Update on Management and Outcomes of Congenital Diaphragmatic Hernia.

Infants with congenital diaphragmatic hernia (CDH) benefit from comprehensive multidisciplinary teams that have experience in caring for the unique and complex issues associated with CDH. Despite prenatal referral to specialized high-volume centers, advanced ventilation strategies and pulmonary hypertension management, and extracorporeal membrane oxygenation, mortality and morbidity remain high. These infants have unique and complex issues that begin in fetal and infant life, but persist through adulthood. Here we will review the literature and share our clinical care pathway for neonatal care and follow up. While many advances have occurred in the past few decades, our work is just beginning to continue to improve the mortality, but also importantly the morbidity of CDH.

Predicting neonatal outcomes in infants with giant omphalocele using prenatal magnetic resonance imaging calculated observed-to-expected fetal lung volumes.

OBJECTIVE: To examine the association between prenatal magnetic resonance imaging (MRI) based observed/expected total lung volume (O/E TLV) and outcome in neonates with giant omphalocele (GO). METHODS: Between 06/2004 and 12/2019, 67 cases with isolated GO underwent prenatal and postnatal care at our institution. MRI-based O/E TLVs were calculated based on normative data from Meyers and from Rypens and correlated with postnatal survival and morbidities. O/E TLV scores were grouped based on severity into <25% (severe), between 25% and 50% (moderate), and >50% (mild) for risk stratification. RESULTS: O/E TLV was calculated for all patients according to Meyers nomograms and for 49 patients according to Rypens nomograms. Survival for GO neonates with severe, moderate, and mild pulmonary hypoplasia based on Meyers O/E TLV categories was 60%, 92%, and 96%, respectively (p = 0.04). There was a significant inverse association between Meyers O/E TLV and risk of neonatal morbidities (p < 0.05). A similar trend was observed with Rypens O/E TLV, but associations were less often significant likely related to the smaller sample size. CONCLUSION: Neonatal outcomes are related to fetal lung size in isolated GO. Assessment of Meyers O/E TLV allows identification of GO fetuses at greatest risk for complications secondary to pulmonary hypoplasia.

Short-Term Neurodevelopmental Outcome in Congenital Diaphragmatic Hernia: The Impact of Extracorporeal Membrane Oxygenation and Timing of Repair.

OBJECTIVES: The purpose of this study was to assess the need and timing of extracorporeal membrane oxygenation in relation to congenital diaphragmatic hernia repair as modifiers of short-term neurodevelopmental outcomes. DESIGN: Retrospective study. SETTING: A specialized tertiary care center. PATIENTS: Between June 2004 and February 2016, a total of 212 congenital diaphragmatic hernia survivors enrolled in our follow-up program. Neurodevelopmental outcome was assessed at a median age of 22 months (range, 5-37) using the Bayley Scales of Infant Development, third edition. Fifty patients (24%) required extracorporeal membrane oxygenation support. Four patients (8%) were repaired prior to cannulation, 25 (50%) were repaired on extracorporeal membrane oxygenation, and 21 (42%) were repaired after decannulation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Children with congenital diaphragmatic hernia, who required extracorporeal membrane oxygenation scored on average 4.6 points lower on cognitive composite (p = 0.031) and 9.2 points lower on the motor composite (p < 0.001). Language scores were similar between groups. Mean scores for children with congenital diaphragmatic hernia repaired on extracorporeal membrane oxygenation were significantly lower for cognition (p = 0.021) and motor (p = 0.0005) outcome. Language scores were also lower, but did not reach significance. A total of 40% of children repaired on extracorporeal membrane oxygenation scored below average in all composites, whereas only 9% of the non-extracorporeal membrane oxygenation, 4% of the repaired post-extracorporeal membrane oxygenation, and 25% of the repaired pre-extracorporeal membrane oxygenation patients scored below average across all domains. Only 20% of congenital diaphragmatic hernia survivors repaired on extracorporeal membrane oxygenation support scored within the average range for all composite domains. Duration of extracorporeal membrane oxygenation support was not associated with a higher likelihood of adverse cognitive (p = 0.641), language (p = 0.147), or motor (p = 0.720) outcome. CONCLUSIONS: Need for extracorporeal membrane oxygenation in congenital diaphragmatic hernia survivors is associated with worse neurocognitive and neuromotor outcome. Need for congenital diaphragmatic hernia repair while on extracorporeal membrane oxygenation is associated with deficits in multiple domains. Overall time on extracorporeal membrane oxygenation did not impact neurodevelopmental outcome.

