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191028P - PRE-NATAL SCREENING, DIAGNOSIS, and TESTING WITH REFERENCE TO DOWN SYNDROME & THALASSEMIA: Ethico-legal Issues

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Presentation at the first workshop of Research Ethics Program - Clinical Ethics: Principle and Methods held at Princess Nourah bint Abdulrahman University, Riyadh on 30 October 2019. By: Professor Omar Hasan Kasule Sr. MB ChB (MUK). MPH (Harvard), DrPH (Harvard) Chairman of the Ethics Committee King Fahad Medical City. 


Down Syndrome/trisomy 21

  • Most common chromosomal anomaly due to duplication of chromosome 21
  • Impaired cognitive ability with an average IQ of 50, impaired physical growth, specific facies,  in addition to other medical complications
  • Confirmation of the diagnosis is by karyotype analysis.
  • The cytogenetic abnormality can be classified into pure trisomy 21, translocation, or mosaicism

 

Thalassemia 1

  • Thalassemia is due to a defect in either the alpha or beta globin chains leading to abnormal red blood cells that hemolyse more often than normal ones causing anemia and other complications such as: pneumonia, iron overload, bone deformities1 and cardiovascular illness (CCF, arrhythmias), infections, enlarged spleen, slow growth, and delayed puberty.
  • In some forms of thalassemia, the abnormality may be in the delta chain. Thalassemia is one of many hemoglobinopathies. Others are: Hb S, Hb C, Hb E, Hb D,Hb O,
  • Thalassemia can occur in combination with other hemoglobinopathies such as hemoglobin E, hemoglobin S, and hemoglobin C. The beta form of thalassemia is particularly prevalent among Mediterranean peoples. South Asians are also affected

1 J Contemp Dent Pract. 2011 Nov 1;12(6):429-33.

 

Thalassemia 2

  • Both alpha and beta thalassemia are inherited as autosomal recessive (i.e. both parents must be carriers for the child to have the disease). Dominant inheritance can also occur.
  • Genetic counseling is needed for carriers of the trait. Trait requires no treatment.
  • Treatment: Blood transfusion. Chelation therapy using deferoxamine, deferiprone, and deferasirox
  • Prenatal diagnosis of thalassemia carried out in Muslim countries such as Pakistan2, Turkey3
  • Prevention by premarital screening and genetic testing4 Man is checked first if he has microcytes the woman is tested. If both are microcytic, their hemoglobin is tested and if positive they are referred to counseling

2 PrenatDiagn. 2011 Aug;31(8):788-91.

3 Hemoglobin. 2011;35(1):47-55.

4 PrenatDiagn. 2009 Jan;29(1):83-8.

 

Thalassemia 3

  • A Saudi study of 329 blood samples from suspected cases was analyzed. 35.9% had normal HB. 36.5% had iron deficiency anemia masking the thalassemia trait. Other anomalies were: HB-F 1.5%, beta-thalassemia 10%, beta-thalassemia and sickle cell disease 3.3%, and sickle cell disease 4%5.
  • Since 2003 the Saudi Ministry of Health mandated pre-marital screening for thalassemia6. A Saudi study showed that the pre-marital thalassemia screening program reduced at-risk marriages7.
  • 88.2% of couples with the beta thalassemia trait at pre-marital screening went ahead and married. Reasons given for marrying: wedding plans could not be canceled, and fear of social stigma8.  Another study found that 98% of screened couples went on to marry for cultural reasons9.

5 Genet Test Mol Biomarkers. 2012 Jan;16(1):25-9.

6 Hemoglobin. 2009;33Suppl 1:S21-4.

7 Ann Saudi Med. 2011 May-Jun;31(3):229-35.

8 J Genet Couns. 2012 Apr;21(2):243-55.

9 PrenatDiagn. 2010 May;30(5):478-81.

 

Definition of prenatal diagnosis / prenatal screening / prenatal genetic testing

  • Testing for diseases or conditions in a fetus or embryo with the aim of diagnosing anomalies
  • Examples of anomalies: neural tube defects, Down syndrome, chromosome abnormalities, genetic diseases, and other conditions, such as spina bifida, cleft palate, Tay Sachs disease, sickle cell anemia, thalassemia, cystic fibrosis, Muscular dystrophy, and fragile X syndrome.

