Genetic Screening of Sperm and Oocyte Donors: Title and subTitle BreakEthical and Policy Implications

Family formation through the use of assisted reproductive technology (ART) has increased steadily since the introduction of in vitro fertilization in 1978. Worldwide, more than 3 million individuals can trace their conception to in vitro fertilization, with nearly 3 in every 100 births in the United States currently attributable to some form of assisted conception.^{1 - 3} Concomitantly increasing are the numbers of births using third-party gamete donors—men and women who contribute sperm and eggs to another individual's or couple's reproductive enterprise. Although inaptly called donors because gamete providers typically receive compensation for their services, these individuals are essential to prospective parents who are without partners, in same-sex relationships, cannot afford advanced reproductive techniques such as microsurgical sperm aspiration, in vitro fertilization, and intracytoplasmic sperm injection, or whose infertility is linked to poor gametic quality.

In this issue of JAMA, Maron et al⁴ report the case of a male donor who unwittingly transmitted hypertrophic cardiomyopathy, a hereditary and potentially lethal cardiac anomaly, to offspring whose parents obtained his donor sperm from a commercial sperm bank. While highlighting the potential public health risks associated with undetected genetic mutations in gamete donors, the authors also raise critical questions about the practicality of comprehensive genetic testing of donors. Cost, coupled with the large and increasing multitude of detectable genetically transmitted diseases, pose significant challenges for ART patients, clinicians, and other professionals.

Legitimate concerns regarding the transmission of genetic disorders prompted Maron et al⁴ to call for a 2-pronged approach, using proactive and reactive measures to address and prevent the introduction of donor-based mutations into the recipient parents' genetic line. First, the authors advocate enhanced donor screening protocols, using family history as well as genetic and diagnostic testing (such as electrocardiogram for hypertrophic cardiomyopathy) to more effectively identify diseases detectable by these methods. Second, the authors suggest recording donor information in a national searchable database to facilitate identification and notification of affected offspring should a genetic disorder arise anywhere in the donor's pedigree.

Mandating comprehensive genetic screening of gamete donors as well as establishing a national donor registry may strike law and policy makers as measured and appropriate responses to prevent multigenerational transmission of donor-based genetic disorders. Before any such legal schemes are established, it is essential to consider the potential effects on each stakeholder in the ART equation, namely gamete donors, intended parents who use donor gametes, commercial sperm banks and egg donor agencies, and the offspring born with the aid of third-party donors.

In the main, gamete donors are unmarried men and women in their 20s and early 30s who are not parents. Individuals in this demographic group typically do not contemplate their own genetic health, let alone that of their offspring, until faced with their own childbearing decisions. For this reason, pretest and posttest genetic counseling should be required elements of any genetic screening protocol. However, evidence from another system of mandatory screening, regional newborn screening programs, indicates these counseling elements are not uniformly met.⁵ Donors need to understand that discovery of genetic information has individual as well as intragenerational and intergenerational significance. To the extent that testing for predisposition to heritable adult-onset disorders such as Alzheimer disease, breast cancer, and colorectal cancer are available, donors must be given the opportunity to make an informed choice about whether they wish to learn the results.

Donor tracing, as a posthoc response once a genetic disorder manifests or is detected in offspring, has generated substantial public debate. Some individuals involved with ART have suggested a mandatory national gamete donor registry.^{6 - 7} Others favor a voluntary registry to centralize, maintain, and disseminate genetic and other medical information about gamete donors. Interest in a national donor database coalesced around a 2008 symposium during which representatives from the sperm and egg donor industry, donor-conceived children and their parents, and ART clinicians reportedly showed support for a voluntary registry,⁸ but to date no such system has been implemented. Hurdles include establishing a consensus regarding content, access, privacy, and financial responsibility. Attempts to enact laws requiring gamete donors to be named on offspring birth certificates have garnered only weak support, reinforcing US norms that protect donor anonymity.⁹

The cost of enhanced genetic donor screening will no doubt pass to gamete recipients, affecting the ability of less wealthy individuals to access this form of third-party reproduction. Those who can proceed will likely welcome the larger pool of health-related information. Geneticists caution, however, that prospective parents should be counseled about the limitations of genetic testing and its relationship to long-term offspring health. Providing recipients a clean genetic bill of health about a chosen donor can lead to a false sense of confidence about the risk of illness their child might face. A significant proportion of some genetic conditions, such as neurofibromatosis, arise from de novo mutations.

Careful counseling is especially advised when donor test results are negative for cancer-susceptibility genetic mutations, such as those found in the early onset breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) genes. Understanding that the majority of breast and ovarian cancers are not linked to these genes will help parents develop a more realistic outlook on their child's overall cancer risk. Morever, preconception counseling should make clear that genetic testing may reduce the risk for specific diseases but cannot eliminate the 3% to 4% risk for birth defects that exists in all live-born children.¹⁰

Current use of genetic screening by sperm and egg donor enterprises is best described as inconsistent, largely because no federal regulations standardize donor screening for genetic anomalies. US Food and Drug Administration guidelines on gamete donation focus primarily on infectious agents, with scant attention paid to genetic disorders.¹¹ Arguably, it is not clear that such a standard would be effective or efficient given that genetic disorders can arise de novo, as well as cluster around demographic features such as race, ethnicity, sex, and religion—thus obviating the need to screen in many populations. In fact, obtaining a detailed family medical history may be just as useful in detecting a donor's likelihood of transmitting certain genetic diseases.¹⁰

Gamete agencies that support screening donors are not without guidance. The American Society for Reproductive Medicine has published practice guidelines for gamete and embryo donation including specific recommendations on genetic screening for gamete donors.¹² Compliance with its guidelines is voluntary, and data suggest the majority of sperm banks and egg donor agencies do not follow the established screening protocols. In the case of sperm banks, only half of all programs reported conducting a chromosome analysis on donor applicants, whereas a quarter of all egg donor agencies reported no screening for oocyte donors.^{10 ,13} Even in centers that did report testing, most did not fully follow the guidelines set forth by the American Society for Reproductive Medicine. While not insurmountable, shifting from an environment of no or low screening to a standard of robust activity will require a period of technical and cultural transition.

Preventing transmission of genetic disorders to donor offspring is vital to individual health, as well as the health of the burgeoning ART field. Incidence of transmission via gamete donors is rare compared with transmission in the general population, but penetrance in any child can be devastating. In addition to hypertrophic cardiomyopathy, gamete donors have been linked to transmission of several disorders including autosomal dominant polycystic kidney disease,¹⁴ cystic fibrosis,¹⁵ and severe congenital neutropenia.¹⁶ With each new case, calls for enhanced screening and mandatory registration of gamete donors understandably grow louder.¹⁷

Opponents of mandatory genetic screening of gamete donors cite cost and the impracticality and low yield associated with a comprehensive approach as a rationale for maintaining the current market-driven program-by-program system. Maron et al⁴ present a strong counterargument, which states that enhanced screening, as suggested by the American Society for Reproductive Medicine, and simple diagnostics such as electrocardiogram, are in the public's best interest. Adding baseline genetic screening to current US Food and Drug Administration regulations and establishing a voluntary registry of gamete donors are sensible enhancements to a field historically vigilant of offspring health and patient confidence.