Congenital Diaphragmatic Hernia Survivors Research Articles

Exercise-Induced Pulmonary Hypertension in Long-Term Survivors of Congenital Diaphragmatic Hernia

ObjectiveTo determine the prevalence of exercise-induced pulmonary hypertension (PH) among long-survivors of congenital diaphragmatic hernia (CDH) repair. Study designThis is a single-center, retrospective cohort study of CDH survivors who underwent exercise stress echocardiography (ESE) at Boston Children’s Hospital from January 2006 to June 2020. PH severity was assessed by echocardiogram at baseline and after exercise. Patients were categorized by right ventricular systolic pressure (RVSP) after exercise: Group 1 - no or mild PH; and Group 2 - moderate or severe PH (RVSP ≥ 60 mmHg or ≥ ½ systemic blood pressure). ResultsEighty-four patients with CDH underwent 173 ESE with median age 8.1 (4.8 – 19.1) years at first ESE. Sixty-four patients were classified as Group 1, 11 as Group 2, and 9 had indeterminate RVSP with ESE. Moderate to severe PH after exercise was found in 8 (10%) patients with no or mild PH at rest. Exercise-induced PH was associated with larger CDH defect size, patch repair, use of ECMO, supplemental oxygen at discharge, and higher WHO functional class. Higher VE/VCO2 slope, lower peak oxygen saturation, and lower percent predicted FEV1 and FEV1/FVC ratio were associated with Group 2 classification. ESE changed management in 9/11 Group 2 patients. PH was confirmed in all 5 Group 2 patients undergoing cardiac catheterization after ESE. ConclusionsAmong long-term CDH survivors, 10% had moderate-severe exercise-induced PH on ESE, indicating ongoing pulmonary vascular abnormalities. Further studies are needed to optimally define PH screening and treatment for patients with repaired CDH.

Quality of life in congenital diaphragmatic hernia survivors treated at a non-ECMO centre from 1998 to 2015: a cross-sectional study

BackgroundSurvival of infants with congenital diaphragmatic hernia (CDH) has increased and more insight is warranted on the long-term issues of this condition.MethodsWe conducted a cross-sectional study on consecutively born infants...

Parent-Reported Health-Related Quality of Life Outcomes and Impact on Family of Congenital Diaphragmatic Hernia Survivors After Repair: A Cross-Sectional Comparison to Healthy Controls

BackgroundCongenital diaphragmatic hernia (CDH) survivors often experience long-term CDH-associated morbidities, including musculoskeletal, gastrointestinal and respiratory issues. This study evaluates parent-reported health-related quality of life (HRQOL) and family impact of the disease. MethodsElectronic medical records (EMR) were reviewed and phone surveys performed with parents of CDH survivors who underwent repair at our institution from 2010 to 2019. They completed the following Pediatric Quality of Life Inventory™ (PedsQL™) questionnaires: Generic Core Scales 4.0 (parent-proxy report) and Family Impact (FI) Module 2.0. Age-matched and gender-matched healthy controls from an existing database were used for comparison. Subgroup analysis of CDH patients alone was also performed. Appropriate statistical analysis was used with p < 0.05 significance. Data are reported as median (range). Ethical approval was obtained. ResultsOf 76 CDH survivors, 45 parents (59 %) consented for study participation. Patients and controls were aged 6 (3–12) years; 51 % were male. In Core Scales, there were significant differences between the groups in the overall scores (p = 0.003) and the psychosocial health sub-scores (p = 0.004), but no difference in the physical health domain scores. In the Family Impact Module, there were no significant differences between the groups in overall scores, in parent HRQOL and in family functioning sub-scores. However, CDH patients with learning disabilities had significantly worse Family Impact Module overall scores compared to CDH patients without learning disabilities (p = 0.04). ConclusionThe overall HRQOL in children with CDH survivors is worse compared to controls, but impact on family appears similar. We highlight the need for long-term follow-up of CDH patients, especially those with learning disabilities. Healthcare providers should formulate tailored care plans to address patient and caregiver needs. Type of studyProspective Study. Level of evidenceLevel III.

