Survival disparities in newborns with congenital diaphragmatic hernia: a national perspective

Purpose

The aim of the study was to examine national outcomes for congenital diaphragmatic hernia (CDH).

Methods

We analyzed the Kids' Inpatient Database for patients admitted at less than 8 days of age.

Results

Overall, 2774 hospitalizations were identified. Most patients were white and had private insurance. Most patients were treated at urban (96%), teaching (75%), and not identified as children's hospital (NIACH) (50%). Birth was the most common admission source at NIACH (91%) and children's unit in general hospital (CUGH) (59%), compared to hospital transfer at children's general hospital (CGH) (81%). Most CDH were repaired through the abdomen (81%), and 25% required extracorporeal membrane oxygenation (ECMO). Most NIACH patients were transferred to another hospital, whereas most at CGH and CUGH were discharged home. Survival to discharge was 66% after excluding hospital transfers. Univariate analysis revealed higher survival for males, birth weight (BW) of 3 kg or more, whites, patients with private insurance, and those in the highest median household income quartile. Survival was 86% after CDH repair but 46% for ECMO. Multivariate analysis identified black race (hazard ratio [HR], 1.536; P = .03) and other race (HR, 1.515; P = .03) as independent predictors of mortality.

Conclusions

Hospital survival for CDH is related to sex, BW, race, and socioeconomic status. Blacks and other non-Hispanic minorities have higher mortality rates.     

Early perfluorodecalin lung distension in infants with congenital diaphragmatic hernia

Background/Purpose: Pulmonary hypoplasia contributes to mortality in infants with severe congenital diaphragmatic hernia (CDH). Accelerated postnatal lung growth with perfluorocarbon lung distension has been demonstrated in animals. The authors present a study measuring perfluorodecalin distension in neonates with severe CDH on extracorporeal membrane oxygenation (ECMO) support. Methods: Six consecutive neonates with CDH requiring ECMO support were recruited. The lungs were filled with perfluorodecalin, and continuous positive airway pressure was applied for 6 to 10 days (mean, 7.7 days [plusmn] 0.7). The perfluorodecalin was exchanged 4 times a day. Radiographic lung projections were measured, and from 2-dimensional measurements an estimated lung volume was calculated using the ECMO cannula as reference. Results: Perfluorodecalin instillation started soon after starting ECMO support (mean, 13.5 [plusmn] 5.3 hours). The volume required to fill the lungs increased significantly (P [lt ] .02). The radiographic dimension of the affected lung increased significantly (mean percentage increase, 272%; P [lt ] .02). The contralateral lung dimension also increased (mean percentage increase 51%; P [lt ] .02). CDH repair was undertaken on ECMO in all cases. All patients survived (follow-up, 3 to 42 months). Conclusions: This protocol of early perfluorodecalin lung distension in infants with severe CDH on ECMO support resulted in significant radiographic lung enlargement. Clinical outcomes are encouraging. Possible mechanisms include alveolar recruitment, alveolar dilatation, and accelerated postnatal lung growth. J Pediatr Surg 38:17-20.     

Developmental outcomes of children with congenital diaphragmatic hernia: A multicenter prospective study

Purpose

To determine developmental outcomes and associated factors in patients with congenital diaphragmatic hernia (CDH) at 2 years of age.

Methods

This is a multicenter prospective study of a CDH birth cohort. Clinical and socioeconomic data were collected. Bayley Scales of Infant Development (BSID-III) and Vineland Adaptive Behavior Scales (VABS-II) were performed at 2 years of age.

Results

BSID-III and VABS-II assessments were completed on 48 and 49 children, respectively. The BSID-III mean cognitive, language, and motor scores were significantly below the norm mean with average scores of 93 ± 15, 95 ± 16, and 95 ± 11. Ten percent (5/47) scored more than 2 standard deviations below the norm on one or more domains. VABS-II scores were similar to BSID-III scores with mean communication, daily living skills, social, motor, adaptive behavior scores of 97 ± 14, 94 ± 16, 93 ± 13, 97 ± 10, and 94 ± 14. For the BSID-III, supplemental oxygen at 28 days, a prenatal diagnosis, need for extracorporeal membrane oxygenation (ECMO) and exclusive tube feeds at time of discharge were associated with lower scores. At 2 years of age, history of hospital readmission and need for tube feeds were associated with lower scores. Lower socioeconomic status correlated with lower developmental scores when adjusted for significant health factors.

Conclusion

CDH patients on average have lower developmental scores at 2 years of age compared to the norm. A need for ECMO, oxygen at 28 days of life, ongoing health issues and lower socioeconomic status are factors associated with developmental delays.     

