The Cambridge textbook of bioethics

Ms. C is 34 and she is getting married for the first-time. She tells her obstetrician/gynecologist that she and Mr. D are hoping to conceive quickly. Both Ms. C and Mr. D are of Ashkenazi Jewish descent. Ms. C’s physician recommends that she undergo prenatal testing for a number of diseases more common in people of Jewish ancestry. Currently, the Ashkenazi Jewish panel includes up to 10 conditions depending on the laboratory (Leib et al., 2005). The conditions include severe conditions such as Tay Sachs disease and more mild conditions such as Gaucher disease type 1. Ms. C has never heard of any of the conditions, but she agrees to follow her physician’s advice.

E is a healthy full-term infant male, who was born 24 hours ago. The nurses inform you that E’s mother refused routine vitamin K supplementation given intramuscularly and the hepatitis B immunization because she does not want to put her son through any more discomfort than the birth process. You come to draw the newborn screen for phenylketonuria and other metabolic conditions before discharge, but she refuses.

What is prenatal testing and newborn screening?

Prenatal testing includes a number of clinical tools to provide reproductive information to individuals or couples either preconception or during pregnancy about their risks of having a child with a health disorder or condition. Prenatal testing involves a number of different types of test including genetic carrier testing, ultrasound, amniocentesis or chorionic villus sampling (CVS), or preimplantation

genetic diagnosis. An individual or couple may be referred for prenatal testing because of genetic risk factors, maternal illnesses that are associated with various birth defects (e.g., maternal diabetes is associated with spina bifida and congenital heart disease), or advanced maternal age (which is a risk factor for certain chromosomal anomalies).

Genetic carrier testing is offered to women and couples to provide risk information about having a child with one or more genetic conditions. Tay Sachs Disease was one of the first conditions for which prenatal carrier testing was developed (Kaback and O’Brien, 1973). It is an autosomal recessive condition, which means that if both parents have one abnormal allele they are asymptomatic carriers who have a 25% chance of having a child affected with the disease. Today, many additional genetic conditions can be tested for depending on prospective parental interest, family history, or ethnicity, with various modes of inheritance. Ideally, carrier testing is performed preconception because this allows for greater decision-making latitude.

Ultrasound is one of the most common screening tests used during pregnancy. In the first trimester, ultrasound is often used to determine that the pregnancy is intrauterine and to determine the number of fetuses. In the first trimester, nuchal translucency can be examined as a screening tool for Down syndrome. In the second trimester, level-2 ultrasound is used to look for congenital anomalies of various organs (e.g., four-chamber examination of the heart).

More invasive techniques are usually reserved for ‘‘high-risk’’ women and ‘‘at-risk’’ couples and fetuses. Both CVS and amniocentesis are techniques that allow for chromosomal analysis of the fetus. While CVS can be done earlier than amniocentesis, it has a slightly higher risk of miscarriage from the procedure itself. Alternatively, some couples will seek preimplantation genetic diagnosis: genetic analysis of embryos during assisted reproduction prior to implantation.

Newborn screening (NBS), by comparison, is a population-based program that seeks to screen newborns for early-onset treatable conditions. Unlike prenatal testing, which targets individuals or couples who are at risk, NBS is designed as a universal public health program. It began in the early 1960s with the development by Robert Guthrie of both an assay to test for elevated levels of phenylalanine, which is diagnostic of phenylketonuria (PKU), and a stable way to collect and store the blood samples using filter paper (the Guthrie card) (Guthrie and Susi, 1963). The Guthrie card allows for the efficient and economical testing of large numbers of samples.

Guthrie piloted the PKU test and the cards in Massachusetts in 1961. The pilot was a success, but the initial medical response was to promote further testing and piloting before widespread implementation (Reilly, 1977). Guthrie and the National Association for Retarded Children (NARC) were impatient and advocated for legislative mandate to ensure universal screening of all infants. By 1976, over 40 states had legislative statutes (Reilly, 1977).

Today, PKU screening is performed universally in all US states, Canadian provinces, and many other countries around the world (National Newborn Screening Status Report, 2006). Many states and countries also test for other conditions, but there is wide variability regarding which conditions are included (Saxena, 2003). In the USA, the most common tests are for PKU, hypothyroidism, hemoglobinopathies (including sickle-cell disease), congenital adrenal hyperplasia, and galactosemia (National Newborn Screening Status Report, 2006). Each of these conditions meets the criteria for

Prenatal testing and newborn screening 105

universal screening as enumerated by Wilson and Jungner (1968). These criteria include (i) that the condition represents an important health problem; (ii) that the natural history of the condition is well understood; (iii) that there is an accepted costeffective treatment which, if begun early, can prevent many if not all of the negative sequelae of the condition; (iv) that the screening test is simple and cheap and acceptable to the population; and

(v) that the follow-up diagnostic testing is highly accurate (Wilson and Jungner, 1968).

