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Professionally responsible management of the ethical and social challenges of antenatal screening and diagnosis of β-thalassemia in a high-risk population

  • Valentina Corda , Federica Murgia , Francesca Dessolis , Stefania Murru , Frank A. Chervenak , Laurence B. McCullough and Giovanni Monni EMAIL logo
Published/Copyright: March 16, 2021
Journal of Perinatal Medicine
From the journal Journal of Perinatal Medicine Volume 49 Issue 7

Abstract

Thalassemias are among the most frequent genetic disorders worldwide. They are an important social and economic strain in high-risk populations. The benefit of β-thalassemia screening programs is growing evident but the capacity to diagnose fetal β-thalassemia exceeds the treatment possibilities and even when treatment before birth becomes feasible, difficult decisions about the relative risks will remain. This paper can be of practical and ethically justified aid when counseling women about screening, diagnosis, and treatment of β-thalassemia. It takes in consideration various social challenges, medical issues such as antenatal screening, preimplantation genetic diagnosis, prenatal diagnosis, non-invasive prenatal testing and prenatal therapy. We also describe the Sardinian experience in applying and promoting high-risk population screening and diagnosis programs and future trends in the management of β-thalassemia.

Keywords: cell free fetal DNA (cffDNA); ethics; non-invasive prenatal testing (NIPT); preimplantation genetic diagnosis (PGD); prenatal diagnosis; prenatal screening; β-thalassemia
Corresponding author: Giovanni Monni, MD, Department of Obstetrics and Gynecology, Prenatal and Preimplantation Genetic Diagnosis, Fetal Therapy, Microcitemico Pediatric Hospital “A. Cao”, via Edward Jenner SNC, post code 09121, Cagliari, Sardinia, Italy, Phone: +(00)39 070 52965546/7, Fax: +(00)39 070 52965514, E-mail:

Acknowledgments

The authors of this manuscript would like to thank Fondazione di Sardegna and Boyana Petrova Tsikalova, MA in English Philology for editing assistance.

  1. Research funding: None declared.

  2. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  3. Competing interests: Authors state no conflict of interest.

References

1. Weatherall, DJ. The inherited diseases of hemoglobin are an emerging global health burden. Blood 2010;115:4331–6. https://doi.org/10.1182/blood-2010-01-251348.Search in Google Scholar

2. Cao, A. William Allan Award address. Am J Hum Genet 1994;54:397–402.Search in Google Scholar

3. Porter, J. Beyond transfusion therapy: new therapies in thalassemia including drugs, alternate donor transplant, and gene therapy. Hematology Am Soc Hematol Educ Program 2018;1:361–70. https://doi.org/10.1182/asheducation-2018.1.361.Search in Google Scholar

4. Lucarelli, G, Galimberti, M, Polchi, P, Angelucci, E, Baronciani, D, Giardini, C, et al.. Bone marrow transplantation in patients with thalassemia. N Engl J Med 1990;322:417–21. https://doi.org/10.1056/nejm199002153220701.Search in Google Scholar

5. Lam, LT, Bresnick, EH. A novel DNA-binding protein, HS2NF5, interact with a functionally important sequence of the human beta-globin locus control region heteromeric protein complex. J Biol Chem 1996;271:32421–9. https://doi.org/10.1074/jbc.271.50.32421.Search in Google Scholar

6. Huisman, THJ, Carver, MFH, Baysal, EA. Syllabus of thalassemia mutation. Augusta, GA, USA: The Sickle Cell Anemia Foundation; 1997:1–309 pp.Search in Google Scholar

7. McCullough, LB, Coverdale, JH, Chervenak, FA. Professional ethics in obstetrics and gynecology. New York and Cambridge: Cambridge University Press; 2020.10.1017/9781316841037Search in Google Scholar

8. Milunsky, A, Milunsky, JM, editors. Genetic disorders and the fetus, 6th ed. Chichester: Wiley-Blackwell; 2010.10.1002/9781444314342Search in Google Scholar

9. WHO. Thalassaemia and other haemoglobinopathies. Agenda item 5.2. In: 59th World Health Assembly; 2006. EB118.R1.Search in Google Scholar

10. Cao, A, Rosatelli, MC, Monni, G, Galanello, R. Screening for thalassemia: a model of success. Obstet Gynecol Clin North Am 2002;29:305–28. https://doi.org/10.1016/s0889-8545(01)00006-7.Search in Google Scholar

