ART in HIV-infected couples

Has the time come for a change of attitude?

Yvon Englert1,4, Jean-Paul Van Vooren2, I. Place1, Corinne Liesnard3, Chantal Laruelle1,2 and Anne Delbaere1

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


    Abstract
 Top
 Abstract
 Introduction
 Brief summary of the...
 The ethical issues
 Acknowledgements
 References
 
Today, in developed countries, many HIV-infected people remain in good health thanks to antiviral medication. A growing number of them want to have children. Medical possibilities for preventing contamination of the partners of seropositive men, through assisted reproduction, and of children thanks to antiviral medicines during pregnancy, are summarized. These changes result in ethical considerations which lead the authors to question the conventional systematic medical advise against pregnancy and has encouraged them to assist reproduction for a number of these couples. Today, the balance between the importance of the message of prevention and the benefit for patients of being assisted in their desire for a child has tilted towards medical intervention. It would seem legitimate today to intervene in the most favourable situations rather than see these couples take the risk of spontaneous conception outside health care structures. This implies the need to adapt medical structures (separate laboratory, appropriate procedure, precise protocols). This approach, which is coherent from the scientific point of view, respects both the autonomy of people carrying HIV as well as the essential interests of the child, in being born uninfected, and also has the enormous advantage of allowing access to parenthood without destroying the consistency of the message of prevention of sexual contamination.

Key words: assisted reproduction/HIV infection/ICSI/sexual transmission/vertical transmission


    Introduction
 Top
 Abstract
 Introduction
 Brief summary of the...
 The ethical issues
 Acknowledgements
 References
 
The characteristics of the epidemic caused by HIV have become dualized over the last ten years: whilst the epidemic continues to wreak havoc in the majority of countries around the world which, due to poverty, do not have access to antiviral drugs, the spread of the infection has slowed down in the developed countries, where the percentage of heterosexual contamination is increasing. The disease still mainly affects young adults, but its prognosis has been changed considerably by the remarkable therapeutic advances made in recent years as a result of major research work. We have also a better understanding of the behaviour of the virus and the conditions for its transmission. From a disease with a generally fatal prognosis in the medium term, seen by some as the modern-day plague, AIDS has now become a serious disease if it is not treated, but can evolve towards chronicity when very demanding antiviral drugs are absorbed correctly. A more comfortable existence opens up for patients. Today, many HIV-infected people are most of the time in a good general state, remain socially integrated, go out to work, etc., and can start making plans for the future again. These plans, quite logically in young couples, may include the desire to have a child. More than for others, `reproducing', `giving life', means for seropositive people transcending the death that lies in wait for them. It is on this desire for a child, about which a discussion is naturally opening in well-off countries with health structures and possibilities of access to treatment, that this article is focused.

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., 2000Go). 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., 1990Go; Jouannet et al., 1990Go). 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., 1992Go).

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., 1998Go; Anderson, 1999Go) 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., 2000Go). 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.


    Brief summary of the relevant medical data
 Top
 Abstract
 Introduction
 Brief summary of the...
 The ethical issues
 Acknowledgements
 References
 
Sexual transmission of HIV
It seems that transmission of HIV during sexual intercourse through vaginal penetration is extremely variable (Royce et al., 1997Go; Peterman et al., 1998Go). Whereas transmission is relatively low in stable couples (non-transmission over extremely long periods is reported), very effective transmission during casual sexual relations has been described (Clumeck et al., 1989Go). Numerous factors are known to explain these variations, such as the infectiousness of the viral strain, the degree of advancement of the disease, the viral load, the sex of the infected partner, the existence of associated sexually transmitted diseases and the nature of the sexual practices (Vernazza et al., 1999Go). The risk of transmission depends more on the number of different sexual partners than the frequency of sexual intercourse. The risk of contamination by sexual contact in a stable couple is between 0.1 and 0.5% (Devincenzi, 1994), much lower than that connected with occasional intercourse, for example as in the case of prostitution (Cameron et al., 1989Go, Mashro et al., 1994Go). Several studies have shown a correlation between the level of infectiousness and the size of the viral load. This notion is observed whatever the means of transmission: blood transfusion (Busch et al., 1996Go), sexual relations (Ragni et al., 1998Go), and vertical mother-child transmission (St Louis et al., 1993Go). One should not draw the hasty conclusion from these observations that in the case of a low or undetectable viral load the risk of contamination disappears. This type of message is untrue and would lead to the abandonment of safe sex by infected people undergoing antiviral treatment. This fear would appear to be justified according to the results of a number of recent surveys (Kravcik et al., 1998Go) but not constantly (Lavoie et al., 1998Go). We know today that the correlation between the circulating viral load and the viral load in the semen, whilst undeniable, is relatively low. In effect, compared with measurements taken from the blood, the spermatic compartment has a certain peripheral autonomy: there is local replication (presence of viral DNA and RNA in the semen), with the viral concentration being sometimes lower and sometimes higher than in the plasma, and the viral strains sometimes separate, with different resistance characteristics (Byrn et al., 1997Go; Coombs et al., 1998Go; Eron et al., 1998Go; Tachet et al., 1999Go). Furthermore, at the present time there is contradictory data in the literature on the extent of the variability of the viral load in the sperm of patients otherwise considered to be stable from the point of the evolution of their illness (Gilliam et al., 1997Go; Coombs et al., 1998Go). All these notions are extremely important in understanding and preventing sexual transmission. Data on the viral concentration in the female genital tract is still fragmentary, essentially due to the variability in sampling techniques, whereas this too is crucial information not only for sexual transmission but also for vertical mother-child transmission. However, unlike the case with semen, a strong correlation has been demonstrated between the viral concentration in the blood and in vaginal secretions (Hart et al., 1999Go), which is very consistent with observations concerning the vertical transmission described below. A certain autonomy of the viral strain is also observed in vaginal secretions (Si-Mohamed et al., 2000Go)