Enteral nutrition support for infants with pulmonary hypoplasia: A qualitative evaluation of caregiver and provider perspectives.

BACKGROUND: Enteral nutrition is a critical intervention that supports the growth of children with pulmonary hypoplasia (PH). We explored the experiences of caregivers and providers caring for children with PH to better understand gaps in knowledge transfer and identify barriers and facilitators to caregiving to inform interventions that may improve support. METHODS: This qualitative study included 10 interviews with caregivers and 10 clinical team members at a single integrated care program for children with PH. An inductive and iterative coding strategy was employed to produce a codebook. After cluster analysis, themes were generated to capture participant sentiments. RESULTS: Themes were defined along a care continuum (1) initiation, (2) adaptation, and (3) maintenance that represented distinct phases of adjustment to enteral nutrition support (1) in the perinatal period and initial neonatal intensive care unit (NICU) admission, (2) from discharge planning through the family's first days at home and establishment of a stable feeding regime, and (3) through long-term follow-up and weaning. Notable subthemes included uncertainty, partnerships in training, and obstacles to adaptation. CONCLUSIONS: Among children with PH, the caregiver-provider relationship during the perinatal and NICU course is critical to promoting caregiver adaptation to the needs of the child. Ongoing considerations to support resource alignment and transition to a stable feeding regimen may facilitate caregiver adjustment to a "new normal," culminating in successful growth and/or weaning. These findings will inform interventions focused on training curricula, discharge planning, and the provision of follow-up in the context of an integrated care program for PH.

Therapy at 30 days of life predicts lung function at 6 to 12 months in infants with congenital diaphragmatic hernia.

INTRODUCTION: Congenital diaphragmatic hernia (CDH) is associated with variable degrees of lung hypoplasia. Pulmonary support at 30 days postnatal age was found to be the strongest predictor of inpatient mortality and morbidity among CDH infants and was also associated with higher pulmonary morbidity at 1 and 5 years. It is not known, however, if there is a relationship between the need for medical therapy at 30 days of life and subsequent abnormalities in lung function as reflected in infant pulmonary function test (iPFT) measurements. OBJECTIVE: We hypothesized that CDH infants who require more intensive therapy at 30 days would have more abnormal iPFT values at the time of their first infant pulmonary function study, reflecting the more severe spectrum of lung hypoplasia. METHODS: A single-institution chart review of all CDH survivors who were enrolled in a Pulmonary Hypoplasia Program (PHP) through July 2019, and treated from 2002 to 2019 was performed. All infants were divided into groups based on their need for noninvasive (supplemental oxygen, high flow therapy, noninvasive mechanical ventilation) or invasive (mechanical ventilation, extracorporeal membrane oxygenation) respiratory assistance, bronchodilators, diuretic use, and pulmonary hypertension (PH) therapy (inhaled and/or systemic drugs) at 30 days. Descriptive and statistical analyses were performed between groups comparing subsequent lung function measurements. RESULTS: A total of 382 infants (median gestational age [GA] 38.4 [interquartile range (IQR) = 37.1-39] weeks, 41.8% female, 70.9% Caucasian) with CDH were enrolled in the PHP through July 2019, and 118 infants underwent iPFT. The median age of the first iPFT was 6.6 (IQR = 5.3-11.7) months. Those requiring any pulmonary support at 30 days had a higher functional residual capacity (FRC) (z) (P = .03), residual volume (RV) (z) (P = .008), ratio of RV to total lung capacity (RV/TLC) (z) (P = .0001), and ratio of FRC to TLC (FRC/TLC) (z) (P = .001); a lower forced expiratory volume at 0.5 seconds (FEV0.5) (z) (P = .03) and a lower respiratory system compliance (Crs) (P = .01) than those who did not require any support. Similarly, those requiring diuretics and/or PH therapy at 30 days had higher fractional lung volumes, lower forced expiratory flows and Crs than infants who did not require such support (P < .05). CONCLUSIONS: Infants requiring any pulmonary support, diuretics and/or PH therapy at 30 postnatal days have lower forced expiratory flows and higher fractional lung volumes, suggesting a greater degree of lung hypoplasia. Our study suggests that the continued need for PH, diuretic or pulmonary support therapy at 30 days can be used as additional risk-stratification measurements for evaluation of infants with CDH.

