Carrier Screening is a Deficient Strategy for Determining Sperm Donor Eligibility and Reducing Risk of Disease in Recipient Children.

AIMS: DNA-based carrier screening is a standard component of donor eligibility protocols practiced by U.S. sperm banks. Applicants who test positive for carrying a recessive disease mutation are typically disqualified. The aim of our study was to examine the utility of a range of screening panels adopted by the industry and the effectiveness of the screening paradigm in reducing a future child's risk of inheriting disease. METHODS: A cohort of 27 donor applicants, who tested negative on an initial cystic fibrosis carrier test, was further screened with three expanded commercial carrier testing panels. These results were then compared to a systematic analysis of the applicants' DNA using next-generation sequencing (NGS) data. RESULTS: The carrier panels detected serious pediatric disease mutations in one, four, or six donor applicants. Because each panel screens distinct regions of the genome, no single donor was uniformly identified as carrier positive by all three panels. In contrast, systematic NGS analysis identified all donors as carriers of one or more mutations associated with severe monogenic pediatric disease. These included 30 variants classified as "pathogenic" based on clinical observation and 66 with a high likelihood of causing gene dysfunction. CONCLUSION: Despite tremendous advances in variant identification, understanding, and analysis, the vast majority of disease-causing mutation combinations remain undetected by commercial carrier screening panels, which cover a narrow, and often distinct, subset of genes and mutations. The biological reality is that all donors and recipients carry serious recessive disease mutations. This challenges the utility of any screening protocol that anchors donor eligibility to carrier status. A more effective approach to reducing recessive disease risk would consider joint comprehensive analysis of both donor and recipient disease mutations. This type of high-resolution recessive disease risk analysis is now available and affordable, but industry practice must be modified to incorporate its use.

Stability of selected serum hormones and lipids after long-term storage in the Janus Serum Bank.

BACKGROUND: The potential value of a biobank depends on the quality of the samples, i.e. how well they reflect the biological or biochemical state of the donors at the time of sampling. Documentation of sample quality has become a particularly important issue for researchers and users of biobank studies. OBJECTIVE: The aim of this study was to investigate the long-term stability of selected components: cholesterol, high density cholesterol (HDLC), low density cholesterol (LDLC), apolipoprotein A1 (apo-A1), apolipoprotein B (apo B), follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), thyroid stimulating hormone (TSH) and free thyroxin (FT4). DESIGN AND METHODS: Samples, stored at -25°C, from 520 men aged 40-49 years at blood sampling distributed in equally sized groups (n=130) according to length of storage, 0, 4, 17 and 29 years, respectively, were used in a cross sectional design. The freshly collected serum samples were used as a reference group to calculate storage related changes. RESULTS: The differences between fresh samples and samples stored for 29 years were substantial for apo-A1 (+12%), apo-B (+22.3%), HDLC (-69.2%), LDLC (+31.3%), and PRL (-33.5%), while total cholesterol, FSH, LH, TSH and FT4 did not show any significant difference. CONCLUSIONS: The study showed large differences in serum level of the selected components. The lipids and apolipoproteins were all changed except for total cholesterol. Most hormones investigated (FSH, LH, TSH and FT4) proved to be stable after 29 years of storage while PRL showed sign of degradation. The observed differences are probably due to long-term storage effects and/or external factors (i.e. diet and smoking).

The ownership that wasn't meant to be: Yearworth and property rights in human tissue.

This paper is concerned with the English Court of Appeal's decision in Yearworth v North Bristol NHS Trust that six men had, for the purposes of their claims against the trust, ownership of the sperm they had produced. The case has been discussed by many commentators and most, if not all, of those who have discussed the case have claimed or assumed that the court held that the claimants had property rights in the sperm they had produced. In this paper, I advance an interpretation of the case that does not regard the court as deciding that the men had property rights (in the narrow sense of that term) in the sperm they had produced. On this view, the 'ownership' that the Court of Appeal purported to vest in each of the men was not a right in rem, a right 'binding the world'. If this is so, it is perhaps unsurprising that some scholars, evaluating the success of the court's reasoning as a justification for vesting the claimants with property rights, have found it to be unsatisfactory.

