Down Syndrome: Antenatal Screening Mathematics, Ethics and Its Implementation in the UK

Abstract

Antenatal screening for Down syndrome involves the application of noninvasive measurements (blood tests or ultrasound scanning) taken early in pregnancy to determine whether a foetus is likely to be affected by Down syndrome, to allow identification of a small proportion of pregnancies (usually up to 5%) in which to carry out an invasive diagnostic test (chorionic villus sampling or amniocentesis). Restriction of the invasive test is advisable because there is a risk of iatrogenic foetal loss as a result of the diagnostic test. New possibilities include analysis of free serum deoxyribonucleic acid to avoid invasive foetal sampling.

Although screening is possible, there remains some controversy over whether it should be done. The Eugenics history of the mid‐twentieth century should give pause for thought over the ethical under‐pinning of this ‘routine’ antenatal test.

Key Concepts:

  • It is possible to screen for foetal aneuploidies in early pregnancy by using a statistical model of normality, and a statistical model of affected pregnancies, from which a risk can be calculated. In future, it may be possible to directly analyse foetal DNA in maternal plasma to carry out the same function.

  • New screening methods using free DNA in serum may soon be introduced.

  • Screening programmes for genetics disease pose questions about medical ethics which are very difficult to answer.

Keywords: Down syndrome; screening; trisomy 21; alpha‐foetoprotein; human chorionic gonadotropin; unconjugated estriol; nuchal fold; ethics

Figure 1.

Population distributions for a‐fetoprotein (AFP) and human chorionic gonadotropin (HCG) for Down syndrome and ‘normal’ pregnancies, assuming equal incidence.

Figure 2.

Population distributions for a‐fetoprotein (AFP) and human chorionic gonadotropin (HCG) for Down syndrome and ‘normal’ pregnancies, with correct incidences. Note that the Down syndrome peak is now hidden by the ‘normal’ peak.

Figure 3.

Illustration to demonstrate how likelihood ratios are calculated.

Figure 4.

Effect of maternal age on screening. As age increases the potential for being identified as being at ‘high risk’ increases. AFP, a‐fetoprotein; HCG, human chorionic gonadotropin; MoM, multiple of the median.

Figure 5.

Age‐related false positive rate for Down syndrome (double) screening.

Figure 6.

Age‐related detection rate for Down syndrome (double) screening.

close

References

Aitken DA, Wallace EM, Crossley JA et al. (1996) Dimeric inhibin A as a marker for Down's syndrome in early pregnancy. New England Journal of Medicine 334: 1231–1236.

Alderson P (2001) Down's syndrome: cost, quality and value of life. Social Science and Medicine 53: 627–638.

Amerlite Diagnostics (1991) Down's Syndrome and Neural Tube Defects Risk Assessment. Trial Results Manual – A Retrospective Study. Amersham: Amerlite Diagnostics.

Baldus M (2001) From diagnosis to decision – decision processes of women in the context of prenatal diagnosis. Praxis der Kinderpsychologie und Kinderpsychiatrie 50: 736–752.

Bell M and Stoneman Z (2000) Reactions to prenatal testing: reflection of religiosity and attitudes toward abortion and people with disabilities. American Journal of Mental Retardation 105: 1–13.

Benn PA, Horne D, Briganti S and Greenstein RM (1995) Prenatal diagnosis of diverse chromosome abnormalities in a population of patients identified by triple‐marker testing as screen positive for Down syndrome. American Journal of Obstetrics and Gynecology 173: 496–501.

Bishop JC, Dunstan FD, Nix BJ, Reynolds TM and Swift A (1993) All MoMs are not equal: some statistical properties associated with reporting results in the form of multiples of the median. American Journal of Human Genetics 52: 425–430.

Boston S (1994) Give Down's babies a chance. BMA News Review August: 34.

Bouchard L, Renaud M, Kremp O and Dallaire L (1995) Selective abortion: a new moral order? Consensus and debate in the medical community. International Journal of Health Services 25: 65–84.

Burton BK, Prins GS and Verp MS (1993) A prospective trial of prenatal screening for Down syndrome by means of maternal serum alpha‐fetoprotein, human chorionic gonadotropin, and unconjugated estriol. American Journal of Obstetrics and Gynecology 169: 526–530.

Camaschella C, Alfarano A, Gottardi E et al. (1990) Prenatal diagnosis of fetal hemoglobin Lepore‐Boston disease on maternal peripheral blood. Blood 75: 2102–2106.

Cheng EY, Luthy DA, Zebelman AM et al. (1993) A prospective evaluation of a second‐trimester screening test for fetal Down syndrome using maternal serum alpha‐fetoprotein, hCG, and unconjugated estriol. Obstetrics and Gynecology 81: 72–77.