Fetoscopic temporary tracheal occlusion for congenital diaphragmatic hernia: prelude to a randomized,controlled trial

Objective

As previously reported, high postnatal mortality seen in fetuses with congenital diaphragmatic hernia (CDH) with liver herniation and low lung-to-head ratio (LHR) appears to be improved in fetuses who undergo fetoscopic temporary tracheal occlusion (TO). To test whether further evolution of this technique produces results that justify a randomized controlled trial comparing prenatal intervention to postnatal care, the authors analyzed 11 additional cases and the cumulative experience with 19 cases.

Methods

The authors analyzed retrospectively the outcome of 11 new and 8 previously reported cases of fetoscopic temporary tracheal occlusion. Various factors were studied including maternal morbidity, antenatal outcome, physiologic lung response, and neonatal course.

Results

Temporary TO can be accomplished using 3 5-mm radially expanding uterine ports without hysterotomy. Obstetric morbidity included mild pulmonary edema in 6 cases, chorioamniotic separation and premature rupture of membranes in 12 patients, and preterm labor and delivery in all patients. Thirteen of 19 (68%) neonates survived for 90 days after delivery; one died in utero, and 5 died after birth. Late mortality included one death caused by sepsis and 2 by complications associated with tracheostomies. Morbidity from gastroesophageal reflux requiring Nissen fundoplication, tracheal injury requiring repair or tracheostomy, and recurrent hernias after diaphragmatic repair were characteristic in longterm survivors.

Conclusions

Fetoscopic temporary TO may improve outcome in poor-prognosis fetuses with CDH. However, complications related to tracheal dissection, premature delivery and late morbidity are significant. This experience has led to simpler techniques for fetoscopic tracheal occlusion and to an National Institutes of Health-sponsored randomized controlled trial comparing fetoscopic tracheal occlusion with optimal postnatal care.     

Predictors of early lung function in patients with congenital diaphragmatic hernia

Purpose

Long-term pulmonary outcomes of congenital diaphragmatic hernia (CDH) have demonstrated airflow obstruction in later childhood. We examined pulmonary function data to assess what factors predict lung function in the first three years of life in children with CDH.

Methods

This was a retrospective study of patients treated for CDH who underwent infant pulmonary function testing (IPFT) between 2006 and 2012. IPFT was performed using the raised volume rapid thoracoabdominal compression technique and plethysmography.

Results

Twenty-nine neonates with CDH had IPFTs in the first 3 years of life. Their mean predicted survival using the CDH Study Group equation was 63% ± 4%. Fourteen infants (48%) required extracorporeal membrane oxygenation (ECMO). The mean age at IPFT was 85.1 ± 5 weeks. Airflow obstruction was the most common abnormality, seen in 14 subjects. 12 subjects had air trapping, and 9 demonstrated restrictive disease. ECMO (p = 0.002), days on the ventilator (p = 0.028), and days on oxygen (p = 0.023) were associated with restrictive lung disease.

Conclusion

Despite following a group of patients with severe CDH, lung function revealed mild deficits in the first three years of life. Clinical markers of increased severity (ECMO, ventilator days, and prolonged oxygen use) are correlated with reduced lung function.     

Administration of prenatal betamethasone suppresses the adrenal-hypophyseal axis in newborns with congenital diaphragmatic hernia

Background

Congenital diaphragmatic hernia (CDH) is a condition that is characterized by pulmonary hypoplasia and pulmonary hypertension. Prenatal betamethasone often is administered to fetuses with CDH to improve pulmonary function. In this study, the authors investigate the possible role of the adrenal-hypophyseal axis in CDH in an animal model and subsequently in human infants with CDH.

Methods

Twin fetal sheep underwent creation of DH or a sham thoracotomy, and levels of plasma and lung ACTH and plasma cortisol were compared. For the human studies, plasma levels of ACTH, cortisol, and DHEA were measured in cord blood samples collected from 9 CDH (5 that received prenatal betamethasone) and compared with those of 14 normal newborns. In both studies, ACTH and cortisol levels were determined by radioimmunoassay (RIA). Human (DHEA) levels were determined by ELISA.

Results

Plasma ACTH and cortisol levels were elevated in fetal DH sheep compared with sham-operated controls; however, levels of ACTH in lung tissues were not different. Human newborns with CDH who have been exposed to prenatal steroids have significantly lower plasma ACTH, cortisol, and DHEA levels than normal newborns and CDH newborns not exposed to prenatal betamethasone.

Conclusions

In an ovine model of CDH, the adrenal-hypophyseal axis appears up-regulated in DH fetuses compared with sham-operated animals. Conversely, the adrenal-hypophyseal axis in human CDH newborns appears normal but is suppressed by the administration of prenatal betamethasone.     

