Prenatal genetic diagnosis: Fetal therapy as a possible solution to a positive test

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Aysha Karim Kiani
Stefano Paolacci
Pietro Scanzano
Sandro Michelini
Natale Capodicasa
Leonardo D’Agruma
Angelantonio Notarangelo
Gerolamo Tonini
Daniela Piccinelli
Kalantary Rad Farshid
Paolo Petralia
Ezio Fulcheri
Francesca Buffelli
Pietro Chiurazzi
Corrado Terranova
Francesco Plotti
Roberto Angioli
Marco Castori
Ondrej Pös
Tomas Szemes
Matteo Bertelli


prenatal diagnosis, prenatal gene therapy, prenatal interventions, prenatal stem cell therapy, fetal drug therapy


Background: Fetal abnormalities cause 20% of perinatal deaths. Advances in prenatal genetic and other types of screening offer great opportunities for identifying high risk pregnancies. Methods: Through a literature search, here we summarise what are the prenatal diagnostic technique that are being used and how those techniques may allow for prenatal interventions. Results: Next generation sequencing and non-invasive prenatal testing are fundamental for clinical diagnostics because of their sensitivity and accuracy in identifying point mutations, aneuploidies, and microdeletions, respectively. Timely identification of genetic disorders and other fetal abnormalities enables early intervention, such as in-utero gene therapy, fetal drug therapy and prenatal surgery. Conclusion: Prenatal intervention is mainly focused on conditions that may cause death or lifelong disabilities, like spina bifida, congenital diaphragm hernia and sacrococcygeal teratoma; and may be an alternative therapeutic option to termination of pregnancy. However, it is not yet widely available, due to lack of specialized centers.


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1 Best S, Wou K, Vora N, Van der Veyver IB, Wapner R, Chitty LS. Promises, pitfalls and practicalities of prenatal whole exome sequencing. Prenat Diagn 2018;38:10–9.
2 Mellis R, Chandler N, Chitty LS. Next-generation sequencing and the impact on prenatal diagnosis. Expert Rev Mol Diagn 2018;18:689–99.
3 Budis J, Gazdarica J, Radvanszky J, Szucs G, Kucharik M, Strieskova L, Gazdaricova I, Harsanyova M, Duris F, Minarik G, Sekelska M, Nagy B, Turna J, Szemes T. Combining count- and length-based z-scores leads to improved predictions in non-invasive prenatal testing. Bioinformatics 2019;35:1284–91.
4 Gazdarica J, Budis J, Duris F, Turna J, Szemes T. Adaptable model parameters in non-invasive prenatal testing lead to more stable predictions. Int J Mol Sci 2019;20:3414.
5 Gazdarica J, Hekel R, Budis J, Kucharik M, Duris F, Radvanszky J, Turna J, Szemes T. Combination of fetal fraction estimators based on fragment lengths and fragment counts in non-invasive prenatal testing. Int J Mol Sci 2019;20:3959.
6 Van Schendel R V., Van El CG, Pajkrt E, Henneman L, Cornel MC. Implementing non-invasive prenatal testing for aneuploidy in a national healthcare system: Global challenges and national solutions. BMC Health Serv Res 2017;17:670.
7 Minarik G, Repiska G, Hyblova M, Nagyova E, Soltys K, Budis J, Duris F, Sysak R, Bujalkova MG, Vlkova-Izrael B, Biro O, Nagy B, Szemes T. Utilization of benchtop next generation sequencing platforms ion torrent PGM and miseq in noninvasive prenatal testing for chromosome 21 trisomy and testing of impact of in silico and physical size selection on its analytical performance. PLoS One 2015;10:e0144811.
