Chromosome Screening Using Noninvasive Prenatal Testing Beyond Trisomy-21: What to Screen for and Why It Matters

Chromosome Screening Using Noninvasive Prenatal Testing Beyond Trisomy-21: What to Screen for and... Abstract With the new and highly accurate noninvasive prenatal test (NIPT), new options for screening become available. I contend that the current state of the art of NIPT is already in need of a thorough ethical investigation and that there are different points to consider before any chromosomal or subchromosomal condition is added to the screening panel of a publicly funded screening program. Moreover, the application of certain ethical principles makes the inclusion of some conditions unethical in a privately funded scheme, even if such screening would enhance a woman’s reproductive autonomy. On the one hand, a screening program aimed solely at the detection of Down syndrome is subject to the technological imperative and should be reassessed in the light of technologies that allow for the detection of conditions that are at least as severe. On the other hand, some chromosomal conditions should not be included in any screening programs, because this would violate certain ethical principles, such as the right of the future child to genetic privacy. aneuploidy, chromosomes, Noninvasive Prenatal Testing, prenatal testing, sex chromosome aneuploidies I. INTRODUCTION: TECHNIQUES AND ETHICS Noninvasive Prenatal Testing (NIPT) is a method to detect certain monogenic diseases as well as chromosomal conditions in the fetus relatively early in pregnancy. NIPT has gained some attention in the ethics literature (de Jong et al., 2011). In this paper, I look at the different chromosomal abnormalities that, in principle, can be detected with state-of-the-art technology used for NIPT and assess the rationale behind the screening as offered in a public health care setting. I focus specifically on those that have not gained much attention in existing ethical literature: the subchromosomal abnormalities and sex chromosome abnormalities (SCAs). I suggest that there is a need for a reassessment of the different conditions resulting from chromosomal abnormalities, both on the genomic level as well as on the subchromosomal level. I will also argue that the ease with which NIPT can be performed early in pregnancy and the use of microarrays, which allows for a more comprehensive chromosomal screening and which makes the use of ever higher resolutions tempting, shows the need to make explicit screening rationales and reasons for inclusion of certain conditions in a public-health-care-supported screening. Also, I argue that certain ethical principles call for the exclusion of screening for certain conditions. Specifically, different chromosomal abnormalities and their phenotype should be assessed separately to decide whether they should be included in a publicly funded screening program, and whether it is ethical to screen for them in any circumstances. NIPT was developed after the detection of cell-free DNA from the fetus in the blood stream of the pregnant woman. NIPT can be used in two contexts. As a diagnostic tool, non-invasive prenatal diagnosis (NIPD) can be used to detect certain monogenic conditions that are known to be inherited, such as achondroplasia or thanatophoric dysplasia and to prevent hemolytic disease in fetuses when the pregnant woman is rhesus negative and she is carrying a rhesus positive fetus (Daley, Hill, and Chitty, 2014). This is done as early as nine weeks in specialized centers. In many countries today, NIPT is being introduced as a screening tool to detect common aneuploidies, albeit primarily driven by the commercial sector, and to eventually replace invasive techniques such as chorionic villae sampling or amniocentesis (Daley, Hill, and Chitty, 2014). At present, this is usually done around the 10th to 12th week of pregnancy, because at this point the percentage of fetal DNA in the blood is high enough to provide an accurate result. In this paper, I shall exclusively deal with the latter implementation of NIPT. NIPT for aneuploidy screening has certain advantages over traditional techniques that involve invasive sampling of the DNA of the placenta or chorion villae. The latter sampling is usually done after a positive first-trimester screening; such screening often consists of a combination test including ultrasound, biological testing of certain markers in the pregnant woman’s serum and statistics based on the woman’s age (Saller and Canick, 2008). The drawback of these invasive techniques is that they could induce a miscarriage of a fetus without chromosomal abnormalities. It is easy to see the advantages of NIPT: Its accuracy has been quoted as being around 99 percent, hence, surpassing the first-trimester combination test. Because it can be performed relatively early in pregnancy, it has been suggested that the impact of a pregnancy termination for the woman may be less than when a pregnancy is terminated later. Some have also suggested that early termination is ethically less problematic because the moral status of the embryo/fetus is relatively low at the start and increases with further stages of development (de Jong et al., 2011; de Jong, Maya, and van Lith, 2015). Moreover, because the procedure involves just a simple blood test without the risk of a miscarriage, prospective parents choosing to undergo aneuploidy screening do not have to make the difficult tradeoff between the risk of inducing a miscarriage and the knowledge of whether or not their fetus has a chromosomal abnormality (Wright and Chitty, 2009; Hill et al., 2012). Although testing for aneuploidies has traditionally been highly associated with the decision to terminate a pregnancy, the possibility to perform a screening test to know early on that the future child has trisomy-21 (Down syndrome) in order to prepare for life with a child with certain disabilities becomes more realistic. It has even been suggested that early detection of Down syndrome in pregnancy could enable early therapeutic interventions, leading to improvement of neurological function (Guedj and Bianchi, 2013). NIPT to detect aneuploidies is still a screening tool; a positive result of the NIPT screening will have to be confirmed by an invasive test. Therefore, in this paper, I use the acronym NIPT for chromosome screening rather than NIPD (Noninvasive Prenatal Diagnosis), which for the moment should be reserved for techniques to diagnose certain monogenic disorders, because these techniques do not require a subsequent invasive test. Offering NIPT at the same time as the combination test may be the solution yielding the most autonomous choice to most women. In this case, the combination test will still be executed to detect other abnormalities, and NIPT would detect aneuploidies (Deans and Newson, 2012). However, concerns about cost effectiveness may result in the possibility that policy makers decide that NIPT is to be adopted by the public health care system as a second-line test, after the pregnancy has been demonstrated to be high risk through the first-trimester combination test (Hulstaert, Neyt, and Gyselaers, 2014). II. CHROMOSOMAL ABNORMALITIES: WHAT THEY MEAN AND WHY IT MATTERS The technologies currently used to analyze cell-free DNA can detect the trisomies 21, 18, and 13, as well as aneuploidies of the sex chromosomes such as monosomy of X (Turner syndrome) trisomy of X (XXX) or XYY or XXY (Klinefelter syndrome). Some can also detect certain submicroscopic chromosomal abnormalities such as large deletions or insertions in the genome, albeit with some restrictions (Buysse et al., 2014; Chitty et al., 2014; de Jong, Maya, and van Lith, 2015). In the future, it is to be expected that resolutions will become higher and that also smaller deletions, insertions, and even point mutations can be detected. This is an entirely different context from NIPD as a diagnostic tool for pregnancies where there is a known risk and where there is a known mutation found in the prospective parents. In this paper, I shall focus on the abnormalities that are already detectable and demonstrate that the advent of NIPT urges one to rethink the rationale for screening. These possibilities will also have impact on thinking about invasive prenatal screening and preimplantation aneuploidy screening. Indeed, the possibility that NIPT is introduced