Congenital Diaphragmatic Hernia

  • Julia Zimmer
  • Prem PuriEmail author
Living reference work entry


Congenital diaphragmatic hernia is a relatively common congenital malformation with a poorly understood etiology. On account of advances in technical equipment and operative and anesthetic treatment modalities, the surgical repair of the diaphragmatic defect either open or minimally invasive is nowadays often unproblematic. However, associated pulmonary hypoplasia and persistent pulmonary hypertension lead postnatally to severe respiratory distress and contribute to the high morbidity and mortality rates in this potential life-threatening condition. Therefore, optimal perioperative stabilization and management by an interdisciplinary team of pediatric surgeons, neonatologists, and anesthetists is crucial for these neonates. Nearly half of the CDH survivors beyond the neonatal period are able to lead a normal healthy and symptom free life. However, many survivors with complex medical and surgical needs require a multidisciplinary comprehensive care for their pulmonary, neurodevelopmental, and nutritive long-term outcome. Clinical and basic research continues to identify underlying gene and protein alterations and through this providing a potential for new treatment options for CDH.


Congenital diaphragmatic hernia Pulmonary hypoplasia Pulmonary hypertension Diaphragmatic repair Animal models Nitrofen 


  1. Abbas PI, Cass DL, Olutoye OO, Zamora IJ, Akinkuotu AC, Sheikh F, et al. Persistent hypercarbia after resuscitation is associated with increased mortality in congenital diaphragmatic hernia patients. J Pediatr Surg. 2015;50(5):739–43.PubMedCrossRefGoogle Scholar
  2. Ackerman KG, Herron BJ, Vargas SO, Huang H, Tevosian SG, Kochilas L, et al. Fog2 is required for normal diaphragm and lung development in mice and humans. PLoS Genet. 2005;1(1):58–65.PubMedCrossRefGoogle Scholar
  3. Ali K, Bendapudi P, Polubothu S, Andradi G, Ofuya M, Peacock J, et al. Congenital diaphragmatic hernia-influence of fetoscopic tracheal occlusion on outcomes and predictors of survival. Eur J Pediatr. 2016;175(8):1071–6.PubMedCrossRefGoogle Scholar
  4. Al-Maary J, Eastwood MP, Russo FM, Deprest JA, Keijzer R. Fetal tracheal occlusion for severe pulmonary hypoplasia in isolated congenital diaphragmatic hernia: a systematic review and meta-analysis of survival. Ann Surg. 2016;264(6):929–33.PubMedCrossRefGoogle Scholar
  5. Bagolan P, Morini F. Long-term follow up of infants with congenital diaphragmatic hernia. Semin Pediatr Surg. 2007;16(2):134–44.PubMedCrossRefGoogle Scholar
  6. Bagolan P, Casaccia G, Crescenzi F, Nahom A, Trucchi A, Giorlandino C. Impact of a current treatment protocol on outcome of high-risk congenital diaphragmatic hernia. J Pediatr Surg. 2004;39(3):313–8; discussion 313–8PubMedCrossRefGoogle Scholar
  7. Beurskens LWJE, Tibboel D, Lindemans J, Duvekot JJ, Cohen-Overbeek TE, Veenma DCM, et al. Retinol status of newborn infants is associated with congenital diaphragmatic hernia. Pediatrics. 2010;126(4):712–20.PubMedCrossRefGoogle Scholar
  8. Bialkowski A, Moenkemeyer F, Patel N. Intravenous sildenafil in the management of pulmonary hypertension associated with congenital diaphragmatic hernia. Eur J Pediatr Surg. 2015;25(2):171–6.Google Scholar
  9. Bishay M, Giacomello L, Retrosi G, Thyoka M, Garriboli M, Brierley J, et al. Hypercapnia and acidosis during open and thoracoscopic repair of congenital diaphragmatic hernia and esophageal atresia: results of a pilot randomized controlled trial. Ann Surg. 2013;258(6):895–900.PubMedCrossRefGoogle Scholar
  10. Bleyl SB, Moshrefi A, Shaw GM, Saijoh Y, Schoenwolf GC, Pennacchio LA, et al. Candidate genes for congenital diaphragmatic hernia from animal models: sequencing of FOG2 and PDGFRalpha reveals rare variants in diaphragmatic hernia patients. Eur J Hum Genet EJHG. 2007;15(9):950–8.PubMedCrossRefGoogle Scholar
  11. Bojanic K, Pritisanac E, Luetic T, Vukovic J, Sprung J, Weingarten TN, et al. Malformations associated with congenital diaphragmatic hernia: impact on survival. J Pediatr Surg. 2015;50(11):1817–22.PubMedCrossRefGoogle Scholar
  12. Boloker J, Bateman DA, Wung J-T, Stolar CJH. Congenital diaphragmatic hernia in 120 infants treated consecutively with permissive hypercapnea/spontaneous respiration/elective repair. J Pediatr Surg. 2002;37(3):357–66.PubMedCrossRefGoogle Scholar