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 15–45% of newborn babies being infected in the absence of medical intervention (St Louis et al.; 1993Go, Working group, 1995). In Europe, the risk of spontaneous transmission, lower than in Africa, is 15–20% (Working group, 1995; Thorne and Newell, 2000Go). 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., 1994Go). The risk is much lower when the viral load is less than 500 copies of RNA per ml (Garcia et al., 1999Go; Mofenson et al., 1999Go), although it is never nil (Rogero and Shaffer, 1999Go). Vertical transmission can occur in-utero (Brossard et al., 1995Go), during birth (Thorne and Newell, 2000Go) or during breastfeeding (Miotti et al., 1999Go). In Europe, where breastfeeding is contra-indicated, 75% of mother-child contaminations occur during birth (Thorne and Newell, 2000Go). 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., 1994Go), 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., 1998Go). Nevirapine would seem to be more effective than Zidovudine in Africa (Guay et al., 1999Go). 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., 2000Go). 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, 1999Go; American College of Obstetricians and Gynecologists, 1999Go). It leads to a 50% reduction of the risk of mother–fetus 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 1–2% in these cases (The European Mode of Delivery Collaboration, 1999Go; International Perinatal HIV group, 1999Go). This approach is profitable in terms of cost-effectiveness (McCornick et al., 1999Go; Halpern et al., 2000Go), its value being well perceived by patients (Baleta, 1999Go) 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, 1999Go). 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., 1999Go; Brocklehurst, 1999Go), 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., 1999Go), whilst a far-reaching American study has revealed no particular pathology in these children (Culnane et al., 1999Go). Furthermore, it is known that mitochondria are a favourite target of antiviral drugs in the class of nucleoside analogues (Brinkman et al., 1998Go).

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., 1985Go), but also other cases in Canada, the United States (Araneta et al., 1995Go) and, quite recently, Germany (Matz et al., 1998Go) 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., 1998Go). 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., 1991Go). 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, 1991Go) and in the semen of men who have had a vasectomy (Anderson et al., 1991Go).

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, 1984Go; Krieger et al., 1991Go; Pudney and Anderson, 1991Go; Van Voorhis et al., 1991Go; Schofield, 1992Go; Dussaux et al., 1993Go; Baccetti et al., 1994Go; Bagasra et al., 1994Go; Nuovo et al., 1994Go; Quayle et al., 1997Go; Pudney et al., 1998Go; Quayle et al., 1998Go). 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., 1977Go; Heimerl et al., 1993Go; Baccetti et al., 1994Go; Pudney et al., 1998Go; Quayle et al., 1998Go; Kim et al., 1999Go). 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., 1992Go; Gilliam et al., 1997Go; Gupta et al., 1997Go; Vernazza et al., 1997Go; Zhang et al., 1998Go). 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., 2000Go). 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., 1998aGo) and one case of ICSI (Marina et al., 1998bGo). 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., 2000Go). 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, 1990Go) 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, 1996Go; De Vincenzi et al., 1997Go; Gray et al., 1998Go; Ross et al., 1999Go). 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., 1995Go; Ross et al., 1999Go) 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., 1999Go). 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., 1988Go), nosocomial contamination between patients has been described both for the HIV virus (Blank et al., 1994Go) and for the HCV virus (Lesourd et al., 2000Go) and cross-contamination in tanks storing biological material has been clearly demonstrated (Tedder et al., 1995Go; Clarke, 1999Go). 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.


