Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Congenital diaphragmatic hernia

Abstract

Congenital diaphragmatic hernia (CDH) is a rare birth defect characterized by incomplete closure of the diaphragm and herniation of fetal abdominal organs into the chest that results in pulmonary hypoplasia, postnatal pulmonary hypertension owing to vascular remodelling and cardiac dysfunction. The high mortality and morbidity rates associated with CDH are directly related to the severity of cardiopulmonary pathophysiology. Although the aetiology remains unknown, CDH has a polygenic origin in approximately one-third of cases. CDH is typically diagnosed with antenatal ultrasonography, which also aids in risk stratification, alongside fetal MRI and echocardiography. At specialized centres, prenatal management includes fetal endoscopic tracheal occlusion, which is a surgical intervention aimed at promoting lung growth in utero. Postnatal management focuses on cardiopulmonary stabilization and, in severe cases, can involve extracorporeal life support. Clinical practice guidelines continue to evolve owing to the rapidly changing landscape of therapeutic options, which include pulmonary hypertension management, ventilation strategies and surgical approaches. Survivors often have long-term, multisystem morbidities, including pulmonary dysfunction, gastroesophageal reflux, musculoskeletal deformities and neurodevelopmental impairment. Emerging research focuses on small RNA species as biomarkers of severity and regenerative medicine approaches to improve fetal lung development.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Diagram of a left Bochdalek CDH, showing liver up and mediastinal shift to the right along with cardiopulmonary compression.
Fig. 2: Schematic drawings and ultrasonography images of relevant sections for calculation of the observed/expected lung-to-head ratio.
Fig. 3: Congenital Diaphragmatic Hernia Study Group defect size diagram, drawn with the diaphragm (defect) on the patient’s left looking up from the abdomen towards the chest.
Fig. 4: Schematic representation of FETO procedure.
Fig. 5: Pathophysiological mechanisms, postnatal phenotypes and management strategies in CDH12,65,66,158,177,178,179,182,193,194,197,201.
Fig. 6: Long-term quality of life, comorbidities and interventions in patients with CDH.

References

  1. Stolar, C. J. H., Dillion, P. W. in Pediatric Surgery (eds. Grosfeld, L., O’Neill J. A., Fonkalsrud E. W. & Coran, A. G.). 809–824 (Mosby, 2012).

  2. Zani, A. & Cozzi, D. A. Giovanni Battista Morgagni and his contribution to pediatric surgery. J. Pediatr. Surg. 43, 729–733 (2008).

    PubMed  Google Scholar 

  3. Montalva, L., Zani, A. in Pearls and Tricks in Pediatric Surgery (eds Lacher, M., St. Peter, S. D. & Zani, A.). 25–34 (Springer, 2021).

  4. Donahoe, P. K., Longoni, M. & High, F. A. Polygenic causes of Congenital Diaphragmatic Hernia produce common lung pathologies. Am. J. Pathol. 186, 2532–2543 (2016). This comprehensive review paper describes the pathogenesis of CDH, specifying cellular and molecular level alterations in fetal hypoplastic lungs.

    PubMed  PubMed Central  Google Scholar 

  5. Byrne, F. A. et al. Severe left diaphragmatic hernia limits size of fetal left heart more than does right diaphragmatic hernia. Ultrasound Obstet. Gynecol. 46, 688–694 (2015).

    CAS  PubMed  Google Scholar 

  6. Ferguson, D. M. et al. Early, postnatal pulmonary hypertension severity predicts inpatient outcomes in congenital diaphragmatic hernia. Neonatology 118, 147–154 (2021).

    PubMed  Google Scholar 

  7. Patel, N. et al. Ventricular dysfunction is a critical determinant of mortality in congenital diaphragmatic hernia. Am. J. Respir. Crit. Care. Med. 200, 1522–1530 (2019). This multicentre prospective study showed that early postnatal ventricular dysfunction occurs frequently in infants with CDH and can be used as an independent marker of severity and clinical outcome.

    PubMed  Google Scholar 

  8. Harting, M. T. & Lally, K. P. The Congenital Diaphragmatic Hernia Study Group registry update. Semin. Fetal Neonatal Med. 19, 370–375 (2014).

    PubMed  Google Scholar 

  9. Wright, N. J. et al. Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study. Lancet 398, 325–339 (2021).

    Google Scholar 

  10. Spoel, M. et al. Lung function in young adults with congenital diaphragmatic hernia; a longitudinal evaluation. Pediatr. Pulmonol. 48, 130–137 (2013).

    PubMed  Google Scholar 

  11. Putnam, L. R. et al. Congenital diaphragmatic hernia defect size and infant morbidity at discharge. Pediatrics 138, e20162043 (2016).

    PubMed  Google Scholar 

  12. Jancelewicz, T. et al. Survival benefit associated with the use of extracorporeal life support for neonates with congenital diaphragmatic hernia. Ann. Surg. 275, e256–e263 (2022). This retrospective cohort study analysed the use of ECLS in a large number of patients with CDH and concluded that ECLS use is associated with a significant survival advantage in infants at high risk who are treated in centres with a high CDH volume and ECLS experience.

    PubMed  Google Scholar 

  13. Faraoni, D., Nasr, V. G., DiNardo, J. A. & Thiagarajan, R. R. Hospital costs for neonates and children supported with extracorporeal membrane oxygenation. J. Pediatr. 169, 69–75.e1 (2016).

    PubMed  Google Scholar 

  14. Raval, M. V., Wang, X., Reynolds, M. & Fischer, A. C. Costs of congenital diaphragmatic hernia repair in the United States-extracorporeal membrane oxygenation foots the bill. J. Pediatr. Surg. 46, 617–624 (2011).

    PubMed  Google Scholar 

  15. Snyder, A. N., Cheng, T. & Burjonrappa, S. A nationwide database analysis of demographics and outcomes related to extracorporeal membrane oxygenation (ECMO) in congenital diaphragmatic hernia. Pediatr. Surg. Int. 37, 1505–1513 (2021).

    PubMed  Google Scholar 

  16. Lewit, R. A. & Jancelewicz, T. Sources of regional and center-level variability in survival and cost of care for congenital diaphragmatic hernia (CDH). J. Pediatr. Surg. 56, 130–135 (2021).

    PubMed  Google Scholar 

  17. Cameron, D. B. et al. Quantifying the burden of interhospital cost variation in pediatric surgery: Implications for the prioritization of comparative effectiveness research. JAMA Pediatr. 171, e163926 (2017).

    PubMed  Google Scholar 

  18. Paoletti, M. et al. Prevalence and risk factors for congenital diaphragmatic hernia: a global view. J. Pediatr. Surg. 55, 2297–2307 (2020). This systematic review of the literature collates all population-based studies conducted on patients with CDH worldwide. This analysis reports the global prevalence of CDH and its associated risk factors and highlights the paucity of epidemiological studies for this condition.

    PubMed  Google Scholar 

  19. McGivern, M. R. et al. Epidemiology of Congenital Diaphragmatic Hernia in Europe: a register-based study. Arch. Dis. Child. Fetal Neonatal Ed. 100, F137–F144 (2015).

    PubMed  Google Scholar 

  20. Yang, W., Carmichael, S. L., Harris, J. A. & Shaw, G. M. Epidemiologic characteristics of congenital diaphragmatic hernia among 2.5 million California births, 1989-1997. Birth Defects Res. A. Clin. Mol. Teratol. 76, 170–174 (2006).

    CAS  PubMed  Google Scholar 

  21. Dott, M. M., Wong, L. Y. & Rasmussen, S. A. Population-based study of congenital diaphragmatic hernia: risk factors and survival in Metropolitan Atlanta, 1968-1999. Birth Defects Res. A. Clin. Mol. Teratol. 67, 261–267 (2003).

    CAS  PubMed  Google Scholar 

  22. Harrison, M. R., Bjordal, R. I., Langmark, F. & Knutrud, O. Congenital diaphragmatic hernia: the hidden mortality. J. Pediatr. Surg. 13, 227–230 (1978).

    CAS  PubMed  Google Scholar 

  23. Burgos, C. M. & Frenckner, B. Addressing the hidden mortality in CDH: a population-based study. J. Pediatr. Surg. 52, 522–525 (2017).

    PubMed  Google Scholar 

  24. Gallot, D. et al. Antenatal detection and impact on outcome of congenital diaphragmatic hernia: a 12-year experience in Auvergne, France. Eur. J. Obstet. Gynecol. Reprod. Biol. 125, 202–205 (2006).

    PubMed  Google Scholar 

  25. Balayla, J. & Abenhaim, H. A. Incidence, predictors and outcomes of congenital diaphragmatic hernia: a population-based study of 32 million births in the United States. J. Matern. Fetal Neonatal Med. 27, 1438–1444 (2014).

    PubMed  Google Scholar 

  26. Bétrémieux, P. et al. Congenital diaphragmatic hernia: prenatal diagnosis permits immediate intensive care with high survival rate in isolated cases. A population-based study. Prenat. Diagn. 24, 487–493 (2004).

    PubMed  Google Scholar 

  27. Hautala, J. et al. Congenital diaphragmatic hernia with heart defect has a high risk for hypoplastic left heart syndrome and major extra-cardiac malformations: 10-year national cohort from Finland. Acta Obstet. Gynecol. Scand. 97, 204–211 (2018).

    PubMed  Google Scholar 

  28. Lee, H. S., Dickinson, J. E., Tan, J. K., Nembhard, W. & Bower, C. Congenital diaphragmatic hernia: Impact of contemporary management strategies on perinatal outcomes. Prenat. Diagn. 38, 1004–1012 (2018).

    PubMed  Google Scholar 

  29. Doné, E. et al. Prenatal diagnosis, prediction of outcome and in utero therapy of isolated congenital diaphragmatic hernia. Prenat. Diagn. 28, 581–591 (2008).

    PubMed  Google Scholar 

  30. Zaiss, I. et al. Associated malformations in congenital diaphragmatic hernia. Am. J. Perinatol. 28, 211–218 (2011).

    PubMed  Google Scholar 

  31. Ladd, W. E. & Gross, R. E. Congenital diaphragmatic hernia. N. Engl. J. Med. 223, 917–925 (1940).

    Google Scholar 

  32. Gross, R. E. The Surgery of Infancy and Childhood (WB Saunders Company; 1953).

  33. Gupta, V. S. et al. Mortality in congenital diaphragmatic hernia: a multicenter registry study of over 5000 patients over 25 years. Ann. Surg. https://doi.org/10.1097/SLA.0000000000005113 (2021).