  13. Brindle ME, Cook EF, Tibboel D, Lally PA, Lally KP. A clinical prediction rule for the severity of congenital diaphragmatic hernias in newborns. Pediatrics. 2014;134(2):e413–9.PubMedCrossRefGoogle Scholar
  14. Britto ISW, Sananes N, Olutoye OO, Cass DL, Sangi-Haghpeykar H, Lee TC, 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 Off J Am Inst Ultrasound Med. 2015;34(10):1721–7.CrossRefGoogle Scholar
  15. Burgos CM, Frenckner B. Addressing the hidden mortality in CDH: a population-based study. J Pediatr Surg. 2017;52(4):522–5.PubMedCrossRefGoogle Scholar
  16. Burgos CM, Uggla AR, Fagerstrom-Billai F, Eklof A-C, Frenckner B, Nord M. Gene expression analysis in hypoplastic lungs in the nitrofen model of congenital diaphragmatic hernia. J Pediatr Surg. 2010;45(7):1445–54.PubMedCrossRefGoogle Scholar
  17. Burgos CM, Modee A, Ost E, Frenckner B. Addressing the causes of late mortality in infants with congenital diaphragmatic hernia. J Pediatr Surg. 2017;52(4):526–9.PubMedCrossRefGoogle Scholar
  18. Candilera V, Bouchè C, Schleef J, Pederiva F. Lung growth factors in the amniotic fluid of normal pregnancies and with congenital diaphragmatic hernia. J Matern Fetal Neonatal Med. 2016;29(13):2104–8.PubMedCrossRefGoogle Scholar
  19. Chandrasekharan PK, Rawat M, Madappa R, Rothstein DH, Lakshminrusimha S. Congenital diaphragmatic hernia – a review. Matern Health Neonatol Perinatol. 2017;3:6.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Chiu PPL, Sauer C, Mihailovic A, Adatia I, Bohn D, Coates AL, et al. The price of success in the management of congenital diaphragmatic hernia: is improved survival accompanied by an increase in long-term morbidity? J Pediatr Surg. 2006;41(5):888–92.PubMedCrossRefGoogle Scholar
  21. Clugston RD, Klattig J, Englert C, Clagett-Dame M, Martinovic J, Benachi A, et al. Teratogen-induced, dietary and genetic models of congenital diaphragmatic hernia share a common mechanism of pathogenesis. Am J Pathol. 2006;169(5):1541–9.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Collin M, Trinder S, Minutillo C, Rao S, Dickinson J, Samnakay N. A modern era comparison of right versus left sided congenital diaphragmatic hernia outcomes. J Pediatr Surg. 2016;51(9):1409–13.PubMedCrossRefGoogle Scholar
  23. Colvin J, Bower C, Dickinson JE, Sokol J. Outcomes of congenital diaphragmatic hernia: a population-based study in Western Australia. Pediatrics. 2005;116(3):e356–63.PubMedCrossRefGoogle Scholar
  24. Congenital Diaphragmatic Hernia Study Group. Estimating disease severity of congenital diaphragmatic hernia in the first 5 minutes of life. J Pediatr Surg. 2001;36(1):141–5.CrossRefGoogle Scholar
  25. Coughlin MA, Werner NL, Gajarski R, Gadepalli S, Hirschl R, Barks J, et al. Prenatally diagnosed severe CDH: mortality and morbidity remain high. J Pediatr Surg. 2016;51(7):1091–5.Google Scholar
  26. Danzer E, Hedrick HL. Neurodevelopmental and neurofunctional outcomes in children with congenital diaphragmatic hernia. Early Hum Dev. 2011;87(9):625–32.PubMedCrossRefGoogle Scholar
  27. Danzer E, Gerdes M, Bernbaum J, D’Agostino J, Bebbington MW, Siegle J, et al. Neurodevelopmental outcome of infants with congenital diaphragmatic hernia prospectively enrolled in an interdisciplinary follow-up program. J Pediatr Surg. 2010;45(9):1759–66.PubMedCrossRefGoogle Scholar
  28. Daodu O, Brindle ME. Predicting outcomes in congenital diaphragmatic hernia. Semin Pediatr Surg. 2017;26(3):136–9.PubMedCrossRefGoogle Scholar
  29. De Coppi P, Deprest J. Regenerative medicine for congenital diaphragmatic hernia: regeneration for repair. European journal of pediatric surgery official journal of Austrian Association of Pediatric. Surgery. 2012;22(5):393–8.Google Scholar
  30. De Coppi P, Deprest J. Regenerative medicine solutions in congenital diaphragmatic hernia. Semin Pediatr Surg. 2017;26(3):171–7.PubMedCrossRefGoogle Scholar
  31. DeKoninck P, Toelen J, Roubliova X, Carter S, Pozzobon M, Russo FM, et al. The use of human amniotic fluid stem cells as an adjunct to promote pulmonary development in a rabbit model for congenital diaphragmatic hernia. Prenat Diagn. 2015;35(9):833–40.PubMedCrossRefGoogle Scholar
  32. Dennett KV, Fligor BJ, Tracy S, Wilson JM, Zurakowski D, Chen C. Sensorineural hearing loss in congenital diaphragmatic hernia survivors is associated with postnatal management and not defect size. J Pediatr Surg. 2014;49(6):895–9.PubMedCrossRefGoogle Scholar
  33. Deprest J, Jani J, Cannie M, Debeer A, Vandevelde M, Done E, et al. Prenatal intervention for isolated congenital diaphragmatic hernia. Curr Opin Obstet Gynecol. 2006a;18(3):355–67.PubMedCrossRefGoogle Scholar