    The ethical issues
 Top
 Abstract
 Introduction
 Brief summary of the...
 The ethical issues
 Acknowledgements
 References
 
The ethical issues involved in counselling in seropositive cases have been developed in the literature, but only up to a certain point. Apart from the necessary reminder of the general rules of medical ethics that are applicable, namely the obligation to provide medical assistance and to treat patients carrying the HIV virus (Emanuel, 1988Go) without ever abandoning them, it is acknowledged today that the first role of the practitioner in this field is that of information and counselling detailing the implications of the disease for sex life and reproduction, as well as to promote `safe sex'. When the desire for a child arises, the first approach consists in examining it openly with patients, remembering that the dynamic of this desire can be different for each member of the couple. It is necessary to work with patients on the meaning of this desire within the particular context of one of the partners being seropositive and to take account not only of the risk of transmission to the child but also of the difficulty of combining being a parent with the constraints of their illness (Delvigne et al., 1990Go). Their feelings in relation to expressing their own needs in the face of the child's needs and the risk of the child becoming an orphan must also be discussed (Kass, 1994Go). In fact, it may happen that this discussion leads to a situation in which, even though there is undeniably a desire for a child, the patients decide to give up the idea due to their condition of having a chronic disease. Nevertheless, the literature shows that, in spite of all the obstacles and difficulties encountered, a not insignificant number of couples in Western Europe (Lindsay et al., 1995Go; Greco et al., 1999Go) and in Africa (Gray et al., 1998Go) do not give up their desire for a child and that seropositivity has relatively little influence on this (Sunderland et al., 1992Go; Sherr, 1995Go; Williams et al., 1996Go). It must be underlined that this observation does not correspond to our personal experience of serodifferent couples who have consulted us for an opinion or had recourse to a donor and perhaps depends to a large extent on the type of population studied. For Delor `the diagnosis of seropositivity may be perceived as a sudden and definitive prohibition on having children and this prohibition may be felt, translated or reinterpreted as an unbearable injury or diminishment of identity that may gave rise to or increase the desire to have a child as a `compensatory measure', a desire that becomes even more impatient when it arises within a subjective timeframe that is felt to be limited' (Delor, 1997Go). If the desire persists, then one should examine the possibility of its being overcome by interfamily circulation of children as happens in certain African societies, through adoption or fostering when possible, or by the use of artificial insemination with donor semen when it is the male partner who is infected by HIV (Delvigne et al., 1990Go). Up to this point, the health professional is not really confronted with an ethical dilemma. He plays the role of both the patient's private adviser and, at the same time, does everything in his power to avoid the risk of the birth of a child infected by the AIDS virus. He undeniably respects the principles of beneficience, non-maleficience, autonomy and justice that are conventionally required in bioethical debates in human medicine. In the case of the use of a sperm donor, the ethical debate (very active during the 1980 and the 1990s) around the concept of the `interest of the child' in not quickly becoming an orphan has decreased considerably due to the extension of the life expectancy of seropositive patients. But when the desire for a biological child persists, that is when the ethical conflict properly speaking begins: it is not a question here of `opposing the desire to procreate', which would undeniably encroach upon the autonomy of patients (Kass, 1994Go) who also, provided that they are fertile (which will generally be the case), fortunately do not need the doctor's authorization to attempt unprotected intercourse. It is more a matter of either adopting an attitude of non-collaboration (guaranteeing the soundness of the message of advising against pregnancy) or, on the contrary, providing medical assistance aimed at minimizing the possible damage of the plan to have a child (at the risk of removing the credibility from the recommendation against pregnancy) (Smith et al., 1990Go). This is a difficult choice because one cannot both provide assistance in reproduction and maintain a firm line of advice against pregnancy. However, a lack of assistance in the desire for pregnancy leads a number of couples to chose to have unprotected sexual intercourse (Mandelbrot et al., 1997Go), an attitude involving risks in relation to the HIV virus which are known and have also been observed, in other situations in which women have been refused access to assisted reproduction (Macaulay et al., 1995Go; Matz et al., 1998Go; Block et al., 1999Go). These couples also tend to distance themselves from the medical structures by which they feel rejected (Nolan, 1990Go). It therefore seems that what must prevail in the medical decision is a balance between the importance of the message advising against pregnancy and the benefit for patients of being assisted in their plans to have a child. Until recent years, the balance was clearly tilted in favour of the firmness of the message not to become pregnant, due to not only the risks of contamination of the child and the short life expectancy of the parents but also the few arguments in favour of the efficacy of medical intervention in relation to unprotected sexual intercourse. The review of the literature above shows that all the parameters have changed and are moving in the direction of intervention by medical teams, seen as dependent on the balance between the principles of non-maleficience on the one hand and beneficience and autonomy on the other: as far as seropositive men are concerned, there is a solid raft of arguments to consider sperm washing as safer than sexual intercourse both for the partner and for the child to be, even if it is too early to know if this safety could be total. In women, the reduction in the risk of vertical transmission by a factor of 10 and the progress made in the knowledge of factors influencing the risk of transmission encourages more selective counselling. As a result of the growing desire for pregnancy in couples, due to the improvement in their state of health and their new longevity, advice against reproduction automatically becomes weaker: maintaining it indiscriminately could paradoxically have a perverse effect of discrediting all messages of prevention as regards reproduction. It is probably more effective to provide assistance based on the inclusion of couples who are in the most favourable situations from the point of view of the risks of transmission and longevity in properly evaluated protocols: the message of advising against pregnancy for patients not fulfilling these criteria would be all the more credible for this.