11. Cao, A, Saba, L, Galanello, R, Rosatelli, MC. Molecular diagnosis and carrier screening for beta thalassemia. J Am Med Assoc 1997;278:1273–77. https://doi.org/10.1001/jama.278.15.1273.Search in Google Scholar

12. He, J, Song, W, Yang, J, Lu, S, Yuan, Y, Guo, J, et al.. Next-generation sequencing improves thalassemia carrier screening among premarital adults in a high prevalence population: the DAI nationality, China. Genet Med 2017;19:1022–31. https://doi.org/10.1038/gim.2016.218.Search in Google Scholar PubMed

13. Shang, X, Peng, Z, Ye, Y, Asan, Zhang, X, Chen, Y, et al.. Rapid targeted next-generation sequencing platform for molecular screening and clinical genotyping in subjects with hemoglobinopathies. EBioMedicine 2017;23:150–9. https://doi.org/10.1016/j.ebiom.2017.08.015.Search in Google Scholar PubMed PubMed Central

14. Zhao, J, Li, J, Lai, Q, Yu, Y. Combined use of gap-PCR and next-generation sequencing improves thalassaemia carrier screening among premarital adults in China. J Clin Pathol 2020;73:488–92. https://doi.org/10.1136/jclinpath-2019-206339.Search in Google Scholar PubMed PubMed Central

15. Kuliev, A, Rechitsky, S, Verlinsky, O, Ivakhnenko, V, Evsikov, S, Wolf, G, et al.. Preimplantation diagnosis of thalassemias. J Assist Reprod Genet 1998;15:219–25. https://doi.org/10.1023/a:1022571822585.10.1023/A:1022571822585Search in Google Scholar

16. De Wert, G, Dondorp, W, Shenfield, F, Devroey, P, Tarlatzis, B, Barri, P, et al.. ESHRE task force on ethics and Law22: preimplantation genetic diagnosis. Hum Reprod 2014;29:1610–17. https://doi.org/10.1093/humrep/deu132.Search in Google Scholar PubMed

17. Traeger-Synodinos, J. Pre-implantation genetic diagnosis. Best Pract Res Clin Obstet Gynaecol 2017;39:74–88. https://doi.org/10.1016/j.bpobgyn.2016.10.010.Search in Google Scholar PubMed

18. Bay, B, Ingerslev, HJ, Lemmen, JG, Degn, B, Rasmussen, IA, Kesmodel, UC. Preimplantation genetic diagnosis: a national multicenter obstetric and neonatal follow-up study. Fertil Steril 2016;106:1363–69.e1. https://doi.org/10.1016/j.fertnstert.2016.07.1092.Search in Google Scholar PubMed

19. Wong, C, Dowling, CE, Saiki, RK, Higuchi, RG, Erlich, HA, Kazazian, HHJr. Characterization of β-thalassaemia mutations using direct genomic sequencing of amplified single copy DNA. Nature 1987;330:384–6. https://doi.org/10.1038/330384a0.Search in Google Scholar PubMed

20. Cao, A, Cossu, P, Monni, G, Rosatelli, MC. Chorionic villus sampling and acceptance rate of prenatal diagnosis. Prenat Diagn 1987;7:531–3. https://doi.org/10.1002/pd.1970070710.Search in Google Scholar PubMed

21. Monni, G, Olla, G, Rosatelli, MC, Cao, A. Second trimester placental biopsy versus amniocentesis for prenatal diagnosis of beta-thalassemia. N Engl J Med 1990;322:60–1. https://doi.org/10.1056/NEJM199001043220115.Search in Google Scholar PubMed

22. Newton, CR, Graham, A, Heptinstall, LE, Powell, SJ, Summers, C, Kalsheker, N, et al.. Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS). Nucleic Acids Res 1989;17:2503–16. https://doi.org/10.1093/nar/17.7.2503.Search in Google Scholar PubMed PubMed Central

23. Saiki, RK, Bugawan, TL, Horn, GT, Mullis, KB, Erlich, HA. Analysis of enzymatically amplified betaglobin and HLA-DQ alpha DNA with allele-specific oligonucleotide probes. Nature 1986;324:163–6. https://doi.org/10.1038/324163a0.Search in Google Scholar PubMed

