Isolated aortic arch anomalies are associated with defect severity and outcome in patients with congenital diaphragmatic hernia.

PURPOSE: Congenital diaphragmatic hernia (CDH) patients often have suspected isolated aortic arch anomalies (IAAA) on imaging. The purpose of this work was to describe the incidence and outcomes of CDH + IAAA patients. METHODS: Cardiovascular data were collected for infants from the CDH Study Group born between 2007 and 2019. IAAA were defined as coarctation of aorta, hypoplastic aortic arch, interrupted aortic arch, and aortic aneurysmal disease on early, postnatal echocardiography. Patients with major cardiac malformations and/or chromosomal abnormalities were excluded. Primary outcomes included the rate of aortic intervention, rates of extracorporeal life support (ECLS) utilization, and mortality. RESULTS: Of 6357 CDH infants, 432 (7%) were diagnosed with a thoracic aortic anomaly. Of these, 165 were diagnosed with IAAA, most commonly coarctation of the aorta (n = 106; 64%) or hypoplastic aortic arch (n = 58; 35%). CDH + IAAA patients had lower birthweights (3 kg vs. 2.9 kg) and Apgar scores (7 vs. 6) than patients without IAAA (both χ2 p < 0.001). CDH + IAAA were less likely to undergo diaphragm repair (72 vs. 87%, p < 0.001), and overall mortality was higher for CDH + IAAA infants (58 vs. 24%, p < 0.001). When controlling for defect size, birth weight, and Apgar, IAAA were significantly associated with mortality (OR 3.3, 95% CI 2.2-5.0; p < 0.01) but not associated with ECLS (OR 0.98, 95% CI 0.65-1.50; p = 0.90). Only 17% (n = 28) of CDH + IAAA patients underwent aortic intervention. CONCLUSIONS: IAAA in CDH are associated with increased mortality. This often simply reflects severity of the defect and thoracic anatomic derangement, as opposed to unique aortic pathology, given few CDH + IAAA patients undergo aortic intervention.

Congenital diaphragmatic hernia-associated pulmonary hypertension.

Congenital diaphragmatic hernia (CDH) is characterized by a developmental insult which compromises cardiopulmonary embryology and results in a diaphragmatic defect, allowing abdominal organs to herniate into the hemithorax. Among the significant pathophysiologic components of this condition is pulmonary hypertension (PH), alongside pulmonary hypoplasia and cardiac dysfunction. Fetal pulmonary vascular development coincides with lung development, with the pulmonary vasculature evolving alongside lung maturation. However, in CDH, this embryologic development is impaired which, in conjunction with external compression, stifle pulmonary vascular maturation, leading to reduced lung density, increased muscularization of the pulmonary vasculature, abnormal vascular responsiveness, and altered molecular signaling, all contributing to pulmonary arterial hypertension. Understanding CDH-associated PH (CDH-PH) is crucial for development of novel approaches and effective management due to its significant impact on morbidity and mortality. Antenatal and postnatal diagnostic methods aid in CDH risk stratification and, specifically, pulmonary hypertension, including fetal imaging and gas exchange assessments. Management strategies include lung protective ventilation, fluid optimization, pharmacotherapies including pulmonary vasodilators and hemodynamic support, and extracorporeal life support (ECLS) for refractory cases. Longitudinal re-evaluation is an important consideration due to the complexity and dynamic nature of CDH cardiopulmonary physiology. Emerging therapies such as fetal endoscopic tracheal occlusion and pharmacological interventions targeting key CDH pathophysiological mechanisms show promise but require further investigation. The complexity of CDH-PH underscores the importance of a multidisciplinary approach for optimal patient care and improved outcomes.

Association of timing of congenital diaphragmatic hernia repair with survival and morbidity for patients not requiring extra-corporeal life support.