Since the mid 1990s, newborn screening programs have expanded rapidly because of the development of tandem mass spectrometry, which allows for testing for numerous conditions at one time (McCandless, 2004). While some of these conditions clearly meet the Wilson and Jungner criteria for population screening, others are not as well understood and may not have available therapies (Pandor et al., 2004). In addition, other screening programs have been developed that do not depend upon the Guthrie card. The most widespread program is hearing screening using otoacoustic emissions or brain stem audio-evoked responses (Davis et al., 1997; Kerschner, 2004).

Why is prenatal testing and newborn screening important?

Ethics

Prenatal testing is important because it promotes informed reproductive decision making, particularly when provided with preand post-test genetic counseling. Prenatal testing and genetic counseling help individuals and couples to understand their personal risk for having a child with an inherited condition. The risk may be as high as 100% (e.g., the risk that a couple who both have sicklecell anemia will pass the disease on to their child) or lower than 1% (e.g., the risk that a woman under 40 years old will give birth to a child with a chromosome abnormality such as Down syndrome). But knowing the probability of inheriting a

106L. F. Ross

gene mutation does not necessarily tell one how severe the condition will be (‘‘variable expression’’), or whether it will present at all (‘‘variable penetrance’’).

Yet not everyone embraces the expansion of prenatal testing. Disability rights advocates question the assumptions that underlie prenatal testing, because positive results often lead to pregnancy termination (Parens and Asch, 2000). Even disability rights advocates who are pro-choice are disturbed by this sequence because they believe that the parents are making a misguided choice, electing to abort a wanted pregnancy based on one trait of the child rather than seeing the fetus as a future child with many traits. They also fear that increased use of prenatal testing will lead to greater discrimination against those who are already living with a particular disability and to greater intolerance for those parents who elect to continue a pregnancy of a child with a known disability (Parens and Asch, 2000).

Newborn screening is important because it allows for the early detection of treatable conditions and thereby prevents serious morbidity and mortality. However, there has been rapid expansion to include conditions that do not meet the traditional public health screening criteria (Botkin et al., 2006). This raises questions about the goals of screening. Historically, the goal was to promote the medical well-being of the child, but now there are those who advocate for NBS to inform parents of future reproductive risks and to promote broader family benefits even if the testing does not offer any direct benefit to the child (Bailey et al., 2005).

Law and policy

Alpha-fetoprotein (AFP) is a marker for fetal neural tube defects and Down syndrome. In 1985, the Department of Professional Liability of the American College of Obstetricians and Gynecologists issued an ‘‘Alert’’ entitled Professional Liability Implications of AFP Tests. The Alert declared that it was ‘‘imperative that every prenatal patient be advised of the availability of this test’’ (American

College of Obstetricians and Gynecologists, 1985). As a result of these liability concerns, maternal serum screening for AFP became the standard of care. This was reinforced in California in 1986 when legislation mandated that all healthcare providers offer such testing to every pregnant patient who begins prenatal care prior to the 20th week of pregnancy (California Code of Regulations, 2002). Today, even greater sensitivity and specificity are achieved by the use of triple screens (AFP, maternal serum human chorionic gondatropin and unconjugated estriol) and quadruple screens (which add dimeric inhibin-A). Serum markers are often used in conjunction with ultrasound for ever greater sensitivity (Reddy and Mennuti, 2006).

The main liability concern for failing to screen women using serum markers is a wrongful birth lawsuit. Wrongful birth cases are becoming more widely recognized in a wide variety of situations in which physicians failed to warn prospective parents that they are at risk of conceiving or giving birth to a child with a serious genetic disorder (Bernstein, 2001; Howlett et al., 2002; Strasser, 2003). In addition, parents can also bring wrongful life suits on behalf of the children. These are more controversial because they must allege that the child would have been better off not being born.

Currently, NBS is a mandatory public health program in most US states. Wyoming and Maryland are the only two states that require informed consent for newborn screening, although 13 other states require that parents be informed about newborn screening before testing (Nelson et al., 2001). All states except South Dakota and Nebraska permit parental refusal of newborn screening for religious or personal reasons (Nelson et al., 2001;

Douglas County, Nebraska v. Josue Anaya and Mary Anaya, 2005).

