RARE DISEASE
Congenital diaphragmatic hernia
Congenital diaphragmatic hernia
Congenital diaphragmatic hernia
Synonyms: CDH
Synonyms: CDH
Synonyms: CDH
Drug discovery
2
drugs
With orphan designations
Overview
Congenital Diaphragmatic Hernia (CDH) is a congenital defect characterized by incomplete diaphragm formation, allowing abdominal organs to herniate into the chest. This impairs pulmonary development, leading to pulmonary hypoplasia, hypertension, and respiratory failure. Prenatal diagnosis via ultrasound/MRI enables risk stratification. Management includes fetal endoscopic tracheal occlusion (FETO) for severe cases, postnatal stabilization with gentle ventilation, ECMO, and delayed surgical repair. Long-term complications include chronic lung disease, reflux, and neurodevelopmental delays [1][5][13].
Therapies
Prenatal: FETO for severe CDH (improves lung growth via tracheal occlusion) [1][8][16].
Postnatal: Gentle ventilation, inhaled nitric oxide, ECMO (used in 25–30% of cases), and delayed surgical repair after cardiorespiratory stabilization [3][13][17].
Long-term: Multidisciplinary follow-up for pulmonary, nutritional, and neurodevelopmental sequelae [1][6][19].
Categories: rare abdominal surgical diseases, rare developmental anomalies during embryogenesis, rare respiratory diseases, rare surgical thoracic diseases
Research Papers
2,257 drug discovery papers about Congenital diaphragmatic hernia, with 7 first-in-class and 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
2,257 drug discovery papers about Congenital diaphragmatic hernia, with 7 first-in-class and 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-08-25 | Testing the waters: the potential of urinary proteomics in congenital diaphragmatic hernia and Tetralogy of Fallot
Congenital diaphragmatic hernia (CDH) is a structural birth defect with an incidence of approximately 1 in 3000. 1 It is due to abnormalities in the development of the pleuroperitoneal folds resulting in herniation of the abdominal organs into the thoracic cavity, impairing proper lung development and function. As a result, patients suffer from pulmonary hypertension (PH), attributed to high pulmonary vascular resistance and abnormal vascular remodeling. 2 , 3 These vascular pathologies ultimately cause significant stress to the right ventricle (RV). Similar RV dysfunction, a leading cause of morbidity and mortality in neonates, is observed in patients with Tetralogy of Fallot (TOF), a congenital disorder caused by a combination of cardiovascular lesions involving ventricular septal defect, overriding aorta, pulmonary stenosis, and RV hypertrophy that occurs in about 3 out of 10,000 births. 4 While CDH and TOF are developmentally different disorders, both often result in PH and eventual RV dysfunction. In CDH, PH is attributed to high pulmonary vascular resistance, while in TOF, PH is primarily due to pulmonary outflow tract stenosis.
2026-08-06 | Vasopressin for hemodynamic support in neonates: current evidence and clinical applications.
To systematically map and synthesize the available evidence on the use of vasopressin for hemodynamic support in neonates. We conducted a scoping review to synthesize available data on indications, dosing, clinical effects, and safety. Twelve studies were included (one randomized trial, eleven observational), encompassing heterogeneous neonatal populations. Vasopressin was primarily used as rescue therapy in refractory shock, including sepsis, persistent pulmonary hypertension of the newborn, and congenital diaphragmatic hernia. Dosing regimens varied widely. Most studies reported improvements in mean arterial blood pressure, with some demonstrating reduced vasoactive support and improved oxygenation. Effects on urine output were variable. Safety reporting was inconsistent; hyponatremia was the most commonly described adverse event, while serious ischemic complications were rarely reported. Vasopressin may improve short-term hemodynamic parameters, but evidence is limited and heterogeneous, with insufficient data to guide optimal use.
2026-06-23 | Predictors of challenging initial intubation and association with outcomes in congenital diaphragmatic hernia.
To assess for differences in congenital diaphragmatic hernia patient characteristics between those requiring single or multiple intubation attempts, and to determine the relationship between number of intubation attempts and time to intubation with outcomes. This was a retrospective cohort study of 205 infants with congenital diaphragmatic hernia born at Texas Children's Hospital. Patient demographics and severity numbers were compared to number of laryngoscopies as a surrogate for intubation attempts. Number of laryngoscopies and time to intubation were compared to clinical outcomes. Binary logistic regression and receiver operating characteristic curve analysis were used. There was no significant difference in baseline characteristics or CDH severity in those requiring single or multiple attempts. Greater number of intubation attempts was not associated with adverse outcomes but there was a significant association between longer time to successful intubation and mortality and higher risk of tracheostomy or death before discharge. Each additional minute before successful intubation was associated with 28% higher odds of mortality (p = 0.031) and 42% higher odds of tracheostomy or death before discharge (p = 0.006) CONCLUSION: Delayed time to intubation but not number of intubation attempts was associated with higher mortality and risk of tracheostomy or death in babies with CDH. Prenatal information including receipt of the FETO procedure, CDH severity markers, gestational age and birth weight cannot reliably be used to predict the likelihood of challenging intubations in infants with CDH.
2026-02-04 | Antiseizure Prescription for Children With Severe Congenital Heart Defects and Children With Gastrointestinal Anomalies.
Children with congenital anomalies (CAs) are at an increased risk of developing epilepsy, but the relative risk (RR) for specific anomaly subtypes remains underexplored. This study aims to estimate the risk of epilepsy, as indicated by antiseizure medication (ASM) prescriptions, among children with various CAs compared to children without anomalies. We utilized data from six European regions participating in the European network for surveillance of congenital anomalies registries, covering births from 2000 to 2015. Children with major CAs, classified by International Classification of Diseases codes, were compared to a reference population without anomalies. Epilepsy was identified based on >1 ASM prescription within a year. RRs were calculated using mixed-effects models to account for registry-specific variations. The study included 60,662 children with anomalies and 1,722,912 reference children, with a mean follow-up of 5.5 years. By age 5 years, ASM prevalence was 17.8 per 1000 in anomaly groups and 2.0 per 1000 in reference children. The highest RRs were observed in children with central nervous system anomalies, including anomalies of the corpus callosum, severe microcephaly, and hydrocephalus. Comparable RRs were found in children with severe congenital heart defects and gastrointestinal anomalies, primarily driven by diaphragmatic hernia. Children with CAs have a significantly higher risk of epilepsy, with central nervous system, chromosomal, severe congenital heart defect, and diaphragmatic hernia being key contributors. This study highlights the importance of tailored monitoring and early intervention for high-risk groups to improve neurological outcomes.
2025-12-08 | Complex Fetal Anomalies: Kluth Type Xc2 Variant Tracheoesophageal Fistula, Srikanth Group III Bronchopulmonary Foregut Malformation, Mirror-Image Dextrocardia with L-Looped Ventricles, Anomalous Coronary Origin from the Pulmonary Artery, and Cardiac-Type Total Anomalous Pulmonary Venous Connection.
We report a fetus at 20 + 5 weeks' gestation with an exceptionally rare constellation of congenital anomalies. Prenatal imaging revealed left congenital diaphragmatic hernia, rightward cardiac displacement, possible tracheoesophageal fistula (TEF), transposition of the great vessels, and a large ventricular septal defect. Autopsy confirmed complete absence of tracheoesophageal separation from the larynx to the carina, consistent with Kluth type Xc2, incorporating extralobar pulmonary sequestration with esophageal communication. The findings met criteria for a communicating bronchopulmonary foregut malformation (CBPFM), Srikanth Group III. Additional anomalies included bilateral pulmonary hypoplasia, bilateral unilobar lungs with eparterial bronchi, mirror-image dextrocardia, L-looped ventricles with concordant atrioventricular and ventriculoarterial alignments, right-sided aortic arch, bilateral superior vena cava, cardiac-type total anomalous pulmonary venous connection with drainage into the morphologic right atrium, and anomalous coronary origin from the pulmonary artery. Cytogenetic studies and whole-exome sequencing were normal. To our knowledge, this is the first report of Kluth type Xc2 TEF with Srikanth Group III CBPFM since Stolte's original description in 1952, and the first to combine this unique constellation. This case broadens the recognized spectrum of foregut and cardiopulmonary maldevelopment and underscores the importance of comprehensive evaluation in fetuses with multiple anomalies.
small molecules
2026-08-19 | Systemic thrombolysis for an intracardiac thrombus in a premature child with a severe diaphragmatic hernia.
Intracardiac thrombus is a rare but difficult-to-treat complication in premature infants, with limited therapeutic options. If an urgent neonatal surgical procedure is needed, rescue systemic thrombolysis may be considered as an option to hasten thrombus resolution. In the present case, we illustrate the successful lysis of a right ventricle intracardiac thrombus in a premature child prior to a neonatal emergent surgery for a severe congenital diaphragmatic hernia. The 1-day-old premature child with right-sided diaphragmatic hernia contracted preoperatively a right ventricle thrombus in the context of an early-onset septic shock. Systemic low-dose thrombolysis with urokinase (2000 then 3000 U/kg/h) was infused for 6 days with resolution of the thrombus and no immediate or delayed intracranial or postcongenital diaphragmatic hernia hemorrhagic complication, performed 72 h after thrombolysis cessation. Low-dose thrombolysis should be discussed if rapid thrombus resolution is required in case of intracardiac thrombus without thrombectomy option.