BACKGROUND: While physiologic stabilization followed by repair has become the accepted paradigm for management of congenital diaphragmatic hernia (CDH), few studies have examined the effect of incremental changes in operative timing on patient outcomes. We hypothesized that later repair would be associated with higher morbidity and mortality. METHODS: Data were queried from the CDH Study Group (CDHSG) from 2007-2020. Patients with chromosomal or cardiac abnormalities and those who were never repaired or required pre-repair extra-corporeal life support (ECLS) were excluded. Time to repair was analyzed both as a continuous variable and by splitting the cohort into top/bottom percentiles. The primary outcome of interest was in-hospital mortality. Secondary outcomes included need for and duration of post-repair ventilatory and nutritional support. RESULTS: A total of 4,104 CDH infants were included. Median time to repair was 4 days (IQR 2-6). On multivariable analysis, high-risk (CDHSG stage C/D) defects and lower birthweight predicted later repair. Overall, in-hospital mortality was 6%. On univariate analysis, there was no difference in the number of days to repair between survivors and non-survivors. On risk-adjusted analysis, single-day changes in day of repair were not associated with increased mortality. Later repair was associated with longer time to reach full oral feeds, increased post-repair ventilator days, and increased need for tube feeds and supplementary oxygen at discharge. CONCLUSIONS: For infants with isolated CDH not requiring pre-operative ECLS, there is no difference in mortality based on timing of repair, but single-day delays in repair are associated with increased post-repair duration of ventilatory and nutritional support.

Birth weight predicts patient outcomes in infants who undergo congenital diaphragmatic hernia repair.

PURPOSE: The purpose of this study was to analyze the clinical characteristics and outcomes of low birthweight (LBW) infants with congenital diaphragmatic hernia (CDH) compared to normal birthweight (NBW) infants with CDH. We hypothesized that LBW was associated with increased mortality, decreased extracorporeal life support (ECLS) utilization, and increased pulmonary morbidity in CDH patients. METHODS: Patients in the CDH Study Group from 2007 to 2018 were included. LBW was defined as <2.5 kg. Clinical characteristics and outcomes for LBW patients were compared to normal birthweight (NBW) patients using univariate and multivariable analyses. RESULTS: Of 5,586 patients, 1,157 (21%) were LBW. LBW infants had more congenital anomalies and larger diaphragmatic defects than NBW infants. ECLS utilization was decreased, and overall mortality was increased among LBW infants compared to NBW infants. A 1 kg increase in birthweight was associated with 34% higher odds of survival after repair (adjusted Odds Ratio 1.34, 95% CI 1.03-1.76; p = .03). LBW infants had longer durations of mechanical ventilation and were more likely to require supplemental oxygen at 30 days and at the time of discharge. CONCLUSION: LBW is a risk factor for mortality and pulmonary morbidity in CDH. Prolonged oxygen requirement and increased length of stay are important considerations when managing this population.

Elevated proBNP levels are associated with disease severity, cardiac dysfunction, and mortality in congenital diaphragmatic hernia.

BACKGROUND: Cardiac dysfunction is a key determinant of outcome in congenital diaphragmatic hernia (CDH). Pro-b-type natriuretic peptide (proBNP) is used as a prognosticator in heart failure and cardiomyopathy. We hypothesized that proBNP levels would be associated with ventricular dysfunction and high-risk disease in CDH. METHODS: Patients in the CDH Study Group (CDHSG) from 2015-2019 with at least one proBNP value were included. Ventricular function was determined using echocardiograms from the first 48 h of life. RESULTS: A total of 2,337 patients were identified, and 212 (9%) had at least one proBNP value. Of those, 3 (1.5%) patients had CDHSG stage A defects, 58 (29.6%) B, 111 (56.6%) C, and 24 (12.2%) D. Patients with high-risk defects (Stage C/D) had higher proBNP compared with low-risk defects (Stage A/B) (14,281 vs. 5,025, p = 0.007). ProBNP was significantly elevated in patients who died (median 14,100, IQR 4,377-22,900 vs 4,911, IQR 1,883-9,810) (p<0.001). Ventricular dysfunction was associated with higher proBNP than normal ventricular function (8,379 vs. 4,778, p = 0.005). No proBNP value was both sensitive and specific for ventricular dysfunction (AUC=0.61). CONCLUSION: Among CDH patients, elevated proBNP was associated with high-risk defects, ventricular dysfunction, and mortality. ProBNP shows promise as a biomarker in CDH-associated cardiac dysfunction.

