1 Fertility clinic and IVF centre of the Université Libre de Bruxelles, 2 Immunodeficiency treatment unit and 3 AIDS Reference Laboratory of the Free University of Brussels (ULB), Brussels, Belgium
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Abstract |
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Key words: assisted reproduction/HIV infection/ICSI/sexual transmission/vertical transmission
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Introduction |
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Medical teams, and more particularly medically assisted reproduction teams, have always been confronted with requests for assistance from seropositive people. These requests are now becoming increasingly numerous and insistent (Hammamah et al., 2000). Traditionally, the advice given to couples was not to embark upon plans for a child due to both the prognosis of the ailment for the parent carrying the virus and the risk of horizontal transmission to the other partner if the man is carrying the virus and vertical transmission to the child if the woman is the one affected. At the very most, against a background of controversy, some teams (including ours) have been practising artificial insemination since the 1980s using spermatozoa from an anonymous donor for women whose partner is seropositive, allowing the couple to become parents with no risk of the disease being transmitted to either the mother or the child (Delvigne et al., 1990
; Jouannet et al., 1990
). Only a few rare pioneers such as Dr Semprini in Milan started performing intraconjugal insemination as from the end of the 1980s with washed spermatozoa from the infected man (Semprini et al., 1992
).
It is undeniable that conditions in the year 2000 have changed: apart from modifications in the prognosis of the disease referred to above, greater knowledge of the parameters linked with the risk of transmission, the data accumulated after the preliminary work in the field of medially assisted reproduction for couples carrying the HIV virus, and the development of therapeutic strategies have dramatically altered the risks of vertical transmission to the newborn child (see below). A number of practitioners are reassessing their position in this field. Some argue in favour of a change of attitude (Jouannet et al., 1998; Anderson, 1999
) and a recent survey carried out among heads of gynaecological departments in France reveals that 47% of them are in agreement with taking charge locally of seropositive women with infertility problems. Forty-two percent of them say that they are prepared to conduct a stimulation of ovulation in a seropositive women, whilst only 3% of them were in favour in a similar survey carried out in 1993 (Bongin et al., 2000
). The ethical dilemma posed by assisted reproduction in couples where one of the partners is HIV-seropositive is particularly difficult, so acute is the clash of values involved. It seemed to us, after over a year of internal debate and on the occasion of the first two pregnancies achieved with the assistance of our team, that it was necessary to take stock of the literature, underline the ethical issues and trace guidelines for the years to come.
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Brief summary of the relevant medical data |
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Mother-child transmission
If, as we have seen, the frequency with which the virus is transmitted during non-traumatic heterosexual intercourse is relatively low, this does not apply to the risk of vertical transmission of HIV, with 1545% of newborn babies being infected in the absence of medical intervention (St Louis et al.; 1993, Working group, 1995). In Europe, the risk of spontaneous transmission, lower than in Africa, is 1520% (Working group, 1995; Thorne and Newell, 2000
). A large number of risk factors and obstetric complications that have been described seem to be confounding factors. These obstetric pathologies and infection by the HIV virus are in fact two situations particularly affecting disadvantaged populations and are associated with the same risk factors. It has been shown by large-scale studies that the risk of mother-child transmission is linked above all to the viral load in the mother's blood measured by the level of viral RNA, not only at the time of delivery but also when pregnancy is diagnosed (Connor et al., 1994
). The risk is much lower when the viral load is less than 500 copies of RNA per ml (Garcia et al., 1999
; Mofenson et al., 1999
), although it is never nil (Rogero and Shaffer, 1999
