Medical and Regenerative Solutions for Congenital Diaphragmatic Hernia: A Perinatal Perspective

Abstract

In the EU-27, 2,100 babies with congenital diaphragmatic hernia (CDH) are born annually. CDH is fatal in 30% of them. Experimental fetal surgery in severe cases results in a survival rate of 50 to 60% at its best. Failure is due to insufficient lung growth, persistent pulmonary hypertension or prematurity induced by the procedure. For nonsurvivors alternative strategies are required. Survivors undergo anatomical repair, but large diaphragmatic defects are closed using a patch. At present the used materials are less than ideal, mainly because of recurrence and chest deformation. To overcome the above limitations, alternative medical therapies (pharmacologic or cell therapy) that are more potent and less invasive are needed. Also a more functional postnatal repair may be possible when using novel scaffolds or engineered constructs. We see a prominent place for autologous amniotic fluid-derived stem cells for these novel strategies, which could be prenatally harvested following appropriate patient selection by noninvasive imaging.

Keywords

diaphragmatic hernia - pulmonary hypoplasia - tissue engineering - stem cell - amniotic fluid

• References

• 1 De Coppi P. Regenerative medicine for congenital malformations. J Pediatr Surg 2013; 48 (2) 273-280
• 2 Adzick NS, Thom EA, Spong CY , et al; MOMS Investigators. A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl J Med 2011; 364 (11) 993-1004
• 3 Deprest JA, Hyett JA, Flake AW, Nicolaides K, Gratacos E. Current controversies in prenatal diagnosis 4: Should fetal surgery be done in all cases of severe diaphragmatic hernia?. Prenat Diagn 2009; 29 (1) 15-19
• 4 Ruano R, Yoshisaki CT, da Silva MM , et al. A randomized controlled trial of fetal endoscopic tracheal occlusion versus postnatal management of severe isolated congenital diaphragmatic hernia. Ultrasound Obstet Gynecol 2012; 39 (1) 20-27
• 5 Jani JC, Nicolaides KH, Gratacós E , et al. Severe diaphragmatic hernia treated by fetal endoscopic tracheal occlusion. Ultrasound Obstet Gynecol 2009; 34 (3) 304-310
• 6 Verbelen T, Lerut T, Coosemans W , et al. Antireflux surgery after congenital diaphragmatic hernia repair: a plea for a tailored approach. Eur J Cardiothorac Surg 2013; 44 (2) 263-267 , discussion 268
• 7 Sinha CK, Islam S, Patel S, Nicolaides K, Greenough A, Davenport M. Congenital diaphragmatic hernia: prognostic indices in the fetal endoluminal tracheal occlusion era. J Pediatr Surg 2009; 44 (2) 312-316
• 8 Lally KP, Lally PA, Lasky RE , et al; Congenital Diaphragmatic Hernia Study Group. Defect size determines survival in infants with congenital diaphragmatic hernia. Pediatrics 2007; 120 (3) e651-e657
• 9 Jani JC, Benachi A, Nicolaides KH , et al; Antenatal-CDH-Registry group. Prenatal prediction of neonatal morbidity in survivors with congenital diaphragmatic hernia: a multicenter study. Ultrasound Obstet Gynecol 2009; 33 (1) 64-69
• 10 Kamata S, Usui N, Kamiyama M , et al. Long-term follow-up of patients with high-risk congenital diaphragmatic hernia. J Pediatr Surg 2005; 40 (12) 1833-1838
• 11 Tsao K, Allison ND, Harting MT, Lally PA, Lally KP. Congenital diaphragmatic hernia in the preterm infant. Surgery 2010; 148 (2) 404-410
• 12 Waag KL, Loff S, Zahn K , et al. Congenital diaphragmatic hernia: a modern day approach. Semin Pediatr Surg 2008; 17 (4) 244-254