Prevalence and patterns of executive function, adaptive function, and behavioral outcomes in preschool and school age children with congenital diaphragmatic hernia

BackgroundExecutive function, adaptive function, and behavioral outcomes in congenital diaphragmatic hernia (CDH) survivors have not been well studied. AimTo evaluate executive and neurobehavioral dysfunction in preschool and early school-aged children with CDH. Study designRetrospective cohort study. SubjectsAll eligible CDH survivors ages 3 to 7 years enrolled in our follow-up program between February 2020 and February 2021. Outcome measuresThe Behavior Rating Inventory of Executive Function (BRIEF), the Adaptive Behavior Assessment System, 2nd Edition (ABAS-II), and the Child Behavior Checklist (CBCL) were used to assess functional and behavioral outcomes. Summary scores were compared to standard population norms. ResultsA total of 100 patients were enrolled during the study period. Of those, 73 parents completed at least one of the questionnaires, resulting in completion of the BRIEF, ABAS-II, and CBCL for 63, 68, and 63 patients, respectively. Preschool children had normal executive function (BRIEF-P) while global executive composite (P = 0.012) and the emotional regulation index (P = 0.010) for school age patients (BRIEF-2) were worse. CDH survivors had favorable adaptive functioning (ABAS-II). Mean CBCL scores for preschool attention problems (P = 0.018), school age attention problems (P = 0.001), and attention deficits hyperactivity problems (P = 0.027) were significantly worse. Prematurity, surrogate markers of disease severity, non-white race, and public insurance status were associated with worse neurobehavioral dysfunction in bivariable analysis. ConclusionsThe majority of preschool and school age CDH survivors have age-appropriate executive, adaptive and behavioral functioning. CDH survivors, however, have lower executive function and attention scores compared with the general population.

Konjenital Diyafragma Hernisi Tanılı Fetüslerde Prognostik Marker Olarak Mide Pozisyonu

Aim: To examine the relationship between stomach position and neonatal survival in congenital diaphragmatic hernia (CDH). &#x0D; Materials and Method: A total of 36 pregnant women with a diagnosis of fetal CDH, aged between 18-45 years and 22-39 weeks of gestation, who applied Ankara City Hospital Perinatology clinic between December 2019 and December 2022, were analyzed retrospectively. Pregnancies were classified into two categories based on neonatal survival. Demographic characteristics, clinical features and contralateral lung size/head circumference (LHR) ratio, stomach position, and other prognostic indicators were evaluated among the survivor (n=8) and non-survivor (n=22) groups. &#x0D; Results: The mean maternal age was 29.30 ± 1.02 (range 17-40), and 36% (13/36) of the patients were primigravid. The median gestational week at diagnosis was 25.10 (13.5-37.6). There was no statistically significant difference between the survivor and non-survivor groups in terms of CDH type, liver position, gestational week at diagnosis, and median LHR. Grade 2 stomach position was found to be statistically significantly higher in the survivor group (p=0.01). Operation rate and 1st-5th minute Apgar scores were higher than in the non-survivor group (p=0.02, p=0.01, and p=0.00, respectively). &#x0D; Conclusion: Stomach position grading in CDH is a practical and applicable method associated with neonatal survival, and grade 2 stomach position may be a marker associated with increased survival in fetuses with CDH regardless of LHR. It may be useful in assessing neonatal prognosis and planning perinatal management, such as maternal transfer to a tertiary center where fetal interventions are available.

Evaluation of brain development and damage using magnetic resonance imaging of congenital diaphragmatic hernia survivors: An analysis using the global brain abnormality score

