further investigation is necessary to determine safety and efficacy.

Fetal Aortic Valvuloplasty for Evolving Hypoplastic Left Heart Syndrome: A Decision Analysis.

BACKGROUND: Fetal aortic valvuloplasty (FAV) may prevent progression of midgestation aortic stenosis to hypoplastic left heart syndrome. However, FAV has well-established risks, and its survival benefit remains unknown. Our primary aim was to determine whether FAV for midgestation aortic stenosis increases survival from fetal diagnosis to age 6 years. METHODS AND RESULTS: We performed a retrospective analysis of 143 fetuses who underwent FAV from 2000 to 2017 and a secondary analysis of the Pediatric Heart Network Single Ventricle Reconstruction trial. Using these results, we developed a decision model to estimate probability of transplant-free survival from fetal diagnosis to age 6 years and postnatal restricted mean transplant-free survival time. FAV was technically successful in 84% of 143 fetuses with fetal demise in 8%. Biventricular circulation was achieved in 50% of 111 live-born infants with successful FAV but in only 16% of the 19 patients with unsuccessful FAV. The model projected overlapping probabilities of transplant-free survival to age 6 years at 75% (95% CI, 67%-82%) with FAV versus 72% (95% CI, 61%-82%) with expectant fetal management, resulting in a restricted mean transplant-free survival time benefit of 1.2 months. When limiting analyses to the improved FAV experience since 2009 to reflect current practice, (probability of technical success [94%], fetal demise [4%], and biventricular circulation [66%]), the model projected that FAV increased the probability of survival to age 6 years to 82% (95% CI, 73%-89%). Expectant management is favored if risk of fetal demise exceeded 12% or probability of biventricular circulation fell below 26%, but FAV remained favored over plausible recent range of technical success. CONCLUSIONS: Our model suggests that FAV provides a modest, medium-term survival benefit over expectant fetal management. Appropriate patient selection and low risk of fetal demise with FAV are critical factors for obtaining a survival benefit.

Neurodevelopmental Outcome in Children after Fetal Cardiac Intervention for Aortic Stenosis with Evolving Hypoplastic Left Heart Syndrome.

OBJECTIVE: To characterize neurodevelopmental outcomes after fetal aortic valvuloplasty for evolving hypoplastic left heart syndrome and determine the risk factors for adverse neurodevelopment. STUDY DESIGN: Questionnaires were mailed to families of children who underwent fetal aortic valvuloplasty from 2000 to 2012, and medical records were reviewed retrospectively. The primary outcome was the General Adaptive Composite score of the Adaptive Behavior Assessment System Questionnaire-Second Edition. Other questionnaires included the Behavior Assessment System for Children, Behavior Rating Inventory of Executive Function, Ages and Stages, and Pediatric Quality of Life Inventory. RESULTS: Among 69 eligible subjects, 52 (75%) completed questionnaires at median age of 5.5 (range 1.3-12) years; 30 (58%) had biventricular status circulation. The General Adaptive Composite mean score (92 ± 17) was lower than population norms (P < .001) and similar to published reports in patients with hypoplastic left heart syndrome without fetal intervention; scores in the single ventricular versus biventricular group were 97 ± 19 vs 89 ± 14, respectively (P = .10). On multivariable analysis, independent predictors of a lower General Adaptive Composite score were total hospital duration of stay in the first year of life (P = .001) and, when forced into the model, biventricular status (P = .02). For all other neurodevelopmental questionnaires (Behavior Assessment System for Children, Behavior Rating Inventory of Executive Function, Ages and Stages, Pediatric Quality of Life Inventory), most subscale scores for patients with biventricular and single ventricular status were similar. CONCLUSION: Children who underwent fetal aortic valvuloplasty have neurodevelopmental delay, similar to patients with hypoplastic left heart syndrome without fetal intervention. Achievement of biventricular circulation was not associated with better outcomes. We infer that innate patient factors and morbidity during infancy have the greatest effect on neurodevelopmental outcomes.

