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Abstract

Thanks to antiretroviral combination therapy, HIV-infected individuals live longer, healthier lives and may wish to have children. Women with HIV can attempt to conceive naturally or through simple self-insemination to minimize the risk of horizontal HIV transmission. Assisted reproduction technology is necessary in couples with infertility, which can either be independent of HIV infection and its treatment or be associated with it. This article summarizes the latest evidence regarding the desire for a child in HIV-positive women and how HIV infection and its treatment may impact female fertility. Current data regarding access to and outcomes of assisted conception programs in HIV-positive women wishing to conceive in both high- and low-income countries is also reviewed.

Keywords

HIV horizontal transmission infertility self-insemination seropositive women vertical transmission

Nearly half of the 37.2 million adults living with HIV/AIDS worldwide are women, and most of them are of child-bearing age [101,1]. Globally, the number of HIV-infected women is progressively on the rise as a result of increasing rates of HIV sexual transmission to women [2,3], which, in industrialized countries, is accompanied by the decrease in mortality owing to effective antiretroviral treatments [4,5]. HIV infection has considerable impact on the lives of women, as they are more vulnerable to infection both socially and biologically. The predominant mode of transmission in most parts of the world is through heterosexual contact, with peaks of incidence through intravenous drug use in certain areas – mainly Eastern Europe.

HIV infection interferes with sexual and reproductive choices in a variety of ways, including concerns regarding sexual transmission to the uninfected man, vertical transmission to the child, and fears regarding declining health and shortened lifespan. In addition, HIV has been shown to impair fertility for a number of reasons, including the effect of advanced HIV disease, interaction with antiretroviral medication and a higher frequency and severity of genital tract infections [6]. As far as fertility is concerned, HIV infection in women is also characterized by unique gynecologic manifestations, such as cervical dysplasia or severe pelvic inflammatory disease (PID), which may impact fertility or complicate the course of pregnancy.

Where available, the introduction of highly active antiretroviral therapy (HAART) into clinical practice has gradually transformed HIV infection from a progressively fatal disease to a chronically manageable infection in substantially asymptomatic individuals. The ability, offered by HAART, to reach undetectable maternal viral loads during pregnancy, together with the choice of elective cesarean section in selected cases of pregnant women and the restriction of breast feeding, has the reduced rates of mother-to-child transmission to negligible levels [7,8].

However, women infected with HIV live in very diverse life conditions and infection settings, which affect the access to HIV treatment and reproductive health services. Effective antiretroviral medication is still widely unavailable for residents in low-income countries. Migrants and refugees from low-to-high income countries, although in theory able to enjoy the advantages of advanced HIV medication and reproductive health services, may be living in conditions that are rather similar to those of women living in low-income countries. Factors including cultural barriers, legal status and trauma may further condition these women in making choices regarding their future and the future of their families [9]. Finally, types and prevalence of infertility factors differ among populations, such as sexually transmitted diseases (STDs) and/or PID, may be more frequent in women injecting drugs and in several developing countries. This ample diversity should be kept in mind when considering the issue of reproduction in HIV-positive women.

In the reassuring context thus created in many developed countries, HIV-infected women with HIV may feel more legitimized in their desire to have a child. Health authorities and professional associations have also changed their former negative approaches of encouraging contraception and discouraging pregnancy towards policies of nondiscrimination of individuals infected by HIV, regarding access to reproductive health services [10,11]. However, notwithstanding the evidence regarding improved HIV-related health on one hand, and the real need for reproductive health services on the other, treatment centers offering fertility options for infertile HIV-infected women are still few in number. The reasons for such paucity may include ethical opposition as well as concerns around the safety of the procedures to healthcare professionals and to other patients attending the centers. As a result, evidence regarding fertility care in HIV-positive women is incomplete and several important questions remain unanswered.

In developing countries, health services for HIV-positive individuals have focused primarily on tackling opportunistic infections and providing antiretroviral treatment, while virtually no attention has been given to provision of reproductive health services for HIV-positive women and men, which is further worsened by substantial stigma associated with HIV infection and impacting on views toward reproduction in the context of HIV [102]. Interviews conducted with healthcare providers and policy makers in Cape Town, South Africa, revealed that among professionals, biomedical and sociological concerns often also clashed with the belief in the right to parenthood in counseling HIV-infected women or in setting up reproductive health services [12].

The offer of advice on reproductive options and services available to all HIV-infected individuals, independent of their HIV disease status or life conditions, is a central means to combat HIV infection as it may lead to a reduction in rates of horizontal and vertical transmission, help women achieve pregnancy by overcoming fertility problems, promote improved health in pregnancy and reduce the risk during child birth. This article aims to review the recent literature regarding fertility and reproductive treatments for HIV-infected women desiring a child.

Desire for parenthood in HIV-positive women

The wish for parenthood is a fundamental instinctive desire for the majority of human beings, which is often independent of life conditions and survival expectancy. Especially in the case of women with a traditional view of family, parenthood can be a primary source of self-expression and self-esteem [12], and a source of social legitimacy and identity [9]. For individuals affected by HIV, this desire may acquire additional significance. Indeed, Italian couples with HIV who had children through an assisted conception program reported that having a child gave them a previously lacking sense of ‘normalcy’ and raised the issue of the child as a continuation of the family and of the love relationship once the infected partner was gone. Some also mentioned the stigma and social pressure derived from the forced childlessness brought upon by HIV [13]. The same findings were confirmed in migrant African women living in Europe as well as in socially marginalized HIV-positive women in the USA [9,14].