24. Mann, K, Hamilton, S, Evans, J, Sibbring, J, Dore, J. ACGS best practice guidelines for use of Quantitative Fluorescence-PCR for the detection of aneuploidy v4. Original guidelines ratified by the UK Clinical Molecular Genetics Society and Association of Clinical Cytogenetics; 2007. Guidelines updated by the Association for Clinical Genetic Science (formally Clinical Molecular Genetics Society and Association of Clinical Cytogenetics), approved 26/11/2018.Search in Google Scholar

25. Monni, G, Zoppi, MA, Axiana, C, Ibba, RM. Changes in the approach for invasive prenatal diagnosis in 35,127 cases at a single center from 1977 to 2004. Fetal Diagn Ther 2006;21:348–54. https://doi.org/10.1159/000092464.Search in Google Scholar PubMed

26. Sabath, DE, Bender, MA, Sankaran, VG, Vamos, E, Kentsis, A, Yi, HS, et al.. Characterization of deletions of the HBA and HBB loci by array comparative genomic hybridization. J Mol Diagn 2016;18:92–9. https://doi.org/10.1016/j.jmoldx.2015.07.011.Search in Google Scholar PubMed PubMed Central

27. Wong, FC, Lo, YM. Prenatal diagnosis innovation: genome sequencing of maternal plasma. Annu Rev Med 2016;67:419–32. https://doi.org/10.1146/annurev-med-091014-115715.Search in Google Scholar PubMed

28. Saba, L, Masala, M, Capponi, V, Marceddu, G, Massidda, M, Rosatelli, MC. Non-invasive prenatal diagnosis of beta-thalassemia by semiconductor sequencing: a feasibility study in the Sardinian population. Eur J Hum Genet 2017;25:600–7. https://doi.org/10.1038/ejhg.2017.26.Search in Google Scholar PubMed PubMed Central

29. Lun, FM, Chiu, RW, Allen Chan, KC, Yeung Leung, T, Kin Lau, T, Dennis Lo, YM. Microfluidics digital PCR reveals a higher than expected fraction of fetal DNA in maternal plasma. Clin Chem 2008;54:1664–72. https://doi.org/10.1373/clinchem.2008.111385.Search in Google Scholar PubMed

30. Lun, FM, Tsui, NB, Chan, KC, Leung, TY, Lau, TK, Charoenkwan, P, et al.. Noninvasive prenatal diagnosis of monogenic diseases by digital size selection and relative mutation dosage on DNA in maternal plasma. Proc Natl Acad Sci USA 2008;105:19920–25. https://doi.org/10.1073/pnas.0810373105.Search in Google Scholar PubMed PubMed Central

31. Lo, YMD, Chan, KC, Sun, H, Chen, EZ, Jiang, P, Lun, FM, et al.. Maternal plasma DNA sequencing reveals the genome-wide genetic and mutational profile of the fetus. Sci Transl Med 2010;2:61ra91. https://doi.org/10.1126/scitranslmed.3001720.Search in Google Scholar PubMed

32. Xiong, L, Barrett, AN, Hua, R, Tan, TZ, Ho, SS, Chan, JK, et al.. Non-invasive prenatal diagnostic testing for β-thalassaemia using cell-free fetal DNA and next generation sequencing. Prenat Diagn 2015;35:258–65. https://doi.org/10.1002/pd.4536.Search in Google Scholar PubMed

33. Monni, G, Ibba, RM, Zoppi, MA, Floris, M. In utero stem cell transplantation. Croat Med J 1998;39:220–3.Search in Google Scholar

34. Derderian, SC, Jeanty, C, Walters, MC, Vichinsky, E, MacKenzie, TC. In utero hematopoietic cell transplantation for hemoglobinopathies. Front Pharmacol 2014;5:278. https://doi.org/10.3389/fphar.2014.00278.Search in Google Scholar PubMed PubMed Central

35. Malik, P. Gene therapy for hemoglobinopathies: tremendous successes and remaining caveats. Mol Ther 2016;24:668–70. https://doi.org/10.1038/mt.2016.57.Search in Google Scholar PubMed PubMed Central

36. Frangoul, H, Altshuler, D, Cappellini, MD, Chen, YS, Domm, J, Eustace, BK, et al.. CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia. N Engl J Med 2020;384:252–60. https://doi.org/10.1056/NEJMoa2031054.Search in Google Scholar

37. Monni, G, Murgia, F, Corda, V, Peddes, C, Iuculano, A, Tronci, L, et al.. Metabolomic investigation of β-thalassemia in chorionic villi samples. J Clin Med 2019;8:798. https://doi.org/10.3390/jcm8060798.Search in Google Scholar