 

Prenatal screening

  • Reasons for pre-natal screening: (a) Routine pre-natal identification of at-risk pregnancies (b) Early detection of congenital anomalies (c) Screening reduces the use of invasive prenatal diagnosis10.
  • Methods of pre-natal screening: (a) Family history (b) Serum screening (c) Molecular tests (d)  Ultrasound.

10 J Matern Fetal Neonatal Med. 2010 Aug;23(8):914-9.

 

Prenatal diagnosis

  • Reasons for pre-natal diagnosis: (a) Reassurance (b) Desire for termination (c) Preparation for abnormal birth (financially, psychologically) (d) In utero treatment for example congenital adrenal hyperplasia.
  • Methods of pre-natal diagnosis: (a) Amniocentesis (Amniocentesis is feasible after week 16) (b) Chorionic villi sampling (c) Percutaneous umbilical cord sampling (d) Ultrasonography (e) CT and MRI.
  • Target groups of prenatal genetic testing: (a) History of congenital anomalies (b) Family history (c) Identification from screening.
  • Optimum time for diagnosis

 

Prenatal genetic testing

  • This is the characterization of the genetic anomaly
  • Confirmatory of the diagnosis

 

Prenatal treatment

  • Intrauterine fetal transfusion
  • Intra-uterine/fetal surgery
  • Intrauterine drug treatment of cardiac arrhythmias and thyroid disorders
  • Neonatal surgery/treatment

 

Reasons for prenatal diagnosis

  • To enable timely medical or surgical treatment of a condition before or after birth.
  • To give the parents the chance to abort a fetus with the diagnosed condition.
  • To give parents the chance to "prepare" psychologically, socially, financially, and medically for a baby with a health problem or disability, or for the likelihood of stillbirth.

 

Approaches of prenatal diagnosis / prenatal screening / prenatal genetic testing

  • Invasive: amniocentesis with karyotyping, chorionic villi sampling11 (trans abdominal or the more risky trans cervical), embryoscopy, fetoscopy, and percutaneous umbilical cord sampling
  • Non-invasive12 13 1. Ultrasonography 2. Maternal serum screens biomarkers 3. Fetal DNA or fetal RNA in maternal serum detecting fetal DNA in maternal blood4. Other tests to detect fetal hemoglobin in maternal serum.

11 Hemoglobin. 2011;35(4):434-8.

12 Genet Med. 2010 May;12(5):298-303.

13 Genet Test Mol Biomarkers. 2012 Sep;16(9):1051-7.

 

Targets of prenatal diagnosis / prenatal screening / prenatal genetic testing

  • Women over the age of 35 (advanced maternal age14)
  • Women who have previously had premature babies or babies with a birth defect, especially heart or genetic problems
  • Women who have high blood pressure, lupus, diabetes, asthma, or epilepsy
  • Women who have family histories or ethnic backgrounds such as HBs and thalassemia prone to genetic disorders, or whose partners have these
  • Women who are pregnant with multiples (twins or more)
  • Women who have previously had miscarriages

14 S Afr Med J. 2011 Jan;101(1):45-8.

 

Down syndrome: screening, diagnosis, genetic testing

  • Pre-natal screening of DS: (a) Use of serum markers for DS like alpha-fetoprotein, PAPPA-A, serum unconjugated estriol, and chorionic gonadotropin15 16 17. Other serum markers are: inhibin-A18, inhibin-D19, ADAM1220. The search is continuing for new biomarkers21 (b) Ultra sound22 with emphasis on nuchal transparency (NT)23 which is not reliable24 but beyond a certain threshold can lead to the decision to skip other screening tests25 and proceed to diagnostic tests. Trimester 1 and 2 markers modestly predict an adverse obstetric outcomes.26 (c) Fetal RNA in maternal serum27

15 NEJM 1992; 327;588-593.

16 Int J Gynaecol Obstet. 2008 Dec;103(3):241-5.

17 J Proteomics. 2012 Jun 18;75(11):3248-57.

18 prenatal disgnosis 1996; 16(2):143-153.