The short-term prognosis of central nervous system in congenital diaphragmatic hernia (CDH) survivors has been determined by magnetic resonance imaging (MRI), but its relationship with acute management is unclear. We aimed to investigate the association between the intubation period and the Global Brain Abnormality Score (GBAS) in CDH survivors using brain MRI. Fifty-seven patients with CDH who were hospitalized at a single NICU between January 2004 and December 2019 were retrospectively reviewed. After excluding 5 patients who died shortly after birth and two who could not be weaned from the ventilator, the acute management of the 50 remaining patients was investigated. We also investigated the relationship between the GBAS and intubation period in 25 patients who underwent brain MRI at discharge. The long-intubation group (intubation ≥12 days) had lower Apgar scores and fetal lung-thoracic ratios, and longer time to radical surgery, and parenteral nutrition and tube feeding periods. Nitric oxide inhalation, liver prolapse, patch closure, and extracorporeal membrane oxygenation were independent risk factors for long-intubation. Eighty-four percent of CDH survivors had some imaging abnormalities, including developmental and signaling abnormalities. In the long-intubation group, the body of the corpus callosum was thin and the cerebral hemispheric space was widened, and GBAS deterioration was significantly related to the intubation period. Brain MRI abnormalities were found in 84% of CDH survivors. Prolonged intubation is associated with worsening of the GBAS. Thus, the duration of intubation may be a surrogate outcome for the neurological prognosis of CDH survivors.

Longitudinal Health Status and Quality of Life in Congenital Diaphragmatic Hernia.

To longitudinally evaluate self-reported health status (HS) and quality of life (QoL) in 8- and 12-year-old survivors of congenital diaphragmatic hernia (CDH). We hypothesized that HS would improve with age-as associated health problems tend to decline-whereas QoL would decrease, as the children start to compare themselves with peers. Self-reported HS and QoL of 133 children born between 1999 and 2013 who had joined our standardized follow-up program were routinely assessed at the ages of 8 and 12 with generic, internationally validated, standardized instruments. Longitudinal evaluation of total and subscale scores was performed using general linear model analyses. In addition, we compared these scores to sex- and age-specific normative data. Between ages 8 and 12, boys born with CDH perceived a decline in HS (mean difference -7.15, P < .001). Self-reported QoL did not change over time in both boys and girls. At both ages, HS was significantly lower than that of healthy peers (effect size = 0.71, P = .001 for boys, and effect size = 0.69, P = .003 for girls), whereas differences in QoL were small. Children born with CDH are at risk for declining HS between 8 and 12 years, but not QoL, compared with healthy peers. Given that children born with CDH tend to grow into deficits, our findings highlight the need for continued somatic and psychological assessments in adolescent and adult CDH survivors.

Beyond the diaphragm and the lung: a multisystem approach to understanding congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) is a birth defect characterized by the incomplete closure of the diaphragm and herniation of abdominal organs into the chest during gestation. This invariably leads to an impairment in fetal lung development (pulmonary hypoplasia) that involves the pulmonary vessels (vascular remodeling) leading to postnatal pulmonary hypertension. Moreover, approximately 60% of CDH survivors have long-term comorbidities, including critical cardiac anomalies, neurodevelopmental impairment, gastroesophageal reflux, and musculoskeletal malformations. While the pathophysiology of the diaphragmatic defect and pulmonary hypoplasia have been studied in detail over the decades, less is known about the other organs affected in CDH. In this review, we searched the literature for reports on other organs beyond the lung and diaphragm in human and experimental models of CDH. We found studies reporting gross morphometric changes and alterations to biological pathways in the heart, brain, liver, kidney, gastrointestinal tract, and musculoskeletal system. Given the paucity of literature and the importance that these comorbidities play in the life of patients with CDH, further studies are needed to comprehensively uncover the pathophysiology of the changes observed in these other organs.

Do FETO CDH survivors need the same follow-up program as non-FETO patients?