Notwithstanding the less favorable health and sociological conditions of HIV-infected individuals, evidence from developing countries shows that a substantial proportion of women continue to desire children despite their HIV status. Motherhood is still seen as normative for married women and social pressures on women to have children may add to their own desire for motherhood.

Until recently, very little was known regarding the fertility intentions of individuals infected with HIV. When treatment options were scarce, the pursuing of this desire could have exposed patients to conflicts with their healthcare providers and the issue was often left undiscussed. However, in recent years, different studies have addressed the issue of reproductive health choices in HIV-infected patients living in different settings.

A Swiss multicenter study evaluating fertility intentions and condom use among 114 HIV-positive individuals showed that 45% of positive women and 38% of positive men expressed desire for children [15].

A Canadian survey investigating reproduction intentions in 230 HIV-positive women revealed that 25.8% of women living with HIV indicated an intention to have children. The frequency of fertility intention was similar to that of the general Canadian population (37%). In this survey, desire for parenthood did not correlate with clinical HIV status determinants, such as mean CD4 cell count, blood viremia and use of HAART [16].

A US descriptive study sought to identify factors that influence HIV-infected women's reproductive intentions in a sample of 322 HIV-infected women [17]. Potential factors influencing the intent to get pregnant included demographic characteristics, HIV-related factors and personal beliefs and attitudes. In this study, traditional gender-role orientation and motivation for child-bearing were the most significant factors in predicting the intent to get pregnant.

A UK audit of supply and demand for reproductive assistance conducted in 2002 of over 15,000 HIV-infected individuals registered in HIV clinics found that 16% of men and 4% of women attending the clinics had sought advice about how to conceive safely. The study identified worrying shortfalls in the supply of information, access to fertility and treatments to reduce risk, including access to specialized antenatal care for HIV-positive women [18].

More recently, Heard et al. evaluated the desire for children and analyzed factors associated with this in a vast sample of 1254 heterosexual HIV-positive women and men of reproductive age who participated in the French VESPA study (555 women and 699 men) [19]. Associations were sought between desire for a child and reproductive potential, cultural aspects and HIV-related health conditions (expressed as CD4 cell count, plasma HIV load and antiretroviral treatment). At the time of analysis, 45% of women reported to already have children. A total of 32% stated that they expected to have children in the future, 6% were trying to have a child and 3% were actually pregnant. In multivariate analysis, HIV-related health status, including advanced disease and being on antiretroviral treatment, was not related to reproductive intentions among either women or men living with HIV.

The independence of fertility desires from HIV-related health status was confirmed in a study that interviewed 61 HIV-positive individuals in Cape Town, half of whom were taking HAART medication and the rest were devoid of treatment [20]. In this study, many respondents expressed a strong personal desire for biological parenthood and HIV brought new significances for their desire for children, symbolizing hope, happiness and a reason to live. Children were also perceived as signifying normality and impersonating the desire to ‘leave something of themselves behind’. Factors that increased the desire for children in this group included social expectations from partners, extended families and the community at large. By contrast, factors that counter-balanced the desire for children included the risks posed by engaging in unprotected sex, concerns about potential infant infection and death, fears that pregnancy might damage the woman's own health and concerns that the child would be orphaned. Finally, it was also clear that there was a strong feeling that society disapproved of reproduction in those infected with HIV. In this study, the factors promoting desire for parenthood often outweighed the concerns relating to infection and disease.

In summary, the frequency of intention to be a parent in women with HIV is high, with rates similar to those observed in the general population. HIV-related health status does not appear to interfere with fertility desires and intentions. Public health authorities and healthcare providers should be made aware of this significant phenomenon, and solutions to allow individuals with HIV to conceive safely or to overcome eventual infertility should be made available.

Fertility in HIV-positive women

HIV-positive women wishing to conceive can achieve pregnancy naturally through unprotected intercourse. When HIV transmission to the male partner is to be avoided, self-insemination of ejaculated sperm is advised. These conception methods are feasible when no infertility factors exist. However, it has been repeatedly shown that infertility and subfertility are common in HIV-positive women. Different confounding factors may partially account for the observed reduction in fertility and their impact may differ among groups of HIV-positive women. In industrialized countries, women are often embarking on pregnancy at a later age owing to voluntary avoidance of pregnancy prior to widespread use of HAART. Intravenous drug abuse, in particular the use of opiates, is a well recognized cause of infection and has been shown to induce dysfunction of the hypothalamic–pituitary–gonadal axis [21]. Documented causes of infertility in HIV-positive women, which may be more prevalent in several developing countries, include cervical infertility owing to the increased incidence of cervical lesions leading to laser ablation, loop excision or conization and tubal infertility due to genital tract infections [22,23]. Finally, it has been speculated but not proven that HIV itself may have an additional impact on fertility, including effects on ovarian reserve [24]. Part of the difficulties in reaching clear conclusions regarding the fertility profile of the HIV-infected individuals relies in the fact that many of the studies investigating this area were conducted locally and on small groups of patients. Large, international efforts are required to elucidate the debated points regarding HIV infection and female fertility.