Chitty LS and Bianchi DW (2013) Noninvasive prenatal testing: the paradigm is shifting rapidly. Prenatal Diagnosis 33(6): 511–513. http://www.ncbi.nlm.nih.gov/pubmed/?term=23686654

Crossley JA, Aitken DA and Connor JM (1991) Prenatal screening for chromosome abnormalities using maternal serum chorionic gonadotrophin, alpha‐fetoprotein, and age. Prenatal Diagnosis 11: 83–101.

Crossley JA, Aitken DA and Connor JM (1993) Second‐trimester unconjugated oestriol levels in maternal serum from chromosomally abnormal pregnancies using an optimized assay. Prenatal Diagnosis 13: 271–280.

Cuckle HS, Wald NJ and Thompson SG (1987) Estimating a woman's risk of having a pregnancy associated with Down's syndrome using her age and serum alpha‐fetoprotein level. British Journal of Obstetrics and Gynaecology 94: 387–402.

Dawson A and Reynolds T (1992) Antenatal screening for Down's syndrome. British Medical Journal 305: 769 (discussion 771).

Dhallan R, Guo X, Emche S et al. (2007) A non‐invasive test for prenatal diagnosis based on fetal DNA present in maternal blood: a preliminary study. Lancet 369: 474–481.

Ferriman EL, Sehmi IK, Jones R and Cuckle HS (1999) The effect of smoking in pregnancy on maternal serum inhibin A levels. Prenatal Diagnosis 19: 372–374.

Gill M, Murday V and Slack J (1987) An economic appraisal of screening for Down's syndrome in pregnancy using maternal age and serum alpha fetoprotein concentration. Social Science and Medicine 24: 725–731.

Gudkov L, Tichtchenko P and Yudin B (1998) Human genetic improvement: a comparison of Russian and British public perceptions. Bulletin of Medical Ethics 134: 20–23.

Haddow JE, Palomaki GE, Knight GJ et al. (1992) Prenatal screening for Down's syndrome with use of maternal serum markers. New England Journal of Medicine 327: 588–593.

Harrison G and Goldie D (2006) Second‐trimester Down's syndrome serum screening: double, triple or quadruple marker testing? Annals of Clinical Biochemistry 43: 67–72.

Hill M, Karunaratna M, Lewis C, Forya F and Chitty L (2013) Views and preferences for the implementation of non‐invasive prenatal diagnosis for single gene disorders from health professionals in the United Kingdom. American Journal of Medical Genetics Part A 161(7): 1612–1618. http://www.ncbi.nlm.nih.gov/pubmed/23696422

Julian C, Huard P, Gouvernet J, Mattei JF and Ayme S (1989) Physicians’ acceptability of termination of pregnancy after prenatal diagnosis in southern France. Prenatal Diagnosis 9: 77–89.

Kellner LH, Weiner Z, Weiss RR et al. (1995) Triple marker (alpha‐fetoprotein, unconjugated estriol, human chorionic gonadotropin) versus alpha‐fetoprotein plus free‐beta subunit in second‐trimester maternal serum screening for fetal Down syndrome: a prospective comparison study. American Journal of Obstetrics and Gynecology 173: 1306–1309.

Kuppermann M, Nease RF, Learman LA et al. (2000) Procedure‐related miscarriages and Down syndrome‐affected births: implications for prenatal testing based on women's preferences. Obstetrics and Gynecology 96: 511–516.

Lemay C, Roussel‐Mizon N, Thepot F and Desmet G (1995) Maternal serum screening for fetal Down's syndrome, a retrospective study. Clinica Chimica Acta 238: 151–162.

Lench N, Barrett A, Fielding S et al. (2013). The clinical implementation of non‐invasive prenatal diagnosis for single‐gene disorders: challenges and progress made. Prenatal Diagnosis 33(6): 555–562. http://www.ncbi.nlm.nih.gov/pubmed/23592512

Lewis C, Silcock C and Chitty LS (2013). Non‐invasive prenatal testing for Down's syndrome: pregnant women's views and likely uptake. Public Health Genomics 25. http://www.ncbi.nlm.nih.gov/pubmed/?term=23886854

Lo YM (1999) Fetal RhD genotyping from maternal plasma. Annals of Medicine 31: 308–312.

Lo YM, Lau TK, Zhang J et al. (1999) Increased fetal DNA concentrations in the plasma of pregnant women carrying fetuses with trisomy 21. Clinical Chemistry 45: 1747–1751.

Lo YM, Patel P, Baigent CN et al. (1993) Prenatal sex determination from maternal peripheral blood using the polymerase chain reaction. Human Genetics 90: 483–488.

Lo YM, Patel P, Sampietro M et al. (1990) Detection of single‐copy fetal DNA sequence from maternal blood. Lancet 335: 1463–1464.