Clinical guidelines for sperm cryopreservation in cancer patients.

No clear clinical guidelines exist on how to counsel male cancer patients about fertility preservation. Detailed counseling is recommended before treatment when issues of collection and storage need to be highlighted. Concern about the quality of sperm collected before and/or after treatment in terms of assisted reproduction is needed, and the potential outcomes should be discussed early as part of cancer survivorship. The discussion should be sensitive and tailored to the ethical situation based on the age of the patient, the severity of the illness, the need to initiate treatment, and genetic risk. Cryopreservation should be attempted/achieved before cancer treatment is initiated. Cryopreservation should not be performed during treatment or for some time after treatment because of the chromosomal and structural damage to sperm from cancer treatment. Contraception should be instigated during this period.

Genetic testing of sperm donors for cystic fibrosis and spinal muscular atrophy: evaluation of clinical utility.

OBJECTIVE: To evaluate the clinical utility of genetic testing for cystic fibrosis (CF) and spinal muscular atrophy (SMA) in sperm donors. STUDY DESIGN: We studied the results of the genetic tests for CF and SMA applied to 372 sperm donor candidates. The CF carrier screening test analysed 32 mutations on the CFTR gene. Regarding SMA, the carrier test studied possible deletions of SMN1/2 by Multiplex Ligation-dependent Probe Amplification (MLPA) methodology. RESULTS: The carrier frequency obtained was greater for SMA than for CF. After adjusting the results obtained for the sensitivity of the tests, and taking into account the prevalence of female carriers in our population, the probability of transmission of the disease to the child from a donor with a negative genetic test was about five times lower in the case of SMA than in CF, although this difference was not statistically significant. The number of donors needed to screen (NNS) to avoid the occurrence of a child being affected by CF and SMA in our population was similar in both cases (1591 vs. 1536). CONCLUSIONS: This study demonstrates the need to include SMA among the diseases for which genetic screening is performed in the process of sperm donor selection. We believe that testing donors for SMA is as important and as useful as doing so for CF.

Lost property? Legal compensation for destroyed sperm: a reflection and comparison drawing on UK and French perspectives.

In a recent case in the UK, six men stored their sperm before undergoing chemotherapy treatment for cancer in case they proved to be infertile after the treatment. The sperm was not properly stored and as a result was inadvertently destroyed. The men sued the NHS Trust that stored the sperm and were in the end successful. This paper questions the basis on which the judgement was made and the rationale behind it, namely that the men 'had ownership' of the sperm, and that compensation was thus due on the grounds that the men's property had been destroyed. We first argue that the claim is erroneous and enhances the tendency towards the commodification of body parts. We then suggest that the men could have been compensated for the harm done to them without granting property rights, and that this would, at least in philosophical and ethical terms, have been more appropriate. To help illustrate this, we draw on a parallel case in French law in which a couple whose embryos had been destroyed were overtly denied ownership rights in them. Finally, we suggest some possible ethical and practical problems if the proprietary view expressed in the UK ruling were to become dominant in law, with particular focus on the storing of genetic information in biobanks. We conclude that, although compensation claims should not necessarily be ruled out, a 'no property in the body' approach should be the default position in cases of detached bodily materials, the alternative being significantly ethically problematic.

Yearworth v. North Bristol NHS trust: a property case of uncertain significance?

It has long been the position in law that, subject to some minor but important exceptions, property cannot be held in the human body, whether living or dead. In the recent case of Yearworth and Others v North Bristol NHS Trust, however, the Court of Appeal for England and Wales revisited the property debate and threw into doubt a number of doctrines with respect to property and the body. This brief article analyses Yearworth, (1) reviewing the facts and the Court's decision with respect to the originators' proprietary and contractual interests in their body and bodily products, (2) considering the significance of relying on property and its use a legal metaphor, (3) questioning the scope of the property right created, and (4) querying whether an alternate conceptual approach to extending rights and a remedy was warranted. It concludes that, while Yearworth engages with, and impacts on, important theoretical and practical issues--from legal, healthcare and research perspectives--it does not offer a great deal of guidance and, for that reason, its precedential significance is in doubt.