  34. Deprest J, Jani J, van Schoubroeck D, Cannie M, Gallot D, Dymarkowski S, et al. Current consequences of prenatal diagnosis of congenital diaphragmatic hernia. J Pediatr Surg. 2006b;41(2):423–30.PubMedCrossRefGoogle Scholar
  35. Deprest J, Nicolaides K, Done’ E, Lewi P, Barki G, Largen E, et al. Technical aspects of fetal endoscopic tracheal occlusion for congenital diaphragmatic hernia. J Pediatr Surg. 2011;46(1):22–32.PubMedCrossRefGoogle Scholar
  36. Devriendt K, Deloof E, Moerman P, Legius E, Vanhole C, de ZF, et al. Diaphragmatic hernia in Denys-Drash syndrome. Am J Med Genet. 1995;57(1):97–101.PubMedCrossRefGoogle Scholar
  37. Doi T, Sugimoto K, Puri P. Up-regulation of COUP-TFII gene expression in the nitrofen-induced hypoplastic lung. J Pediatr Surg. 2009;44(2):321–4.PubMedCrossRefGoogle Scholar
  38. Doi T, Sugimoto K, Ruttenstock E, Dingemann J, Puri P. Prenatal retinoic acid upregulates pulmonary gene expression of PI3K and AKT in nitrofen-induced pulmonary hypoplasia. Pediatr Surg Int. 2010;26(10):1011–5.PubMedCrossRefGoogle Scholar
  39. Eastwood MP, Russo FM, Toelen J, Deprest J. Medical interventions to reverse pulmonary hypoplasia in the animal model of congenital diaphragmatic hernia: a systematic review. Pediatr Pulmonol. 2015;50(8):820–38.PubMedCrossRefGoogle Scholar
  40. Fleck S, Bautista G, Keating SM, Lee T-H, Keller RL, Moon-Grady AJ, et al. Fetal production of growth factors and inflammatory mediators predicts pulmonary hypertension in congenital diaphragmatic hernia. Pediatr Res. 2013;74(3):290–8.PubMedPubMedCentralCrossRefGoogle Scholar
  41. Friedman S, Chen C, Chapman JS, Jeruss S, Terrin N, Tighiouart H, et al. Neurodevelopmental outcomes of congenital diaphragmatic hernia survivors followed in a multidisciplinary clinic at ages 1 and 3. J Pediatr Surg. 2008;43(6):1035–43.PubMedCrossRefGoogle Scholar
  42. Fujishiro J, Ishimaru T, Sugiyama M, Arai M, Suzuki K, Kawashima H, et al. Minimally invasive surgery for diaphragmatic diseases in neonates and infants. Surg Today. 2016;46(7):757–63.PubMedCrossRefGoogle Scholar
  43. Gaboli M, de la Cruz OA, de Aguero MIBG, Moreno-Galdo A, Perez GP, de Querol MS-S. Use of palivizumab in infants and young children with severe respiratory disease: a Delphi study. Pediatr Pulmonol. 2014;49(5):490–502.PubMedCrossRefGoogle Scholar
  44. Gallot D, Boda C, Ughetto S, Perthus I, Robert-Gnansia E, Francannet C, et al. Prenatal detection and outcome of congenital diaphragmatic hernia: a French registry-based study. Ultrasound Obstet Gynecol Off J Int Soc Ultrasound Obstet Gynecol. 2007;29(3):276–83.CrossRefGoogle Scholar
  45. Garcia AV, Fingeret AL, Thirumoorthi AS, Hahn E, Leskowitz MJ, Aspelund G, et al. Lung to head ratio in infants with congenital diaphragmatic hernia does not predict long term pulmonary hypertension. J Pediatr Surg. 2013;48(1):154–7.PubMedCrossRefGoogle Scholar
  46. Glick PL, Stannard VA, Leach CL, Rossman J, Hosada Y, Morin FC, et al. Pathophysiology of congenital diaphragmatic hernia II: the fetal lamb CDH model is surfactant deficient. J Pediatr Surg. 1992;27(3):382–7; discussion 387–8PubMedCrossRefGoogle Scholar
  47. Golden J, Jones N, Zagory J, Castle S, Bliss D. Outcomes of congenital diaphragmatic hernia repair on extracorporeal life support. Pediatr Surg Int. 2017;33(2):125–31.PubMedCrossRefGoogle Scholar
  48. Goonasekera C, Ali K, Hickey A, Sasidharan L, Mathew M, Davenport M, et al. Mortality following congenital diaphragmatic hernia repair: the role of anesthesia. Paediatr Anaesth. 2016;26(12):1197–201.PubMedCrossRefGoogle Scholar
  49. Gosemann J-H, Friedmacher F, Fujiwara N, Alvarez LAJ, Corcionivoschi N, Puri P. Disruption of the bone morphogenetic protein receptor 2 pathway in nitrofen-induced congenital diaphragmatic hernia. Birth Defects Res B Dev Reprod Toxicol. 2013;98(4):304–9.PubMedCrossRefGoogle Scholar
  50. Grivell RM, Andersen C, Dodd JM. Prenatal interventions for congenital diaphragmatic hernia for improving outcomes. Cochrane Database Syst Rev. 2015;11:CD008925.Google Scholar
  51. Guignabert C, Tu L, Girerd B, Ricard N, Huertas A, Montani D, et al. New molecular targets of pulmonary vascular remodeling in pulmonary arterial hypertension: importance of endothelial communication. Chest. 2015;147(2):529–37.PubMedCrossRefGoogle Scholar