Impact of HIV infection on fertility

Early evaluations of the impact of HIV infection on fertility, conducted prior to the introduction of HAART, indicated decreased pregnancy rates in HIV-positive women in comparison with seronegative controls [25], and fertility impairment was correlated to lower CD4 counts and progressive HIV disease [26]. These findings have been confirmed in later studies conducted in lower income countries where a large proportion of women are not treated with HAART [27 –29]. Loko et al. analyzed the incidence of pregnancy and live births in 473 HIV-positive women from Côte d'Ivoire in relation to their CD4 counts. In women with CD4 cell counts of less than 200, 200–349, 350–499 and over 500 cells/mm³, the incidence of pregnancy was 3.7, 5.1, 10.5 and 10.5%, respectively (p = 0.02), and the percentage of live births was 22, 69, 62 and 53%, respectively (p = 0.01) [27].

The mechanisms by which HIV affects fertility were investigated. A large analysis of prospective data compared menstrual cycle data collected in 802 HIV-infected women with 273 HIV-negative controls [30]. The associations between HIV serostatus and the probabilities of having polymenorrhea or amenorrhea were assessed. After adjustment for demographic characteristics, BMI and substance use, seropositivity only slightly increased the odds of having both polymenorrhea and amenorrhea, indicating that HIV serostatus has little overall effect on amenorrhea and menstrual cycle length. However, higher viral loads and lower CD4⁺ counts were associated with increased cycle variability and polymenorrhea.

Studies investigating the impact of HIV on ovulatory function, expressed by follicle-stimulating hormone (FSH) and progesterone blood levels, are inconclusive. A small study investigating the prevalence of early menopause by evaluating FSH and progesterone levels in stored serum samples of 52 HIV-positive women aged 20–42 years demonstrated no evidence of ovulation in 48% of the women during the study period, and elevated FSH levels in 8% of the samples were observed [31]. These results may indicate a trend towards higher anovulation rates and increased frequency of early menopause, but their validity is largely impaired by the limited sample size. By contrast, two other studies investigating menstrual cycle data in HIV-positive women demonstrated no evidence of a significantly increased incidence of oligomenorrhea or amenorrhea in these women [30,32].

Genital tract infections in HIV-positive women

Several studies revealed a significantly increased rate of tubal factor infertility in HIV-positive women [33] (40% of cases with tubal occlusion vs 14% in an unscreened subfertile population) [34]. This fact may be explained by the finding of greater frequency and morbidity from genital tract infections in HIV-positive women, which may have an impact on fertility as well as increasing the risk of both horizontal and vertical transmission of the virus [35]. Several studies have observed substantial perturbation of vaginal flora in HIV-positive women with less than 20% presenting with lactobacillus-dominant flora [36]. Women lacking lactobacilli are at higher risk of acquiring STDs, including HIV.

Published evidence indicates an increased severity of PID in HIV-positive women and has demonstrated high rates of PID from genital tract commensals rather than sexually transmitted pathogens [37].

In 2000, Irwin et al. published a study investigating the influence of HIV infection on clinical and microbiologic characteristics of PID in 207 affected women [38]. A total of 44 (21.25%) women with PID were HIV positive, indicating a high prevalence of PID in women with HIV. HIVpositive women had higher PID severity rates, expressed by the presence of infectious adnexal masses, compared with seronegative women (19.5 vs 16%, respectively; p = 0.05). In addition, women with HIV were hospitalized more often and for longer periods of time (7 vs 4 days) and were subjected more frequently to invasive procedures (15.9 vs 3.7%). The enrolment period of this study (1992–1994) preceded the introduction of HAART and it is unknown whether these findings would still apply to HIV-positive women who now enjoy a wide access to HAART. Another study published in 1998 has demonstrated a similar length of hospitalization and duration of antibiotic treatment of PID in HIV-positive and HIV-negative women [39]. However in this study, both women and investigators were aware of HIV serostatus leading to possible bias.

A more recent study evaluated the effect of HIV infection and degree of immune suppression on the treatment outcome of women with laparoscopically verified salpingitis in a double-blind manner [40]. A total of 140 women were included, 38% of which were revealed to be HIV-1 positive. HIV-1-infected women had more severe disease as clinically measured through calculation of the clinical severity scoring system and application of the laparoscopic scoring system (38% HIV-1-infected vs 24% HIV-negative; p = 0.02). Other findings that positively correlated with HIV infection were elevated temperature at presentation and presence of chronic pelvic and perihepatic adhesions. Among HIV-infected women, CD4 cell count was not associated with severity of PID. Although not significant, there was a trend towards a longer time to reach clinical improvement in HIV-positive women with severe disease versus HIV-negative controls. This study supports the existing recommendation of hospitalization and systemic antibiotic treatment for severe acute salpingitis and outpatient treatment for less severe cases, for both HIV-1-negative and -positive patients.

The observation of higher rates of tubal infertility in women with HIV in comparison with HIV-negative controls was recently confirmed in a cross-sectional study in 130 noninfertile couples seeking pregnancy in which the woman was HIV infected [24]. The majority of women had a good infectious status, did not have sexually transmitted infections and had regular cycles. However, tubal occlusion on hysterosalpingogram was present in 27.8% of the women with no proven fertility.

Hence, although not always straightforward, the bulk of published evidence points to increased tubal infertility and reduced ovarian reserve in HIV-positive women.