    Article  PubMed  Google Scholar 

  34. The Canadian Pediatric Surgery Network. CAPSNet 2019 Annual Report 2019 (CAPSNet, 2019).

  35. Bhat, Y. R., Kumar, V. & Rao, A. Congenital diaphragmatic hernia in a developing country. Singap. Med. J. 49, 715–718 (2008).

    CAS  Google Scholar 

  36. Ekenze, S. O., Ajuzieogu, O. V. & Nwomeh, B. C. Challenges of management and outcome of neonatal surgery in Africa: a systematic review. Pediatr. Surg. Int. 32, 291–299 (2016).

    PubMed  Google Scholar 

  37. Ammar, S. et al. Risk factors of early mortality after neonatal surgery in Tunisia. J. Pediatr. Surg. 55, 2233–2237 (2020).

    PubMed  Google Scholar 

  38. Pober, B. R. Genetic aspects of human congenital diaphragmatic hernia. Clin. Genet. 74, 1–15 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Oh, T., Chan, S., Kieffer, S. & Delisle, M. F. Fetal outcomes of prenatally diagnosed congenital diaphragmatic hernia: nine years of clinical experience in a canadian tertiary hospital. J. Obstet. Gynaecol. Can. 38, 17–22 (2016).

    PubMed  Google Scholar 

  40. Merrell, A. J. et al. Muscle connective tissue controls development of the diaphragm and is a source of congenital diaphragmatic hernias. Nat. Genet. 47, 496–504 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Sefton, E. M., Gallardo, M. & Kardon, G. Developmental origin and morphogenesis of the diaphragm, an essential mammalian muscle. Dev. Biol. 440, 64–73 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Lally, K. P. et al. Standardized reporting for congenital diaphragmatic hernia — an international consensus. J. Pediatr. Surg. 48, 2408–2415 (2013). This report from the CDHSG shows that the diaphragmatic defect assessed with the CDHSG staging system and presence of a severe cardiac anomaly are reliable predictors of outcome. This article highlights the importance of a standardized reporting system for CDH to conduct prospective trials in patients with this condition.

    PubMed  Google Scholar 

  43. McAteer, J. P., Hecht, A., De Roos, A. J. & Goldin, A. B. Maternal medical and behavioral risk factors for congenital diaphragmatic hernia. J. Pediatr. Surg. 49, 34–38 (2014).

    PubMed  Google Scholar 

  44. Kitagawa, M., Hislop, A., Boyden, E. A. & Reid, L. Lung hypoplasia in congenital diaphragmatic hernia. A quantitative study of airway, artery, and alveolar development. Br. J. Surg. 58, 342–346 (1971).

    CAS  PubMed  Google Scholar 

  45. Nguyen, T. M. et al. The proportion of alveolar type 1 cells decreases in murine hypoplastic congenital diaphragmatic hernia lungs. PLoS ONE 14, e0214793 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Bargy, F., Beaudoin, S. & Barbet, P. Fetal lung growth in congenital diaphragmatic hernia. Fetal Diagn. Ther. 21, 39–44 (2006).

    CAS  PubMed  Google Scholar 

  47. Geggel, R. L. et al. Congenital diaphragmatic hernia: arterial structural changes and persistent pulmonary hypertension after surgical repair. J. Pediatr. 107, 457–464 (1985).

    CAS  PubMed  Google Scholar 

  48. Russell, M. K. et al. Congenital diaphragmatic hernia candidate genes derived from embryonic transcriptomes. Proc. Natl Acad. Sci. USA 109, 2978–2983 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Rottier, R. & Tibboel, D. Fetal lung and diaphragm development in congenital diaphragmatic hernia. Semin. Perinatol. 29, 86–93 (2005).

    PubMed  Google Scholar 

  50. van Loenhout, R. B., Tibboel, D., Post, M. & Keijzer, R. Congenital diaphragmatic hernia: comparison of animal models and relevance to the human situation. Neonatology 96, 137–149 (2009).

    PubMed  Google Scholar 

  51. Antounians, L., Figueira, R. L., Sbragia, L. & Zani, A. Congenital diaphragmatic hernia: state of the art in translating experimental research to the bedside. Eur. J. Pediatr. Surg. 29, 317–327 (2019).

    PubMed  Google Scholar 

  52. Wynn, J., Yu, L. & Chung, W. K. Genetic causes of congenital diaphragmatic hernia. Semin. Fetal Neonatal Med. 19, 324–330 (2014).

    PubMed  PubMed Central  Google Scholar 

  53. Pober, B. R. et al. Infants with Bochdalek diaphragmatic hernia: sibling precurrence and monozygotic twin discordance in a hospital-based malformation surveillance program. Am. J. Med. Genet. A 138A, 81–88 (2005).

    PubMed  PubMed Central  Google Scholar 

  54. Enns, G. M. et al. Congenital diaphragmatic defects and associated syndromes, malformations, and chromosome anomalies: a retrospective study of 60 patients and literature review. Am. J. Med. Genet. 79, 215–225 (1998).

    CAS  PubMed  Google Scholar 

  55. Longoni, M. et al. Genome-wide enrichment of damaging de novo variants in patients with isolated and complex congenital diaphragmatic hernia. Hum. Genet. 136, 679–691 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Yu, L. et al. De novo copy number variants are associated with congenital diaphragmatic hernia. J. Med. Genet. 49, 650–659 (2012).

    CAS  PubMed  Google Scholar 

  57. Qi, H. et al. De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders. PLoS Genet. 14, e1007822 (2018).

    PubMed  PubMed Central  Google Scholar 

  58. Yu, L. et al. Increased burden of de novo predicted deleterious variants in complex congenital diaphragmatic hernia. Hum. Mol. Genet. 24, 4764–4773 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Yu, L. et al. Whole exome sequencing identifies de novo mutations in GATA6 associated with congenital diaphragmatic hernia. J. Med. Genet. 51, 197–202 (2014).

    CAS  PubMed  Google Scholar 

  60. Yu, L. et al. Variants in GATA4 are a rare cause of familial and sporadic congenital diaphragmatic hernia. Hum. Genet. 132, 285–292 (2013).

    CAS  PubMed  Google Scholar 

  61. Bielinska, M. et al. Molecular genetics of congenital diaphragmatic defects. Ann. Med. 39, 261–274 (2007).

    CAS  PubMed  Google Scholar 

  62. Veenma, D. C., de Klein, A. & Tibboel, D. Developmental and genetic aspects of congenital diaphragmatic hernia. Pediatr. Pulmonol. 47, 534–545 (2012).

    CAS  PubMed  Google Scholar 

  63. Qiao, L. et al. Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 as candidate risk gene. Am. J. Hum. Genet. 108, 1964–1980 (2021). This study delineates the contribution of de novo genetic variants to the development of CDH and adds to the previous literature on genetic causes of this disease.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Qiao, L. et al. Likely damaging de novo variants in Congenital Diaphragmatic Hernia patients are associated with worse clinical outcomes. Genet. Med. 22, 2020–2028 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Khoshgoo, N. et al. Prenatal microRNA miR-200b therapy improves nitrofen-induced pulmonary hypoplasia associated with congenital diaphragmatic hernia. Ann. Surg. 269, 979–987 (2019).

    PubMed  Google Scholar 

  66. Antounians, L. et al. Fetal lung underdevelopment is rescued by administration of amniotic fluid stem cell extracellular vesicles in rodents. Sci. Transl. Med. 13, eaax5941 (2021). This is the first study to show that a regenerative medicine approach using stem cell-based extracellular vesicles promotes lung development in experimental models of pulmonary hypoplasia.

    CAS  PubMed  Google Scholar 

  67. Pereira-Terra, P. et al. Unique tracheal fluid microRNA signature predicts response to FETO in patients with congenital diaphragmatic hernia. Ann. Surg. 262, 1130–1140 (2015). This study was the first to interrogate the microRNA signature in tracheal fluid of patients with severe CDH who underwent fetal intervention (FETO). The microarray analysis identified potential microRNA-based biomarkers of disease severity.

    PubMed  Google Scholar 

  68. Coste, K. et al. Metabolic disturbances of the vitamin A pathway in human diaphragmatic hernia. Am. J. Physiol. Lung Cell Mol. Physiol. 308, L147–L157 (2015).

    CAS  PubMed  Google Scholar 

  69. Kool, H. M. et al. Inhibition of retinoic acid signaling induces aberrant pericyte coverage and differentiation resulting in vascular defects in congenital diaphragmatic hernia. Am. J. Physiol. Lung Cell Mol. Physiol. 317, L317–L331 (2019).

    CAS  PubMed  Google Scholar 

  70. Kitterman, J. A. The effects of mechanical forces on fetal lung growth. Clin. Perinatol. 23, 727–740 (1996).

    CAS  PubMed  Google Scholar 

  71. Nobuhara, K. K. & Wilson, J. M. The effect of mechanical forces on in utero lung growth in congenital diaphragmatic hernia. Clin. Perinatol. 23, 741–752 (1996).

    CAS  PubMed  Google Scholar 

  72. Harrison, M. R., Bressack, M. A., Churg, A. M. & de Lorimier, A. A. Correction of congenital diaphragmatic hernia in utero. II. Simulated correction permits fetal lung growth with survival at birth. Surgery 88, 260–268 (1980).

    CAS  PubMed  Google Scholar 

  73. Harrison, M. R., Jester, J. A. & Ross, N. A. Correction of congenital diaphragmatic hernia in utero. I. The model: intrathoracic balloon produces fatal pulmonary hypoplasia. Surgery 88, 174–182 (1980).

    CAS  PubMed  Google Scholar 

  74. Harrison, M. R., Ross, N. A. & de Lorimier, A. A. Correction of congenital diaphragmatic hernia in utero. III. Development of a successful surgical technique using abdominoplasty to avoid compromise of umbilical blood flow. J. Pediatr. Surg. 16, 934–942 (1981).

    CAS  PubMed  Google Scholar 

  75. Nelson, C. M. et al. Microfluidic chest cavities reveal that transmural pressure controls the rate of lung development. Development 144, 4328–4335 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Morgan, J. T., Stewart, W. G., McKee, R. A. & Gleghorn, J. P. The mechanosensitive ion channel TRPV4 is a regulator of lung development and pulmonary vasculature stabilization. Cell Mol. Bioeng. 11, 309–320 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Derderian, S. C. et al. Mass effect alone may not explain pulmonary vascular pathology in severe congenital diaphragmatic hernia. Fetal Diagn. Ther. 39, 117–124 (2016).