• 13 Laituri CA, Garey CL, Valusek PA , et al. Outcome of congenital diaphragmatic hernia repair depending on patch type. Eur J Pediatr Surg 2010; 20 (6) 363-365
• 14 De Coppi P, Deprest J. Regenerative medicine for congenital diaphragmatic hernia: regeneration for repair. Eur J Pediatr Surg 2012; 22 (5) 393-398
• 15 Moss RL, Chen CM, Harrison MR. Prosthetic patch durability in congenital diaphragmatic hernia: a long-term follow-up study. J Pediatr Surg 2001; 36 (1) 152-154
• 16 Grethel EJ, Cortes RA, Wagner AJ , et al. Prosthetic patches for congenital diaphragmatic hernia repair: Surgisis vs Gore-Tex. J Pediatr Surg 2006; 41 (1) 29-33 , discussion 29–33
• 17 Garriboli M, Eaton S, Pierro A, De Coppi P. More patches or more lung in congenital diaphragmatic hernia?. J Pediatr Surg 2012; 47 (10) 1968-1969
• 18 Tsai J, Sulkowski J, Adzick NS, Hedrick HL, Flake AW. Patch repair for congenital diaphragmatic hernia: is it really a problem?. J Pediatr Surg 2012; 47 (4) 637-641
• 19 Romao RL, Nasr A, Chiu PP, Langer JC. What is the best prosthetic material for patch repair of congenital diaphragmatic hernia? Comparison and meta-analysis of porcine small intestinal submucosa and polytetrafluoroethylene. J Pediatr Surg 2012; 47 (8) 1496-1500
• 20 Mitchell IC, Garcia NM, Barber R, Ahmad N, Hicks BA, Fischer AC. Permacol: a potential biologic patch alternative in congenital diaphragmatic hernia repair. J Pediatr Surg 2008; 43 (12) 2161-2164
• 21 Brouwer KM, Daamen WF, Reijnen D , et al. Repair of surgically created diaphragmatic defect in rat with use of a crosslinked porous collagen scaffold. J Tissue Eng Regen Med 2013; 7 (7) 552-561
• 22 Brouwer KM, Daamen WF, van Lochem N, Reijnen D, Wijnen RM, van Kuppevelt TH. Construction and in vivo evaluation of a dual layered collagenous scaffold with a radial pore structure for repair of the diaphragm. Acta Biomater 2013; 9 (6) 6844-6851
• 23 Brouwer KM, Wijnen RM, Reijnen D, Hafmans TG, Daamen WF, van Kuppevelt TH. Heparinized collagen scaffolds with and without growth factors for the repair of diaphragmatic hernia: construction and in vivo evaluation. Organogenesis 2013; 9 (3) 161-167
• 24 Cannie MM, Jani JC, Van Kerkhove F , et al. Fetal body volume at MR imaging to quantify total fetal lung volume: normal ranges. Radiology 2008; 247 (1) 197-203
• 25 Nawapun K, Sandaite I, Dekoninck P , et al. A comparison of matching fetuses by body volume or gestational age for calculation of the observed to expected total fetal lung volume (o/e TFLV) in fetuses with isolated congenital diaphragmatic hernia (CDH). Ultrasound Obstet Gynecol 2014; Mar 6. doi: 10.1002/uog.13356. [Epub ahead of print]
• 26 Mullassery D, Ba'ath ME, Jesudason EC, Losty PD. Value of liver herniation in prediction of outcome in fetal congenital diaphragmatic hernia: a systematic review and meta-analysis. Ultrasound Obstet Gynecol 2010; 35 (5) 609-614
• 27 Mayer S, Klaritsch P, Petersen S , et al. The correlation between lung volume and liver herniation measurements by fetal MRI in isolated congenital diaphragmatic hernia: a systematic review and meta-analysis of observational studies. Prenat Diagn 2011; 31 (11) 1086-1096
• 28 Cannie MM, Cordier AG, De Laveaucoupet J , et al. Liver-to-thoracic volume ratio: use at MR imaging to predict postnatal survival in fetuses with isolated congenital diaphragmatic hernia with or without prenatal tracheal occlusion. Eur Radiol 2013; 23 (5) 1299-1305