Clinical outcome with assisted reproduction treatment

In the absence of infertility factors, self-insemination and artificial insemination can be used to eliminate the risk of HIV transmission to the uninfected male partner [41]. Self-insemination is a viable, low-cost option for serodiscordant couples for female HIV positivity. However, as HIV-positive women are at increased risk of subfertility, fertility investigations should be initiated if conception does not occur within six cycles of self-insemination [42]. The negative impact of HIV on female fertility, together with a reluctance of some couples in collecting and injecting the male partner's sperm means that a significant proportion of women with HIV need assisted conception treatments comprising artificial insemination, in vitro fertilization techniques or ovum donation.

Natural conception through unprotected intercourse, although undeniably more acceptable to couples, poses the risk of horizontal transmission. In the era of HAART, with its significant reduction in blood HIV viremia, some authors doubt the importance of protecting the uninfected partner during the low number of coital acts targeted at conception.

Barreiro et al. studied natural pregnancies in 22 HIV-positive women as part of a cohort of 62 HIV-serodiscordant couples, where the infected partner had suppressed viremia following treatment with HAART, attempting conception naturally [43]. The study revealed no cases of HIV transmission to the uninfected partner and one case of mother-to-child transmission. The study was retrospective and no information was provided regarding the means by which couples attempted to limit the risk of transmission (i.e., intercourse limited to the day of ovulation) and the number of coital acts necessary to achieve pregnancy. In addition, the population studied was limited to couples who achieved pregnancy, with no follow-up data on couples trying to conceive in this way and those who failed in their attempts. The authors concluded that natural conception merits further attention and proposed that in HIV-infected couples, medical assistance could be limited to the diagnosis and treatment of genital tract infections, which are known to increase the risk of HIV transmission, and to the investigation of infertility factors.

In this case as well in that of other publications on natural conception, the seemingly reassuring evidence of the lack of HIV transmission in HIV-positive individuals receiving HAART treatment needs to be weighted against the generally low probability of HIV sexual transmission (one every 500–3000 acts of unprotected intercourse, depending on blood viremia) [44], and on occasional reports of the presence of HIV viral shedding in the genital compartment. In HIV-positive aviremic men, Bujan et al. reported on the occasional presence of HIV in semen [45]. Two recent studies evaluated the dynamics of HIV shedding in vaginal fluids of women with suppressed blood HIV viremia. One study, conducted in 38 HIV-positive women evaluated the presence of HIV in cervical, vaginal and blood samples during the third trimester of pregnancy. In this study, viral load in vaginal secretions did not correlate with that in blood (Spearman's rank correlation coefficient, r = 0.26). The authors concluded that pregnant women with undetectable HIV viremia could still be at risk of transmitting the virus vertically during vaginal delivery, suggesting the continuing need for either antiretroviral prophylaxis during vaginal delivery or the use of elective cesarean sections [46].

A prospective observational study conducted in HIV-1-seropositive nonpregnant Kenyan female sex workers with advanced disease who had started an antiretroviral combination regimen (stavudine, lamivudine and nevirapine) revealed a rapid and significant decrease of cervical and vaginal shedding of HIV RNA and proviral DNA. However, at the end of the first month of treatment, 35% of participants still had detectable genital HIV-1 RNA at one or both genital sites. HIV-1 RNA levels ranged from 52 to 1258 copies/swab in cervical secretions and from 135 to 1332 copies/swab in vaginal secretions. The limitations of this study were the failure to use hypersensitive quantification assays for measuring the residual HIV viral load, and a design that was limited to evaluating the effect of treatment initiation and not of its duration and the interaction with various independent risk factors, including genital ulcer disease, hormonal contraception and even the menstrual stage in itself. With this in mind, the authors conclude that while the observed reduction in viral shedding may lower transmission risk, genital mucosal HIV-1 RNA and infected cells may persist in a significant proportion of women despite treatment [47].

Hence, at the time of writing, the data on the safety of unprotected intercourse in HIV-infected discordant couples attempting to conceive are rather limited and cannot provide reassurance to either healthcare professionals or patients. In the case of HIV-positive women, self-insemination is a minimal cost, simple, home-based method that effectively eliminates horizontal transmission risk without incurring many of the negative aspects of medically assisted conception, such as cost and invasiveness.

Several centers providing assisted conception services to women with HIV report lower rates of fertilization and of clinical pregnancy in comparison with HIV-negative controls [21,48 –50]. These lower success rates are based on a reduced response to superovulation [49].

Terriou et al. evaluated the outcome of intracytoplasmic sperm injection (ICSI) in 29 HIVpositive women comparing success rates with two HIV-negative control groups [51]. In the group consisting of HIV-positive women, the authors observed significantly higher cancellation rates and these were particularly high among women with detectable blood viremia. Duration of ovarian stimulation and total injected recombinant FSH dose were also higher in HIV-positive women. By contrast, the fertilization rate was higher in the HIV-infected group, possibly owing to the fact that ICSI was used as a means of preventing HIV infection rather than for the treatment of suboptimal male sperm parameters. The final outcome, in terms of pregnancy rates, was comparable to the seronegative-matched control group.