    PubMed  Google Scholar 

  78. Guilbert, T. W., Gebb, S. A. & Shannon, J. M. Lung hypoplasia in the nitrofen model of congenital diaphragmatic hernia occurs early in development. Am. J. Physiol. Lung Cell Mol. Physiol. 279, L1159–L1171 (2000).

    CAS  PubMed  Google Scholar 

  79. Massolo, A. C. et al. Fetal cardiac dimensions in congenital diaphragmatic hernia: relationship with gestational age and postnatal outcomes. J. Perinatol. 41, 1651–1659 (2021).

    PubMed  Google Scholar 

  80. Vogel, M. et al. Significance and outcome of left heart hypoplasia in fetal congenital diaphragmatic hernia. Ultrasound Obstet. Gynecol. 35, 310–317 (2010).

    CAS  PubMed  Google Scholar 

  81. Baumgart, S. et al. Cardiac malposition, redistribution of fetal cardiac output, and left heart hypoplasia reduce survival in neonates with congenital diaphragmatic hernia requiring extracorporeal membrane oxygenation. J. Pediatr. 133, 57–62 (1998).

    CAS  PubMed  Google Scholar 

  82. Stressig, R., Fimmers, R., Eising, K., Gembruch, U. & Kohl, T. Preferential streaming of the ductus venosus and inferior caval vein towards the right heart is associated with left heart underdevelopment in human fetuses with left-sided diaphragmatic hernia. Heart 96, 1564–1568 (2010).

    PubMed  Google Scholar 

  83. Patel, N., Massolo, A. C. & Kipfmueller, F. Congenital diaphragmatic hernia-associated cardiac dysfunction. Semin. Perinatol. 44, 151168 (2020).

    PubMed  Google Scholar 

  84. Iritani, I. Experimental study on embryogenesis of congenital diaphragmatic hernia. Anat. Embryol. 169, 133–139 (1984).

    CAS  Google Scholar 

  85. Cilley, R. E., Zgleszewski, S. E., Krummel, T. M. & Chinoy, M. R. Nitrofen dose-dependent gestational day-specific murine lung hypoplasia and left-sided diaphragmatic hernia. Am. J. Physiol. 272, L362–L371 (1997).

    CAS  PubMed  Google Scholar 

  86. Keijzer, R., Liu, J., Deimling, J., Tibboel, D. & Post, M. Dual-hit hypothesis explains pulmonary hypoplasia in the nitrofen model of congenital diaphragmatic hernia. Am. J. Pathol. 156, 1299–1306 (2000). This seminal paper addresses the pathogenesis of pulmonary hypoplasia secondary to CDH by postulating the occurrence of two insults, one affecting both lungs before diaphragm development and one affecting the ipsilateral lung after defective diaphragm development.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Ackerman, K. G. et al. Fog2 is required for normal diaphragm and lung development in mice and humans. PLoS Genet. 1, 58–65 (2005).

    CAS  PubMed  Google Scholar 

  88. Featherstone, N. C. et al. Airway smooth muscle dysfunction precedes teratogenic congenital diaphragmatic hernia and may contribute to hypoplastic lung morphogenesis. Am. J. Respir. Cell Mol. Biol. 35, 571–578 (2006).

    CAS  PubMed  Google Scholar 

  89. Jesudason, E. C. Small lungs and suspect smooth muscle: congenital diaphragmatic hernia and the smooth muscle hypothesis. J. Pediatr. Surg. 41, 431–435 (2006).

    PubMed  Google Scholar 

  90. van Loenhout, R. B. et al. The pulmonary mesenchymal tissue layer is defective in an in vitro recombinant model of nitrofen-induced lung hypoplasia. Am. J. Pathol. 180, 48–60 (2012).

    PubMed  Google Scholar 

  91. Fox, Z. D. et al. Fetal lung transcriptome patterns in an ex vivo compression model of diaphragmatic hernia. J. Surg. Res. 231, 411–420 (2018).

    CAS  PubMed  Google Scholar 

  92. Gilbert, R. M., Schappell, L. E. & Gleghorn, J. P. Defective mesothelium and limited physical space are drivers of dysregulated lung development in a genetic model of congenital diaphragmatic hernia. Development 148, dev199460 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Kunisaki, S. M. et al. Human induced pluripotent stem cell-derived lung organoids in an ex vivo model of the congenital diaphragmatic hernia fetal lung. Stem Cell Transl. Med. 10, 98–114 (2021).

    CAS  Google Scholar 

  94. Jancelewicz, T. & Brindle, M. E. Prediction tools in congenital diaphragmatic hernia. Semin. Perinatol. 44, 151165 (2020).

    PubMed  Google Scholar 

  95. Ba’ath, M. E., Jesudason, E. C. & Losty, P. D. How useful is the lung-to-head ratio in predicting outcome in the fetus with congenital diaphragmatic hernia? A systematic review and meta-analysis. Ultrasound Obstet. Gynecol. 30, 897–906 (2007).

    PubMed  Google Scholar 

  96. Benachi, A., Cordier, A. G., Cannie, M. & Jani, J. Advances in prenatal diagnosis of congenital diaphragmatic hernia. Semin. Fetal Neonatal Med. 19, 331–337 (2014).

    PubMed  Google Scholar 

  97. Longoni, M., Pober, B. R. & High, F. A. Congenital Diaphragmatic Hernia Overview. GeneReviews [online], https://www.ncbi.nlm.nih.gov/books/NBK1359/ (updated 5 Nov 2020).

  98. Jancelewicz, T. et al. Risk-stratification enables accurate single-center outcomes assessment in congenital diaphragmatic hernia (CDH). J. Pediatr. Surg. 54, 932–936 (2019).

    PubMed  Google Scholar 

  99. Hassan, M. et al. Risk stratification helps identify congenital diaphragmatic hernia (CDH) infants in need of formal neurodevelopmental assessment: observations from a structured, interdisciplinary long-term follow-up clinic. J. Pediatr. Surg. 13, 846–850 (2022).

    Google Scholar 

  100. Albanese, C. T. et al. Fetal liver position and perinatal outcome for congenital diaphragmatic hernia. Prenat. Diagn. 18, 1138–1142 (1998).

    CAS  PubMed  Google Scholar 

  101. Metkus, A. P., Filly, R. A., Stringer, M. D., Harrison, M. R. & Adzick, N. S. Sonographic predictors of survival in fetal diaphragmatic hernia. J. Pediatr. Surg. 31, 148–151 (1996).

    CAS  PubMed  Google Scholar 

  102. Lipshutz, G. S. et al. Prospective analysis of lung-to-head ratio predicts survival for patients with prenatally diagnosed congenital diaphragmatic hernia. J. Pediatr. Surg. 32, 1634–1636 (1997).

    CAS  PubMed  Google Scholar 

  103. Russo, F. M. et al. Proposal for standardized prenatal ultrasound assessment of the fetus with congenital diaphragmatic hernia by the European reference network on rare inherited and congenital anomalies (ERNICA). Prenat. Diagn. 38, 629–637 (2008).

    Google Scholar 

  104. Jani, J. et al. Observed to expected lung area to head circumference ratio in the prediction of survival in fetuses with isolated diaphragmatic hernia. Ultrasound Obstet. Gynecol. 30, 67–71 (2007).

    CAS  PubMed  Google Scholar 

  105. Deprest, J. A., Flemmer, A. W., Gratacos, E. & Nicolaides, K. Antenatal prediction of lung volume and in-utero treatment by fetal endoscopic tracheal occlusion in severe isolated congenital diaphragmatic hernia. Semin. Fetal Neonatal Med. 14, 8–13 (2009).

    PubMed  Google Scholar 

  106. Senat, M. V. et al. Prognosis of isolated congenital diaphragmatic hernia using lung-area-to-head-circumference ratio: variability across centers in a national perinatal network. Ultrasound Obstet. Gynecol. 51, 208–213 (2018).

    PubMed  Google Scholar 

  107. Peralta, C. F., Cavoretto, P., Csapo, B., Vandecruys, H. & Nicolaides, K. H. Assessment of lung area in normal fetuses at 12-32 weeks. Ultrasound Obstet. Gynecol. 26, 718–724 (2005).

    CAS  PubMed  Google Scholar 

  108. Britto, I. S. et al. Standardization of sonographic lung-to-head ratio measurements in isolated congenital diaphragmatic hernia: impact on the reproducibility and efficacy to predict outcomes. J. Ultrasound Med. 34, 1721–1727 (2015).

    PubMed  Google Scholar 

  109. Goodfellow, T., Hyde, I., Burge, D. M. & Freeman, N. V. Congenital diaphragmatic hernia: the prognostic significance of the site of the stomach. Br. J. Radiol. 60, 993–935 (1987).

    CAS  PubMed  Google Scholar 

  110. Hasegawa, T. Use of lung-thorax transverse area ratio in the antenatal evaluation of lung hypoplasia in congenital diaphragmatic hernia. J. Clin. Ultrasound 18, 705–709 (1990).

    CAS  PubMed  Google Scholar 

  111. Ruano, R. et al. Fetal lung volume and quantification of liver herniation by magnetic resonance imaging in isolated congenital diaphragmatic hernia. Ultrasound Obstet. Gynecol. 43, 662–669 (2014).

    CAS  PubMed  Google Scholar 

  112. Gorincour, G. et al. Prenatal prognosis of congenital diaphragmatic hernia using magnetic resonance imaging measurement of fetal lung volume. Ultrasound Obstet. Gynecol. 26, 738–744 (2005).

    CAS  PubMed  Google Scholar 

  113. Zamora, I. J. et al. Prenatal MRI fetal lung volumes and percent liver herniation predict pulmonary morbidity in congenital diaphragmatic hernia (CDH). J. Pediatr. Surg. 49, 688–693 (2014).

    PubMed  Google Scholar 

  114. Barnewolt, C. E. et al. Percent predicted lung volumes as measured on fetal magnetic resonance imaging: a useful biometric parameter for risk stratification in congenital diaphragmatic hernia. J. Pediatr. Surg. 42, 193–197 (2007).