• 29 Ruano R, Lazar DA, Cass DL , et al. Fetal lung volume and quantification of liver herniation by magnetic resonance imaging in isolated congenital diaphragmatic hernia. Ultrasound Obstet Gynecol 2013; Oct 11. doi: 10.1002/uog.13223. [Epub ahead of print]
• 30 Kitano Y, Okuyama H, Saito M , et al. Re-evaluation of stomach position as a simple prognostic factor in fetal left congenital diaphragmatic hernia: a multicenter survey in Japan. Ultrasound Obstet Gynecol 2011; 37 (3) 277-282
• 31 Datin-Dorriere V, Rouzies S, Taupin P , et al. Prenatal prognosis in isolated congenital diaphragmatic hernia. Am J Obstet Gynecol 2008; 198 (1) e1-e5
• 32 Cordier AG, Cannie MM, Guilbaud L , et al. Stomach position versus liver-to-thoracic volume ratio in left-sided congenital diaphragmatic hernia. J Matern Fetal Neonatal Med 2014; ; Apr 25. [Epub ahead of print]
• 33 Moschidou D, Mukherjee S, Blundell MP , et al. Valproic acid confers functional pluripotency to human amniotic fluid stem cells in a transgene-free approach. Mol Ther 2012; 20 (10) 1953-1967
• 34 Barberi T, Bradbury M, Dincer Z, Panagiotakos G, Socci ND, Studer L. Derivation of engraftable skeletal myoblasts from human embryonic stem cells. Nat Med 2007; 13 (5) 642-648
• 35 Goudenege S, Lebel C, Huot NB , et al. Myoblasts derived from normal hESCs and dystrophic hiPSCs efficiently fuse with existing muscle fibers following transplantation. Mol Ther 2012; 20 (11) 2153-2167
• 36 Tabor A, Philip J, Madsen M, Bang J, Obel EB, Nørgaard-Pedersen B. Randomised controlled trial of genetic amniocentesis in 4606 low-risk women. Lancet 1986; 1 (8493) 1287-1293
• 37 Cananzi M, Atala A, De Coppi P. Stem cells derived from amniotic fluid: new potentials in regenerative medicine. Reprod Biomed Online 2009; 18 (Suppl. 01) 17-27
• 38 De Coppi P, Bartsch Jr G, Siddiqui MM , et al. Isolation of amniotic stem cell lines with potential for therapy. Nat Biotechnol 2007; 25 (1) 100-106
• 39 Gucciardo L, Ochsenbein-Kölble N, Ozog Y , et al. A comparative study on culture conditions and routine expansion of amniotic fluid-derived mesenchymal progenitor cells. Fetal Diagn Ther 2013; 34 (4) 225-235
• 40 Zia S, Toelen J, Mori da Cunha M, Dekoninck P, De Coppi P, Deprest J. Routine clonal expansion of mesenchymal stem cells derived from amniotic fluid for perinatal applications. Prenat Diagn 2013; 33 (10) 921-928
• 41 Dekoninck P, Toelen J, Zia S , et al. Routine isolation and expansion late mid trimester amniotic fluid derived mesenchymal stem cells in a cohort of fetuses with congenital diaphragmatic hernia. Eur J Obstet Gynecol Reprod Biol 2014; Apr 19. pii: S0301-2115(14)00216-4. doi: 10.1016/j.ejogrb.2014.04.007. [Epub ahead of print]
• 42 Fauza DO, Marler JJ, Koka R, Forse RA, Mayer JE, Vacanti JP. Fetal tissue engineering: diaphragmatic replacement. J Pediatr Surg 2001; 36 (1) 146-151
• 43 Kunisaki SM, Fuchs JR, Kaviani A , et al. Diaphragmatic repair through fetal tissue engineering: a comparison between mesenchymal amniocyte- and myoblast-based constructs. J Pediatr Surg 2006; 41 (1) 34-39 , discussion 34–39
• 44 Fuchs JR, Kaviani A, Oh JT , et al. Diaphragmatic reconstruction with autologous tendon engineered from mesenchymal amniocytes. J Pediatr Surg 2004; 39 (6) 834-838 , discussion 834–838
• 45 Turner CG, Klein JD, Steigman SA , et al. Preclinical regulatory validation of an engineered diaphragmatic tendon made with amniotic mesenchymal stem cells. J Pediatr Surg 2011; 46 (1) 57-61
• 46 Ijsselstijn H, Pacheco BA, Albert A , et al. Prenatal hormones alter antioxidant enzymes and lung histology in rats with congenital diaphragmatic hernia. Am J Physiol 1997; 272 (6 Pt 1) L1059-L1065