Autism spectrum disorder and neurodevelopmental delays in children with giant omphalocele.

OBJECTIVE: To determine the prevalence and identify risk factors of autism spectrum disorders (ASDs) and neurodevelopmental delays in giant omphalocele (GO) survivors. MATERIALS AND METHODS: The study cohort consists of 47 GO survivors enrolled in our follow-up program between 07/2004 and 12/2015. All patients underwent assessments at 2 years of age or older. Outcomes were assessed by either the Bayley Scales of Infant Development II (prior 2006) or III (after 2006), or the Wechsler Preschool and Primary Scale of Intelligence (children older than 4 years). ASD diagnosis was made based on the Diagnostic and Statistical Manual of Mental Disorders IV (prior to 2014) or 5 criteria. RESULTS: The prevalence of ASD in GO children is 16 times higher than the general population (P = 0.0002). ASD patients were more likely to be diagnosed with neurodevelopmental and neurofunctional delays, language disorders, and genetic abnormalities (P < 0.01). While 53.2% of GO children scored within the average range for all developmental domains, 19.1% scored within the mildly delayed and 27.7% in the severe delayed range in at least one domain. Prolonged respiratory support, pulmonary hypertension, gastroesophageal reflux disease, feeding problems, prolonged hospitalization, abnormal BAER hearing screen, presence of delayed motor coordination, and hypotonicity were associated with delayed scores (P < 0.05). CONCLUSIONS: There is a significant rate of ASD in GO survivors. Neurodevelopmental delays, language delays, and genetic abnormalities were strongly associated with ASD. Neurological impairments were present in nearly half of GO children. Surrogate markers of disease severity were associated with below average neurodevelopmental scores. Level of evidence Level IV.

Rate and Risk Factors Associated with Autism Spectrum Disorder in Congenital Diaphragmatic Hernia.

To determine the rate and predictors of autism spectrum disorder (ASD) in congenital diaphragmatic hernia (CDH). Between 06/2004 and 09/2015 a total of 110 CDH survivors underwent neurodevelopmental (ND) testing and screening for ASD, followed by a full autism diagnostic evaluation if indicated at our institution. We found a 9 time higher rate of ASD in CDH children compared to the general population (P = 0.0002). Multiple patient-related and clinical variables risk factors of ASD were identified by univariate analysis. However, only short-term and long-term neurodevelopmental delays were strongly associated with ASD in CDH by multivariate comparisons. There is a striking prevalence of ASD in CDH survivors and our findings suggest that all CDH children should be regularly screened for ASD.

Reduced oxygen concentration for the resuscitation of infants with congenital diaphragmatic hernia.

OBJECTIVE: To evaluate whether infants with congenital diaphragmatic hernia (CDH) can be safely resuscitated with a reduced starting fraction of inspired oxygen (FiO2) of 0.5. STUDY DESIGN: A retrospective cohort study comparing 68 patients resuscitated with starting FiO2 0.5 to 45 historical controls resuscitated with starting FiO2 1.0. RESULTS: Reduced starting FiO2 had no adverse effect upon survival, duration of intubation, need for ECMO, duration of ECMO, or time to surgery. Furthermore, it produced no increase in complications, adverse neurological events, or neurodevelopmental delay. The need to subsequently increase FiO2 to 1.0 was associated with female sex, lower gestational age, liver up, lower lung volume-head circumference ratio, decreased survival, a higher incidence of ECMO, longer time to surgery, periventricular leukomalacia, and lower neurodevelopmental motor scores. CONCLUSION: Starting FiO2 0.5 may be safe for the resuscitation of CDH infants. The need to increase FiO2 to 1.0 during resuscitation is associated with worse outcomes.

Short-Term Neurodevelopmental Outcome in Children Born With High-Risk Congenital Lung Lesions.

