1. EMGO Institute for Health and Care Research Quality of Care Martina Cornel Professor of Community Genetics & Public Health Genomics Prenatal screening strategies: promote health as well as informed choice? Community Genetics, Dept Clinical Genetics Brocher Foundation Geneva 4th April 2013

2. ASHG definition genetic counselling “Genetic counselling is a communication process that deals with the human problems associated with the occurrence or risk of occurrence of a genetic disorder in a family. This process involves an attempt by one or more appropriately trained persons to help the individual or family to: (1) comprehend the medical facts including the diagnosis, probable course of the disorder, and the available management, (2) appreciate the way heredity contributes to the disorder and the risk of recurrence in specified relatives, (3) understand the alternatives for dealing with the risk of recurrence, (4) choose a course of action which seems to them appropriate in view of their risk, their family goals, and their ethical and religious standards and act in accordance with that decision, and (5) to make the best possible adjustment to the disorder in an affected family member and/or to the risk of recurrence of that disorder.”

3. The goal of prenatal screening Protect child health –Screening for Rhesus during pregnancy –(Ultrasound: adapt health care to fetal diagnosis, for instance delivery in hospital, cardiac surgery nearby) Offer pregnant women (couples) reproductive choices –Prenatal diagnosis and abortion –Prepare for birth of affected child

4. The goal of prenatal screening Low prevalence of morbidity/mortality –Public health paradigm High percentage of informed decisions –As in genetic/reproductive health care, community genetics: interest/autonomy of individual pregnant women is central Both apply!

5. Genetics: during pregnancy Rhesus negative women / Anti-D: –Routine antenatal anti-D prophylaxis (RAADP) is recommended as a treatment option for all pregnant women who are rhesus D (RhD) negative and who are not known to be sensitised to the RhD antigen. (NICE, UK) –in pregnancy [28–34 weeks] and within 17 h postpartum to prevent isoimmunisation Healthy motherhood: an urgent call to action Thelancet.com DOI:10.1016/S0140-6736(06)69389-6

6. RhD: fetal DNA in maternal blood Design PCR that detects presence of RhD gene in plasma RhD negative woman; –If present, it must be fetal! Cave: not all RhD negative women have complete deletion – present PCR is more sophisticated to distinguish also mutated RhD genes; Male RhD+ Female RhD+ Female RhD-

7. 2011: NIPT for Down screening? BMJ 2011: trisomy 21 PLoS One 2011: also tris 13&18

8. A priori risk of women: 1 in 5 Positive predictive value is 39,760/40,080=99,2% (in 1 in 100 women with positive NIPT the child is healthy). Chance that child has DS with negative result is 1-(159,680/159,920)= 0,0015 is 1 op 666. DSNo DSTotal NIPT test result positive (DS) 39,76032040,080 NIPT test results negative (no DS) 240159,680159,920 40,000160,000200,000 Sens 99,4%Spec 99,8%

9. A priori risk of women: 1 in 200 Positive predictive value is 994/1392=71% (in 1 in 4 women with positive NIPT the child is healthy). Chance that child has DS with negative result is 1-(198,602/198,608)= 0,00003 is 1 op 33,000. DSNo DSTotaal NIPT test result positive (DS) 9943981392 NIPT test results negative (no DS) 6198,602198,608 1000199,000200,000 Sens 99,4%Spec 99,8%

10. A priori risk of women: 1 in 1000 Positive predictive value is 199/599=33% (in 2 in 3 women with positive NIPT the child is healthy). Chance that child has DS with negative result is 1-(199,400/199,401)= is 1 op 199,000. DSNo DSTotaal NIPT test result positive (DS) 199400599 NIPT test results negative (no DS) 1199,400199,401 200199,800200,000 Sens 99,4%Spec 99,8%

12. Clinical geneticsPublic health Individualism & autonomy => insurance payment Collectivism & paternalism => government funding Goal: Empower counselees Outcome: informed choice, personal control Goal: Promote health and prevent disease Outcome: uptake, compliance, decrease number affected, economic benefits Perspective of clinical genetics vs. Public health

13. Public health activities Seat belts Health promotion Tabacco tax Etc etc

14. Folic acid and neural tube defects 1991 MRC trial: 70% risk reduction extra folic acid starting 1 month before conception untill 3 months thereafter.