• 47 Lally KP, Bagolan P, Hosie S , et al; Congenital Diaphragmatic Hernia Study Group. Corticosteroids for fetuses with congenital diaphragmatic hernia: can we show benefit?. J Pediatr Surg 2006; 41 (4) 668-674 , discussion 668–674
• 48 Jeppesen PB. Pharmacologic options for intestinal rehabilitation in patients with short bowel syndrome. JPEN J Parenter Enteral Nutr 2014; 38 (1, Suppl) 45S-52S
• 49 Rosenstock J, Hanefeld M, Shamanna P , et al. Beneficial effects of once-daily lixisenatide on overall and postprandial glycemic levels without significant excess of hypoglycemia in Type 2 diabetes inadequately controlled on a sulfonylurea with or without metformin (GetGoal-S). J Diabetes Complications 2014; 28 (3) 386-392
• 50 Romaní-Pérez M, Outeiriño-Iglesias V, Gil-Lozano M, González-Matías LC, Mallo F, Vigo E. Pulmonary GLP-1 receptor increases at birth and exogenous GLP-1 receptor agonists augmented surfactant-protein levels in litters from normal and nitrofen-treated pregnant rats. Endocrinology 2013; 154 (3) 1144-1155
• 51 Wideman RD, Yu IL, Webber TD , et al. Improving function and survival of pancreatic islets by endogenous production of glucagon-like peptide 1 (GLP-1). Proc Natl Acad Sci U S A 2006; 103 (36) 13468-13473
• 52 Lin H, Wang Y, Xiong Z, Tang Y, Liu W. Effect of antenatal tetrandrine administration on endothelin-1 and epidermal growth factor levels in the lungs of rats with experimental diaphragmatic hernia. J Pediatr Surg 2007; 42 (10) 1644-1651
• 53 Xu C, Liu W, Chen Z, Wang Y, Xiong Z, Ji Y. Effect of prenatal tetrandrine administration on transforming growth factor-beta1 level in the lung of nitrofen-induced congenital diaphragmatic hernia rat model. J Pediatr Surg 2009; 44 (8) 1611-1620
• 54 Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev 2006; (4) CD000399
• 55 Bagolan P, Morini F. Long-term follow up of infants with congenital diaphragmatic hernia. Semin Pediatr Surg 2007; 16 (2) 134-144
• 56 Stenmark KR, Abman SH. Lung vascular development: implications for the pathogenesis of bronchopulmonary dysplasia. Annu Rev Physiol 2005; 67: 623-661
• 57 Okoye BO, Losty PD, Lloyd DA, Gosney JR. Effect of prenatal glucocorticoids on pulmonary vascular muscularisation in nitrofen-induced congenital diaphragmatic hernia. J Pediatr Surg 1998; 33 (1) 76-80
• 58 Schmidt AF, Gonçalves FL, Nassr AC, Pereira LA, Farmer D, Sbragia L. Antenatal steroid and tracheal occlusion restore vascular endothelial growth factor receptors in congenital diaphragmatic hernia rat model. Am J Obstet Gynecol 2010; 203 (2) e13-e20
• 59 Davey M, Shegu S, Danzer E , et al. Pulmonary arteriole muscularization in lambs with diaphragmatic hernia after combined tracheal occlusion/glucocorticoid therapy. Am J Obstet Gynecol 2007; 197 (4) e1-e7
• 60 Roubliova XI, Lewi PJ, Verbeken EK , et al. The effect of maternal betamethasone and fetal tracheal occlusion on pulmonary vascular morphometry in fetal rabbits with surgically induced diaphragmatic hernia: a placebo controlled morphologic study. Prenat Diagn 2009; 29 (7) 674-681
• 61 Montedonico S, Nakazawa N, Puri P. Retinoic acid rescues lung hypoplasia in nitrofen-induced hypoplastic foetal rat lung explants. Pediatr Surg Int 2006; 22 (1) 2-8
• 62 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) 367-372
• 63 Tzimas G, Nau H. The role of metabolism and toxicokinetics in retinoid teratogenesis. Curr Pharm Des 2001; 7 (9) 803-831
• 64 Valappil S, Kurkar M, Howell R. Outcome of pregnancy in women treated with all-trans retinoic acid; a case report and review of literature. Hematology 2007; 12 (5) 415-418
• 65 Baquero H, Soliz A, Neira F, Venegas ME, Sola A. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics 2006; 117 (4) 1077-1083
• 66 Shue EH, Schecter SC, Gong W , et al. Antenatal maternally-administered phosphodiesterase type 5 inhibitors normalize eNOS expression in the fetal lamb model of congenital diaphragmatic hernia. J Pediatr Surg 2014; 49 (1) 39-45 , discussion 45
• 67 Luong C, Rey-Perra J, Vadivel A , et al. Antenatal sildenafil treatment attenuates pulmonary hypertension in experimental congenital diaphragmatic hernia. Circulation 2011; 123 (19) 2120-2131
• 68 Yamamoto Y, Thebaud B, Vadivel A, Eaton F, Jain V, Hornberger LK. Doppler parameters of fetal lung hypoplasia and impact of sildenafil. Am J Obstet Gynecol 2014; Mar 11. pii: S0002-9378(14)00218-X. doi: 10.1016/j.ajog.2014.03.013. [Epub ahead of print]
• 69 Buckley SM, Waddington SN, Jezzard S , et al. Factors influencing adenovirus-mediated airway transduction in fetal mice. Mol Ther 2005; 12 (3) 484-492
• 70 Pollack JA, Moise Jr KJ, Tyson WR, Galan HL. The role of fetal breathing motions compared with gasping motions in pulmonary airway uptake of intra-amniotic iron dextran. Am J Obstet Gynecol 2003; 189 (4) 958-962
• 71 Fewell JE, Johnson P. Upper airway dynamics during breathing and during apnoea in fetal lambs. J Physiol 1983; 339: 495-504
• 72 Kalache KD, Chaoui R, Hartung J, Wernecke KD, Bollmann R. Doppler assessment of tracheal fluid flow during fetal breathing movements in cases of congenital diaphragmatic hernia. Ultrasound Obstet Gynecol 1998; 12 (1) 27-32
• 73 Berry SM, Stone J, Norton ME, Johnson D, Berghella V ; Society for Maternal-Fetal Medicine (SMFM). Fetal blood sampling. Am J Obstet Gynecol 2013; 209 (3) 170-180
• 74 Hashimoto B, Filly RA, Callen PW, Parer JT. Absorption of fetal intraperitoneal blood after intrauterine transfusion. J Ultrasound Med 1987; 6 (8) 421-423
• 75 Fox C, Martin W, Somerset DA, Thompson PJ, Kilby MD. Early intraperitoneal transfusion and adjuvant maternal immunoglobulin therapy in the treatment of severe red cell alloimmunization prior to fetal intravascular transfusion. Fetal Diagn Ther 2008; 23 (2) 159-163
• 76 Deprest J, Nicolaides K, Done' E , et al. Technical aspects of fetal endoscopic tracheal occlusion for congenital diaphragmatic hernia. J Pediatr Surg 2011; 46 (1) 22-32
• 77 Muensterer OJ, Nicola T, Farmer S, Harmon CM, Ambalavanan N. Temporary fetal tracheal occlusion using a gel plug in a rabbit model of congenital diaphragmatic hernia. J Pediatr Surg 2012; 47 (6) 1063-1066
• 78 Elattal R, Rich BS, Harmon CM, Muensterer OJ. Pulmonary alveolar and vascular morphometry after gel plug occlusion of the trachea in a fetal rabbit model of CDH. Int J Surg 2013; 11 (7) 558-561
• 79 Angelini A, Castellani C, Ravara B , et al. Stem-cell therapy in an experimental model of pulmonary hypertension and right heart failure: role of paracrine and neurohormonal milieu in the remodeling process. J Heart Lung Transplant 2011; 30 (11) 1281-1293
• 80 Garcia O, Carraro G, Navarro S , et al. Cell-based therapies for lung disease. Br Med Bull 2012; 101: 147-161
• 81 Anversa P, Kajstura J, Leri A, Loscalzo J. Tissue-specific adult stem cells in the human lung. Nat Med 2011; 17 (9) 1038-1039