earlier on in pregnancy and with relatively few burdens on the woman or her fetus demonstrates the urgency of the need to rethink screening of the chromosomes, but it is not the only context for which this discussion is relevant. Trisomy-21 is probably the first chromosomal condition for which NIPT will be deployed in a public health care setting. Indeed, for those countries who wish to deploy it as a second-line test, after the pregnancy has been acknowledged as “high risk” through a combination test, it may initially be the only condition screened for. The use of NIPT for Down syndrome screening has been widely discussed in the ethics literature. Trisomy-21 is an interesting case in that it was the first chromosomal abnormality identified and it has a long history in the context of prenatal screening. Many current policy documents will stress that the rationale behind trisomy-21 screening is to offer pregnant women the autonomous choice to decide whether they want to raise a child with a disability or not. This emphasis on personal choice aims to answer the criticism that such screening is deployed and funded in order to avoid the birth of handicapped children (Dondorp and van Lith, 2015; Wilkinson, 2015). Authors have wondered whether such a “pure choice model” is ever enough to warrant a publicly funded screening program, because surely many other opportunities for offering autonomous choice could be thought of that are not funded, such as sex selection, a technical possibility today (Wilkinson, 2015). Hence, this autonomous choice is always in relation to the possibility of having, in this case, a child with Down syndrome. However, from its inception, welfare considerations, calculations of the lifetime surplus cost of a Down child, and the idea of preventing disability have been part of the decision to implement screening for the condition. This suggests that offering autonomous choice may be the rationale by which genetic counselors should operate in offering advice to pregnant women, but it is not the only reason why screening for a given condition is implemented in the first place (Munthe, 1996; Munthe, 2015). Such calculations have also been done in the context of NIPT for trisomy-21 (Ohno and Caughey, 2013; Song, Musci, and Caughey, 2013). Also, the choice for Down as the primary object of screening cannot be defended with arguments related to the well-being of persons with Down syndrome or their caretakers alone. Such defense would imply that those who hold this opinion are able to demonstrate that the quality of life of persons with Down syndrome or their caretakers is below a certain threshold of acceptable well-being. Unless the threshold is set quite high, this claim cannot be substantiated. Empirical studies have shown that people with Down syndrome are often capable of happiness and experience substantial well-being, as do their parents and siblings (Skotko and Levine, 2006; Skotko, Levine, and Goldstein, 2011a, 2011b, 2011c). Ethicists and disability-rights philosophers have wondered whether the relative ease with which the NIPT test can be administered and the lack of risk for miscarriage may, through routinization of the practice, erode informed decision making and increase the number of terminations of viable fetuses, such as those with trisomy-21 (Benn and Chapman, 2009; Schmitz, Netzer, and Henn, 2009). Vardit Ravitsky (2009) has argued that this does not have to be the case automatically: Proper counseling of couples, including the opportunity for prospective parents to discuss with parents of children with Down syndrome, will allow for NIPT to be presented as a screening tool to allow prospective parents to prepare themselves for a life with a child with certain disabilities, as well as to decide whether to continue a pregnancy or not. The NIPT test for Down syndrome may serve the principle of reproductive autonomy even more than before, because choosing to undergo an invasive test to determine whether the fetus will have a disability already implied the risk that the woman will miscarry because of the procedure. As such, NIPT opens up another possibility, namely, knowing about the disability and continuing the pregnancy. Trisomy-13 and trisomy-18 can in principle be detected by all platforms deployed for NIPT, although specificity and sensitivity is lower than for trisomy-21. These aneuploidies are associated with a severe phenotype, and the vast majority of such pregnancies will be spontaneously aborted. Babies born with these conditions are severely disabled and will almost certainly die within the first year. Provided that one is not against pregnancy termination per se, screening and termination of such pregnancies may not seem to be associated with ethical issues. However, it has been argued by Verweij et al. (2014), in the context of the low predictive value of NIPT for trisomy-13, that screening for diseases that are lethal in the fetal or early neonatal period may do more harm than good because it is at the expense of serious concerns. Hence, policy makers will have to decide based on current data about specificity and sensitivity of the NIPT test whether including these trisomies in the test is desirable. The fact that microarrays, rather than karyotyping, can be used with NIPT offers challenges and opportunities. Although the official aim of Down syndrome screening was to give future parents autonomous choice, this autonomous choice was limited by the technology that would allow genetic counselors only to discover an extra chromosome. When screening becomes more comprehensive, this poses certain challenges, but also provides the opportunity to reassess screening rationale. In a recent paper, Christian Munthe (2015) states that the possibility of including many conditions in the screening test may seem to support a radical individualization of how prenatal screening is organized. Indeed, as I shall argue, if a public health system aims to give prospective parents the opportunity to choose for themselves whether they are up to raising a child with disabilities, in principle they should endorse screening for conditions that some may consider at least as severe as trisomy-21. However, offering a real choice also presupposes that society offers enough support for those who wish to proceed with such pregnancies. This decision would call for, as Munthe argues, a drastic downscaling of prenatal testing to target a much more narrowly selected range of severe conditions, while at the same time freeing up resources for support of those living with the conditions. For Munthe, these considerations apply to state-funded schemes. I will argue in the rest of this paper that screening for some chromosomal conditions may violate ethical principles as well, and would therefore make problematic the claim that private screening for a wider range of conditions is acceptable if people wish to have more reproductive options (Munthe, 2015). I will demonstrate the need for the reassessment of screening rationales with two examples that are already technically feasible: submicroscopic abnormalities and the SCAs. Submicroscopic Abnormalities Some platforms used for NIPT can also detect submicroscopic chromosomal abnormalities, typically deletions or duplications of a portion of chromosomal DNA. Variations in copy number are thought to be responsible for most human variation, but such deletions and insertions are also associated with some conditions that are considered to be severe disabilities, often with associated with intellectual disabilities (Menten et al., 2006). However, the predictive value of screening for such syndromes is low, because they are rare and because they have a variable phenotype. Therefore, screening for them early in pregnancy may, just as with trisomy-13 and trisomy-18, cause anxiety, and it may not be in the interest of the pregnant women that these chromosomal abnormalities are included in a publicly funded screening panel, specifically with regard to conditions that have a mild or highly variable phenotype. Some of these conditions, however, are more readily associated with a distinct phenotype. In the context of the incidental findings of copy number variations (CNV) after invasive prenatal diagnosis, it has been argued that only certain CNVs will be reported that have sufficient clinical relevance and enough penetrance, with the 22q11 deletion