Association between pulmonary vein stenosis and necrotizing enterocolitis or gastrointestinal pathology: A case-control study.

Objective: Pulmonary vein stenosis (PVS) is an emerging cause of pulmonary hypertension in preterm infants. It is an often lethal condition with poor long.term prognosis and high mortality. Previous work suggests an association between necrotizing enterocolitis (NEC) and PVS, supporting a possible role for inflammatory processes due to gastrointestinal (GI) pathology as an associated risk factor for PVS. Study Description: We performed a matched case-control study where infants with PVS were matched for gestational age with infants without PVS. Hospital records were reviewed for prior history of NEC or other gut pathology. Results: Twenty-four PVS patients were matched with 68 controls; 63% of patients (15/24) had prior GI pathology as opposed to 19% (13/68) of controls. The GI pathology group had a significantly higher growth restriction and C-reactive protein. The mean gradient across the pulmonary veins was higher in the gut pathology group versus controls, as was mortality (29% vs. 9%). Conclusions: The previously described association between PVS and intestinal pathology was further strengthened by this study. The presence of GI pathology should lead to early surveillance and intervention for PVS.

Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 as candidate risk gene.

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease-associated genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (lon peptidase 1, mitochondrial) and ALYREF (Aly/REF export factor) as candidate CDH-associated genes on the basis of de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 affected individuals and 11,220 ancestry-matched population control individuals and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in affected familial individuals. Approximately 3% of our CDH cohort who are heterozygous with ultra-rare predicted damaging variants in LONP1 have a range of clinical phenotypes, including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium-specific deletion of Lonp1 die immediately after birth, most likely because of the observed severe reduction of lung growth, a known contributor to the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies.

Likely damaging de novo variants in congenital diaphragmatic hernia patients are associated with worse clinical outcomes.

PURPOSE: Congenital diaphragmatic hernia (CDH) is associated with significant mortality and long-term morbidity in some but not all individuals. We hypothesize monogenic factors that cause CDH are likely to have pleiotropic effects and be associated with worse clinical outcomes. METHODS: We enrolled and prospectively followed 647 newborns with CDH and performed genomic sequencing on 462 trios to identify de novo variants. We grouped cases into those with and without likely damaging (LD) variants and systematically assessed CDH clinical outcomes between the genetic groups. RESULTS: Complex cases with additional congenital anomalies had higher mortality than isolated cases (P = 8 × 10-6). Isolated cases with LD variants had similar mortality to complex cases and much higher mortality than isolated cases without LD (P = 3 × 10-3). The trend was similar with pulmonary hypertension at 1 month. Cases with LD variants had an estimated 12-17 points lower scores on neurodevelopmental assessments at 2 years compared with cases without LD variants, and this difference is similar in isolated and complex cases. CONCLUSION: We found that the LD genetic variants are associated with higher mortality, worse pulmonary hypertension, and worse neurodevelopment outcomes compared with non-LD variants. Our results have important implications for prognosis, potential intervention and long-term follow up for children with CDH.

Improving Neonatal Follow-up: A Quality Improvement Study Analyzing In-hospital Interventions and Long-term Show Rates.

Neonatal follow-up (NFU) clinics play an essential role in the multidisciplinary care of preterm patients. Despite the inherent value of NFU clinics, many clinical programs report poor compliance with follow-up visits. Preterm infants followed with difficulty in the long-term have higher rates of disability and lower IQ scores, even after adjustment of significant perinatal and sociodemographic variables. This quality improvement study aimed to improve the show rate for preterm infants from 60% to 80% at the initial 6-month adjusted age visit by implementing a multilevel education bundle. METHODS: Participants included neonatal intensive care unit (NICU) physicians, physician extenders, registered nurses, and parents of preterm patients admitted to the NICU who qualified for NFU. Our 75-bed NICU is the regional perinatal center within an urban free-standing children's hospital. Our bundle included NICU provider education, discharge planning, and parent education. A tracking system was developed to identify qualifying patients to streamline workflow. RESULTS: The monthly first visit show rate improved from 60% to 76% during the intervention period. Seventy-five percent of families who received parent education presented for their initial visit, compared to 51% of families who did not receive parent education. In anonymous surveys of families who presented for their initial visits, 95% indicated that bedside education played the most important role in appointment attendance. Interdisciplinary rounds are crucial for reaching all families before discharge. CONCLUSION: Implementing a multidimensional in-hospital education bundle and tracking system is feasible and can improve NFU clinic show rates, but may require dedicated personnel for sustainability.

Comparative outcomes of right versus left congenital diaphragmatic hernia: A multicenter analysis.