Congenital diaphragmatic hernia (CDH) survivors are at risk of developing significant chronic health conditions and disabilities. The main purpose of this study was to compare the outcomes of CDH infants at 2years of age (2y) according to whether the infants had undergone fetoscopic tracheal occlusion (FETO) during the prenatal period and characterize the relationship between morbidity at 2y and perinatal characteristics. Retrospective cohort single center study. Eleven years of clinical follow-up data (from 2006 to 2017) were collected. Prenatal and neonatal factors as well as growth, respiratory, and neurological evaluations at 2y were analyzed. One hundred and fourteen CDH survivors were evaluated. Failure to thrive (FTT) was present in 24.6% of patients, gastroesophageal reflux disease (GERD) in 22.8%, 28.9% developed respiratory problems, and 22% had neurodevelopment disabilities. Prematurity and birth weight < 2500g were related to FTT and respiratory morbidity. Time to reach full enteral nutrition and prenatal severity markers seemed to influence all outcomes, but FETO therapy itself only had an effect on respiratory morbidity. Some variables related to postnatal severity (ECMO, patch closure, days on mechanic ventilation, and vasodilator treatment) were associated with almost all outcomes. Conclusion: CDH patients have specific morbidities at 2y, most of them related to lung hypoplasia severity. Only respiratory problems were related to FETO therapy itself. The implementation of a specific multidisciplinary follow-up program for CDH patients is essential to provide them the best standard of care, but, more severe patients, regardless of whether they received prenatal therapy, need a more intensive follow-up. What is Known: • Antenatal fetoscopic endoluminal tracheal occlusion (FETO) increases survival in more severe congenital diaphragmatic hernia patients. • Congenital diaphragmatic hernia survivors are at risk of developing significant chronic health conditions and disabilities. Very limited data are available about the follow-up in patients with congenital diaphragmatic hernia and FETO therapy. What is New: • CDH patients have specific morbidities at 2 years of age, most of them related to lung hypoplasia severity. • FETO patients present more respiratory problems at 2 years of age but they don't have an increased incidence of other morbidities. More severe patients, regardless of whether they received prenatal therapy, need a more intensive follow-up.

Long-Term Functional Outcomes at 1-Year After Hospital Discharge in Critically Ill Neonates With Congenital Diaphragmatic Hernia.

Congenital diaphragmatic hernia (CDH) is a birth defect associated with long-term morbidity. Our objective was to examine longitudinal change in Functional Status Scale (FSS) after hospital discharge in CDH survivors. Single-center retrospective cohort study. Center for comprehensive CDH management at a quaternary, free-standing children's hospital. Infants with Bochdalek CDH were admitted to the ICU between January 2009 and December 2019 and survived until hospital discharge. None. One hundred forty-two infants (58% male, mean birth weight 3.08 kg, 80% left-sided defects) met inclusion criteria. Relevant clinical data were extracted from the medical record to calculate FSS (primary outcome) at hospital discharge and three subsequent outpatient follow-up time points. The median (interquartile range [IQR]) FSS score at hospital discharge was 8.0 (7.0-9.0); 39 patients (27.5%) had at least moderate impairment (FSS ≥ 9). Median (IQR) FSS at 0- to 6-month ( n = 141), 6- to 12-month ( n = 141), and over 12-month ( n = 140) follow-up visits were 7.0 (7.0-8.0), 7.0 (6.0-8.0), and 6.0 (6.0-7.0), respectively. Twenty-one patients (15%) had at least moderate impairment at over 12-month follow-up; median composite FSS scores in the over 12-month time point decreased by 2.0 points from hospital discharge. Median feeding domain scores improved by 1.0 (1.0-2.0), whereas other domain scores remained without impairment. Multivariable analysis demonstrated right-sided, C- or D-size defects, extracorporeal membrane oxygenation use, cardiopulmonary resuscitation, and chromosomal anomalies were associated with impairment. The majority of CDH survivors at our center had mild functional status impairment (FSS ≤ 8) at discharge and 1-year follow-up; however, nearly 15% of patients had moderate impairment during this time period. The feeding domain had the highest level of functional impairment. We observed unchanged or improving functional status longitudinally over 1-year follow-up after hospital discharge. Longitudinal outcomes will guide interdisciplinary management strategies in CDH survivors.

Congenital diaphragmatic hernia survival in an English regional ECMO center

IntroductionCongenital diaphragmatic hernia (CDH) remains a cause of neonatal death. Our aims are to describe contemporary rates of survival and the variables associated with this outcome, contrasting these with our...