BACKGROUND: This study sought to evaluate neurodevelopmental outcome in survivors of high-risk congenital lung lesions (CLLs) who underwent prenatal intervention or postnatal surgery within the first month of life. METHODS: Forty-five high-risk CLL survivors underwent assessment using the Bayley Scales of Infant Development, 3rd Edition between July 2004 and December 2016. Scores were grouped as average, at-risk, and delayed based on SD intervals. Correlations between outcome and risk factors were analyzed by Fisher's exact test or two-sided t test as appropriate, with significant p values <0.05. RESULTS: Open prenatal intervention was required in 13 (28.9%) children (fetal surgical resection, n = 4 , ex utero intrapartum treatment, n = 9), whereas 32 (71.1%) children had respiratory distress postnatally and required resection within the first month of life. Mean age at follow-up was 19.3 ± 10.3 months. Mean composite scores were within the expected average range. A total of 62.2% scored within the average range for all domains. At-risk scores were found in 26.7% of children in at least one domain, and 11.1% had delays in at least one domain. Neurodevelopmental outcome was similar between treatment groups. Prolonged ventilator support and neonatal intensive care unit stay, need for supplemental oxygen at day of life 30, gastroesophageal reflux disease, and delayed enteral feeding were associated with neurologic delays (all p < 0.05). CONCLUSIONS: Neurodevelopmental scores for high-risk CLL survivors in infancy and toddlerhood are age appropriate. Neither fetal intervention nor the need for postnatal resection within the first month of life increases the risk of delays. Surrogate markers of a complicated neonatal course are predictive of adverse outcome.

Neurodevelopmental outcomes at 5years of age in congenital diaphragmatic hernia.

OBJECTIVE: To evaluate neurodevelopmental sequelae in congenital diaphragmatic hernia (CDH) children at 5years of age. MATERIALS AND METHODS: The study cohort of 35 CDH patients was enrolled in our follow-up program between 06/2004 and 09/2014. The neurodevelopmental outcomes assessed at a median of 5years (range, 4-6) included cognition (Wechsler Preschool and Primary Scale of Intelligence [WPPSI], n=35), Visual-Motor-Integration (n=35), academic achievement (Woodcock-Johnson Tests of Achievement, n=25), and behavior problems (Child Behavior Check List [CBCL], n=26). Scores were grouped as average, borderline, or extremely low by SD intervals. RESULTS: Although mean Full (93.9±19.4), Verbal (93.4±18.4), and Performance (95.2±20.9) IQ were within the expected range, significantly more CDH children had borderline (17%) and extremely low (17%) scores in at least one domain compared to normative cohorts (P<0.02). The Visual-Motor-Integration score was below population average (P<0.001). Academic achievement scores were similar to expected means for those children who were able to complete testing. CBCL scores for the emotionally reactive (23%) and pervasive developmental problems scales (27%) were more likely to be abnormal compared to normal population scores (P=0.02 and P=0.0003, respectively). Autism was diagnosed in 11%, which is significantly higher than the general population (P<0.01). Univariate analysis suggests that prolonged NICU stay, prolonged intubation, tracheostomy placement, pulmonary hypertension, autism, hearing impairment, and developmental delays identified during infancy are associated with worse cognitive outcomes (P<0.05). CONCLUSION: The majority of CDH children have neurodevelopmental outcomes within the average range at 5years of age. However, rates of borderline and extremely low IQ scores are significantly higher than in the general population. CDH survivors are also at increased risk for developing symptoms of emotionally reactive and pervasive developmental problems. Risk of autism is significantly elevated. Disease severity and early neurological dysfunction appear to be predictive of longer-term impairments.

Growth trajectory and neurodevelopmental outcome in infants with congenital diaphragmatic hernia.

PURPOSE: The purpose of this study was to evaluate the impact of impaired growth on short-term neurodevelopmental (ND) outcomes in CDH survivors. METHODS: Between 9/2005-12/2014, 84 of 215 (39%) CDH survivors underwent ND assessment at 12months of age using the BSID-III. RESULTS: Mean cognitive, language, and motor scores were 92.6±13.5, 87.1±11.6, and 87.0±14.4, respectively (normal 100±15). 51% of patients scored 1 SD below the population mean in at least one domain, and 13% scored 2 SD below the population mean. Group-based trajectory analysis identified two trajectory groups ('high' and 'low') for weight, length, and head circumference (HC) z-scores. (Fig. 1) 74% of the subjects were assigned to the 'high' trajectory group for weight, 77% to the 'high' height group, and 87% to the 'high' HC group, respectively. In multivariate analysis, longer NICU stay (p<0.01) was associated with lower cognitive scores. Motor scores were 11 points higher in the 'high' HC group compared to the 'low' HC group (p=0.05). Motor scores were lower in patients with longer NICU length of stay (p<0.001). CONCLUSIONS: At 1 year, half of CDH survivors had a mild delay in at least one developmental domain. Low HC trajectory was associated with worse neurodevelopmental outcomes. TYPE OF STUDY: Prognosis Study/Retrospective Study. LEVEL OF EVIDENCE: Level II.