Genetic testing of sperm donors: survey of current practices.

OBJECTIVE: To determine which genetic tests are being performed on sperm donor applicants in the United States. DESIGN: An electronic survey was distributed to 26 sperm banks to evaluate their genetic testing practices. SETTING: Sperm banks in the United States. PATIENT(S): Not applicable. INTERVENTION(S): None. Survey of current practices. MAIN OUTCOME MEASURE(S): Survey of current practices. RESULT(S): Cystic fibrosis (CF) carrier screening, chromosome analyses, and hemoglobin evaluations are performed on the majority of sperm donor applicants. Tay-Sachs disease carrier screening is performed on most donors with Jewish heritage but there is significant variation in screening for other disorders that occur with increased frequency in this population. Individual sperm banks use different laboratory tests for evaluation of the same conditions, with each test having different carrier detection rates and interpretations. CONCLUSION(S): The genetic testing performed on sperm donors varies significantly at sperm banks across the United States. Therefore, recipients should be clearly informed about the specific evaluations performed on their donor of interest. Thus it is important that sperm banks employ genetic professionals to evaluate the donors' and recipients' medical histories and perform a genetic risk assessment. This will allow clients to make informed decisions about use of semen specimens from an anonymous sperm donor.

Young males' experiences of sperm banking following a cancer diagnosis - a qualitative study.

Existing research into sperm banking by young males following a cancer diagnosis is predominantly quantitative; little is known about personal experiences, psychosocial and attitudinal barriers to it amongst patients and/or professionals, or the later impact of potential or actual subfertility when banking has or has not taken place. This qualitative study used single in-depth interviews with 16 males aged 13 to 20 at diagnosis (16 to 30 years at interview) to report retrospectively on their experiences, concerns and satisfactions. There was support for sperm banking, including among those who declined to bank or failed to do so successfully. Many reported that, when successful, it eased any later fertility-related concerns by offering a possible alternative route to biological fatherhood. There was satisfaction with levels of understanding, recall and decision making, though lack of clarity about consent conditions. Sperm bank professionals were less likely than oncology staff to achieve good rapport. Improvements to consent arrangements, facilities, written information and sharing of results were suggested. Small numbers from minority ethnic or disabled communities meant that any uniqueness in their experiences could not be identified. While some improvements to the process of sperm banking and follow-up can be acted upon with minimal implications, others may be more complex.

Paternity following treatment for testicular cancer.

BACKGROUND: Studies of fertility in men treated for testicular cancer have mainly addressed serum follicle-stimulating hormone levels and sperm parameters. We assessed post-treatment paternity among long-term survivors of testicular cancer. METHODS: Men (n = 1814) who had been treated for unilateral testicular cancer in Norway during 1980 through 1994 were invited to participate in a national multi-center follow-up survey in 1998 through 2002. The participants were allocated to five groups according to the treatment received after orchiectomy, including treatment at relapse (surveillance, retroperitoneal lymph node dissection, radiotherapy, low-dose chemotherapy [i.e., < or = 850 mg cisplatin], and high-dose chemotherapy [i.e., > 850 mg cisplatin]). Cox proportional hazards analysis was used to assess predictive factors for post-treatment paternity. Statistical tests were two-sided. RESULTS: A total of 1433 men were assessable, of whom 827 were fathers at diagnosis. Post-treatment conception was attempted by 554 men, among whom the overall 15-year actuarial post-treatment paternity rate was 71% (95% confidence interval [CI] = 66% to 75%) without the use of cryopreserved semen. This rate ranged from 48% (95% CI = 30% to 69%) in the high-dose chemotherapy group to 92% (95% CI = 78% to 98%) in the surveillance group (P < .001). The median actuarial time from diagnosis to the birth of the first child after treatment was 6.6 years overall but varied according to treatment. Assisted reproductive technologies were used by 22% of the couples who attempted conception after treatment. Dry ejaculation, treatment group, pretreatment fatherhood, and marital status were statistically significant independent predictors for post-treatment fatherhood, with dry ejaculation as the most important negative factor. CONCLUSIONS: Although the overall paternity rate after treatment for testicular cancer was high, the ability to conceive and the time to conception reflected the intensity of treatment. These data may help inform patients about their future ability to father biological children.

