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2007
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2006
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Ulrike Sonnenberg-Schwan, Carole Gilling-Smith, Michael Weigel

The optimization of antiretroviral therapy has led to great improvements in both the quality of life and life expectancy of people living with HIV/AIDS, at least in countries where HAART is widely available. A growing number of men and women living with HIV/AIDS feel encouraged to include parenthood in the planning of their lives. Procreation without risk, or at very low risk of infection for the uninfected partner or prospective child, is now an option for couples in which one or both partners are HIV-infected. The low materno-fetal transmission rate that can be achieved today has added to the acceptance of planned motherhood in seropositive women.

Procreative options for HIV-affected couples theoretically vary from unprotected intercourse to several techniques of assisted reproduction, donor insemination or adoption. Usually, couples are advised against unprotected intercourse, as the priority is to prevent infection in the uninfected partner or child.

Average transmission rates for unprotected heterosexual intercourse are hardly useful in individual counseling situations. They can vary greatly depending on the stage of HIV disease, viral load or presence of other sexually transmittable diseases (Wawer 2005). Data hint to a low risk of transmission in case of totally suppressed viral load but are still limited. HIV can sometimes be detected in semen or genital secretions even when viral load in blood plasma is below the limit of detection. In other words, couples should not risk unprotected intercourse only on the basis of the infected partner having an undetectable load. Consistent use of condoms can decrease the transmission risk in heterosexual relationships by 80-85 % (Davis 1999) and abstention from condom use, restricted to the time of ovulation, has been proposed as an option for discordant couples. Mandelbrot et al. (1997) reported a transmission rate of 4 % in 92 couples using carefully timed, but unprotected intercourse to conceive. Infections were restricted to couples who also reported inconsistent use of condoms outside the fertile period. In a small retrospective Spanish study (Barreiro et al. 2006) no infections occurred in a cohort of 62 HIV discordant couples who conceived by timed intercourse. All HIV-infected partners had a viral load below detectability. . These data so far cannot support unprotected intercourse limited to ovulation time without further protection as being a safe option for couples.

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Donor insemination is an alternative safe option for a small number of couples, but due to legal restrictions it is only offered in a minority of centers. In the UK, for example, there are no restrictions on donor insemination, whereas in Germany the access is limited. In addition, most couples wish for a child that is the biological offspring of both parents. Adoption in many countries is merely a theoretical option: HIV infection of one partner usually renders this procedure very difficult, or even impossible in most countries. To minimize the risk of HIV transmission, the following options are recommended: § Self-insemination or assisted reproduction in case of infection in the female partner § Assisted reproduction with processed sperm in case of infection in the male partner In several European countries, as well as in the US and Japan (Kato 2006), reproductive assistance for couples affected by HIV has been set up in the past few years. Equal access for HIV-positive women and men is granted in most, but not all of these countries. The safety of sperm washing The technique of processing sperm from HIV-positive men prior to the insemination of their HIV-negative partners was first published by Semprini et al. in 1992. The first inseminations with sperm, washed free of HIV, were carried out in Italy and Germany as early as 1989 and 1991, respectively. Up to mid 2003, more than 1,800 couples had been treated in about 4,500 cycles, applying various techniques of assisted reproduction. More than 500 children have been born with no single seroconversion reported in the centers closely following the protocol of washing and testing the sperm prior to assisted reproductive techniques. Native ejaculate mainly consists of three fractions: spermatozoa, seminal plasma and nuclear concomitant cells. HIV progenome and virus has so far been detected in the seminal plasma, the concomitant cells, and occasionally in immobile spermatozoa. Several studies have indicated that viable, motile spermatozoa are not likely to be a target for HIV infection (Pena 2003, Gilling-Smith 2003). Motile spermatozoa can be isolated by standardized preparation techniques. After separation of the spermatozoa from plasma fractions and NSC (non-spermatozoa cells), the spermatozoa are washed twice with culture medium and resuspended in fresh culture medium. Incubation for 20-60 minutes allows motile sperm to "swim-up" to the supernatant. To be more certain that it is not contaminated with viral particles, an aliquot of the sample should be tested for HIV nucleic acid using highly sensitive detection methods (Weigel 2001, Gilling-Smith 2003, Pasquier 2006). Depending on the method, the lowest limit of detection is 10cp/ml. After having studied the effectiveness of several methods of sperm processing, Anderson (2005) concluded that the combination of gradient density centrifugation and swim-up allows a 10,000-fold decrease of HIV-1 concentration in sperm. Since HIV could theoretically remain undetected, sperm washing is currently regarded as