2026-07-24 | Meta-analysis of prostacyclin therapy for persistent pulmonary hypertension with congenital diaphragmatic hernia.
To evaluate the efficacy and safety of prostacyclin in the treatment of persistent pulmonary hypertension in congenital diaphragmatic hernia. A systematic literature search was conducted in four main databases (PubMed, Web of Science, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL). The protocol was registered in advance in the International Prospective of Systematic Reviews (CRD420261325458). A total of nine studies were included involving a total of 7009 infants in this systematic review and meta-analysis. GRADE assessment revealed substantial heterogeneity in the quality of evidence across outcomes, with most outcomes rated very low quality and only one rated moderate quality. Studies were performed meta-analysis, which showed the use of prostacylin resulted a statistically significant decrease in the OI compared to the control group (Mean Difference (MD), 9.34; I2 0%; p < 0.00001), no statistically significant in mortality (OR, 0.83; I2 84%; p = 0.70), ECMO (OR = 4.9; I2 98%; p = 0.27), BNP (std MD, 6.98; I2 98%; p = 0.31), FiO2 (SMD = 8.0;, I2 64%; p = 0.11), Systolic orientation of IVS curvature (SMD = 0.69; I2 97%; p = 0.32), Diastolic orientation of IVS differences (MD = 0.62; I2 93% p = 0.26). After applying the Hartung-Knapp adjustment, with the exception of BNP, the pooled effects of the other outcomes were not statistically significant, and there was high heterogeneity in measures such as ECMO and ventricular septal curvature. In conclusion, this meta-analysis has confirmed that prostacyclin may temporarily improve oxygenation. However, after applying the Hartung-Knapp adjustment, with the exception of BNP, the pooled effects of the other outcomes were not statistically significant, and there was high heterogeneity in measures such as ECMO and ventricular septal curvature. Further validation through high-quality studies are still needed. PROSPERO: CRD420261325458.
2026-07-20 | Reduced KLF4 expression in endothelial cells triggers pulmonary vascular abnormalities associated with experimental congenital diaphragmatic hernia.
Congenital diaphragmatic hernia (CDH) is a rare anomaly with an incidence of 1 in 3000 live births and characterized by defective closure of the diaphragm, lung hypoplasia, and pulmonary vascular remodeling. Although several genes associated with the occurrence of CDH, no clear genetic component has been identified. Previously, we showed that CDH patients have vascular abnormalities already early in development, and that perivascular cells are affected in CDH. In the current study, we focused on early abnormalities in the nitrofen-induced CDH mouse model. Transcriptome analysis of FACS-sorted perivascular and endothelial cell populations from lungs of control and experimental mouse CDH revealed a high similarity in GO terms of differentially expressed genes (DEGs) between these populations, suggesting a disturbed interaction between endothelial cells and pericytes. The disturbed interaction is the basis for the aberrant development of the pulmonary vasculature in CDH. Furthermore, the RNA sequence data revealed reduced expression of the Kruppel like factor 4 (Klf4) gene in endothelial cells of CDH, which was confirmed with protein expression analysis. Furthermore, we show that KLF4 is an important up stream regulator of genes associated with vascular development and confirm that members of the NOTCH signaling pathway are differentially expressed, indicating that NOTCH signaling is disturbed in CDH. Collectively, our data support the importance of KLF4 in pulmonary angiogenesis and contribute to our previous data that pulmonary vessels in CDH patients are already affected before birth, which in turn may impact therapeutic strategies to reduce pulmonary hypertension associated with CDH.
2026-07-17 | Pulse pressure as an early mortality predictor in neonates with congenital diaphragmatic hernia on veno-arterial ECMO.
Early prognostic markers for pediatric patients receiving extracorporeal membrane oxygenation (ECMO), particularly those with congenital diaphragmatic hernia (CDH), remain poorly defined. This study aimed to evaluate pulse pressure (PP) as an early hemodynamic indicator of mortality in neonates with CDH undergoing veno-arterial (VA) ECMO. We retrospectively analyzed newborns who underwent VA ECMO as primary rescue therapy for isolated CDH. Perinatal characteristics, arterial blood gas parameters, and blood pressure (BP) during the first 48 h post-ECMO were evaluated and compared between survivors and non-survivors. Among 33 neonates, 20 (60.6%) survived. ECMO flow rates or systolic, diastolic, and mean BP did not differ between the group. However, PP at 24 h (20.0 mmHg [17.8-26.3] vs. 12.0 mmHg [10.0-13.0], p < 0.001) and 48 h (24.0 mmHg [20.0-28.8] vs. 12.0 mmHg [10.0-14.0], p < 0.001) post-ECMO was significantly higher in survivors. Receiver operating characteristic analysis demonstrated that PP was am early predictor of survival, with optimal cutoff values of 20 mmHg at 24 h and 17 mmHg at 48 h. Early recovery of PP was a strong predictor of survival in neonates with CDH requiring VA-ECMO. Further research is required to determine whether interventions to enhance pulsatility can improve clinical outcomes in this high-risk population.
2026-06-24 | Targeted use of Prostaglandin E1 Therapy in “Duct-dependent” Congenital Diaphragmatic Hernia
Dana Levinkopf, Abhijit Bhattacharya, David Healy, Giulia Vanina Cantone, Anna Claudia Massolo, Flaminia Pugnaloni, Ann Marie Heuchan, Florian Kipfmueller,
cell therapies
2026-09-28 | MODERN APPROACHES TO THE DIAGNOSIS AND TREATMENT OF CONGENITAL DIAPHRAGMATIC HERNIA IN CHILDREN: A LITERATURE REVIEW
Congenital diaphragmatic hernia (CDH) in children is a severe congenital disorder whose clinical course is determined not only by the presence of a diaphragmatic defect but also by the degree of pulmonary hypoplasia, persistent pulmonary hypertension, and associated congenital anomalies. Despite advances in prenatal diagnosis, neonatal intensive care, and modern surgical technologies, the management of neonates with severe forms of CDH remains challenging, and optimal approaches to prognostic assessment and treatment selection continue to evolve. OBJECTIVE. To systematize and critically analyze current evidence regarding the etiology, pathogenesis, diagnosis, treatment, and prognosis of congenital diaphragmatic hernia in children based on the principles of evidence-based medicine. MATERIALS AND METHODS. A systematic search, content analysis, descriptive analysis, and comparative analysis of current scientific literature, systematic reviews, meta-analyses, multicenter clinical studies, international guidelines, and consensus documents on CDH were performed. The search was conducted in the PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar databases. Publications addressing the pathogenesis, prenatal and postnatal diagnosis, intensive care, surgical treatment, and prognostic assessment of CDH were included in the analysis; more than 90 sources were reviewed at the initial stage. RESULTS. The main prognostic factors in CDH were found to include the degree of pulmonary hypoplasia, severity of pulmonary hypertension, size of the diaphragmatic defect, intrathoracic liver position, and presence of associated congenital anomalies. Current prenatal diagnosis is based on ultrasonography with assessment of the lung-to-head ratio (LHR) and observed-to-expected LHR (O/E LHR), supplemented by fetal magnetic resonance imaging (MRI) to determine lung volume and anatomical characteristics. The fundamental principle of postnatal management is “stabilization before operation,” including early intubation, gentle ventilation, gastric decompression, management of pulmonary hypertension, and, when indicated, high-frequency ventilation, inhaled nitric oxide, and extracorporeal membrane oxygenation (ECMO). Surgical repair is performed after cardiorespiratory stabilization has been achieved. Thoracoscopic and laparoscopic techniques may be used in stable patients, whereas the choice of repair technique is determined by the size of the defect and the availability of native diaphragmatic tissue. Promising areas of development include fetoscopic endoluminal tracheal occlusion (FETO), advances in minimally invasive technologies, biocompatible materials, and personalized treatment approaches. CONCLUSIONS. Current management of congenital diaphragmatic hernia in children should be based on a comprehensive multidisciplinary approach involving early prenatal diagnosis, prognostic assessment, and stabilization of the neonate prior to surgical repair. The combination of modern intensive care strategies, minimally invasive surgery, ECMO, and selective use of FETO expands the therapeutic options for severe forms of CDH. Further research is needed to refine prognostic models, standardize indications for fetal and extracorporeal therapies, and improve long-term treatment outcomes.
2026-08-06 | Bioprinting of BSA membranes with C2C12 and NIH 3T3 pre-cellularized PLGA microscaffold : a step toward diaphragmatic hernia patches.