8 Kucharik M, Gnip A, Hyblova M, Budis J, Strieskova L, Harsanyova M, Duris F, Radvanszky J, Minarik G, Szemes T. Non-invasive prenatal testing by low coverage genomic sequencing: Detection limits of screened chromosomal microdeletions. bioRxiv 2019;686345. doi:10.1101/686345
9 Koumbaris G, Achilleos A, Nicolaou M, Loizides C, Tsangaras K, Kypri E, Mina P, Sismani C, Velissariou V, Christopoulou G, Constantoulakis P, Manolakos E, Papoulidis I, Stambouli D, Ioannides M, Patsalis P. Targeted capture enrichment followed by NGS: Development and validation of a single comprehensive NIPT for chromosomal aneuploidies, microdeletion syndromes and monogenic diseases. Mol Cytogenet 2019;12:48.
10 van der Meij KRM, Sistermans EA, Macville MVE, Stevens SJC, Bax CJ, Bekker MN, Bilardo CM, Boon EMJ, Boter M, Diderich KEM, de Die-Smulders CEM, Duin LK, Faas BHW, Feenstra I, Haak MC, Hoffer MJV, den Hollander NS, Hollink IHIM, Jehee FS, Knapen MFCM, Kooper AJA, van Langen IM, Lichtenbelt KD, Linskens IH, van Maarle MC, Oepkes D, Pieters MJ, Schuring-Blom GH, Sikkel E, Sikkema-Raddatz B, Smeets DFCM, Srebniak MI, Suijkerbuijk RF, Tan-Sindhunata GM, van der Ven AJEM, van Zelderen-Bhola SL, Henneman L, Galjaard RJH, Van Opstal D, Weiss MM. TRIDENT-2: National implementation of genome-wide non-invasive prenatal testing as a first-tier screening test in the Netherlands. Am J Hum Genet 2019;105:1091–101.
11 Budis J, Gazdarica J, Radvanszky J, Harsanyova M, Gazdaricova I, Strieskova L, Frno R, Duris F, Minarik G, Sekelska M, Nagy B, Szemes T. Non-invasive prenatal testing as a valuable source of population specific allelic frequencies. J Biotechnol 2019;299:72–8.
12 Pös O, Budiš J, Szemes T. Recent trends in prenatal genetic screening and testing. F1000Research 2019;8:F1000.
13 Bayón JC, Orruño E, Portillo MI, Asua J. The consequences of implementing non-invasive prenatal testing with cell-free foetal DNA for the detection of Down syndrome in the Spanish National Health Service: A cost-effectiveness analysis. Cost Eff Resour Alloc 2019;17:6.
14 Kostenko E, Chantraine F, Vandeweyer K, Schmid M, Lefevre A, Hertz D, Zelle L, Bartha JL, Di Renzo GC. Clinical and economic impact of adopting noninvasive prenatal testing as a primary screening method for fetal aneuploidies in the general pregnancy population. Fetal Diagn Ther 2019;45:413–23.
15 Walker BS, Jackson BR, Lagrave D, Ashwood ER, Schmidt RL. A cost-effectiveness analysis of cell free DNA as a replacement for serum screening for Down syndrome. Prenat Diagn 2015;35:440–6.
16 Horn R, Parker M. Opening Pandora’s box? Ethical issues in prenatal whole genome and exome sequencing. Prenat Diagn 2018;38:20–5.
17 Harris S, Gilmore K, Hardisty E, Lyerly AD, Vora NL. Ethical and counseling challenges in prenatal exome sequencing. Prenat Diagn 2018;38:897–903.
18 Dennis Lo YM, Corbetta N, Chamberlain PF, Rai V, Sargent IL, Redman CWG, Wainscoat JS. Presence of fetal DNA in maternal plasma and serum. Lancet 1997;350:485–7.
19 Ashoor G, Syngelaki A, Poon LCY, Rezende JC, Nicolaides KH. Fetal fraction in maternal plasma cell-free DNA at 11-13 weeks’ gestation: Relation to maternal and fetal characteristics. Ultrasound Obstet Gynecol 2013;41:26–32.