Englert et al. investigated the impact of HIV-positive serology on assisted reproduction treatment (ART) outcome in a retrospective case-control study of 74 IVF/ICSI cycles in seropositive women and 148 HIV-seronegative controls [52]. Matching criteria included age, type of assisted conception technique, tubal disease and cycle rank. Cycle cancellation rate was higher in the seropositive group. For noncancelled cycles, significantly more gonadotropin units were administered for HIV-positive women compared with controls to achieve similar estradiol levels, stimulation duration and number of oocytes collected (3286.4 ± 11861.1 UI vs 2849.7 ± 1375.8 UI; p = 0.04). Fertilization rate was significantly lower for HIV-seropositive women in comparison with controls (50.7 vs 65.1%; p = 0.001) as was pregnancy rate (14.9 vs 33.8%; p =0.03). The authors concluded that HIV-seropositive patients demonstrated decreased reproductive potential in terms of ovarian response to stimulation as well as in terms of fertilization and implantation.

Another published study compared 27 HIV-positive infertile women with 77 HIV-negative controls [21]. All patients were asymptomatic and the mean CD4 cell count was 574 cells/mm³. In this study, the number of embryos transferred was significantly lower in the HIV-positive women compared with seronegative controls (1.3 vs 1.9; p = 0.035).

Ohl et al. reported a series of 50 HIV-infected women receiving ART owing to the presence of documented infertility factors, including repeated failure of self-insemination, tubal occlusion, male infertility, amenorrhea and cervical infertility [48]. The rate of pregnancy per embryo transfer was 23.9%, which was noticeably lower than the 48.8% rate observed in the author's previous series of HIV discordant couples where the male was HIV positive. The age of HIV-positive women accessing ART, which was significantly higher than that of HIV-negative women with an HIV-positive partner, was cited as one possible explanation for the lower pregnancy rate per embryo transfer. Another factor mentioned was the center's deliberate policy of preferential singleembryo transfer to avoid gemellar pregnancies in HIV-positive women.

In a matched-control prospective study of 50 IVF cycles in 35 HIV-infected women matched against 50 cycles in 37 HIV-negative women with a seropositive male partners, Coll et al. showed a statistically significant reduction in pregnancy rate with IVF in the seropositive women compared with HIV-negative serodiscordant couples with positive male partners and HIV-negative couples (16.2 vs 42.5 and 37.5, respectively; p = 0.013) [50]. The only variable noted to have a significant effect on the occurrence of ovarian resistance was the woman's CD4 cell count prior to treatment. By contrast, the presence of HIV or use of HAART did not appear to have a negative effect on pregnancy rates in HIV-positive women undergoing ovum donation. The results of this study support the finding that HIV-infected women undergoing IVF have an adjusted lower pregnancy rate. A parallel study on HIV-infected women undergoing ovum donation showed no effect of HIV infection on pregnancy rates. It is possible that ovarian resistance to hyperstimulation may be involved in this effect because a greater number of units of gonadotropin were required in order to stimulate these patients adequately. It has been noted that this observed ovarian resistance may reflect an underlying subclinical hypogonadism. The potential basis for this phenomenon is not readily evident. HIV should not have a direct impact on the human oocyte because no receptors for HIV have been described on either the cumulus cells or on the surface of the oocyte [53]. One hypothesis is that antiretroviral drugs may produce a toxic effect on mitochondrial function within the ovary [21,50].

Increased risks in pregnancy

Pregnancy itself does not worsen the immunological status of HIV-positive women and is not correlated with disease progression [54], but the treatment of HIV infection during pregnancy merits particular attention.

A recent study described a 3-year follow-up of pregnant women in treatment with various antiretroviral regimens – HAART, short-term HAART and zidovudine monotherapy aimed, essentially, only to control the risk of vertical transmission while offering virtually no protection to the woman against progression of HIV disease [55]. A total of 311 HIV-infected mothers were followed up during pregnancy and after delivery for an average period of 33 months. At the time of last follow-up, the entire cohort showed a significant rise in median CD4 counts and a reduction in median viral load, 98% of women had an AIDS progression-free survival and 63% of mothers were receiving HAART. The authors concluded that past concerns suggesting that pregnancy might lead to increased mortality and morbidity in HIV-infected women were revealed as untrue and that the results of the study can reinforce the growing confidence of HIV-infected women who wish to have children as progression to AIDS is an infrequent event thanks to the availability of HAART, regardless of the type of therapy taken during pregnancy.

In considering the use and type of antiretroviral agents for HIV-infected women during pregnancy, it is important to take into account two separate but related issues: the treatment of maternal HIV infection and antiretroviral chemoprophylaxis to reduce the risk of perinatal HIV transmission. While being the cornerstone of mother-to-child prevention owing to the reduction in maternal blood viral load, antiretroviral drugs may present significant safety issues to the mother and child [101]. Hence, treatment decisions for HIV-positive pregnant women should carefully balance the expected benefits towards control of HIV infection with the expected toxicities to the mother and unborn child.

Some of the drugs used in antiretroviral combinations have shown teratogenic and carcinogenic properties in animal models. In addition, some of the common adverse effects of antiretrovirals, such as anemia, nausea/vomiting, aminotransferase elevation and hyperglycemia, may contribute to, or exacerbate, pregnancy symptoms.