The diaphragm is a physical barrier separating the thoracic and abdominal cavities. Its physiological function is fundamental to pulmonary ventilation. Congenital diaphragmatic hernia (CDH) is a malformation that leaves a hole in the diaphragm during fetal development. Synthetic nondegradable membranes are currently used for the repair of diaphragm holes. However, these membranes do not help cells to adhere and proliferate. There is a need for biodegradable membranes composed of muscular and fibroblast cells to replicate a simplified diaphragmatic tissue. We thus developed a biocompatible and biodegradable salt-compacted albumin membrane. C2C12 myoblasts were bioprinted as central spokes, surrounded by a ring of NIH 3T3 fibroblasts, onto albumin membranes. We used bioink based on methacrylated collagen and hyaluronic acid, containing porous poly(D,L-lactic-co-glycolic acid) solid microscaffolds to protect myoblast and fibroblast cells against mechanical stress during extrusion printing. We found that metabolic activity of C2C12 myoblast increased by 215% in the presence of a polylysine-coated microscaffolds, compared to those cultured without microscaffolds. Microscaffolds loaded with C2C12 and NIH 3T3 cells increased viability (30% and 15%) and cell activity (527% and 567%) either after co-culture (5.6% increased viability and 588% cell activity) bioprinting on albumin membrane, compared to cells in bioink without microscaffolds. Cell-loaded microscaffolds embedded in bioink enhance C2C12 to NIH3T3 cross-migration on albumin membrane. This work is a preliminary proof of concept of cellularization of myoblasts and fibroblasts by extrusion bioprinting on a new biodegradable albumin membrane designed for diaphragmatic hernia patches.
2026-07-30 | Transamniotic stem cell therapy (TRASCET).
Transamniotic stem cell therapy (TRASCET) constitutes the least invasive approach to prenatal stem cell delivery described to date. This strategy is largely based on the recently discovered active transport of donor cells from the amniotic fluid to the placenta directly through the amnio-placental interface. From a simple amniocentesis, via the placenta, donor cells of different phenotypes can reach the fetal circulation and virtually any fetal anatomical site, including, and particularly, the fetal bone marrow. As a result, TRASCET has shown broad therapeutic potential in an assortment of animal models. First reported experimentally only a little over a decade ago, it has yet to be attempted clinically, though clinical translation may be imminent. Much of TRASCET's appeal lies in the fact that, in large part, it constitutes a form of replenishment therapy based on the magnification of naturally occurring processes in the distinctive environment of the maternal-fetal unit. Despite significant experimental advances, much promise and perhaps excessive publicity, most cell-based therapies have yet to deliver meaningful large-scale impact to patient care. The few exceptions have been therapies based on the amplification of the normal biological role played by donor cells in their natural environment. TRASCET falls in that category. Further, while fetal stem cells possess unique characteristics when compared with postnatal stem cells, so does the fetus when compared with any other age group, converging into a scenario that enables therapeutic paradigms exclusive to prenatal life. This review summarizes the biological basis, diversity of applications and operability of the TRASCET principle.
2026-07-21 | Extracellular vesicles in perinatal conditions: A minimally invasive approach to regenerative medicine.
Extracellular vesicles (EVs) are lipid bilayer-delimited nanoparticles released by cells to act as mediators of intercellular communication during organ development, injury, and repair. EVs carry cargo (bioactive proteins, lipids, and nucleic acids) that reflects the status of the parent cell and is transferred to recipient cells to regulate biological processes, such as inflammation, immune responses, and tissue regeneration. These properties have made EVs promising tools for investigating disease pathogenesis, improving diagnostic and prognostic accuracy, and developing cell-free regenerative therapies for conditions characterized by dysregulation of multiple biological pathways. EVs are particularly relevant in diseases that affect the pediatric population where pathogenesis often remains poorly understood, access to affected tissues is limited, and treatment options are frequently inadequate. This review summarizes current evidence on EV applications in fetal and neonatal disorders, including necrotizing enterocolitis, congenital diaphragmatic hernia, and bronchopulmonary dysplasia, and highlights emerging data in biliary atresia, spina bifida, short bowel syndrome, and Hirschsprung's disease. In this age group, human milk and amniotic fluid represent particularly attractive biologically accessible sources of EVs, combining therapeutic potential with feasibility of clinical application. Building on robust preclinical evidence, the field is now advancing toward clinical translation, but several aspects still need to be addressed such as cargo heterogeneity, scalability of production, dosing, biodistribution, safety, and regulatory standardization. Herein, we discuss the translational challenges and future directions that will shape the clinical application of EVs in perinatal conditions.
2026-06-01 | Risk Stratification and Fetal Therapies for Congenital Diaphragmatic Hernia.
Congenital diaphragmatic hernia (CDH) remains one of the most challenging congenital anomalies encountered by neonatologists and pediatric surgeons, with outcomes largely determined before birth. Although surgical repair of the diaphragmatic defect is essential, postnatal morbidity and mortality are primarily driven by antenatal pulmonary hypoplasia, abnormal pulmonary vascular development, and associated cardiac dysfunction that culminate in respiratory failure and pulmonary hypertension. Advances in prenatal imaging have enabled increasingly refined risk stratification, allowing for the identification of fetuses who are at highest risk for postnatal cardiopulmonary failure. Within this framework, fetal therapies, most notably fetoscopic endoluminal tracheal occlusion, have emerged as the first interventions shown to improve survival in carefully selected cases of severe CDH. However, uncertainty persists regarding optimal patient selection, timing, complications, and the generalizability of outcomes across health care systems. In this review, we examine the pathophysiologic rationale for fetal lung recruitment therapies, contemporary approaches to prenatal diagnosis and severity stratification, and the evidence supporting current fetal interventions. We also discuss how fetal therapy alters postnatal surgical and extracorporeal membrane oxygenation decision-making and highlight emerging prenatal strategies aimed at modifying lung and vascular development before birth. By framing CDH as a prenatal cardiopulmonary disease with postnatal surgical manifestations, we aim to provide a cohesive framework for multidisciplinary counseling, referral, and perioperative planning in the evolving era of fetal therapy.
gene therapies
2026-05-13 | Modeling patient variants of Cnot1 and Cdc42bpb results in distinct forms of congenital diaphragmatic hernia in mice.
Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly characterized by impairment of both diaphragm and lung development in utero. CDH presents as a spectrum of forms and severities, with diaphragm defects arising in the dorsal/posterior region typically correlating with more severe pulmonary disease and higher risk of mortality than those appearing in ventral/anterior regions. The genetic etiology underlying CDH is complex, with many genes implicated showing variable expressivity and incomplete penetrance in both human patients and mouse models. Here we present in vivo validation of two genes previously unassociated with CDH: the CDC42-interacting kinase CDC42BPB; and CNOT1, a scaffolding protein of the CCR4-NOT protein complex, critical for mRNA regulation through modifications such as deadenylation. Each gene was found to have a damaging, de novo missense variant in a recent large-scale CDH patient sequencing screen. Loss of Cdc42bpb leads to ventral diaphragmatic hernias, heart septal defects and minor lung epithelial differentiation defects in mouse embryos. Installation of the orthologous patient-specific missense variant through CRISPR/Cas9 editing leads to less severe ventral diaphragm defects. Mouse embryos with either one or two copies of the orthologous Cnot1 variant, c.1867C>T (p.R623W), develop dorsal diaphragmatic hernias with low (<50%) penetrance, and mutants showed alterations in mRNA isoform expression consistent with the molecular role of Cnot1 in RNA splicing. These results underscore the power of in vivo functional modeling to validate genes and patient-specific variants uncovered by patient sequencing, reveal two previously unrecognized genetic causes of CDH, and highlight the heterogeneity of different patient anatomic presentations.
2025-12-14 | Clinical trials in fetal surgery - changing care for complex pregnancies.
Fetal therapy has continued to expand in treatable conditions and surgical approaches. To maintain the evidence-based approach to optimizing patient care and outcomes, clinical trials investigating these interventions is essential. All trials must take in consideration both the potential benefit to the fetus or fetuses with the maternal and perinatal risks. In this review we discuss clinical trials in fetal therapy which have changed the field and provided the highest level of evidence possible. Large-scale trials have been performed in the management of Twin-to-Twin Transfusion Syndrome (TTTS), Spina bifida, Lower Urinary Tract Obstruction (LUTO) and Congenital Diaphragmatic Hernia (CDH). As molecular biology and advanced prenatal diagnostics continues to develop, future trials in gene and enzyme therapy remain on the horizon.
2025-07-30 | Advances in Fetal Surgery: A Narrative Review of Therapeutic Interventions and Future Directions.
Fetal surgery has emerged as a viable option for the management of selected congenital anomalies that result in severe or lethal outcomes if left untreated until birth. Conditions such as spina bifida, urinary tract obstruction, congenital cystic adenomatoid malformation, diaphragmatic hernia, sacrococcygeal teratoma, and twin-twin transfusion syndrome have shown improved prognosis after in utero intervention, open, or fetoscopically. Despite significant advances in surgical methods and anesthesia, preterm labor remains a primary concern. Stem cell transplantation and in utero gene therapy are developing, and they have the potential to expand the treatment window, as they minimize maternal complications. Hematopoietic stem cell transplantation, which is based on the immaturity of the fetal immune system, is a promising treatment for inherited disorders. Although many procedures of fetal interventions are now established, their safety and efficacy must be ensured and this requires optimal patient selection and choice of appropriate timing for intervention, adherence to ethical principles, and continuous research. Therefore, a multidisciplinary team, including specialists in maternal-fetal medicine, pediatric surgery, anesthesiology, neonatology, psychosocial support, and bioethics, is essential to guide comprehensive, patient-centered care. Fetal surgery is an evolving field that offers hope for conditions previously considered untreatable before birth.
2024-12-11 | Fetal Tracheal Occlusion Correlates with Normalized YAP Expression and Alveolar Epithelial Differentiation in Congenital Diaphragmatic Hernia.
Congenital diaphragmatic hernia (CDH) is characterized by incomplete closure of the diaphragm. Although the ensuing compression to the fetal lung causes lung hypoplasia, specific cellular phenotypes and developmental signaling defects in the alveolar epithelium in CDH are not fully understood. Employing lung samples from human CDH, a surgical lamb model, and a nitrofen rat model, we investigated whether lung compression impairs alveolar epithelial differentiation and Yes-associated protein (YAP)-mediated mechanosensing. We showed that CDH in humans and lambs caused defective alveolar epithelial differentiation manifested by more alveolar epithelial type II (ATII) cells, fewer ATI cells, and the emergence of cells coexpressing ATI and ATII markers. Associated with these alveolar epithelial defects, we found a decrease in the level and nuclear localization of YAP. Reduced YAP and abnormal distal lung development were evident as early as 21 weeks of gestation in human CDH. In addition, rat fetuses with CDH also showed diminished nuclear YAP and more abundant ATII cells. In contrast, the littermates without the hernia had no such alveolar phenotypes. Furthermore, fetal tracheal occlusion in the surgical lamb model of CDH fully normalized nuclear YAP and rescued alveolar epithelial defects in a gestational age-dependent manner. Taken together, our findings across species indicate that lung compression in CDH is sufficient to disrupt alveolar epithelial differentiation and impair YAP signaling. Tracheal occlusion can restore nuclear YAP and rescue the alveolar defects in CDH, depending on the timing and the duration of this prenatal surgical intervention.
2022-11-29 | Neonatal mortality in singleton pregnancies: a 20-year retrospective study from a tertiary perinatal unit in Hong Kong
The global neonatal death (NND) rate has been declining in recent decades, but there are no comprehensive data concerning the characteristics of NNDs in Hong Kong. This study investigated the trends and aetiologies of NNDs among singleton pregnancies in Hong Kong.This study included all cases of NND from singleton pregnancies in a tertiary hospital in Hong Kong between 2000 and 2019. The rates, clinical characteristics, and aetiologies of NND were compared between the first (2000-2009) and the second (2010-2019) decades.The NND rate decreased from 1.66/1000 livebirths (97 cases) in the first decade to 1.32/1000 livebirths (87 cases) in the second decade. Congenital or genetic abnormalities (82 cases) caused 44.6% of all NNDs. There was a significant reduction from 0.82/1000 livebirths in the first decade to 0.52/1000 livebirths in the second decade (P=0.037). Other causes of NND were prematurity (69 cases; 37.5%), sepsis (16 cases; 8.7%), hypoxic-ischaemic encephalopathy (15 cases; 8.2%), and sudden infant death syndrome (2 cases; 1.1%). Gestational age-specific neonatal mortality for moderately preterm neonates (31-33 weeks of gestation) significantly decreased from 34.73/1000 in 2000-2009 to 8.63/1000 in 2010-2019 (P=0.001), but there were no significant changes in neonatal mortality for other gestations.The NND rate in Hong Kong is among the lowest worldwide. Neonatal deaths in our centre declined over the past two decades, mainly because of improvements in the prenatal diagnosis and treatment of congenital or genetic abnormalities, as well as an improved survival rate among moderately preterm neonates.
other
2023-04-14 | Upregulated TSP1 and CD47 expression in the lung in nitrofen-induced congenital diaphragmatic hernia.
Persistent pulmonary hypertension remains a major cause of mortality and morbidity in congenital diaphragmatic hernia (CDH). The secreted glycoprotein thrombospondin-1 (TSP1), a ligand for receptor CD47, is widely expressed on both systemic and pulmonary vascular cells. TSP1-CD47 signaling has been reported to be one of the pathogeneses of pulmonary hypertension (PH). After creating a nitrofen-induced CDH rat model, fetuses were sacrificed on D17, D19 and D21 and divided into a control group and a CDH group. Quantitative real-time polymerase chain reaction was performed to determine the pulmonary gene expression of TSP1, CD47 and Runx3 (a regulator of TSP1). An immunofluorescence study was performed to evaluate the expression and localization of TSP1, CD47 and Runx3. The relative mRNA expression of pulmonary TSP1, CD47 and Runx3 on D21 was significantly increased in the CDH group (p = 0.005, p = 0.001, p = 0.046, and p = 0.002, respectively). The immunofluorescence study also confirmed the overexpression of TSP1, CD47 and Runx3 in the CDH group. Our results provide evidence that TSP1-CD47 signaling is involved in the pathogenesis of PH in a nitrofen-induced CDH model. Our data suggest that anti-CD47 antibodies can be novel therapeutic targets for the treatment of PH in CDH.
2023-04-14 | Role of microRNAs in Congenital Diaphragmatic Hernia-Associated Pulmonary Hypertension.
Epigenetic regulators such as microRNAs (miRNAs) have a key role in modulating several gene expression pathways and have a role both in lung development and function. One of the main pathogenetic determinants in patients with congenital diaphragmatic hernia (CDH) is pulmonary hypertension (PH), which is directly related to smaller lung size and pulmonary microarchitecture alterations. The aim of this review is to highlight the importance of miRNAs in CDH-related PH and to summarize the results covering this topic in animal and human CDH studies. The focus on epigenetic modulators of CDH-PH offers the opportunity to develop innovative diagnostic tools and novel treatment modalities, and provides a great potential to increase researchers' understanding of the pathophysiology of CDH.
2022-09-28 | Fibroblast-derived Hgf controls recruitment and expansion of muscle during morphogenesis of the mammalian diaphragm.
The diaphragm is a domed muscle between the thorax and abdomen essential for breathing in mammals. Diaphragm development requires the coordinated development of muscle, connective tissue, and nerve, which are derived from different embryonic sources. Defects in diaphragm development cause the common and often lethal birth defect, congenital diaphragmatic hernias (CDH). HGF/MET signaling is required for diaphragm muscularization, but the source of HGF and the specific functions of this pathway in muscle progenitors and effects on phrenic nerve have not been explicitly tested. Using conditional mutagenesis in mice and pharmacological inhibition of MET, we demonstrate that the pleuroperitoneal folds (PPFs), transient embryonic structures that give rise to the connective tissue in the diaphragm, are the source of HGF critical for diaphragm muscularization. PPF-derived HGF is directly required for recruitment of MET+ muscle progenitors to the diaphragm and indirectly (via its effect on muscle development) required for phrenic nerve primary branching. In addition, HGF is continuously required for maintenance and motility of the pool of progenitors to enable full muscularization. Localization of HGF at the diaphragm's leading edges directs dorsal and ventral expansion of muscle and regulates its overall size and shape. Surprisingly, large muscleless regions in HGF and Met mutants do not lead to hernias. While these regions are likely more susceptible to CDH, muscle loss is not sufficient to cause CDH.
2021-12-14 | Respiratory syncytial virus bronchiolitis in congenital diaphragmatic hernia: A systematic review of prevalence rates and palivizumab prophylaxis.
The seasonality of respiratory syncytial virus (RSV) epidemics have been disrupted during the COVID-19 pandemic, possibly because of lockdowns and social restrictions reducing viral transmission. Given uncertainties around the severity of upcoming RSV bronchiolitis epidemics, debate exists whether palivizumab (RSV prophylaxis) should be administered to infants with Congenital Diaphragmatic Hernia (CDH), who may be vulnerable due to lung hypoplasia and pulmonary hypertension. To evaluate (1) if CDH infants have higher risk of admission with RSV bronchiolitis than infants in the general population; (2) if palivizumab prophylaxis may reduce this risk. We included all eligible studies examining the risk(s) of RSV-positive bronchiolitis requiring hospital admission in (1) CDH infants without palivizumab prophylaxis versus infants in the general population and (2) CDH infants with prophylaxis versus CDH infants without prophylaxis. The primary outcome evaluated was the risk of admission with RSV bronchiolitis. Data are reported descriptively and meta-analysed when appropriate. Three eligible retrospective cohort studies were identified: one study found CDH to be an independent risk factor for RSV hospitalisation (odds ratio, 3.30; 95% confidence interval [CI], 2.01-4.4); two studies compared RSV hospitalisation rates in CDH patients who had palivizumab versus those that did not. The pooled risk ratio was 1.11 (95% CI, 0.29-4.23; p = .88). Overall, the quality of evidence was considered poor and one study was industry funded. Whether CDH infants are at particular risk of severe bronchiolitis remains unclear. There is no evidence from this current systematic review that CDH infants should routinely receive palivizumab vaccination prophylaxis.
2021-10-26 | Extracellular Vesicles and Their miRNA Content in Amniotic and Tracheal Fluids of Fetuses with Severe Congenital Diaphragmatic Hernia Undergoing Fetal Intervention.
Infants with congenital diaphragmatic hernia (CDH) are at high risk of postnatal mortality due to lung hypoplasia and arterial pulmonary hypertension. In severe cases, prenatal intervention by fetal endoscopic tracheal occlusion (FETO) can improve survival by accelerating lung growth. However, postnatal mortality remains in the range of about 50% despite fetal treatment, and there is currently no clear explanation for this different clinical response to FETO. We evaluated the concentration of extracellular vesicles (EVs) and associated microRNA expression in amniotic and tracheal fluids of fetuses with CDH undergoing FETO, and we examined the association between molecular findings and postnatal survival. We observed a higher count of EVs in the amniotic fluid of non-survivors and in the tracheal fluid sampled in utero at the time of reversal of tracheal occlusion, suggesting a pro-inflammatory lung reactivity that is already established in utero and that could be associated with a worse postnatal clinical course. In addition, we observed differential regulation of four EV-enclosed miRNAs (miR-379-5p, miR-889-3p; miR-223-3p; miR-503-5p) in relation to postnatal survival, with target genes possibly involved in altered lung development. Future research should investigate molecular therapeutic agents targeting differentially regulated miRNAs to normalize their expression and potentially improve clinical outcomes.
proteins
2026-08-25 | Testing the waters: the potential of urinary proteomics in congenital diaphragmatic hernia and Tetralogy of Fallot
Congenital diaphragmatic hernia (CDH) is a structural birth defect with an incidence of approximately 1 in 3000. 1 It is due to abnormalities in the development of the pleuroperitoneal folds resulting in herniation of the abdominal organs into the thoracic cavity, impairing proper lung development and function. As a result, patients suffer from pulmonary hypertension (PH), attributed to high pulmonary vascular resistance and abnormal vascular remodeling. 2 , 3 These vascular pathologies ultimately cause significant stress to the right ventricle (RV). Similar RV dysfunction, a leading cause of morbidity and mortality in neonates, is observed in patients with Tetralogy of Fallot (TOF), a congenital disorder caused by a combination of cardiovascular lesions involving ventricular septal defect, overriding aorta, pulmonary stenosis, and RV hypertrophy that occurs in about 3 out of 10,000 births. 4 While CDH and TOF are developmentally different disorders, both often result in PH and eventual RV dysfunction. In CDH, PH is attributed to high pulmonary vascular resistance, while in TOF, PH is primarily due to pulmonary outflow tract stenosis.
2026-08-06 | Vasopressin for hemodynamic support in neonates: current evidence and clinical applications.
To systematically map and synthesize the available evidence on the use of vasopressin for hemodynamic support in neonates. We conducted a scoping review to synthesize available data on indications, dosing, clinical effects, and safety. Twelve studies were included (one randomized trial, eleven observational), encompassing heterogeneous neonatal populations. Vasopressin was primarily used as rescue therapy in refractory shock, including sepsis, persistent pulmonary hypertension of the newborn, and congenital diaphragmatic hernia. Dosing regimens varied widely. Most studies reported improvements in mean arterial blood pressure, with some demonstrating reduced vasoactive support and improved oxygenation. Effects on urine output were variable. Safety reporting was inconsistent; hyponatremia was the most commonly described adverse event, while serious ischemic complications were rarely reported. Vasopressin may improve short-term hemodynamic parameters, but evidence is limited and heterogeneous, with insufficient data to guide optimal use.
2026-06-23 | Predictors of challenging initial intubation and association with outcomes in congenital diaphragmatic hernia.
To assess for differences in congenital diaphragmatic hernia patient characteristics between those requiring single or multiple intubation attempts, and to determine the relationship between number of intubation attempts and time to intubation with outcomes. This was a retrospective cohort study of 205 infants with congenital diaphragmatic hernia born at Texas Children's Hospital. Patient demographics and severity numbers were compared to number of laryngoscopies as a surrogate for intubation attempts. Number of laryngoscopies and time to intubation were compared to clinical outcomes. Binary logistic regression and receiver operating characteristic curve analysis were used. There was no significant difference in baseline characteristics or CDH severity in those requiring single or multiple attempts. Greater number of intubation attempts was not associated with adverse outcomes but there was a significant association between longer time to successful intubation and mortality and higher risk of tracheostomy or death before discharge. Each additional minute before successful intubation was associated with 28% higher odds of mortality (p = 0.031) and 42% higher odds of tracheostomy or death before discharge (p = 0.006) CONCLUSION: Delayed time to intubation but not number of intubation attempts was associated with higher mortality and risk of tracheostomy or death in babies with CDH. Prenatal information including receipt of the FETO procedure, CDH severity markers, gestational age and birth weight cannot reliably be used to predict the likelihood of challenging intubations in infants with CDH.
2026-02-04 | Antiseizure Prescription for Children With Severe Congenital Heart Defects and Children With Gastrointestinal Anomalies.
Children with congenital anomalies (CAs) are at an increased risk of developing epilepsy, but the relative risk (RR) for specific anomaly subtypes remains underexplored. This study aims to estimate the risk of epilepsy, as indicated by antiseizure medication (ASM) prescriptions, among children with various CAs compared to children without anomalies. We utilized data from six European regions participating in the European network for surveillance of congenital anomalies registries, covering births from 2000 to 2015. Children with major CAs, classified by International Classification of Diseases codes, were compared to a reference population without anomalies. Epilepsy was identified based on >1 ASM prescription within a year. RRs were calculated using mixed-effects models to account for registry-specific variations. The study included 60,662 children with anomalies and 1,722,912 reference children, with a mean follow-up of 5.5 years. By age 5 years, ASM prevalence was 17.8 per 1000 in anomaly groups and 2.0 per 1000 in reference children. The highest RRs were observed in children with central nervous system anomalies, including anomalies of the corpus callosum, severe microcephaly, and hydrocephalus. Comparable RRs were found in children with severe congenital heart defects and gastrointestinal anomalies, primarily driven by diaphragmatic hernia. Children with CAs have a significantly higher risk of epilepsy, with central nervous system, chromosomal, severe congenital heart defect, and diaphragmatic hernia being key contributors. This study highlights the importance of tailored monitoring and early intervention for high-risk groups to improve neurological outcomes.
2025-12-08 | Complex Fetal Anomalies: Kluth Type Xc2 Variant Tracheoesophageal Fistula, Srikanth Group III Bronchopulmonary Foregut Malformation, Mirror-Image Dextrocardia with L-Looped Ventricles, Anomalous Coronary Origin from the Pulmonary Artery, and Cardiac-Type Total Anomalous Pulmonary Venous Connection.
We report a fetus at 20 + 5 weeks' gestation with an exceptionally rare constellation of congenital anomalies. Prenatal imaging revealed left congenital diaphragmatic hernia, rightward cardiac displacement, possible tracheoesophageal fistula (TEF), transposition of the great vessels, and a large ventricular septal defect. Autopsy confirmed complete absence of tracheoesophageal separation from the larynx to the carina, consistent with Kluth type Xc2, incorporating extralobar pulmonary sequestration with esophageal communication. The findings met criteria for a communicating bronchopulmonary foregut malformation (CBPFM), Srikanth Group III. Additional anomalies included bilateral pulmonary hypoplasia, bilateral unilobar lungs with eparterial bronchi, mirror-image dextrocardia, L-looped ventricles with concordant atrioventricular and ventriculoarterial alignments, right-sided aortic arch, bilateral superior vena cava, cardiac-type total anomalous pulmonary venous connection with drainage into the morphologic right atrium, and anomalous coronary origin from the pulmonary artery. Cytogenetic studies and whole-exome sequencing were normal. To our knowledge, this is the first report of Kluth type Xc2 TEF with Srikanth Group III CBPFM since Stolte's original description in 1952, and the first to combine this unique constellation. This case broadens the recognized spectrum of foregut and cardiopulmonary maldevelopment and underscores the importance of comprehensive evaluation in fetuses with multiple anomalies.
small molecules
2026-08-19 | Systemic thrombolysis for an intracardiac thrombus in a premature child with a severe diaphragmatic hernia.
Intracardiac thrombus is a rare but difficult-to-treat complication in premature infants, with limited therapeutic options. If an urgent neonatal surgical procedure is needed, rescue systemic thrombolysis may be considered as an option to hasten thrombus resolution. In the present case, we illustrate the successful lysis of a right ventricle intracardiac thrombus in a premature child prior to a neonatal emergent surgery for a severe congenital diaphragmatic hernia. The 1-day-old premature child with right-sided diaphragmatic hernia contracted preoperatively a right ventricle thrombus in the context of an early-onset septic shock. Systemic low-dose thrombolysis with urokinase (2000 then 3000 U/kg/h) was infused for 6 days with resolution of the thrombus and no immediate or delayed intracranial or postcongenital diaphragmatic hernia hemorrhagic complication, performed 72 h after thrombolysis cessation. Low-dose thrombolysis should be discussed if rapid thrombus resolution is required in case of intracardiac thrombus without thrombectomy option.
2026-07-24 | Meta-analysis of prostacyclin therapy for persistent pulmonary hypertension with congenital diaphragmatic hernia.
To evaluate the efficacy and safety of prostacyclin in the treatment of persistent pulmonary hypertension in congenital diaphragmatic hernia. A systematic literature search was conducted in four main databases (PubMed, Web of Science, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL). The protocol was registered in advance in the International Prospective of Systematic Reviews (CRD420261325458). A total of nine studies were included involving a total of 7009 infants in this systematic review and meta-analysis. GRADE assessment revealed substantial heterogeneity in the quality of evidence across outcomes, with most outcomes rated very low quality and only one rated moderate quality. Studies were performed meta-analysis, which showed the use of prostacylin resulted a statistically significant decrease in the OI compared to the control group (Mean Difference (MD), 9.34; I2 0%; p < 0.00001), no statistically significant in mortality (OR, 0.83; I2 84%; p = 0.70), ECMO (OR = 4.9; I2 98%; p = 0.27), BNP (std MD, 6.98; I2 98%; p = 0.31), FiO2 (SMD = 8.0;, I2 64%; p = 0.11), Systolic orientation of IVS curvature (SMD = 0.69; I2 97%; p = 0.32), Diastolic orientation of IVS differences (MD = 0.62; I2 93% p = 0.26). After applying the Hartung-Knapp adjustment, with the exception of BNP, the pooled effects of the other outcomes were not statistically significant, and there was high heterogeneity in measures such as ECMO and ventricular septal curvature. In conclusion, this meta-analysis has confirmed that prostacyclin may temporarily improve oxygenation. However, after applying the Hartung-Knapp adjustment, with the exception of BNP, the pooled effects of the other outcomes were not statistically significant, and there was high heterogeneity in measures such as ECMO and ventricular septal curvature. Further validation through high-quality studies are still needed. PROSPERO: CRD420261325458.
2026-07-20 | Reduced KLF4 expression in endothelial cells triggers pulmonary vascular abnormalities associated with experimental congenital diaphragmatic hernia.
Congenital diaphragmatic hernia (CDH) is a rare anomaly with an incidence of 1 in 3000 live births and characterized by defective closure of the diaphragm, lung hypoplasia, and pulmonary vascular remodeling. Although several genes associated with the occurrence of CDH, no clear genetic component has been identified. Previously, we showed that CDH patients have vascular abnormalities already early in development, and that perivascular cells are affected in CDH. In the current study, we focused on early abnormalities in the nitrofen-induced CDH mouse model. Transcriptome analysis of FACS-sorted perivascular and endothelial cell populations from lungs of control and experimental mouse CDH revealed a high similarity in GO terms of differentially expressed genes (DEGs) between these populations, suggesting a disturbed interaction between endothelial cells and pericytes. The disturbed interaction is the basis for the aberrant development of the pulmonary vasculature in CDH. Furthermore, the RNA sequence data revealed reduced expression of the Kruppel like factor 4 (Klf4) gene in endothelial cells of CDH, which was confirmed with protein expression analysis. Furthermore, we show that KLF4 is an important up stream regulator of genes associated with vascular development and confirm that members of the NOTCH signaling pathway are differentially expressed, indicating that NOTCH signaling is disturbed in CDH. Collectively, our data support the importance of KLF4 in pulmonary angiogenesis and contribute to our previous data that pulmonary vessels in CDH patients are already affected before birth, which in turn may impact therapeutic strategies to reduce pulmonary hypertension associated with CDH.
2026-07-17 | Pulse pressure as an early mortality predictor in neonates with congenital diaphragmatic hernia on veno-arterial ECMO.
Early prognostic markers for pediatric patients receiving extracorporeal membrane oxygenation (ECMO), particularly those with congenital diaphragmatic hernia (CDH), remain poorly defined. This study aimed to evaluate pulse pressure (PP) as an early hemodynamic indicator of mortality in neonates with CDH undergoing veno-arterial (VA) ECMO. We retrospectively analyzed newborns who underwent VA ECMO as primary rescue therapy for isolated CDH. Perinatal characteristics, arterial blood gas parameters, and blood pressure (BP) during the first 48 h post-ECMO were evaluated and compared between survivors and non-survivors. Among 33 neonates, 20 (60.6%) survived. ECMO flow rates or systolic, diastolic, and mean BP did not differ between the group. However, PP at 24 h (20.0 mmHg [17.8-26.3] vs. 12.0 mmHg [10.0-13.0], p < 0.001) and 48 h (24.0 mmHg [20.0-28.8] vs. 12.0 mmHg [10.0-14.0], p < 0.001) post-ECMO was significantly higher in survivors. Receiver operating characteristic analysis demonstrated that PP was am early predictor of survival, with optimal cutoff values of 20 mmHg at 24 h and 17 mmHg at 48 h. Early recovery of PP was a strong predictor of survival in neonates with CDH requiring VA-ECMO. Further research is required to determine whether interventions to enhance pulsatility can improve clinical outcomes in this high-risk population.
2026-06-24 | Targeted use of Prostaglandin E1 Therapy in “Duct-dependent” Congenital Diaphragmatic Hernia
Dana Levinkopf, Abhijit Bhattacharya, David Healy, Giulia Vanina Cantone, Anna Claudia Massolo, Flaminia Pugnaloni, Ann Marie Heuchan, Florian Kipfmueller,
cell therapies
2026-09-28 | MODERN APPROACHES TO THE DIAGNOSIS AND TREATMENT OF CONGENITAL DIAPHRAGMATIC HERNIA IN CHILDREN: A LITERATURE REVIEW
Congenital diaphragmatic hernia (CDH) in children is a severe congenital disorder whose clinical course is determined not only by the presence of a diaphragmatic defect but also by the degree of pulmonary hypoplasia, persistent pulmonary hypertension, and associated congenital anomalies. Despite advances in prenatal diagnosis, neonatal intensive care, and modern surgical technologies, the management of neonates with severe forms of CDH remains challenging, and optimal approaches to prognostic assessment and treatment selection continue to evolve. OBJECTIVE. To systematize and critically analyze current evidence regarding the etiology, pathogenesis, diagnosis, treatment, and prognosis of congenital diaphragmatic hernia in children based on the principles of evidence-based medicine. MATERIALS AND METHODS. A systematic search, content analysis, descriptive analysis, and comparative analysis of current scientific literature, systematic reviews, meta-analyses, multicenter clinical studies, international guidelines, and consensus documents on CDH were performed. The search was conducted in the PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar databases. Publications addressing the pathogenesis, prenatal and postnatal diagnosis, intensive care, surgical treatment, and prognostic assessment of CDH were included in the analysis; more than 90 sources were reviewed at the initial stage. RESULTS. The main prognostic factors in CDH were found to include the degree of pulmonary hypoplasia, severity of pulmonary hypertension, size of the diaphragmatic defect, intrathoracic liver position, and presence of associated congenital anomalies. Current prenatal diagnosis is based on ultrasonography with assessment of the lung-to-head ratio (LHR) and observed-to-expected LHR (O/E LHR), supplemented by fetal magnetic resonance imaging (MRI) to determine lung volume and anatomical characteristics. The fundamental principle of postnatal management is “stabilization before operation,” including early intubation, gentle ventilation, gastric decompression, management of pulmonary hypertension, and, when indicated, high-frequency ventilation, inhaled nitric oxide, and extracorporeal membrane oxygenation (ECMO). Surgical repair is performed after cardiorespiratory stabilization has been achieved. Thoracoscopic and laparoscopic techniques may be used in stable patients, whereas the choice of repair technique is determined by the size of the defect and the availability of native diaphragmatic tissue. Promising areas of development include fetoscopic endoluminal tracheal occlusion (FETO), advances in minimally invasive technologies, biocompatible materials, and personalized treatment approaches. CONCLUSIONS. Current management of congenital diaphragmatic hernia in children should be based on a comprehensive multidisciplinary approach involving early prenatal diagnosis, prognostic assessment, and stabilization of the neonate prior to surgical repair. The combination of modern intensive care strategies, minimally invasive surgery, ECMO, and selective use of FETO expands the therapeutic options for severe forms of CDH. Further research is needed to refine prognostic models, standardize indications for fetal and extracorporeal therapies, and improve long-term treatment outcomes.
2026-08-06 | Bioprinting of BSA membranes with C2C12 and NIH 3T3 pre-cellularized PLGA microscaffold : a step toward diaphragmatic hernia patches.
The diaphragm is a physical barrier separating the thoracic and abdominal cavities. Its physiological function is fundamental to pulmonary ventilation. Congenital diaphragmatic hernia (CDH) is a malformation that leaves a hole in the diaphragm during fetal development. Synthetic nondegradable membranes are currently used for the repair of diaphragm holes. However, these membranes do not help cells to adhere and proliferate. There is a need for biodegradable membranes composed of muscular and fibroblast cells to replicate a simplified diaphragmatic tissue. We thus developed a biocompatible and biodegradable salt-compacted albumin membrane. C2C12 myoblasts were bioprinted as central spokes, surrounded by a ring of NIH 3T3 fibroblasts, onto albumin membranes. We used bioink based on methacrylated collagen and hyaluronic acid, containing porous poly(D,L-lactic-co-glycolic acid) solid microscaffolds to protect myoblast and fibroblast cells against mechanical stress during extrusion printing. We found that metabolic activity of C2C12 myoblast increased by 215% in the presence of a polylysine-coated microscaffolds, compared to those cultured without microscaffolds. Microscaffolds loaded with C2C12 and NIH 3T3 cells increased viability (30% and 15%) and cell activity (527% and 567%) either after co-culture (5.6% increased viability and 588% cell activity) bioprinting on albumin membrane, compared to cells in bioink without microscaffolds. Cell-loaded microscaffolds embedded in bioink enhance C2C12 to NIH3T3 cross-migration on albumin membrane. This work is a preliminary proof of concept of cellularization of myoblasts and fibroblasts by extrusion bioprinting on a new biodegradable albumin membrane designed for diaphragmatic hernia patches.
2026-07-30 | Transamniotic stem cell therapy (TRASCET).