as an example (Brady et al., 2014). This deletion is linked with DiGeorge syndrome (velo-cardio-facial syndrome), which is characterized by cleft lip/cleft palate, cardiac insufficiency, and psychological problems. Many patients will suffer from schizophrenia. Preimplantation Genetic Diagnosis has been performed for 22q11 deletion, and the syndrome is detectible through some platforms used for NIPT (Emanuel et al., 2001). This begs the question whether 22q11 should be part of routine NIPT screening, provided it is technically feasible and readily implementable. It is informative to make a comparison with the widely accepted screening for Down. In the case of 22q11 deletion, can we really say whether this condition is actually less severe than Down syndrome? It is true that trisomy-21 leads to a highly recognizable “congenital” phenotype, but still this phenotype is variable as well and not de facto related to lesser wellbeing. We could make the opposite reasoning: If it is decided that certain CNVs are not screened for due to issues related to prevalence or variability of the phenotype, how can we then warrant the widely accepted screening for Down syndrome? It may be defended that trisomy-21 screening has been available and possible for decades, regardless of the progress that has been made with regard to treatment and management of the syndrome. However, if this is the case, one should admit that the endorsement of this type of screening is technology-driven (and hence subject to the so-called technological imperative), rather than related to procreative choice or to intrinsic quality of life. Indeed, why offer a choice here and not for any other possible chromosomal conditions with comparable severity? The problem with a technology-driven screening program in the prenatal context is that it must answer the criticism of disability-rights philosophers who state that the offering of such tests already assumes a negative attitude toward the condition and the people having the condition (Davis, 2010). This is especially so if screening programs target one specific condition and neglect others that may be at least as severe (Munthe, 2015). NIPT, due to its noninvasiveness, may offer a unique possibility here that was not so readily available with invasive screening. Because the test can be done fairly easily, without risk to the fetus, the possibility of offering the test to prepare for living with a child with certain challenges gives prominence equal to the possibility for termination. This is true for all conditions that are congenital with sufficient penetrance. Prenatal counseling and preparation should be adequate and should include discussion with parents of children with the condition. Gynecologists and counselors administering the test should be trained to offer both options (preparation/termination) as equally valid. On the one hand, a test honestly aimed at enhancing a pregnant woman’s reproductive autonomy should therefore offer screening for trisomy-21 and other congenital conditions linked with subchromosomal abnormalities, provided that the positive predictive value is high enough, and include pretest and posttest counseling that offers a balanced view of all the options, including the opportunity to speak with representatives of patients or parents’ organizations. On the other hand, a public screening program specifically targeted at detecting Down syndrome, even when other conditions that are at least as severe can be easily detected, is subject to the disability critique and should reassess its screening rationales. In the previous paragraph, I have argued that, when more comprehensive screening techniques are available, limiting publicly funded screening to only trisomy-21 while not screening for conditions that may be equally or more severe is undesirable. In the next paragraph, I will argue that screening for some other conditions, whether privately or publicly funded, violates ethical principles. I shall use the example of SCAs to prove my point. Sex Chromosome Abnormalities Most current technologies will also allow for the detection of abnormal numbers of sex chromosomes, the so-called SCAs. In the context of NIPT, but also in the context of Invasive Prenatal Screening and Preimplantation Genetic Screening, policy makers shall have to decide whether to screen for and/or to communicate such findings. SCA’s are an excellent example of the fact that the current idea that abnormalities on the level of the genome (in this case, having an extra chromosome) need not necessarily be considered detrimental and worse than subchromosomal or genetic abnormalities. I shall focus on Klinefelter syndrome (XXY or XXXY) and XYY syndrome, the former because of its link with infertility and the latter because of its link with hyperactivity and autism. In Klinefelter’s syndrome, males have one or more extra chromosomes. It is a good example of how descriptions of conditions based on diagnostic findings may be biased. Indeed, the classic Klinefelter phenotype is a male with hypogonadism, female features, long stature, and fewer IQ points than average. However, Klinefelter has also been diagnosed in men visiting fertility centers due to infertility problems, but without additional problems (Lanfranco et al., 2004; Visootsak and Graham, 2006). Indeed, there are potentially many more men with an extra X chromosome who have a normal phenotype. In fact, it seems that reduced fertility is the only factor that is a constant. So should such a condition be screened for and, if found, be communicated to the pregnant woman? Such communication could lead to the following consequences: either the pregnancy is terminated, or the pregnancy is continued, resulting in the fact that the child will be known to have an extra X chromosome at birth. The first option, termination, could be defended on the principle of procreative autonomy: A pregnant woman should be allowed to decide for herself whether to continue a pregnancy of a Klinefelter male. However, autonomous choice presumes having enough information on which to base this decision. The only constant in Klinefelter is the infertility. Is infertility as a constant a good enough reason to terminate? Or is the possibility to terminate for infertility enough reason to include sex chromosome aneuploidies in a state endorsed and funded screening program? With regard to the second option, to include it for informational purposes, there is still no consensus about whether presymptomatic detection of Klinefelter has any therapeutic benefits (Herlihy et al., 2010; Herlihy et al., 2011). Moreover, the one thing that will be known about the fetus that is prenatally diagnosed with Klinefelter is that he will almost certainly be infertile. I contend that the knowledge of one’s own infertility, as it is only applicable to adulthood, is a condition that is invisible, private, and thus it is up to the individual to decide whether to know this or to communicate this to others, including to parents. In their 2015 paper, Deans et al. contend that NIPT should not be used for adult-onset diseases, carrier status, or nonserious threats. They quote the risk for objectivation of children: they state that curiosity with regard to children’s genetic endowments may be incompatible with being a virtuous parent, because it is testimony to a certain objectivation of children. Therefore, including genetic differences that are not related to serious diseases in a screening program is ethically unacceptable (Deans, Clarke, and Newson, 2015). Given that infertility is the only constant in Klinefelter, I claim that the prenatal diagnosis of Klinefelter for informational purposes entails a violation of the future child’s chromosomal and reproductive privacy and that there is insufficient knowledge to weigh potential advantages and disadvantages of this knowledge. At the point of the screening, it is not known how the relation between the parent(s) and their future son will develop, and whether he would feel comfortable discussing his infertility with his parents. Moreover, how knowledge of one’s son’s infertility influences the relation between parents and their son is also unknown. Therefore, I conclude that the right to privacy of the future child is more important than the prospective parents’ right to know the genetic or chromosomal makeup of their fetus for informational purposes