Long-term exercise and pulmonary function outcomes in a contemporary cohort of children with congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) survivors are at risk for long-term exercise impairment and pulmonary morbidity, but the generalizability of prior reported cohorts are limited by reduced disease severity and older surgical eras. We assessed the mid-childhood exercise and pulmonary function outcomes in a contemporary cohort of CDH survivors. In this retrospective cohort study, we identified 36 consecutive pediatric CDH survivors who underwent cardiopulmonary exercise testing (CPET) and spirometry from 2014 to 2021. Inferential statistics compared survivors with age-, sex-, and size-matched healthy controls; univariate analyses identified factors associated with abnormal testing. Maximal effort CPET and resting spirometry were completed by 27/36 (75%) and 31/36 (86%) subjects, respectively (median age: 8.1 years [interquartile range: 7.5, 10]; 16 females [44%]). Abnormal CPET (percent predicted [pp] peak VO2  < 80%) was more common in the CDH cohort (12 vs. 1, p < 0.001) and associated with longer neonatal intensive care unit (NICU) stay (p = 0.02) and oxygen therapy at discharge (p = 0.03). Exercise impairment was mild (pp peak VO2 70%-80%), moderate (60%-70%), and severe (<60%) in 6, 4, and 2 survivors, respectively. Abnormal spirometry was more common in the CDH cohort (21 vs. 3, p < 0.001; obstructive [n = 15], restrictive [n = 6]) and associated with decreased gestational age (p = 0.046), longer mechanical ventilation in the NICU (p = 0.02), and orthopedic abnormalities (p = 0.03). Exercise capacity was normal or mildly impaired in most CDH survivors, however, approximately two-thirds demonstrated abnormal spirometry. Impaired exercise capacity and lung function were associated with severity of lung disease postnatally. These data support cardiopulmonary follow-up throughout childhood.

Right to left ventricular volume ratio is associated with mortality in congenital diaphragmatic hernia

BackgroundCongenital diaphragmatic hernia (CDH) is associated with high neonatal mortality. We performed this study to test the hypothesis that left ventricular (LV) and right ventricular (RV) volumes assessed by three-dimensional echocardiography may be associated with mortality in CDH.MethodsThis study was a single-center retrospective cohort study involving 35 infants with CDH. RV and LV end-diastolic volume (RVEDV and LVEDV, respectively) were measured by three-dimensional echocardiography and were corrected by birth body weight (BBW) on day 1. RVEDV/BBW, LVEDV/BBW, and LVEDV/RVEDV were compared between CDH survivors and non-survivors. Receiver-operating characteristic curve analysis was performed to assess the predictive ability for mortality of the echocardiographic parameters.ResultsComparing CDH non-survivors (n = 6) with survivors (n = 29), respectively, RVEDV/BBW was significantly larger (2.54 ± 0.33 vs 1.86 ± 0.35 ml/kg; P < 0.01), LVEDV/BBW was significantly smaller (0.86 ± 0.21 vs 1.22 ± 0.33 ml/kg; P < 0.001), and LVEDV/RVEDV was significantly lower (0.34 ± 0.06 vs 0.66 ± 0.18; P < 0.001). The area under the curve for LVEDV/RVEDV was the largest (0.98).ConclusionsThree-dimensional echocardiographic volume imbalance between the RV and LV was remarkable in CDH non-survivors. The LVEDV/RVEDV ratio may be associated with mortality in CDH.ImpactMortality with congenital diaphragmatic hernia (CDH) is high, and evaluating left and right ventricular structures and functions may be helpful in assessing the prognosis.Three-dimensional (3D) echocardiography indicated that the left ventricular end-diastolic volume/right ventricular end-diastolic volume ratio within 24 h after birth was associated with mortality in CDH infants.The usefulness of this ratio should be validated in prospective multicenter studies involving larger numbers of patients.

Seasonal Variation of Congenital Diaphragmatic Hernia: A Review of the Literature and Database Report from the United States and Canada.

