Ethical issues in lab and diagnostic testing

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SPECIAL ISSUE PAPERS

PRENATAL SCREENING: CURRENT PRACTICE, NEW DEVELOPMENTS, ETHICAL CHALLENGES

ANTINA DE JONG, IDIT MAYA AND JAN M.M. VAN LITH

Keywords prenatal screening, NIPT, ethical issues, informed consent, reproductive autonomy

ABSTRACT Prenatal screening pathways, as nowadays offered in most Western coun- tries consist of similar tests. First, a risk-assessment test for major aneuploides is offered to pregnant women. In case of an increased risk, invasive diagnostic tests, entailing a miscarriage risk, are offered. For decades, only conventional karyotyping was used for final diagnosis. Moreover, several foetal ultrasound scans are offered to detect major congenital anomalies, but the same scans also provide relevant information for optimal support of the pregnancy and the delivery.

Recent developments in prenatal screening include the application of microarrays that allow for identifying a much broader range of abnomalities than karyotyping, and non-invasive prenatal testing (NIPT) that enables reducing the number of invasive tests for aneuploidies considerably. In the future, broad NIPT may become possible and affordable.

This article will briefly address the ethical issues raised by these tech- nological developments. First, a safe NIPT may lead to routinisation and as such challenge the central issue of informed consent and the aim of pre- natal screening: to offer opportunity for autonomous reproductive choice. Widening the scope of prenatal screening also raises the question to what extent ‘reproductive autonomy’ is meant to expand. Finally, if the same test is used for two different aims, namely detection of foetal anomalies and pregnancy-related problems, non-directive counselling can no longer be taken as a standard. Our broad outline of the ethical issues is meant as an introduction into the more detailed ethical discussions about prenatal screening in the other articles of this special issue.

INTRODUCTION

Most developed countries have some form of prenatal screening for Down’s syndrome and other major foetal anomalies. This article gives a general overview of current practice in developed countries, looks at future scenarios and charts the main ethical challenges. As such, it serves as an introduction to the other articles in this special issue that will address in more depth various ethical questions regarding current and future prenatal testing scenarios. The contributions reflect the oral presentations and discussions at a conference on ‘Individualised choice: a

new approach to reproductive autonomy in prenatal screening?’, held at the Brocher Foundation, Switzerland, on 6–7 April 2013.

In this article screening is defined as the systematic offer by health professionals of a medical investigation to the population, or to specific population groups, address- ing persons who themselves have no health problems or a family history that would give them an indication for being tested. The core notion of the concept is that screening is an offer on the initiative of the health system or society, rather than a medical intervention in answer to a patient’s complaint or health problem.

Address for correspondence: Mrs Antina de Jong, Maastricht University – Health, Ethics &Society, PO Box 616 6200 MD Maastricht, Netherlands. Email: antina.dejong@planet.nl Conflict of interest statement: No conflicts declared

Bioethics ISSN 0269-9702 (print); 1467-8519 (online) doi:10.1111/bioe.12123 Volume 29 Number 1 2015 pp 1–8

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Screening aims at obtaining population health gains through early detection that enables prevention or treat- ment. Examples include prenatal screening for infectious diseases or routine foetal rhesus typing. These tests are offered with the aim of contributing to a healthy outcome of the pregnancy for mother and child. But prenatal screening is also offered for finding foetal abnormalities such as Down’s syndrome, the detection of which does not allow for any options other than a choice between continuing or terminating the pregnancy. How could this be in line with the general prevention paradigm of screen- ing: aiming at population health gains? One might of course say that the aim is ‘to reduce the birth prevalence of the disorder (. . .) by identifying (. . ..) couples who can have prenatal diagnosis and selective termination of preg- nancy.’1 However, this interpretation is generally regarded as morally problematic, as it would seem to favour the use of abortion as a means of reducing the number of people with specific disorders, handicaps or

other medical needs. This has led to the general view that prenatal screening for foetal abnormalities should be regarded as serving the aim of providing pregnant women and their partners with options for reproductive choice.2

CURRENT PRACTICE: THE PRENATAL SCREENING PATHWAY

In many Western countries such as the United Kingdom and the Netherlands, well-organised routine foetal anomaly screening programmes with clear guidelines exist (Figure 1). These are issued by national screening committees.3 These programmes include both forms of

1 J. Murray et al. Screening for Cystic Fibrosis. Health Technol Assess 1999; 3: i–104.

2 Health Council of the Netherlands. Screening Between Hope and Hype. The Hague: Health Council of the Netherlands, 2008. 3 http://fetalanomaly.screening.nhs.uk/; http://www.rivm.nl/Documen ten_en_publicaties/Professioneel_Praktisch/Draaiboeken/Preventie _Ziekte_Zorg/Draaiboek_prenatale_screening_downsyndroom_en _Structureel_Echoscopisch_Onderzoek. 4 This information was originally developed by the UK National Screening Committee/NHS Screening Programmes (www.screening .nhs.uk) and is used under the Open Government Licence v1.0.