  52. Hagadorn JI, Brownell EA, Herbst KW, Trzaski JM, Neff S, Campbell BT. Trends in treatment and in-hospital mortality for neonates with congenital diaphragmatic hernia. J Perinatol Off J Calif Perinatal Assoc. 2015;35(9):748–54.CrossRefGoogle Scholar
  53. Harrison MR, Adzick NS, Flake AW, Jennings RW, Estes JM, MacGillivray TE, et al. Correction of congenital diaphragmatic hernia in utero: VI. Hard-earned lessons. J Pediatr Surg. 1993;28(10):1411–7; discussion 1417–8PubMedCrossRefGoogle Scholar
  54. Harrison MR, Adzick NS, Bullard KM, Farrell JA, Howell LJ, Rosen MA, et al. Correction of congenital diaphragmatic hernia in utero VII: a prospective trial. J Pediatr Surg. 1997;32(11):1637–42.PubMedCrossRefGoogle Scholar
  55. Harrison MR, Keller RL, Hawgood SB, Kitterman JA, Sandberg PL, Farmer DL, et al. A randomized trial of fetal endoscopic tracheal occlusion for severe fetal congenital diaphragmatic hernia. N Engl J Med. 2003;349(20):1916–24.PubMedCrossRefGoogle Scholar
  56. Harting MT. Congenital diaphragmatic hernia-associated pulmonary hypertension. Semin Pediatr Surg. 2017;26(3):147–53.PubMedCrossRefGoogle Scholar
  57. High FA, Bhayani P, Wilson JM, Bult CJ, Donahoe PK, Longoni M. De novo frameshift mutation in COUP-TFII (NR2F2) in human congenital diaphragmatic hernia. Am J Med Genet A. 2016;170(9):2457–61.PubMedPubMedCentralCrossRefGoogle Scholar
  58. Hille ETM, van Straaten HI, Verkerk PH. Prevalence and independent risk factors for hearing loss in NICU infants. Acta Paediatr (Oslo, Norway 1992). 2007;96(8):1155–8.CrossRefGoogle Scholar
  59. Hollinger LE, Harting MT, Lally KP. Long-term follow-up of congenital diaphragmatic hernia. Semin Pediatr Surg. 2017;26(3):178–84.PubMedCrossRefGoogle Scholar
  60. Hutcheon JA, Butler B, Lisonkova S, Marquette GP, Mayer C, Skoll A, et al. Timing of delivery for pregnancies with congenital diaphragmatic hernia. BJOG Int J Obstet Gynaecol. 2010;117(13):1658–62.CrossRefGoogle Scholar
  61. IJsselstijn H, Zimmermann LJ, Bunt JE, de Jongste JC, Tibboel D. Prospective evaluation of surfactant composition in bronchoalveolar lavage fluid of infants with congenital diaphragmatic hernia and of age-matched controls. Crit Care Med. 1998;26(3):573–80.PubMedCrossRefGoogle Scholar
  62. Iritani I. Experimental study on embryogenesis of congenital diaphragmatic hernia. Anat Embryol. 1984;169(2):133–9.PubMedCrossRefGoogle Scholar
  63. Jaillard SM, Pierrat V, Dubois A, Truffert P, Lequien P, Wurtz AJ, et al. Outcome at 2 years of infants with congenital diaphragmatic hernia: a population-based study. Ann Thorac Surg. 2003;75(1):250–6.PubMedCrossRefGoogle Scholar
  64. Jancelewicz T, LT V, Keller RL, Bratton B, Lee H, Farmer D, et al. Long-term surgical outcomes in congenital diaphragmatic hernia: observations from a single institution. J Pediatr Surg. 2010;45(1):155–60; discussion 160PubMedCrossRefGoogle Scholar
  65. Jay PY, Bielinska M, Erlich JM, Mannisto S, Pu WT, Heikinheimo M, et al. Impaired mesenchymal cell function in Gata4 mutant mice leads to diaphragmatic hernias and primary lung defects. Dev Biol. 2007;301(2):602–14.PubMedCrossRefGoogle Scholar
  66. Jeanty C, Kunisaki SM, MacKenzie TC. Novel non-surgical prenatal approaches to treating congenital diaphragmatic hernia. Semin Fetal Neonatal Med. 2014;19(6):349–56.PubMedCrossRefGoogle Scholar
  67. Kays DW. ECMO in CDH: is there a role? Semin Pediatr Surg. 2017;26(3):166–70.PubMedCrossRefGoogle Scholar
  68. 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. 2000;156(4):1299–306.PubMedPubMedCentralCrossRefGoogle Scholar
  69. Kluth D, Keijzer R, Hertl M, Tibboel D. Embryology of congenital diaphragmatic hernia. Semin Pediatr Surg. 1996;5(4):224–33.PubMedGoogle Scholar
  70. Kobayashi H, Puri P. Plasma endothelin levels in congenital diaphragmatic hernia. J Pediatr Surg. 1994;29(9):1258–61.PubMedCrossRefGoogle Scholar
  71. Kool H, Mous D, Tibboel D, de Klein A, Rottier RJ. Pulmonary vascular development goes awry in congenital lung abnormalities. Birth Defects Res C Embryo Today. 2014;102(4):343–58.PubMedCrossRefGoogle Scholar
  72. Lakshminrusimha S, Mathew B, Leach CL. Pharmacologic strategies in neonatal pulmonary hypertension other than nitric oxide. Semin Perinatol. 2016;40(3):160–73.Google Scholar
  73. Lally KP, Lasky RE, Lally PA, Bagolan P, Davis CF, Frenckner BP, et al. Standardized reporting for congenital diaphragmatic hernia – an international consensus. J Pediatr Surg. 2013;48(12):2408–15.PubMedCrossRefGoogle Scholar