The etiology of congenital diaphragmatic hernia (CDH) remains unknown and only 10 to 30% of patients have a genetic cause. Seasonal variation is known to contribute to the development of some congenital anomalies. Our aim was to investigate whether CDH births have seasonal variation. A literature review was conducted for CDH and seasonality. Moreover, data from the CDH International Patient Registry Database were collected for infants with due dates between 2008 and 2014. Due dates were used to determine seasonal distribution of births. Birth rates per month in the United States and Canada were extracted from publicly available databases. Data were analyzed using analysis of variance and contingency tables. First, the literature review revealed 11 articles, of which 3 were eligible for inclusion. These studies reported conflicting results on seasonality of CDH. Second, we extracted due dates from the CDH International Patient Registry Database (1,259 patients) and found that there were fewer due dates in winter months (12.1 ± 4 patients/month) than in summer (16.7 ± 6 patients/month; p = 0.011) and fall months (16.3 ± 5 patients/month; p = 0.022). Although this trend was similar to that of all births in the United States and Canada, a lower incidence was observed in winter for CDH infants (20.2%) than for the general population (24.1%, p = 0.0012). CDH survival rate did not vary by season. This study provides evidence for a seasonal variation of CDH births. No causative link was established between CDH development and seasonality. Population-based studies with a focus on exposome data are needed to explain seasonal variation in CDH.

Neuropsychological outcome in survivors of congenital diaphragmatic hernia at 5 years of age, what does it tell?

Previous studies have frequently reported neurocognitive deficits in children born with congenital diaphragmatic hernia (CDH) at school age, which may contribute to academic difficulties. Yet, age at onset of these deficits is currently unknown. We evaluated neurocognitive skills with possible determinants in preschool children born with CDH. Eligible 5-year-old children born with CDH (2010–2015) who participated in our prospective structural follow-up program were included. We used the WPPSI-III to assess intelligence, subtests of the Kaufman-ABC for memory, and NEPSY-II to assess inhibition and attention. We included 63 children. Their test scores generally were within or significantly above normal range: total IQ = 103.4 (15.7) (p = 0.13); Verbal memory = 10.2 (2.8) (p = 0.61); Visuospatial memory = 11.4 (2.6) (p < 0.01); Inhibition = 10.5 (2.2), (p = 0.10). In univariable analyses, length of ICU-stay was negatively associated with IQ, and maximum vasoactive inotropic score and open repair were negatively associated with inhibition skills. In multivariable regression analysis, the latter association remained (B = 5.52, p = 0.04 (CI 0.32–10.72)).   Conclusions: In these tested 5-year-old children born with CDH, neuropsychological outcome was normal on average. While problems in 8-year-olds are common, we did not detect onset of these problems at age 5. Yet, we cannot rule out that this cohort had a relatively mild level of disease severity; therefore, conclusions should be interpreted with caution. However, given the growing-into-deficit hypothesis, meaning that deviant brain development in early life is revealed once higher cognitive brain functions are demanded, follow-up should be conducted up to school age, and preferably beyond.What is Known:• Children born with CDH are at risk for academic difficulties at school age.• Whether these difficulties can be detected already before school age is unknown.What is New:• At age 5 years, intelligence, inhibition, attention, and memory skills were all within normal range, or even above, in children with CDH. This is supportive of the growing-into-deficit hypothesis in this patient population.• Those who underwent open surgical correction had poorer inhibition skills than those who were corrected with minimal access surgery.

Impact of bowel rotation and fixation on obstructive complications in congenital diaphragmatic hernia

Aim of the studySmall bowel obstruction (SBO) is a known complication after congenital diaphragmatic hernia (CDH) repair, which can require surgery and even extensive bowel resection causing short bowel syndrome (SBS). We investigate whether specific bowel rotation and fixation can be used as a predictor for SBO including volvulus. MethodsA retrospective review of 256 CDH survivors following repair from 2003 to 2020 was performed. Operative notes and upper gastrointestinal series (UGI) were screened to determine the rotation and fixation of the bowel. Primary outcomes included SBO occurrence, SBO treated surgically, and volvulus. For statistical analysis Fisher's exact test was utilized. ResultsTwenty-two (9%) patients presented with SBO and majority, 19 (86%), required surgery. Adhesion were observed in 10 (45%), recurrence in 5 (23%), and extensive volvulus leading to SBS in 3 (14%). Both rotation and fixation were recorded in 117 (46%). Presence of left CDH with malrotation and nonfixation was a significant predictor for SBO requiring surgery (P<0.05 vs all other groups). All 3 patients with extensive volvulus had left CDH with nonfixed bowel (100%), however only 1 had malrotation (33%). ConclusionsMalrotation and nonfixation are associated with increased SBO in CDH. Normal rotation is not protective and patients are still at risk for volvulus resulting in SBS. SBO requiring surgical intervention is common in CDH. Bowel rotation and fixation are important determinants that, should be routinely documented and education about the risk of SBO should be included in family counseling. Level of EvidenceLevel IV – Case Series

Proteomic Profiling of Hypoplastic Lungs Suggests an Underlying Inflammatory Response in the Pathogenesis of Abnormal Lung Development in Congenital Diaphragmatic Hernia.

