A decade of the United Kingdom sperm-washing program: untangling the transatlantic divide
2010; Elsevier BV; Volume: 94; Issue: 6 Linguagem: Inglês
10.1016/j.fertnstert.2010.03.074
ISSN1556-5653
AutoresJames Nicopoullos, Paula Almeida, Maria Vourliotis, Carole Gilling‐Smith,
Tópico(s)Demographic Trends and Gender Preferences
ResumoFertility assistance to HIV-positive men is now accepted practice in many parts of the world. We analyze the legislative, ethical, and clinical factors that explain the differences across continents with the aim of opening up the debate within the United States on whether clinics can justify denying HIV-infected men the opportunity of parenting through a now well-established risk reduction method with a proved safety record. Fertility assistance to HIV-positive men is now accepted practice in many parts of the world. We analyze the legislative, ethical, and clinical factors that explain the differences across continents with the aim of opening up the debate within the United States on whether clinics can justify denying HIV-infected men the opportunity of parenting through a now well-established risk reduction method with a proved safety record. The introduction of highly active antiretroviral therapy (HAART) during the 1990s has seen a radical change in the quality of life, long-term prognosis, and life expectancy of those infected and led to the redefinition of HIV as a chronic disease (1Scandlyn J. When AIDS became a chronic disease.West J Med. 2000; 172: 130-133Crossref PubMed Scopus (51) Google Scholar). This in turn has created a demand for methods that can enable infected patients to have children without generating any risk to their partner or child. Sperm washing, originally proposed by Semprini et al. (2Semprini A.E. Levi-Setti P. Bozzo M. Ravizza M. Taglioretti A. Sulpizio P. et al.Insemination of HIV-negative women with processed semen of HIV-positive partners.Lancet. 1992; 340: 1317-1319Abstract Full Text PDF PubMed Scopus (290) Google Scholar), resting on the observation that HIV is present as free virus in the seminal plasma and as cell-associated virus in the leukocytes or nonsperm cells but does not appear to be able to attach to, or infect, spermatozoa (3Baccetti B. Benedetto A. Burrini A.G. Collodel G. Elia C. Piomboni P. et al.HIV particles detected in spermatozoa of patients with AIDS.J Submicrosc Cytol Pathol. 1991; 23: 339-345PubMed Google Scholar, 4Bagasra O. Farzadegan H. Seshamma T. Oakes J.W. Saah A. Pomerantz R.J. Detection of HIV-1 proviral DNA in sperm from HIV-1–infected men.Aids. 1994; 8: 1669-1674Crossref PubMed Scopus (146) Google Scholar, 5Quayle A.J. Xu C. Mayer K.H. Anderson D.J. T lymphocytes and macrophages, but not motile spermatozoa, are a significant source of human immunodeficiency virus in semen.J Infect Dis. 1997; 176: 960-968Crossref PubMed Scopus (238) Google Scholar, 6Quayle A.J. Xu C. Tucker L. Anderson D.J. The case against an association between HIV-1 and sperm: molecular evidence.J Reprod Immunol. 1998; 41: 127-136Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar), has become standard practice in European centers.The first series of successful cases were reported in Milan in 1992 (2Semprini A.E. Levi-Setti P. Bozzo M. Ravizza M. Taglioretti A. Sulpizio P. et al.Insemination of HIV-negative women with processed semen of HIV-positive partners.Lancet. 1992; 340: 1317-1319Abstract Full Text PDF PubMed Scopus (290) Google Scholar) and, in the United Kingdom, the Chelsea and Westminster Assisted Conception Unit began to offer a formal sperm washing program in 1999 with 245 couples treated with 439 cycles of IUI, 114 cycles of IVF, and 117 cycles of intracytoplasmic sperm injection (ICSI). Overall a pregnancy rate (PR) and ongoing PR per couple of 45.4% and 36.3% has been achieved with 127 clinical pregnancies, 102 infants born, and 12 pregnancies ongoing with no reported seroconversions.Treatment availability: regulatory and legal issuesIt has become evident, however, that the acceptability of sperm-washing as a treatment, both in terms of safety and ethics, the inclusion criteria for patient treatment, the wash protocol and the types of assisted reproductive treatments (ART) offered differ significantly both within and between continents. Within Europe, the establishment of the collaborative group "CREAThE" (Centre for REproductive Assisted Techniques for HIV in Europe), primarily has tried to address these variations by pooling knowledge, experience, and results from the centers offering sperm washing to improve the service offered to HIV-serodiscordant couples and assess safety and efficacy of the method. CREAThE published the largest series to date of >3,000 