Empirical studies

One of the most controversial questions in prenatal testing is ‘‘what counts as success?’’ (Chadwick, 1993; Clarke, 1993). Is it a success only if parents choose to terminate a pregnancy because a fetal

disorder is discovered, or is it a success if informed parents decide to continue the pregnancy? Depending on what one views as success might influence how one counsels prospective parents. The data show that non-geneticist healthcare practitioners (e.g., primary care physicians and obstetricians) are generally more directive than genetic counselors regarding an abnormal prenatal test (Geller et al., 1993; Marteau et al., 1994). That said, there are data that even genetic counselors show bias (Michie et al., 1997) or that patients read between the lines (Anderson, 1999). There are also empirical data that show wide variation with respect to how individuals and couples use the prenatal testing information both within and between countries (Drake et al., 1996; Mansfield et al., 1999).

Although disability rights advocates are concerned that increased prenatal testing will lead to decreased support and increased stigmatization of persons with disabilities, the empirical data do not support this concern. Rather, the period since the mid 1980s has been quite progressive in the legislation and policies designed to promote opportunities for individual with disabilities. In the USA, the passage of the Americans with Disabilities Act (ADA) of 1990 has been heralded as an important advance in promoting opportunities for persons with disabilities (Blanck and Marti, 1996; Befort, 2004; McCleary-Jones, 2005). There are also global initiatives aimed at improving the lives of individuals with disabilities (Walsh, 2004; International Disability Alliance, 2006) as well as specific legislation and policies in many countries (Canadian Human Rights Commission, 2005; Directgov (UK), 2006).

Empirical studies in NBS are scant. Clearly more studies are needed to determine if early diagnosis improves outcome. This is particularly important as we move away from newborn screening for conditions that represent a medical emergency in the newborn period to conditions with natural histories that are less well known or that are currently untreatable (Grosse et al., 2006). National and international collaborative studies are needed

to understand genotypic–phenotypic correlations and to rigorously test various treatments in rare metabolic conditions (Guttler et al., 1999; Emery and Rutgers, 2001; Goss et al., 2002). They are also needed to determine short-term and long-term impact of false-positive results (Sorenson et al., 1984; Tluczek et al., 1992; Gurain et al., 2006). Because of the rarity of many conditions, Botkin (2005) has argued that expanded NBS should only be done with parental permission under a research protocol.

The evaluation of NBS must include all aspects of the screening program, which begins with blood spot acquisition and includes confirmatory testing and long-term management (American Academy of Pediatrics, Newborn Screening Task Force, 2000). Empirical data show that there are many loopholes in the process (Stoddard and Farrell, 1997; Desposito et al., 2001; Farrell et al., 2001; Mandl et al., 2002; Hoff and Hoyt, 2006; Therrell et al., 2006). A study of pediatricians found that many did not have a system in place to ensure that testing had occurred but assumed that no news was good news (Desposito et al., 2001). In addition, each US state has a different process by which to add or subtract new conditions (Hiller et al., 1997; Therrell et al., 2006). There is also wide variation in standards between the different US state laboratories and how states track long-term results (Hoff and Hoyt, 2006; Therrell et al., 2006).

How should I approach prenatal testing and newborn screening in practice?

Individuals and couples may not be aware that they carry certain gene mutations which may affect the health or well-being of their fetus. Taking a detailed family health history as well as reviewing the woman’s health and health management (e.g., what medications she is taking) can provide great insight into the risks of having a child with a disorder or condition. The number of conditions that can be tested for prenatally is growing rapidly. Prenatal counseling should always precede

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prenatal testing in order to allow women and couples to think about what type of testing they wish to undergo. It should not be presumed that anything that can be screened for should be screened for, nor should it be presumed that all individuals and couples share similar attitudes about specific disabilities or disorders. Rather, the decision to undergo different types of prenatal test is a personal issue that will reflect how a woman or couple balances risks and benefits of testing. Healthcare providers should discuss with women and couples about how they want to proceed with a pregnancy, what they understand about their own health risks and the potential risks to the fetus, and determine other risk factors.

Clearly, women and couples have a moral and legal right to know what is available, and what are their risks based on clinical and social factors (e.g., whether or not they smoke or drink), their demography, and their family health histories. Preconception testing offers individuals and couples greater options in terms of using donor gametes or other forms of assisted reproduction, preimplantation diagnosis, or adoption. For a couple where a pregnancy already exists at the time they learn of genetic risk factors, this new awareness can be anxiety provoking, require rapid decision making, and put a substantial amount of stress on the couple (Ormond and Ross, 2006). When deciding whether or not to have prenatal diagnosis, prospective parents need to think about the perceived burden associated with having an affected child, what level of risk (e.g., miscarriage of a healthy fetus) they are willing to take in order to obtain information regarding specific genetic diseases, and the degree of certainty that testing will provide (Ormond and Ross, 2006). For example, a couple might weigh the potentially beneficial and highly accurate information that invasive prenatal diagnosis can provide against the increased risk of miscarriage that is associated with these procedures.