Figure 1. Routine prenatal screening pathway used in the UK.4

Antina de Jong, Idit Maya and Jan M.M. van Lith2

prenatal screening identified in the introduction. It starts at the first prenatal appointment, although for high risk groups preconception counselling would be ideal. It is supported by a health professional educational pro- gramme, patient information, and regular audits of all aspects of the programme. Underpinning the programme is the notion that women and their families should under- stand the purpose of all tests before they participate in testing.

The first prenatal visit

At the first visit, either preconceptionally or prenatally, the midwife will take a history of the prospective parents to determine if there is any significant family, past obstet- ric or medical history that indicates that the pregnancy might be at increased risk. Further management of high risk pregnancies will not be discussed further here, because these have specific testing routes.

At this first appointment, several routine blood tests are taken to measure maternal haemoglobin levels, screen for potential haemoglobinopathy carriers (if results indi- cate these may be present, further blood tests are done to confirm status), perform routine virology to confirm immunological status regarding rubella immunity, syphi- lis and HIV, and to screen for red cell antibodies, and confirm Rhesus D status (RhD). In pregnancy, RhD− mothers with a RhD+ baby can develop antibodies to D+ blood if the foetus’ blood cells enter the mother’s blood stream. In a future pregnancy with a D+ foetus, these antibodies can transfer to the foetus and destroy red blood cells causing anaemia, jaundice and potentially postnatal death (haemolytic disease of the newborn). To prevent this, RhD− mothers are given anti-D immuno- globulin at 28 weeks of gestation.

At this same first visit, the midwife will discuss screen- ing for Down’s syndrome which is optimally done in the first trimester. Following the explanation of the purpose of this test, the woman is asked to opt in or out of this testing.

Down’s syndrome screening (DSS)

The next step in the prenatal pathway is screening for Down’s syndrome (DS). In many developed countries this is offered to all women in the first or early second trimester. It is done by using a combination of risk factors including maternal age, maternal serum biomarkers and ultrasound markers5 to determine a pregnancy specific risk of the foetus having DS. The exact format of DSS varies depending on national and local facilities and

policy. In many countries a combination of maternal age, serum markers (PAPP_A and beta-HCG) and nuchal translucency (NT) (the thickness of the fluid filled area at the back of the foetal neck) is used to determine a preg- nancy specific risk on Down syndrome. If the risk is estimated to be above a certain cut-off level (e.g. ≥1:150 or 1:200) the mother is offered an invasive test (chorionic villus sampling or amniocentesis) for definitive diagnosis. Both invasive tests carry a small risk of miscarriage that is generally estimated to be of around 0.5–1%.6 Using this policy, the combined test identifies approximately 85% of DS affected pregnancies for a 3% false positive rate.

Notably, NIPT for DS is increasingly being offered as a second-tier screening test to those woman who are found to be at increased risk for DS. If the NIPT-result is positive, invasive testing is offered.7

In addition to screening for DS there are other sug- gested ‘benefits’ of screening for DS. The screening requires an ultrasound scan to accurately date the preg- nancy and at this scan major structural abnormalities may be detected, for example anencephaly, anterior abdominal wall defects and major limb anomalies.8 Fur- thermore, multiple pregnancies may be detected. The DSS further allows for screening for the other major trisomies, trisomy 13 and 18. An increased NT (≥3.5mm) in the combined test is associated with an increased risk of a major heart anomaly and a variety of other structural abnormalities such as diaphragmatic hernia as well as genetic syndromes.9 If the karyotype is normal, it is usual practice to refer women with an increased NT for a detailed cardiac scan and also for a detailed foetal anomaly scan at 20 weeks of gestation.10 If these scans are both normal, the risk of other adverse findings is reduced but still remains higher than in the general population11

and parents can find the anxiety caused significant.12

5 K.H. Nicolaides. Screening for Fetal Aneuploidies at 11 to 13 weeks. Prenat Diagn 2011; 31: 7–15.

6 A. Tabor & Z. Alfirevic. Update on Procedure-Related Risks for Prenatal Diagnosis Techniques. Fetal Diagn Ther 2010; 27: 1–7. A recent estimation, based on a systematic review of literature and meta- analysis, suggests that this procedure-related risk of miscarriage follow- ing amniocentesis and CVS is much lower than currently quoted: R. Akolekar et al. Procedure-related risk of miscarriage following amnio- centesis and chorionic villus sampling: a systematic review and meta- analysis. Ultrasound Obstetr Gynecol 2014. DOI: 10.1002/uog.14636. 7 American College of Obstetricians and Gynecologists Committee on

Genetics (ACOG). Committee Opinion No. 545: Noninvasive prenatal testing for fetal aneuploidy. Obstet Gynecol 2012; 120: 1532–1534. 8 A. Syngelaki et al. Challenges in the Diagnosis of Fetal Non-

Chromosomal Abnormalities at 11–13 Weeks. Prenat Diagn 2011; 31: 90–102.