BACKGROUND: Congenital diaphragmatic hernia (CDH) occurs in 1 out of 2500-3000 live births. Right-sided CDHs (R-CDHs) comprise 25% of all CDH cases, and data are conflicting on outcomes of these patients. The aim of our study was to compare outcomes in patients with right versus left CDH (L-CDH). METHODS: We analyzed a multicenter prospectively enrolled database to compare baseline characteristics and outcomes of neonates enrolled from January 2005 to January 2019 with R-CDH vs. L-CDH. RESULTS: A total of 588, 495 L-CDH, and 93 R-CDH patients with CDH were analyzed. L-CDHs were more frequently diagnosed prenatally (p=0.011). Lung-to-head ratio was similar in both cohorts. R-CDHs had a lower frequency of primary repair (p=0.022) and a higher frequency of need for oxygen at discharge (p=0.013). However, in a multivariate analysis, need for oxygen at discharge was no longer significantly different. There were no differences in long-term neurodevelopmental outcomes assessed at two year follow up. There was no difference in mortality, need for ECMO, pulmonary hypertension, or hernia recurrence. CONCLUSION: In this large series comparing R to L-CDH patients, we found no significant difference in mortality, use of ECMO, or pulmonary complications. Our study supports prior studies that R-CDHs are relatively larger and more often require a patch or muscle flap for repair. TYPE OF STUDY: Prognosis study LEVEL OF EVIDENCE: Level II.

Resting energy expenditure in infants with congenital diaphragmatic hernia without respiratory support at time of neonatal hospital discharge.

BACKGROUND: Infants with congenital diaphragmatic hernia (CDH) are at risk for growth failure because of inadequate caloric intake and high catabolic stress. There is limited data on resting energy expenditure (REE) in infants with CDH. AIMS: To assess REE via indirect calorimetry (IC) in term infants with CDH who are no longer on respiratory support and nearing hospital discharge with advancing post-conceptional age and to assess measured-to-predicted REE using predictive equations. METHODS: A prospective cohort study of term infants with CDH who were no longer on respiratory support and nearing hospital discharge was conducted to assess REE via IC and caloric intake. Baseline characteristics and hospital course data were collected. Three day average caloric intake around time of IC testing was calculated. Change in REE with advancing post-conceptional age and advancing post-natal age was assessed. The average measured-to-predicted REE was calculated for the cohort using predictive equations [22]. RESULTS: Eighteen infants with CDH underwent IC. REE in infants with CDH increased with advancing postconceptional age (r2 = 0.3, p < 0.02). The mean REE for the entire group was 53.2 +/- 10.9 kcal/kg/day while the mean caloric intake was 101.2 +/- 17.4 kcal/kg/day. The mean measured-to-predicted ratio for the cohort was in the normal metabolic range (1.10 +/- 0.17) with 50% of infants considered hypermetabolic and 11% of infants considered hypo-metabolic. CONCLUSIONS: Infant survivors of CDH repair who are without respiratory support at time of neonatal hospital discharge have REE, as measured by indirect calorimetry, that increases with advancing post-conceptional age and that is within the normal metabolic range when compared to predictive equations. LEVEL OF EVIDENCE: III.

Improvement of Immediate Performance in Neonatal Resuscitation Through Rapid Cycle Deliberate Practice Training.

BACKGROUND: Simulation training is an effective method to teach neonatal resuscitation (NR), yet many pediatrics residents do not feel comfortable with NR. Rapid cycle deliberate practice (RCDP) allows the facilitator to provide debriefing throughout the session. In RCDP, participants work through the scenario multiple times, eventually reaching more complex tasks once basic elements have been mastered. OBJECTIVE: We determined if pediatrics residents have improved observed abilities, confidence level, and recall in NR after receiving RCDP training compared to the traditional simulation debriefing method. METHODS: Thirty-eight pediatrics interns from a large academic training program were randomized to a teaching simulation session using RCDP or simulation debriefing methods. The primary outcome was the intern's cumulative score on the initial Megacode Assessment Form (MCAF). Secondary outcome measures included surveys of confidence level, recall MCAF scores at 4 months, and time to perform critical interventions. RESULTS: Thirty-four interns were included in analysis. Interns in the RCDP group had higher initial MCAF scores (89% versus 84%, P < .026), initiated positive pressure ventilation within 1 minute (100% versus 71%, P < .05), and administered epinephrine earlier (152 s versus 180 s, P < .039). Recall MCAF scores were not different between the 2 groups. CONCLUSIONS: Immediately following RCDP interns had improved observed abilities and decreased time to perform critical interventions in NR simulation as compared to those trained with the simulation debriefing. RCDP was not superior in improving confidence level or retention.

Constructing a Culturally Informed Spanish Decision-Aid to Counsel Latino Parents Facing Imminent Extreme Premature Delivery.

Objective How Latino parents perceive and understand antenatal counseling for extreme prematurity, < 26 weeks of gestational age (GA), is not clear. We aim to characterize Latino parental perceptions of antenatal counseling in order to construct and validate a Spanish decision-aid (SDA) to improve parental knowledge of prematurity after antenatal consults. Methods This is a three-phased, prospective, multicenter study. First, interviews of 22 Latino parents with a history of birth < 26 weeks GA were conducted. Thematic analysis identified themes valued during antenatal counseling for decisions regarding neonatal resuscitation. Next, we incorporated these themes into the SDA. Finally, improvement in knowledge of prematurity in two Spanish-speaking groups, 'experienced' parents with a history of extremely premature birth and 'naïve' adult Latino volunteers, was measured using a multiple choice test before and after simulated counseling with the SDA. Result Twenty-two interviews generated seven unique themes. An SDA was constructed that preserved six themes paralleled by those found in a previously studied English population, and addressed a novel theme of "intercultural linguistic barriers" unique to our population. Knowledge scores rose in "naive" volunteers, 41 ± 12% to 71 ± 15% (P < 0.001), after simulated counseling with the SDA. 'Experienced' parents had a ceiling effect in knowledge scores, 62 ± 9% to 65 ± 11% (P = 0.22). The SDA was well received by participants. Conclusions for Practice Interviews of Latino parents with a history of premature birth generated similar themes to English-speaking parents, with intercultural linguistic barriers as a novel theme. An SDA for Latino parents facing extremely premature birth may improve comprehension of antenatal counseling.