  74. Lansdale N, Alam S, Losty PD, Jesudason EC. Neonatal endosurgical congenital diaphragmatic hernia repair: a systematic review and meta-analysis. Ann Surg. 2010;252(1):20–6.PubMedCrossRefGoogle Scholar
  75. Levin DL. Morphologic analysis of the pulmonary vascular bed in congenital left-sided diaphragmatic hernia. J Pediatr. 1978;92(5):805–9.PubMedCrossRefGoogle Scholar
  76. Liao SL, Luks FI, Piasecki GJ, Wild YK, Papadakis K, Paepe ME. De. Late-gestation tracheal occlusion in the fetal lamb causes rapid lung growth with type II cell preservation. J Surg Res. 2000;92(1):64–70.PubMedCrossRefGoogle Scholar
  77. Logan JW, Cotten CM, Goldberg RN, Clark RH. Mechanical ventilation strategies in the management of congenital diaphragmatic hernia. Semin Pediatr Surg. 2007;16(2):115–25.PubMedCrossRefGoogle Scholar
  78. Mahood TH, Johar DR, Iwasiow BM, Xu W, Keijzer R. The transcriptome of nitrofen-induced pulmonary hypoplasia in the rat model of congenital diaphragmatic hernia. Pediatr Res. 2016;79(5):766–75.PubMedCrossRefGoogle Scholar
  79. Mann PC, Morriss FH, Klein JM. Prediction of survival in infants with congenital diaphragmatic hernia based on stomach position, surgical timing, and oxygenation index. Am J Perinatol. 2012;29(5):383–90.PubMedCrossRefGoogle Scholar
  80. Masumoto K, Nagata K, Uesugi T, Yamada T, Kinjo T, Hikino S, et al. Risk of respiratory syncytial virus in survivors with severe congenital diaphragmatic hernia. Pediatr Int Off J Jpn Pediatr Soc. 2008;50(4):459–63.CrossRefGoogle Scholar
  81. Masumoto K, Teshiba R, Esumi G, Nagata K, Takahata Y, Hikino S, et al. Improvement in the outcome of patients with antenatally diagnosed congenital diaphragmatic hernia using gentle ventilation and circulatory stabilization. Pediatr Surg Int. 2009;25(6):487–92.PubMedCrossRefGoogle Scholar
  82. McGivern MR, Best KE, Rankin J, Wellesley D, Greenlees R, Addor M-C, et al. Epidemiology of congenital diaphragmatic hernia in Europe: a register-based study. Arch Dis Child Fetal Neonatal Ed. 2015;100(2):F137–44.PubMedCrossRefGoogle Scholar
  83. McHoney M. Congenital diaphragmatic hernia, management in the newborn. Pediatr Surg Int. 2015;31(11):1005–13.PubMedCrossRefGoogle Scholar
  84. Mendelsohn C, Lohnes D, Decimo D, Lufkin T, LeMeur M, Chambon P, et al. Function of the retinoic acid receptors (RARs) during development (II). Multiple abnormalities at various stages of organogenesis in RAR double mutants. Development. 1994;120(10):2749–71.PubMedGoogle Scholar
  85. Metkus AP, Filly RA, Stringer MD. Harrison, Adzick NS. Sonographic predictors of survival in fetal diaphragmatic hernia. J Pediatr Surg. 1996;31(1):148–51; discussion 151–2PubMedCrossRefGoogle Scholar
  86. Molkentin JD. The zinc finger-containing transcription factors GATA-4, -5, and -6. Ubiquitously expressed regulators of tissue-specific gene expression. J Biol Chem. 2000;275(50):38949–52.PubMedCrossRefGoogle Scholar
  87. Morini F, Goldman A, Pierro A. Extracorporeal membrane oxygenation in infants with congenital diaphragmatic hernia: a systematic review of the evidence. Eur J Pediatr Surg. 2006;16(6):385–91.Google Scholar
  88. Morini F, Capolupo I, van Weteringen W, Reiss I. Ventilation modalities in infants with congenital diaphragmatic hernia. Semin Pediatr Surg. 2017;26(3):159–65.PubMedCrossRefGoogle Scholar
  89. Motoyama J, Liu J, Mo R, Ding Q, Post M, Hui CC. Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus. Nat Genet. 1998;20(1):54–7.PubMedCrossRefGoogle Scholar
  90. Moyer V, Moya F, Tibboel R, Losty P, Nagaya M, Lally KP. Late versus early surgical correction for congenital diaphragmatic hernia in newborn infants. Cochrane Database Syst Rev. 2002;3:CD001695.Google Scholar
  91. Mugford M, Elbourne D, Field D. Extracorporeal membrane oxygenation for severe respiratory failure in newborn infants. Cochrane Database Syst Rev. 2008;3:CD001340.Google Scholar
  92. Muratore CS, Nguyen HT, Ziegler MM, Wilson JM. Stretch-induced upregulation of VEGF gene expression in murine pulmonary culture: a role for angiogenesis in lung development. J Pediatr Surg. 2000;35(6):906–12; discussion 912–3PubMedCrossRefGoogle Scholar
  93. Muratore CS, Utter S, Jaksic T, Lund DP, Wilson JM. Nutritional morbidity in survivors of congenital diaphragmatic hernia. J Pediatr Surg. 2001;36(8):1171–6.PubMedCrossRefGoogle Scholar
  94. Mychaliska G, Bryner B, Dechert R, Kreutzman J, Becker M, Hirschl R. Safety and efficacy of perflubron-induced lung growth in neonates with congenital diaphragmatic hernia: results of a prospective randomized trial. J Pediatr Surg. 2015;50(7):1083–7.PubMedCrossRefGoogle Scholar
