Basic and translational science advances in congenital diaphragmatic hernia

Congenital Diaphragmatic Hernia (CDH) is a birth defect that is characterized by lung hypoplasia, pulmonary hypertension and a diaphragmatic defect that allows herniation of abdominal organs into the thoracic cavity. Although widely unknown to the public, it occurs as frequently as cystic fibrosis (1:2500). There is no monogenetic cause, but different animal models revealed various biological processes and epigenetic factors involved in the pathogenesis. However, the pathobiology of CDH is not sufficiently understood and its mortality still ranges between 30 and 50%. Future collaborative initiatives are required to improve our basic knowledge and advance novel strategies to (prenatally) treat the abnormal lung development. This review focusses on the genetic, epigenetic and protein background and the latest advances in basic and translational aspects of CDH research.     

Standardized postnatal management of infants with congenital diaphragmatic hernia in Europe: the CDH EURO Consortium consensus

Congenital diaphragmatic hernia (CDH) is associated with high mortality and morbidity. To date, there are no standardized protocols for the treatment of infants with this anomaly. However, protocols based on the literature and expert opinion might improve outcome. This paper is a consensus statement from the CDH EURO Consortium prepared with the aim of achieving standardized postnatal treatment in European countries. During a consensus meeting between high-volume centers with expertise in the treatment of CDH in Europe (CDH EURO Consortium), the most recent literature on CDH was discussed. Thereafter, 5 experts graded the studies according to the Scottish Intercollegiate Guidelines Network (SIGN) Criteria. Differences in opinion were discussed until full consensus was reached. The final consensus statement, therefore, represents the opinion of all consortium members. Multicenter randomized controlled trials on CDH are lacking. Use of a standardized protocol, however, may contribute to more valid comparisons of patient data in multicenter studies and identification of areas for further research.     

The genetics of congenital diaphragmatic hernia

Congenital diaphragmatic hernia (CDH) is a common birth defect with a high mortality and morbidity. A clear understanding of the pathogenesis of CDH is critical for determining prognosis and planning treatment, but to date, information on the genetic etiology of both nonsyndromic and syndromic CDH is limited. This paper summarizes the current knowledge concerning the genes, syndromes, and chromosome aberrations associated with CDH in humans and in animal model systems. Mutations in several different genes have been described in syndromic CDH, but there is only one mutation that has been reported in non-syndromic CDH to date. However, animal models suggest that genes involved in cell migration, myogenesis, and connective tissue formation are critical to normal diaphragm formation, and these data provide a starting point for the search for other genes involved in the pathogenesis of CDH.     

Prediction tools in congenital diaphragmatic hernia

Because congenital diaphragmatic hernia (CDH) is characterized by a spectrum of severity, risk stratification is an essential component of care. In both the prenatal and postnatal periods, accurate prediction of outcomes may inform clinical decision-making, care planning, and resource allocation. This review examines the history and utility of the most well-established risk prediction tools currently available, and provides recommendations for their optimal use in the management of CDH patients.     

Associated malformations in congenital diaphragmatic hernia

Congenital diaphragmatic hernia (CDH) is a severe neonatal anomaly. The aim of this study was to evaluate the frequency and types of malformations associated with CDH. The outcome was compared with that in newborns with CDH alone. The study included 362 fetuses and newborns at a single national center for CDH. Associated malformations and chromosomal aberrations were noted prenatally and postnatally. The neonatal outcome was assessed relative to the use of extracorporeal membrane oxygenation (ECMO) and the mortality rate. At least one associated malformation was diagnosed in 143 cases (39.5%). Altogether, 272 associated malformations were found. Only 50 (18.4%) anomalies were diagnosed antenatally. In 62 (17.1%) cases, 102 major malformations were found along with CDH, with a prenatal detection rate of 35.3%. The associated malformations were very heterogeneous, but cardiovascular malformations were the most common. Newborns with major anomalies, chromosomal aberrations, or syndromes additional to CDH had a significantly lower survival rate than newborns with an isolated CDH. Associated malformations did not affect the rate of ECMO treatment. Associated malformations in CDH are frequent and heterogeneous, and diligent and experienced antenatal and postnatal care is important.     