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.


    Acknowledgements
 Top
 Abstract
 Introduction
 Brief summary of the...
 The ethical issues
 Acknowledgements
 References
 
This work was supported by a grant from the Belgian Fonds National pour la Recherche Scientifique.


    Notes
 
4 To whom correspondance should be addressed at: Hôpital Erasme, Route de Lennik 808, 1070 Brussels, Belgium. E-mail: ferticlin{at}med.ulb.ac.be Back


    References
 Top
 Abstract
 Introduction
 Brief summary of the...
 The ethical issues
 Acknowledgements
 References
 
American College of Obstetricians and Gynecologists (1999) ACOG opinion an scheduled cesarean delivery and the prevention of vertical transmission of HIV infection. Int. J. Gynecol. Obstet., 66, 305–306[ISI][Medline]

Anderson, D.J. (1999) Assisted reproduction for couples infected with the human immunodeficiency virus type 1. Fertil. Steril., 72, 592–594[ISI][Medline]

Anderson, D.J., O'Brien, T.R., Politch, J.A. et al. (1992) Effects of disease stage and Zidovudine therapy on the detection of human immunodeficiency virus type 1 in semen [see comments]. JAMA, 267, 2769–2774[Abstract]

Anderson, D.J., Politsh, J.A., Martinez, A. et al. (1991) White blood cells and HIV-1 in semen from vasectomized seropositive men. Lancet, 338, 573–574

Anonyme (1990) C.D.C.: HIV infection and artificial insemination with processed semen. MMRW, 39, 249, 255–256

Araneta, M.R., Mascola, L., Eller, A. et al. (1995) HIV transmission through Donor Artificial Insemination. JAMA, 273, 854–858[Abstract]

Baccetti, B., Benedetto, A., Burrini, A.G. et al. (1994) HIV-particles in spermatozoa of patients with AIDS and their transfer into the oocyte. J. Cell. Biol., 27, 903–914

Bagasra, O., Farzadegan, H., Seshamma, T. et al. (1994) Detection of HIV-1 proviral DNA in sperm from HIV-1-infected men. AIDS, 8, 1669–1674[ISI][Medline]

Baleta, A. (1999) Huge percentage of women volunteer for Zidovudine project. Lancet, 353, 219[Medline]

Barratt, C., Englert, Y., Gottlieb, C. et al. (1998) Gamete Donation Guidelines. The Corsendonk consensus statements for the european union. Hum. Reprod., 13, (Suppl. 2)

Beckerman, K., Morris, A. and Stik, A. (1999) Mode of delivery and the risk of vertical transmission of HIV-1. N. Engl. J. Med., 341, 205–206[Free Full Text]

Blanche, S., Tardieu, M., Rustin, P. et al. (1999) Persistant mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. Lancet, 354, 1084–1089[ISI][Medline]

Blank, S., Simonds, R.J., Weisfuse, I. et al. (1994) Possible nosocomial transmission of HIV. Lancet, 344, 512–514[ISI][Medline]

Block, M., Carr A., Vasak, E. et al. (1999) The use of human immunodeficiency virus postexposure prophylaxis after successful artificial insemination. Am. J. Obstet. Gynecol., 181, 760–761[ISI][Medline]

Bongin, A., Durand-Reville, M., Loizeau, S. et al. (2000) La femme VIH seropositive état des lieux en France. Communication au Congrès Le désir d'enfant chez les couples VIH sérodifférents Toulouse, Mai, 35–36

Brinkman, K., Ter Hofstede, H.J.M., Burger, D.M. et al. (1998) Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS, 12, 1735–1744[ISI][Medline]

Brocklehurst, P. (1999) Comment on abstracts from the literature. J. Pediatrics, 135, 649

Brossard, Y., Aubin, J.T., Mandelbrot L. et al. (1995) Frequency of early in utero HIV-1 infection: a blind DNA polymerase chain reaction study on 100 fetal thymuses. AIDS, 9, 359–366[ISI][Medline]