Management and outcomes of scoliosis in children with congenital diaphragmatic hernia.

PURPOSE: The purpose of this study was to evaluate the management and outcomes of CDH patients with scoliosis. METHODS: From January 1996 to August 2015, 26 of 380 (7%) CDH patients were diagnosed with scoliosis. Six (23%) were prenatally diagnosed by ultrasound, and 9 (35%) were diagnosed postnatally. The remaining 11 (42%) developed scoliosis after discharge. Mean follow-up was 6.6years. RESULTS: Among the 15 patients with congenital scoliosis, there were 2 (13%) perinatal deaths. Five of the 13 (38%) survivors required orthopedic surgery, and 2 have required bracing. The mean age at initial surgery was 7years. These five children underwent an average of 2.8 (range 1-7) expansions or revisions. All surgical patients required supplemental oxygen at 28days of life, and 1 required a tracheostomy. None of the 11 patients who developed scoliosis later in life required surgery, but 3 have required bracing. Six of the 11 (55%) required a patch repair for CDH compared to 158 of 264 (60%) CDH patients without scoliosis (p=0.73). CONCLUSIONS: Early diagnosis of scoliosis in CDH patients is associated with a high rate of surgery. There was not a higher incidence of patch repair among patients who developed scoliosis. LEVEL OF EVIDENCE: Prognosis. Retrospective study, level II.

Younger gestational age is associated with increased risk of adverse neurodevelopmental outcome during infancy in congenital diaphragmatic hernia.

BACKGROUND: The purpose of the study was to investigate the impact of gestational age (GA) on short-term neurodevelopmental (ND) outcomes in congenital diaphragmatic hernia survivors. MATERIALS: Between 6/2004 and 2/2013, 135 consecutive CDH patients underwent ND assessment using the Bayley Scales of Infant Development-III at a median follow-up age of 13months (range, 5-36). ND delay was defined by a score of ≤85 in any of the composite scales. Severe impairment was defined as a score of ≤69 in at least one domain. The effect of GA was evaluated as continuous and categorical variables. GA at delivery was grouped into full term (39-41weeks), near term (37-38), late preterm (34-36), and preterm (24-33). RESULTS: Median GA at delivery was 38weeks (range, 24-41). Fifty (37%) patients were delivered full term, 59 (44%) near term, 16 (12%) late preterm, and 10 (7%) preterm. CDH children born before 39weeks' gestation were more likely to score below average (P=0.005) with corrected age for at least one composite score compared to full term peers. Cognitive (P=0.06) and language (P=0.08) scores tended to be lower in the near-term and late-preterm group compared to full-term CDH infants. Patients born near term and late preterm had significantly lower motor composite and fine motor scores compared to full-term children (P=0.009 and P<0.01, respectively). Preterm children scored the lowest in all composite scales (P<0.05). CONCLUSIONS: Compared to term infants, not only preterm but also late preterm and near-term CDH children carry an increased risk of ND delays. Motor performance appears most susceptible to earlier delivery.

Timing of repair of congenital diaphragmatic hernia in patients supported by extracorporeal membrane oxygenation (ECMO).