A definition of gentle ventilation in congenital diaphragmatic hernia: a survey of neonatologists and pediatric surgeons.

Ventilation practices have changed significantly since the initial reports in the mid 1980 of successful use of permissive hypercapnia and spontaneous ventilation [often called gentle ventilation (GV)] in infants with congenital diaphragmatic hernia (CDH). However, there has been little standardization of these practices or of the physiologic limits that define GV. We sought to ascertain among Diaphragmatic Hernia Research and Exploration; Advancing Molecular Science (DHREAMS) centers' GV practices in the neonatal management of CDH. Pediatric surgeons and neonatologists from DHREAMS centers completed an online survey on GV practices in infants with CDH. The survey gathered data on how individuals defined GV including ventilator settings, blood gas parameters and other factors of respiratory management. A total of 87 respondents, from 12 DHREAMS centers completed the survey for an individual response rate of 53% and a 92% center response rate. Approximately 99% of the respondents defined GV as accepting higher carbon dioxide (PCO2) and 60% of the respondents also defined GV as accepting a lower pH. There was less consensus about the use of sedation and neuromuscular blocking agents in GV, both within and across the centers. Acceptable pH and PCO2 levels are broader than the goal ranges. Despite a lack of formal standardization, the results suggest that GV practice is consistently defined as the use of permissive hypercapnia with mild respiratory acidosis and less consistently with the use of sedation and neuromuscular blocking agents. GV is the reported practice of surveyed neonatologists and pediatric surgeons in the respiratory management of infants with CDH.

Predictors of low weight and tube feedings in children with congenital diaphragmatic hernia at 1 year of age.

OBJECTIVES: Congenital diaphragmatic hernia (CDH) survivors often have gastrointestinal disorders, and limited outcome data exist. This study reviewed risk factors for low weight and use of feeding tubes after CDH repair at 1 year of age. The hypothesis was that patients who required extracorporeal membrane oxygenation (ECMO) or with significant pulmonary arterial hypertension (PAH) would have lower weight percentiles and more often require tube feedings. METHODS: A retrospective chart review of 89 infants with CDH diagnosed in the neonatal period was conducted. Statistical analysis was performed using χ test, Fisher exact test, and logistic regression. RESULTS: Seventy-two patients (81%) survived to 1 year of age. Of these patients, 35% were <5th percentile for weight and 18% were receiving tube feedings. Both ECMO and PAH were associated with an increased risk for requiring tube feedings at 1 year of age, with respective odds ratios of 6.00 (P = 0.01) and 15.75 (P = 0.02); however, neither ECMO nor PAH was associated with low weight at 1 year of age. No statistical correlation was found between an abnormal pH probe and tube feedings at 1 year of age. CONCLUSIONS: Patients with CDH are at increased risk for having a weight <5th percentile at 1 year of age. A history of ECMO and PAH are independently associated with an increased requirement for tube feedings at 1 year of age. Close nutritional monitoring and counseling should be considered in all of the patients with CDH, particularly those with a history of ECMO or PAH.

Pulmonary vein stenosis and necrotising enterocolitis: is there a possible link with necrotising enterocolitis?

OBJECTIVES: While acquired pulmonary vein stenosis (PVS) is an often lethal anomaly with poor long-term prognosis and high mortality, little is known about the causes of this disease process. The purpose of this study was to describe the possible association between acquired PVS and necrotising enterocolitis (NEC) in premature infants. STUDY DESIGN: We performed a retrospective review of all premature infants (<37 weeks' gestation) diagnosed with acquired PVS in our institution. Babies with congenital heart disease with known association with PVS were excluded. The hospital records were reviewed for prior history of NEC, as defined by Bell's staging criteria. We also reviewed serial echocardiograms performed during their hospitalisation. Outcomes assessed were worsening or resolution of the PVS and death. RESULTS: Twenty patients met inclusion criteria and were diagnosed with acquired PVS. The median gestational age was 27 weeks. 50% (10/20) of the infants had NEC during their hospital course. The NEC group had significantly lower birth weights in comparison to the non-NEC group. There was no difference between groups with regards to the age at diagnosis of PVS. The mean gradient across the pulmonary veins was higher in the NEC group, as was mortality. CONCLUSIONS: There appears to be a high incidence of NEC in premature infants who are diagnosed with acquired PVS. Future large controlled studies are needed to further analyse this association and to evaluate the possible role of abdominal inflammation in the development of PVS in premature infants.