or, for that matter, for the avoidance of a diagnostic odyssey that may happen if the child does have symptoms. This is a variant of a child’s right to genetic privacy, grounded in a child’s right not to know (or have others know) his or her genetic (and chromosomal) makeup (Davis, 2010; Hens, 2013; Cutas and Hens, 2015). An objection to my claim would be that the right to genetic privacy applies to the future child and not to the fetus in utero. At this point, the reproductive autonomy of the future mother and her right to decide whether or not to continue the pregnancy based on knowledge of the chromosomal makeup of her child may trump rights of future children that may or may not come into existence. One could argue that the right to decide whether or not to bring a male fetus with an extra X chromosome to term is more important than the rights of potential children. I state that reproductive autonomy is limited by considerations about rights and well-beings of children, when born. The only way in which the reproductive rights of the prospective parent(s) and potential children in this case will be safeguarded is to disallow screening for Klinefelter for informational purposes, and only allow it if it can be safeguarded that the prospective parent(s) will want to terminate the pregnancy upon discovery of a chromosomal condition because there then will be no future child. As I have argued earlier in this paper, state funding of a screening program whose primary aim is the termination of a pregnancy with an only constant risk that the future child will be infertile seems unwarranted because infertility is not a severe congenital condition. Moreover, including a clause in the consent form before the screening that would force a woman to terminate a pregnancy upon the discovery of chromosomal conditions violates her right to change her mind in the light of her growing relationship with the child she carries, which is an equally important aspect of reproductive autonomy, and is in my view draconian in the light of the consent form’s primary aim: to safeguard the unborn fetus’s future right of genetic and chromosomal privacy. Therefore, although I admit that this challenges the extent of the right to reproductive autonomy, I conclude that in the case of mild chromosomal and genetic abnormalities, the right to genetic and chromosomal privacy trumps the right of prospective parents to decide whether or not to carry to term a child with such conditions. Hence, I argue that screening for Klinefelter syndrome prenatally should not be in a state funded screening program because it violates ethical principles. Arguments based on the right to chromosomal privacy and the uncertainty of therapeutic benefits also apply to XYY syndrome. This syndrome has historically been wrongly associated with an increased level of criminality. There seems to be, however, an increased risk for hyperactivity, and in some cases it is linked with autism (Bauer et al., 1980; Tartaglia et al., 2012; Margari et al., 2014). This case is interesting because on a societal level the question whether and to what extent neurological differences such as Attention Deficit Hyperactivity Disorder or Autism Spectrum Disorder are actually diseases or conditions rather than variants of normal behavior is still ongoing. Some proponents of the neurodiversity movement claim that it is the lack of support that exists in society for neurodiverse individuals that makes neurological difference a disability; otherwise, it would not be a medical disability (Baron-Cohen, 2000; Glannon, 2007). The question whether the public health system should endorse screening (and potential termination) for a condition that may (or may not) lead to a condition that may very well be a social disability rather than a medical one is still unresolved. In case of termination, the fact that this chromosomal condition may very well lead to a normal phenotype without problems makes inclusion of screening for XYY in a publicly funded screening program undesirable. As with screening for informational purposes, arguments similar to those for infertility apply: By analogy with recommendations regarding the presymptomatic genetic screening of minors, this information, because it is not immediately actionable, belongs to the future child’s right to chromosomal privacy (Bauer et al., 1980; Hens, 2013). Indeed, besides the right of a child not to know certain genetic information about himself, it is uncertain whether knowing that a child is at risk of developing a neurological difference influences how parents perceive and behave toward their child (Marchant and Robert, 2008; Jordan and Fu Chang Tsai, 2010). In the light of these uncertainties, screening for XYY prenatally should not be part of a publicly funded state program and violates ethical principles. III. CONCLUSION The advent of chromosomal screening in the context of NIPT raises many ethical questions that are not completely different from those raised in the context of invasive prenatal screening. However, the fact that this can be done early in pregnancy through a noninvasive process makes the question of what to screen for more pertinent. This reflection hopes to have shed some light on how prenatal screening programs should be assessed. This assessment is necessary for all chromosomal and subchromosomal conditions that are considered to be included in the screening, in order to avoid the criticism that the screening is subject to the technological imperative and nothing more. First, the (sub)chromosomal condition that is considered should be assessed for its positive predictive value. Unless this is high enough, including it in the screening may cause unnecessary anxiety for the pregnant women and does nothing to increase reproductive choice. (Sub)chromosomal conditions that are sufficiently associated with a congenital disability should be included in a publicly funded screening, because such screening should not be solely aimed at detecting trisomy-21. Also, such screening should not have as a main objective the prevention of the birth of children with certain challenges. The possibility for NIPT to be used as a way to prepare for, and in the future also to improve, the outcomes of a child with challenges should be given equal importance to the possibility of terminating a pregnancy, and women and their partners should be given adequate information about the prospects of a given condition in order to respect their reproductive autonomy as much as possible. Third, reproductive autonomy and the parental right to know should always be balanced against the question of whether the condition is congenital or potentially variable in phenotype. The case of sex chromosome aneuploidies, which in many cases does not lead to congenital problems and may be symptomless, demonstrates that in some cases the ideal of NIPT as a way to prepare for the birth of a child with certain characteristics, or to satisfy the parental right to know, or even curiosity, is not adequate and violates certain ethical principles. Testing for SCAs with NIPT to allow termination of such pregnancies should not be state funded because these do not qualify as severe diseases and hence do not warrant public health care spending. Testing for SCAs for informational purposes may violate the right of the future child to chromosomal privacy. The possibility for NIPT analysis to be accessed through direct-to-consumer testing (after all, it is only a blood sample) complicates this matter even further. I have argued that a state funded NIPT screening scheme should de facto rule out screening for extra X or Y chromosomes, and such screening contravenes ethical principles such as the right of the child to genetic privacy. Therefore, I conclude that, provided at least equal weight is given to the possibility to use this information to prepare for children with certain challenges, screening for trisomy-21 and certain submicroscopic chromosomal conditions strongly associated with severe phenotypes can be defended and that for the sex chromosome aneuploidies it cannot. ACKNOWLEDGMENTS This paper is based on a presentation I gave at the colloquium “Disability Detection and Fetal Decision-Making through Non-Invasive Prenatal Testing (NIPT),” organized by the Centre for Bionetworking of the University of Sussex in Brighton. 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Chromosome Screening Using Noninvasive Prenatal Testing Beyond Trisomy-21: What to Screen for and Why It Matters