9 C.M. Bilardo et al. Increased Nuchal Translucency in Euploid Fetuses–What Should we be Telling the Parents? Prenat Diagn 2010; 30: 93–102. 10 Practices slightly differ between countries. For example, in Israel an earlier ultrasound scan is offered in case of an increased NT. 11 Bilardo op.cit. note 9. 12 J. Fisher. First-trimester Screening: Dealing with the Fall-Out. Prenat Diagn 2011; 31: 46–49.

Prenatal Screening: Current Practice, New Developments, Ethical Challenges 3

Varying combinations of the serum markers used for DSS may also be used to predict other adverse pregnancy outcomes such as intrauterine growth retardation (IUGR) and pre-eclampsia,13 although this is still under debate. For women with abnormal maternal biomarkers suggestive of IUGR, serial scanning for growth is often undertaken.

Invasive follow-up testing

Following invasive testing performed by CVS or amnio- centesis, respectively the chorionic villi and amniocytes are analysed. It is common practice to first perform rapid aneuploidy exclusion using a molecular technique, either quantitative fluorescent polymerase chain reaction (qfPCR) or fluorescent in-situ hybridisation (FISH), which will detect the major trisomies (13, 18 and 21) and Turners syndrome (45XO). Results are issued in 1–3 working days. Full karyotyping is then performed follow- ing culturing of the cells. This takes 10–14 days and involves microscopic examination of cells and can detect other chromosomal rearrangements, many of which confer high risk of adverse outcome. However, this approach will not detect very small (submicroscopic) changes, known as copy number variations (CNVs), some of which can confer high risk of serious develop- mental problems and are now known to account for around 10–25% of the underlying pathology in children with previously undiagnosed learning and developmental disability.14 Recent technical developments have allowed for the use of microarray- technology as an alternative for conventional karyotyping (see below).

Routine foetal anomaly scanning

The final point in the prenatal screening pathway is the foetal anomaly scan. In most countries this is performed between 18 and 21 weeks of gestation. The focus is gen- erally on the detection of major foetal anomalies that require treatment early in the postnatal period and so may require special arrangements to be made for deliv- ery. Anomalies indicating serious handicaps also lead, if local policy permits, to discussion on the possible termi- nation of pregnancy.15 For the majority of families a routine scan gives reassurance that the baby shows no abnormalities, but it must be remembered that still 2–4%

of the babies are born with a structural abnormality. Most of these cases occur in low risk families; they account for around 30% of perinatal deaths and are a major cause of perinatal morbidity.16 Detection rates for different abnormalities vary, but reasonable target rates for detection of common major abnormalities by ultra- sound performed by trained sonographers working to a set protocol are given in Table 1. Sonograpic detection of foetal anomalies gives parents options, including the opportunity to discuss the prognosis with relevant paedi- atric specialists, allows organisation of the timing and place of delivery, and facilitates prompt and appropriate postnatal treatment where required. In some situations there may also be the opportunity for prenatal treatment, for example the medical treatment of foetal cardiac arrhythmias,17 or in-utero surgical intervention for foe- tuses with diaphragmatic hernia or spina bifida.18 Whilst the majority of women gain significant reassurance from anomaly scanning, the detection of minor anomalies or those associated with an uncertain prognosis, e.g. mild ventriculomegaly, can cause significant parental anxiety and concerns which can last well beyond the prenatal period. Women need to be advised before scanning that a major abnormality may be detected, but that they also need to be aware that not all abnormalities are detected at the time of the routine scan for a number of reasons. Apart from being a screening test for foetal anomalies, the routine scan at around 20 weeks also provides infor- mation (e.g. on the growth of the foetus and the amount of amnion fluid) that is important for optimal support of the pregnancy and the delivery. Moreover, pregnant

13 R. van Ravenswaaij et al. First-trimester Serum PAPP-A and fβ-hCG Concentrations and other Maternal Characteristics to Estab- lish Logistic Regression-Based Predictive Rules for Adverse Pregnancy Outcome. Prenat Diagn 2011; 31: 50–57. 14 E. Lisenka et al. Genomic microarrays in mental retardation: from copy number variation to gene, from research to diagnosis. J Med Genet 2010; 47: 289–297. 15 S.H. Eik-Nes. The 18-week Fetal Examination and Detection of Anomalies. Prenat Diagn 2010; 30: 624–630.