  95. Nakazawa N, Montedonico S, Takayasu H, Paradisi F, Puri P. Disturbance of retinol transportation causes nitrofen-induced hypoplastic lung. J Pediatr Surg. 2007;42(2):345–9.PubMedCrossRefGoogle Scholar
  96. Nobuhara KK, Wilson JM. Pathophysiology of congenital diaphragmatic hernia. Semin Pediatr Surg. 1996;5(4):234–42.PubMedGoogle Scholar
  97. Nobuhara KK, Fauza DO, DiFiore JW, Hines MH, Fackler JC, Slavin R, et al. Continuous intrapulmonary distension with perfluorocarbon accelerates neonatal (but not adult) lung growth. J Pediatr Surg. 1998;33(2):292–8.PubMedCrossRefGoogle Scholar
  98. Okuyama H, Usui N, Hayakawa M, Taguchi T. Appropriate timing of surgery for neonates with congenital diaphragmatic hernia: early or delayed repair? Pediatr Surg Int. 2017;33(2):133–8.PubMedCrossRefGoogle Scholar
  99. Oliveira CA, Troster EJ, Pereira CR. Inhaled nitric oxide in the management of persistent pulmonary hypertension of the newborn: a meta-analysis. Rev Hosp Clin. 2000;55(4):145–54.CrossRefGoogle Scholar
  100. Oluyomi-Obi T, Van Mieqhem T, Ryan G. Fetal imaging and therapy for CDH-current status. Semin Pediatr Surg. 2017;26(3):140–6.PubMedCrossRefGoogle Scholar
  101. Oue T, Shima H, Taira Y, Puri P. Administration of antenatal glucocorticoids upregulates peptide growth factor gene expression in nitrofen-induced congenital diaphragmatic hernia in rats. J Pediatr Surg. 2000;35(1):109–12.PubMedCrossRefGoogle Scholar
  102. Park HW, Lee BS, Lim G, Choi Y-S, Kim EA-R, Kim K-S. 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. 2013;28(6):924–8.PubMedPubMedCentralCrossRefGoogle Scholar
  103. Partridge EA, Bridge C, Donaher JG, Herkert LM, Grill E, Danzer E, et al. Incidence and factors associated with sensorineural and conductive hearing loss among survivors of congenital diaphragmatic hernia. J Pediatr Surg. 2014;49(6):890–4; discussion 894PubMedCrossRefGoogle Scholar
  104. Pepicelli CV, Lewis PM, McMahon AP. Sonic hedgehog regulates branching morphogenesis in the mammalian lung. Curr Biol CB. 1998;8(19):1083–6.PubMedCrossRefGoogle Scholar
  105. Pierro A. Hypercapnia and acidosis during the thoracoscopic repair of oesophageal atresia and congenital diaphragmatic hernia. J Pediatr Surg. 2015;50(2):247–9.PubMedCrossRefGoogle Scholar
  106. Puligandla PS, Grabowski J, Austin M, Hedrick H, Renaud E, Arnold M, et al. Management of congenital diaphragmatic hernia: a systematic review from the APSA outcomes and evidence based practice committee. J Pediatr Surg. 2015;50(11):1958–70.PubMedCrossRefGoogle Scholar
  107. Puri P, Doi T. Congenital diaphragmatic hernia. In: Puri P, editor. Newborn surgery. London: Hodder Arnold; 2011. p. 361–8.CrossRefGoogle Scholar
  108. Puri P, Nakazawa N. Congenital diaphragmatic hernia. In: Puri P, Höllwarth ME, editors. Pediatric surgery: diagnosis and management. Berlin/London: Springer; 2009. p. 307–13.CrossRefGoogle Scholar
  109. Putnam LR, Tsao K, Morini F, Lally PA, Miller CC, Lally KP, et al. Evaluation of variability in inhaled nitric oxide use and pulmonary hypertension in patients with congenital diaphragmatic hernia. JAMA Pediatr. 2016;170(12):1188.PubMedCrossRefGoogle Scholar
  110. Rais-Bahrami K, Robbins ST, Reed VL, Powell DM, Short BL. Congenital diaphragmatic hernia. Outcome of preoperative extracorporeal membrane oxygenation. Clin Pediatr. 1995;34(9):471–4.CrossRefGoogle Scholar
  111. Reiss I, Schaible T, van den Hout L, Capolupo I, Allegaert K, van Heijst A, et al. Standardized postnatal management of infants with congenital diaphragmatic hernia in Europe: the CDH EURO consortium consensus. Neonatology. 2010;98(4):354–64.PubMedCrossRefGoogle Scholar
  112. Resch B. Respiratory syncytial virus infection in high-risk infants – an update on Palivizumab prophylaxis. Open Microbiol J. 2014;8:71–7.PubMedPubMedCentralCrossRefGoogle Scholar
  113. Robertson CMT, Tyebkhan JM, Hagler ME, Cheung P-Y, Peliowski A, Etches PC. Late-onset, progressive sensorineural hearing loss after severe neonatal respiratory failure. Otol Neurotol. 2002;23(3):353–6.Google Scholar
  114. Ruano R, Takashi E, da Silva MM, Campos JADB, Tannuri U, Zugaib M. Prediction and probability of neonatal outcome in isolated congenital diaphragmatic hernia using multiple ultrasound parameters. Ultrasound Obstet Gynecol Off J Int Soc Ultrasound Obstet Gynecol. 2012;39(1):42–9.CrossRefGoogle Scholar