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Abstract

Abstract With the new and highly accurate noninvasive prenatal test (NIPT), new options for screening become available. I contend that the current state of the art of NIPT is already in need of a thorough ethical investigation and that there are different points to consider before any chromosomal or subchromosomal condition is added to the screening panel of a publicly funded screening program. Moreover, the application of certain ethical principles makes the inclusion of some conditions unethical in a privately funded scheme, even if such screening would enhance a woman’s reproductive autonomy. On the one hand, a screening program aimed solely at the detection of Down syndrome is subject to the technological imperative and should be reassessed in the light of technologies that allow for the detection of conditions that are at least as severe. On the other hand, some chromosomal conditions should not be included in any screening programs, because this would violate certain ethical principles, such as the right of the future child to genetic privacy. aneuploidy, chromosomes, Noninvasive Prenatal Testing, prenatal testing, sex chromosome aneuploidies I. INTRODUCTION: TECHNIQUES AND ETHICS Noninvasive Prenatal Testing (NIPT) is a method to detect certain monogenic diseases as well as chromosomal conditions in the fetus relatively early in pregnancy. NIPT has gained some attention in the ethics literature (de Jong et al., 2011). In this paper, I look at the different chromosomal abnormalities that, in principle, can be detected with state-of-the-art technology used for NIPT and assess the rationale behind the screening as offered in a public health care setting. I focus specifically on those that have not gained much attention in existing ethical literature: the subchromosomal abnormalities and sex chromosome abnormalities (SCAs). I suggest that there is a need for a reassessment of the different conditions resulting from chromosomal abnormalities, both on the genomic level as well as on the subchromosomal level. I will also argue that the ease with which NIPT can be performed early in pregnancy and the use of microarrays, which allows for a more comprehensive chromosomal screening and which makes the use of ever higher resolutions tempting, shows the need to make explicit screening rationales and reasons for inclusion of certain conditions in a public-health-care-supported screening. Also, I argue that certain ethical principles call for the exclusion of screening for certain conditions. Specifically, different chromosomal abnormalities and their phenotype should be assessed separately to decide whether they should be included in a publicly funded screening program, and whether it is ethical to screen for them in any circumstances. NIPT was developed after the detection of cell-free DNA from the fetus in the blood stream of the pregnant woman. NIPT can be used in two contexts. As a diagnostic tool, non-invasive prenatal diagnosis (NIPD) can be used to detect certain monogenic conditions that are known to be inherited, such as achondroplasia or thanatophoric dysplasia and to prevent hemolytic disease in fetuses when the pregnant woman is rhesus negative and she is carrying a rhesus positive fetus (Daley, Hill, and Chitty, 2014). This is done as early as nine weeks in specialized centers. In many countries today, NIPT is being introduced as a screening tool to detect common aneuploidies, albeit primarily driven by the commercial sector, and to eventually replace invasive techniques such as chorionic villae sampling or amniocentesis (Daley, Hill, and Chitty, 2014). At present, this is usually done around the 10th to 12th week of pregnancy, because at this point the percentage of fetal DNA in the blood is high enough to provide an accurate result. In this paper, I shall exclusively deal with the latter implementation of NIPT. NIPT for aneuploidy screening has certain advantages over traditional techniques that involve invasive sampling of the DNA of the placenta or chorion villae. The latter sampling is usually done after a positive first-trimester screening; such screening often consists of a combination test including ultrasound, biological testing of certain markers in the pregnant woman’s serum and statistics based on the woman’s age (Saller and Canick, 2008). The drawback of these invasive techniques is that they could induce a miscarriage of a fetus without chromosomal abnormalities. It is easy to see the advantages of NIPT: Its accuracy has been quoted as being around 99 percent, hence, surpassing the first-trimester combination test. Because it can be performed relatively early in pregnancy, it has been suggested that the impact of a pregnancy termination for the woman may be less than when a pregnancy is terminated later. Some have also suggested that early termination is ethically less problematic because the moral status of the embryo/fetus is relatively low at the start and increases with further stages of development (de Jong et al., 2011; de Jong, Maya, and van Lith, 2015). Moreover, because the procedure involves just a simple blood test without the risk of a miscarriage, prospective parents choosing to undergo aneuploidy screening do not have to make the difficult tradeoff between the risk of inducing a miscarriage and the knowledge of whether or not their fetus has a chromosomal abnormality (Wright and Chitty, 2009; Hill et al., 2012). Although testing for aneuploidies has traditionally been highly associated with the decision to terminate a pregnancy, the possibility to perform a screening test to know early on that the future child has trisomy-21 (Down syndrome) in order to prepare for life with a child with certain disabilities becomes more realistic. It has even been suggested that early detection of Down syndrome in pregnancy could enable early therapeutic interventions, leading to improvement of neurological function (Guedj and Bianchi, 2013). NIPT to detect aneuploidies is still a screening tool; a positive result of the NIPT screening will have to be confirmed by an invasive test. Therefore, in this paper, I use the acronym NIPT for chromosome screening rather than NIPD (Noninvasive Prenatal Diagnosis), which for the moment should be reserved for techniques to diagnose certain monogenic disorders, because these techniques do not require a subsequent invasive test. Offering NIPT at the same time as the combination test may be the solution yielding the most autonomous choice to most women. In this case, the combination test will still be executed to detect other abnormalities, and NIPT would detect aneuploidies (Deans and Newson, 2012). However, concerns about cost effectiveness may result in the possibility that policy makers decide that NIPT is to be adopted by the public health care system as a second-line test, after the pregnancy has been demonstrated to be high risk through the first-trimester combination test (Hulstaert, Neyt, and Gyselaers, 2014). II. CHROMOSOMAL ABNORMALITIES: WHAT THEY MEAN AND WHY IT MATTERS The technologies currently used to analyze cell-free DNA can detect the trisomies 21, 18, and 13, as well as aneuploidies of the sex chromosomes such as monosomy of X (Turner syndrome) trisomy of X (XXX) or XYY or XXY (Klinefelter syndrome). Some can also detect certain submicroscopic chromosomal abnormalities such as large deletions or insertions in the genome, albeit with some restrictions (Buysse et al., 2014; Chitty et al., 2014; de Jong, Maya, and van Lith, 2015). In the future, it is to be expected that resolutions will become higher and that also smaller deletions, insertions, and even point mutations can be detected. This is an entirely different context from NIPD as a diagnostic tool for pregnancies where there is a known risk and where there is a known mutation found in the prospective parents. In this paper, I shall focus on the abnormalities that are already detectable and demonstrate that the advent of NIPT urges one to rethink the rationale for screening. These possibilities will also have impact on thinking about invasive prenatal screening and preimplantation aneuploidy screening. Indeed, the possibility that NIPT is introduced earlier on in