38. Rosatelli, MC, Tuveri, T, Scalas, MT, Leoni, GB, Sardu, R, Faà, V, et al.. Molecular screening and fetal diagnosis of β-thalassemia in the Italian population. Hum Genet 1992;88:590–2.Search in Google Scholar

39. Cao, A, Rosatelli, C, Galanello, R, Monni, G, Olla, G, Cossu, P, et al.. The prevention of thalassemia in Sardinia. Clin Genet 1989;36:277–85.Search in Google Scholar

40. Cao, A, Congiu, R, Sollaino, MC, Desogus, MF, Demartis, FR, Loi, D, et al.. Thalassaemia and glucose-6-phosphate dehydrogenase screening in 13- to 14-year-old students of the Sardinian population: preliminary findings. Community Genet 2008;11:121–8. https://doi.org/10.1159/000113873.Search in Google Scholar

41. Monni, G, Peddes, C, Iuculano, A, Ibba, RM. From prenatal to preimplantation genetic diagnosis of β-thalassemia. Prevention model in 8748 cases: 40 years of single center experience. J Clin Med 2018;7:35. https://doi.org/10.3390/jcm7020035.Search in Google Scholar

42. Cao, A, Saba, L, Galanello, R, Rosatelli, MC. Molecular diagnosis and carrier screening for beta thalassemia. J Am Med Assoc 1997;278:1273–7. https://doi.org/10.1001/jama.278.15.1273.Search in Google Scholar

43. Rosatelli, MC, Dozy, A, Faa, V, Meloni, A, Sardu, R, Saba, L, et al.. Molecular characterization of beta-thalassemia in the Sardinian population. Am J Hum Genet 1992;50:422–6.Search in Google Scholar

44. Cao, A, Falchi, AM, Tuveri, T, Scalas, MT, Monni, G, Rosatelli, MC. Prenatal diagnosis of thalassemia major by fetal blood analysis: experience with 1000 cases. Prenat Diagn 1986;6:159–67. https://doi.org/10.1002/pd.1970060302.Search in Google Scholar

45. Rosatelli, C, Falchi, AM, Tuveri, T, Scalas, MT, Di Tucci, A, Monni, G, et al.. Prenatal diagnosis of beta-thalassaemia with the synthetic-oligomer technique. Lancet 1985;1:241–3. https://doi.org/10.1016/s0140-6736(85)91026-8.Search in Google Scholar

46. Monni, G, Ibba, RM, Lai, R, Cau, G, Mura, S, Olla, G, et al.. Early transabdominal chorionic villus sampling in couples at high genetic risk. Am J Obstet Gynecol 1993;168:170–3. https://doi.org/10.1016/s0002-9378(12)90908-4.Search in Google Scholar

47. Monni, G, Cau, G, Usai, V, Perra, G, Lai, R, Ibba, G, et al.. Preimplantation genetic diagnosis for beta-thalassaemia: the Sardinian experience. Prenat Diagn 2004;24:949–54. https://doi.org/10.1002/pd.1051.Search in Google Scholar PubMed

48. 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. https://doi.org/10.1002/uog.20353.Search in Google Scholar PubMed

49. Monni, G, Ibba, RM, Olla, G, Rosatelli, MC, Cao, A. Prenatal diagnosis of beta-thalassaemia by secondtrimester chorionic villus sampling. Prenat Diagn 1988;8:447–51. https://doi.org/10.1002/pd.1970080609.Search in Google Scholar PubMed

50. Palomba, ML, Monni, G, Lai, R, Cau, G, Olla, G, Cao, A. Psychological implications and acceptability of preimplantation diagnosis. Hum Reprod 1994;9:360–2. https://doi.org/10.1093/oxfordjournals.humrep.a138508.Search in Google Scholar PubMed

Received: 2021-01-15
Accepted: 2021-02-16
Published Online: 2021-03-16
Published in Print: 2021-09-27