16 T.-H. Bui & V. Meiner. State of the art in prenatal diagnosis. In: Leuzinger-Bohleber M et al., editors. The Janus Face of Prenatal Diag- nostics. A European Study Bridging Ethics, Psycholanalysis, and Medi- cine. London: Karnac Books, 2008. p. 61–86. 17 L. Hui & D.W. Bianchi. Prenatal Pharmacotherapy for Fetal Anomalies: a 2011 Update. Prenat Diagn 2011; 31: 735–743. 18 J. Jani et al. Tracheal Diameter at Birth in Severe Congenital Dia- phragmatic Hernia Treated by Fetal Endoscopic Tracheal Occlusion. Prenat Diagn 2011; 31: 699–704. M.W. Bebbington et al. Open Fetal Surgery for Myelomeningocele. Prenat Diagn 2011; 31: 689–694.

Table 1. Detection rates for routine foetal anomaly screening programmes

Anomaly Detection rate

Anencephaly 98% Open spina bifida 90% Cleft lip 75% Diaphragmatic hernia 60% Gastroschisis 98% Exomphalos 80% Serious cardiac anomaly 50% Bilateral renal agenesis 84% Lethal skeletal dysplasia 60%

Antina de Jong, Idit Maya and Jan M.M. van Lith4

women (or couples) tend to see the scan as a first oppor- tunity to see their future child.

NEW DEVELOPMENTS

Prenatal microarrays

The positive experience using microarrays in postnatal testing and the fact that several research studies have shown their usefulness in prenatal testing, has contrib- uted to their introduction in prenatal testing cascades. Particularly in foetuses with increased nuchal translu- cency or structural abnormalities, pathogenic CNVs can be detected in up to 6% of cases with a normal karyo- type.19 This has led to many services offering microarrays for prenatal diagnosis, particularly in foetuses with sonographic abnormalities, but some centres also after a positive DSS-test. Microarrays have a place in prenatal diagnosis, although its exact application is still under debate.20 Recently, the American College of Obstetrics and Gynecologists (ACOG) stated that chromosomal microarray should be recommended in any invasive pre- natal test done due to ultrasound abnormalities, and should be considered as a possible alternative to foetal karyotype in every other invasive test, regardless of indi- cation (including DSS-test, advanced maternal age, or pure maternal anxiety).21

A microarray screens all the chromosomes in one test and can detect many very small variants that cannot be detected by traditional karyotyping looking at chromo- somes down the microscope. Data generated by an array can be compared with data on many thousands of vari- ants held in international, anonymised databases. Conse- quently, the clinical significance of many, but not all, changes can be assessed. All individuals carry many of these ‘sub-microscopic’ changes, most of which are not clinically significant and can be inherited from a (healthy) parent. In some cases it will be necessary to test parental chromosomes to determine whether a change is inherited and potentially benign.

There are several types of microarrays.22 Some are tar- geted, e.g. bacterial artificial chromosomes (BAC) arrays,

and will only detect abnormalities in specific areas of the chromosome. These are advantageous in that they can be designed to cover those areas known to include the severe microdeletion and duplication syndromes23 and that the interpretation of results is more straightforward. Others, oligonucleotide array comparative genomic hybridisation platforms and single nucleotide polymor- phism (SNP) arrays, can either be designed to target these areas or can be used to cover the whole genome. In whole genome arrays the detection is optimised but there is a risk of increased detection of variants of unknown significance (VOUS), which can result in difficulty in interpretation and counselling. The potential for detecting a wider range of abnormalities, as well as the variants of unknown sig- nificance, raises significant ethical issues in the prenatal setting and highlights the need for expert pre- and post-test counselling.24 Because such a large number of potential findings are possible with any type of whole genome arrays (regardless of technology), databases are used to deter- mine if specific copy number variants have been previously reported and whether they are considered pathogenic, benign or of unknown clinical significance.

Prenatal use of cell free foetal DNA in maternal plasma: testing for foetal Rhesus typing and aneuploidies

Current practice (as described above) means that the 40% of mothers carrying a RhD- foetus receive anti-D unnec- essarily. In the UK this equates to around 15,000 women a year who are exposed to a human blood product unnec- essarily (anti-D is generated by injecting RhD-women with D- antibodies) and, as anti-D is expensive, it also results in significant costs to the health service.