pregnancy and with relatively few burdens on the woman or her fetus demonstrates the urgency of the need to rethink screening of the chromosomes, but it is not the only context for which this discussion is relevant. Trisomy-21 is probably the first chromosomal condition for which NIPT will be deployed in a public health care setting. Indeed, for those countries who wish to deploy it as a second-line test, after the pregnancy has been acknowledged as “high risk” through a combination test, it may initially be the only condition screened for. The use of NIPT for Down syndrome screening has been widely discussed in the ethics literature. Trisomy-21 is an interesting case in that it was the first chromosomal abnormality identified and it has a long history in the context of prenatal screening. Many current policy documents will stress that the rationale behind trisomy-21 screening is to offer pregnant women the autonomous choice to decide whether they want to raise a child with a disability or not. This emphasis on personal choice aims to answer the criticism that such screening is deployed and funded in order to avoid the birth of handicapped children (Dondorp and van Lith, 2015; Wilkinson, 2015). Authors have wondered whether such a “pure choice model” is ever enough to warrant a publicly funded screening program, because surely many other opportunities for offering autonomous choice could be thought of that are not funded, such as sex selection, a technical possibility today (Wilkinson, 2015). Hence, this autonomous choice is always in relation to the possibility of having, in this case, a child with Down syndrome. However, from its inception, welfare considerations, calculations of the lifetime surplus cost of a Down child, and the idea of preventing disability have been part of the decision to implement screening for the condition. This suggests that offering autonomous choice may be the rationale by which genetic counselors should operate in offering advice to pregnant women, but it is not the only reason why screening for a given condition is implemented in the first place (Munthe, 1996; Munthe, 2015). Such calculations have also been done in the context of NIPT for trisomy-21 (Ohno and Caughey, 2013; Song, Musci, and Caughey, 2013). Also, the choice for Down as the primary object of screening cannot be defended with arguments related to the well-being of persons with Down syndrome or their caretakers alone. Such defense would imply that those who hold this opinion are able to demonstrate that the quality of life of persons with Down syndrome or their caretakers is below a certain threshold of acceptable well-being. Unless the threshold is set quite high, this claim cannot be substantiated. Empirical studies have shown that people with Down syndrome are often capable of happiness and experience substantial well-being, as do their parents and siblings (Skotko and Levine, 2006; Skotko, Levine, and Goldstein, 2011a, 2011b, 2011c). Ethicists and disability-rights philosophers have wondered whether the relative ease with which the NIPT test can be administered and the lack of risk for miscarriage may, through routinization of the practice, erode informed decision making and increase the number of terminations of viable fetuses, such as those with trisomy-21 (Benn and Chapman, 2009; Schmitz, Netzer, and Henn, 2009). Vardit Ravitsky (2009) has argued that this does not have to be the case automatically: Proper counseling of couples, including the opportunity for prospective parents to discuss with parents of children with Down syndrome, will allow for NIPT to be presented as a screening tool to allow prospective parents to prepare themselves for a life with a child with certain disabilities, as well as to decide whether to continue a pregnancy or not. The NIPT test for Down syndrome may serve the principle of reproductive autonomy even more than before, because choosing to undergo an invasive test to determine whether the fetus will have a disability already implied the risk that the woman will miscarry because of the procedure. As such, NIPT opens up another possibility, namely, knowing about the disability and continuing the pregnancy. Trisomy-13 and trisomy-18 can in principle be detected by all platforms deployed for NIPT, although specificity and sensitivity is lower than for trisomy-21. These aneuploidies are associated with a severe phenotype, and the vast majority of such pregnancies will be spontaneously aborted. Babies born with these conditions are severely disabled and will almost certainly die within the first year. Provided that one is not against pregnancy termination per se, screening and termination of such pregnancies may not seem to be associated with ethical issues. However, it has been argued by Verweij et al. (2014), in the context of the low predictive value of NIPT for trisomy-13, that screening for diseases that are lethal in the fetal or early neonatal period may do more harm than good because it is at the expense of serious concerns. Hence, policy makers will have to decide based on current data about specificity and sensitivity of the NIPT test whether including these trisomies in the test is desirable. The fact that microarrays, rather than karyotyping, can be used with NIPT offers challenges and opportunities. Although the official aim of Down syndrome screening was to give future parents autonomous choice, this autonomous choice was limited by the technology that would allow genetic counselors only to discover an extra chromosome. When screening becomes more comprehensive, this poses certain challenges, but also provides the opportunity to reassess screening rationale. In a recent paper, Christian Munthe (2015) states that the possibility of including many conditions in the screening test may seem to support a radical individualization of how prenatal screening is organized. Indeed, as I shall argue, if a public health system aims to give prospective parents the opportunity to choose for themselves whether they are up to raising a child with disabilities, in principle they should endorse screening for conditions that some may consider at least as severe as trisomy-21. However, offering a real choice also presupposes that society offers enough support for those who wish to proceed with such pregnancies. This decision would call for, as Munthe argues, a drastic downscaling of prenatal testing to target a much more narrowly selected range of severe conditions, while at the same time freeing up resources for support of those living with the conditions. For Munthe, these considerations apply to state-funded schemes. I will argue in the rest of this paper that screening for some chromosomal conditions may violate ethical principles as well, and would therefore make problematic the claim that private screening for a wider range of conditions is acceptable if people wish to have more reproductive options (Munthe, 2015). I will demonstrate the need for the reassessment of screening rationales with two examples that are already technically feasible: submicroscopic abnormalities and the SCAs. Submicroscopic Abnormalities Some platforms used for NIPT can also detect submicroscopic chromosomal abnormalities, typically deletions or duplications of a portion of chromosomal DNA. Variations in copy number are thought to be responsible for most human variation, but such deletions and insertions are also associated with some conditions that are considered to be severe disabilities, often with associated with intellectual disabilities (Menten et al., 2006). However, the predictive value of screening for such syndromes is low, because they are rare and because they have a variable phenotype. Therefore, screening for them early in pregnancy may, just as with trisomy-13 and trisomy-18, cause anxiety, and it may not be in the interest of the pregnant women that these chromosomal abnormalities are included in a publicly funded screening panel, specifically with regard to conditions that have a mild or highly variable phenotype. Some of these conditions, however, are more readily associated with a distinct phenotype. In the context of the incidental findings of copy number variations (CNV) after invasive prenatal diagnosis, it has been argued that only certain CNVs will be reported that have sufficient clinical relevance and enough penetrance, with the 22q11 deletion as an example (Brady et al., 2014). This deletion is linked with DiGeorge syndrome (velo-cardio-facial syndrome), which is characterized by cleft lip/cleft palate, cardiac insufficiency, and psychological problems. Many patients will suffer from schizophrenia. Preimplantation Genetic Diagnosis has been performed for 22q11 deletion, and the syndrome is detectible through some platforms used for NIPT (Emanuel et al., 2001). This begs the question whether 22q11 should be part of routine NIPT screening, provided it is technically feasible and readily implementable. It is informative to make a comparison with the widely accepted screening for Down. In the case of 22q11 deletion, can we really say whether this condition is actually less severe than Down syndrome? It is true that trisomy-21 leads to a highly recognizable “congenital” phenotype, but still this phenotype is variable as well and not de facto related to lesser wellbeing. We could make the opposite reasoning: If it is decided that certain CNVs are not screened for due to issues related to prevalence or variability of the phenotype, how can we then warrant the widely accepted screening for Down syndrome? It may be defended that trisomy-21 screening has been available and possible for decades, regardless of the progress that has been made with regard to treatment and management of the syndrome. However, if this is the case, one should admit that the endorsement of this type of screening is technology-driven (and hence subject to the so-called technological imperative), rather than related to procreative choice or to intrinsic quality of life. Indeed, why offer a choice here and not for any other possible chromosomal conditions with comparable severity? The problem with a technology-driven screening program in the prenatal context is that it must answer the criticism of disability-rights philosophers who state that the offering of such tests already assumes a negative attitude toward the condition and the people having the condition (Davis, 2010). This is especially so if screening programs target one specific condition and neglect others that may be at least as severe (Munthe, 2015). NIPT, due to its noninvasiveness, may offer a unique possibility here that was not so readily available with invasive screening. Because the test can be done fairly easily, without risk to the fetus, the possibility of offering the test to prepare for living with a child with certain challenges gives prominence equal to the possibility for termination. This is true for all conditions that are congenital with sufficient penetrance. Prenatal counseling and preparation should be adequate and should include discussion with parents of children with the condition. Gynecologists and counselors administering the test should be trained to offer both options (preparation/termination) as equally valid. On the one hand, a test honestly aimed at enhancing a pregnant woman’s reproductive autonomy should therefore offer screening for trisomy-21 and other congenital conditions linked with subchromosomal abnormalities, provided that the positive predictive value is high enough, and include pretest and posttest counseling that offers a balanced view of all the options, including the opportunity to speak with representatives of patients or parents’ organizations. On the other hand, a public screening program specifically targeted at detecting Down syndrome, even when other conditions that are at least as severe can be easily detected, is subject to the disability critique and should reassess its screening rationales. In the previous paragraph, I have argued that, when more comprehensive screening techniques are available, limiting publicly funded screening to only trisomy-21 while not screening for conditions that may be equally or more severe is undesirable. In the next paragraph, I will argue that screening for some other conditions, whether privately or publicly funded, violates ethical principles. I shall use the example of SCAs to prove my point. Sex Chromosome Abnormalities Most current technologies will also allow for the detection of abnormal numbers of sex chromosomes, the so-called SCAs. In the context of NIPT, but also in the context of Invasive Prenatal Screening and Preimplantation Genetic Screening, policy makers shall have to decide whether to screen for and/or to communicate such findings. SCA’s are an excellent example of the fact that the current idea that abnormalities on the level of the genome (in this case, having an extra chromosome) need not necessarily be considered detrimental and worse than subchromosomal or genetic abnormalities. I shall focus on Klinefelter syndrome (XXY or XXXY) and XYY syndrome, the former because of its link with infertility and the latter because of its link with hyperactivity and autism. In Klinefelter’s syndrome, males have one or more extra chromosomes. It is a good example of how descriptions of conditions based on diagnostic findings may be biased. Indeed, the classic Klinefelter phenotype is a male with hypogonadism, female features, long stature, and fewer IQ points than average. However, Klinefelter has also been diagnosed in men visiting fertility centers due to infertility problems, but without additional problems (Lanfranco et al., 2004; Visootsak and Graham, 2006). Indeed, there are potentially many more men with an extra X chromosome who have a normal phenotype. In fact, it seems that reduced fertility is the only factor that is a constant. So should such a condition be screened for and, if found, be communicated to the pregnant woman? Such communication could lead to the following consequences: either the pregnancy is terminated, or the pregnancy is continued, resulting in the fact that the child will be known to have an extra X chromosome at birth. The first option, termination, could be defended on the principle of procreative autonomy: A pregnant woman should be allowed to decide for herself whether to continue a pregnancy of a Klinefelter male. However, autonomous choice presumes having enough information on which to base this decision. The only constant in Klinefelter is the infertility. Is infertility as a constant a good enough reason to terminate? Or is the possibility to terminate for infertility enough reason to include sex chromosome aneuploidies in a state endorsed and funded screening program? With regard to the second option, to include it for informational purposes, there is still no consensus about whether presymptomatic detection of Klinefelter has any therapeutic benefits (Herlihy et al., 2010; Herlihy et al., 2011). Moreover, the one thing that will be known about the fetus that is prenatally diagnosed with Klinefelter is that he will almost certainly be infertile. I contend that the knowledge of one’s own infertility, as it is only applicable to adulthood, is a condition that is invisible, private, and thus it is up to the individual to decide whether to know this or to communicate this to others, including to parents. In their 2015 paper, Deans et al. contend that NIPT should not be used for adult-onset diseases, carrier status, or nonserious threats. They quote the risk for objectivation of children: they state that curiosity with regard to children’s genetic endowments may be incompatible with being a virtuous parent, because it is testimony to a certain objectivation of children. Therefore, including genetic differences that are not related to serious diseases in a screening program is ethically unacceptable (Deans, Clarke, and Newson, 2015). Given that infertility is the only constant in Klinefelter, I claim that the prenatal diagnosis of Klinefelter for informational purposes entails a violation of the future child’s chromosomal and reproductive privacy and that there is insufficient knowledge to weigh potential advantages and disadvantages of this knowledge. At the point of the screening, it is not known how the relation between the parent(s) and their future son will develop, and whether he would feel comfortable discussing his infertility with his parents. Moreover, how knowledge of one’s son’s infertility influences the relation between parents and their son is also unknown. Therefore, I conclude that the right to privacy of the future child is more important than the prospective parents’ right to know the genetic or chromosomal makeup of their fetus for informational purposes or, for that