15. 1993/1994/1995 -RCTs: MRC Trial (1991) and Czeizel (1992) -Folic acid can avoid >70% of neural tube defects -Who tells mothers-to-be?? -Some countries advise/campaign: -eat more fruits & vegetables -add folate to food (flour, bread) -use supplements -Cornel MC, Erickson JD. Comparison of national policies on periconceptional use of folic acid to prevent spina bifida and anencephaly (SBA). Teratol 1997;55(2):134-7.

16. Getting pregnant? Ask before conception! First pregnancy health visit often at 12 weeks, when organogenesis is finished At 2 weeks after expected menstrual period, the neural tube is closed (or anencephaly or spina bifida exists)

17. Countries fortifying flour B 9/11 2010 www.cdc.gov/mmwr/preview/mmwrhtml/figures/m5931a2f3.gif

19. Ethical principles Paternalism Directiveness (informed choice)

20. Prevention of birth defects as public health task? Provide information on folic acid Fortify flour Add Iodide to salt Inform about effects of smoking & alcohol Vaccinate against rubella Genetics??? Protect against radiation Inherited diseases??

21. Clinical genetics A disease in my family: am I at risk? Is my child at risk? Can a DNA test give certainty? Medical specialty –(physicians 4 y additional training)

22. Principles Non-directiveness –(vs. coercive aspects of eugenics) Autonomy or self-determination of client Goal: informed decision making –(vs. preventing birth defects or genetic disorders) –Goal <> potential consequence

23. Moral framework for genetic testing Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Genetic Testing for Health Purposes (Council of Europe 2008). The primacy of the interests and welfare of the individual human being over the sole interest of society or science, non-discrimination and appropriate test quality are important criteria mentioned in this convention, as are appropriate information, counselling and consent.

24. Where is the individual in genetics?

25. Clinical genetics Individualism & autonomy => insurance payment Goal: Empower counselees Outcome: informed choice, personal control

26. Clinical geneticsPublic health Individualism & autonomy => insurance payment Collectivism & paternalism => government funding Goal: Empower counselees Outcome: informed choice, personal control Goal: Promote health and prevent disease Outcome: uptake, compliance, decrease number affected, economic benefits Perspective of clinical genetics vs. Public health

27. The term “prevention” Should be avoided in ethically sensitive reproductive choices Public health should rather develop adequate information to all and testing of high quality to allow individuals to make their own informed decisions Van El e.a. 2011 JOCG (Witness seminar NL genetic screening criteria)

28. Who decides in health care? Physicians and other health care workers in general have to follow professional guidance. Is a genetic test available in a country? –Ministry, health care insurance Does the physician offer it to a specific patient? –Limited room for individual decision making physician Does the patient accept? –In the end it is always the patient who decides, if the offer has been made.

29. Responsibilities Public health authorities: collective issues –Protect children –Quality control of information provision and laboratory quality for prenatal screening Medical professionals (obstetrician, clinical geneticist, midwife) –Help pregnant women make their own informed choice

30. If health care does not offer it… What if the test is not available in health care…???

32. EASAC-FEAM: Main messages MAIN MESSAGES All kinds of genetic testing require an appropriate and relevant level of professional advice On the whole, DTC GT has little clinical value at present and, on occasion, has potential to be harmful We would not wish to encourage EU citizens to use DTC GT at the present time

33. Especial caution is warranted for DTC in specific respects For those with symptoms or at known increased risk Monogenic, high penetrance, serious disorders Prenatal screening, carrier testing in children Nutrigenomic testing Pharmacogenetic testing

34. THANK YOU FOR YOUR ATTENTION