Cell-free foetal DNA (cffDNA) was identified in the maternal circulation in 1997.25 It is present in the mater- nal circulation from four weeks of gestation, but it only represents a small fraction of total circulating DNA, the majority being maternal in origin.26 The proportion of cffDNA increases with gestation but is cleared from the circulation within an hour or two of delivery.27 This means the cffDNA is pregnancy-specific and can there- fore be used for genetic diagnosis in the foetus. Testing

19 J.L. Callaway. The Clinical Utility of Microarray Technologies applied to Prenatal Cytogenetics in the Presence of a Normal Conven- tional Karyotype: a Review of the Literature. Prenat Diagn 2013; 33: 1–5; S.C. Hillman. Use of Prenatal Chromosomal Microarray: Prospec- tive Cohort Study and Systematic Review and Meta-Analysis. Ultra- sound Obstet Gynecol 2013; 41: 610–620. 20 J.A. Crolla, R. Wapner & J.M. van Lith. Controversies in Prenatal Diagnosis 3: Should Everyone Undergoing Invasive Testing have a Microarray? Prenat Diagn 2013. DOI: 10.1002/pd.4287. 21 The American College of Obstetricians and Gynecologists Commit- tee on Genetics & The Society for Maternal-Fetal Medicine. Committee Opinion No. 581. The use of chromosomal microarray analysis in pre- natal diagnosis. Obstet Gynecol 2013; 122: 1374–1377. 22 P.D. Brady & J.R. Vermeesch. Genomic Microarrays: a Technology Overview. Prenat Diagn 2012; 32: 336–343.

23 A. Weise et al. Microdeletion and Microduplication Syndromes. J Histochem Cytochem 2012; 60: 346–358. 24 G. McGillivray et al. Genetic Counselling and Ethical Issues with Chromosome Microarray Analysis in Prenatal Testing. Prenat Diagn 2012; 32: 389–395. 25 Y.M. Lo et al. Presence of fetal DNA in maternal plasma and serum. Lancet 1997; 350: 485–487. 26 F.M.F. Lun et al. Microfluidics Digital PCR Reveals a Higher than Expected Fraction of Fetal DNA in Maternal Plasma. Clin Chem 2008; 54: 1664–1672. 27 Y.M.D. Zhang et al. Rapid Clearance of Fetal DNA from Maternal Plasma. Am J Hum Genet 1999; 64: 218–224.

Prenatal Screening: Current Practice, New Developments, Ethical Challenges 5

this cffDNA in the blood of RhD-women can determine the foetal RhD type. This has proven to be very accurate at various gestational ages and is now used routinely to type the foetal RhD status in RhD- mothers. Only those mothers found to be carrying a RhD+ foetus are then offered anti-D immunoprophylaxis.28 This allows for savings in anti-D administration and prevents unneces- sary exposure to a human blood product.

A major advance in foetal chromosome testing has been the development of non-invasive prenatal testing (NIPT) for aneuploidy based on analysis of cell free foetal DNA in maternal plasma. As described above, cffDNA is present in the maternal circulation from early in pregnancy. However, the high background level of maternal chromosome 21 cfDNA in maternal plasma29

makes NIPT for DS and other aneuploidies more chal- lenging than the testing described above for foetal Rhesus status, because the latter searches the presence or absence of an allele not present in the mother. For aneuploidy diagnosis, detection of the relatively small changes in the level of individual chromosome-specific fragments in maternal plasma indicating that the foetus has aneuploidy, must be very accurately quantified. Several large-scale validation studies using next generation sequencing have now been conducted, mostly in higher- risk populations. Overall these report detection rates for DS of more than 99% with a false positive rate of 0.1– 1%.30 If these results are confirmed in large-scale studies in low-risk populations, NIPT will be regarded as a much better alternative than present DSS-tests (combined test, quadruple test).31 The great advantage of NIPT over those tests is the large decrease in the need for invasive follow-up testing, entailing an equivalent reduction of iatrogenic pregnancy losses.32 Recent studies have already shown that NIPT may be a highly effective screening method for risk assessment of foetal trisomies 21, 18, and 13 in general pregnant populations as well.33

NIPT can also detect other aneuploidies including trisomy 18, trisomy 13 and sex chromosome abnormali- ties.34 However, there is a consistently reported false posi- tive rate and false negative rates have been mentioned as well.35 This is a reflection of the fact that cffDNA is shed from the placenta,36 and that when screening for aneuploidy it is the total cfDNA that is analysed, not just the foetal component. Thus, discrepant results have been reported as a result of cell lines arising in the placenta (confined placental mosaicism):37 detection of maternal chromosomal rearrangements38 and even maternal tumours secreting an abnormal chromosome compliment are mentioned.39

Whereas in the past NIPT has been projected as a possible one-step aneuploidy test after which confirma- tion by invasive testing of a positive result would no longer be needed, this is not yet where we are now. At present, NIPT for aneuploidy is considered as an advanced screening test and most authorities recommend invasive testing for confirmation of positive results.40

A negative NIPT result does not necessarily mean that there is no chromosomal abnormality present. We