cycles of treatment pooled from nine centers with no evidence of seroconversion in the uninfected partner or child on follow-up (7Bujan L. Hollander L. Coudert M. Gilling-Smith C. Vucetich A. Guibert J. et al.Safety and efficacy of sperm washing in HIV-1–serodiscordant couples where the male is infected: results from the European CREAThE network.Aids. 2007; 21: 1909-1914Crossref PubMed Scopus (169) Google Scholar).The Code of Practice of the Human Fertilisation and Embryology Authority, the United Kingdom regulatory body that regulates, licenses, and inspects all United Kingdom clinics providing ART states that "where an individual is shown to be HIV positive, the treatment center is expected to offer counseling from the treatment centre's own qualified counselor and also arrange specialist HIV counseling" (8Human Fertilisation and Embryology Authority. Code of Practice, 6th ed. London: HFEA, 2003.Google Scholar). In 2003, a press release from the then chair stated that "we cannot deny people who are HIV positive the chance to have a healthy baby, unaffected by the virus" (8Human Fertilisation and Embryology Authority. Code of Practice, 6th ed. London: HFEA, 2003.Google Scholar).In 2004, the ethics taskforce of the European Society of Human Reproduction and Embryology (ESHRE) concluded that if certain precautions are taken (suitable treatment compliance, avoidance of other risk factors such as drug abuse, treatment in reference centers with established protocols, a separate adapted laboratory, as well as separate tanks for storage of infected material, and appropriate multidisciplinary support) medical assistance to reproduction of HIV-positive people is ethically acceptable. It also recommended against the treatment of serodiscordant couples, a recommendation yet to be reviewed.A United Kingdom audit of demand for ART in HIV-infected patients found that 16% of men and 4% of women attending HIV specialist clinics had enquired about fertility treatment and 30% and 26% of fertility centers stated that they planned to start treating HIV-positive men and women respectively (9Frodsham L.C. Boag F. Barton S. Gilling-Smith C. Human immunodeficiency virus infection and fertility care in the United Kingdom: demand and supply.Fertil Steril. 2006; 85: 285-289Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar). Despite these findings, few have set up the appropriate laboratory precautions or viral testing required to proceed with treatment (10Gilling-Smith C. Almeida P. HIV, hepatitis B and hepatitis C and infertility: reducing risk.Hum Fertil. 2003; 6: 106-112Crossref Scopus (28) Google Scholar).Within the United States, the barriers to overcome to provide sperm-washing have been considerable. The 1990 recommendation from the Centers for Disease Control and Prevention (CDC) (11Cdc - Center for Disease Control and Prevention: HIV-1 infection and artificial insemination with processed semen.MMWR Morb Mortal Wkly Rep. 1990; 39: 255-256Google Scholar) against insemination of HIV-positive semen that has been washed to decrease viral load has not been updated despite the number of published cycles in the literature. One study in 2006 estimated that only 3% of U.S. fertility clinics admitted to providing treatment to HIV-positive men (12Sauer M.V. American physicians remain slow to embrace the reproductive needs of human immunodeficiency virus–infected patients.Fertil Steril. 2006; 85: 295-297Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). More recently, a web-based survey of members of the American Society for Reproductive Medicine (ASRM) painted an equally bleak picture. From the 22% of units that responded, 40% reported policies on treatment, 51% reported requests for treatment, and 64% reported offering treatment to HIV-serodiscordant couples. The commonest treatments offered to couples with HIV-positive men were reproductive surgery (50%), ovulation induction (46%), and ICSI (45%: although the study did not specify the use of infected partner samples) with 29% of those offering treatment testing washed specimens for HIV (13Stanitis J.A. Grow D.R. Wiczyk H. Fertility services for human immunodeficiency virus–positive patients: provider policy, practice, and perspectives.Fertil Steril. 2008; 89: 1154-1158Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar). The respondents identified the low volume of requests, concern for child welfare, a lack of laboratory policy, and the potential legal risk as the commonest barriers to treatment.The ethics committee of the ASRM had stated previously that "fertility services cannot be withheld ethically from individuals with chronic viral infections, including HIV, if a center has the resources to provide care and that those that do not have the resources or facilities to provide care should facilitate referral to a center with protocols in place to manage such patients" (14ASRMThe Practice Committee of the American Society for Reproductive Medicine: Guidelines for reducing the risk of viral transmission during fertility treatment.Fertil Steril. 