a very effective risk reduction, but not a risk-free method. Several studies have shown that sperm washing can also reduce the risk of HCV in couples with male HCV-coinfection (Gilling-Smith 2003, Chu 2006). Most of the European centers that offer assisted reproduction to HIV-discordant couples are part of the CREATHE-network, which aims to optimize treatment and safety of the methods as well as to compile an extensive database. There are high hopes that soon sufficient clinical cases can be reported to demonstrate the safety and reliability of sperm washing. Pre-conceptual counseling The initial counseling of the couple should not only consider extensive information on all reproductive options available, diagnostics and prerequisites for reproductive treatment, but also the psychosocial situation of the couple. Important issues to discuss are the financial situation, current psychosocial problems, the importance of a network of social support from family or friends, and planning and perspectives about the future as a family, including possible disability or death of one of the partners (Nakhuda 2005). A supporting, empathic and accepting mode of counseling is advisable, as many couples feel distressed if their motives for, or entitlement to, parenthood are questioned. The risks of unprotected intercourse or improper condom use, not only during reproductive treatment but at all times, should be discussed (Sauer 2006). In cases where professional psychosocial services are not integrated, co-operation with organizations in the AIDS counseling system or self-help groups is advisable. Possible stress occurring during the work-up and treatment of the couple should be discussed as well as doubts or fears. Many couples for example are afraid that their test results might indicate that parenthood is impossible. If the male partner is HIV-infected, the couple need to know that the risk of HIV infection can be minimized, but not excluded. HIV-positive women have to be informed about the risks of vertical transmission and the necessary steps to avoid it. In any case, couples should know that even using state-of-the-art reproductive techniques, achieving a pregnancy cannot be guaranteed. Table 1: Pre-treatment investigations General Comprehensive medical and psycho-social history Female examination Gynecological examination, sonography, tubal patency test, basal temperature if necessary, endocrine profile, cervical smear (cytology, microbiology) (UK: 2-5 FSH/LH and mid-luteal progesterone to evaluate female fertility) Serology (rubella, toxoplasmosis, syphilis, CMV, HBV, HCV) HIV-specific assessments HIV-associated and accompanying symptoms Blood glucose, GOT, GPT, GGT, complete blood count Ultra-sensitive HIV-PCR, CD4+/CD8+ T-cell counts HIV antibody test of the partner Male examination Spermiogram, semen culture Serology (HBV, HCV, TPHA) Chlamydia PCR Male HIV infection Following the decision to conceive with reproductive assistance, the couple should undergo a thorough sexual health and infection screen, including information about the male partner's HIV status. The possibility of HIV infection in the female partner also has to be excluded. In some cases, it might be necessary to treat genital infections before starting reproductive treatment. Table 1 shows the investigations as provided in the German recommendations for assisted reproduction in HIV-discordant couples (Weigel 2001), revised in 2007 (Tandler-Schneider 2007). There are small differences between the European centers. For the UK recommendations see Gilling-Smith et al. 2003. After sperm washing and testing for HIV, spermatozoa can be utilized in three different reproductive techniques depending on whether the couples have any additional fertility issues: intra-uterine insemination (IUI), extracorporal fertilization by conventional in-vitro fertilization (IVF) and intracytoplasmic sperm injection followed by embryonic transfer. According to the German recommendations, the choice of method depends on the results of gynecological and andrological investigations and the couple's preference. The success rate using IUI has been shown to be reduced if the sperm is washed and then cryopreserved before use. This is necessary in some centers where PCR testing of the washed sample for HIV cannot be done on the day of insemination. This, together with the fact that semen quality can be impaired in some HIV-infected men (Dulioust 2002, Müller 2003, Nicopoullos 2004, Bujan 2007), results in a number of couples being advised to have IVF or ICSI. Couples should be informed about three further important aspects: · Sperm-washing and testing can greatly reduce the risk of infection, but cannot exclude it completely. Following recent study results, this risk seems to be only theoretical and cannot be expressed in percentages. § During treatment, consistent condom use is of utmost importance. HIV infection of the woman in the early stages of pregnancy can increase the risk of transmission to the child. Sauer (2006) reported a case of seroconversion in a woman already enrolled in a reproductive treatment program, prior to the first treatment, presumably due to condom breakage. § Most couples attending European centers have to pay for treatment costs themselves. These are dependent on the type of technique applied, and range from about 500 to 5,000 Euro per cycle. An exception is France, where couples have cost-free access to treatment. In Germany, health insurances sometimes cover a part of the costs, but they are not obliged to. § Even the most sophisticated techniques cannot guarantee successful treatment. § Following successful treatment, couples are usually monitored for HIV status for 6-12 months after childbirth, depending on the center. A new approach is the use