28 F.B. Clausen. Report of the First nationally Implemented Clinical Routine Screening for Fetal RHD in D- pregnant Women to Ascertain the Requirement for Antenatal RhD Prophylaxis. Transfusion 2012; 52: 752–758. 29 Lun, op.cit. note 26. 30 E.M. Boon & B.H. Faas. Benefits and limitations of whole genome versus targeted approaches for non-invasive prenatal testing for fetal aneuploidies. Prenat Diagn 2013; 33: 563–568. 31 D.W. Bianchi et al. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med 2014; 370: 799–808. 32 D.W. Bianchi, D. Oepkes & A. Ghidini. Current Controversies in Prenatal Diagnosis 1: Should Noninvasive DNA Testing be the Stand- ard Screening Test for Down Syndrome in All Pregnant Women? Prenat Diagn 2013; 3: 1–6. 33 G. Fairbrother et al. Clinical experience of noninvasive prenatal testing with cell-free DNA for fetal trisomies 21, 18, and 13, in a general screening population. Prenat Diagn 2013; 33: 580–583; M.M. Gil et al. Analysis of Cell-Free DNA in Maternal Blood in Screening for Aneuploidies: Meta-Analysis. Fetal Diagn Ther 2014; DOI: 10.1002/ uog.12504.

34 T. Futch et al. Initial Clinical Laboratory Experience in Non- invasive Prenatal Testing for Fetal Aneuploidy from maternal Plasma DNA Samples. Prenat Diagn 2013; 33: 569–574; D. Liang et al. Non- invasive Prenatal Testing of Fetal Whole Chromosome Aneuploidy by Massively Parallel Sequencing. Prenat Diagn 2013; 33: 409–415; G.E. Palomaki et al. DNA Sequencing of Maternal Plasma to detect Down Syndrome: An International Clinical Validation Study. Genet Med 2011; 13: 913–20; M.E. Norton et al. Non-Invasive Chromosomal Evaluation (NICE) Study: Results of a Multicenter Prospective Cohort Study for Detection of Fetal Trisomy 21 and Trisomy 18. Am J Obstet Gynecol 2012; 207: 137.e1–137.e8; D.W. Bianchi & L. Wilkins-Haug. Integration of noninvasive DNA testing for aneuploidy into prenatal care: what has happened since the rubber met the road? Clin Chem 2014; 60: 78–87. 35 R.E. Reiss & A.M. Cherry. AJOG 2013; 209: 160–161; M.T. Mennuti et al. AJOG 2013; 209: 415–419; Y. Wang et al. Prenat Diagn 2013; 33: 1207–1230. 36 M. Alberry et al. Free Fetal DNA in Maternal Plasma in Anembryonic Pregnancies: Confirmation that the Origin is the Tropho- blast. Prenat Diagn 2007; 27: 415–418. 37 T.K. Lau et al. Secondary Findings from Non-Invasive Prenatal Testing for Common Fetal Aneuploidies by Whole Genome Sequencing as a Clinical Service. Prenat Diagn 2013; 33: 602–608; M. Pan et al. Discordant Results between Fetal Karyotyping and Non-Invasive Pre- natal Testing by Maternal Plasma Sequencing in a Case of Uniparental Disomy 21 due to Trisomic Rescue. Prenat Diagn 2013; 33: 598–601. 38 Lau, op.cit. note 37. 39 C.M. Osborne et al. Discordant Non-Invasive Prenatal Testing Results in a Patient Subsequently Diagnosed with Metastatic Disease. Prenat Diagn 2013; 33: 609–611. 40 ACOG, op.cit. note 7; P.A. Benn et al. Prenatal Detection of Down Syndrome using Massively parallel Sequencing (MPS): a Rapid Response Statement from a Committee on behalf of the Board of the International Society for Prenatal Diagnosis. Prenat Diagn 2012; 32: 1–2; S. Langlois & J.A. Brock. Genetics Committee. Current Status in Non-Invasive Prenatal Detection of Down Syndrome, Trisomy 18 and Trisomy 13 using Cell-Free DNA in Maternal Plasma. J Obstet Gynaecol Can 2013; 35: 177–181.

Antina de Jong, Idit Maya and Jan M.M. van Lith6

already mentioned that there is a small false-negative rate associated with NIPT,41 and that at present NIPT gener- ally screens for the major trisomies. This is consistent with the scope of current combined testing, but it differs from invasive testing because NIPT does not detect other chromosomal rearrangements or micro-deletion syn- dromes which might be detected by karyotyping or microarray analysis as described above.