    PubMed  Google Scholar 

  115. Shieh, H. F. et al. Percent predicted lung volume changes on fetal magnetic resonance imaging throughout gestation in congenital diaphragmatic hernia. J. Pediatr. Surg. 52, 933–937 (2017).

    PubMed  Google Scholar 

  116. Lazar, D. A. et al. Defining “liver-up”: does the volume of liver herniation predict outcome for fetuses with isolated left-sided congenital diaphragmatic hernia. J. Pediatr. Surg. 47, 1058–1062 (2012).

    PubMed  Google Scholar 

  117. Kolbe, A. B. et al. Reproducibility of lung and liver volume measurements on fetal magnetic resonance imaging in left-sided congenital diaphragmatic hernia. Fetal Diagn. Ther. 48, 258–264 (2021).

    PubMed  Google Scholar 

  118. Kilian, A. K., Büsing, K. A., Schuetz, E. M., Schaible, T. & Neff, K. W. Fetal MR lung volumetry in congenital diaphragmatic hernia (CDH): prediction of clinical outcome and the need for extracorporeal membrane oxygenation (ECMO). Klin. Padiatr. 221, 295–301 (2009).

    CAS  PubMed  Google Scholar 

  119. Worley, K. C. et al. Fetal magnetic resonance imaging in isolated diaphragmatic hernia: volume of herniated liver and neonatal outcome. Am. J. Obstet. Gynecol. 200, 318.e1–6 (2009).

    Google Scholar 

  120. Khmour, A. Y., Konduri, G. G., Sato, T. T., Uhing, M. R. & Basir, M. A. Role of admission gas exchange measurement in predicting congenital diaphragmatic hernia survival in the era of gentle ventilation. J. Pediatr. Surg. 49, 1197–1201 (2014).

    PubMed  Google Scholar 

  121. Congenital Diaphragmatic Hernia Study Group. Estimating disease severity of Congenital Diaphragmatic Hernia in the first 5 minutes of life. J. Pediatr. Surg. 36, 141–145 (2001).

    Google Scholar 

  122. Brindle, M. E., Cook, E. F., Tibboel, D., Lally, P. A. & Lally, K. P. A clinical prediction rule for the severity of congenital diaphragmatic hernias in newborns. Pediatrics 134, e413–e419 (2014). This CDHSG publication described a generalizable scoring system for CDH that can be calculated rapidly at the bedside for selection of transfer of infants with CDH to high-volume centres as well as for consideration of advanced medical therapies.

    PubMed  Google Scholar 

  123. Ruttenstock, E. et al. Best oxygenation index on day 1: a reliable marker for outcome and survival in infants with congenital diaphragmatic hernia. Eur. J. Pediatr. Surg. 25, 3–8 (2015).

    PubMed  Google Scholar 

  124. Coleman, A. J. et al. First 24-h SNAP-II score and highest PaCO2 predict the need for ECMO in congenital diaphragmatic hernia. J. Pediatr. Surg. 48, 2214–2218 (2013).

    PubMed  Google Scholar 

  125. Grizelj, R. et al. Survival prediction of high-risk outborn neonates with congenital diaphragmatic hernia from capillary blood gases. BMC Pediatr. 16, 114 (2016).

    PubMed  PubMed Central  Google Scholar 

  126. Schultz, C. M., DiGeronimo, R. J. & Yoder, B. A. Congenital diaphragmatic hernia: a simplified postnatal predictor of outcome. J. Pediatr. Surg. 42, 510–516 (2007).

    PubMed  Google Scholar 

  127. Bent, D. P., Nelson, J., Kent, D. M. & Jen, H. C. Population-based validation of a clinical prediction model for congenital diaphragmatic hernias. J. Pediatr. 201, 160–165.e1 (2018).

    PubMed  PubMed Central  Google Scholar 

  128. Clohse, K. et al. Application of a postnatal prediction model of survival in CDH in the era of fetal therapy. J. Matern. Fetal Neonatal Med. 33, 1818–1823 (2020).

    CAS  PubMed  Google Scholar 

  129. Patel, M. J., Bell, C. S., Lally, K. P., Lally, P. A. & Katakam, L. I. Lowest PaCO2 on the first day of life predicts mortality and morbidity among infants with congenital diaphragmatic hernia. J. Perinatol. 39, 229–236 (2019).

    CAS  PubMed  Google Scholar 

  130. Yoder, B. A., Lally, P. A. & Lally, K. P. Does a highest pre-ductal O2 saturation <85% predict non-survival for congenital diaphragmatic hernia. J. Perinatol. 32, 947–952 (2012).

    CAS  PubMed  Google Scholar 

  131. Park, H. W. et al. A simplified formula using early blood gas analysis can predict survival outcomes and the requirements for extracorporeal membrane oxygenation in congenital diaphragmatic hernia. J. Korean Med. Sci. 28, 924–928 (2013).

    PubMed  PubMed Central  Google Scholar 

  132. Keller, R. L. et al. Congenital diaphragmatic hernia: endothelin-1, pulmonary hypertension, and disease severity. Am. J. Respir. Crit. Care Med. 182, 555–561 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Steurer, M. A. et al. B-type natriuretic peptide: prognostic marker in congenital diaphragmatic hernia. Pediatr. Res. 76, 549–554 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Casaccia, G. et al. Birth weight and McGoon Index predict mortality in newborn infants with congenital diaphragmatic hernia. J. Pediatr. Surg. 41, 25–28 (2006).

    PubMed  Google Scholar 

  135. Suda, K., Bigras, J. L., Bohn, D., Hornberger, L. K. & McCrindle, B. W. Echocardiographic predictors of outcome in newborns with congenital diaphragmatic hernia. Pediatrics 105, 1106–1109 (2000).

    CAS  PubMed  Google Scholar 

  136. Dao, D. T. et al. Early left ventricular dysfunction and severe pulmonary hypertension predict adverse outcomes in “low-risk” congenital diaphragmatic hernia. Pediatr. Crit. Care Med. 21, 637–646 (2020).

    PubMed  PubMed Central  Google Scholar 

  137. Hunter, C. E., Saenz, Z. M., Nunez, D., Timsina, L. & Gray, B. W. Inter- and intra-rater reliability of a grading system for congenital diaphragmatic hernia defect size. J. Surg. Res. 233, 82–87 (2019).

    PubMed  Google Scholar 

  138. Werner, N. L. et al. Prenatal and postnatal markers of severity in congenital diaphragmatic hernia have similar prognostic ability. Prenat. Diagn. 36, 107–111 (2016).

    CAS  PubMed  Google Scholar 

  139. Lally, K. P. et al. Defect size determines survival in infants with congenital diaphragmatic hernia. Pediatrics 120, e651–e657 (2007).

    PubMed  Google Scholar 

  140. Hedrick, M. H. et al. Congenital high airway obstruction syndrome (CHAOS): a potential for perinatal intervention. J. Pediatr. Surg. 29, 271–274 (1994).

    CAS  PubMed  Google Scholar 

  141. Khan, P. A., Cloutier, M. & Piedboeuf, B. Tracheal occlusion: a review of obstructing fetal lungs to make them grow and mature. Am. J. Med. Genet. C Semin. Med. Genet. 145C, 125–138 (2007).

    PubMed  Google Scholar 

  142. Nguyen, T. M. et al. Stretch increases alveolar type 1 cell number in fetal lungs through ROCK-Yap/Taz pathway. Am. J. Physiol. Lung Cell Mol. Physiol. 321, L814–L826 (2021).

    CAS  PubMed  Google Scholar 

  143. Carmel, J. A., Friedman, F. & Adams, F. H. Fetal tracheal ligation and lung development. Am. J. Dis. Child. 109, 452–456 (1965).

    CAS  PubMed  Google Scholar 

  144. DiFiore, J. W. et al. Experimental fetal tracheal ligation reverses the structural and physiological effects of pulmonary hypoplasia in congenital diaphragmatic hernia. J. Pediatr. Surg. 29, 248–256 (1994).

    CAS  PubMed  Google Scholar 

  145. Hedrick, M. H. et al. Plug the lung until it grows (PLUG): a new method to treat congenital diaphragmatic hernia in utero. J. Pediatr. Surg. 29, 612–617 (1994).

    CAS  PubMed  Google Scholar 

  146. Beierle, E. A., Langham, M. R. & Cassin, S. In utero lung growth of fetal sheep with diaphragmatic hernia and tracheal stenosis. J. Pediatr. Surg. 31, 141–147 (1996).

    CAS  PubMed  Google Scholar 

  147. Skarsgard, E. D. et al. Fetal endoscopic tracheal occlusion (‘Fetendo-PLUG’) for congenital diaphragmatic hernia. J. Pediatr. Surg. 31, 1335–1338 (1996).

    CAS  PubMed  Google Scholar 

  148. Deprest, J. A. et al. Tracheoscopic endoluminal plugging using an inflatable device in the fetal lamb model. Eur. J. Obstet. Gynecol. Reprod. Biol. 81, 165–169 (1998).

    CAS  PubMed  Google Scholar 

  149. Flageole, H. et al. The plug-unplug sequence: an important step to achieve type II pneumocyte maturation in the fetal lamb model. J. Pediatr. Surg. 33, 299–303 (1998).

    CAS  PubMed  Google Scholar 

  150. Harrison, M. R. et al. Correction of congenital diaphragmatic hernia in utero VIII: response of the hypoplastic lung to tracheal occlusion. J. Pediatr. Surg. 31, 1339–1348 (1996).

    CAS  PubMed  Google Scholar 

  151. Deprest, J., Gratacos, E. & Nicolaides, K. H. Fetoscopic tracheal occlusion (FETO) for severe congenital diaphragmatic hernia: evolution of a technique and preliminary results. Ultrasound Obstet. Gynecol. 24, 121–126 (2004).

    CAS  PubMed  Google Scholar 

  152. Gregoir, C. et al. Fertility, pregnancy and gynecological outcomes after fetoscopic surgery for congenital diaphragmatic hernia. Hum. Reprod. 31, 2024–2030 (2016).

    CAS  PubMed  Google Scholar 

  153. Jani, J. C. et al. Severe diaphragmatic hernia treated by fetal endoscopic tracheal occlusion. Ultrasound Obstet. Gynecol. 34, 304–310 (2009).

    CAS  PubMed  Google Scholar 

  154. Jani, J. C. et al. Prenatal prediction of neonatal morbidity in survivors with congenital diaphragmatic hernia: a multicenter study. Ultrasound Obstet. Gynecol. 33, 64–69 (2009).

