Preimplantation Genetic Diagnosis

A key breakthrough in modern laboratory medicine, preimplantation genetic diagnosis (PGD) detects genetic abnormalities that cause birth defects or fatal illnesses, allowing embryos to be chosen before being implanted into a uterus, thereby avoiding selective pregnancy terminations. While this technology provides a lot of answers, its increasing sophistication is raising new questions about how to resolve the ethical controversies it creates.

A special January 2014 issue of Clinical Chemistry focusing on women's health explores some of these ethical issues, highlighting how the rapid pace of scientific discovery can sometimes outpace society's old categories for ethics in healthcare (Clin Chem 2014; doi:10.1373/clinchem.2013.202515). Next generation sequencing and other advancements are enabling labs to use PGD in new ways beyond the scope of simply improving chances for a successful pregnancy and avoiding disease.

The power of this technique will make dealing with the ethical implications unavoidable, wrote ethicist Arthur Caplan, PhD, an author of the Clinical Chemistry article. "I believe that the future of PGD is in both looking for traits that parents do not want in their children and in selecting for traits that they do very much want to try to pass on. The morality of eugenics, both negative—eliminating unwanted traits—and positive—selecting for desired traits—will surely loom very large as the key moral question facing those offering PGD and those seeking to utilize it." Caplan is the director of the division of medical ethics at NYU Langone Medical Center in New York City.

An Evolving Technology

An evolving technique, PGD is not only the concern of researchers and academics. It has been used for more than 20 years to prevent the transmission of specific disorders, including autosomal recessive disorders such as cystic fibrosis and autosomal dominant disorders such as myotonic dystrophy. PGD can also be applied to carriers of chromosomal translocations who are at risk of transmitting an unbalanced chromosomal rearrangement that predisposes to miscarriage. The most up-to-date technique involves genetically analyzing five cells that are removed from an embryo biopsy on day 5 or 6 of development.

"Couples are determined to be at risk of having an affected child either because they already have an affected child, they themselves are affected with a condition, or they test positive for a mutation on prenatal genetic screening," explained Eric Forman, MD. "The typical paradigm is for couples to undergo in vitro fertilization (IVF), produce embryos, and have those embryos tested for the presence of a specific genetic disorder." Forman is an assistant professor at the Rutgers Robert Wood Johnson School of Medicine in New Brunswick, N.J., and practicing physician at Reproductive Medicine Associates of New Jersey in Basking Ridge.

Another major application of PGD is to screen embryos for aneuploidy. "Embryonic aneuploidy is the principle cause of failed implantation and miscarriage. It also contributes to the age-related increased risk of infertility," Forman noted. "More recently, with preimplantation genetic screening, embryos are tested to determine whether they have the normal complement of 46 chromosomes. Over the last few years, comprehensive chromosome screening strategies have been developed to test each chromosome and preferentially replace a chromosomally normal, euploid embryo in the uterus."

PGD has dramatically improved the success rate of IVF, according to Mark Hughes, MD, PhD, CEO of Genesis Genetics in Plymouth, Mich. "Because approximately 40 percent of IVF embryos have the wrong number of chromosomes, and virtually all of those do not produce a pregnancy, the success rate of IVF has recently sky-rocketed because preimplantation genetic screening allows for a single embryo to be transferred—avoiding multiple gestation—with upwards of 80 percent likelihood of a pregnancy," he said.

A more controversial application of PGD involves selecting an embryo whose human leukocyte antigen (HLA) profile is a match for an existing sibling with a disease. Called a savior sibling, such an embryo deemed free of disease is implanted with the intent to be born to serve as a stem cell or organ donor to the diseased sibling, explained Susan Wolf, JD, McKnight Presidential Professor of law, medicine and public policy at the University of Minnesota in Minneapolis. The first successful use of this technology took place in 2000 at the University of Minnesota. Parents had stem cells harvested from a second child's umbilical cord to aid their daughter, who suffered from the rare blood disorder Fanconi anemia, which leads to bone marrow failure.

 

On the Horizon

With rapidly advancing genetic technology, it is possible to learn even more about the genetic status of embryos. Next generation sequencing creates the potential to determine an embryo's whole genome. "This may allow embryos to be screened for de novo mutations which are not necessarily transmitted from the parents," Forman said. "Recent studies suggest that even chromosomally normal fetuses in ongoing pregnancies have a substantial risk of possessing clinically relevant insertions or deletions, called indels. It may be possible to screen for these indels prior to embryo transfer." Furthermore, innovations such as clustered regularly interspaced short palindromic repeats technology introduce the possibility of correcting regions of the genome with pathologic mutations, potentially transforming this area of medicine from PGD to preimplantation genetic treatment.