Transamniotic stem cell therapy (TRASCET) constitutes the least invasive approach to prenatal stem cell delivery described to date. This strategy is largely based on the recently discovered active transport of donor cells from the amniotic fluid to the placenta directly through the amnio-placental interface. From a simple amniocentesis, via the placenta, donor cells of different phenotypes can reach the fetal circulation and virtually any fetal anatomical site, including, and particularly, the fetal bone marrow. As a result, TRASCET has shown broad therapeutic potential in an assortment of animal models. First reported experimentally only a little over a decade ago, it has yet to be attempted clinically, though clinical translation may be imminent. Much of TRASCET's appeal lies in the fact that, in large part, it constitutes a form of replenishment therapy based on the magnification of naturally occurring processes in the distinctive environment of the maternal-fetal unit. Despite significant experimental advances, much promise and perhaps excessive publicity, most cell-based therapies have yet to deliver meaningful large-scale impact to patient care. The few exceptions have been therapies based on the amplification of the normal biological role played by donor cells in their natural environment. TRASCET falls in that category. Further, while fetal stem cells possess unique characteristics when compared with postnatal stem cells, so does the fetus when compared with any other age group, converging into a scenario that enables therapeutic paradigms exclusive to prenatal life. This review summarizes the biological basis, diversity of applications and operability of the TRASCET principle.
2026-07-21 | Extracellular vesicles in perinatal conditions: A minimally invasive approach to regenerative medicine.
Extracellular vesicles (EVs) are lipid bilayer-delimited nanoparticles released by cells to act as mediators of intercellular communication during organ development, injury, and repair. EVs carry cargo (bioactive proteins, lipids, and nucleic acids) that reflects the status of the parent cell and is transferred to recipient cells to regulate biological processes, such as inflammation, immune responses, and tissue regeneration. These properties have made EVs promising tools for investigating disease pathogenesis, improving diagnostic and prognostic accuracy, and developing cell-free regenerative therapies for conditions characterized by dysregulation of multiple biological pathways. EVs are particularly relevant in diseases that affect the pediatric population where pathogenesis often remains poorly understood, access to affected tissues is limited, and treatment options are frequently inadequate. This review summarizes current evidence on EV applications in fetal and neonatal disorders, including necrotizing enterocolitis, congenital diaphragmatic hernia, and bronchopulmonary dysplasia, and highlights emerging data in biliary atresia, spina bifida, short bowel syndrome, and Hirschsprung's disease. In this age group, human milk and amniotic fluid represent particularly attractive biologically accessible sources of EVs, combining therapeutic potential with feasibility of clinical application. Building on robust preclinical evidence, the field is now advancing toward clinical translation, but several aspects still need to be addressed such as cargo heterogeneity, scalability of production, dosing, biodistribution, safety, and regulatory standardization. Herein, we discuss the translational challenges and future directions that will shape the clinical application of EVs in perinatal conditions.
2026-06-01 | Risk Stratification and Fetal Therapies for Congenital Diaphragmatic Hernia.
Congenital diaphragmatic hernia (CDH) remains one of the most challenging congenital anomalies encountered by neonatologists and pediatric surgeons, with outcomes largely determined before birth. Although surgical repair of the diaphragmatic defect is essential, postnatal morbidity and mortality are primarily driven by antenatal pulmonary hypoplasia, abnormal pulmonary vascular development, and associated cardiac dysfunction that culminate in respiratory failure and pulmonary hypertension. Advances in prenatal imaging have enabled increasingly refined risk stratification, allowing for the identification of fetuses who are at highest risk for postnatal cardiopulmonary failure. Within this framework, fetal therapies, most notably fetoscopic endoluminal tracheal occlusion, have emerged as the first interventions shown to improve survival in carefully selected cases of severe CDH. However, uncertainty persists regarding optimal patient selection, timing, complications, and the generalizability of outcomes across health care systems. In this review, we examine the pathophysiologic rationale for fetal lung recruitment therapies, contemporary approaches to prenatal diagnosis and severity stratification, and the evidence supporting current fetal interventions. We also discuss how fetal therapy alters postnatal surgical and extracorporeal membrane oxygenation decision-making and highlight emerging prenatal strategies aimed at modifying lung and vascular development before birth. By framing CDH as a prenatal cardiopulmonary disease with postnatal surgical manifestations, we aim to provide a cohesive framework for multidisciplinary counseling, referral, and perioperative planning in the evolving era of fetal therapy.
gene therapies
2026-05-13 | Modeling patient variants of Cnot1 and Cdc42bpb results in distinct forms of congenital diaphragmatic hernia in mice.
Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly characterized by impairment of both diaphragm and lung development in utero. CDH presents as a spectrum of forms and severities, with diaphragm defects arising in the dorsal/posterior region typically correlating with more severe pulmonary disease and higher risk of mortality than those appearing in ventral/anterior regions. The genetic etiology underlying CDH is complex, with many genes implicated showing variable expressivity and incomplete penetrance in both human patients and mouse models. Here we present in vivo validation of two genes previously unassociated with CDH: the CDC42-interacting kinase CDC42BPB; and CNOT1, a scaffolding protein of the CCR4-NOT protein complex, critical for mRNA regulation through modifications such as deadenylation. Each gene was found to have a damaging, de novo missense variant in a recent large-scale CDH patient sequencing screen. Loss of Cdc42bpb leads to ventral diaphragmatic hernias, heart septal defects and minor lung epithelial differentiation defects in mouse embryos. Installation of the orthologous patient-specific missense variant through CRISPR/Cas9 editing leads to less severe ventral diaphragm defects. Mouse embryos with either one or two copies of the orthologous Cnot1 variant, c.1867C>T (p.R623W), develop dorsal diaphragmatic hernias with low (<50%) penetrance, and mutants showed alterations in mRNA isoform expression consistent with the molecular role of Cnot1 in RNA splicing. These results underscore the power of in vivo functional modeling to validate genes and patient-specific variants uncovered by patient sequencing, reveal two previously unrecognized genetic causes of CDH, and highlight the heterogeneity of different patient anatomic presentations.
2025-12-14 | Clinical trials in fetal surgery - changing care for complex pregnancies.
Fetal therapy has continued to expand in treatable conditions and surgical approaches. To maintain the evidence-based approach to optimizing patient care and outcomes, clinical trials investigating these interventions is essential. All trials must take in consideration both the potential benefit to the fetus or fetuses with the maternal and perinatal risks. In this review we discuss clinical trials in fetal therapy which have changed the field and provided the highest level of evidence possible. Large-scale trials have been performed in the management of Twin-to-Twin Transfusion Syndrome (TTTS), Spina bifida, Lower Urinary Tract Obstruction (LUTO) and Congenital Diaphragmatic Hernia (CDH). As molecular biology and advanced prenatal diagnostics continues to develop, future trials in gene and enzyme therapy remain on the horizon.
2025-07-30 | Advances in Fetal Surgery: A Narrative Review of Therapeutic Interventions and Future Directions.
Fetal surgery has emerged as a viable option for the management of selected congenital anomalies that result in severe or lethal outcomes if left untreated until birth. Conditions such as spina bifida, urinary tract obstruction, congenital cystic adenomatoid malformation, diaphragmatic hernia, sacrococcygeal teratoma, and twin-twin transfusion syndrome have shown improved prognosis after in utero intervention, open, or fetoscopically. Despite significant advances in surgical methods and anesthesia, preterm labor remains a primary concern. Stem cell transplantation and in utero gene therapy are developing, and they have the potential to expand the treatment window, as they minimize maternal complications. Hematopoietic stem cell transplantation, which is based on the immaturity of the fetal immune system, is a promising treatment for inherited disorders. Although many procedures of fetal interventions are now established, their safety and efficacy must be ensured and this requires optimal patient selection and choice of appropriate timing for intervention, adherence to ethical principles, and continuous research. Therefore, a multidisciplinary team, including specialists in maternal-fetal medicine, pediatric surgery, anesthesiology, neonatology, psychosocial support, and bioethics, is essential to guide comprehensive, patient-centered care. Fetal surgery is an evolving field that offers hope for conditions previously considered untreatable before birth.
2024-12-11 | Fetal Tracheal Occlusion Correlates with Normalized YAP Expression and Alveolar Epithelial Differentiation in Congenital Diaphragmatic Hernia.
Congenital diaphragmatic hernia (CDH) is characterized by incomplete closure of the diaphragm. Although the ensuing compression to the fetal lung causes lung hypoplasia, specific cellular phenotypes and developmental signaling defects in the alveolar epithelium in CDH are not fully understood. Employing lung samples from human CDH, a surgical lamb model, and a nitrofen rat model, we investigated whether lung compression impairs alveolar epithelial differentiation and Yes-associated protein (YAP)-mediated mechanosensing. We showed that CDH in humans and lambs caused defective alveolar epithelial differentiation manifested by more alveolar epithelial type II (ATII) cells, fewer ATI cells, and the emergence of cells coexpressing ATI and ATII markers. Associated with these alveolar epithelial defects, we found a decrease in the level and nuclear localization of YAP. Reduced YAP and abnormal distal lung development were evident as early as 21 weeks of gestation in human CDH. In addition, rat fetuses with CDH also showed diminished nuclear YAP and more abundant ATII cells. In contrast, the littermates without the hernia had no such alveolar phenotypes. Furthermore, fetal tracheal occlusion in the surgical lamb model of CDH fully normalized nuclear YAP and rescued alveolar epithelial defects in a gestational age-dependent manner. Taken together, our findings across species indicate that lung compression in CDH is sufficient to disrupt alveolar epithelial differentiation and impair YAP signaling. Tracheal occlusion can restore nuclear YAP and rescue the alveolar defects in CDH, depending on the timing and the duration of this prenatal surgical intervention.