Cornelia de Lange syndrome and congenital diaphragmatic hernia.

PURPOSE: There is a known association between Cornelia de Lange syndrome (CdLS) and congenital diaphragmatic hernia (CDH), with CDH being the cause of death in 5%-20% of CdLS cases. We aimed to identify and describe patients with CDLS and CDH. We hypothesized that CdLS would be associated with high-risk CDH and poor outcomes. METHODS: CDH Study Group patients from 1995 to 2019 were included. Those with CdLS were reviewed retrospectively. Rates of repair and outcomes were compared between patients with and without CdLS. RESULTS: We identified 9,251 CDH patients. Of those, 21 had confirmed CdLS. CdLS patients had a lower birth weight (2.2±0.57 kg) than non-CdLS patients (2.9±0.64 kg) (p<0.001). 5-min Apgar scores were lower in CdLS patients (6, 4-7) than non-CdLS patients (7, 5-8) (p=0.014). Only 33% of CdLS patients underwent diaphragmatic repair compared to 84.2% of non-CdLS patients (p<0.001). Mortality was 76% for CdLS patients compared with 29% for non-CdLS patients (p<0.001). Of the 7 CdLS patients who underwent repair, 5 survived to hospital discharge. CONCLUSIONS: Infants with CdLS and CDH have a poor prognosis. However, CdLS patients who undergo repair can survive to discharge; therefore, the concomitant diagnosis of CdLS and CDH is not necessarily a contraindication to repair. Early recognition of these anomalies can assist with counseling and prognostication. TYPE OF STUDY: Retrospective comparative study LEVEL OF EVIDENCE: III.

Prenatally versus postnatally diagnosed congenital diaphragmatic hernia - Side, stage, and outcome.

AIM: To compare outcomes between prenatally and postnatally diagnosed CDH in a large multicenter database of prospectively collected data and evaluate factors associated with poorer outcome for prenatally diagnosed CDH. MATERIAL AND METHODS: We used information from the multicenter, multinational CDH Study Group database on patients born between 2007 and 2015. We compared differences between prenatally and postnatally diagnosed CDH with respect to survival, side, size, ECMO needs, associated major cardiac malformations and liver position. RESULTS: 3746 cases of CDH were entered in the registry between 2007 and 2015, with an overall survival of 71%. Of those, 68% had a prenatal diagnosis. Survival rates were significantly better in the postnatally diagnosed group, 83 vs 65%. There was a higher proportion of bigger defect sizes, C and D, in the prenatally diagnosed group, but the survival rates were similar when patients were stratified by defect size. The rate of ECMO utilization was higher overall in the prenatally diagnosed group, 33 vs 22%, but it was similar within similar defect sizes. Right-sided defects are more commonly missed at prenatal screening than left-sided CDH, 53 vs 35% (p < 0.0001). CONCLUSIONS: Prenatally diagnosed CDH is associated with larger defect sizes compared to those with a postnatal diagnosis, and consequently have higher morbidity and mortality. Right-sided CDH are more often missed at prenatal ultrasound. The increasing rate of prenatal detection requires a clear understanding of accurate risk stratification, in order to counsel families and to provide appropriate perinatal management. LEVEL OF EVIDENCE: I for a Prognosis Study - This is a high-quality, prospective cohort study with 99% of patients followed to the study end point (death or discharge).

The Congenital Diaphragmatic Hernia Study Group registry update.

The Congenital Diaphragmatic Hernia Study Group (CDHSG) is an international consortium of centers that prospectively collect and voluntarily contribute data about live-born CDH patients they manage. These data are compiled to form a registry from which any participating center may utilize the dataset to answer specific clinical questions and monitor outcomes. Since its inception in 1995, 112 centers have participated (including 66 centers from 13 countries currently active), data on more than eight thousand total children have been collected, and 35 manuscripts have been generated using registry data. This review covers the formation and structure of the CDH study group and registry, including function, center involvement, and the evolution of data collection. We also review reports generated by the CDHSG, with particular focus on the work after 2008. International multicenter consortiums, such as the CDHSG, allow physicians that manage uncommon, complex, heterogeneous diseases to develop evidence-based hypotheses and conclusions for clinical questions.