). Vertical transmission can occur in-utero (Brossard et al., 1995
), during birth (Thorne and Newell, 2000
) or during breastfeeding (Miotti et al., 1999
). In Europe, where breastfeeding is contra-indicated, 75% of mother-child contaminations occur during birth (Thorne and Newell, 2000
). Since the publication of the American study demonstrating the major benefit obtained from the use of Zidovudine on the risk of mother-child transmission (8.3% in the treated group as opposed to 25.5% in the placebo group) (Connor et al., 1994
), all observations have confirmed the value of antiviral treatment, even when the drug is administered over a short period around the birth (Wade et al., 1998
). Nevirapine would seem to be more effective than Zidovudine in Africa (Guay et al., 1999
). In Europe and the USA, double and triple therapies are prescribed to protect the child but also the mother. The measured benefit of antiviral therapies is estimated to be a 2/3 reduction of the risk of vertical transmission (Jackson et al., 2000
). The value of systematic use of a Caesarean section before labour and in the case of intact membranes is also well demonstrated (The European mode of delivery collaboration, 1999
; American College of Obstetricians and Gynecologists, 1999
). It leads to a 50% reduction of the risk of motherfetus transmission. The combination of drug therapy and Caesarean section further increases the benefit obtained and several recent analyses suggest a risk of vertical transmission of 12% in these cases (The European Mode of Delivery Collaboration, 1999
; International Perinatal HIV group, 1999
). This approach is profitable in terms of cost-effectiveness (McCornick et al., 1999
; Halpern et al., 2000
), its value being well perceived by patients (Baleta, 1999
) and the community, leading the New England Journal of Medicine to recently publish an editorial recently stating that `The success of perinatal operations leads some to consider that elimination of the infection of newborn babies by the HIV virus is an objective that could be attained in the United States' (Rogero and Shaffer, 1999
). It therefore seems that, were it not for problems of accessibility for pregnant women to the modern health structures available in Western Europe, neonatal contamination by the HIV virus should become rare. Research should then be focused on new forms of treatment such as combined therapies (Mc Gowan et al., 1999), which even call into question (due to their efficacy) the need for a systematic Caesarean (Beckerman et al., 1999
; Brocklehurst, 1999
), and more detailed attention should be given to the question for the child of the innocuity of antiviral molecules, a subject which is still highly controversial and of crucial importance: a French group has described a very rare pathology of the mitochondria in several children exposed to Zidovudine (Blanche et al., 1999
), whilst a far-reaching American study has revealed no particular pathology in these children (Culnane et al., 1999
). Furthermore, it is known that mitochondria are a favourite target of antiviral drugs in the class of nucleoside analogues (Brinkman et al., 1998
).
Use of medically assisted reproduction in seropositive cases
Unfortunately, it has been amply demonstrated that the semen used in artificial insemination can transmit infection by the HIV-1 virus: let us remember the first case of infection in artificial insemination with a donor (AID) in Australia (Stewart et al., 1985), but also other cases in Canada, the United States (Araneta et al., 1995
) and, quite recently, Germany (Matz et al., 1998
) which have underlined the need for semen donors to be screened and for frozen semen to be placed in quarantine for a period of 6 months, after which the spermatozoa is used in AID only if a new test carried out on the donor is negative (Barratt et al., 1998
). These accidents also demonstrated that semen alone, independently of any sexual contact, could transmit the virus with a frequency similar overall to situations of occasional sexual intercourse [4 out of 8 (50%) in Australia and 7 out of 199 (3.52%) in the USA]. The presence of viral particles has been demonstrated in the liquid component of the semen in free form and in the cellular component in the intracellular form, both through culture and through PCR (Mermin et al., 1991
). The presence of viral particles has been confirmed through an autopsy in the white cells of the tissues of the entire male genital tract (Pudney and Anderson, 1991
) and in the semen of men who have had a vasectomy (Anderson et al., 1991
).