2022-11-29 | Neonatal mortality in singleton pregnancies: a 20-year retrospective study from a tertiary perinatal unit in Hong Kong
The global neonatal death (NND) rate has been declining in recent decades, but there are no comprehensive data concerning the characteristics of NNDs in Hong Kong. This study investigated the trends and aetiologies of NNDs among singleton pregnancies in Hong Kong.This study included all cases of NND from singleton pregnancies in a tertiary hospital in Hong Kong between 2000 and 2019. The rates, clinical characteristics, and aetiologies of NND were compared between the first (2000-2009) and the second (2010-2019) decades.The NND rate decreased from 1.66/1000 livebirths (97 cases) in the first decade to 1.32/1000 livebirths (87 cases) in the second decade. Congenital or genetic abnormalities (82 cases) caused 44.6% of all NNDs. There was a significant reduction from 0.82/1000 livebirths in the first decade to 0.52/1000 livebirths in the second decade (P=0.037). Other causes of NND were prematurity (69 cases; 37.5%), sepsis (16 cases; 8.7%), hypoxic-ischaemic encephalopathy (15 cases; 8.2%), and sudden infant death syndrome (2 cases; 1.1%). Gestational age-specific neonatal mortality for moderately preterm neonates (31-33 weeks of gestation) significantly decreased from 34.73/1000 in 2000-2009 to 8.63/1000 in 2010-2019 (P=0.001), but there were no significant changes in neonatal mortality for other gestations.The NND rate in Hong Kong is among the lowest worldwide. Neonatal deaths in our centre declined over the past two decades, mainly because of improvements in the prenatal diagnosis and treatment of congenital or genetic abnormalities, as well as an improved survival rate among moderately preterm neonates.
other
2023-04-14 | Upregulated TSP1 and CD47 expression in the lung in nitrofen-induced congenital diaphragmatic hernia.
Persistent pulmonary hypertension remains a major cause of mortality and morbidity in congenital diaphragmatic hernia (CDH). The secreted glycoprotein thrombospondin-1 (TSP1), a ligand for receptor CD47, is widely expressed on both systemic and pulmonary vascular cells. TSP1-CD47 signaling has been reported to be one of the pathogeneses of pulmonary hypertension (PH). After creating a nitrofen-induced CDH rat model, fetuses were sacrificed on D17, D19 and D21 and divided into a control group and a CDH group. Quantitative real-time polymerase chain reaction was performed to determine the pulmonary gene expression of TSP1, CD47 and Runx3 (a regulator of TSP1). An immunofluorescence study was performed to evaluate the expression and localization of TSP1, CD47 and Runx3. The relative mRNA expression of pulmonary TSP1, CD47 and Runx3 on D21 was significantly increased in the CDH group (p = 0.005, p = 0.001, p = 0.046, and p = 0.002, respectively). The immunofluorescence study also confirmed the overexpression of TSP1, CD47 and Runx3 in the CDH group. Our results provide evidence that TSP1-CD47 signaling is involved in the pathogenesis of PH in a nitrofen-induced CDH model. Our data suggest that anti-CD47 antibodies can be novel therapeutic targets for the treatment of PH in CDH.
2023-04-14 | Role of microRNAs in Congenital Diaphragmatic Hernia-Associated Pulmonary Hypertension.
Epigenetic regulators such as microRNAs (miRNAs) have a key role in modulating several gene expression pathways and have a role both in lung development and function. One of the main pathogenetic determinants in patients with congenital diaphragmatic hernia (CDH) is pulmonary hypertension (PH), which is directly related to smaller lung size and pulmonary microarchitecture alterations. The aim of this review is to highlight the importance of miRNAs in CDH-related PH and to summarize the results covering this topic in animal and human CDH studies. The focus on epigenetic modulators of CDH-PH offers the opportunity to develop innovative diagnostic tools and novel treatment modalities, and provides a great potential to increase researchers' understanding of the pathophysiology of CDH.
2022-09-28 | Fibroblast-derived Hgf controls recruitment and expansion of muscle during morphogenesis of the mammalian diaphragm.
The diaphragm is a domed muscle between the thorax and abdomen essential for breathing in mammals. Diaphragm development requires the coordinated development of muscle, connective tissue, and nerve, which are derived from different embryonic sources. Defects in diaphragm development cause the common and often lethal birth defect, congenital diaphragmatic hernias (CDH). HGF/MET signaling is required for diaphragm muscularization, but the source of HGF and the specific functions of this pathway in muscle progenitors and effects on phrenic nerve have not been explicitly tested. Using conditional mutagenesis in mice and pharmacological inhibition of MET, we demonstrate that the pleuroperitoneal folds (PPFs), transient embryonic structures that give rise to the connective tissue in the diaphragm, are the source of HGF critical for diaphragm muscularization. PPF-derived HGF is directly required for recruitment of MET+ muscle progenitors to the diaphragm and indirectly (via its effect on muscle development) required for phrenic nerve primary branching. In addition, HGF is continuously required for maintenance and motility of the pool of progenitors to enable full muscularization. Localization of HGF at the diaphragm's leading edges directs dorsal and ventral expansion of muscle and regulates its overall size and shape. Surprisingly, large muscleless regions in HGF and Met mutants do not lead to hernias. While these regions are likely more susceptible to CDH, muscle loss is not sufficient to cause CDH.
2021-12-14 | Respiratory syncytial virus bronchiolitis in congenital diaphragmatic hernia: A systematic review of prevalence rates and palivizumab prophylaxis.
The seasonality of respiratory syncytial virus (RSV) epidemics have been disrupted during the COVID-19 pandemic, possibly because of lockdowns and social restrictions reducing viral transmission. Given uncertainties around the severity of upcoming RSV bronchiolitis epidemics, debate exists whether palivizumab (RSV prophylaxis) should be administered to infants with Congenital Diaphragmatic Hernia (CDH), who may be vulnerable due to lung hypoplasia and pulmonary hypertension. To evaluate (1) if CDH infants have higher risk of admission with RSV bronchiolitis than infants in the general population; (2) if palivizumab prophylaxis may reduce this risk. We included all eligible studies examining the risk(s) of RSV-positive bronchiolitis requiring hospital admission in (1) CDH infants without palivizumab prophylaxis versus infants in the general population and (2) CDH infants with prophylaxis versus CDH infants without prophylaxis. The primary outcome evaluated was the risk of admission with RSV bronchiolitis. Data are reported descriptively and meta-analysed when appropriate. Three eligible retrospective cohort studies were identified: one study found CDH to be an independent risk factor for RSV hospitalisation (odds ratio, 3.30; 95% confidence interval [CI], 2.01-4.4); two studies compared RSV hospitalisation rates in CDH patients who had palivizumab versus those that did not. The pooled risk ratio was 1.11 (95% CI, 0.29-4.23; p = .88). Overall, the quality of evidence was considered poor and one study was industry funded. Whether CDH infants are at particular risk of severe bronchiolitis remains unclear. There is no evidence from this current systematic review that CDH infants should routinely receive palivizumab vaccination prophylaxis.
2021-10-26 | Extracellular Vesicles and Their miRNA Content in Amniotic and Tracheal Fluids of Fetuses with Severe Congenital Diaphragmatic Hernia Undergoing Fetal Intervention.
Infants with congenital diaphragmatic hernia (CDH) are at high risk of postnatal mortality due to lung hypoplasia and arterial pulmonary hypertension. In severe cases, prenatal intervention by fetal endoscopic tracheal occlusion (FETO) can improve survival by accelerating lung growth. However, postnatal mortality remains in the range of about 50% despite fetal treatment, and there is currently no clear explanation for this different clinical response to FETO. We evaluated the concentration of extracellular vesicles (EVs) and associated microRNA expression in amniotic and tracheal fluids of fetuses with CDH undergoing FETO, and we examined the association between molecular findings and postnatal survival. We observed a higher count of EVs in the amniotic fluid of non-survivors and in the tracheal fluid sampled in utero at the time of reversal of tracheal occlusion, suggesting a pro-inflammatory lung reactivity that is already established in utero and that could be associated with a worse postnatal clinical course. In addition, we observed differential regulation of four EV-enclosed miRNAs (miR-379-5p, miR-889-3p; miR-223-3p; miR-503-5p) in relation to postnatal survival, with target genes possibly involved in altered lung development. Future research should investigate molecular therapeutic agents targeting differentially regulated miRNAs to normalize their expression and potentially improve clinical outcomes.
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Drug Discovery Landscape
2 orphan drug designations for Congenital diaphragmatic hernia.
2 orphan drug designations for Congenital diaphragmatic hernia.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Rhizobium rhizogenes, lipopolysaccharide | other | EMA | — | Crazy Science & Business S.L. |
Sildenafil | small molecules | EMA | Avivia Beheer BV |
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