Busch, M.P., Operskalski, E.A., Mosley, J.W. et al. (1996) Factors influencing human immunodeficiency virus type 1 transmission by blood transfusion. Transfusion Safety Study Group. J. Infect. Dis., 174, 26–33[ISI][Medline]

Byrn, R.A., Zhang, D., Eyre, R. et al. (1997) HIV-1 in semen: an isolated virus reservoir [letter]. Lancet, 350, 1141[ISI][Medline]

Cameron, D.W., Simonsen, J.N., D'Costa, L.J. et al. (1989) Female to male transmission of human immunodeficiency virus type 1: risk factors for seroconversion in men. Lancet, ii, 403–407

Clarke, G.N. (1999) Sperm cryopreservation: is there a significant risk of cross- contamination? Hum. Reprod., 14, 2941–2943[Free Full Text]

Clumeck, N., Taelman, H., Hermans, P. et al. (1989) A cluster of HIV infection among heterosexual people without apparent risk factors. N. Engl. J. Med., 321, 1460–1462[ISI][Medline]

Connor, E.M., Sperling, R., Gelber, R. et al. (1994) Reduction of maternal-infant transmission of human immunodeficiency virus tyupe 1 with Zidovudine treatment. N. Engl. J. Med., 331, 1173–1180[Abstract/Free Full Text]

Coombs, R.W., Speck, C.E., Hughes, J.P. et al. (1998) Association between culturable human immunodeficiency virus type 1 (HIV- 1) in semen and HIV-1 RNA levels in semen and blood: evidence for compartmentalization of HIV-1 between semen and blood. J. Infect. Dis., 177, 320–330[ISI][Medline]

Culnane, M., Fowler, M., Lee, S.S. et al. (1999) Lack of long-term effects of in utero exposure to Zidovudine among uninfected children born to HIV-infected women. JAMA, 281, 151–157[Abstract/Free Full Text]

De Vincenzi, I. (1994) A longitudinal study of human immunodeficiency virus transmission by heterosexual partners. N. Engl. J. Med., 331, 341–346[Abstract/Free Full Text]

De Vincenzi, I., Jadand, C., Couturier, E. et al. (1997) Pregnancy and contraception in a French cohort of HIV-infected women. SEROCO Study Group. AIDS, 11, 333–338[ISI][Medline]

Delor, F. (1997) Chapitre 10. Relations sexuelles, désir d'enfant et perception du temps. In (ed) L'Harmattan Seropositifs. 271–319

Delvigne, A., Gustin, M.L., Englert, Y. et al. (1990) Le sida: indication d'insémination artificielle avec sperme de donneur anonyme? J. Gynecol. Obstet. Biol. Reprod., 19, 751–758[Medline]

Dussaux, E., Guetard, D., Douguet, C. et al. (1993) Spermatozoa as potential carriers of HIV. Res. Virol., 144, 487–495[ISI][Medline]

Emanuel, E.J. (1988) Do physicians have an obligation to treat patients with AIDS? N. Engl. J. Med., 318, 1686–1690[ISI][Medline]

Eron, J.J., Vernazza, P.L., Johnston, D.M. et al. (1998) Resistance of HIV-1 to antiretroviral agents in blood and seminal plasma: implications for transmission. AIDS, 12, F181–189[ISI][Medline]

Garcia, P.M., Kalesh, L.A., Pitt, J. et al. (1999) Maternal levels of plasma human immunodeficiency virus type 1 RNA and the risk of perinatal transmission. N. Engl. J. Med., 341, 394–402[Abstract/Free Full Text]

Gilliam, B.L., Dyer, J.R., Fiscus, S.A. et al. (1997) Effects of reverse transcriptase inhibitor therapy on the HIV-1 viral burden in semen. J. Acquir. Immune. Defic. Syndr. Hum. Retrovirol., 15, 54–60[ISI][Medline]

Gray, R.H., Wawer, M.J., Serwadda, D. et al. (1998) Population-based study of fertility in women with HIV-1 infection in Uganda. Lancet, 351, 98–103[ISI][Medline]

Greco, P., Vimercati, A., Fiore, J.R. et al. (1999) Reproductive choice in individuals HIV-1 infected in south eastern Italy. J. Perinat. Med., 27, 173–177[ISI][Medline]

Guay, L.A., Musoke, P., Fleming, T. et al. (1999) Intrapartum and neonatal single-dose nevirapine compared with Zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda. HIVNET 012 randomized trial. Lancet, 354, 795–802[ISI][Medline]

Gupta, P., Mellors, J., Kingsley, L. et al. (1997) High viral load in semen of human immunodeficiency virus type 1- infected men at all stages of disease and its reduction by therapy with protease and nonnucleoside reverse transcriptase inhibitors. J. Virol., 71, 6271–6275[Abstract]