© 2021 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

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  2. Editorial
  3. Introduction to the cesarean section articles
  4. Highlight Section: Cesarean Section
  5. Three kinds of caesarean sections: the foetal/neonatal perspective
  6. The neonatal respiratory morbidity associated with early term caesarean section – an emerging pandemic
  7. Vaginal birth after cesarean (VBAC): fear it or dare it? An evaluation of potential risk factors
  8. Nationwide implementation of a decision aid on vaginal birth after cesarean: a before and after cohort study
  9. Induction of labor at 39 weeks and risk of cesarean delivery among obese women: a retrospective propensity score matched study
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  11. An evidence-based cesarean section suggested for universal use
  12. Online survey on uterotomy closure techniques in caesarean section
  13. Analysis of cesarean section rates in two German hospitals applying the 10-Group Classification System
  14. Reviews
  15. Pregnancy in incarcerated women: need for national legislation to standardize care
  16. Imaging diagnosis and legal implications of brain injury in survivors following single intrauterine fetal demise from monochorionic twins – a review of the literature
  17. Mini Review
  18. Professionally responsible management of the ethical and social challenges of antenatal screening and diagnosis of β-thalassemia in a high-risk population
  19. Opinion Paper
  20. Teaching and training the total percutaneous fetoscopic myelomeningocele repair
  21. Corner of Academy
  22. Chronic hypertension in pregnancy: synthesis of influential guidelines
  23. Original Articles
  24. The effects of pre-pregnancy obesity and gestational weight gain on maternal lipid profiles, fatty acids and insulin resistance
  25. Determination of organic pollutants in meconium and its relationship with fetal growth. Case control study in Northwestern Spain
  26. Betamethasone as a potential treatment for preterm birth associated with sterile intra-amniotic inflammation: a murine study
  27. Diagnostic accuracy of modified Hadlock formula for fetal macrosomia in women with gestational diabetes and pregnancy weight gain above recommended
  28. Vasa previa: when antenatal diagnosis can change fetal prognosis
  29. Mode of delivery and adverse short- and long-term outcomes in vertex-presenting very preterm born infants: a European population-based prospective cohort study
  30. Short Communication
  31. Reference ranges for sphingosine-1-phosphate in neonates
https://doi.org/10.1515/jpm-2021-0021
Keywords for this article
cell free fetal DNA (cffDNA); ethics; non-invasive prenatal testing (NIPT); preimplantation genetic diagnosis (PGD); prenatal diagnosis; prenatal screening; β-thalassemia

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Introduction to the cesarean section articles
  4. Highlight Section: Cesarean Section
  5. Three kinds of caesarean sections: the foetal/neonatal perspective
  6. The neonatal respiratory morbidity associated with early term caesarean section – an emerging pandemic
  7. Vaginal birth after cesarean (VBAC): fear it or dare it? An evaluation of potential risk factors
  8. Nationwide implementation of a decision aid on vaginal birth after cesarean: a before and after cohort study
  9. Induction of labor at 39 weeks and risk of cesarean delivery among obese women: a retrospective propensity score matched study
  10. Cervical ripening after cesarean section: a prospective dual center study comparing a mechanical osmotic dilator vs. prostaglandin E2
  11. An evidence-based cesarean section suggested for universal use
  12. Online survey on uterotomy closure techniques in caesarean section
  13. Analysis of cesarean section rates in two German hospitals applying the 10-Group Classification System
  14. Reviews
  15. Pregnancy in incarcerated women: need for national legislation to standardize care
  16. Imaging diagnosis and legal implications of brain injury in survivors following single intrauterine fetal demise from monochorionic twins – a review of the literature
  17. Mini Review
  18. Professionally responsible management of the ethical and social challenges of antenatal screening and diagnosis of β-thalassemia in a high-risk population
  19. Opinion Paper
  20. Teaching and training the total percutaneous fetoscopic myelomeningocele repair
  21. Corner of Academy
  22. Chronic hypertension in pregnancy: synthesis of influential guidelines
  23. Original Articles
  24. The effects of pre-pregnancy obesity and gestational weight gain on maternal lipid profiles, fatty acids and insulin resistance
  25. Determination of organic pollutants in meconium and its relationship with fetal growth. Case control study in Northwestern Spain
  26. Betamethasone as a potential treatment for preterm birth associated with sterile intra-amniotic inflammation: a murine study
  27. Diagnostic accuracy of modified Hadlock formula for fetal macrosomia in women with gestational diabetes and pregnancy weight gain above recommended
  28. Vasa previa: when antenatal diagnosis can change fetal prognosis
  29. Mode of delivery and adverse short- and long-term outcomes in vertex-presenting very preterm born infants: a European population-based prospective cohort study
  30. Short Communication
  31. Reference ranges for sphingosine-1-phosphate in neonates
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