20 Norwitz ER, Levy B. Noninvasive prenatal testing: The future is now. Rev Obstet Gynecol 2013;6:48–62.
21 Salomon LJ, Sotiriadis A, Wulff CB, Odibo A, Akolekar R. Risk of miscarriage following amniocentesis or chorionic villus sampling: systematic review of literature and updated meta-analysis. Ultrasound Obstet Gynecol 2019;54:442–51.
22 Gregg AR, Skotko BG, Benkendorf JL, Monaghan KG, Bajaj K, Best RG, Klugman S, Watson MS. Noninvasive prenatal screening for fetal aneuploidy, 2016 update: A position statement of the American College of Medical Genetics and Genomics. Genet Med 2016;18:1056–65.
23 Sekelska M, Izsakova A, Kubosova K, Tilandyova P, Csekes E, Kuchova Z, Hyblova M, Harsanyova M, Kucharik M, Budis J, Szemes T, Minarik G. Result of prospective validation of the trisomy Test® for the detection of chromosomal trisomies. Diagnostics 2019;9:138.
24 Beaudet AL. Using fetal cells for prenatal diagnosis: History and recent progress. Am J Med Genet Part C Semin Med Genet 2016;172:123–7.
25 Pös O, Budis J, Kubiritova Z, Kucharik M, Duris F, Radvanszky J, Szemes T. Identification of structural variation from NGS-based non-invasive prenatal testing. Int J Mol Sci 2019;20:4403.
26 Sekelská M, Izsáková A, Kubošová K, Tilandyová P, Csekes E, Kúchová Ž, Hýblová M, Lukačková R, Landlová D, Križan P, Haršanyová M, Budiš J, Kucharik M, Szemes T, Minárik G. Detection and validation of subchromosomal aberrations detected as additional findings in routine noninvasive prenatal testing for common trisomies. newsLab 2019;2:69–71.
27 Verweij EJT, Oepkes D. Prenatal treatment of genetic diseases in the unborn. In: Noninvasive Prenatal Testing (NIPT): Applied Genomics in Prenatal Screening and Diagnosis. 2018. 353–67.
28 Phithakwatchara N, Nawapun K, Panchalee T, Viboonchart S, Mongkolchat N, Wataganara T. Current strategy of fetal therapy I: Principles of in-utero treatment, pharmacologic intervention, stem cell transplantation and gene therapy. J Fetal Med 2017;4:131–8.
29 Spagnolo AG. La promessa del test prenatale non invasivo (NIPT) basato sul DNA / The promise of noninvasive prenatal testing (NIPT) based on DNA. Med e Morale 2016;65:397–401.
30 Harrison MR, Keller RL, Hawgood SB, Kitterman JA, Sandberg PL, Farmer DL, Lee H, Filly RA, Farrell JA, Albanese CT. A randomized trial of fetal endoscopic tracheal occlusion for severe fetal congenital diaphragmatic hernia. N Engl J Med 2003;349:1916–24.
31 Senat MV, Deprest J, Boulvain M, Paupe A, Winer N, Ville Y. Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome. N Engl J Med 2004;351:136–44.
32 Adzick NS, Thom EA, Spong CY, Brock JW, Burrows PK, Johnson MP, Howell LJ, Farrell JA, Dabrowiak ME, Sutton LN, Gupta N, Tulipan NB, D’Alton ME, Farmer DL. A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl J Med 2011;364:993–1004.
33 Rajabi F, Picker JD. New innovations: Therapies for genetic conditions. Curr Genet Med Rep 2014;2:113–23.
34 Massaro G, Mattar CNZ, Wong AMS, Sirka E, Buckley SMK, Herbert BR, Karlsson S, Perocheau DP, Burke D, Heales S, Richard-Londt A, Brandner S, Huebecker M, Priestman DA, Platt FM, Mills K, Biswas A, Cooper JD, Chan JKY, Cheng SH, Waddington SN, Rahim AA. Fetal gene therapy for neurodegenerative disease of infants. Nat Med 2018;24:1317–23.