PURPOSE: The optimal timing of repair for congenital diaphragmatic hernia (CDH) in patients requiring extracorporeal membrane oxygenation (ECMO) is controversial. Repair during ECMO may improve respiratory function by restoring normal anatomy. However, there is increased risk of complications including surgical bleeding. The purpose of this study was to examine the impact of timing of CDH repair on outcomes in a large cohort of patients treated at a single institution. METHODS: We retrospectively reviewed charts of all CDH patients in our Pulmonary Hypoplasia Program from 2004 to 2013. Categorical variables were analyzed by Fisher's exact test and continuous variables by Mann-Whitney t-test (p<0.05). RESULTS: A total of 77 CDH patients required ECMO support during the study dates. Of these, 16 patients did not survive to repair, 3 patients were repaired prior to cannulation, 41 patients were repaired during ECMO, and 17 patients were repaired after decannulation. Survival was 67%, 43.9%, and 100% for those repaired prior to, during, or post ECMO, respectively, with statistical significance associated with repair after decannulation (P<0.0001). Operative bleeding requiring transfusion occurred in 12 patients repaired on ECMO, while no significant bleeding occurred in patients repaired after decannulation (P=0.003). CONCLUSION: Outcomes were improved in CDH patients undergoing surgical repair following ECMO with significantly increased survival, lower rates of surgical bleeding, and decreased total duration of ECMO therapy compared to patients repaired on ECMO. In patients who can be successfully weaned from ECMO, our study supports a role for delayed repair off ECMO with reduced operative morbidity and increased survival.

Patient characteristics are important determinants of neurodevelopmental outcome during infancy in giant omphalocele.

OBJECTIVE: To examine patient-specific factors as potential predictors of neurodevelopmental (ND) outcome in children with giant omphalocele (GO). MATERIALS: Between 06/2005 and 07/2012, 31 consecutive GO survivors underwent ND assessment using the BSID-III at a median of 24months (range 6-35). ND delay was defined by a score of ≤84 in any composite score. Severe impairments were defined as a score of ≤69 in at least one domain. Correlations between ND outcome and patient-specific factors were analyzed by one-way ANOVA, chi-square, or logistic regression as appropriate. RESULTS: The mean cognitive score (86.8±16.8) was in the low average range. Mean language (83.2±21.1) and motor (81.5±16.2) scores were below average. Forty-six-percent scored within the average range for all scales. Mild deficits were found in 19%, and 35% had severe delays in at least one domain. Hypotonicity was present in 55%. Autism was suspected/confirmed in 13%. Predictors of lower ND scores were prolonged ventilator support (P<0.01), high-frequency oscillatory ventilation (P<0.01), tracheostomy placement (P<0.001), O2 supplementation at day of life 30 (P<0.02), pulmonary hypertension (P<0.02), delayed enteral feeding (P=0.01), need for feeding tube (P<0.001), GERD (P=0.05), abnormal BAER hearing screen (P<0.006), prolonged hospitalization (P=0.01), and failure to thrive (P=0.001). Autism was associated with delays in cognitive and language outcomes (P<0.03). Delayed staged closure (P=0.007), older age at final repair (P=0.03), and hypotonicity (P=0.02) were associated with motor dysfunction. CONCLUSIONS: Neurological impairments were present in more than half of GO survivors. Disease severity was associated with ND dysfunction. Autism and hypotonicity were often co-morbidities with ND delays and poor motor function.

Incidence and factors associated with sensorineural and conductive hearing loss among survivors of congenital diaphragmatic hernia.

PURPOSE: The reported incidence of sensorineural hearing loss (SNHL) in long-term survivors of congenital diaphragmatic hernia varies widely in the literature. Conductive hearing loss (CHL) is also known to occur in CDH patients, but has been less widely studied. We sought to characterize the incidence and risk factors associated with SNHL and CHL in a large cohort of CDH patients who underwent standardized treatment and follow-up at a single institution. METHODS: We retrospectively reviewed charts of all CDH patients in our pulmonary hypoplasia program from January 2004 through December 2012. Categorical variables were analyzed by Fisher's exact test and continuous variables by Mann-Whitney t-test (p≤0.05). RESULTS: A total of 112 patients met study inclusion criteria, with 3 (2.7%) patients diagnosed with SNHL and 38 (34.0%) diagnosed with CHL. SNHL was significantly associated with requirement for ECMO (p=0.0130), prolonged course of hospitalization (p=0.0011), duration of mechanical ventilation (p=0.0046), requirement for tracheostomy (p=0.0013), and duration of loop diuretic (p=0.0005) and aminoglycoside therapy (p=0.0003). CONCLUSIONS: We have identified hearing anomalies in over 30% of long-term CDH survivors. These findings illustrate the need for routine serial audiologic evaluations throughout childhood for all survivors of CDH and stress the importance of targeted interventions to optimize long-term developmental outcomes pertaining to speech and language.