  115. Ruano R, Lazar DA, Cass DL, Zamora IJ, Lee TC, Cassady CI, et al. Fetal lung volume and quantification of liver herniation by magnetic resonance imaging in isolated congenital diaphragmatic hernia. Ultrasound Obstet Gynecol Off J Int Soc Ultrasound Obstet Gynecol. 2014;43(6):662–9.CrossRefGoogle Scholar
  116. Ruttenstock E, Wright N, Barrena S, Krickhahn A, Castellani C, Desai AP, 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. 2015;25(1):3–8.Google Scholar
  117. Sadler TW. Langman’s medical embryology. 11th ed. Baltimore: William & Wilkins; 2009.Google Scholar
  118. Sananes N, Britto I, Akinkuotu AC, Olutoye OO, Cass DL, Sangi-Haghpeykar H, et al. Improving the prediction of neonatal outcomes in isolated left-sided congenital diaphragmatic hernia by direct and indirect sonographic assessment of liver herniation. J Ultrasound Med Off J Am Inst Ultrasound Med. 2016;35(7):1437–43.CrossRefGoogle Scholar
  119. Scott DA, Cooper ML, Stankiewicz P, Patel A, Potocki L, Cheung SW. Congenital diaphragmatic hernia in WAGR syndrome. Am J Med Genet A. 2005;134(4):430–3.PubMedCrossRefGoogle Scholar
  120. Shieh HF, Graham CD, Brazzo JA, Zurakowski D, Fauza DO. Comparisons of human amniotic mesenchymal stem cell viability in FDA-approved collagen-based scaffolds: implications for engineered diaphragmatic replacement. J Pediatr Surg. 2017a;52(6):1010–3.PubMedCrossRefGoogle Scholar
  121. Shieh HF, Wilson JM, Sheils CA, Smithers CJ, Kharasch VS, Becker RE, et al. Does the ex utero intrapartum treatment to extracorporeal membrane oxygenation procedure change morbidity outcomes for high-risk congenital diaphragmatic hernia survivors? J Pediatr Surg. 2017b;52(1):22–5.PubMedCrossRefGoogle Scholar
  122. Sigalet DL, Nguyen LT, Adolph V, Laberge JM, Hong AR, Guttman FM. Gastroesophageal reflux associated with large diaphragmatic hernias. J Pediatr Surg. 1994;29(9):1262–5.PubMedCrossRefGoogle Scholar
  123. Snoek KG, Capolupo I, Morini F, van Rosmalen J, Greenough A, van Heijst A, et al. Score for neonatal acute physiology-II predicts outcome in congenital diaphragmatic hernia patients. Pediatr Crit Care Med. 2016a;17(6):540–6.Google Scholar
  124. Snoek KG, Capolupo I, van Rosmalen J, LdJ-vd H, Vijfhuize S, Greenough A, et al. Conventional mechanical ventilation versus high-frequency oscillatory ventilation for congenital diaphragmatic hernia: a randomized clinical trial (the VICI-trial). Ann Surg. 2016b;263(5):867–74.PubMedCrossRefGoogle Scholar
  125. Steinhorn RH, Fineman J, Kusic-Pajic A, Cornelisse P, Gehin M, Nowbakht P, et al. Bosentan as adjunctive therapy for persistent pulmonary hypertension of the newborn: results of the randomized multicenter placebo-controlled exploratory trial. J Pediatr. 2016;177:90–96.e3.PubMedCrossRefGoogle Scholar
  126. Stevens TP, van Wijngaarden E, Ackerman KG, Lally PA, Lally KP. Timing of delivery and survival rates for infants with prenatal diagnoses of congenital diaphragmatic hernia. Pediatrics. 2009;123(2):494–502.PubMedCrossRefGoogle Scholar
  127. Sugimoto K, Takayasu H, Nakazawa N, Montedonico S, Puri P. Prenatal treatment with retinoic acid accelerates type 1 alveolar cell proliferation of the hypoplastic lung in the nitrofen model of congenital diaphragmatic hernia. J Pediatr Surg. 2008;43(2):367–72.PubMedCrossRefGoogle Scholar
  128. Sullivan KM, Hawgood S, Flake AW, Harrison MR, Adzick NS. Amniotic fluid phospholipid analysis in the fetus with congenital diaphragmatic hernia. J Pediatr Surg. 1994;29(8):1020–3; discussion 1023–4PubMedCrossRefGoogle Scholar
  129. Takahashi T, Zimmer J, Friedmacher F, Puri P. Follistatin-like 1 expression is decreased in the alveolar epithelium of hypoplastic rat lungs with nitrofen-induced congenital diaphragmatic hernia. J Pediatr Surg. 2017;52(5):706–9.PubMedCrossRefGoogle Scholar
  130. Terui K, Nagata K, Ito M, Yamoto M, Shiraishi M, Taguchi T, et al. Surgical approaches for neonatal congenital diaphragmatic hernia: a systematic review and meta-analysis. Pediatr Surg Int. 2015;31(10):891–7.PubMedCrossRefGoogle Scholar
  131. Tiryaki S, Ozcan C, Erdener A. Initial oxygenation response to inhaled nitric oxide predicts improved outcome in congenital diaphragmatic hernia. Drugs R&D. 2014;14(4):215–9.CrossRefGoogle Scholar
  132. Tracy S, Chen C. Multidisciplinary long-term follow-up of congenital diaphragmatic hernia: a growing trend. Semin Fetal Neonatal Med. 2014;19(6):385–91.PubMedCrossRefGoogle Scholar