    CAS  PubMed  Google Scholar 

  155. Doné, E. et al. Predictors of neonatal morbidity in fetuses with severe isolated congenital diaphragmatic hernia undergoing fetoscopic tracheal occlusion. Ultrasound Obstet. Gynecol. 42, 77–83 (2013).

    PubMed  Google Scholar 

  156. Reiss, I. et al. Standardized postnatal management of infants with congenital diaphragmatic hernia in Europe: the CDH EURO Consortium consensus. Neonatology 98, 354–364 (2010).

    CAS  PubMed  Google Scholar 

  157. Snoek, K. G. et al. Standardized postnatal management of infants with congenital diaphragmatic hernia in Europe: The CDH EURO Consortium Consensus-2015 Update. Neonatology 110, 66–74 (2016). This report from the European CDH Consortium Consensus provides an updated statement on the key recommendations for the standardized postnatal management of patients with CDH.

    PubMed  Google Scholar 

  158. Deprest, J. A. et al. Randomized trial of fetal surgery for severe left diaphragmatic hernia. N. Engl. J. Med. 385, 107–118 (2021). This is the first report from the randomized controlled trial conducted in fetuses with severe left-sided CDH receiving FETO at 27–29 weeks of gestation. This trial showed a significant benefit of FETO over expectant care with respect to survival to discharge.

    PubMed  Google Scholar 

  159. Nawapun, K. et al. In vivo evidence by magnetic resonance volumetry of a gestational age dependent response to tracheal occlusion for congenital diaphragmatic hernia. Prenat. Diagn. 35, 1048–1056 (2015).

    PubMed  Google Scholar 

  160. Jani, J. C., Nicolaides, K. H., Gratacós, E., Vandecruys, H. & Deprest, J. A. Fetal lung-to-head ratio in the prediction of survival in severe left-sided diaphragmatic hernia treated by fetal endoscopic tracheal occlusion (FETO). Am. J. Obstet. Gynecol. 195, 1646–1650 (2006).

    PubMed  Google Scholar 

  161. Deprest, J. A. et al. Randomized trial of fetal surgery for moderate left diaphragmatic hernia. N. Engl. J. Med. 385, 119–129 (2021).

    PubMed  Google Scholar 

  162. Van Calster, B. et al. The randomized TOTAL-trials on fetal surgery for congenital diaphragmatic hernia: re-analysis using pooled data. Am. J. Obstet. Gynecol. https://doi.org/10.1016/j.ajog.2021.11.1351 (2022).

    Article  PubMed  Google Scholar 

  163. Stolar, C. J. H., Flake, A. W. & Losty, P. D. Fetal surgery for severe left diaphragmatic hernia. N. Engl. J. Med. 385, 2111–2112 (2021).

    PubMed  Google Scholar 

  164. Stolar, C. J. H., Flake, A. W. & Losty, P. D. Fetal surgery for severe left diaphragmatic hernia. J. Pediatr. Surg. 57, 552–553 (2022).

    PubMed  Google Scholar 

  165. Deprest, J. A., Nicolaides, K. H. & Benachi, A. Fetal surgery for severe left diaphragmatic hernia. Reply. N. Engl. J. Med. 385, 2112 (2021).

    PubMed  Google Scholar 

  166. Russo, F. et al. Antenatal management of CDH: what’s next? Prenat. Diagn. 42, 291–300 (2022).

    PubMed  Google Scholar 

  167. Jancelewicz, T. et al. Toward standardized management of congenital diaphragmatic hernia: an analysis of practice guidelines. J. Surg. Res. 243, 229–235 (2019).

    PubMed  Google Scholar 

  168. Puligandla, P. S. et al. Diagnosis and management of congenital diaphragmatic hernia: a clinical practice guideline. CMAJ 190, E103–E112 (2018). This publication is the current guidelines of CDH care from the Canadian CDH Collaborative, and provides evidence-based recommendations regarding prenatal diagnosis, perinatal management including surgery, and long-term follow-up.

    PubMed  PubMed Central  Google Scholar 

  169. Guner, Y. et al. Management of congenital diaphragmatic hernia treated with extracorporeal life support: interim guidelines consensus statement from the Extracorporeal Life Support Organization. ASAIO J. 67, 113–120 (2021).

    CAS  PubMed  Google Scholar 

  170. Kinsella, J. P. et al. The left ventricle in congenital diaphragmatic hernia: implications for the management of pulmonary hypertension. J. Pediatr. 197, 17–22 (2018).

    PubMed  Google Scholar 

  171. Cochius-den Otter, S. C. M. et al. Routine intubation in newborns with congenital diaphragmatic hernia. Pediatrics 146, e20201258 (2020).

    PubMed  Google Scholar 

  172. Foglia, E. E. et al. Initiating resuscitation before umbilical cord clamping in infants with congenital diaphragmatic hernia: a pilot feasibility trial. Arch. Dis. Child. Fetal Neonatal Ed. 105, 322–326 (2020).

    PubMed  Google Scholar 

  173. Kashyap, A. J. et al. Physiologically based cord clamping improves cardiopulmonary haemodynamics in lambs with a diaphragmatic hernia. Arch. Dis. Child. Fetal Neonatal Ed. 105, 18–25 (2020).

    PubMed  Google Scholar 

  174. Lefebvre, C. et al. Feasibility and safety of intact cord resuscitation in newborn infants with congenital diaphragmatic hernia (CDH). Resuscitation 120, 20–25 (2017).

    PubMed  Google Scholar 

  175. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04373902 (2022).

  176. Le Duc, K. et al. Efficacy of intact cord resuscitation compared to immediate cord clamping on cardiorespiratory adaptation at birth in infants with isolated congenital diaphragmatic hernia (CHIC). Children 8, 339 (2021).

    PubMed  PubMed Central  Google Scholar 

  177. Azarow, K. et al. Congenital diaphragmatic hernia — a tale of two cities: the Toronto experience. J. Pediatr. Surg. 32, 395–400 (1997).

    CAS  PubMed  Google Scholar 

  178. Wung, J. T., Sahni, R., Moffitt, S. T., Lipsitz, E. & Stolar, C. J. Congenital diaphragmatic hernia: survival treated with very delayed surgery, spontaneous respiration, and no chest tube. J. Pediatr. Surg. 30, 406–409 (1995).

    CAS  PubMed  Google Scholar 

  179. Morini, F., Capolupo, I., van Weteringen, W. & Reiss, I. Ventilation modalities in infants with congenital diaphragmatic hernia. Semin. Pediatr. Surg. 26, 159–165 (2017).

    PubMed  Google Scholar 

  180. Snoek, K. G. et al. Conventional mechanical ventilation versus high-frequency oscillatory ventilation for congenital diaphragmatic hernia: a randomized clinical trial (The VICI-trial). Ann. Surg. 263, 867–874 (2016). This international multicentre randomized clinical trial assessing conventional versus high-frequency oscillation ventilation in infants with CDH showed no superiority of one approach over the other for survival and development of bronchopulmonary dysplasia. Secondary outcomes, such as ventilation time and need for ECLS, favoured conventional ventilation.

    PubMed  Google Scholar 

  181. Fuyuki, M. et al. Prognosis of conventional vs. high-frequency ventilation for congenital diaphragmatic hernia: a retrospective cohort study. J. Perinatol. 41, 814–823 (2021).

    PubMed  Google Scholar 

  182. Gupta, V. S. & Harting, M. T. Congenital diaphragmatic hernia-associated pulmonary hypertension. Semin. Perinatol. 44, 151167 (2020).

    PubMed  Google Scholar 

  183. Barrington, K. J., Finer, N., Pennaforte, T. & Altit, G. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst. Rev. 1, CD000399 (2017).

    PubMed  Google Scholar 

  184. Kipfmueller, F. et al. Continuous intravenous sildenafil as an early treatment in neonates with congenital diaphragmatic hernia. Pediatr. Pulmonol. 53, 452–460 (2018).

    PubMed  Google Scholar 

  185. Putnam, L. R. et al. Evaluation of variability in inhaled nitric oxide use and pulmonary hypertension in patients with congenital diaphragmatic hernia. JAMA Pediatr. 170, 1188–1194 (2016).

    PubMed  Google Scholar 

  186. Campbell, B. T. et al. Inhaled nitric oxide use in neonates with congenital diaphragmatic hernia. Pediatrics 134, e420–e426 (2014).

    PubMed  Google Scholar 

  187. Lawrence, K. M. et al. Inhaled nitric oxide is associated with improved oxygenation in a subpopulation of infants with congenital diaphragmatic hernia and pulmonary hypertension. J. Pediatr. 219, 167–172 (2020).

    CAS  PubMed  Google Scholar 

  188. Carpentier, E. et al. Safety and tolerability of subcutaneous treprostinil in newborns with congenital diaphragmatic hernia and life-threatening pulmonary hypertension. J. Pediatr. Surg. 52, 1480–1483 (2017).

    CAS  PubMed  Google Scholar 

  189. Patel, N. Use of milrinone to treat cardiac dysfunction in infants with pulmonary hypertension secondary to congenital diaphragmatic hernia: a review of six patients. Neonatology 102, 130–136 (2012).

    PubMed  Google Scholar 

  190. Lawrence, K. M. et al. Treprostinil improves persistent pulmonary hypertension associated with congenital diaphragmatic hernia. J. Pediatr. 200, 44–49 (2018).

    CAS  PubMed  Google Scholar 

  191. Lakshminrusimha, S. et al. Milrinone in congenital diaphragmatic hernia — a randomized pilot trial: study protocol, review of literature and survey of current practices. Matern. Health Neonatol. Perinatol. 3, 27 (2017).

    PubMed  PubMed Central  Google Scholar 

  192. Patel, N. & Kipfmueller, F. Cardiac dysfunction in congenital diaphragmatic hernia: pathophysiology, clinical assessment, and management. Semin. Pediatr. Surg. 26, 154–158 (2017).

    PubMed  Google Scholar 

  193. Moenkemeyer, F. & Patel, N. Right ventricular diastolic function measured by tissue Doppler imaging predicts early outcome in congenital diaphragmatic hernia. Pediatr. Crit. Care Med. 15, 49–55 (2014).

    PubMed  Google Scholar 

  194. Le Duc, K. et al. Prostaglandin E1 in infants with congenital diaphragmatic hernia (CDH) and life-threatening pulmonary hypertension. J. Pediatr. Surg. 55, 1872–1878 (2020).