Storing reproduction for oncological patients: some points for discussion.

Since the introduction of sophisticated techniques of assisted reproduction such as IVF and ICSI, all male patients that undergo a cancer treatment jeopardizing their future fertility status should be offered the opportunity to bank their semen. Only azoospermic semen samples are to be rejected for pre-treatment banking. Patients who became severely oligospermic or azoospermic after chemotherapy but did not bank their semen, are often not allowed to have assisted reproduction because of the concerns about the mutagenic aspects of their treatment. In a small case series (n = 10), we recovered testicular sperm for ICSI in 40% of patients who became azoospermic after chemotherapy. Since, so far, the few clinical data available do no not suggest an increased risk for congenital anomalies in children born from patients obtaining a pregnancy during chemotherapy, the question remains whether the concerns raised about treating patients who became oligozoospermic or azoospermic or even about semen banking during chemotherapy are incontestable.

Reasons for rejecting potential donors from a sperm bank program.

PURPOSE: Recruiting donors to a sperm bank program is difficult and slow because of high dropout rates and high rejection rates. The profile of successful and unsuccessful donors was determined at our sperm bank. METHODS: A total of 199 men was screened from 1986 to 1994 in the anonymous sperm bank donor programs; 174 (87%) men dropped out or did not meet minimum guidelines. The study included 25 accepted donors and 20 rejected men (of 52 rejected donors, only 20 donors who came for two consecutive semen analyses were selected). Sperm quality variables and demographic data were compared between the groups. RESULTS: Accepted donors had significantly better semen quality in motility, velocity, linearity, and ALH than did rejected donors (P < 0.01). More rejected donors than accepted donors were single (P < 0.01). A higher percentage of accepted donors consumed caffeine (P < 0.001), and they were more likely to have college degrees (P < 0.03). CONCLUSIONS: These results indicate that loss of interest and poor semen quality were the major reasons for rejection of donors in our anonymous donor sperm bank program.

Public Health Service inter-agency guidelines for screening donors of blood, plasma, organs, tissues, and semen for evidence of hepatitis B and hepatitis C.

Several infectious agents transmit through infected blood and blood products. To decrease the potential for disease transmission, donors are screened for risk factors by medical history and for evidence of infection by specific testing. The Food and Drug Administration (FDA) currently requires that all donations of whole blood and transfusable components as well as plasma for fractionation into injectable derivatives be subjected to a serologic test for syphilis, hepatitis B surface antigen (HBsAg), and antibody to the human immunodeficiency virus (anti-HIV). The FDA also currently recommends testing donations of whole blood and components for transfusion for antibody to human T lymphotropic virus type I (anti-HTLV-I) and antibody to hepatitis C virus (anti-HCV), and is considering recommending testing for antibody to hepatitis B core antigen (anti-HBc). Blood banks in the United States voluntarily began testing donations for anti-HBc and alanine aminotransferase (ALT) in 1986 and 1987 and for anti-HCV in 1990.

Screening of karyotype and semen quality in an artificial insemination program: acceptance and rejection criteria.

Semen quality and karyotype were screened in all men offering to be donors for an artificial insemination (AID) program. The criteria for accepting or rejecting semen have now been set with respect to this sample of the population. There was no evidence of differences between the pregnancy rates of the accepted donors. One of 172 potential donors with a clear medical history had a chromosomal abnormality, 4 had pericentric inversions of chromosome 9, and 14 had other heterochromatic variants. Of the recipients of AID, 5 of 196 women had chromosomal abnormalities, and 12 had heterochromatic variants.