19 PrenatDiagn. 2008 Sep;28(9):833-8.

20 PrenatDiagn. 2010 Jun;30(6):561-4.

21 PLoS One. 2009 Nov 24;4(11):e8010.

22 Genet Med. 2009 Sep;11(9):669-81.

23 Obstet Gynecol. 2009 Oct;114(4):829-38.

24 Minerva Ginecol. 2011 Dec;63(6):491-4.

25 J ObstetGynaecol Can. 2009 Mar;31(3):227-35.

26 PrenatDiagn. 2010 May;30(5):471-7.

27 J Perinat Med. 2012 Feb 13;40(4):319-27.

 

  • Prenatal diagnosis of DS: chromosomal analysis (karyotyping) from amniotic fluid28.
  • Prenatal genetic testing of DS: DNA analysis. (a) Test for trisomy in maternal blood.  (b) Use of epigenetic markers and real-time PCR29 30  (c) Array of genetic tests based on the genome raises issues of informed consent since the scope of the results cannot be determined in advance31.

28 Prenatal diagnosis 2002; 22(1): 29-33.

29 Expert OpinBiolTher. 2012 Jun;12 Suppl 1:S155-61.

30 ClinBiochem. 2009 May;42(7-8):672-5.

31 Hum Mutat. 2012 Jun;33(6):916-22.

 

Thalassemia: screening, diagnosis, genetic testing

  • Inadequate parental knowledge of beta thalassemia screening32
  • Prenatal screening: fetal DNA in maternal serum for beta thalassemia33 and alpha thalassemia34.
  • Prenatal diagnosis: (a) Capillary electrophoresis35. Hb typing is as accurate as DNA analysis36.

32 J Coll Physicians Surg Pak. 2012 Apr;22(4):218-21.

33 Expert OpinBiolTher. 2012 Jun;12 Suppl 1:S181-7.

34 PrenatDiagn. 2012 Jan;32(1):45-9.

35 Eur J Haematol. 2009 Jul;83(1):57-65.

36 Hemoglobin. 2009;33(1):17-23.

 

Ethico-legal issues in pre-natal procedures

  • Full disclosure
  • Autonomy and informed consent:
  • Justice
  • Privacy and confidentiality
  • Pregnancy termination
  • Issues relating to the testing procedure
  • Other issues

 

Full disclosure

  • 2 aspects of disclosure (a) disclosure of the procedures to be used, benefits, and risks (b) disclosure of bad news after screening and diagnosis.
  • Families must be given up-to-date balanced information about DS in a supportive and respectful manner. Health care workers with specific knowledge of DS should deliver DS prenatal diagnosis news in person37.

37 Am J Med Genet A. 2009 Nov;149A(11):2361-7

 

Autonomy and informed consent 1

  • The physician’s duty is to inform the patient about prenatal diagnosis. It should not be assumed patients know.
  • Information is given before an informed decision on DS screening38 or pre-conception39. Experiential information helps couples decide about DS screening40. Having knowledge did not lead to participation in DS screening41. Attitude affects women’s decisions42.
  • Risk: Algorithm for risk determination to select those for DS screening based on maternal age, fetal NT, maternal PAPP-A, and free beta-hCG levels43. The risk score is the chance a baby has a birth defect the most common is 1:270. The decision to undergo a high-risk test is based on the risk score. Information about the numerical risk score after DS screening influenced the uptake of diagnostic test44.

38 PrenatDiagn. 2009 Feb;29(2):120-8.

39 Am J Med Genet A. 2012 Mar;158A(3):485-97.

40 PrenatDiagn. 2012 Jan;32(1):57-63.

41 Patient EducCouns. 2012 Jun;87(3):351-9.

42 PrenatDiagn. 2010 Nov;30(11):1086-93.

43 Eur J ObstetGynecolReprod Biol. 2009 Jun;144(2):140-5.

44 PrenatDiagn. 2010 Jun;30(6):522-30.

 

Autonomy and informed consent 2

  • Decision-making is a shared responsibility between the physician and the woman. Women and family physicians willing to engage in shared decision-making for DS screening45. Family physicians in Quebec exerted minimal effort to involve women in decision-making on DS screening46. Midwives could book DS screening47.
  • The decision before the woman is between producing an abnormal baby vs procedure-related miscarriage48.
  • Testing minors and adolescents should we wait. Adolescent mothers are less likely than older women to make an informed decision about DS screening49.

