Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, NC, USA.
Abstract
We wished to determine how clinicians manage sperm donors whose offspring have chromosomal or structural abnormalities. A directed, multiple-choice survey was given to reproductive endocrinologists and obstetrical geneticists to assess management of sperm donors whose offspring have chromosomal or structural abnormalities. The questionnaire was completed by 66 reproductive endocrinologists and obstetrical geneticists. Abnormalities and the most common inheritance modes included: Trisomy 21 (aneuploidy, maternal origin), Turner syndrome (aneuploidy, paternal origin), cleft lip/palate (multifactorial), VATER sequence (vertebral defects, imperforate anus, tracheo-esophageal fistula, radial and renal dysplasia, sporadic inheritance), and Hurler syndrome (autosomal recessive). Response choices were: (i) remove donor from programme, (ii) inform potential recipients of prior pregnancy outcomes and continue to use donor, or (iii) further study donor to assess karyotype/mutations. Inheritance mode appeared to influence decisions to remove donors from sperm banks; however, no clear consensus was noted. Guidelines exist for screening potential gamete donors, but not for managing donors whose offspring has a chromosomal or structural abnormality. Guidelines must be developed to manage sperm donors with untoward pregnancy outcomes.
Key words: sperm donors/gamete donors/chromosomal abnormality/structural abnormality
Introduction
A 1987 survey estimated that therapeutic donor insemination (DI) resulted in ~30000 births per year in the USA (United States Congress, Office of Technology Assessment, 1988). In the UK, the Human Fertilisation and Embryology Authority (HFEA) indicated that 1671 live births from DI occurred in 1994 (Fifth Annual Report, 1996
). Most cryopreserved DI semen is from commercial sperm banks. Since semen from a single donor in the USA can result in many pregnancies, deBoer et al. has suggested limiting donors to 25 per 800 000 population (deBoer et al., 1995
), as did a 1997 American College of Obstetricians and Gynecologists (ACOG) committee opinion (American College of Obstetricians and Gynecologists, 1995
). To limit the risk of consanguinity, the 1993 American Society for Reproductive Medicine (ASRM) guidelines suggested limiting the number of pregnancies to 10 per donor (The American Fertility Society, 1993
). In the UK, the HFEA is the statutory body that regulates, licenses and monitors clinics, and limits donors to ten pregnancies.
At the University of North Carolina at Chapel Hill (UNC-CH), 700 DI cycles were performed last year in accordance with ASRM guidelines. ACOG and ASRM address genetic screening for gamete donors, but neither addresses donor disposition once a child with structural or chromosomal abnormalities is born. ACOG has recommended that a three-generation pedigree be undertaken for genetic disorders and to determine the donor's ethnic background. Genetic diseases in the following categories are especially important:
The French CECOS Federation, an association of various centres providing semen cryopreservation and distribution, has provided guidelines for semen donor screening (Jalbert et al.1989). Similar guidelines to ACOG and ASRM have been provided. CECOS states that some genetic elements justify exclusion of the donor; for example, a severe autosomal dominant condition, a confirmed heterozygosity for an autosomal recessive disease, or a chromosome anomaly.
With a risk of structural and chromosomal abnormalities in the general population of 25%, ~900 DI births in the USA would theoretically result in chromosomal or structural abnormalities annually (based on 3% of 30000 births from DI per year). The actual occurrence of donors producing a genetic abnormality may be lower since sperm donors are excluded if their family genetic history is questionable. In fact, in 1996, a malformation rate of only 1.9% was noted in the 1298 deliveries conceived through DI and recorded by the French Federation of CECOS and IFRAES in Toulouse (Thepot, 1998). Additionally, the British Andrology Society issued revised guidelines in 1999 that should further reduce the incidence of chromosomal abnormalities in offspring. The major alterations included an upper donor age limit (<40 years old) and more extensive screening for chromosomal abnormalities (British Andrology Society, 1999
).
Survey and responses
We sought to determine how infertility or genetics specialists would manage a sperm donor whose resultant pregnancy had such a chromosomal or structural abnormality. A written questionnaire, with answers obtained anonymously, assessed how 66 reproductive endocrinologists and obstetrical geneticists would manage a donor of offspring with a chromosomal or structural abnormality. Five conditions were presented, with explanations for inheritance modes: Trisomy 21, Turner syndrome, cleft lip/palate, VATER sequence, and Hurler syndrome. Identical hypothetical scenarios involved a donor with 15 normal births. If the next pregnancy showed one of the conditions, the clinician chose an action: (i) remove donor from the programme; (ii) inform future recipients of this untoward pregnancy and continue using the donor; or (iii) study the donor to assess karyotype/mutations.
Of 66 respondents, 29 (44%) were reproductive endocrinologists and 37 (56%) were geneticists. We examined responses for the group and by specialty, using Stata statistical software (Stata Corporation, College Station, TX, USA) for analyses. We used Fisher exact test for nx2 comparisons, and unpaired t-tests for differences in the mean for continuous variables in stratified analyses. Except for Turner syndrome, there were no significant differences between the responses of reproductive endocrinologists and geneticists.
