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OBJECTIVE: To evaluate genetic testing utilization and diagnostic yield in infants with esophageal atresia (EA)/tracheoesophageal fistula (TEF) over the past 12 years to inform future practices and individualize prognostication and management. STUDY DESIGN: A retrospective cohort study was performed for all infants with EA or EA/TEF hospitalized between January 2011 and January 2023 at a quaternary children's hospital. For each infant, demographic information, prenatal and postnatal history, and genetic testing were reviewed. RESULTS: There were 212 infants who were classified as follows: 1) complex/syndromic with EA/TEF plus an additional major anatomic anomaly (n = 114, of which 74 met VACTERL criteria); 2) isolated/nonsyndromic EA/TEF (n = 88) and 3) isolated/nonsyndromic EA (n = 10). A range of genetic tests were sent with varying diagnostic rates including karyotype analysis in 12 (all with complex/syndromic phenotypes and all positive), chromosomal microarray analysis in 189 (114 of whom were complex/syndromic with an overall diagnostic rate of 3/189), single gene testing for CHD7 in 18 (4 positive), and exome analysis in 37 complex/syndromic patients (8 positive). CONCLUSIONS: EA/TEF with and without additional anomalies is genetically heterogeneous with a broad range of associated phenotypes. While the genetic etiology of EA/TEF with or without VACTERL remains largely unknown, genome wide testing (exome or genome) including copy number analysis is recommended over chromosomal microarray testing. We anticipate that expanded genetic/genomic testing modalities such as RNA sequencing and tissue specific molecular testing are needed in this cohort to improve our understanding of the genomic contributors to EA/TEF.

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OBJECTIVES: To describe the scope of left ventricular (LV) dysfunction and left heart hypoplasia (LHH) in infants with congenital diaphragmatic hernia (CDH), to determine associations with CDH severity, and to evaluate the odds of extracorporeal membrane oxygenation (ECMO) and death with categories of left heart disease. STUDY DESIGN: Demographic and clinical variables were collected from a single-center, retrospective cohort of patients with CDH from January 2017 through May 2022. Quantitative measures of LV function and LHH were prospectively performed on initial echocardiograms. LHH was defined as ≥2 of the following: z score ≤ -2 of any left heart structure or LV end-diastolic volume <3 mL. LV dysfunction was defined as shortening fraction <28%, ejection fraction <60%, or global longitudinal strain <20%. The exposure was operationalized as a 4-group categorical variable (LV dysfunction +/-, LHH +/-). Logistic regression models evaluated associations with ECMO and death, adjusting for CDH severity. RESULTS: One hundred eight-two patients (80.8% left CDH, 63.2% liver herniation, 23.6% ECMO, 12.1% mortality) were included. Twenty percent demonstrated normal LV function and no LHH (LV dysfunction-/LHH-), 37% normal LV function with LHH (LV dysfunction-/LHH+), 14% LV dysfunction without LHH (LV dysfunction+/LHH-), and 28% both LV dysfunction and LHH (LV dysfunction+/LHH+). There was a dose-response effect between increasing severity of left heart disease, ECMO use, and mortality. LV dysfunction+/LHH + infants had the highest odds of ECMO use and death, after adjustment for CDH severity [OR (95% CI); 1.76 (1.20, 2.62) for ECMO, 2.76 (1.63, 5.17) for death]. CONCLUSIONS: In our large single-center cohort, patients with CDH with LV dysfunction+/LHH + had the highest risk of ECMO use and death.

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OBJECTIVE: To assess brain development in fetuses with congenital diaphragmatic hernia (CDH) using a fetal Total Maturation Score (fTMS). STUDY DESIGN: This is a retrospective cohort study using data from a single-center clinical registry. Neonates with an antenatal diagnosis of CDH between 2014 and 2020 and prenatal brain magnetic resonance imaging (MRI) (n = 48) were included. We compared our study sample with historical healthy controls (n = 48). The relationship between fTMS and gestational age (GA), as well as the association between fTMS and key prenatal variables and placental pathologic findings, were evaluated. RESULTS: Compared with healthy controls, neonates with CDH had a significant delay in fTMS (P value <.001). Within the CDH cohort, there was no significant difference in fTMS based on CDH severity, intrathoracic liver position, right vs left CDH, sex, presence of abnormal echocardiogram findings, treatment with extracorporeal membrane oxygenation (ECMO), or in-hospital mortality. Placentas of neonates with CDH had a high proportion of fetal vascular malperfusion (56%) and chronic inflammation (67%), and relatively large placentas had a protective effect on prenatal brain maturation (P value = .025). CONCLUSIONS: Prenatal brain maturation in neonates with CDH is delayed. Placental pathology may influence fetal brain development. The etiology and clinical impact of prenatal brain immaturity in neonates with CDH warrant further investigation.