of PrEP (pre-exposure prophylaxis) to limit the susceptibility of the uninfected woman during timed intercourse. In 2004, a small study was initiated in Switzerland (Vernazza 2006). Couples are advised to have unprotected intercourse only at the time of ovulation. During the 24 hours before having intercourse the female partner takes two doses of Tenofovir. Viral load of the HIV-positive partner should be below detectability to further lower the risk of HIV transmission. The acceptance of this procedure is high. First data indicate a higher pregnacy rate than after insemination with processed sperm (Vernazza 2007): Between 2004 and 2007 21 couplesfollowed the procedure, the pregnancy rate was 70%. No female infection was detected. A similar project was initiated in Germany in 2007. Female HIV infection HIV-positive women with unimpaired fertility can conceive by self-insemination. Similar to cases in which the male partner is infected, a fertility screen and further investigations are recommended (see Table 1 for the revised German guidelines , . (Tandler-Schneider 2007)) In some cases, ovarian stimulation may be advisable. Ovarian stimulation, however, requires highly qualified supervision to avoid multiple gestations. It is important to time ovulation accurately (i.e., by use of computer-based ovulation kits or urine sticks). A simple inexpensive way of determining whether the cycles are ovulatory, which can be helpful in women who have regular cycles, is a basal temperature chart beginning about three months before the first self-insemination. At the time of ovulation, couples can either have protected intercourse with a spermicide-free condom and introduce the ejaculate into the vaginal cavity afterwards, or the ejaculate can be vaginally injected using a syringe or applied with a portio cap after masturbation. Thus, the conception remains in the private sphere of the couple. More than two inseminations per cycle are not advisable, as the fraction of motile sperm in the ejaculate can decrease with any additional tries. Furthermore, the couple might experience psychological strain through extensive planning. After 6-12 months of unsuccessful self-insemination, the couple should have further fertility investigations with a view to assisted conception. Fertility disorders Fertility disorders in HIV-positive women seem to have a higher prevalence than in an age-matched HIV-negative population (Ohl 2005), but data still show some conflicting results. The reasons discussed include an increased rate of upper genital tract infections (Sobel 2000), menstrual disorders, and cervical infertility (Gilles 2005). Coll (2006) assumes the possibility of subclinical hypogonadism, potentially due to mitochondrial dysfunction. In some cases, women will only be able to conceive by assisted reproduction. Dependent on the fertility status of both partners, IVF and ICSI can be considered as methods of choice. Recent data reported from the Strasbourg program indicated infertility problems in most HIV-positive women. IVF and ICSI were far more effective than IUI (Ohl 2005). In the Barcelona program, Coll (2006) observed a decreased pregnancy rate in HIV-positive women after IVF compared to age-matched HIV-negative controls and HIV-positive women who received donated oocytes. Results indicated a decreased ovarian response to hyperstimulation in HIV-positive women. A slightly impaired ovarian response to stimulation during 66 ICSI cycles in 29 HIV-positive women was also described by Terriou (2005). Martinet (2006) found no difference in ovarian response between HIV-positive and HIV-negative women in Brussels. Although many centers throughout Europe offer assisted reproduction if the male partner is infected, access to treatment for HIV-positive women is currently only possible in Belgium, France, Germany, Great Britain, and Spain. Outside of Europe, some US centers offer reproductive assistance to seropositive women. HIV infection of both partners A growing number of HIV-concordant couples now seek reproductive counseling. In some centers, these couples are also accepted for reproductive treatment. One option for couples without fertility disorders might also be timed unprotected intercourse. The discussion pertaining to the transmission of mutated drug-resistant virus between partners, is still ongoing. Up until now, only a very small number of "super infections" have been published, and they only occurred in individuals who were not on a HAART regimen (Marcus 2005). Couples should be offered the same range of fertility counseling and screening as HIV-discordant couples. The current health of each partner should be carefully evaluated with a full report from their HIV physician. Psychosocial aspects § Experiences, from more than a decade of counseling, show the importance of offering professional psychosocial support to couples before, as well as during, and after reproductive treatment. § Up to one third of the couples decide against the realization of their wish for parenthood after in-depth counseling (Vernazza 2006). Accepting the desire to become parents and dealing with the underlying motives as well as the psychosocial situation in an empathic way enables couples to see obstacles as well as to develop alternative perspectives if this wish cannot be realized for various reasons. § Frustration and disappointment may accompany failures or strains during treatment (i.e., unsuccessful treatment cycles, premature termination of pregnancy). Left alone with these strains, couples sometimes decide to conceive using unprotected intercourse, to avoid further stress. Depending on the risk perception of the partners, this decision may sometimes be well planned, but other times be born out of despair. These couples might be at