MacDonald ML, Wagner RM and Slotnick RN (1991) Sensitivity and specificity of screening for Down syndrome with alpha‐ fetoprotein, hCG, unconjugated estriol, and maternal age. Obstetrics and Gynecology 77: 63–68.

Macri JN, Kasturi RV, Krantz DA et al. (1990) Maternal serum Down syndrome screening: free beta‐protein is a more effective marker than human chorionic gonadotropin. American Journal of Obstetrics and Gynecology 163: 1248–1253.

Mancini G, Perona M, Dall'Amico D et al. (1994) Maternal serum markers. Estimation of the risk of Down's syndrome: a prospective study. International Journal of Clinical and Laboratory Research 24: 49–53.

Merkatz IR, Nitowsky HM, Macri JN and Johnson WE (1984) An association between low maternal serum alpha‐fetoprotein and fetal chromosomal abnormalities. American Journal of Obstetrics and Gynecology 148: 886–894.

Milunsky A, Nebiolo LM and Bellet D (1993) Maternal serum screening for chromosome defects: human chorionic gonadotropin versus its free‐beta subunit. Fetal Diagnosis and Therapy 8: 221–224.

Mooney RA, Peterson CJ, French CA, Saller Jr DN and Arvan DA (1994) Effectiveness of combining maternal serum alpha‐fetoprotein and hCG in a second‐trimester screening program for Down syndrome. Obstetrics and Gynecology 84: 298–303.

Moyer A, Brown B, Gates E et al. (1999) Decisions about prenatal testing for chromosomal disorders: perceptions of a diverse group of pregnant women. Journal of Women's Health and Gender‐based Medicine 8: 521–531.

Nakić Radoš S, Košec V and Gall V (2013) The psychological effects of prenatal diagnostic procedures: maternal anxiety before and after invasive and noninvasive procedures. Prenatal Diagnosis 33(12): 1194–1200. doi:10.1002/pd.4223.

National Screening Committee (2006) Policy Position. http://www.library.nhs.uk/screening/ViewResource.aspx?resID=35689&tabID=288&catID=8562

National Screening Committee (2014) First trimester combined screening for trisomy 13 and trisomy 18: external review against programme appraisal criteria for the UK National Screening Committee (UK NSC). http://www.screening.nhs.uk/t18andt13

Norgaard‐Pedersen B, Larsen SO, Arends J, Svenstrup B and Tabor A (1990) Maternal serum markers in screening for Down syndrome. Clinical Genetics 37: 35–43.

Norup M (1997) Attitudes towards abortion in the Danish population. Bioethics 11: 439–449.

Phillips OP, Elias S, Shulman LP et al. (1992) Maternal serum screening for fetal Down syndrome in women less than 35 years of age using alpha‐fetoprotein, hCG, and unconjugated estriol: a prospective 2‐year study. Obstetrics and Gynecology 80: 353–358.

Piggott M, Wilkinson P and Bennett J (1994) Implementation of an antenatal serum screening programme for Down's syndrome in two districts (Brighton and Eastbourne). The Brighton and Eastbourne Down's Syndrome Screening Group. Journal of Medical Screening 1: 45–49.

Reynolds TM (1998) Antenatal screening for Down's syndrome. Lancet 352: 1145.

Reynolds TM (2000) Down's syndrome screening: a controversial test, with more controversy to come! Journal of Clinical Pathology 53: 893–898.

Reynolds TM, John R and Spencer K (1993a) Utility of unconjugated estriol in screening for Down syndrome is not proven. Clinical Chemistry 39: 2023–2026.

Reynolds TM, Nix AB, Dunstan FD and Dawson AJ (1993b) Age‐specific detection and false‐positive rates: an aid to counseling in Down syndrome risk screening. Obstetrics and Gynecology 81: 447–450.

Reynolds TM and Penney MD (1990) The mathematical basis of multivariate risk screening: with special reference to screening for Down's syndrome associated pregnancy. Annals of Clinical Biochemistry 27(5): 452–458.

Ryall RG, Staples AJ, Robertson EF and Pollard AC (1992) Improved performance in a prenatal screening programme for Down's syndrome incorporating serum‐free hCG subunit analyses. Prenatal Diagnosis 12: 251–261.

Santalahti P, Hemminki E, Latikka AM and Ryynanen M (1998) Women's decision‐making in prenatal screening. Social Science and Medicine 46: 1067–1076.

Snijders RJ, Noble P, Sebire N, Souka A and Nicolaides KH (1998) UK multicentre project on assessment of risk of trisomy 21 by maternal age and fetal nuchal‐translucency thickness at 10–14 weeks of gestation. Fetal Medicine Foundation First Trimester Screening Group. Lancet 352: 343–346.

Spencer K (2001) Age related detection and false positive rates when screening for Down's syndrome in the first trimester using fetal nuchal translucency and maternal serum free beta hCG and PAPP‐A. British Journal of Obstetrics and Gynaecology 108: 1043–1046.

Spencer K and Carpenter P (1993) Prospective study of prenatal screening for Down's syndrome with free beta human chorionic gonadotropin. British Medical Journal 307: 764–769.

Spencer K, Coombes EJ, Mallard AS and Ward AM (1992) Free beta human choriogonadotropin in Down's syndrome screening: a multicentre study of its role compared with other biochemical markers. Annals of Clinical Biochemistry 29(5): 506–518.

Spencer K, Souter V, Tul N, Snijders R and Nicolaides KH (1999) A screening program for trisomy 21 at 10–14 weeks using fetal nuchal translucency, maternal serum free beta‐human chorionic gonadotropin and pregnancy‐associated plasma protein‐A. Ultrasound in Obstetrics and Gynecology 13: 231–237.

Stone S, Henley R, Reynolds T and John R (1993) A comparison of total and free beta‐HCG assays in Down syndrome screening. Prenatal Diagnosis 13: 535–537.

Stuck J, Faine J and Boldt A (2001) The perceptions of Lutheran pastors toward prenatal genetic counseling and pastoral care. Journal of Genetic Counseling 10: 251–263.

Suchy SF and Yeager MT (1990) Down syndrome screening in women under 35 with maternal serum hCG. Obstetrics and Gynecology 76: 20–24.

Tonks A, Hodgkiss S and Gardosis J (2006) 3‐stage contingency screening for Down's syndrome: reults of the Stafford Pilot. NHS Perinatal Institute. http://www.perinatal.org.uk/screening/resources/Stafford_3C_Pilot_Report.pdf

Verloes A, Schoos R, Herens C, Vintens A and Koulischer L (1995) A prenatal trisomy 21 screening program using alpha‐fetoprotein, human chorionic gonadotropin, and free estriol assays on maternal dried blood. American Journal of Obstetrics and Gynecology 172: 167–174.

Verma L, Macdonald F, Leedham P et al. (1998) Rapid and simple prenatal DNA diagnosis of Down's syndrome. Lancet 352: 9–12.

Wald N, Densem J, Stone R and Cheng R (1993) The use of free beta‐hCG in antenatal screening for Down's syndrome. British Journal of Obstetrics and Gynaecology 100: 550–557.

Wald NJ, Cuckle HS, Densem JW et al. (1988) Maternal serum screening for Down's syndrome in early pregnancy. British Medical Journal 297: 883–887.

Wald NJ, Kennard A, Densem JW et al. (1992) Antenatal maternal serum screening for Down's syndrome: results of a demonstration project. British Medical Journal 305: 391–394.

Wald NJ, Rodeck C, Hackshaw AK et al. (2003) First and second trimester antenatal screening for Down's syndrome: the results of the serum, urine and ultrasound screening study (SURUSS). Health Technology Assessment 7(11): 1–77.

Walknowska J, Conte FA and Grumbach MM (1969) Practical and theoretical implications of fetal–maternal lymphocyte transfer. Lancet 1: 1119–1122.

Wenstrom KD, Williamson RA, Grant SS, Hudson JD and Getchell JP (1993) Evaluation of multiple‐marker screening for Down syndrome in a statewide population. American Journal of Obstetrics and Gynecology 169: 793–797.

Further Reading

Boston S (1994b) Too Deep for Tears: Eighteen Years After the Death of Will, My Son. London: Rivers Oram Press. ISBN 978–0044408918.

Glad J (2006) Future Human Evolution: Eugenics in the Twenty‐First Century. Schuylkill Haven, PA: Hermitage Books. ISBN 978–1557791542.

Grudzinskas JG, Chard T, Chapman M and Cuckle H (eds) (1994) Screening for Down's Syndrome. Cambridge: Cambridge University Press. ISBN 0–521–45271‐6.

Grudzinskas JG and Ward RHT (eds) (1997) Screening for Down Syndrome in the First Trimester. London: RCOG Press. ISBN 0–902331‐98‐1.

Kerr A and Shakespeare T (1988) Genetic Politics: From Eugenics to Genome. Cheltenham: New Clarion Press.

Lo YM (2000) Fetal DNA in maternal plasma: biology and diagnostic applications. Clinical Chemistry 46: 1903–1906.

Mackellar C and Bechtel C (eds) (2014) The Ethics of the New Eugenics. Oxford: Berghahn Books. ISBN 978‐1‐78238‐120‐4.

Reynolds T (2009) The ethics of antenatal screening: lessons from cnut. Clinical Biochemist Reviews 30: 187–196.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Reynolds, Tim M(Aug 2014) Down Syndrome: Antenatal Screening Mathematics, Ethics and Its Implementation in the UK. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005635.pub3]