Halpern, M.T., Read, J.S., Ganoczy, D.A. et al. (2000) Cost-effectiveness of cesarean section delivery to prevent mother-to-child transmission of HIV-1. AIDS, 14, 691–700[ISI][Medline]

Hammamah, S., Girard, M., Goyaux, N. et al. (2000) Couples sérodifférents: la demande auprès des centres biologiques d'assistance médicale à la procréation. Communication au congrès Le désir d'enfant chez les couples VIH sérodifférents Toulouse pp. 25–27

Hart, C.E., Lennox, J.L., Pratt-Palmore, M. et al. (1999) Correlation of human immunodeficiency virus type 1 RNA levels in blood and the female genital tract. JID, 179, 871–882[Medline]

Heimerl, H., Zumbusch, R., Gurtler, L. et al. (1993) Which cell type in semen is the major source of HIV-DNA? Intern. Conf. on Aids, 9, 449, Abstract PO-B20–1882

International Perinatal HIV group (1999) The mode of delivery and the risk of vertical transmission of meta analyses of 15 prospective cohort studies human immunodeficiency virus type 1-a. N. Engl. J. Med., 340, 977–987[Abstract/Free Full Text]

Jackson, J.B., Becker-Pergola, G., Guay, L. et al. (2000) Identification of the K103N resistance mutation in Ugandan women receiving nevirapine to prevent HIV-1 vertical transmission. AIDS, 14, F111–115[ISI][Medline]

Jouannet, P., Alnot, M.O., Kunstmann, J.M. et al. (1990) Demandes d'IAD faites par des couples dont l'homme a des anticorps sériques anti-HIV. Contr. Fert. Sex., 18, 603–604[ISI]

Jouannet, P., Dulioust, E., Kunstmann, J.M. et al. (1998) Management of fertile and infertile HIV positive patients wanting to become parents. In Kempers R.D. et al. (Eds) Fertility and Reproductive Medicine. Elsevier, pp 487–495

Kass, N.E. (1994) Policy, ethics, and reproductive choice: pregnancy and childbearing among HIV-infected women. Acta Paediatr., 400, Suppl, 95–98

Kim, L.U., Johnson, M.R., Barton, S. et al. (1999) Evaluation of sperm washing as a potential method of reducing HIV transmission in HIV-discordant couples wishing to have children. AIDS, 13, 645–651[ISI][Medline]

Kravcik, S., Victor, G., Houston, S. et al. (1998) Effect of antiretroviral therapy and viral load on the perceived risk of HIV transmission and the need for safer sexual practices. J. Acquir. Immune. Defic. Syndr. Hum. Retrovirol., 19, 124–129[ISI][Medline]

Krieger, J.N., Coombs, R.W., Collier, A.C. et al. (1991) Recovery of human immunodeficiency virus type 1 from semen: minimal impact of stage of infection and current antiviral chemotherapy. J. Infect. Dis., 163, 386–388[ISI][Medline]

Kunstmann, J.M., Guibert, J., Merlet, F. et al. (2000) AMP intra conjugale : quelle stratégie de prise en charge ? Expérience protocole NECO. Communication à la journée : Le désir d'enfant chez les couples VIH sérodifférents. Toulouse, pp. 31–32

Lasheeb, A.S., King, J., Ball, J.K. et al. (1977) Semen characteristics in HIV-1 positive men and the effect of semen washing. Genitourin. Med., 73, 303–305

Lavoie, R., Otis, J., Leclerc, R. et al. (1998) Attitudes towards the triple-therapies and safer sex : what a mix! 12th international conference on AIDS, Geneva June/July (abstract 34277)

Lesourd, F., Izopet, J., Mervan, C. et al. (2000) Transmissions of hepatitis C virus during the ancillary procedures for assisted conception. Hum. Reprod., 15, 1083–1085[Abstract/Free Full Text]

Lindsay, M.K., Grant, J., Peterson, H.B. et al. (1995) The impact of knowledge of human immunodeficiency virus serostatus on contraceptive choice and repeat pregnancy. Obstet. Gynecol., 85, 675–679[Abstract/Free Full Text]

Macaulay, L., Kitzinger, J., Green, G. et al. (1995) Unconventional conceptions and HIV. Aids Care, 7, 261–75[ISI][Medline]

Mandelbrot, L., Heard, I., Henrion-Geant, E. et al. (1997) Natural conceptions in HIV-negative women with HIV-infected partners. Lancet, 349, 850–851[ISI][Medline]

Marina, S., Marina, F., Alcolea, R. et al. (1998a) Human immunodeficiency virus type 1–serodiscordant couples can bear healthy children after undergoing intrauterine insemination. Fertil. Steril., 70, 35–39[ISI][Medline]