2008; 90: S156-S162Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). Furthermore, they encourage viremia of <10,000 copies per milliliter before treatment and testing of the processed sample for HIV RNA before insemination where available to further reduce risk and do not advocate against insemination techniques, actively stating "trauma to the cervix or uterus during the IUI procedure must be minimized" (14ASRMThe Practice Committee of the American Society for Reproductive Medicine: Guidelines for reducing the risk of viral transmission during fertility treatment.Fertil Steril. 2008; 90: S156-S162Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). This is supported by the American College of Obstetricians and Gynecologists, which states that ART "should not be denied to HV-infected couples solely on the basis of their positive serostatus" (15Committee on Ethics of the American College of Obstetricians and Gynecologists. Human immunodeficiency virus: physicians' responsibilities. ACOG Committee Opinion, No. 255, April 2001.Google Scholar).Although the medical body guidance is not dissimilar to that in Europe, the impetus for initiating the arduous safeguards for treatment appear to be further encumbered in the United States by the legislative and legal minefield that exists. As previously reviewed (13Stanitis J.A. Grow D.R. Wiczyk H. Fertility services for human immunodeficiency virus–positive patients: provider policy, practice, and perspectives.Fertil Steril. 2008; 89: 1154-1158Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar), there are state-by-state differences in the laws surrounding the use of HIV-positive semen with some classifying it as a felony (Delaware and Indiana) and others a misdemeanor (Illinois), further complicated by laws less specifically referring to exposure to infected bodily fluids as either a felony in seven states or misdemeanor in three states. In contrast to these concerns and the concern about civil lawsuits, should a partner or a child seroconvert, there is the paradoxical concern of successful prosecution under the American Disabilities Act of 1990 with refusal to treat HIV-positive patients.The lack of a national regulatory body analogous to the HFEA with any federal authority for reproductive policy may also hamper efforts to address inequalities in treatment availability, highlighted by the lack of even a federal mandate on HIV testing before donating sperm for treatment. Progress is therefore often only possible on an individual state basis as recently demonstrated in California. Up until 2008, the California Health and State Code prohibited the transfer of sperm from HIV-positive men and thereby prohibiting their treatment whereas treatment of HIV-positive women was allowed. A survey, highlighting that 65% of clinics would be willing to treat HIV-discordant couples with an infected male should state law change, was instrumental in amending the law to allow the use of semen from an HIV-positive man for ART with a designated partner after mutual informed consent (16Barnhart N. Shannon M. Weber S. Cohan D. Assisted reproduction for couples affected by human immunodeficiency virus in California.Fertil Steril. 2009; 91: 1540-1543Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar).Choice of treatment modality and protocolThe choice of treatment modality and protocol is also seemingly subject to international variation. Within our unit the decision on which ART treatment modality to use is dependent almost entirely on subfertility factors identified during initial work-up with IUI first line in those with voluntary subfertility only or in cases of mild male factor or endometriosis. Thereafter, IVF is used as first line in those with a tubal factor and ICSI when required for a more significant male factor. A potential further factor in the decision may be the presence or absence of state funding for treatment. Although funding for the treatment of HIV-positive patients, either as pure risk reduction or as part of state-funded treatment of subfertility appears to be on the increase, the majority of patients continue to self-fund. Although seminal parameters may warrant more invasive treatment, restricted funds may limit the options available to a couple to IUI, as well as limiting the number of treatment cycles. Furthermore, a quality control test for detectable HIV RNA after sperm washing is mandatory within our unit (and across the majority of CREAThE members) before the sample being used for treatment, regardless of treatment modality used (IUI, IVF, and ICSI). This is supported by our recent analysis of 186 seminal samples from the men with undetectable viral load on HAART that demonstrated 18 (9.7%) were found to have demonstrable virus (370–18,000 copies per milliliter [17Nicopoullos J.D.M. Vourliotis M. Wood R. Almeida P. Gilling-Smith C. A decade of the sperm-washing program: where are we now? Proceedings of British Fertility Society, Edinburgh.Human Fertility. 