Most evidence regarding the outcomes and adverse effects of antiretroviral therapy in HIV-infected pregnant women have mainly focused on the fetus and the infant and, to a lesser extent, on the mother. However, different studies indicate that antiretroviral regimens may impact and complicate the course of pregnancy.

Suy et al. analyzed the incidence of risk factors for pre-eclampsia and fetal death in 472 HIV-infected and 8686 HIV-negative pregnant women treated at the same institute [56]. The study found significantly higher rates of preeclampsia and of fetal death in HIV-positive women. In multivariate models, both HIV infection and use of HAART prior to pregnancy were identified as independent risk factors for both preeclampsia and fetal death. Insulin levels in pregnancy were significantly higher in women who developed preeclampsia versus those who did not.

Marti et al. showed an increase in pre-natal complications in a cohort of 167 HIV-positive women who gave birth in a hospital in Madrid between the years 1997 and 2003 [57]. Gestational diabetes mellitus was diagnosed in 8.9% of patients. All the cases of gestational diabetes were in women treated with combined antiretroviral therapy, and the majority were receiving a three-drug regimen containing a protease inhibitor. The risk of developing this pathology was greater among women receiving antiretroviral therapy prior to pregnancy. The premature delivery rate was 29% and the rate of low birth weight was 28%.

The European Collaborative Study assessed the association between type and timing of initiation of antiretroviral therapy and duration of pregnancy in 3920 mother–child pairs [58]. In this study, prematurity rate was 17% with a median gestational age of 39 weeks. In a multivariate analysis, adjusted for maternal CD4 count and intravenous drug use, the odds ratio of prematurity for infants exposed to combination therapy, with and without a protease inhibitor was 2.60 and 1.82, respectively, compared with no treatment or to treatment with a single antiretroviral agent.

As a result of the above, current treatment guidelines distinguish between women who are in treatment, who need to start it to control their HIV-related infection, who are at immediate risk of disease progression and who need to be treated with antiretrovirals for the sole purpose of chemoprophylaxis against mother-to-child transmission. When a woman is already in treatment, her treatment should be maintained throughout pregnancy but her regimen may require adjustments to eliminate the drugs most dangerous to the fetus. When HIV infection is diagnosed during pregnancy, or when a treatment-naive woman plans to become pregnant, the initiation of treatment should be postponed until week 28, unless the risk for disease progression is imminent [59,103].

Limiting the risks connected with assisted reproduction techniques

In vitro fertilization techniques in HIV-positive women involve risks of viral transmission and contamination during surgical and laboratory procedures, such as aspiration of oocytes and follicular fluid, fertilization, incubation, cryopreservation and embryo transfer. The invasive procedures required during IVF have the potential of increasing viral transmission to the egg or the embryo. Laboratory manipulations may be associated with risk of HIV transmission to personnel, and storage in tanks and incubators might result in contamination of embryos and gametes of HIV-uninfected patients.

Risk of vertical transmission

The impact of the invasive procedures used during ART on vertical transmission risk is unknown and the numbers of children born so far are small. Gonadotropin stimulation could increase viral load and a significant rise in serum viral load has been demonstrated in women undergoing superovulatory cycles in comparison with unstimulated menstrual cycles. HIV has been detected in follicular fluid samples and endometrial samples of women undergoing IVF even when they have a negative serum viral load through the use of HAART [60,61]. Contact with infected blood during oocyte retrieval could lead to HIV contamination of the oocyte and the embryos may become infected during passage of the transfer catheter. However, it is speculated that viral infection of the oocyte or the embryo at this early stage in development could result in implantation failure or early pregnancy loss [33]. HIV-positive women conceiving spontaneously are recognized to have an increased early miscarriage rate and this may be attributable to the loss of infected embryos. It has been shown that the highest risk for maternal-to-fetal HIV transmission occurs late in pregnancy, owing to fetal–maternal exchanges at the end of gestation, and during labor. Since ART procedures are applied at the very beginning of pregnancy, it is highly unlikely that they may be responsible for HIV transmission to the child [62].

It has been suggested that the risk of HIV transmission to the embryo could be reduced by performing ICSI in all HIV-positive women requiring in vitro fertilization, with complete decoronization followed by repeat oocytes washing [51]. There are no substantive data to support this practice.

A final point is that genital tract infections in HIV-infected women significantly increase the risk of vertical transmission to the newborn [63], and should be treated prior to delivery.

In conclusion, in HIV-infected women, treatment of genital tract infection, antiretroviral treatment during pregnancy and at the time of delivery, elective caesarean section in selected cases (e.g., when serum viral load remains high despite HAART) and the avoidance of breastfeeding are measures that have collectively led to a fall in vertical transmission risk from more than 30% to less than 2% [64 –67]. There are no indications suggesting that rates of HIV transmission in pregnancies following assisted conception techniques will be higher compared with those observed in natural conception, but large prospective studies are necessary before this assumption can be confirmed.

Risk of contamination to other patients/tissues

The European Union Tissues and Cells Directive (2004) states that centers involved in the handling of gametes and embryos, as well as all other human tissues and cells, must adopt a quality-system approach working to community standards and specifications [68]. The latter have still to be defined. However, the treatment of HIV-infected individuals in reproductive laboratories poses specific challenges as these environments are specifically designed to favor cell survival and culture, making it an ideal place for viral replication and contamination. The transmission risks involved in reproductive treatment of HIV-positive women are threefold, namely transmission to other uninfected patients, to laboratory and medical staff and to stored gametes and/or embryos.