Marina, S., Marina, F., Alcolea, R. et al. (1998b) Pregnancy following intracytoplasmic sperm injection from an HIV-1- seropositive man. Hum. Reprod., 13, 3247–3249[Abstract]

Mashro, T.D., Satten, G.A., Nophresorn, T. et al. (1994) Probability of female-to-male transmission of HIV-1 in Thaïland. Lancet, 343, 204–207[ISI][Medline]

Matz, B., Kupfer, B., Ko, Y. et al. (1998) HIV-1 infection by artificial insemination. Lancet, 351, 728[ISI][Medline]

McCornick, M., Davidson, E.C., Stato, M.A. (1999) Preventing perinatal transmission of human immunodeficiency virus in the United States. Obstet. Gynaecol., 94, 795–798[Abstract/Free Full Text]

McGowan, J.P., Crane, M., Wionia, A. et al. (1999) Combination antiretroviral therapy in human immunodeficiency virus-infected pregnant women. Obstet. Gynecol., 94, 641–646[Abstract/Free Full Text]

Mermin, J.H., Holodniy, M., Katzenstein, D.A. et al. (1991) Detection of human immunodeficiency virus DNA and RNA in semen by the Polymerase Chain Reaction. J. Infect. Dis., 164, 769[ISI][Medline]

Miotti, P.G., Taha, T.E.T., Kumwenda, N.I. et al. (1999) HIV transmission from breastfeeding – a study in Malawi. JAMA, 282, 744–749[Abstract/Free Full Text]

Mofenson, L.M., Lambert, J.S., Stiehm, E.R. et al. (1999) Risk factors for perinatal transmission of human immunodeficiency virus type 1 in women treated with Zidovudine. Pediatric AIDS Clinical Trials Group Study 185 Team. N. Engl. J. Med., 341, 385–393[Abstract/Free Full Text]

Nolan, K. (1990) Human immunodeficiency virus infection, women, and pregnancy: ethical issues in: HIV Disease in pregnancy. Obstet. and Gynecol. Clin. North America, 17, 651–668

Nuovo, G.J., Becker, J., Simsir, A. et al. (1994) HIV-1 nucleic acids localize to the spermatogonia and their progeny. A study by polymerase chain reaction in situ hybridization. Am. J. Pathol., 144, 1142–1148[Abstract]

Peterman, T.A., Stoneburner, R.L., Allen, J. et al. (1998) Risk of HIV transmission from heterosexual adults with transfusion-associated infections. JAMA, 259, 55–88[Abstract]

Pudney, J. and Anderson, D.J. (1991) Orchitis and human immunodeficiency virus type 1 infected cells in reproductive tissues from men with acquired immune deficiency syndrome. Am. J. Pathol., 139, 149–160[Abstract]

Pudney, J., Nguyen, H., Xu, C. et al. (1998) Microscopic evidence against HIV-1 infection of germ cells or attachment to sperm [corrected and republished in J. Reprod Immunol. (1999) 44, 57–77]. J. Reprod. Immunol., 41, 105–125

Quayle, A.J., Xu, C., Mayer, K.H. et al. (1997) T lymphocytes and macrophages, but not motile spermatozoa, are a significant source of human immunodeficiency virus in semen. J. Infect. Dis., 176, 960–968[ISI][Medline]

Quayle, A.J., Xu, C., Tucker, L. et al. (1998) The case against an association between HIV-1 and sperm: molecular evidence. J. Reprod. Immunol., 41, 127–136[ISI][Medline]

Ragni, M.V., Faruki, H. and Kingsley, L.A. (1998) Heterosexual HIV-1 transmission and viral load in hemophilic patients. J. Acquir. Immun. Defic. Synd. Hum. Retroviral, 17, 42–45[ISI][Medline]

Rogero, M.F. and Shaffer, N. (1999) Reducing the risk of maternal-infant transmission of HIV by attacking the virus. N. Engl. J. Med., 341, 441–442[Free Full Text]

Ross, A., Morgan, D., Lubega, R. et al. (1999) Reduced fertility associated with HIV: the contribution of pre-existing subfertility. AIDS, 13, 2133–2141[ISI][Medline]

Royce, R.A., Semy, A., Cates, W. et al. (1997) Sexual transmission of HIV. N. Engl. J. Med., 336, 1072–1078[Free Full Text]

Schofield, V. (1992) Sperm as vectors and cofactors for HIV-1 transmission. J. NIH Res., 4, 105–108

Semprini, A.E., Levi-Setti, P., Bozzo, M. et al. (1992) Insemination of HIV- negative women with processed semen of HIV- positive partners. Lancet, 340, 1317–1319[ISI][Medline]