The pathogenesis of lung hypoplasia in congenital diaphragmatic hernia (CDH), a common birth defect, is poorly understood. The diaphragmatic defect can be repaired surgically, but the abnormal lung development contributes to a high mortality in these patients. To understand the underlying pathobiology, we compared the proteomic profiles of fetal rat lungs at the alveolar stage (E21) that were either exposed to nitrofen in utero (CDH lungs, n=5) or exposed to vehicle only (non-CDH control lungs, n=5). Pathway analysis of proteomic datasets showed significant enrichment in inflammatory response proteins associated with cytokine signaling and Epstein Barr Virus in nitrofen CDH lungs. Among the 218 significantly altered proteins between CDH and non-CDH control lungs were Tenascin C, CREBBP, LYN, and STAT3. We showed that Tenascin C was decreased around the distal airway branches in nitrofen rat lungs and human CDH lungs, obtained from stillborn fetuses that did not receive pre- or postnatal treatment. In contrast, STAT3 was significantly increased in the airway epithelium of nitrofen lungs at E21. STAT3 inhibition after direct nitrofen exposure to fetal rat lung explants (E14.5) partially rescued the hypoplastic lung phenotype ex vivo by increasing peripheral lung budding. Moreover, we demonstrated that several STAT3-associated cytokines (IL-15, IL-9, andIL-2) are increased in fetal tracheal aspirates of CDH survivors compared with nonsurvivors after fetoscopic endoluminal tracheal occlusion. With our unbiased proteomics approach, we showed for the first time that downstream inflammatory processes are likely involved in the pathogenesis of abnormal lung development in CDH.

Long-Term Outcomes of Congenital Diaphragmatic Hernia: Report of a Multicenter Study in Japan.

Background: Treatment modalities for neonates with congenital diaphragmatic hernia (CDH) have greatly improved in recent years, with a concomitant increase in survival. However, long-term outcomes restrict the identification of optimal care pathways for CDH survivors in adolescence and adulthood. Therefore, we evaluated the long-term outcomes within the Japanese CDH Study Group (JCDHSG). Methods: Participants were born with CDH between 2006 and 2018 according to the JCDHSG. Participants were enrolled in the database at 1.5, 3, 6, and 12 years old. Follow-up items included long-term complications, operations for long-term complication, and home medical care. Results: A total of 747 patients were included in this study, with 626 survivors (83.8%) and 121 non-survivors (16.2%). At 1.5, 3, 6, and 12 years old, 45.4%, 36.5%, 34.8%, and 43.6% developed complications, and 20.1%, 14.7%, 11.5%, and 5.1% of participants required home care, respectively. Recurrence, pneumonia, pneumothorax, gastroesophageal reflux disease, and intestinal obstruction decreased with age, and thoracic deformity increased with age. Conclusions: As CDH survival rates improve, there is a need for continued research and fine-tuning of long-term care to optimize appropriate surveillance and long-term follow-up.

Small Bowel Obstruction After Neonatal Repair of Congenital Diaphragmatic Hernia-Incidence and Risk-Factors Identified in a Large Longitudinal Cohort-Study.