35 Schneider H, Faschingbauer F, Schuepbach-Mallepell S, Körber I, Wohlfart S, Dick A, Wahlbuhl M, Kowalczyk-Quintas C, Vigolo M, Kirby N, Tannert C, Rompel O, Rascher W, Beckmann MW, Schneider P. Prenatal correction of X-linked hypohidrotic ectodermal dysplasia. N Engl J Med 2018;378:1604–10.
36 Almeida-Porada G, Waddington SN, Chan JKY, Peranteau WH, MacKenzie T, Porada CD. In utero gene therapy consensus statement from the IFeTIS. Mol Ther 2019;27:705–7.
37 Egholm M, Buchardt O, Christensen L, Behrens C, Freier SM, Driver DA, Berg RH, Kim SK, Norden B, Nielsen PE. PNA hybridizes to complementary oligonucleotides obeying the Watson-Crick hydrogen-bonding rules. Nature 1993;365:566–8.
38 Ricciardi AS, Bahal R, Farrelly JS, Quijano E, Bianchi AH, Luks VL, Putman R, López-Giráldez F, Coşkun S, Song E, Liu Y, Hsieh WC, Ly DH, Stitelman DH, Glazer PM, Saltzman WM. In utero nanoparticle delivery for site-specific genome editing. Nat Commun 2018;9:2481.
39 Ledford H. Gene therapy in mouse fetuses treats deadly disease. Nature 2018;559:313–5.
40 Shaw SWS, Blundell MP, Pipino C, Shangaris P, Maghsoudlou P, Ramachandra DL, Georgiades F, Boyd M, Thrasher AJ, Porada CD, Almeida-Porada G, Cheng PJ, David AL, De Coppi P. Sheep CD34+ amniotic fluid cells have hematopoietic potential and engraft after autologous in utero transplantation. Stem Cells 2015;33:122–32.
41 Steven Shaw SW, Bollini S, Nader KA, Gastadello A, Mehta V, Filppi E, Cananzi M, Gaspar HB, Qasim W, de Coppi P, David AL. Autologous transplantation of amniotic fluid-derived mesenchymal stem cells into sheep fetuses. Cell Transplant 2011;20:1015–31.
42 Alhajjat AM, Shaaban AF. Maternal and fetal immune response to in utero stem cell transplantation. Curr Stem Cell Reports 2018;4:182–7.
43 Nasef A, Fouillard L, El-Taguri A, Lopez M. Human bone marrow-derived mesenchymal stem cells. Libyan J Med 2007;2:190–201.
44 Le Blanc K, Götherström C, Ringdén O, Hassan M, McMahon R, Horwitz E, Anneren G, Axelsson O, Nunn J, Ewald U, Nordén-Lindeberg S, Jansson M, Dalton A, Åström E, Westgren M. Fetal mesenchymal stem-cell engraftment in bone after in utero transplantation in a patient with severe osteogenesis imperfecta. Transplantation 2005;79:1607–14.
45 Ramachandra DL, Shaw S-WS, Shangaris P, Loukogeorgakis S, Guillot P V., De Coppi P, David AL. Corrigendum: In utero therapy for congenital disorders using amniotic fluid stem cells. Front Pharmacol 2015;6:39.
46 Loukogeorgakis SP, Shangaris P, Bertin E, Franzin C, Piccoli M, Pozzobon M, Subramaniam S, Tedeschi A, Kim AG, Li H, Fachin CG, Dias AIBS, Stratigis JD, Ahn NJ, Thrasher AJ, Bonfanti P, Peranteau WH, David AL, Flake AW, De Coppi P. In utero transplantation of expanded autologous amniotic fluid stem cells results in long-term hematopoietic engraftment. Stem Cells 2019;37:1176–88.
47 McClain LE, Flake AW. In utero stem cell transplantation and gene therapy: Recent progress and the potential for clinical application. Best Pract Res Clin Obstet Gynaecol 2016;31:88–98.