    PubMed  Google Scholar 

  195. Patel, N. et al. Early postnatal ventricular dysfunction is associated with disease severity in patients with congenital diaphragmatic hernia. J. Pediatr. 203, 400–407.e1 (2018).

    PubMed  Google Scholar 

  196. Zhaorigetu, S., Gupta, V. S., Jin, D. & Harting, M. T. Cardiac energy metabolism may play a fundamental role in congenital diaphragmatic hernia-associated ventricular dysfunction. J. Mol. Cell. Cardiol. 157, 14–16 (2021).

    CAS  PubMed  Google Scholar 

  197. Seetharamaiah, R., Younger, J. G., Bartlett, R. H. & Hirschl, R. B. Factors associated with survival in infants with congenital diaphragmatic hernia requiring extracorporeal membrane oxygenation: a report from the Congenital Diaphragmatic Hernia Study Group. J. Pediatr. Surg. 44, 1315–1321 (2009).

    PubMed  Google Scholar 

  198. Guner, Y. S. et al. Outcome analysis of neonates with congenital diaphragmatic hernia treated with venovenous vs venoarterial extracorporeal membrane oxygenation. J. Pediatr. Surg. 44, 1691–1701 (2009).

    PubMed  Google Scholar 

  199. Delaplain, P. T. et al. Predictors of long ECMO runs for congenital diaphragmatic hernia. J. Pediatr. Surg. 55, 993–997 (2020).

    PubMed  Google Scholar 

  200. Rafat, N. & Schaible, T. Extracorporeal membrane oxygenation in congenital diaphragmatic hernia. Front. Pediatr. 7, 336 (2019).

    PubMed  PubMed Central  Google Scholar 

  201. Zani, A., Zani-Ruttenstock, E. & Pierro, A. Advances in the surgical approach to congenital diaphragmatic hernia. Semin. Fetal Neonatal Med. 19, 364–369 (2014).

    PubMed  Google Scholar 

  202. Putnam, L. R. et al. Minimally invasive vs open congenital diaphragmatic hernia repair: is there a superior approach. J. Am. Coll. Surg. 224, 416–422 (2017).

    PubMed  Google Scholar 

  203. Okawada, M. et al. Thoracoscopic repair of congenital diaphragmatic hernia in neonates: findings of a multicenter study in Japan. Surg. Today 51, 1694–1702 (2021).

    PubMed  Google Scholar 

  204. Pierro, A. Hypercapnia and acidosis during the thoracoscopic repair of oesophageal atresia and congenital diaphragmatic hernia. J. Pediatr. Surg. 50, 247–249 (2015).

    PubMed  Google Scholar 

  205. Zani, A. et al. Intraoperative acidosis and hypercapnia during thoracoscopic repair of congenital diaphragmatic hernia and esophageal atresia/tracheoesophageal fistula. Paediatr. Anaesth. 27, 841–848 (2017).

    PubMed  Google Scholar 

  206. Gross, E., Stolar C. J. H. in Operative Pediatric Surgery (eds Coran, A., Spitz, L. W.) 186-194 (Taylor & Francis Group, Boca Raton, 2013).

  207. Zani, A. et al. International survey on the management of congenital diaphragmatic hernia. Eur. J. Pediatr. Surg. 26, 38–46 (2016).

    PubMed  Google Scholar 

  208. Verla, M. A. et al. Does creating a dome reduce recurrence in congenital diaphragmatic hernia following patch repair? J. Pediatr. Surg. 57, 637–642 (2022).

    PubMed  Google Scholar 

  209. Bax, N. M. & Collins, D. L. The advantages of reconstruction of the dome of the diaphragm in congenital posterolateral diaphragmatic defects. J. Pediatr. Surg. 19, 484–487 (1984).

    CAS  PubMed  Google Scholar 

  210. Hollinger, L. E. et al. A risk-stratified analysis of delayed congenital diaphragmatic hernia repair: does timing of operation matter? Surgery 156, 475–482 (2014).

    PubMed  Google Scholar 

  211. Delaplain, P. T. et al. Potential survival benefit with repair of congenital diaphragmatic hernia (CDH) after extracorporeal membrane oxygenation (ECMO) in select patients: study by ELSO CDH Interest Group. J. Pediatr. Surg. 54, 1132–1137 (2019).

    PubMed  Google Scholar 

  212. Bryner, B. S. et al. Congenital diaphragmatic hernia requiring extracorporeal membrane oxygenation: does timing of repair matter. J. Pediatr. Surg. 44, 1165–1172 (2009).

    PubMed  PubMed Central  Google Scholar 

  213. Dao, D. T. et al. Surgical repair of congenital diaphragmatic hernia after extracorporeal membrane oxygenation cannulation: early repair improves survival. Ann. Surg. 274, 186–194 (2021).

    PubMed  Google Scholar 

  214. Maxwell, D., Baird, R. & Puligandla, P. Abdominal wall closure in neonates after congenital diaphragmatic hernia repair. J. Pediatr. Surg. 48, 930–934 (2013).

    PubMed  Google Scholar 

  215. Wang, Q., Liu, Q., Zang, J., Wang, J. & Chen, J. Risk factors affecting postoperative pulmonary function in congenital diaphragmatic hernia. Ann. Surg. Treat. Res. 98, 206–213 (2020).

    PubMed  PubMed Central  Google Scholar 

  216. Aihole, J. S. et al. A clinical study on congenital diaphragmatic hernia in neonates: our institutional experience. J. Indian Assoc. Pediatr. Surg. 23, 131–139 (2018).

    PubMed  PubMed Central  Google Scholar 

  217. Kurland, Y. et al. Neurally adjusted ventilatory assist in neonates with congenital diaphragmatic hernia. J. Perinatol. 41, 1910–1915 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. Bairdain, S. et al. Nutritional outcomes in survivors of congenital diaphragmatic hernia (CDH)-factors associated with growth at one year. J. Pediatr. Surg. 50, 74–77 (2015).

    PubMed  Google Scholar 

  219. Pierog, A. et al. Predictors of low weight and tube feedings in children with congenital diaphragmatic hernia at 1 year of age. J. Pediatr. Gastroenterol. Nutr. 59, 527–530 (2014).

    PubMed  Google Scholar 

  220. Terui, K. et al. Impact of nutrition in the treatment of congenital diaphragmatic hernia. Pediatr. Int. 61, 482–488 (2019).

    PubMed  Google Scholar 

  221. Gien, J. et al. Short-term weight gain velocity in infants with congenital diaphragmatic hernia (CDH). Early Hum. Dev. 106-107, 7–12 (2017).

    PubMed  Google Scholar 

  222. Haliburton, B. et al. Long-term nutritional morbidity for congenital diaphragmatic hernia survivors: failure to thrive extends well into childhood and adolescence. J. Pediatr. Surg. 50, 734–738 (2015).

    PubMed  Google Scholar 

  223. Bathgate, J. R., Rigassio Radler, D., Zelig, R., Lagoski, M. & Murthy, K. Nutrition interventions associated with favorable growth in infants with congenital diaphragmatic hernia. Nutr. Clin. Pract. 36, 406–413 (2021).

    PubMed  Google Scholar 

  224. Mehta, N. M. et al. Guidelines for the provision and assessment of nutrition support therapy in the pediatric critically ill patient: Society of Critical Care Medicine and American Society for Parenteral and Enteral Nutrition. Pediatr. Crit. Care Med. 18, 675–715 (2017).

    PubMed  Google Scholar 

  225. Zozaya, C. et al. Predicting full enteral feeding in the postoperative period in infants with congenital diaphragmatic hernia. Eur. J. Pediatr. Surg. 27, 431–436 (2017).

    PubMed  Google Scholar 

  226. Leeuwen, L. et al. Congenital diaphragmatic hernia and growth to 12 years. Pediatrics 140, e20163659 (2017).

    PubMed  Google Scholar 

  227. Marseglia, L. et al. Gastroesophageal reflux and congenital gastrointestinal malformations. World J. Gastroenterol. 21, 8508–8515 (2015).

    PubMed  PubMed Central  Google Scholar 

  228. Arcos-Machancoses, J. V., Ruiz Hernández, C., Martin de Carpi, J. & Pinillos Pisón, S. A systematic review with meta-analysis of the prevalence of gastroesophageal reflux in congenital diaphragmatic hernia pediatric survivors. Dis. Esophagus https://doi.org/10.1093/dote/dox158 (2018).

  229. Zanini, A. et al. Follow-up of congenital diaphragmatic hernia: need for routinary assessment of acid gastroesophageal reflux with pH-metry. Eur. J. Pediatr. Surg. 28, 502–507 (2018).

    PubMed  Google Scholar 

  230. Verla, M. A. et al. Prenatal imaging features and postnatal factors associated with gastrointestinal morbidity in congenital diaphragmatic hernia. Fetal Diagn. Ther. 47, 252–260 (2020).

    PubMed  Google Scholar 

  231. Rosen, R. et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J. Pediatr. Gastroenterol. Nutr. 66, 516–554 (2018).

    PubMed  PubMed Central  Google Scholar 

  232. Diamond, I. R. et al. Predicting the need for fundoplication at the time of congenital diaphragmatic hernia repair. J. Pediatr. Surg. 42, 1066–1070 (2007).

    PubMed  Google Scholar 

  233. Verbelen, T. et al. Antireflux surgery after congenital diaphragmatic hernia repair: a plea for a tailored approach. Eur. J. Cardiothorac. Surg. 44, 263–268 (2013).

    PubMed  Google Scholar 

  234. Bagolan, P. & Morini, F. Long-term follow up of infants with congenital diaphragmatic hernia. Semin. Pediatr. Surg. 16, 134–144 (2007).

    PubMed  Google Scholar 

  235. McHoney, M. Congenital diaphragmatic hernia. Early Hum. Dev. 90, 941–946 (2014).

    PubMed  Google Scholar 

  236. Maier, S. et al. Preventive antireflux surgery in neonates with congenital diaphragmatic hernia: a single-blinded prospective study. J. Pediatr. Surg. 46, 1510–1515 (2011).

    PubMed  Google Scholar 

  237. Jancelewicz, T., Chiang, M., Oliveira, C. & Chiu, P. P. Late surgical outcomes among congenital diaphragmatic hernia (CDH) patients: why long-term follow-up with surgeons is recommended. J. Pediatr. Surg. 48, 935–941 (2013).