The congenital diaphragmatic hernia composite prognostic index correlates with survival in left-sided congenital diaphragmatic hernia

PurposeWe developed the congenital diaphragmatic hernia congenital prognostic index (CDH-CPI) to incorporate all known prognostic variables into a single composite index to improve prognostic accuracy. The purpose of this study is to examine the ability of the CDH-CPI to predict survival in patients with left-sided congenital diaphragmatic hernia and to determine if the index has a stronger correlation with survival than each of the individual components.MethodsA retrospective review of patients with left-sided congenital diaphragmatic hernia between 2004 and 2010 was conducted. Ten prenatal parameters of the CDH-CPI were collected, total score was tabulated, and patients stratified according to total score and survival.ResultsSixty-four patients with a prenatal diagnosis of left-sided congenital diaphragmatic hernia were identified. Patients with a CDH-CPI score of 8 or higher had a significantly higher survival than patients with a CDH-CPI score of lower than 8. The CDH-CPI has the strongest correlation with survival compared with the individual parameters measured. The CDH-CPI correlates with extracorporeal membrane oxygenation use, and 75% of patients with a score of 5 or lower were placed on extracorporeal membrane oxygenation.ConclusionsThe CDH-CPI accurately stratifies survival in left-sided congenital diaphragmatic hernia. The amalgamation of 10 prenatal parameters of the CDH-CPI may be a better prenatal predictor than any single prognostic variable currently used.     

Continuous intrapulmonary distension with perfluorocarbon accelerates lung growth in infants with congenital diaphragmatic hernia: initial experience

BACKGROUND/PURPOSE: The authors have shown previously in an animal model that neonatal lung growth can be accelerated by continuous intrapulmonary distension with a perfluorocarbon (PFC). The authors now describe a preliminary clinical experience with this therapeutic concept in a select group of infants with congenital diaphragmatic hernia (CDH). METHODS: Neonates with very high predicted mortality rate caused by CDH had their lungs completely filled with PFC while on extracorporeal life support (ECLS); (n = 5). A continuous positive pressure of 7 to 10 cm H2O was maintained via the endotracheal tube for 3 to 7 days (mean, 5.6 +/- 0.87 days). The areas of both lungs (L) then were measured daily from digitized chest x-rays and divided by the area of the corresponding L1 vertebrae (V), to create an L/V index, so as to control for variable roentgenographic techniques. Immediately after removal of PFC, blood gas data were collected off ECLS. RESULTS: At the end of continuous pulmonary distension, all patients showed improvements in oxygenation and ventilation. The ipsilateral lungs showed significant increase of the L/V index with time (P =.003) and of L/V's daily change (P <.0001), suggesting accelerated lung growth. Overall survival rate was 40% (2 of 5). Of the 3 patients that had 7 days of distension, 2 survived. CONCLUSIONS: Continuous intrapulmonary distension with PFC for up to 1 week accelerated ipsilateral lung growth, improved gas exchange, and increased survival of CDH infants with profound pulmonary hypoplasia marooned on ECLS. Additional trials of PFC-based pulmonary distension in similar infants are warranted.     

Abnormal platelet-derived growth factor signaling accounting for lung hypoplasia in experimental congenital diaphragmatic hernia

Purpose

The pathogenesis of pulmonary hypoplasia in congenital diaphragmatic hernia (CDH) is not fully understood. Platelet-derived growth factor A (PDGFA) and platelet-derived growth factor receptor α (PDGFRα) play a crucial role in lung development. It has been reported that PDGF induces H₂O₂-production and that oxidative stress may be an important mechanism for the impaired lung development in the nitrofen rat model. We hypothesized that pulmonary expression of PDGFA and PDGFRα is altered in the nitrofen induced CDH model.

Materials and Methods

Pregnant rats received 100 mg nitrofen or vehicle on gestational day 9 (D9) and were sacrificed on D15, D18 or D21. RNA was extracted from fetal left lungs and mRNA levels of PDGFA and PDGFRα were determined using real-time polymerase chain reaction. Immunohistochemistry for protein expression of PDGFA and PDGFRα was performed. Pulmonary H₂O₂ was measured colorimetrically.

Results

mRNA levels of PDGFRα at D15 (4.50 ± 0.87) and PDGFA at D18 (2.90 ± 1.38) were increased in the nitrofen group (P < .05). Immunohistochemistry revealed increased pulmonary expression of PDGFRα and PDGFA. H₂O₂ content was significantly higher in the nitrofen group.

Conclusions

Increased expression of PDGFA and PDGFRα suggests that pulmonary hypoplasia in the nitrofen CDH model may be owing to PDGF-induced oxidative stress during lung development.