Data regarding the risk of viral transmission to uninfected patients during ARTs are not available for HIV, but this risk has been demonstrated for both hepatitis B virus and hepatitis C virus infection [69,70]. Transmission may occur during all invasive procedures involved in ART as a result of contamination of the ultrasound probes, oocyte retrieval equipment or embryotransfer catheters. Hence, all instruments used during invasive procedures should be disposable and discarded after use. Where this is not possible, additional precautions are recommended after handling of infectious samples, represented by thorough sanitization and sterilization using nonembryotoxic material. These additional procedures are time consuming as all incubators containing oocytes and embryos need to remain shut, to avoid damage by potentially toxic vapors.

Oocyte retrieval is an invasive procedure and contamination of follicular fluid with blood is frequent. Studies investigating the presence of HIV in follicular fluid are limited and the number of cases studied are small. Published results aiming to identify an association between HIV plasma viral load, use of HAART and viral contamination of follicular fluid are contradictory [60,61]. At present, all oocyte samples from HIV-infected women should be regarded as infectious, independent of the woman's viral load.

In order to minimize transmission risk in the laboratory setting, it is important to separate known infected or unscreened cases from known uninfected cases in both space and time. Separation of high-risk cases in space is the gold standard that will maximally minimize risk. It is recommended that reproduction clinics establish a separate high-risk laboratory or area for the manipulation of gametes and embryos from infected patients with dedicated vertical laminar flow hoods and micromanipulation equipment for managing infected samples. Where this is not feasible, owing to cost and space issues, separation in time can be achieved by ensuring infected cases are last on the list of treatments for the day or are carried out on a separate day to noninfected cases. To limit the risk of infection to laboratory personnel, appropriate protective wear should be employed when handling samples from infected or unscreened patients, or from women with an unknown HIV status [71].

Viral cross-contamination to gametes and embryos stored in freezing tanks has also been shown [72] since straws may leak or shatter. Some recommend the use of separate tanks and freezing machines for each infection or combination of infections, but this solution is demanding in terms of cost and space. A more practical solution consists in the use of heat-sealed straws made from shatterproof material.

A more cost-effective approach to managing virally infected patients requiring ARTs would be to provide dedicated high-risk laboratories for this purpose within a regional area to balance the additional cost of building and equipment (incubators, flow hoods, storage tanks, etc.) to a larger population size [71].

Ethical & medico-legal aspects of offering treatment

In the earlier days of HIV infection, management guidelines recommended pregnancy to be discouraged or deferred in HIV-positive women owing to poor prognosis and the risk of perinatal transmission [73,74]. These were abandoned in favor of the modern counseling approach that is nondirective and supportive of the woman's reproductive choices [104]. The provision of reproductive counseling and care to women with HIV has a sound ethical background as one of the main goals of these treatments is to reduce the risk of transmission to the uninfected partner and unborn child.

Providing infertility treatment to HIV-positive women with fertility issues or unstable disease raises more critical ethical aspects. Vertical transmission risk or AIDS-defining symptoms are regarded by some as unacceptable determinants in the decision to assist reproduction. Our position, shared by the leading professional organizations, now considers that ARTs should not be denied to HIV-infected couples solely on the basis of their positive HIV serostatus [75 –78], and that HIV-positive patients should be provided with the opportunity to have children safely.

The International Federation of Gynecology and Obstetrics (FIGO) committee for the ethical aspects of human reproduction and women's health reviewed some of the ethical issues regarding HIV and fertility treatment [76]. The aspects raised by the committee included the horizontal transmission risk to the uninfected partner, life expectancy of the infected individual, high-risk behavior and lifestyle issues and support network if the infected individual becomes seriously ill or dies. The recommendations of FIGO state that it is essential to offer appropriate advice to all individuals who are infected (or whose partner is infected with HIV), that reproductive treatments that reduce the chance of exposure are of proven efficiency. The committee, therefore, concludes that it is ethical to offer ARTS, and that any restriction on access to assisted reproduction should be clearly justified and not based on discrimination.

According to the ethics and law task force of the European Society of Human Reproduction and Embryology (ESHRE) who summarized the ethical dilemmas concerning offering assisted reproduction to couples with HIV [76], the offer of reproductive services to individuals infected with HIV generates conflicts between two ethical principles – respect for the autonomy of the patient to decide about his/her reproduction and the principle of beneficence as expressed in the concerns for the welfare of the child. The task force also distinguished between fertile and infertile couples. In the case of fertile couples, the rationale for intervention is avoiding harm to the uninfected spouse and the future offspring. As these couples are able to procreate by themselves, the contribution of the physician is directed at risk reduction rather than helping with conception. Where the couple also suffers from infertility and there is a need to assist conception as well as reduce transmission risks, the physician assumes a special responsibility for the future offspring. The task force proposed that the acceptability of any risk should be determined by considering a variety of factors, which, in the case of an HIV-positive woman, can be summarized as follows: a significant reduction in the risk of vertical transmission to less than 2% owing to the combination of antiretroviral therapy, cesarean section and avoidance of breast feeding; radical improvement in life expectancy of HIV-positive individuals in order to limit the risk that the child could be orphaned at a vulnerable age; negligible risk of disease progression or death of the mother caused by pregnancy itself if the mother is well at the outset; and effective HAART that can be used safely in pregnancy without severe side effects to the mother or teratogenic effects on the conceptus. Hence, the task force concluded that the additional risk of transmitting the disease to the child is not excessively high, compared with risks accepted for the older individuals, women, people with chromosomal abnormalities or multiple pregnancies, and should be considered acceptable. The same taskforce did not deem it acceptable to offer assisted reproduction services to couples in which both partners are infected with HIV, although it has been argued that such risk was acceptable provided the issue of child welfare was addressed [77].