    PubMed  Google Scholar 

  238. Hollinger, L. E., Harting, M. T. & Lally, K. P. Long-term follow-up of congenital diaphragmatic hernia. Semin. Pediatr. Surg. 26, 178–184 (2017). This publication outlined the specific long-term challenges faced by patients with CDH and presented an algorithm for a multidisciplinary long-term follow-up programme.

    PubMed  Google Scholar 

  239. Nagata, K. et al. Risk factors for the recurrence of the congenital diaphragmatic hernia-report from the long-term follow-up study of Japanese CDH study group. Eur. J. Pediatr. Surg. 25, 9–14 (2015).

    PubMed  Google Scholar 

  240. Putnam, L. R. et al. Factors associated with early recurrence after congenital diaphragmatic hernia repair. J. Pediatr. Surg. 52, 928–932 (2017).

    PubMed  Google Scholar 

  241. Moss, R. L., Chen, C. M. & Harrison, M. R. Prosthetic patch durability in congenital diaphragmatic hernia: a long-term follow-up study. J. Pediatr. Surg. 36, 152–154 (2001).

    CAS  PubMed  Google Scholar 

  242. Loff, S. et al. Implantation of a cone-shaped double-fixed patch increases abdominal space and prevents recurrence of large defects in congenital diaphragmatic hernia. J. Pediatr. Surg. 40, 1701–1705 (2005).

    PubMed  Google Scholar 

  243. Sydorak, R. M. et al. Reversed latissimus dorsi muscle flap for repair of recurrent congenital diaphragmatic hernia. J. Pediatr. Surg. 38, 296–300 (2003).

    CAS  PubMed  Google Scholar 

  244. Mills, J., Safavi, A. & Skarsgard, E. D. Chylothorax after congenital diaphragmatic hernia repair: a population-based study. J. Pediatr. Surg. 47, 842–846 (2012).

    PubMed  Google Scholar 

  245. Ivy, D. D. et al. Pediatric pulmonary hypertension. J. Am. Coll. Cardiol. 62, D117–D126 (2013).

    PubMed  Google Scholar 

  246. Lusk, L. A., Wai, K. C., Moon-Grady, A. J., Steurer, M. A. & Keller, R. L. Persistence of pulmonary hypertension by echocardiography predicts short-term outcomes in congenital diaphragmatic hernia. J. Pediatr. 166, 251–6.e1 (2015).

    PubMed  Google Scholar 

  247. Dillon, P. W., Cilley, R. E., Mauger, D., Zachary, C. & Meier, A. The relationship of pulmonary artery pressure and survival in congenital diaphragmatic hernia. J. Pediatr. Surg. 39, 307–312 (2004).

    PubMed  Google Scholar 

  248. Abman, S. H. et al. Pediatric pulmonary hypertension: guidelines from the american heart association and american thoracic society. Circulation 132, 2037–2099 (2015).

    PubMed  Google Scholar 

  249. Harting, M. T. Congenital diaphragmatic hernia-associated pulmonary hypertension. Semin. Pediatr. Surg. 26, 147–153 (2017).

    PubMed  Google Scholar 

  250. Wong, M. et al. Pulmonary hypertension in congenital diaphragmatic hernia patients: prognostic markers and long-term outcomes. J. Pediatr. Surg. 53, 918–924 (2018).

    PubMed  Google Scholar 

  251. Kraemer, U. S. et al. Characteristics of infants with congenital diaphragmatic hernia who need follow-up of pulmonary hypertension. Pediatr. Crit. Care Med. 19, e219–e226 (2018).

    PubMed  Google Scholar 

  252. Cauley, R. P. et al. Pulmonary support on day 30 as a predictor of morbidity and mortality in congenital diaphragmatic hernia. J. Pediatr. Surg. 48, 1183–1189 (2013).

    PubMed  PubMed Central  Google Scholar 

  253. King, S. K. et al. Congenital diaphragmatic hernia: observed/expected lung-to-head ratio as a predictor of long-term morbidity. J. Pediatr. Surg. 51, 699–702 (2016).

    PubMed  Google Scholar 

  254. Schaible, T. et al. Prediction of chronic lung disease, survival and need for ECMO therapy in infants with congenital diaphragmatic hernia: additional value of fetal MRI measurements? Eur. J. Radiol. 81, 1076–1082 (2012).

    CAS  PubMed  Google Scholar 

  255. Cauley, R. P. et al. Pulmonary support on day of life 30 is a strong predictor of increased 1 and 5-year morbidity in survivors of congenital diaphragmatic hernia. J. Pediatr. Surg. 50, 849–855 (2015).

    PubMed  Google Scholar 

  256. Hayward, M. J. et al. Predicting inadequate long-term lung development in children with congenital diaphragmatic hernia: an analysis of longitudinal changes in ventilation and perfusion. J. Pediatr. Surg. 42, 112–116 (2007).

    PubMed  Google Scholar 

  257. Wigen, R. B., Duan, W., Moraes, T. J. & Chiu, P. P. L. Predictors of long-term pulmonary morbidity in children with congenital diaphragmatic hernia. Eur. J. Pediatr. Surg. 29, 120–124 (2019).

    PubMed  Google Scholar 

  258. Haliburton, B. et al. Pulmonary function and nutritional morbidity in children and adolescents with congenital diaphragmatic hernia. J. Pediatr. Surg. 52, 252–256 (2017).

    PubMed  Google Scholar 

  259. Lally, K. P. & Engle, W. Postdischarge follow-up of infants with congenital diaphragmatic hernia. Pediatrics 121, 627–632 (2008).

    PubMed  Google Scholar 

  260. Benoist, G. et al. Risk of readmission for wheezing during infancy in children with congenital diaphragmatic hernia. PLoS ONE 11, e0155556 (2016).

    PubMed  PubMed Central  Google Scholar 

  261. Panitch, H. B. et al. Lung function over the first 3 years of life in children with congenital diaphragmatic hernia. Pediatr. Pulmonol. 50, 896–907 (2015).

    PubMed  Google Scholar 

  262. Bojanić, K. et al. Cardiopulmonary exercise performance is reduced in congenital diaphragmatic hernia survivors. Pediatr. Pulmonol. 51, 1320–1329 (2016).

    PubMed  Google Scholar 

  263. van der Cammen-van Zijp, M. H. et al. Deterioration of exercise capacity after neonatal extracorporeal membrane oxygenation. Eur. Respir. J. 38, 1098–1104 (2011).

    PubMed  Google Scholar 

  264. Dao, D. T. et al. Longitudinal analysis of pulmonary function in survivors of congenital diaphragmatic hernia. J. Pediatr. 216, 158–164.e2 (2020).

    PubMed  Google Scholar 

  265. Vu, L. T., McFarland, C., Bratton, B. & Lee, H. Closer look at the nutritional outcomes of patients after primary repair of congenital diaphragmatic hernia. J. Pediatr. Gastroenterol. Nutr. 65, 237–241 (2017).

    PubMed  Google Scholar 

  266. Rudra, S. et al. Gastrostomy tube placement in infants with congenital diaphragmatic hernia: frequency, predictors, and growth outcomes. Early Hum. Dev. 103, 97–100 (2016).

    PubMed  PubMed Central  Google Scholar 

  267. Howell, H. B., Farkouh-Karoleski, C., Weindler, M. & Sahni, R. Resting energy expenditure in infants with congenital diaphragmatic hernia without respiratory support at time of neonatal hospital discharge. J. Pediatr. Surg. 53, 2100–2104 (2018).

    PubMed  Google Scholar 

  268. Fitzgerald, D. A., Kench, A., Hatton, L. & Karpelowsky, J. Strategies for improving early nutritional outcomes in children with oesophageal atresia and congenital diaphragmatic hernia. Paediatr. Respir. Rev. 25, 25–29 (2018).

    PubMed  Google Scholar 

  269. Morandi, A. et al. Endoscopic surveillance for congenital diaphragmatic hernia: unexpected prevalence of silent esophagitis. Eur. J. Pediatr. Surg. 26, 291–295 (2016).

    PubMed  Google Scholar 

  270. Montalva, L., Raffler, G., Riccio, A., Lauriti, G. & Zani, A. Neurodevelopmental impairment in children with congenital diaphragmatic hernia: not an uncommon complication for survivors. J. Pediatr. Surg. 55, 625–634 (2020).

    PubMed  Google Scholar 

  271. Van der Veeken, L. et al. Prenatal cerebellar growth is altered in congenital diaphragmatic hernia on ultrasound. Prenat. Diagn. 42, 330–337 (2022).

    PubMed  Google Scholar 

  272. Amoils, M., Crisham Janik, M. & Lustig, L. R. Patterns and predictors of sensorineural hearing loss in children with congenital diaphragmatic hernia. JAMA Otolaryngol. Head Neck Surg. 141, 923–926 (2015).

    PubMed  Google Scholar 

  273. Wilson, M. G., Riley, P., Hurteau, A. M., Baird, R. & Puligandla, P. S. Hearing loss in congenital diaphragmatic hernia (CDH) survivors: is it as prevalent as we think. J. Pediatr. Surg. 48, 942–945 (2013).

    PubMed  Google Scholar 

  274. Alenazi, A. et al. The prevalence of hearing loss in children with congenital diaphragmatic hernia: a longitudinal population-based study. J. Pediatr. Surg. 56, 226–229 (2021).

    PubMed  Google Scholar 

  275. Danzer, E. et al. Short-term neurodevelopmental outcome in congenital diaphragmatic hernia: the impact of extracorporeal membrane oxygenation and timing of repair. Pediatr. Crit. Care Med. 19, 64–74 (2018).

    PubMed  Google Scholar 

  276. Boyle, K. et al. Neurologic outcomes after extracorporeal membrane oxygenation: a systematic review. Pediatr. Crit. Care Med. 19, 760–766 (2018).

    PubMed  PubMed Central  Google Scholar 

  277. Engle, W. A. et al. Adult outcomes after newborn respiratory failure treated with extracorporeal membrane oxygenation. Pediatr. Crit. Care Med. 18, 73–79 (2017).

    PubMed  Google Scholar 

  278. Bevilacqua, F. et al. Does ventilatory time retain its validity in predicting neurodevelopmental outcome at two years of age in high-risk congenital diaphragmatic hernia survivors. Am. J. Perinatol. 34, 248–252 (2017).