Pediatricians and other healthcare providers who take care of newborns need to be aware of the NBS laws that exist in their jurisdiction. They ought to be aware of what conditions are tested for, what is

available for those parents who want expanded screening, and whether parents can refuse state screening. Healthcare providers should encourage parents to screen their children, particularly for those conditions that meet the Wilson and Jungner (1968) criteria because clinical diagnoses may not occur until after irreversible morbidity has developed. Parents need to understand that the blood spot is a screening test and that definitive testing may be necessary to confirm or refute a positive screen. Parents also need to understand that even if a child is not found to have a disease, some of the screening tests uncover carrier information and that this may have implications about their own future reproductive risks as well as for their families (Laird et al., 1996; Parsons et al., 2003).

The cases

Ms. C was tested and found to be a carrier of cystic fibrosis and Tay Sachs disease. Her husband underwent the full panel as well and he was found not to be a carrier of any of the conditions. The couple was informed that they were not at risk for Tay Sachs Disease and that their risk for having a child with cystic fibrosis was low (<0.05%), but not zero because there are over 1100 mutations, and the prenatal panel only includes the more common mutations (Palomaki et al., 2004; American College of Obstetricians and Gynecologists Committee on Genetics, 2005). They could get greater certainty but not 100% by doing a full gene analysis at a cost of $1500, which they elected not to do. Ms. C and her husband gave birth 1 year later to a healthy baby boy. He has no signs or symptoms consistent with cystic fibrosis.

Despite repeated attempts to convince E’s mother to have her child undergo the newborn screen, she refused. Prior to discharge, the physician emphasized the importance of discussing her refusal with her child’s pediatrician, and encouraged E’s mother to bring the Guthrie card to her child’s first pediatric appointment. E’s mother did

bring the Guthrie card to her pediatrician and discussed the ‘‘pros and cons’’ of testing, the meaning of a screening test, and the probability of a false positive, a true positive, and a true negative. The pediatrician explained to E’s mother and father that the mode of inheritance for most of these conditions made it unlikely that one could determine risk by family history; and that clinical diagnoses could be too little too late. The pediatrician explained that she was very supportive of the screening program, and in fact, that she often recommended that her patients purchase an expanded screen that included conditions not currently screened for in their state. She provided brochures for the private laboratories that perform expanded newborn screening. The physician also stated that she was willing to respect their refusal, in part because the likelihood of a positive result was small, but that a delayed diagnosis could lead to a worse outcome for the infant. After further conversation, the parents elected to have the child screened by the state but did not want to send an additional sample to a private laboratory. The state screen was negative.

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Ms. F and Mr. G are trying to have a child. They have been having sexual intercourse approximately three times a week for the past year, and daily around the time when Ms. F thinks she is ovulating. They are both 38 years old. Ms. F has had regular menstrual cycles up to the last three months, in which she has had only two. They are worried they have delayed starting a family too long and will not be able to afford the expensive fertility treatment they may require at Ms. F’s age. They have questions regarding the success of in vitro fertilization and the possibility of having twins or triplets.

What is assisted reproduction?

Assisted reproduction enables the deliberate manipulation of the processes and materials of human reproduction outside of sexual intercourse. In describing the practices that constitute assisted reproduction, it must be understood that all such practices are embedded with ethical issues, whether standard therapies such as ovulation induction (Messinis, 2005), insemination with donor sperm (Daniels et al., 2006), and in vitro fertilization (IVF) (Steptoe and Edwards, 1978); emerging practices such as pre-implantation genetic diagnosis (PGD) (Handyside, 1990; Nisker and Gore-Langton, 1995); or practices prohibited under law in many countries, such as the purchase or bartering of oocytes (Gurmankin, 2001; Nisker, 1996, 1997, 2001).

Ovulation induction through clomiphene citrate has been practiced for over 30 years (Messinis, 2005). This oral therapeutic strategy can assist 50–80% of women with ovulatory dysfunction become pregnant, depending on the etiology of their disorder (with the exception of premature ovarian failure) (Messinis, 2005). Aromatase inhibitors are new oral ovulation induction agents (Casper and Mitwally, 2006; Holzer et al., 2006). When these are unsuccessful in inducing ovulation, menotropins (also referred to as gonadotropins) may be used (Messinis, 2005). This is a much riskier strategy, with side effects including ovarian hyperstimulation syndrome (Budev et al., 2005) and the creation of high-order multiple pregnancies (Barrett and Bocking, 2000a, b).