ObjectiveIn patients with a congenital diaphragmatic hernia (CDH), postoperative small bowel obstruction (SBO) is a life-threatening event. Literature reports an incidence of SBO of 20% and an association with patch repair and ECMO treatment. Adhesions develop due to peritoneal damage and underly various biochemical and cellular processes. This longitudinal cohort study is aimed at identifying the incidence of SBO and the risk factors of surgical, pre-, and postoperative treatment.MethodsWe evaluated all consecutive CDH survivors born between January 2009 and December 2017 participating in our prospective long-term follow-up program with a standardized protocol.ResultsA total of 337 patients were included, with a median follow-up of 4 years. SBO with various underlying causes was observed in 38 patients (11.3%) and significantly more often after open surgery (OS). The majority of SBOs required surgical intervention (92%). Adhesive SBO (ASBO) was detected as the leading cause in 17 of 28 patients, in whom surgical reports were available. Duration of chest tube insertion [odds ratio (OR) 1.22; 95% CI 1.01–1.46, p = 0.04] was identified as an independent predictor for ASBO in multivariate analysis. Beyond the cut-off value of 16 days, the incidence of serous effusion and chylothorax was higher in patients with ASBO (ASBO/non-SBO: 2/10 vs. 3/139 serous effusion, p = 0.04; 2/10 vs. 13/139 chylothorax, p = 0.27). Type of diaphragmatic reconstruction, abdominal wall closure, or ECMO treatment showed no significant association with ASBO. A protective effect of one or more re-operations has been detected (RR 0.16; 95% CI 0.02–1.17; p = 0.049).ConclusionThoracoscopic CDH repair significantly lowers the risk of SBO; however, not every patient is suitable for this approach. GoreTex®-patches do not seem to affect the development of ASBO, while median laparotomy might be more favorable than a subcostal incision. Neonates produce more proinflammatory cytokines and have a reduced anti-inflammatory capacity, which may contribute to the higher incidence of ASBO in patients with a longer duration of chest tube insertion, serous effusion, chylothorax, and to the protective effect of re-operations. In the future, novel therapeutic strategies based on a better understanding of the biochemical and cellular processes involved in the pathophysiology of adhesion formation might contribute to a reduction of peritoneal adhesions and their associated morbidity and mortality.

Anti-reflux surgery in children with congenital diaphragmatic hernia: A prospective cohort study on a controversial practice

IntroductionGastro-esophageal reflux disease (GERD) is the most frequent long-term morbidity of congenital diaphragmatic hernia (CDH) survivors. Performing a preventive fundoplication during CDH repair remains controversial. This study aimed to: (1) Analyze the variability in practices regarding preventive fundoplication; (2) Identify predictive factors for fundoplication.(3) Evaluate the impact of preventive fundoplication on gastro-intestinal outcomes in children with a CDH patch repair; MethodsThis prospective multi-institutional cohort study (French CDH Registry) included CDH neonates born in France between January 1st, 2010-December 31st, 2018. Patch CDH was defined as need for synthetic patch or muscle flap repair. Main outcome measures included need for curative fundoplication, tube feed supplementation, failure to thrive, and oral aversion. ResultsOf 762 CDH neonates included, 81 underwent fundoplication (10.6%), either preventive or curative. Median follow-up was 3.0 years (IQR: 1.0–5.0).(1) Preventive fundoplication is considered in only 31% of centers. The rates of both curative fundoplication (9% vs 3%, p = 0.01) and overall fundoplication (20% vs 3%, p < 0.0001) are higher in centers that perform preventive fundoplication compared to those that do not.(2) Predictive factors for preventive fundoplication were: prenatal diagnosis (p = 0.006), intra-thoracic liver (p = 0.005), fetal tracheal occlusion (p = 0.002), CDH-grade C-D (p < 0.0001), patch repair (p < 0.0001). After CDH repair, 8% (n = 51) required curative fundoplication (median age: 101 days), for which a patch repair was the only independent predictive factors identified upon multivariate analysis.(3) In neonates with patch CDH, preventive fundoplication did not decrease the need for curative fundoplication (15% vs 11%, p = 0.53), and was associated with higher rates of failure to thrive (discharge: 81% vs 51%, p = 0.03; 6-months: 81% vs 45%, p = 0.008), tube feeds (6-months: 50% vs 21%, p = 0.02; 2-years: 65% vs 26%, p = 0.004), and oral aversion (6-months: 67% vs 37%, p = 0.02; 1-year: 71% vs 40%, p = 0.03). ConclusionsChildren undergoing a CDH patch repair are at high risk of requiring a curative fundoplication. However, preventive fundoplication during a patch repair does not decrease the need for curative fundoplication and is associated with worse gastro-intestinal outcomes in children. Level of evidenceII – Prospective Study.