48 Health Departments of the United Kingdom. Gene Therapy Advisory Committee: Report on the potential use of gene therapy in utero. Dis Markers 1998;14:151–4.
49 Olaloko O, Mohammed R, Ojha U. Evaluating the use of corticosteroids in preventing and treating bronchopulmonary dysplasia in preterm neonates. Int J Gen Med 2018;11:265–74.
50 Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 1972;50:515–25.
51 Al-Enazy S, Ali S, Albekairi N, El-Tawil M, Rytting E. Placental control of drug delivery. Adv Drug Deliv Rev 2017;116:63–72.
52 Rytting E, Ahmed MS. Fetal drug therapy. In: Clinical Pharmacology During Pregnancy. 2013. 55–72.
53 Harrison MR, Ross NA, de Lorimier AA. 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 1981;16:934–42.
54 Long C, Lankford L, Wang A. Stem cell-based in utero therapies for spina bifida: Implications for neural regeneration. Neural Regen Res 2019;14:260.
55 Brei T, Houtrow A. Spina bifida. J Pediatr Rehabil Med 2017;10:165–6.
56 Meuli M, Moehrlen U. Fetal surgery for myelomeningocele is effective: A critical look at the whys. Pediatr Surg Int 2014;30:689–97.
57 Clayton DB, Tanaka ST, Trusler L, Thomas JC, Pope IV JC, Adams MC, Brock JW. Long-term urological impact of fetal myelomeningocele closure. J Urol 2011;186:1581–5.
58 Zambelli H, Carelli E, Honorato D, Marba S, Coelho G, Carnevalle A, Iscaife A, de Silva E, Barini R, Sbragia L. Assessment of neurosurgical outcome in children prenatally diagnosed with myelomeningocele and development of a protocol for fetal surgery to prevent hydrocephalus. Child’s Nerv Syst 2007;23:421–5.
59 Adzick NS, Sutton LN, Crombleholme TM, Flake AW. Successful fetal surgery for spina bifida. Lancet 1998;352:1675.
60 Lee H, Hirose S, Harrison MR. Prenatal diagnosis and fetal therapy. In: Pediatric Surgery. 2012. 77–88.
61 Zuccaro G. Why fetal neurosurgery? Child’s Nerv Syst 2017;33:1081–2.
62 Tovar JA. Congenital diaphragmatic hernia. Orphanet J Rare Dis 2012;7:1.
63 Basurto D, Russo FM, Van der Veeken L, Van der Merwe J, Hooper S, Benachi A, De Bie F, Gomez O, Deprest J. Prenatal diagnosis and management of congenital diaphragmatic hernia. Best Pract Res Clin Obstet Gynaecol 2019;58:93–106.
64 Harrison MR, Adzick NS, Longaker MT, Goldberg JD, Rosen MA, Filly RA, Evans MI, Golbus MS. Successful repair in utero of a fetal diaphragmatic hernia after removal of herniated viscera from the left thorax. N Engl J Med 1990;322:1582–4.
65 Swamy R, Embleton N, Hale J. Sacrococcygeal teratoma over two decades: Birth prevalence, prenatal diagnosis and clinical outcomes. Prenat Diagn 2008;28:1048–51.
66 Bullard KM, Harrison MR. Before the horse is out of the barn: Fetal surgery for hydrops. Semin Perinatol 1995;19:462–73.
67 Walton JM, Rubin SZ, Soucy P, Benzie R, Ash K, Nimrod C. Fetal tumors associated with hydrops: The role of the pediatric surgeon. J Pediatr Surg 1993;28:1151–3.
68 Hirose S, Farmer DL. Fetal surgery for sacrococcygeal teratoma. Clin Perinatol 2003;30:493–506.
69 Walz PC, Schroeder JW. Prenatal diagnosis of obstructive head and neck masses and perinatal airway management: The Ex utero intrapartum treatment procedure. Otolaryngol Clin North Am 2015;48:191–207.