Provision of sperm, by other than the woman’s partner, was one of the earliest forms of assisted reproduction and has been encompassed in medical practice for 50 years (Daniels et al., 2006). Sperm donation is a common practice when a woman’s partner has sperm of low count or quality or carries a communicable disease, when she is in a lesbian relationship, or if she is single. Oocytes may be provided to women who no longer have an ‘‘ovarian reserve,’’ because of their advanced age (Pastor et al., 2005) or having undergone cancer treatment (Byrne et al., 1999; Nisker et al., 2006).

Menotropin ovarian stimulation create multiple oocytes for IVF (Abramov et al., 1999). When the

oocytes reach approximately 2 cm in diameter, they are matured with human chorionic gonadotropin and approximately 36 hours later are removed through transvaginal ultrasonographic-guided needles (Yuzpe et al., 1989). The oocytes are placed in Petri dishes under strict sterile conditions, sperm is added, and if fertilization occurs, the embryos are microscopically observed for two days (up to four days if the plan is to transfer blastocysts) (Blake et al., 2002). Embryos are then transferred to the uterus (Min et al., 2006) (one or two embryos preferred, but often more in older women), and the remaining embryos are cryopreserved for transfer in nontreatment cycles (Trounson and Mohr, 1983). Cryopreserved embryos no longer required for reproductive purposes are usually donated to research (Nisker and White, 2005) or discarded. They may, however, be donated to another couple, although this rarely occurs for a number of reasons, including parental fear of allowing a child for another couple that is genetically related to their own (Newton et al., 2003; Nachtigall et al., 2005). Pregnancy rates for IVF exceed 25% per cycle for women/couples whose infertility etiology may be blocked Fallopian tubes, endometriosis, sperm problems (with intracytoplasmic sperm injection) (Van Steirteghem et al., 1994) or unexplained. They become higher following the transfer of cryopreserved embryos (Alsalili et al., 1995; Mishell, 2001). The risks of IVF are in both the menotropin stimulation (Abramov et al., 1999; Buckett et al., 2005) and the surgery (Alsalili et al., 1995). There are also risks to the child and family unit, such as those owing to multiple births (Barrett and Bocking, 2000a, b).

Gestational agreements (Rodgers et al., 1997; Ber, 2000) are often used in conjunction with assisted reproduction practices (Mykitiuk and Wallrap, 2002; Rivard and Hunter, 2005). Although the more common type of gestational agreement occurs when the gestational carrier is impregnated with the sperm of the partner of a woman who, because of medical problems, cannot gestate her own embryo/fetus, gestational agreements may also include those in which the embryo’s genetic makeup has resulted from an oocyte other than that of

the gestational carrier, sperm other than that of the man for whom the embryo/fetus is being gestated, or both (Rodgers et al., 1997).

A relatively new area relates to the genetic scrutiny of embryos by PGD (Handyside et al., 1990; Nisker and Gore-Langton, 1995), or most recently, preimplantation genetic haplotyping (PGH) (Renwick et al., 2006). The embryos or polar bodies (Verlinsky et al., 1990) are assessed genetically through polymerase chain reaction (Mullis and Faloona, 1987) or fluorescent in situ hybridization (Delhanty et al., 1993). Genetic determinations of an embryo through PGD may be used not only to implant embryos to avoid a specific genetic characteristic but also to implant embryos with particular characteristics, for example embryos of a specific histocompatibility in a savior sibling scenario (Pennings et al., 2002), embryos that will result in a child who is deaf (Levy, 2002) or who has Duchene’s dwarfism (Nunes, 2006).

Why is assisted reproduction important?

Assisted reproduction enables subfertile heterosexual couples, single women, and women in lesbian relationships to have children. In addition, individuals and couples who carry genetic conditions may wish to use assisted reproduction in order to avoid passing (or to deliberately pass) these conditions on to their children. Thus, assisted reproduction is important for both medical and social indications.

Assisted reproduction is increasingly important as many women delay having a child until they have employment and financial security. Delay in becoming pregnant predisposes a woman not only to deplete her ovarian reserve but also to develop other etiologies of infertility, such as endometriosis or tubal occlusion, as well as lengthening her exposure to environmental toxins (Younglai et al., 2002), an under-researched area (Royal Commission on New Reproductive Technologies, 1993).

Assisted reproduction is also increasingly important as more women are surviving cancer treatment, including leukemias in girls and adolescents,