Surgical management of the newborn with congenital diaphragmatic hernia

Despite advances in the surgical treatment and medical management over the last 20 years, neonates with congenital diaphragmatic hernia (CDH) remain one of the most challenging patient groups for all clinicians. Treatment strategies have shifted from emergent surgical repair and maximum ventilatory support to delayed repair and preoperative hemodynamic stabilization with lung-sparing ventilation strategies and extracorporeal membrane oxygenation. Subsequently, overall survival has improved to as high as 80% in some centers. However, specific treatment criteria are vague and highly variable amongst centers. This lack of consensus of these treatment modalities remains elusive due to the heterogeneity in disease severity as well as heterogeneity in patient care amongst centers. As a result of the rare incidence of disease and limited experience of individual centers, the evidence for CDH is typically reported as a homogenous disease largely supported by case series and networked-based studies. To better evaluate the data and compare treatment strategies, a classification and stratification of disease and centers is needed.     

Evidence-based management of infants with congenital diaphragmatic hernia

The mortality rate associated with congenital diaphragmatic hernia (CDH) varies widely between centers and remains relatively high despite widespread use of new therapeutic modalities. Many of these have been implemented without properly controlled studies. Over the past 10 to 15 years, only 9 randomized trials enrolling a total of approximately 250 infants with CDH have been published. The limited evidence available suggests that better outcomes are observed by delivering infants with CDH at experienced centers, by delaying surgical repair until hemodynamic and respiratory stability is achieved, and by the judicious utilization of nonaggressive mechanical ventilation and permissive hypercapnea. Other therapeutic modalities, such as high frequency oscillatory ventilation, inhaled nitric oxide, and ECMO, may provide additional advantages for selected infants. There is a dire need to establish networks of centers that manage enough infants with CDH, to conduct appropriately sized randomized trials that can answer some of the critical questions about the management and long-term outcome of these infants.     

Follow up of infants with congenital diaphragmatic hernia

Survival of patients with congenital diaphragmatic hernia has improved with the introduction of more sophisticated treatments. Long-term follow up has led to the recognition of pulmonary morbidity not previously recognized. In addition, extrapulmonary problems associated with the survival of these high-risk infants are now being identified. This review describes associated morbidities in congenital diaphragmatic hernia survivors and their predictors.     

Antenatal diagnosis of congenital diaphragmatic hernia

Congenital diaphragmatic hernia occurs in approximately 1 of 2200 live births and is associated with a high degree of morbidity and mortality. Poor outcome in these cases is primarily related to the presence of additional anomalies or abnormal karyotype and the development of pulmonary and cardiovascular complications. Prenatal diagnosis occurs in approximately 50% of cases. Multiple ultrasound markers have been identified as being predictive of outcome. Three-dimensional ultrasound, fetal echocardiography, and magnetic resonance imaging have been identified as additional imaging modalities that can assist in making the antenatal diagnosis and accurately assessing perinatal outcome.     

Extracorporeal membrane oxygenation in infants with congenital diaphragmatic hernia

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly which impairs normal pulmonary development leading to acute and chronic respiratory failure, pulmonary hypoplasia, pulmonary hypertension, and mortality. CDH is the most common non-cardiac indication for neonatal ECMO. Prenatal and postnatal predictors of CDH severity aid in patient selection. Centers vary in preferred mode of ECMO and timing of CDH repair. Survivors of severe CDH with ECMO are at risk for long-term sequelae including neurodevelopmental delays.     