matter, for the avoidance of a diagnostic odyssey that may happen if the child does have symptoms. This is a variant of a child’s right to genetic privacy, grounded in a child’s right not to know (or have others know) his or her genetic (and chromosomal) makeup (Davis, 2010; Hens, 2013; Cutas and Hens, 2015). An objection to my claim would be that the right to genetic privacy applies to the future child and not to the fetus in utero. At this point, the reproductive autonomy of the future mother and her right to decide whether or not to continue the pregnancy based on knowledge of the chromosomal makeup of her child may trump rights of future children that may or may not come into existence. One could argue that the right to decide whether or not to bring a male fetus with an extra X chromosome to term is more important than the rights of potential children. I state that reproductive autonomy is limited by considerations about rights and well-beings of children, when born. The only way in which the reproductive rights of the prospective parent(s) and potential children in this case will be safeguarded is to disallow screening for Klinefelter for informational purposes, and only allow it if it can be safeguarded that the prospective parent(s) will want to terminate the pregnancy upon discovery of a chromosomal condition because there then will be no future child. As I have argued earlier in this paper, state funding of a screening program whose primary aim is the termination of a pregnancy with an only constant risk that the future child will be infertile seems unwarranted because infertility is not a severe congenital condition. Moreover, including a clause in the consent form before the screening that would force a woman to terminate a pregnancy upon the discovery of chromosomal conditions violates her right to change her mind in the light of her growing relationship with the child she carries, which is an equally important aspect of reproductive autonomy, and is in my view draconian in the light of the consent form’s primary aim: to safeguard the unborn fetus’s future right of genetic and chromosomal privacy. Therefore, although I admit that this challenges the extent of the right to reproductive autonomy, I conclude that in the case of mild chromosomal and genetic abnormalities, the right to genetic and chromosomal privacy trumps the right of prospective parents to decide whether or not to carry to term a child with such conditions. Hence, I argue that screening for Klinefelter syndrome prenatally should not be in a state funded screening program because it violates ethical principles. Arguments based on the right to chromosomal privacy and the uncertainty of therapeutic benefits also apply to XYY syndrome. This syndrome has historically been wrongly associated with an increased level of criminality. There seems to be, however, an increased risk for hyperactivity, and in some cases it is linked with autism (Bauer et al., 1980; Tartaglia et al., 2012; Margari et al., 2014). This case is interesting because on a societal level the question whether and to what extent neurological differences such as Attention Deficit Hyperactivity Disorder or Autism Spectrum Disorder are actually diseases or conditions rather than variants of normal behavior is still ongoing. Some proponents of the neurodiversity movement claim that it is the lack of support that exists in society for neurodiverse individuals that makes neurological difference a disability; otherwise, it would not be a medical disability (Baron-Cohen, 2000; Glannon, 2007). The question whether the public health system should endorse screening (and potential termination) for a condition that may (or may not) lead to a condition that may very well be a social disability rather than a medical one is still unresolved. In case of termination, the fact that this chromosomal condition may very well lead to a normal phenotype without problems makes inclusion of screening for XYY in a publicly funded screening program undesirable. As with screening for informational purposes, arguments similar to those for infertility apply: By analogy with recommendations regarding the presymptomatic genetic screening of minors, this information, because it is not immediately actionable, belongs to the future child’s right to chromosomal privacy (Bauer et al., 1980; Hens, 2013). Indeed, besides the right of a child not to know certain genetic information about himself, it is uncertain whether knowing that a child is at risk of developing a neurological difference influences how parents perceive and behave toward their child (Marchant and Robert, 2008; Jordan and Fu Chang Tsai, 2010). In the light of these uncertainties, screening for XYY prenatally should not be part of a publicly funded state program and violates ethical principles. III. CONCLUSION The advent of chromosomal screening in the context of NIPT raises many ethical questions that are not completely different from those raised in the context of invasive prenatal screening. However, the fact that this can be done early in pregnancy through a noninvasive process makes the question of what to screen for more pertinent. This reflection hopes to have shed some light on how prenatal screening programs should be assessed. This assessment is necessary for all chromosomal and subchromosomal conditions that are considered to be included in the screening, in order to avoid the criticism that the screening is subject to the technological imperative and nothing more. First, the (sub)chromosomal condition that is considered should be assessed for its positive predictive value. Unless this is high enough, including it in the screening may cause unnecessary anxiety for the pregnant women and does nothing to increase reproductive choice. (Sub)chromosomal conditions that are sufficiently associated with a congenital disability should be included in a publicly funded screening, because such screening should not be solely aimed at detecting trisomy-21. Also, such screening should not have as a main objective the prevention of the birth of children with certain challenges. The possibility for NIPT to be used as a way to prepare for, and in the future also to improve, the outcomes of a child with challenges should be given equal importance to the possibility of terminating a pregnancy, and women and their partners should be given adequate information about the prospects of a given condition in order to respect their reproductive autonomy as much as possible. Third, reproductive autonomy and the parental right to know should always be balanced against the question of whether the condition is congenital or potentially variable in phenotype. The case of sex chromosome aneuploidies, which in many cases does not lead to congenital problems and may be symptomless, demonstrates that in some cases the ideal of NIPT as a way to prepare for the birth of a child with certain characteristics, or to satisfy the parental right to know, or even curiosity, is not adequate and violates certain ethical principles. Testing for SCAs with NIPT to allow termination of such pregnancies should not be state funded because these do not qualify as severe diseases and hence do not warrant public health care spending. Testing for SCAs for informational purposes may violate the right of the future child to chromosomal privacy. The possibility for NIPT analysis to be accessed through direct-to-consumer testing (after all, it is only a blood sample) complicates this matter even further. I have argued that a state funded NIPT screening scheme should de facto rule out screening for extra X or Y chromosomes, and such screening contravenes ethical principles such as the right of the child to genetic privacy. Therefore, I conclude that, provided at least equal weight is given to the possibility to use this information to prepare for children with certain challenges, screening for trisomy-21 and certain submicroscopic chromosomal conditions strongly associated with severe phenotypes can be defended and that for the sex chromosome aneuploidies it cannot. ACKNOWLEDGMENTS This paper is based on a presentation I gave at the colloquium “Disability Detection and Fetal Decision-Making through Non-Invasive Prenatal Testing (NIPT),” organized by the Centre for Bionetworking of the University of Sussex in Brighton. 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