• 82 Anversa P, Perrella MA, Kourembanas S, Choi AM, Loscalzo J. Regenerative pulmonary medicine: potential and promise, pitfalls and challenges. Eur J Clin Invest 2012; 42 (8) 900-913
• 83 Carraro G, Perin L, Sedrakyan S , et al. Human amniotic fluid stem cells can integrate and differentiate into epithelial lung lineages. Stem Cells 2008; 26 (11) 2902-2911
• 84 Jones CP, Rankin SM. Bone marrow-derived stem cells and respiratory disease. Chest 2011; 140 (1) 205-211
• 85 O'Reilly M, Thébaud B. The promise of stem cells in bronchopulmonary dysplasia. Semin Perinatol 2013; 37 (2) 79-84
• 86 Pederiva F, Ghionzoli M, Pierro A, De Coppi P, Tovar JA. Amniotic fluid stem cells rescue both in vitro and in vivo growth, innervation, and motility in nitrofen-exposed hypoplastic rat lungs through paracrine effects. Cell Transplant 2013; 22 (9) 1683-1694
• 87 Mou H, Zhao R, Sherwood R , et al. Generation of multipotent lung and airway progenitors from mouse ESCs and patient-specific cystic fibrosis iPSCs. Cell Stem Cell 2012; 10 (4) 385-397
• 88 Berry RM, Bliss L, Caley S, Lombardo PA, Wolf LE. Recent developments in health care law: culture and controversy. HEC Forum 2013; 25 (1) 1-24
• 89 Holm S. Going to the roots of the stem cell controversy. Bioethics 2002; 16 (6) 493-507
• 90 Nisbet MC. The competition for worldviews: values, information, and public support for stem cell research. Int J Public Opin Res 2005; 17 (1) 90-112
• 91 Klimanskaya I. Embryonic stem cells from blastomeres maintaining embryo viability. Semin Reprod Med 2013; 31 (1) 49-55
• 92 Chung Y, Klimanskaya I, Becker S , et al. Embryonic and extraembryonic stem cell lines derived from single mouse blastomeres. Nature 2006; 439 (7073) 216-219
• 93 Pfeffer N. What British women say matters to them about donating an aborted fetus to stem cell research: a focus group study. Soc Sci Med 2008; 66 (12) 2544-2554
• 94 Parolini O, Alviano F, Bergwerf I , et al. Toward cell therapy using placenta-derived cells: disease mechanisms, cell biology, preclinical studies, and regulatory aspects at the round table. Stem Cells Dev 2010; 19 (2) 143-154
• 95 Kent J. The fetal tissue economy: from the abortion clinic to the stem cell laboratory. Soc Sci Med 2008; 67 (11) 1747-1756
• 96 Yoshizawa RS. Review: Public perspectives on the utilization of human placentas in scientific research and medicine. Placenta 2013; 34 (1) 9-13
• 97 Dickenson DL. The lady vanishes: what's missing from the stem cell debate. J Bioeth Inq 2006; 3 (1-2) 43-54
• 98 Gucciardo L, De Koninck P, Verfaillie C, Lories R, Deprest J. Perception and Knowledge About Stem Cell and Tissue Engineering Research: A Survey Amongst Researchers and Medical Practitioners in Perinatology. Stem Cell Rev 2014; Mar 20. [Epub ahead of print]
• 99 Wagner AM, Krenger W, Holzgreve W, Bürkli P, Surbek DV. Use of human embryonic stem cells and umbilical cord blood stem cells for research and therapy: a prospective survey among health care professionals and patients in Switzerland. Transfusion 2013; 53 (11) 2681-2689
• 100 Katz G, Mills A, Garcia J , et al. Banking cord blood stem cells: attitude and knowledge of pregnant women in five European countries. Transfusion 2011; 51 (3) 578-586
• 101 Franklin SB, Hunt C, Cornwell G , et al. hESCCO: development of good practice models for hES cell derivation. Regen Med 2008; 3 (1) 105-116
• 102 Jordens CF, O'Connor MA, Kerridge IH , et al. Religious perspectives on umbilical cord blood banking. J Law Med 2012; 19 (3) 497-511