Trisomy 21, an autosomal aneuploidy most commonly (8090%) of maternal origin, has a recurrence rate for full trisomy 21 of 12%. A paternal balanced translocation in the presented scenario is statistical unlikely since the donor has produced 14 `normal' offspring. Of the respondents, 79% would keep the donor in the pool.
Turner syndrome, a sex chromosome aneuploidy commonly (80%) of paternal origin, has a recurrence rate of <1%. Of the respondents, 54% would continue using a donor with a Turner syndrome offspring, with geneticists being more likely than endocrinologists to continue using the donor (70 versus 34%, P = 0.019 ). Of the endocrinologists, 45% would remove the donor.
Cleft lip/palate has a multifactorial inheritance mode and a 4% recurrence rate; 60% of the respondents would continue using the donor, and 38% would not.
VATER sequence, with vertebral defects, imperforate anus, tracheoesophageal fistula, radial dysplasia, and renal abnormalities, has a sporadic inheritance mode of unknown etiology; offspring from a couple with an affected child are thought to have the same risk as the general population. Of the respondents, 65% would continue using the donor, and 33% would not.
Hurler syndrome has autosomal recessive inheritance. Homozygous affected individuals show severe mucopolysaccharidoses from an enzyme -L-Iduronidase deficiency. A phenotypically normal donor with an affected child is an obligate carrier who passes an abnormal allele to 50% of his children. Of the respondents, 83% would remove this donor from the pool.
Discussion
Because sperm donor screening for more than basic abnormalities is time- and cost-prohibitive, many centres manage donors with untoward pregnancy outcomes individuallythere is no management consensus. Thus, it appears that in our survey respondents' answers were subjective and may reflect their exposure to an infrequent or never observed occurrence. Inheritance mode appeared to provide a basis for respondents' decisions. Most respondents would remove the donor from the pool only in a severe autosomal recessive condition such as Hurler syndrome, where the donor is a carrier. With VATER sequence, a decision to remove a donor might reflect the severity of the deformity. Although future offspring are no more likely to have this condition than the general population, a third of respondents would remove the donor from the pool, despite the statistical improbability of recurrence.
Endocrinologists and geneticists responded similarly, except for Turner syndrome. Geneticists were twice as likely as endocrinologists to continue using a donor with a Turner syndrome child. Geneticists, with their Mendelian training, may be more aware of the recurrence risk for Turner syndrome (<1%) than endocrinologists; the latter may also be biased by the mention of paternal inheritance.
A clinician might remove any donor from the DI pool once an abnormal pregnancy is detected, but several factors must be noted. Donors must go through time-consuming and expensive screening that is paid for by the DI programme, no matter how often a donor's gametes are used. Removing donors shifts the financial burden to future recipients. Abnormal DI offspring may be unreported, unrecognized, or reported months after the donor sperm has been used in other recipients. With no international consensus, there are no explicit guidelines for donor disposition, and no uniformity among specialists. In our questionnaire, no management consensus emerged regarding abnormal offspring. We acknowledge that our report is an `opinion poll' which asked what action reproductive and genetic clinicians might take in response to an orchestrated situation. We hope that this report will generate further discussion in hopes of better defining a uniform management algorithm. Presently, the UNC-CH Assisted Reproductive Technologies Ethics Committee modified the programme's consent form to remove a donor from the programme if the chance for a recurrence of an abnormality is higher than in the background population. Also, abnormal offspring resulting from DI are discussed by the committee.
Notes
1 To whom correspondence should be addressed at: OB/Gyn214 MacNider Building, CB#7516, UNC-Chapel Hill, NC 27599-7516, USA. Email: Jeffrey_Kuller{at}med.unc.edu
References
American College of Obstetricians and Gynecologists (1995) Genetic screening of gamete donors. ACOG Committee Opinion No.192, Washington, DC, USA.
British Andrology Society (1999) Guidelines for the screening of semen donors for donor insemination. Hum. Reprod., 14, 18231826.
deBoer, A., Oosterwijk, J.C. and Ritgers-Aris, C.A. (1995) Determination of a maximum number of artificial inseminations by donor children per sperm donor. Fertil. Steril., 63, 419421.[ISI][Medline]
Fifth Annual Report and Accounts (1996) Human Fertilisation and Embryology Authority.
Jalbert, P., Leonard, C., Salva, J. and David, G. (1989) Genetic aspects of artificial insemination with donor semen: The French CECOS Federation guidelines. Am. J. Med. Genet., 33, 269275.[ISI][Medline]
The American Fertility Society (1993) Guidelines for gamete donation. Fertil. Steril., 59, 1S9S.[Medline]
Thepot, F. (1998) 1997 results of medical assisted procreation with third-party donations and autopreservation: CECOS French Federation. Contraception, Fertilite, Sexualite, 26, 476480.
United States Congress, Office of Technology Assessment (1988) Artificial insemination practice in the United States: summary of a 1987 survey-background paper. United States Government Printing Office, Washington, DC.