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OBJECTIVE: To evaluate associations between cardiac catheterization (cath) hemodynamics, quantitative measures of right ventricular (RV) function by echocardiogram, and survival in patients with congenital diaphragmatic hernia (CDH). STUDY DESIGN: This single-center retrospective cohort study enrolled patients with CDH who underwent index cath from 2003 to 2022. Tricuspid annular plane systolic excursion z score, RV fractional area change, RV free wall and global longitudinal strain, left ventricular (LV) eccentricity index, RV/LV ratio, and pulmonary artery acceleration time were measured from preprocedure echocardiograms. Associations between hemodynamic values, echocardiographic measures, and survival were evaluated by Spearman correlation and Wilcoxon rank sum test, respectively. RESULTS: Fifty-three patients (68% left-sided, 74% liver herniation, 57% extracorporeal membrane oxygenation, 93% survival) underwent cath (39 during index hospitalization, 14 later) including device closure of a patent ductus arteriosus in 5. Most patients (n = 31, 58%) were on pulmonary hypertension treatment at cath, most commonly sildenafil (n = 24, 45%) and/or intravenous treprostinil (n = 16, 30%). Overall, hemodynamics were consistent with precapillary pulmonary hypertension. Pulmonary capillary wedge pressure was >15 mm Hg in 2 patients (4%). Lower fractional area change and worse ventricular strain were associated with higher pulmonary artery pressure while higher LV eccentricity index and higher RV/LV ratio were associated with both higher pulmonary artery pressure and higher pulmonary vascular resistance. Hemodynamics did not differ based on survival status. CONCLUSIONS: Worse RV dilation and dysfunction by echocardiogram correlate with higher pulmonary artery pressure and pulmonary vascular resistance on cath in this CDH cohort. These measures may represent novel, noninvasive clinical trial targets in this population.

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OBJECTIVES: We aimed to determine the prevalence of electrographic seizures and associated odds of adverse outcomes of electrographic seizures in neonates with congenital diaphragmatic hernia (CDH) receiving extracorporeal membrane oxygenation (ECMO). DESIGN: Retrospective, descriptive case series. SETTING: Neonatal ICU (NICU) in a quaternary care institution. PATIENTS: All neonates with CDH receiving ECMO undergoing continuous electroencephalographic monitoring (CEEG) and follow-up between January 2012 and December 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All eligible neonates with CDH receiving ECMO underwent CEEG (n = 75). Electrographic seizures occurred in 14 of 75 (19%): they were exclusively electrographic-only in nine of 14, both electrographic-only and electroclinical in three of 14, and electroclinical only in two of 14. Two neonates developed status epilepticus. We identified an association between presence of seizures, rather than not, and longer duration of initial session of CEEG monitoring (55.7 hr [48.2-87.3 hr] vs 48.0 hr [43.0-48.3 hr]; p = 0.001). We also found an association between presence of seizures, rather than not, and greater odds of use of a second CEEG monitoring (12/14 vs 21/61; odds ratio [OR], 11.43 [95% CI, 2.34-55.90; p = 0.0026). Most neonates with seizures (10/14), experienced their onset of seizures more than 96 hours after the start of ECMO. Overall, the presence of electrographic seizures, compared with not, was associated with lower odds of survival to NICU discharge (4/14 vs 49/61; OR 0.10 [95% CI 0.03 to 0.37], p = 0.0006). Also, the presence of seizures-rather than not-was associated with greater odds of a composite of death and all abnormal outcomes on follow-up (13/14 vs 26/61; OR, 17.5; 95% CI, 2.15-142.39; p = 0.0074). CONCLUSIONS: Nearly one in five neonates with CDH receiving ECMO developed seizures during the ECMO course. Seizures were predominantly electrographic-only and when present were associated with great odds of adverse outcomes. The current study provides evidence to support standardized CEEG in this population.

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OBJECTIVE: To describe our experience with treprostinil, evaluate correlations with cardiac function, and assess for adverse effects in neonates with congenital diaphragmatic hernia-related pulmonary hypertension (CDH-PH). STUDY DESIGN: A retrospective review of a single-center prospective registry at a quaternary care children's hospital. Patients included in the study had CDH-PH treated with treprostinil between April 2013 and September 2021. Assessed outcomes were brain-type natriuretic peptide levels and quantitative echocardiographic parameters collected at baseline, 1 week, 2 weeks, and 1 month after treprostinil initiation. Right ventricular (RV) function was assessed by tricuspid annular plane systolic excursion Z-score and speckle tracking echocardiography (global longitudinal and free wall strain). Septal position and left ventricular (LV) compression were assessed by eccentricity index and M-mode Z-scores. RESULTS: Fifty-one patients were included, with an average expected/observed lung-to-head ratio of 28.4 ± 9.0%. Most patients required extra-corporeal membrane oxygenation (n = 45, 88%). Survival to hospital discharge was 31/49 (63%). Treprostinil was initiated at a median age of 19 days with a median effective dose of 34 ng/kg/minute. Median baseline brain-type natriuretic peptide level decreased from 416.9 pg/mL to 120.5 pg/mL after 1 month. Treprostinil was associated with improved tricuspid annular plane systolic excursion Z-score, RV global longitudinal strain, RV free wall strain, LV eccentricity index, and LV diastolic and systolic dimensions, reflecting less compression by the RV, regardless of ultimate patient survival. No serious adverse effects were recorded. CONCLUSIONS: In neonates with CDH-PH, treprostinil administration is well tolerated and is associated with improved RV size and function.

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OBJECTIVE: To evaluate genetic testing use in infants with congenital diaphragmatic hernia (CDH) over the past decade to better inform future practices and individualize prognostication and management. STUDY DESIGN: A retrospective cohort study was performed of all infants with CDH enrolled in the Pulmonary Hypoplasia Program at Children's Hospital of Philadelphia, born between January 2011 and February 2021. For each infant, demographic information, prenatal and postnatal history, and genetic testing were reviewed. RESULTS: The charts of 411 infants were analyzed. Overall, 22% (n = 89) were complex/syndromic and 78% (n = 322) were isolated/nonsyndromic. Mortality was significantly higher in complex/syndromic infants (P < .001) and in infants with diagnostic genetic testing (P < .001). Microarray was diagnostic in 9% (n = 34/399) and exome sequencing was diagnostic in 38% (n = 15/39). Genetic testing was diagnostic in 57% (n = 51/89) of complex/syndromic infants, but in only 2% of isolated/nonsyndromic infants (n = 8/322). Overall, genetic testing was diagnostic in 14% (n = 56). CONCLUSIONS: The high diagnostic rate in this cohort highlights the utility of comprehensive genetic testing in infants with CDH. However, 43% of complex/syndromic and 98% of isolated/nonsyndromic infants do not have a genetic etiology identified. This finding underscores the need for additional genetic and genomic studies (eg, whole genome, RNA sequencing) to identify novel genes and mutational mechanisms (single genes, regulatory elements, complex traits) that will allow for improved diagnostic rates and ultimately individualized management of infants with CDH.

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OBJECTIVE: To evaluate the associations between the primary indication for extracorporeal membrane oxygenation (ECMO) in neonates and neurodevelopmental outcomes at 12 and 24 months of age. STUDY DESIGN: This is a retrospective cohort study of neonates treated with ECMO between January 2006 and January 2016 in the Children's Hospital of Philadelphia newborn/infant intensive care unit. Primary indication for ECMO was classified as medical (eg, meconium aspiration syndrome) or surgical (eg, congenital diaphragmatic hernia). Primary study endpoints were assessed with the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). Groups were compared with standard bivariate testing and multivariable regression. RESULTS: A total of 191 neonates met the study's inclusion criteria, including 96 with a medical indication and 95 with a surgical indication. Survival to discharge was 71%, with significantly higher survival in the medical group (82% vs 60%; P = .001). Survivors had high rates of developmental therapies and neurosensory abnormalities. Developmental outcomes were available for 66% at 12 months and 70% at 24 months. Average performance on the Bayley-III was significantly below expected population normative values. Surgical patients had modestly lower the Bayley-III scores over time; most notably, 15% of medical infants and 49% of surgical infants had motor delay at 24 months (P = .03). CONCLUSIONS: In this single-center cohort, surgical patients had lower survival rates and higher incidence of motor delays. Strategies to reduce barriers to follow-up and improve rates of postdischarge developmental surveillance and intervention in this high-risk population are needed.

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OBJECTIVES: To determine which patients with congenital diaphragmatic hernia (CDH) and pulmonary hypertension (PH) benefit from inhaled nitric oxide (iNO) treatment by comparing characteristics and outcomes of iNO responders to nonresponders. STUDY DESIGN: We performed a retrospective chart review of infants with CDH treated at our center between 2011 and 2016. In a subset of patients, iNO was initiated for hypoxemia or echocardiographic evidence of extrapulmonary right to left shunting. Initial post-treatment blood gases were reviewed, and patients were classified as responders (increased PaO2 >20 mm Hg) or nonresponders. Baseline characteristics, echocardiograms and outcomes were compared between groups with Fisher exact tests and Mann-Whitney t tests, as appropriate. RESULTS: During the study period, 95 of 131 patients with CDH (73%) were treated with iNO. All patients with pretreatment echocardiograms (n = 90) had echocardiographic evidence of PH. Thirty-eight (40%) patients met treatment response criteria. Responders had significant improvements in PaO2 (51 ± 3 vs 123 ± 7 mm Hg, P < .01), alveolar-arterial gradient (422 ± 30 vs 327 ± 27 mm Hg, P < .01), and PaO2 to FiO2 ratio (82 ± 10 vs 199 ± 15 mm Hg, P < .01). Nonresponders were more likely to have left ventricular systolic dysfunction (27% vs 8%, P = .03) on echocardiogram. Responders were less likely to require extracorporeal membrane support (50 vs 24%, P = .02). CONCLUSIONS: iNO treatment is associated with improved oxygenation and reduced need for ECMO in a subpopulation of patients with CDH with PH and normal left ventricular systolic function.

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