Prenatal Counseling and Care for Single-Ventricle Heart Disease: One Center's Model for Care.

Advances in prenatal imaging allow early detection of single-ventricle congenital heart disease, which may enhance prenatal care and maximize care options and decision making. Boston Children's Hospital's Advanced Fetal Care Center and fetal cardiology program provide prenatal counseling and care for single-ventricle congenital heart disease. Key points for optimal prenatal counseling and education include explanation of the diagnosis, delivery, the first surgery, cardiac neurodevelopmental issues, feeding and growth issues, quality of life and long-term care, family stressors, and fetal cardiac intervention. Such counseling and education help families make the difficult decisions required in this situation.

Perinatal and infant outcomes of prenatal diagnosis of heterotaxy syndrome (asplenia and polysplenia).

Patients with heterotaxy syndrome (HS) have a range of anomalies and outcomes. There are limited data on perinatal outcomes after prenatal diagnosis. To determine the factors influencing perinatal and infant outcomes, we analyzed prenatal and postnatal variables in fetuses with HS from 1995 to 2011. Of 154 fetuses with HS, 61 (40%) had asplenia syndrome (ASP) and 93 (60%) had polysplenia syndrome (PSP). In the ASP group, 22 (36%) patients were elected for termination of pregnancy, 4 (10%) had fetal death, and 35 of 39 (90%) continued pregnancies were live born. In the PSP group, 12 (13%) patients were elected for termination of pregnancy, 5 (6%) had fetal death (4 with bradyarrhythmia), and 76 of 81 (94%) continued pregnancies were live born. Bradyarrhythmia was the only predictor of fetal death. In the live-born ASP group, 43% (15 of 35) died, 7 because of pulmonary vein stenosis, 4 postoperatively, and 4 because of noncardiac causes. In the live-born PSP group, 13% (10 of 76) died, 5 postoperatively, 2 from bradyarrhythmia, 1 from a cardiac event, and 2 from noncardiac causes. Pulmonary vein stenosis and noncardiac anomalies were independent risk factors for postnatal death. Only 8% of ASP patients achieved biventricular circulation, compared with 65% of PSP patients. In the live-born cohort, the 5-year survival rate was 53% for ASP and 86% for PSP. In conclusion, most PSP patients are currently alive with biventricular circulation in contrast with few ASP patients. Bradyarrhythmia was the only predictor of fetal death. Pulmonary vein stenosis and noncardiac anomalies were predictors of postnatal death.

Fetal aortic valvuloplasty for evolving hypoplastic left heart syndrome: postnatal outcomes of the first 100 patients.

BACKGROUND: Fetal aortic valvuloplasty can be performed for severe midgestation aortic stenosis in an attempt to prevent progression to hypoplastic left heart syndrome (HLHS). A subset of patients has achieved a biventricular (BV) circulation after fetal aortic valvuloplasty. The postnatal outcomes and survival of the BV patients, in comparison with those managed as HLHS, have not been reported. METHODS AND RESULTS: We included 100 patients who underwent fetal aortic valvuloplasty for severe midgestation aortic stenosis with evolving HLHS from March 2000 to January 2013. Patients were categorized based on postnatal management as BV or HLHS. Clinical records were reviewed. Eighty-eight fetuses were live-born, and 38 had a BV circulation (31 from birth, 7 converted after initial univentricular palliation). Left-sided structures, namely aortic and mitral valve sizes and left ventricular volume, were significantly larger in the BV group at the time of birth (P<0.01). After a median follow-up of 5.4 years, freedom from cardiac death among all BV patients was 96±4% at 5 years and 84±12% at 10 years, which was better than HLHS patients (log-rank P=0.04). There was no cardiac mortality in patients with a BV circulation from birth. All but 1 of the BV patients required postnatal intervention; 42% underwent aortic or mitral valve replacement. On the most recent echocardiogram, the median left ventricular end-diastolic volume z score was +1.7 (range, -1.3 to +8.2), and 80% had normal ejection fraction. CONCLUSIONS: Short- and intermediate-term survival among patients who underwent fetal aortic valvuloplasty and achieved a BV circulation postnatally is encouraging. However, morbidity still exists, and ongoing assessment is warranted.

Perinatal outcome in fetuses with heterotaxy syndrome and atrioventricular block or bradycardia.

Congenital atrioventricular (AV) block is commonly associated with heterotaxy syndrome; together they have reportedly low survival rates (10-25%). However, information about perinatal outcome and predictors of non-survival after prenatal diagnosis of this association is scarce. Therefore, we studied fetuses with heterotaxy syndrome and bradycardia or AV-block diagnosed between 1995 and 2011, and analyzed pre and post-natal variables. The primary outcome was death and the secondary outcome was pacemaker placement. Of the 154 fetuses with heterotaxy syndrome, 91 had polysplenia syndrome, 22/91(24%) with bradycardia or AV-block. Thirteen (59%) patients had sinus bradycardia at diagnosis, 8 (36%) complete AV block, and 1 (5%) second-degree AV-block. Three patients elected for termination of pregnancy (3/22, 14%), 4 had spontaneous fetal demise (4/22, 18%), and 15 (15/22, 68%) were live-born. Of the fetuses with bradycardia/AV-block, 30% presented with hydrops, 20% had ventricular rates <55 beats/min, and 10% had cardiac dysfunction. Excluding termination of pregnancy, 15/19 fetuses (79%) survived to birth. Among the 15 live-born patients, 4 had bradycardia and 11 had AV-block. A further 3 patients died in infancy, all with AV-block who required pacemakers in the neonatal period. Thus, the 1-year survival rate, excluding termination of pregnancy, was 63% (12/19). Of the remaining 12 patients, 9 required pacemaker. Predictors of perinatal death included hydrops (p < 0.0001), ventricular dysfunction (p = 0.002), prematurity (p = 0.04), and low ventricular rates (p = 0.04). In conclusion, we found a higher survival rate (63%) than previously published in patients with heterotaxy syndrome and AV block or bradycardia diagnosed prenatally. Hydrops, cardiac dysfunction, prematurity and low ventricular rates were predictors of death.

Biventricular conversion after single ventricle palliation in patients with small left heart structures: short-term outcomes.

BACKGROUND: Patients with borderline small left heart (LH) structures who initially undergo single ventricle palliation (SVP) may eventually become candidates for biventricular conversion (BC). The purpose of this study was to describe our surgical experience with BC in patients with small LH. METHODS: We reviewed our institution's records for patients who underwent BC after an initial SVP between 1995 and 2012. Patients underwent an aortopulmonary amalgamation procedure as a part of their initial palliation. Data on imaging, BC operative details, and re-interventions after BC were collected. RESULTS: Twenty-eight patients underwent BC. Twenty patients had hypoplastic left heart syndrome (HLHS), 7 patients had unbalanced common atrioventricular canal (uCAVC), and 1 had interrupted aortic arch with VSD. Stage of palliation at BC was stage 1 in 6 patients (21.4%), bidirectional Glenn in 19 (67.9%), and Fontan in 3 (10.7%). Prior to BC, the median left ventricular end-diastolic volume (LVEDV) by echocardiography was 58.1 mL/m(2) in the HLHS group and 28.1 mL/m(2) in the uCAVC group. After BC, the LVEDV increased to 91.3 mL/m(2) in the HLHS group and 58.5 mL/m(2) in the uCAVC group (p < 0.05 compared with pre-BC in both groups). Right ventricular pressure was less than half systemic in 8 patients (53.3% of those measured). Seventeen patients (61%) have required either catheter-based or surgical re-intervention. Twenty-five patients (89.3%) were alive at a median follow-up of 2.6 years. CONCLUSIONS: Biventricular conversion can be applied to patients with HLHS and uCAVC and borderline LH with acceptable short-term results. Left heart size increases after BC, but follow-up for potential left atrial hypertension is warranted.