2009; 12: 215Google Scholar]). This highlights the continued importance of appropriate risk-reduction techniques such as sperm washing in even the healthiest cohort of HIV-positive men and with the current level of evidence would not allow us to yet support a recent Swiss suggestion that "HIV-positive individuals without additional sexually transmitted diseases and on effective antiretroviral therapy are sexually non-infectious" (18Vernazza P. Hirshel B. Bernasconi E. Flepp M. Les personnes séropositives ne souffrant d'aucune autre MST et suivant un traitement antirétroviral efficace ne transmettent pas le VIH par voie sexuelle.Bulletin des médecins suisses. 2008; 89: 165-169Google Scholar).In contrast, the ART of choice remains a controversial debate within Europe itself and between continents. The major factor that has driven U.S. practice toward ICSI as a first-line treatment modality regardless of seminal or female factors is the 1990 CDC recommendation against insemination (11Cdc - Center for Disease Control and Prevention: HIV-1 infection and artificial insemination with processed semen.MMWR Morb Mortal Wkly Rep. 1990; 39: 255-256Google Scholar). This stems from a single case of HIV transmission to the female partner of an infected man after IUI of processed sperm. The sperm washing in this case, however, excluded a density gradient step and would not meet the current standards expected of units regularly undertaking IUI and also did not include a postwash viral test. The recent review from Columbia University that demonstrated the potential for a highly successful treatment program within these U.S. constraints used ICSI for fresh cycles without postwash viral testing (19Sauer M.V. Wang J.G. Douglas N.C. Nakhuda G.S. Vardhana P. Jovanovic V. et al.Providing fertility care to men seropositive for human immunodeficiency virus: reviewing 10 years of experience and 420 consecutive cycles of in vitro fertilization and intracytoplasmic sperm injection.Fertil Steril. 2009; 91: 2455-2460Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). Beyond the CDC, the argument in favor of this protocol is the avoidance of minimizing oocyte contact with seminal plasma and cells by the use of only a single sperm per oocyte. The argument against postwash testing with this protocol is the inability to characterize the cells chosen for ICSI and a lack of evidence of HIV detection in previous swim-up samples used for ICSI (19Sauer M.V. Wang J.G. Douglas N.C. Nakhuda G.S. Vardhana P. Jovanovic V. et al.Providing fertility care to men seropositive for human immunodeficiency virus: reviewing 10 years of experience and 420 consecutive cycles of in vitro fertilization and intracytoplasmic sperm injection.Fertil Steril. 2009; 91: 2455-2460Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). The counterargument advocated in Europe, remains the potential unnecessary cost implications, potential consequences of ovarian stimulation, potential increase in obstetric complications in the multiple pregnancies generated, as well as the potential for an increase in de novo chromosomal abnormalities.Although the inclusion of the swim-up, which is now no longer part of our protocol, may further minimize the presence of potentially virus-bearing cells, the European consensus was in favor of viral testing in all cycles regardless of treatment modality even after a swim-up preparation as a further safeguard and remains so. As a consequence, the viral testing assays continue to undergo strict quality control monitoring (20Pasquier C. Anderson D. Andreutti-Zaugg C. Baume-Berkenbosch R. Damond F. Devaux A. et al.Multicenter quality control of the detection of HIV-1 genome in semen before medically assisted procreation.J Med Virol. 