45 PrenatDiagn. 2011 Apr;31(4):319-26.

46 PrenatDiagn. 2010 Feb;30(2):115-21.

47 PrenatDiagn. 2011 Oct;31(10):985-9.

48 Health Econ. 2008 May;17(5):557-77.

49 J PediatrAdolesc Gynecol. 2011 Feb;24(1):29-34.

 

Justice

  • Disparities in screening by socio-economic status persist50.
  • Asian women in England are less likely to be offered DS screening51.
  • Ethnic minorities are less likely to participate in DS screening52.
  • Cost barriers to screening, diagnosis, and testing.
  • In Holland,      ethnic differences were found in knowledge about DS screening53.

50 BJOG. 2008 Aug;115(9):1087-95.

51 PrenatDiagn. 2008 Dec;28(13):1245-50.

52 PrenatDiagn. 2009 Dec;29(13):1262-9.

53 Patient EducCouns. 2009 Nov;77(2):279-88.

 

Privacy and confidentiality

  • Disclosure to the family after permission of the woman
  • Disclosure to the husband?
  • Self-disclosure could implicate family members

 

Pregnancy termination

  • Prenatal screening and diagnosis: a slippery slope to abortion, eugenics, and genocide?
  • US 1995-2011 termination rate after DS screening was 67%54 Pregnancy termination: 86% in Iran favored termination in case of a fetus affected by thalassemia55
  • Factors of termination decision: Multiple factors affected the termination decision after prenatal diagnosis of DS56. External moral authority is needed to make termination decisions after prenatal diagnosis normal professional ethics are not sufficient57. Consideration of the quality of life for the mentally or physically disabled. Technical and legal limits for termination.
  • Post-termination support and counseling.

54 PrenatDiagn. 2012 Feb;32(2):142-53.

55 Hemoglobin. 2010;34(1):49-54.

56 J Midwifery Womens Health. 2012 Mar-Apr;57(2):156-64.

57 J Med Ethics. 2012 Jul;38(7):399-402.

 

Issues related to the test

•      Performance characteristics of the test: sensitivity, specificity. Safety. False positive and false negative

•      Funding: cost-effective to screen DS and neural tube defects together58

•      Perceived disability burden versus procedural risk. Risk of abortion from amniocentesis

•      Anxiety in women undergoing DS screening59

•      DS screening-related miscarriage is 13 per 100,00060

•      Counseling before and after the procedure. The time between counseling and the procedure. Discuss the impact of results.

58 Community Genet. 2008;11(6):359-67.

59 PrenatDiagn. 2008 May;28(5):417-21.

60 Community Genet. 2008;11(6):359-67.

 

Other Issues in prenatal diagnosis

•     Limitations of diagnosis i.e. informative ways of testing

•  DS screening is not increasing co-morbidities by longer survival61

61 Pediatrics. 2009 Jan;123(1):256-61.

 

Case studies on DS

  • Case #1:a 38-year-old mother with one live delivery of a Down syndrome baby is pregnant for the second time. The husband insists on a pre-natal diagnosis but she refuses.
  • Case #2:A 40-year-old gynecologist recently married and became pregnant. Her husband insists on prenatal diagnosis but she refuses.
  • Case #3: 35-year-old mother of 2 previous normal children asks for amniocentesis to discover if the baby is normal. The director of the health clinic refuses fearing she may consider abortion.
  • Case #4: Down syndrome society petitioned the Ministry of Health to make Down syndrome screening mandatory for pregnant women aged 30 and above.
  • Case #5: A doctor obtained consent to do a down screening on a 45-year-old pregnant woman. When she came for the results he refused to disclose them because nurses had told him she had talked about aborting abnormal fetii while in the waiting room.

 

Case studies on Thalassemia

  • Case #1: two first cousins wanted to marry. The geneticist told them that they were both carriers and that 1 in every 4 children would get the disease. They went ahead and married because a proportion of 25% was too low a risk.
  • Case #2: a 4-year-old child had repeated episodes of anemia that responded to transfusion. The doctors without getting parental permission carried out and found a positive test for thalassemia disease. Problems occurred in the family because both parents had results of pre-marital testing that showed that neither was a carrier of thalassemia.