    PubMed  Google Scholar 

  279. Danzer, E. et al. Rate and risk factors associated with autism spectrum disorder in congenital diaphragmatic hernia. J. Autism Dev. Disord. 48, 2112–2121 (2018).

    PubMed  Google Scholar 

  280. Leeuwen, L. et al. Risk factors of impaired neuropsychologic outcome in school-aged survivors of neonatal critical illness. Crit. Care Med. 46, 401–410 (2018).

    PubMed  Google Scholar 

  281. Schiller, R. M. et al. Neurobiologic correlates of attention and memory deficits following critical illness in early life. Crit. Care Med. 45, 1742–1750 (2017).

    PubMed  Google Scholar 

  282. Schiller, R. M. et al. Neuropsychological follow-up after neonatal ECMO. Pediatrics 138, e20161313 (2016).

    PubMed  Google Scholar 

  283. Schiller, R. M. et al. Working memory training following neonatal critical illness: a randomized controlled trial. Crit. Care Med. 46, 1158–1166 (2018).

    PubMed  Google Scholar 

  284. Morini, F., Valfrè, L. & Bagolan, P. Long-term morbidity of congenital diaphragmatic hernia: a plea for standardization. Semin. Pediatr. Surg. 26, 301–310 (2017).

    PubMed  Google Scholar 

  285. Jancelewicz, T. et al. Long-term surgical outcomes in congenital diaphragmatic hernia: observations from a single institution. J. Pediatr. Surg. 45, 155–160 (2010).

    PubMed  Google Scholar 

  286. Safavi, A. et al. Multi-institutional follow-up of patients with congenital diaphragmatic hernia reveals severe disability and variations in practice. J. Pediatr. Surg. 47, 836–841 (2012).

    PubMed  Google Scholar 

  287. Tracy, S. & Chen, C. Multidisciplinary long-term follow-up of congenital diaphragmatic hernia: a growing trend. Semin. Fetal Neonatal Med. 19, 385–391 (2014).

    PubMed  Google Scholar 

  288. Chiu, P. P. & Ijsselstijn, H. Morbidity and long-term follow-up in CDH patients. Eur. J. Pediatr. Surg. 22, 384–392 (2012).

    PubMed  Google Scholar 

  289. Peetsold, M. G. et al. Psychological outcome and quality of life in children born with congenital diaphragmatic hernia. Arch. Dis. Child. 94, 834–840 (2009).

    CAS  PubMed  Google Scholar 

  290. Öst, E., Nisell, M., Frenckner, B., Mesas Burgos, C. & Öjmyr-Joelsson, M. Parenting stress among parents of children with congenital diaphragmatic hernia. Pediatr. Surg. Int. 33, 761–769 (2017).

    PubMed  PubMed Central  Google Scholar 

  291. Aite, L. et al. Seeing their children in pain: symptoms of posttraumatic stress disorder in mothers of children with an anomaly requiring surgery at birth. Am. J. Perinatol. 33, 770–775 (2016).

    PubMed  Google Scholar 

  292. Kubota, A. et al. Major neonatal surgery: psychosocial consequence of the patient and mothers. J. Pediatr. Surg. 51, 364–367 (2016).

    PubMed  Google Scholar 

  293. Power, B., Shibuya, S., Lane, B., Eaton, S. & De Coppi, P. Long-term feeding issue and its impact on the daily life of congenital diaphragmatic hernia survivors: results of the first patient-led survey. Pediatr. Surg. Int. 36, 63–68 (2020).

    PubMed  Google Scholar 

  294. Fritz, K. A., Khmour, A. Y., Kitzerow, K., Sato, T. T. & Basir, M. A. Health-related quality of life, educational and family outcomes in survivors of congenital diaphragmatic hernia. Pediatr. Surg. Int. 35, 315–320 (2019).

    PubMed  Google Scholar 

  295. Amin, R. et al. Long-term quality of life in neonatal surgical disease. Ann. Surg. 268, 497–505 (2018).

    PubMed  Google Scholar 

  296. Morsberger, J. L. et al. Parent reported long-term quality of life outcomes in children after congenital diaphragmatic hernia repair. J. Pediatr. Surg. 54, 645–650 (2019).

    PubMed  Google Scholar 

  297. Öst, E., Frenckner, B., Nisell, M., Burgos, C. M. & Öjmyr-Joelsson, M. Health-related quality of life in children born with congenital diaphragmatic hernia. Pediatr. Surg. Int. 34, 405–414 (2018).

    PubMed  PubMed Central  Google Scholar 

  298. Sheikh, F. et al. Assessment of quality of life outcomes using the pediatric quality of life inventory survey in prenatally diagnosed congenital diaphragmatic hernia patients. J. Pediatr. Surg. 51, 545–548 (2016).

    PubMed  Google Scholar 

  299. Chen, C. et al. Impact on family of survivors of congenital diaphragmatic hernia repair: a pilot study. J. Pediatr. Surg. 42, 1845–1852 (2007).

    PubMed  Google Scholar 

  300. Hinton, L., Locock, L., Long, A. M. & Knight, M. What can make things better for parents when babies need abdominal surgery in their first year of life? A qualitative interview study in the UK. BMJ Open 8, e020921 (2018).

    PubMed  PubMed Central  Google Scholar 

  301. Jacobs, R., Boyd, L., Brennan, K., Sinha, C. K. & Giuliani, S. The importance of social media for patients and families affected by congenital anomalies: a Facebook cross-sectional analysis and user survey. J. Pediatr. Surg. 51, 1766–1771 (2016).

    PubMed  Google Scholar 

  302. IJsselstijn, H. et al. Defining outcomes following congenital diaphragmatic hernia using standardised clinical assessment and management plan (SCAMP) methodology within the CDH EURO consortium. Pediatr. Res. 84, 181–189 (2018).

    PubMed  Google Scholar 

  303. Herrera-Rivero, M. et al. Circulating microRNAs are associated with pulmonary hypertension and development of chronic lung disease in congenital diaphragmatic hernia. Sci. Rep. 8, 10735 (2018).

    PubMed  PubMed Central  Google Scholar 

  304. Fabietti, I. et al. Extracellular vesicles and their miRNA content in amniotic and tracheal fluids of fetuses with severe congenital diaphragmatic hernia undergoing fetal intervention. Cells 10, 1493 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  305. Wagner, R. et al. Can circular RNAs be used as prenatal biomarkers for congenital diaphragmatic hernia. Eur. Respir. J. 55, 1900514 (2020).

    PubMed  Google Scholar 

  306. Vergote, S. et al. The TOTAL trial dilemma: a survey among professionals on equipoise regarding fetal therapy for severe congenital diaphragmatic hernia. Prenat. Diagn. 41, 179–189 (2021).

    PubMed  Google Scholar 

  307. Russo, F. M. et al. Fetal endoscopic tracheal occlusion reverses the natural history of right-sided congenital diaphragmatic hernia: European multicenter experience. Ultrasound Obstet. Gynecol. 57, 378–385 (2021).

    CAS  PubMed  Google Scholar 

  308. Montalva, L., Lauriti, G. & Zani, A. Congenital heart disease associated with congenital diaphragmatic hernia: a systematic review on incidence, prenatal diagnosis, management, and outcome. J. Pediatr. Surg. 54, 909–919 (2019).

    PubMed  Google Scholar 

  309. Coughlin, M. A., Gupta, V. S., Ebanks, A. H., Harting, M. T. & Lally, K. P. Incidence and outcomes of patients with congenital diaphragmatic hernia and pulmonary sequestration. J. Pediatr. Surg. 56, 1126–1129 (2021).

    PubMed  Google Scholar 

  310. Mesas Burgos, C., Frenckner, B., Harting, M. T., Lally, P. A. & Lally, K. P. Congenital diaphragmatic hernia and associated omphalocele: a study from the CDHSG registry. J. Pediatr. Surg. 55, 2099–2104 (2020).

    PubMed  Google Scholar 

  311. Nelson, S. M. et al. Rescue of the hypoplastic lung by prenatal cyclical strain. Am. J. Respir. Crit. Care Med. 171, 1395–1402 (2005).

    PubMed  Google Scholar 

  312. Al-Maary, J., Eastwood, M. P., Russo, F. M., Deprest, J. A. & Keijzer, R. Fetal tracheal occlusion for severe pulmonary hypoplasia in isolated congenital diaphragmatic hernia: a systematic review and meta-analysis of survival. Ann. Surg. 264, 929–933 (2016).

    PubMed  Google Scholar 

  313. Araujo Júnior, E., Tonni, G., Martins, W. P. & Ruano, R. Procedure-related complications and survival following fetoscopic endotracheal occlusion (FETO) for severe congenital diaphragmatic hernia: systematic review and meta-analysis in the FETO era. Eur. J. Pediatr. Surg. 27, 297–305 (2017).

    PubMed  Google Scholar 

Download references

Acknowledgements

A.Z. is supported by the Canadian Institutes of Health Research project grant 175300 and SickKids Foundation R00DH00000. W.K.C. is supported by grant NICHD P01 HD068250. J.D. has been supported by WT101957 from the Wellcome Trust and NS/A/000027/1 from the Engineering and Physical Sciences Research Council of the UK, and by the Great Ormond Street Hospital and University College London Hospital Charities. R.K. is supported by project grants (148797, 178347 and 178387) from the Canadian Institutes of Health Research and is the inaugural Thorlakson Chair of Surgical Research for the University of Manitoba.

Author information

Authors and Affiliations

Authors

Contributions

Introduction (A.Z., P.S.P. and R.K.); Epidemiology (A.Z. and M.T.H.); Mechanisms/pathophysiology (W.K.C., S.M.K., L.A., P.S.P. and R.K.); Diagnosis, screening and prevention (J.D., T.J., S.M.K., N.P. and L.A.); Management (J.D., M.T.H., T.J., N.P. and P.S.P.); Quality of life (L.A., P.S.P., A.Z. and M.T.H.); Outlook (A.Z., S.M.K. and R.K.).

Corresponding author

Correspondence to Augusto Zani.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Disease Primers thanks Hiroomi Okuyama, Oluyinka Olurotimi Olutoye, Prem Puri, Thomas F. Schaible and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Zani, A., Chung, W.K., Deprest, J. et al. Congenital diaphragmatic hernia. Nat Rev Dis Primers 8, 37 (2022). https://doi.org/10.1038/s41572-022-00362-w

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41572-022-00362-w

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing