Assessment of extremely premature lambs supported by the Extrauterine Environment for Neonatal Development (EXTEND).

BACKGROUND: Our team has previously reported physiologic support by the EXTra-uterine Environment for Neonatal Development (EXTEND) of 105 to 117 days gestational age (GA) lambs for up to 28 days with normal organ maturation. However, the fetal lamb brain matures more rapidly, requiring the study of 90-105 day GA fetal lambs to assess more neurodevelopmentally equivalent lambs to the 23-25 week GA extreme premature infant. METHODS: Extremely preterm lambs (90-95 days of GA) were delivered by C-section and supported by EXTEND. Estimated circuit flows were maintained at around 325 ml/kg/min. After support on EXTEND, MRI and histopathologic analysis were performed and compared to 105-112 days GA control lambs. RESULTS: The extremely preterm group includes 10 animals with a mean GA of 91.6 days, a mean weight at cannulation of 0.98 kg and a mean length of stay on EXTEND of 13.5 days (10-21 days). Hemodynamics and oxygenation showed stable parameters. Animals showed growth and physiologic cardiac function. MRI volumetric and diffusion analysis was comparable to controls. Histologic brain analysis revealed no difference between study groups. CONCLUSION: EXTEND appears to support brain and cardiac development in an earlier gestation, less mature, lamb model. IMPACT: Prolonged (up to 21 days) physiological support of extremely preterm lambs of closer neurodevelopmental equivalence to the 24-28 gestational week human was achieved using the EXTEND system. EXTEND treatment supported brain growth and development in extremely preterm fetal lambs and was not associated with intraventricular hemorrhage or white matter injury. Daily echocardiography demonstrated physiologic heart function, absence of cardiac afterload, and normal developmental increase in cardiac chamber dimensions. This study demonstrates hemodynamic and metabolic support by the EXTEND system in the extremely preterm ovine model.

Unique model of chronic hypoxia in fetal lambs demonstrates abnormal contrast-enhanced ultrasound brain perfusion.

BACKGROUND: Children with congenital heart disease (CHD) demonstrate long-term neurodevelopmental impairments. We investigated contrast-enhanced ultrasound (CEUS) cerebral perfusion in a fetal animal model exposed to sub-physiologic oxygen at equivalent levels observed in human fetuses with CHD. METHODS: Fifteen fetal lambs [hypoxic animals (n = 9) and normoxic controls (n = 6)] maintained in an extrauterine environment underwent periodic brain CEUS. Perfusion parameters including microvascular flow velocity (MFV), transit time, and microvascular blood flow (MBF) were extrapolated from a standardized plane; regions of interest (ROI) included whole brain, central/thalami, and peripheral parenchymal analyses. Daily echocardiographic parameters and middle cerebral artery (MCA) pulsatility indices (PIs) were obtained. RESULTS: Hypoxic lambs demonstrated decreased MFV, increased transit time, and decreased MBF (p = 0.026, p = 0.016, and p < 0.001, respectively) by whole brain analyses. MFV and transit time were relatively preserved in the central/thalami (p = 0.11, p = 0.08, p = 0.012, respectively) with differences in the peripheral parenchyma (all p < 0.001). In general, cardiac variables did not correlate with cerebral CEUS perfusion parameters. Hypoxic animals demonstrated decreased MCA PI compared to controls (0.65 vs. 0.78, respectively; p = 0.027). CONCLUSION: Aberrations in CEUS perfusion parameters suggest that in environments of prolonged hypoxia, there are regional microvascular differences incompletely characterized by MCA interrogation offering insights into fetal conditions which may contribute to patient outcomes. IMPACT: This work utilizes CEUS to study cerebral microvascular perfusion in a unique fetal animal model subjected to chronic hypoxic conditions equal to fetuses with congenital heart disease. CEUS demonstrates altered parameters with regional differences that are incompletely characterized by MCA Doppler values. These findings show that routine MCA Doppler interrogation may be inadequate in assessing microvascular perfusion differences. To our knowledge, this study is the first to utilize CEUS to assess microvascular perfusion in this model. The results offer insight into underlying conditions and physiological changes which may contribute to known neurodevelopmental impairments in those with congenital heart disease.

Clinical Risk Assessment and Prediction in Congenital Heart Disease Across the Lifespan: JACC Scientific Statement.

Congenital heart disease (CHD) comprises a range of structural anomalies, each with a unique natural history, evolving treatment strategies, and distinct long-term consequences. Current prediction models are challenged by generalizability, limited validation, and questionable application to extended follow-up periods. In this JACC Scientific Statement, we tackle the difficulty of risk measurement across the lifespan. We appraise current and future risk measurement frameworks and describe domains of risk specific to CHD. Risk of adverse outcomes varies with age, sex, genetics, era, socioeconomic status, behavior, and comorbidities as they evolve through the lifespan and across care settings. Emerging technologies and approaches promise to improve risk assessment, but there is also need for large, longitudinal, representative, prospective CHD cohorts with multidimensional data and consensus-driven methodologies to provide insight into time-varying risk. Communication of risk, particularly with patients and their families, poses a separate and equally important challenge, and best practices are reviewed.

Progesterone for Neurodevelopment in Fetuses With Congenital Heart Defects: A Randomized Clinical Trial.

Importance: Neurodevelopmental outcomes for children with congenital heart defects (CHD) have improved minimally over the past 20 years. Objectives: To assess the feasibility and tolerability of maternal progesterone therapy as well as the magnitude of the effect on neurodevelopment for fetuses with CHD. Design, Setting, and Participants: This double-blinded individually randomized parallel-group clinical trial of vaginal natural progesterone therapy vs placebo in participants carrying fetuses with CHD was conducted between July 2014 and November 2021 at a quaternary care children's hospital. Participants included maternal-fetal dyads where the fetus had CHD identified before 28 weeks' gestational age and was likely to need surgery with cardiopulmonary bypass in the neonatal period. Exclusion criteria included a major genetic or extracardiac anomaly other than 22q11 deletion syndrome and known contraindication to progesterone. Statistical analysis was performed June 2022 to April 2024. Intervention: Participants were 1:1 block-randomized to vaginal progesterone or placebo by diagnosis: hypoplastic left heart syndrome (HLHS), transposition of the great arteries (TGA), and other CHD diagnoses. Treatment was administered twice daily between 28 and up to 39 weeks' gestational age. Main Outcomes and Measures: The primary outcome was the motor score of the Bayley Scales of Infant and Toddler Development-III; secondary outcomes included language and cognitive scales. Exploratory prespecified subgroups included cardiac diagnosis, fetal sex, genetic profile, and maternal fetal environment. Results: The 102 enrolled fetuses primarily had HLHS (n = 52 [50.9%]) and TGA (n = 38 [37.3%]), were more frequently male (n = 67 [65.7%]), and without genetic anomalies (n = 61 [59.8%]). The mean motor score differed by 2.5 units (90% CI, -1.9 to 6.9 units; P = .34) for progesterone compared with placebo, a value not statistically different from 0. Exploratory subgroup analyses suggested treatment heterogeneity for the motor score for cardiac diagnosis (P for interaction = .03) and fetal sex (P for interaction = .04), but not genetic profile (P for interaction = .16) or maternal-fetal environment (P for interaction = .70). Conclusions and Relevance: In this randomized clinical trial of maternal progesterone therapy, the overall effect was not statistically different from 0. Subgroup analyses suggest heterogeneity of the response to progesterone among CHD diagnosis and fetal sex. Trial Registration: ClinicalTrials.gov Identifier: NCT02133573.

Is there an increased risk of genetic abnormalities in fetuses with congenital heart disease in the setting of growth restriction?

OBJECTIVE: To determine if the presence of fetal growth restriction (FGR) is associated with an increased risk of genetic abnormalities in the setting of congenital heart disease (CHD). METHODS: This was a retrospective cohort study involving pregnancies that met the following criteria: (i) prenatal diagnosis of CHD, (ii) singleton live-birth, and (iii) genetic testing was performed either pre- or postnatally. Genetic results were reviewed by a clinical geneticist for updated variant classification. Fetal growth was stratified as appropriate for gestational age (AGA) or FGR. RESULTS: Of the total of 445 fetuses that met the study criteria, 325 (73.0%) were AGA and 120 (27.0%) were FGR. Genetic abnormalities were detected in 131 (29.4%) pregnancies. There was a higher rate of genetic abnormalities (36.7% vs. 26.8%, p = 0.04), which was driven by aneuploidies (20.8% vs. 8.9%, p = 0.0006) in the FGR population. Early onset growth restriction was associated with a higher rate of genetic abnormalities (44.5% vs. 25.9%, p = 0.03). The rate of genetic abnormalities was significantly higher in the shunt category as compared to remainder of the cardiac anomalies (62.5% in shunt lesions vs. 24.7%, p < 0.00001). The rates of FGR (40.9% vs. 21.4%, p < 0.0001) and genetic abnormalities (52% vs. 20.4%, p < 0.0001) were significantly higher in the presence of extra-cardiac anomalies (ECA). CONCLUSION: The presence of FGR in fetal CHD population was associated with underlying genetic abnormalities, specifically aneuploidies. Patients should be appropriately counseled regarding the higher likelihood of a genetic condition in the presence of FGR, early onset FGR, shunt lesions and ECA.

Single-cell multiomics guided mechanistic understanding of Fontan-associated liver disease.

The Fontan operation is the current standard of care for single-ventricle congenital heart disease. Individuals with a Fontan circulation (FC) exhibit central venous hypertension and face life-threatening complications of hepatic fibrosis, known as Fontan-associated liver disease (FALD). The fundamental biology and mechanisms of FALD are little understood. Here, we generated a transcriptomic and epigenomic atlas of human FALD at single-cell resolution using multiomic snRNA-ATAC-seq. We found profound cell type-specific transcriptomic and epigenomic changes in FC livers. Central hepatocytes (cHep) exhibited the most substantial changes, featuring profound metabolic reprogramming. These cHep changes preceded substantial activation of hepatic stellate cells and liver fibrosis, suggesting cHep as a potential first "responder" in the pathogenesis of FALD. We also identified a network of ligand-receptor pairs that transmit signals from cHep to hepatic stellate cells, which may promote their activation and liver fibrosis. We further experimentally demonstrated that activins A and B promote fibrotic activation in vitro and identified mechanisms of activin A's transcriptional activation in FALD. Together, our single-cell transcriptomic and epigenomic atlas revealed mechanistic insights into the pathogenesis of FALD and may aid identification of potential therapeutic targets.

Fontan Junctional Rhythm-Innocent Bystander or Silent Killer?

This Viewpoint discusses the impact of sinus node dysfunction and escape junctional rhythm associated with the Fontan procedure on patient outcomes.

Prenatal cardiac findings and 22q11.2 deletion syndrome: Fetal detection and evaluation.

Clinical features of 22q11.2 microdeletion syndrome (22q11.2DS) are highly variable between affected individuals and frequently include a subset of conotruncal and aortic arch anomalies. Many are diagnosed with 22q11.2DS when they present as a fetus, newborn or infant with characteristic cardiac findings and subsequently undergo genetic testing. The presence of an aortic arch anomaly with characteristic intracardiac anomalies increases the likelihood that the patient has 22q11.2 DS, but those with an aortic arch anomaly and normal intracardiac anatomy are also at risk. It is particularly important to identify the fetus at risk for 22q11.2DS in order to prepare the expectant parents and plan postnatal care for optimal outcomes. Fetal anatomy scans now readily identify aortic arch anomalies (aberrant right subclavian artery, right sided aortic arch or double aortic arch) in the three-vessel tracheal view. Given the association of 22q11.2DS with aortic arch anomalies with and without intracardiac defects, this review highlights the importance of recognizing the fetus at risk for 22q11.2 deletion syndrome with an aortic arch anomaly and details current methods for genetic testing. To assist in the prenatal diagnosis of 22q11.2DS, this review summarizes the seminal features of 22q11.2DS, its prenatal presentation and current methods for genetic testing.

Enlarged cavum septum pellucidum and small thymus as markers for 22q11.2 deletion syndrome.

BACKGROUND: Enlarged cavum septum pellucidum (CSP) and hypoplastic thymus are proposed extra-cardiac fetal markers for 22q11.2 deletion syndrome. We sought to determine if they were part of the fetal phenotype of our cohort of fetuses with 22q11.2 deletion syndrome. METHODS: Case-control study of fetuses evaluated from 2016 to 2022. The study group included fetuses with laboratory confirmation of 22q11.2 deletion syndrome. The control group included pregnancies with conotruncal cardiac anomalies with normal microarray as well as structurally normal fetuses with normal microarray. The CSP and thymus were routinely measured during anatomical ultrasound in all patients at their initial visit at 27.1 ± 4.7 weeks. The CSP and thymus measurements were classified as abnormal if they were >95% or <5% for gestational age, respectively. The groups were compared using analysis of variance or Kruskal-Wallis for continuous variables and Fisher's exact test for categorical variables. Logistic regression was performed, and a Receiver Operating Characteristic (ROC) curve was constructed. RESULTS: We identified 47 fetuses with 22q11.2 deletion syndrome and compared them to 47 fetuses with conotruncal anomalies and normal microarray and 47 structurally normal fetuses with normal microarray. 51% (24/47) of fetuses with 22q11.2 deletion syndrome had an enlarged CSP compared to 6% (3/47) of fetuses with a conotruncal anomaly and normal microarray and none of the structurally normal fetuses (p < 0.001). Of the fetuses with 22q11.2 deletion syndrome, 83% (39/47) had a hypoplastic or absent thymus compared to 9% (4/47) of the fetuses with a conotruncal anomaly and normal microarray and none of the structurally normal fetuses (p < 0.001). 87% (41/47) of the fetuses with 22q11.2 deletion syndrome had conotruncal cardiac anomalies. Logistic regression revealed that both enlarged CSP and hypoplastic/absent thymus were associated with 22q11.2 deletion syndrome. The area under the ROC curve for the two markers was 0.94. CONCLUSION: An enlarged CSP and hypoplastic/absent thymus appear to be part of the fetal phenotype of 22q11.2 deletion syndrome. These markers are associated with conotruncal anomalies in the setting of 22q11.2 deletion syndrome but not in normal controls or fetuses with conotruncal defects and normal microarrays.

Effect of patient factors, center, and era on Fontan timing: An observational study using the Pediatric Health Information Systems Database.

BACKGROUND: There are no consensus guidelines defining optimal timing for the Fontan operation, the last planned surgery in staged palliation for single-ventricle heart disease. OBJECTIVES: Identify patient-level characteristics, center-level variation, and secular trends driving Fontan timing. METHODS: A retrospective observational study of subjects who underwent Fontan from 2007 to 2021 at centers in the Pediatric Health Information Systems database was performed using linear mixed-effects modeling in which age at Fontan was regressed on patient characteristics and date of operation with center as random effect. RESULTS: We included 10,305 subjects (40.4% female, 44% non-white) at 47 centers. Median age at Fontan was 3.4 years (IQR 2.6-4.4). Hypoplastic left heart syndrome (-4.4 months, 95%CI -5.5 to -3.3) and concomitant conditions (-2.6 months, 95%CI -4.1 to -1.1) were associated with younger age at Fontan. Subjects with technology-dependence (+4.6 months, 95%CI 3.1-6.1) were older at Fontan. Black (+4.1 months, 95%CI 2.5-5.7) and Asian (+8.3 months, 95%CI 5.4-11.2) race were associated with older age at Fontan. There was significant variation in Fontan timing between centers. Center accounted for 10% of variation (ICC 0.10, 95%CI 0.07-0.14). Center surgical volume was not associated with Fontan timing (P = .21). Operation year was associated with age at Fontan, with a 3.1 month increase in age for every 5 years (+0.61 months, 95%CI 0.48-0.75). CONCLUSIONS: After adjusting for patient-level characteristics there remains significant inter-center variation in Fontan timing. Age at Fontan has increased. Future studies addressing optimal Fontan timing are warranted.

Parental Impressions and Perspectives of Efficacy in Prenatal Counseling for Single Ventricle Congenital Heart Disease.

Although commonly performed, optimal techniques, strategies, and content to achieve the most effective prenatal counseling have not been explored. We investigate the efficacy of prenatal counseling via survey feedback of parents of children with prenatally diagnosed single ventricle. Grades of counseling using a Likert scale (1-5) were solicited to assess: (1) overall impression of quantity of counseling, (2) explanation of the heart defect, (3) preparation for heart surgery, (4) preparation for hospital course and care, (5) preparation for complications and outcomes of a Fontan circulation, and (6) preparation for neurological, school-related, or behavioral problems. Impressions were solicited concerning specific providers. A comprehensive fetal counseling score was calculated for each participant. Burden of care including length of hospitalization was explored as impacting prenatal counseling grades. There were 59 survey respondents. Average age of the children at the time of survey was 4.6 ± 3.3 years (range 1-10 years). Highest grades were for explanation of the heart condition, with lowest grades for preparation for neurological, school-related, or behavioral problems. Cardiac surgeon received the highest with social worker lowest grade for provider. Negative correlation was found between the composite fetal counseling score and parental recollection of length of hospitalization (Pearson r = - 0.357, p < 0.01). Prenatal counseling for neurological, school-related, and behavioral problems in single ventricle is deficient. Further studies analyzing prenatal counseling techniques and content can help improve upon the delivery of this important aspect of prenatal care.

The Placenta in Congenital Heart Disease: Form, Function and Outcomes.

The maternal-fetal environment, controlled and modulated by the placenta, plays a critical role in the development and well-being of the fetus, with long-term impact through programming of lifelong health. The fetal cardiovascular system and placenta emerge at the same time embryologically, and thus placental form and function are altered in the presence of congenital heart disease (CHD). In this review, we report on what is known about the placenta from a structural and functional perspective when there is CHD. We describe the various unique pathologic findings as well as the diagnostic imaging tools used to characterize placental function in utero. With growing interest in the placenta, a standardized approach to characterizing placental pathology has emerged. Furthermore, application of ultrasonography techniques and magnetic resonance imaging now allow for insights into placental blood flow and functionality in vivo. An improved understanding of the intriguing relationship between the placenta and the fetal cardiovascular system will provide opportunities to develop novel ways to optimize outcomes. Once better understood, therapeutic modulation of placental function offered during the vulnerable period of fetal plasticity may be one of the most impactful ways to alter the course of CHD and its complications.

Risks of Single Fetal Demise after Laser for Twin-Twin Transfusion Syndrome.

INTRODUCTION: The aim of the study was to determine if markers of donor placental insufficiency and recipient cardiac dysfunction increase the risk for single fetal demise (SFD) after laser for twin-twin transfusion syndrome (TTTS). METHODS: Single-center retrospective review of patients who had laser for TTTS. Risk factors for donor and recipient demise within 1 week were compared in pregnancies with SFD and pregnancies with dual survival using χ2 or Fisher's exact test. Multivariate logistic regression was then performed. RESULTS: Of 398 procedures, 305 (76.6%) had dual survival, 36 (9.0%) had donor demise, 28 (7.0%) had recipient demise, and 9 (2.3%) had dual demise. The remaining 20 (5.0%) patients had complicated courses with pregnancy loss or further intervention. In the 64 pregnancies with SFD, 29 (81%) in the donor group and 20 (71%) in the recipient group occurred in the first postoperative week. For the donor demise group, estimated fetal weight (EFW) <10%, EFW <3%, EFW <1%, EFW discordance >25%, and EFW discordance >30% did not increase the risk for donor demise except in cases that also had umbilical artery absent or reversed end diastolic flow (AREDF). Donor AREDF was the only independent risk factor for early donor demise. For the recipient demise group, recipient abnormal venous Dopplers were associated with increased risk while EFW discordance >25% was associated with decreased risk of recipient loss. DISCUSSION/CONCLUSION: In our cohort, donor growth restriction did not increase the risk of early donor demise after laser unless there was also donor AREDF. Donor AREDF was an independent risk factor for donor demise likely due to the severity of placental insufficiency. Abnormal recipient venous Doppler indices increased the risk of early recipient loss while a large intertwin discordance decreased the risk. This may be explained by profound overload in cases with recipient abnormal venous Doppler velocimetry and a lower risk of substantial fluid shifts from a relatively smaller donor territory when there is a large discordance.

Fetal Doppler Echocardiographic Assessment Predicts Severe Postnatal Obstruction in Total Anomalous Pulmonary Venous Connection.

BACKGROUND: Obstructed total anomalous pulmonary venous connection (TAPVC) is a form of critical congenital heart disease that usually requires urgent postnatal intervention. Knowing which patients have severe obstruction can aid delivery planning. The authors previously developed a novel quantitative metric of pulmonary venous flow, the pulmonary venous variability index (PVVI). The aim of this study was to test the hypothesis that fetal PVVI and vertical vein Doppler velocities are associated with severe pulmonary vein obstruction postnatally. METHODS: A retrospective cohort study of neonates with prenatally diagnosed TAPVC was performed. Patients who underwent fetal echocardiography at the Children's Hospital of Philadelphia with Doppler interrogation of the vertical vein were included for analysis. Twenty-nine patients met criteria (21 with heterotaxy, 18 with supracardiac TAPVC). The latest gestation fetal echocardiogram was used. Severe pulmonary vein obstruction was defined as preoperative death or urgent surgery or catheter-based intervention (first day of life). Measurements of PVVI, defined as (maximum velocity - minimum velocity)/mean velocity, were made offline. Wilcoxon rank sum models were used to assess the associations of severe obstruction and PVVI and maximum, mean, and minimum velocities. RESULTS: The mean gestational age at the latest fetal echocardiographic examination was 35 weeks (range, 30-39 weeks). Twelve of the 29 patients (41%) met criteria for severe pulmonary vein obstruction. Lower PVVI was associated with greater risk for severe pulmonary venous obstruction (P = .008). The maximum, mean, and minimum velocities in the vertical vein were all significantly associated with severe pulmonary venous obstruction (P = .03, P = .03, and P = .007, respectively). Qualitative assessment of obstruction was not significantly associated with the outcome. Interobserver reliability for all vertical vein Doppler metrics was high (intraclass correlation coefficient > 0.9). CONCLUSIONS: Fetal PVVI and maximum, mean, and minimum velocities are associated with severe postnatal pulmonary vein obstruction in TAPVC. Accurate prediction of obstructed TAPVC could allow safer delivery planning. Further research with larger sample sizes is needed to identify the ideal cutoff values for these Doppler measures.

A Path FORWARD: Development of a Comprehensive Multidisciplinary Clinic to Create Health and Wellness for the Child and Adolescent with a Fontan Circulation.

Today, it is anticipated most individuals diagnosed with single-ventricle malformation will survive surgical reconstruction through a successful Fontan operation. As greater numbers of patients survive, so has the recognition that individuals with Fontan circulation face a variety of challenges. The goal of a normal quality and duration of life will not be reached by all. The hurdles fall into a variety of domains. From a cardiovascular perspective, the Fontan circulation is fundamentally flawed by its inherent nature of creating a state of chronically elevated venous pressure and congestion, accompanied by a relatively low cardiac output. Ventricular dysfunction, atrioventricular valve regurgitation, and arrhythmia may directly impact cardiac performance and can progress with time. Problems are not limited to the cardiovascular system. Fontan circulatory physiology impacts a multitude of biological processes and health parameters outside the heart. The lymphatic circulation is under strain manifesting as variable degrees of protein-rich lymph loss and immune system dysregulation. Organ system dysfunction develops through altered perfusion profiles. Liver fibrosis is ubiquitous, and a process of systemic fibrogenesis in response to circulatory stressors may affect other organs as well. Somatic growth and development can be delayed. Behavioral and mental health problems are common, presenting as clinically important levels of anxiety and depression. Most striking is the high variability in prevalence and magnitude of these complications within the population, indicating the likelihood of additional factors enhancing or mitigating their emergence. We propose that optimal care for the individual with single ventricle and a Fontan circulation is ideally offered in a comprehensive multidisciplinary manner, with attention to elements that are beyond cardiac management alone. In this report, we share the concepts, our experiences, and perspectives on development of a clinic model-the "Fontan rehabilitation, wellness and resilience development" or FORWARD program. We provide insights into the mechanics of our multidisciplinary model of care and the benefits offered serving our growing population of individuals with a Fontan circulation and their families.

Impact of Maternal-Fetal Environment on Mortality in Children With Single Ventricle Heart Disease.

BACKGROUND Children with single ventricle heart disease have significant morbidity and mortality. The maternal-fetal environment (MFE) may adversely impact outcomes after neonatal cardiac surgery. We hypothesized that impaired MFE would be associated with an increased risk of death after stage 1 Norwood reconstruction. METHODS AND RESULTS We performed a retrospective cohort study of children with hypoplastic left heart syndrome (and anatomic variants) who underwent stage 1 Norwood reconstruction between 2008 and 2018. Impaired MFE was defined as maternal gestational hypertension, preeclampsia, gestational diabetes, and/or smoking during pregnancy. Cox proportional hazards regression models were used to investigate the association between impaired MFE and death while adjusting for confounders. Hospital length of stay was assessed with the competing risk of in-hospital death. In 273 children, the median age at stage 1 Norwood reconstruction was 4 days (interquartile range [IQR], 3-6 days). A total of 72 children (26%) were exposed to an impaired MFE; they had more preterm births (18% versus 7%) and a greater percentage with low birth weights <2.5 kg (18% versus 4%) than those without impaired MFE. Impaired MFE was associated with a higher risk of death (hazard ratio [HR], 6.05; 95% CI, 3.59-10.21; P<0.001) after adjusting for age at surgery, Hispanic ethnicity, genetic syndrome, cardiac diagnosis, surgeon, and birth era. Children with impaired MFE had almost double the risk of prolonged hospital stay (HR, 1.95; 95% CI, 1.41-2.70; P<0.001). CONCLUSIONS Children exposed to an impaired MFE had a higher risk of death following stage 1 Norwood reconstruction. Prenatal exposures are potentially modifiable factors that can be targeted to improve outcomes after pediatric cardiac surgery.