  133. van den Hout L, Reiss I, Felix JF, Hop WCJ, Lally PA, Lally KP, et al. Risk factors for chronic lung disease and mortality in newborns with congenital diaphragmatic hernia. Neonatology. 2010;98(4):370–80.PubMedCrossRefGoogle Scholar
  134. Vitali SH, Arnold JH. Bench-to-bedside review: ventilator strategies to reduce lung injury – lessons from pediatric and neonatal intensive care. Crit Care. 2005;9(2):177–83.PubMedCrossRefGoogle Scholar
  135. Walleyo A, Debus A, Kehl S, Weiss C, Schönberg SO, Schaible T, et al. Periodic MRI lung volume assessment in fetuses with congenital diaphragmatic hernia: prediction of survival, need for ECMO, and development of chronic lung disease. AJR Am J Roentgenol. 2013;201(2):419–26.PubMedCrossRefGoogle Scholar
  136. Weaver KL, Baerg JE, Okawada M, Miyano G, Barsness KA, Lacher M, et al. A multi-institutional review of Thoracoscopic congenital diaphragmatic hernia repair. J Laparoendosc Adv Surg Tech A. 2016;26(10):825–30.PubMedCrossRefGoogle Scholar
  137. Wilson MG, Riley P, Hurteau A-M, Baird R, Puligandla PS. Hearing loss in congenital diaphragmatic hernia (CDH) survivors: is it as prevalent as we think? J Pediatr Surg. 2013;48(5):942–5.PubMedCrossRefGoogle Scholar
  138. Wu S, Zang N, Zhu J, Pan Z, Wu C. Congenital diaphragmatic eventration in children: 12years’ experience with 177 cases in a single institution. J Pediatr Surg. 2015;50(7):1088–92.PubMedCrossRefGoogle Scholar
  139. Wynn J, Aspelund G, Zygmunt A, Stolar CJH, Mychaliska G, Butcher J, et al. Developmental outcomes of children with congenital diaphragmatic hernia: a multicenter prospective study. J Pediatr Surg. 2013a;48(10):1995–2004.PubMedCrossRefGoogle Scholar
  140. Wynn J, Krishnan U, Aspelund G, Zhang Y, Duong J, Stolar CJH, et al. Outcomes of congenital diaphragmatic hernia in the modern era of management. J Pediatr. 2013b;163(1):114–119.e1.PubMedPubMedCentralCrossRefGoogle Scholar
  141. Wynn J, Yu L, Chung WK. Genetic causes of congenital diaphragmatic hernia. Semin Fetal Neonatal Med. 2014;19(6):324–30.PubMedPubMedCentralCrossRefGoogle Scholar
  142. Yamataka T, Puri P. Active collagen synthesis by pulmonary arteries in pulmonary hypertension complicated by congenital diaphragmatic hernia. J Pediatr Surg. 1997;32(5):682–7.PubMedCrossRefGoogle Scholar
  143. You L-R, Takamoto N, C-T Y, Tanaka T, Kodama T, Demayo FJ, et al. Mouse lacking COUP-TFII as an animal model of Bochdalek-type congenital diaphragmatic hernia. Proc Natl Acad Sci U S A. 2005;102(45):16351–6.PubMedPubMedCentralCrossRefGoogle Scholar
  144. Yu L, Sawle AD, Wynn J, Aspelund G, Stolar CJ, Arkovitz MS, et al. Increased burden of de novo predicted deleterious variants in complex congenital diaphragmatic hernia. Hum Mol Genet. 2015;24(16):4764–73.PubMedPubMedCentralCrossRefGoogle Scholar
  145. Yuan W, Rao Y, Babiuk RP, Greer JJ, JY W, Ornitz DMA. Genetic model for a central (septum transversum) congenital diaphragmatic hernia in mice lacking Slit3. Proc Natl Acad Sci U S A. 2003;100(9):5217–22.PubMedPubMedCentralCrossRefGoogle Scholar
  146. Yuniartha R, Alatas FS, Nagata K, Kuda M, Yanagi Y, Esumi G, et al. Therapeutic potential of mesenchymal stem cell transplantation in a nitrofen-induced congenital diaphragmatic hernia rat model. Pediatr Surg Int. 2014;30(9):907–14.PubMedCrossRefGoogle Scholar
  147. Zani A, Zani-Ruttenstock E, Pierro A. Advances in the surgical approach to congenital diaphragmatic hernia. Semin Fetal Neonatal Med. 2014;19(6):364–9.PubMedCrossRefGoogle Scholar
  148. Zhu Y, Wu Y, Pu Q, Ma L, Liao H, Liu L. Minimally invasive surgery for congenital diaphragmatic hernia: a meta-analysis. Hernia the journal of hernias and abdominal wall. Surgery. 2016;20(2):297–302.Google Scholar
  149. Zimmer J, Takahashi T, Hofmann AD, Puri P. Decreased Endoglin expression in the pulmonary vasculature of nitrofen-induced congenital diaphragmatic hernia rat model. Pediatr Surg Int. 2017a;33(2):263–8.PubMedCrossRefGoogle Scholar
  150. Zimmer J, Takahashi T, Hofmann AD, Puri P. Downregulation of KCNQ5 expression in the rat pulmonary vasculature of nitrofen-induced congenital diaphragmatic hernia. J Pediatr Surg. 2017b;52(5):702–5.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  1. 1.National Children’s Research CentreOur Lady’s Children’s HospitalDublinIreland
  2. 2.Department of Pediatric SurgeryHannover Medical SchoolHannoverGermany
  3. 3.School of Medicine and Medical Science and Conway Institute of Biomedical ResearchUniversity College DublinDublinIreland

Personalised recommendations