risk of infection: in 56 HIV-discordant couples participating in the Milan program who attempted spontaneous conception after failing to conceive with artificial insemination, at least one infection occurred (Semprini 2005). § Psychiatric co-morbidities in one or both partners (i.e., substance abuse, psychoses) can be reasons to at least postpone treatment. Professional diagnosis and support will be necessary in these cases. § Often, the central importance of the wish for parenthood of many migrant couples is overlooked in parts of the medical and psychosocial counseling system. Language or communication difficulties on both sides, ignorance of different cultural backgrounds and lack of acceptance of "strange" life-styles can lead to feelings of discrimination, isolation, helplessness or despair in couples. § Issues concerning the welfare of the child should be openly discussed during reproductive counseling (Frodsham 2004). Many couples are concerned about a potential negative effect of antiretroviral drugs on their offspring. Severe impairment of the health of the prospective parents might lead to concerns for the future well-being of the child. The future Following the improvements in morbidity and mortality of men and women living with HIV/AIDS, healthcare professionals encounter a growing number of couples or individuals who are contemplating parenthood. Having a child is the expression of a fulfilled partnership and an important perspective of life. This is no less true in couples afflicted with HIV/AIDS. In the medical and psychosocial care of patients, it is important to create an environment where reproductive aspects and parenting can be discussed on an open and non-judgmental basis. Future priorities include continued reporting of data pertaining to the applied methodologies as well as to the outcomes, reporting of adverse results and the follow-up of couples (Giles 2005). The first steps towards optimizing semen processing procedures, namely quality control of virus detection in processed sperm and laboratory safety, have already been taken (Politch 2004, Pasquier 2006, Gilling-Smith 2005). Meikle (2006) criticizes the current state of "fragmented knowledge" regarding infertility service practices for HIV-positive patients. Long-term outcomes in couples that received reproductive assistance, health outcomes among children, both in medical as well as in psychosocial terms, and consensus regarding best practices or surveillance of care provided by clinics have received little notice until now. A great number of couples cannot afford to pay for the high costs of treatment, or travel long distances, sometimes even to other countries, to reach specialized units. There is an urgent need to develop strategies for the counseling and support of these couples. The use of donated oocytes in reproductive services for HIV-positive women (Coll 2006) is limited in several countries due to legal and ethical considerations. It even enables treatment of women who have reached an age where reproductive assistance is not usually offered anymore due to the high risk of miscarriages and malformation and the low success rate of assisted reproduction techniques. Medical and technical progress open a wider range of options for couples, but aside from comparing higher or lower success rates, there is an urgent need to discuss psychological and psychosocial issues pertaining to the welfare of parents and child. For further information please contact: Ulrike Sonnenberg-Schwan Clinical Psychologist AAWS/DAIG e.V., Wasserturmstr. 20, D - 81827 München Phone: ++49-89-43766972, Fax: ++49-89-43766999 E-mail: ulrike.sonnenberg-schwan@t-online.de Carole Gilling-Smith, MA, FRCOG, PhD Consultant Gynecologist, Assisted Conception Unit Chelsea & Westminster Hospital 369 Fulham Road, GB - London SW10 9NH Phone: + 41-20-8746-8585; E-mail: cgs@agoraclinic.co.uk References 1. Al-Khan A, Colon J, Palta V et al. Assisted reproductive technology for men an women infected with human immunodeficiency virus type 1. Clin Infect Dis 2003; 36: 195-200. http://www.natap.org/2003/feb/020103_7.htm 2. Anderson DJ. 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Encouraging results despite complexity of multidisciplinary care of HIV-infected women with assisted reproduction. Hum Reprod 2005; 20 (11): 3134-6.http://amedeo.com/lit.php?id=16006462 24. Pasquier C, Anderson D Andreotti-Zaugg C et al. Multicenter quality control of the detection of HIV-Genome in semen before medically assisted procreation. J Med Vir 2006; 78: 877-882 25. Pena JE, Thornton MH, Sauer MV. Assessing the clinical utility of in vitro fertilization with intracytoplasmatic sperm injection in human immunodeficiency virus type 1 serodiscordant couples: report of 113 consecutive cycles. Fertil Steril 2003; 80: 356-62. http://amedeo.com/lit.php?id=12909499 26. Pena JE, Thornton MH, Sauer MV. Complications of in vitro fertilization with intracytoplasmativ sperm injection in human immunodeficiency virus serodiscordant couples. Arch Gynec Obstet 2003; Aug; 268(3):198-201 27. Politch JA, Xu c, Tucker L, Anderson DJ. 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Weigel MM, Kremer H, Sonnenberg-Schwan U, Gölz J et al. Diagnostics and treatment of HIV-discordant couples who wish to have children. Eur J Med Res 2001; 6: 317-21. http://amedeo.com/lit.php?id=11496900 38. Vernazza PL, Hollander L, Semprini AE et al. HIV-discordant couples and parenthood: how are we dealing with the risk of transmission? AIDS 2006, 20: 635-6. http://amedeo.com/lit.php?id=16470136 39. Vernazza P, Brenner I, Graf I (2007). Pre-exposure prophylaxis and timed intercourse for HIV-discordant couples willing to conceive a child. Poster Nr. MoPDC01, International AIDS Conference, Sydney, Australia, July 2007