Caplan told CLN he believes it soon will be possible to screen for risk factors of a disease. "Instead of looking to see if an embryo will produce a person with hemophilia, you will be able to check if an embryo is at high-risk for getting certain diseases, such as breast cancer or hemophilia," he said.

In addition, using PGD to select desirable traits based on personal and social values, called "designer babies," will continue to be explored, according to Ann Gronowski, PhD, a professor of pathology and immunology and obstetrics and gynecology at Washington University School of Medicine in St. Louis, Mo.

In fact, Mountain View, Calif.-based 23andMe, a genetic testing company that sells at-home DNA kits directly to consumers, announced a patent in 2013 that will allow people to shop for gamete donors using a proprietary, so-called genetic calculator. "This is supposedly looking at traits in the genome of a gamete donor—say, a male sperm donor—in order to identify the perfect mate," Hughes said. But, he believes, there will never be enough sperm donors, let alone oocyte donors, available to make any reasonable genetic profile choices. "The number of donors is diminishing due to privacy, legal, and financial issues, and a recipient's selection choice will be much more focused on broad categories such as ethnicity, intelligence, and body stature," he added.

Ethical Questions

While many couples and ethicists believe it is preferable to selectively transfer unaffected embryos, rather than conceive spontaneously and terminate abnormal pregnancies, this opinion is not universal. Debate also surrounds the appropriate indications for PGD. "While most experts agree that PGD is acceptable for conditions that are lethal or create lifelong handicaps, the ethical status of milder conditions, psychiatric conditions, and conditions that do not have a clinical phenotype until adulthood are more controversial," Forman noted. For example, a woman who is a carrier for the BRCA mutation possesses a significant risk of developing ovarian and breast cancer, but this mutation has no impact until adulthood. Even so, some women may prefer to prevent their future female offspring from having to live with the increased risk of cancer.

The concept of savior siblings also brings up ethical quandaries. Wolf, who formerly served on the ethics committee of the American Society for Reproductive Medicine, points out that a young child does not have the capacity to consent or object to serving as a donor. This brings up many questions, such as, is it unfair to have a second child for the purposes of serving as a donor? What are the limits to how far parents and physicians should go in using a second child as a donor? What psychological and long-term impact will all of this have on the second child? And what if, as a child ages, he or she does not want to undergo procedures?

Although rare, there have also been cases of couples with an inherited condition, such as deafness or dwarfism, requesting PGD with the intent of producing, rather than preventing, a child who is affected with their condition. Wolf questions whether parents should be able to affirmatively select transferred embryos that would result in a child with a physical challenge, such as deafness. "Parents will argue that it's not a disorder, it's a cultural choice, and that there is something important and valuable about deaf culture," she said.

Finally, the use of PGD for "designer babies," such as non-medical gender selection, sparks similar controversy. "What if we could test for things such as height, eye color, or IQ?" Gronowski asked. "Do we allow any kind of testing or are there types of testing that should not ever be allowed? Some have called PGD a form of eugenics. Where is the line between preventing disease and eugenics? Who should draw those lines?"

As advances in PGD unfold, Wolf said many issues will be raised because a massive amount of information will be created about all sorts of traits and risks that a child-to-be may face. "I think there is a real ethical concern that parents and clinicians may not have the wisdom to appropriately deal with that much information and make ethically appropriate choices," she said.

No Easy Answers

While unanimity doesn't exist, for most conditions ethicists see PGD as a matter of patient autonomy. "Couples should be educated on the available options with current medical technology," Forman said. "Some may prefer to roll the dice and hope for a spontaneously conceived unaffected child." In the case of autosomal recessive diseases, this occurs 75% of the time, although two-thirds of children will carry the mutation. Other couples will opt to undergo IVF and preferentially transfer unaffected embryos or carriers if no unaffected embryos are available.

As an ethicist, Wolf wonders how it is possible to balance the rights and choices of parents and people who wish to be parents with the welfare of the children they create.

Currently, no federal or state provisions specifically address the application of PGD. "The decision to proceed is left to the province of the treating physician and the prospective parents," Forman said. PGD is legal in most countries where assisted reproductive technology (ART) is available, although some countries, such as Switzerland and Australia, have outlawed PGD

Caplan believes politicians don't get involved in regulating PGD because it is controversial. However, he thinks their intervention could be beneficial. For instance, "there could be oversight in terms of using a child's bone marrow at a minimum age," he said. "There could also be laws regarding which disabilities are severe enough to screen for." But on the subject of designer babies, "the ability to choose gender or other desirable traits should be condemned," he said.