As mentioned above in sexual transmission, the relationship between the viral concentration in the plasma and the semen is not constant and there is no agreement in the literature today on the extent of the variation of the concentration in viral particles measured on samples taken successively from the same patient considered to be clinically stable. There is still no unanimous answer to the crucial question of whether the spermatozoon can itself act as a vector for the virus (Zagury, 1984; Krieger et al., 1991
; Pudney and Anderson, 1991
; Van Voorhis et al., 1991
; Schofield, 1992
; Dussaux et al., 1993
; Baccetti et al., 1994
; Bagasra et al., 1994
; Nuovo et al., 1994
; Quayle et al., 1997
; Pudney et al., 1998
; Quayle et al., 1998
). On the other hand, it is clearly established that methods of preparing the semen in which the seminal fluid and other cellular elements are separated from the spermatozoa by washing may reduce the viral load up to a level undetectable by the most sensitive techniques (PCR-RNA and PCR-DNA) (Lasheeb et al., 1977
; Heimerl et al., 1993
; Baccetti et al., 1994
; Pudney et al., 1998
; Quayle et al., 1998
; Kim et al., 1999
). It has also been demonstrated that antiviral treatments that are very active at the plasmatic level reduce the viral load in the spermatozoa (Anderson et al., 1992
; Gilliam et al., 1997
; Gupta et al., 1997
; Vernazza et al., 1997
; Zhang et al., 1998
). All these data have led some teams to use assisted reproduction techniques allowing serodifferent couples in which the man is carrying the virus to have children using the man's own sperm. Dr Semprini, the pioneer of the use of intraconjugal insemination with washed sperm, has recently announced over 2000 inseminations, a hundred cycles of IVF and a few ICSI cycles in 800 women, allowing the birth of 350 children without viral contamination (Semprini et al., 2000
). A Spanish team has reported 101 intraconjugal inseminations with washed spermatozoa in 63 women, having led to the birth of 37 children without any contamination (Marina et al., 1998a
) and one case of ICSI (Marina et al., 1998b
). An ongoing French collaborative study is systematically using ICSI to keep to a minimum any contact between the infected biological material and the receiver, and reports 49 ICSI cycles and 17 current pregnancies (Kunstmann et al., 2000
). It should however be underlined that a case of contamination was reported in the USA at the beginning of the 1990s using a partially similar method (Anonyme, 1990
) and that Dr Semprini's large series has never been the subject of a meticulous publication covering its methodology or follow-up.
On the other hand, there are no studies in the literature on assisted reproduction in seropositive women, whilst we have seen, for example, that various centres in France appear to be assisting such requests, either to prevent contamination of the spouse or in the case of associated infertility, especially as it seems that the fertility of these couples is lower than that of the general population (Stephenson and Griffioen, 1996; De Vincenzi et al., 1997
; Gray et al., 1998
; Ross et al., 1999
). This lack of data is even more surprising when we consider that several authors have emphasized that even though women know they are seropositive, they do not give up the idea of motherhood (Lindsay et al., 1995
; Ross et al., 1999
) and that the tendency over the last few years has been towards a higher frequency of decisions by seropositive women to try to satisfy their desire to be mothers (Greco et al., 1999
). Perhaps this gap in the literature can be explained by interest being too focused on the technical aspects to the detriment of reflection on the desire for children that these women may have.
Helping these couples through assisted reproduction means having appropriate facilities: whilst the risk of contamination of the staff is extremely low (Weiss et al., 1988), nosocomial contamination between patients has been described both for the HIV virus (Blank et al., 1994
) and for the HCV virus (Lesourd et al., 2000
) and cross-contamination in tanks storing biological material has been clearly demonstrated (Tedder et al., 1995
; Clarke, 1999
). It therefore seems essential to evaluate each stage in these complex technologies very carefully to ensure their safety as much as possible. It is necessary to keep separate facilities for treating the biological liquids of these patients and to develop special safety procedures both for the sake of the staff and for the prevention of inter-patient contamination. The logical approach we followed is to build one separate laboratory for IVF, ICSI and semen preparation for contaminated patients. This would enable us to deal with inseminations or ICSI procedures in the case of infected semen but also to combine the procedure needed for the viral problem with an eventual treatment for male or female infertility. Regular training of all the staff is also indispensable.
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The ethical issues |
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This is why we choose to open the fertility clinic to couples carrying the HIV virus and to develop the necessary techniques to provide them with assistance in their plans for a child in the best possible conditions. In our view, this discussion implies that there should be no discrimination between fertile couples and those combining viral contamination with sterility, a situation suggested to be more frequent than in the general population. It is necessary to develop an IVF programme adapted to couples with the virus, carried out in a laboratory kept strictly separate from the general IVF laboratory. It is nonetheless true that, as with other types of special requests for assistance in reproduction, one should progress step by step, in accordance with the following principles: every request is admissible in principle and must be welcomed and given due attention. The medical team, through the use of a conscience clause, must keep a margin for manoeuvre making it possible to refrain from participating in plans for a child that it considers problematical. Continuous assessment of the results and of new research data must condition the gradual adaptation of indications of medically assisted reproduction for couples where one of the partners is seropositive. This approach, coherent from the scientific point of view, respectful of both the autonomy of people carrying the HIV virus and the interest of the child in being born uninfected also has the enormous advantage of allowing access to parenthood without destroying the consistency and coherence of the message of prevention of sexual contamination.
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Acknowledgements |
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Notes |
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References |
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