The role of ECMO in the management of congenital diaphragmatic hernia

Congenital diaphragmatic hernia (CDH) is the most common indication for extra-corporeal membrane oxygenation (ECMO) for neonatal respiratory failure. CDH management is evolving with advanced prenatal diagnostic imaging modalities. The risk profiles of infants receiving ECMO for CDH are shifting towards higher risk. Many clinicians are developing and following clinical practice guidelines to standardize and optimize the care of CDH neonates. Despite these efforts, there are significant differences in the practice patterns among ECMO centers as to how and when they choose to initiate ECMO for CDH, when they believe repair is safe, as well as many other nuances that are based on center experience or style. The purpose of this report is to summarize our current understanding of the new and recent developments regarding management of infants with CDH managed with ECMO.     

Prenatal anatomical imaging in fetuses with congenital diaphragmatic hernia

The role of prenatal ultrasound and magnetic resonance imaging in the diagnosis and management of congenital diaphragmatic hernia (CDH) is reviewed. Topics include morphologic imaging and vascular assessment of the developing lung, the value of imaging parameters as prognostic predictors in CDH and the role of imaging following percutaneous fetoscopic endoluminal tracheal occlusion.     

The use of extracorporeal membrane oxygenation in infants with congenital diaphragmatic hernia

The use of extracorporeal membrane oxygenation (ECMO) has revolutionized the care of the critical infant born with a congenital diaphragmatic hernia (CDH). In some respects, this is surprising given our current lack of understanding regarding optimal preoperative ventilation strategy, identification of patients most likely to benefit from ECMO, and the correct timing of hernia repair for the infant treated with ECMO. Historically, repair of CDH was considered one of the few true pediatric surgical emergencies. Mortality, however, was high. In the 1970s, ECMO was first utilized as a rescue therapy following repair of CDH when conventional methods failed. In the 1980s, advancements in neonatal intensive care and an understanding of the pathophysiology of pulmonary hypertension associated with CDH led to a strategy involving preoperative stabilization and delayed surgical intervention. Historical reviews demonstrate an improvement of survival in infants treated with ECMO from 56% to 71%. This paper will outline the advances in the care of the CDH patient and the approach used for treatment with ECMO.     

Long term follow-up in congenital diaphragmatic hernia

Survivorship of patients with congenital diaphragmatic hernia (CDH) has created a unique cohort of children, adolescents and adults with complex medical and surgical needs. Morbidities specific to this disease benefit from multi-specialty care, and the long term follow up of these patients offers a tremendous opportunity for research and collaboration. Herein we aim to offer an overview of the challenges that modern CDH survivors face, and include a risk-stratified algorithm as a general guideline for a multi-specialty follow up program.     

Fetal lung growth in congenital diaphragmatic hernia

BACKGROUND: In spite of significant therapeutic progress, the prognosis of congenital diaphragmatic hernia (CDH) remains pejorative in those forms in which the liver is herniated into the chest. The severity of this malformation relies on the pulmonary hypoplasia due to lung compression by the herniated viscera in the thoracic cavity, particularly the liver. This impaired growth concerns the whole pulmonary tissue, i.e. both the vessels and the alveoli. For the clinician, it is mandatory to know the evolution pattern of the lesions, to define the best time to treat them. AIM AND METHOD: The aim of this work was to study the pulmonary lesions along the gestation in fetuses affected byCDH. This morphological study was carried out on 134 human fetuses aged from 22 to 40 weeks of gestation. Anatomical and histological analysis focused on lung weight, alveolar count and wall thickness of the distal vessels. RESULTS: The results indicate that the pulmonary lesions worsen as the pregnancy continues, particularly beyond 30 weeks of gestation. CONCLUSION: Such an anatomical study should bring to the clinicians useful data to enhance the management of the patients.     

Innovations in the surgical management of congenital diaphragmatic hernia

Surgical management of congenital diaphragmatic hernia (CDH) remains a challenge for all clinicians. While the treatment strategies for CDH have evolved from emergent surgical intervention to initial hemodynamic stabilization with delayed surgical repair, surgical innovations have remained limited in the last 20 years. Advances in surgical approaches, such as minimally invasive surgery and alternatives to diaphragmatic replacement, have focused on improvements in surgical morbidity.