There are, however, clear rules in pediatric transplantation for parents making decisions about their minor children, and whether to donate to a sibling or not, Hughes noted. "These have been in effect for decades, and PGD does not and should not alter these well accepted and widely practiced medical norms," he said.

Professional genetic and reproductive societies also ought to issue more guidelines and opinions, such as requiring that couples get counseling from a licensed professional who is independent of a PGD laboratory before making any decisions, according to Caplan. "Parents should learn about the pluses and minuses of different conditions, and possibly meet families who have children with certain conditions," he said.

Sandra Darilek, MS, CGC, who serves on the board of directors of the National Society of Genetic Counselors, emphasized that couples who consider these technologies benefit from counseling about their advantages, limitations, and risks. "While PGD is available for a number of conditions, it may not be able to be performed in every case in which an embryo is at risk for a genetic disease," she said. Darilek is an assistant professor at Baylor College of Medicine in Houston.

"It is important to note that while PGD and preimplantation genetic screening reduce genetic risks, they do not eliminate them," Darilek added. "Prenatal testing through chorionic villus sampling or amniocentesis is still strongly recommended to confirm PGD and preimplantation genetic screening results."

Indeed, said Hughes, these technologies reduce a couple's risk down to 1–2% from 25–50%, "but testing one cell for one gene mutation will never be as reliable as testing millions of cells from a conventional prenatal amniocentesis."

As science advances medicine's capabilities, ethical quandaries seem bound to grow in complexity, according to Caplan. "PGD techniques are still primitive and in their early stages of development," he said. "We've only recently mapped the genome and don't fully understand the role genes play in certain traits and behaviors. That will present more opportunities for engineering and give us more to work with."

The larger issue, according to Hughes, is what is the difference between a disease and a trait? And, who decides that? "Few people would argue that spinal muscular atrophy and Fanconi anemia are terrible diseases, while a person's eye color and ear wax consistency are traits," he said. "But there is a huge gray zone in between, and it is changing and evolving with time."

For instance, when Genesis Genetics first performed PGD for cystic fibrosis, many children didn't live through their teens. "Today, with modern pulmonary and gastrointestinal medical advances, many individuals with this disease are now in their 30s and having children of their own," Hughes said. "This is progress—but is it now less ethical to perform PGD for cystic fibrosis than in 1992?"

The Laboratory's Point of View

Laboratory professionals who work in the ART field are aware of the favorable safety profile of IVF and embryo biopsy. "Having seen the impact a given medical condition can have on an affected child, most laboratory professionals believe the benefit of preventing an affected child outweighs the risks of ART and is preferable to termination of an ongoing pregnancy," Forman said.

The safety and reliability of PGD has been validated to a sufficient extent by both the American Society for Reproductive Medicine and Society of Assisted Reproductive Technology, as they consider it "standard clinical practice," rather than an experimental procedure, Forman noted.

According to Hughes, many couples come to Genesis Genetics seeking a savior sibling for quite a number of genetic disorders—mostly hematological ones such as sickle cell or genetic anemias, and for some inborn errors of metabolism as well. "Some couples achieve a healthy, cord-matching pregnancy on the first try," he said. "Others have tried many times and the statistics don't work for them. This is why screening embryos for a set of traits is a silly idea."

Hughes explained that an IVF cycle may produce one or two embryos that are disease-free and a transplant match. "But, these two must be growing well to have a chance for uterine implantation, and they must have the correct number of chromosomes," he noted. "So, the danger is that the roller coaster of hope and disappointment occurs over and over."

Hughes believes most lab professionals are opposed to embryo sex selection. "I went into science and medicine to diagnose, treat, and hopefully cure disease," he said. "The last time I checked, one's gender was not a disease. There is no pain or suffering and no reason for a doctor or clinical laboratory professional to be involved in it." Nonetheless, some couples do come to Genesis Genetics with this goal in mind. Most want a girl.

In speaking with several PGD laboratory directors, Gronowski said they agree that thoughtful, ethical decision-making is necessary. Most laboratories have committees to discuss the ethics of testing requests and they require patients to undergo genetic counseling.

Karen Appold is a freelance writer who lives in Lehigh Valley, Pa. Her email address is [email protected].