Semprini, A., Vucetich, A., Onela, M. et al. (2000) Amp intra conjugale : quelle strategie de prise en charge? L'expérience italienne. Communication à la journée: Le désir d'enfant chez les couples VIH sérodifférents. Toulouse, 28–29

Sherr, L. (1995) Psychological aspects of providing care for women with HIV infection in HIV infection in women. In (eds) Minkoff, H.L., Dehovitz, J.A. and Duerr, A. Raven Press Ltd. New York, 107–123

Si-Mohamed, Kazatchkine, M.D., Heard, I. et al. (2000) Selection of drug-resistant variants in the female genital tract of human Immunodeficiency virus type 1-infected women receiving antiretroviral therapy. JID, 182, 112–122[Medline]

Smith, J.R., Reginald, P.W., Forster, S.M. (1990) Safe sex and conception: a dilemna. Lancet, 335, 359

St Louis, M.E., Kamenga, M., Brown, C. et al. (1993) Risk for perinatal HIV-1 transmission according to maternal immunologic, virologic, and placental factors. JAMA, 269, 2853–2859[Abstract]

Stephenson, J.M. and Griffioen, A. (1996) The effect of HIV diagnosis on reproductive experience. Study Group for the Medical Research Council Collaborative Study of Women with HIV. AIDS, 10, 1683–1687[ISI][Medline]

Stewart, G.J., Tyler, J.P., Cunningham, A.L. et al. (1985) Transmission of human T-cell lymphotropic virus type III (HTLV-III) by artificial insemination by donor. Lancet, ii, 581–585

Sunderland, A., Minkoff, H.L., Handte, J. et al. (1992) The impact of human immunodeficiency virus serostatus on reproductive decisions of women. Obstet. Gynecol., 79, 1027–1031[Abstract]

Tachet, A., Dulioust, E., Salmon, D. et al. (1999) Detection and quantification of HIV-1 in semen: identification of a subpopulation of men at high potential risk of viral sexual transmission. AIDS, 13, 823–831[ISI][Medline]

Tedder, R.S., Zuckerman, M.A., Goldstone, A.H. et al. (1995) Hepatitis B transmission from contaminated cryopreservation tank. Lancet, 346, 137–140[ISI][Medline]

The European Mode of Delivery Collaboration (1999) Elective caesarean-section versus vaginal delivery in prevention of vertical HIV-1 transmission: a randomized clinical trial. Lancet, 353, 1035–1039[ISI][Medline]

Thorne, C. and Newell, M.L. (2000) Epidemiology of HIV infection in the newborn. Early Hum. Dev., 58, 1–16[ISI][Medline]

Van Voorhis, B.J., Martinez, A., Mayer, K. et al. (1991) Detection of human immunodeficiency virus type 1 in semen from seropositive men using culture and polymerase chain reaction deoxyribonucleic acid amplification techniques. Fertil. Steril., 55, 588–594[ISI][Medline]

Vernazza, P.L., Gilliam, B.L., Dyer, J. et al. (1997) Quantification of HIV in semen: correlation with antiviral treatment and immune status. AIDS, 11, 987–993[ISI][Medline]

Vernazza, P.L., Eron, J.J., Fiscus, S.A. et al. (1999) Sexual transmission of HIV: infectiousness and prevention. AIDS, 13, 155–166[ISI][Medline]

Wade, N.A., Birkhead, G.S., Warren, B.L. et al. (1998) Abbreviated regimens of Zidovudine prophylaxis and perinatal transmission of the human immunodeficiency virus. N. Engl. J. Med., 339, 1409–1414[Abstract/Free Full Text]

Weiss, S.H., Goedert, J.J. Gartner, S. et al. (1988) Risk of human immunodeficiency virus (HIV-1) infection among laboratory workers. Science, 239, 68–71[ISI][Medline]

Williams, H.A., Watkins, C.E., Risby, J.A. (1996) Reproductive decision-making and determinants of contraceptive use in HIV-infected women. Clin. Obstet. Gynecol., 39, 333–343[ISI][Medline]

Working group on mother-to-child transmission of HIV (1995) Rates of mother-to-child transmission of HIV-1 in Africa, America and Europe: results from 13 perinatal studies. J. Acquir. Immun. Defic. Syndr., 8, 506–510

Zagury, D. (1984) HTLV-III in cell cultived from semen of two patients with AIDS. Science, 226, 449[ISI][Medline]

Zhang, H., Dornadula, G., Beumont, M. et al. (1998) Human immunodeficiency virus type 1 in the semen of men receiving highly active antiretroviral therapy [see comments]. N. Engl. J. Med., 339, 1803–1809[Abstract/Free Full Text]