NIPT for a wider range of chromosomal abnormalities may become possible as detection of other chromosomal rearrangements using next generation sequencing has been reported. The scope of this so-called “second gen- eration NIPT” will range from whole-chromosome to subchromosome abnormalities.42 The depth of sequenc- ing required is significantly higher than for standard NIPT, making the cost of testing currently too high for routine use.43 However, research efforts have recently concentrated on finding ways to make this feasible in a routine clinical setting.44 In proof of principle studies it has been demonstrated that using cffDNA in maternal plasma, the whole genome of the foetus can be sequenced and made available for analysis.45 In a still further-away scenario, this means that it will become possible to use maternal blood for testing the foetus for any mutations, risk factors, or other variants that its genome may contain.

ETHICAL ISSUES

Benefits and challenges of NIPT as a better DSS-test

The better test characteristics of NIPT as a screening test for Down’s syndrome is also an important benefit in view of what is generally regarded as the aim of prenatal screening for foetal abnormalities, namely to facilitate reproductive choice for pregnant women (and their part- ners). Women who decline prenatal screening with the present DSS-tests because they do not want to expose

their pregnancy to a miscarriage risk to avoid what in 9 out of 10 cases will be a false alarm, may find screening with NIPT more acceptable. This means that more women or couples can benefit from the reproductive options that the screening intends to provide. Moreover, the higher sensitivity of NIPT means that less women or couples will be falsely reassured by the message that they will not have a child with Down’s syndrome. Finally, counselling can be more straightfoward, without the need to explain the complexity of risk-assessment. Together these features mean that with NIPT, DSS-screening can be safer and can better achieve its aim. Costs permitting, this means there is a strong ethical case for replacing current DSS-tests with NIPT.

However, the flipside of these same benefits is what has been referred to as the risk of ‘routinisation’,46

meaning that the greater ease and safety of NIPT may lead to it being regarded by both pregnant women and professionals as a harmless blood test that one need not think long about. Routinisation may thus lead to an erosion of informed decision-making.47 A connected concern is that there will be subtle pressure from healthcare providers and social environments to accept the screening offer, leading to women feeling the need to justify their non-participation or fearing that they will be held responsible if they turn out to have a child with a condition or handicap that ‘could have been prevented’.48

Furthermore, when considering NIPT it is important to note that health professionals and women place differ- ent values on different aspects of testing, with women valuing safety most highly, whilst health professionals value accuracy.49 These factors mean that careful consid- eration must be given as to how to implement NIPT in the public sector so that the needs of women or couples are met whilst ensuring the fundamental principle of maintenance of informed decision-making.50

41 Cf ops.cit. note 35; Boon, Faas, op.cit. note 30; J.M.E. Walsh & J.D. Goldberg. Fetal Aneuploidy Detection by Maternal Plasma DNA Sequencing: a Technology Assessment. Prenat Diagn, 2013; 33: 514– 520. 42 Bianchi, Wilkins-Haug, op.cit. note 34. 43 S. Chen et al. A Method for Non-Invasive Detection of Fetal Large Deletions/Duplications by Low Coverage massively Parallel Sequenc- ing. Prenat Diagn 2013; 33: 584–590; A. Srinivasan et al. Non-Invasive Detection of Fetal Sub-Chromosome Abnormalities via Deep Sequenc- ing of Maternal Plasma. Am J Hum Genet 2013; 92: 167–176. 44 Bianchi, Wilkins-Haug, op.cit. note 34. 45 J.O. Kitzman et al. Noninvasive Whole-Genome Sequencing of a Human Foetus. Science Transl Med 2012; 4: 137ra76; Y.M. Lo et al. Maternal Plasma DNA Sequencing Reveals the Genome-Wide Genetic and Mutational Profile of the Foetus. Science Transl Med 2010; 2: 61ra91.

46 C. Lewis, C. Silcock & L.S. Chitty. Non-Invasive Prenatal Testing for Down’s Syndrome: Pregnant Women’s Views and Likely Uptake. Public Health Genomics 2013; 16: 223–232. 47 Ibid; A. van den Heuvel et al. Will the Introduction of Non-Invasive Prenatal Diagnostic Testing erode Informed Choices? An Experimental Study of Health Care Professionals. Patient Educ Couns 2010; 78: 24–28. 48 R. van Schendel. Attitudes of pregnant women and male partners towards non-invasive prenatal testing and widening the scope of prena- tal screening. Eur J Hum Genet 2014; DOI: 10.1038/ejhg.2014.32. 49 M. Hill et al. Women’s and Health Professionals’ Preferences for Prenatal Tests for Down Syndrome: a Discrete Choice Experiment to Contrast Noninvasive Prenatal Diagnosis with Current Invasive Tests. Genet Med 2012; 14: 905–913. 50 M.A. Allyse et al. Best Ethical Practices for Clinicians and Labora- tories in the Provision of Noninvasive Prenatal Testing. Prenat Diagn 2013; 33: 656–661; H. Skirton & C. Patch. Factors Affecting the Clinical Use of Non-Invasive Prenatal Testing: a Mixed Methods Systematic Review. Prenat Diagn 2013; 33: 532–541.

Prenatal Screening: Current Practice, New Developments, Ethical Challenges 7

Widening scope of prenatal screening for foetal abnormalities

As the above overview has shown, there is a tendency to widen the scope of testing in the context of prenatal screening for foetal abnormalities. At present, this is most visible in the use of broad-scope microarrays as a follow-up after abnormal ultrasound findings or an abnormal DSS-test. As the scope of prenatal microarray testing is often (much) wider than the outcome of the preceding scan or screening test would require it to be, this practice can (to that extent) be regarded as a de facto form of additional genomic screening, although it is not presented or justified as such.51

As soon as NIPT can be affordably and reliably used for screening beyond the major trisomies, a further wid- ening can be expected. A conceivable first step may be NIPT for all chromosomal abnormalities that at present can be seen with karyotyping, including the relatively mild sex chromosome abnormalities. It is striking that the normative framework for prenatal screening, with its emphasis on ‘reproductive choice’ does not provide much guidance when it comes to determining what the scope of a responsible screening offer would be. Without qualifi- cation, the classical formulation of the aim of prenatal screening in terms of ‘providing reproductive choice’ may end up making reproductive choice an end in itself, apart from any connection with the realm of reproductive health risks that would be needed to justify a publicly or collectively funded screening programme. Moreover, it is at least not obvious that widening the scope of testing will lead to providing pregnant women or couples with more meaningful reproductive choices. Findings of unclear sig- nificance and information overload may lead to under- mining rather than promoting such choices. Together, these considerations call for the development of addi- tional ethical guidance.

Same test for different aims

A third issue that arises from the above overview is that the same prenatal tests, including NIPT, can be used for screening with different aims. If used in screening for anomalies such as foetal Down’s syndrome, the aim would be reproductive choice. Whereas if the same test is used in prenatal screening for pregnancy-related

conditions, such as foetal RhD-status, the aim is to con- tribute to a healthy outcome of the pregnancy. What makes this convergence challenging from an ethical point of view is that those different aims are ideally reflected in distinct counselling styles. With regard to prenatal screening for foetal abnormalities, there is consensus that, ideally, counselling should be non-directive. However, with regard to testing that may benefit the health of the future child and of the pregnant woman, things are different. In that case, professionals may well insist that women who have decided to carry the preg- nancy to term, have a moral responsibility (within limits of proportionality) to protect the future child from avoid- able harm. The classical ethics of non-directive counsel- ling is not without qualification applicable in that context. In order to avoid confusing moral messages, it seems important to keep the information and counselling for these two forms of prenatal screening apart as far as possible. This picture of overlapping aims will become even more complex with the further development of forms of foetal therapy, meaning that after detection of certain foetal abnormalities, in utero treatment may be a third option next to continuing or terminating the preg- nancy.52 The ethics of parental (maternal) and profes- sional responsibility with regard to such choices is still to be worked out.

Antina de Jong, PhD, LLM, is an ethicist and lawyer. She works as a legal advisor at the Education Council of the Netherlands. In 2013, she completed her PhD-thesis ‘Prenatal screening à la carte? Ethical reflec- tion on the scope of testing for foetal anomalies’ at the Maastricht University. Formerly, she was a legislative and policy advisor at the Netherlands Council of State and at the Dutch Data Protection Author- ity. The main areas of her work relate to healthcare, privacy and education.

Idit Maya, MD, is a medical doctor specialising in Internal Medicine and Medical Genetics at (respectively) the Hasharon Hospital and the Rabin Medical Center, Peta Tikva. She is also Senior Geneticist CMA (Chromosomal Micro Array Analysis) in the laboratory at Recanati Genetic Institute, Rabin Medical Center. She is also head of the Genomic programme for physiscians, Recanati Genetic Institute, and Sackler Faculty of Medicine, Tel Aviv University; all in Israel.

Jan van Lith, MD, PhD, is professor and chairman of Obstetrics and Fetal Medicine at the Leiden University Medical Centre (LUMC) and president of the International Society for Prenatal Diagnosis and Therapy (ISPD). He has been actively involved in the development and organisation of prenatal diagnosis and screening in the Netherlands since the early 1990s. His PhD was on first trimester Down’s syndrome screening (1993).

51 A. de Jong et al. Microarrays as a Diagnostic Tool in Prenatal Screening Strategies: Ethical Reflection. Hum Genet 2014; 133: 163–172.

52 D.W. Bianchi. From prenatal genomic diagnosis to fetal personal- ized medicine: progress and challenges. Nat Med 2012; 18: 1041–1051.

Antina de Jong, Idit Maya and Jan M.M. van Lith8

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