2006; 78: 877-882Crossref PubMed Scopus (32) Google Scholar), and efforts continue to be made to standardize assays and assay protocols between units.In complete contrast to U.S. policy, the Dutch consensus of embryologists, virologists, and gynecologists is not to perform ICSI in HIV-positive men because of the theoretical danger of producing a new endogenous retrovirus in the human genome and possible infection of the embryo as a consequence of injecting a single sperm potentially carrying an HIV particle directly into the oocyte (21van Leeuwen E. Prins J.M. Jurriaans S. Boer K. Reiss P. Repping S. et al.Reproduction and fertility in human immunodeficiency virus type–1 infection.Hum Reprod Update. 2007; 13: 197-206Crossref PubMed Scopus (35) Google Scholar). As supported by the safety data from New York, there is little scientific support for such a policy, which excluded the 33% of HIV-positive men in the Netherlands who had insufficient semen quality for insemination procedures.Further idiosyncrasies include the selection criteria for treatment. Although we have no arbitrary cutoff for CD4 or viral load, our protocol is in keeping with Sauer et al. (19Sauer M.V. Wang J.G. Douglas N.C. Nakhuda G.S. Vardhana P. Jovanovic V. et al.Providing fertility care to men seropositive for human immunodeficiency virus: reviewing 10 years of experience and 420 consecutive cycles of in vitro fertilization and intracytoplasmic sperm injection.Fertil Steril. 2009; 91: 2455-2460Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar) who state that their men require evidence of stable disease for 6 months by virtue of stable viral load and CD4 counts (they specify 250 cells per cubic millimeter, respectively). In contrast some centers necessitate men to have undetectable viral loads before treatment (regardless of general well-being and clinical need for HAART), thereby excluding those most at risk using unprotected intercourse and most in need of ART. A study in 92 HIV-negative women with HIV-positive partners using this timed intercourse alone highlighted such risks with a 4% seroconversion rate (22Mandelbrot L. Heard I. Henrion-Geant E. Henrion R. Natural conception in HIV-negative women with HIV-infected partners.Lancet. 1997; 349: 850-851Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar).Success of treatmentDifferences in patient population, indications for treatment, and frozen embryo transfer policies make direct comparisons of treatment outcome impossible. For combined IVF, ICSI, and frozen ET cycles, our CPR and ongoing PR per transfer of 33.0% and 26.8% appear not to compare favorably to the Columbia decade with overall clinical pregnancy rate and ongoing PR per transfer of 46% and 39%. The U.S. data demonstrate an approximate 2-year difference in mean age, as well as the inclusion of the use of donor oocytes that would be expected to improve outcome. Similarly, the use of ICSI as first line also may skew the outcome data in favor of the United States by virtue of a higher proportion of the United Kingdom cohort likely to have concomitant fertility factors that may impact outcome. Further analysis of the data demonstrates the potential effect of the United Kingdom ET policy on outcome. Mean number of embryos transferred in our unit and from the data of Sauer et al. (19Sauer M.V. Wang J.G. Douglas N.C. Nakhuda G.S. Vardhana P. Jovanovic V. et al.Providing fertility care to men seropositive for human immunodeficiency virus: reviewing 10 years of experience and 420 consecutive cycles of in vitro fertilization and intracytoplasmic sperm injection.Fertil Steril. 2009; 91: 2455-2460Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar) is 2.0 and 3.0, respectively. Although not demonstrated, a crude implantation rate of approximately 21.6% for their fresh cycles can be calculated by factoring in the multiple PR (41%) with the number of ETs (270), which although higher than the 18.9% for our fresh cycles, is less disparate than the pregnancy outcome.The small increase in implantation rate may be offset by the potential neonatal consequences of the stated 41% multiple PR. As well as the clinical considerations, with the burden of management of neonatal care on state-funded specialist units, the impetus toward minimizing multiple pregnancy within United Kingdom has led to by potential HFEA sanctions should the multiple PR not drop to the national average by January 2010 and 3,000 cycles of treatment pooled from nine centers with no evidence of seroconversion in the uninfected partner or child on follow-up (7Bujan L. Hollander L. Coudert M. Gilling-Smith C. Vucetich A. Guibert J. et al.Safety and efficacy of sperm washing in HIV-1–serodiscordant couples where the male is infected: results from the European CREAThE network.Aids. 2007; 21: 1909-1914Crossref PubMed Scopus (169) Google Scholar).The Code of Practice of the Human Fertilisation and Embryology Authority, the United Kingdom regulatory body that
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