One of the ethical issues that have been raised in the debate on offering assisted conception to couples with HIV regards the welfare of the child, deemed of particular relevance in cases in which the male partner is infected as well. Frodsham et al. reviewed issues connected with child welfare in their patients [79]. Issues that emerged mostly included HIV medication with potential teratogenic effect in the woman, alcohol use and progressive HIV disease.

It is clear that the impact of different ethical aspects (i.e., risk of transmission and/or being orphaned) may be different in different populations or countries in relation to the life conditions and standard of care of HIV infection.

Future perspective

Where available, HAART has dramatically changed the life expectancy and quality of life of individuals with HIV, transforming the disease from a mortal one into a chronically manageable infection. Individuals who have access to adequate standard of treatment have all reason to hope to have children and see them through to adulthood. In the case of HIV-positive women, reproductive assistance and counseling play a dual role: limiting the risk of sexual and vertical transmission and overcoming an infertility problem. HIV infection and its treatment can impact fertility in different direct and indirect ways. Severe immune system depression can impact ovulation and ovarian reserve, HIV infection is associated with increased frequency and severity of genital tract infection that can result in tubal infertility. Finally, antiretroviral medication may lead to subclinical hypogonadism that is probably due to mitochondrial toxicity.

Infertility treatments for women with HIV are available but their accessibility is limited. As a result, data on the fertility profile of these women and the outcome of reproductive treatment are incomplete, and most derive from retrospective evaluation or studies conducted in limited numbers of patients. More information is needed to shed light on different aspects of the reproductive care of women with HIV, and this information should come from large-scale, prospective, multicenter studies.

The Centres for Reproductive Assistance Techniques to HIV Couples in Europe (CREAThE), is a not-for-profit network linking the major European centers offering reproductive assistance to individuals with HIV. CREAThE aims to improve the standard and availability of reproductive health services offered to couples affected by HIV and other sexually transmissible infections. CREAThE has recently published an extensive retrospective analysis on the outcome of reproductive treatments to couples where the man is HIV positive [80]. A total of 1036 HIV-discordant couples for male seropositivity were included and 3390 cycles of sperm washing followed by assisted conception techniques analyzed. The result of female HIV testing after ART was known in 967 out of 1036 women (7.1% lost to follow-up) and all tests recorded were negative. The calculated probability of contamination was equal to zero (95% CI: 0–0.09%). Thanks to the large number of couples involved, this publication was able to demonstrate that sperm washing can significantly reduce HIV-1 transmission risk to the uninfected female partner.

Executive summary

Reviews the state of evidence regarding fertility and reproductive treatments for HIV-infected women desiring a child.

Fertility desires and intentions in women with HIV are similar to the general population, in both high- and low-income countries, and health status does not seem to interfere with plans for parenthood.

HIV-positive women appear to have increased rates of tubal infertility and reduced ovarian reserve.

Data on safety of unprotected intercourse in HIV-infected discordant couples attempting to conceive are rather limited and can not provide reassurance to either healthcare professionals or patients. To eliminate the risk of HIV transmission to the partner, HIV-positive women may opt for self-insemination.

HIV-infected women undergoing IVF have an adjusted lower pregnancy rate, possibly owing to the toxic effect of antiretroviral drugs on mitochondrial function within the ovary.

Pregnancy does not worsen the immunological status of HIV-positive women and is not correlated with disease progression. In pregnant women, decisions regarding HIV therapy should be based on a balance between maternal health, antiretroviral side effect and the risk of vertical transmission.

Treatment of genital tract infection, antiretroviral treatment during pregnancy and delivery, elective cesarean section in selected cases and the avoidance of breastfeeding led to a fall in vertical transmission risk from more than 30 to less than 2%.

Data regarding the risk of HIV transmission to uninfected patients during assisted reproduction procedures are not available. To minimize such a risk, reproduction clinics should establish a separate high-risk laboratory for the manipulation of gametes and embryos from infected patients with dedicated vertical laminar flow hoods and micromanipulation equipment for managing infected samples.

Providing infertility treatment to HIV-positive women with fertility issues or unstable disease involves several ethical dilemmas, such as the risk of vertical transmission or of being orphaned. However, assisted reproductive technologies should not be denied to HIV-infected couples solely on the basis of their positive HIV serostatus, and patients should be provided with the opportunity to conceive safely.

In HIV-positive women, reproductive assistance and counseling play a dual role: limiting the risk of sexual and vertical transmission and overcoming an infertility problem. Public health authorities and healthcare providers should be made aware of fertility desires in HIV-positive women, and solutions to allow individuals with HIV to conceive safely, or to overcome eventual infertility, should be made available.

In another multicenter analysis of CREAThE, Pasquier et al. compared the performance of different laboratory assays used to evaluate the presence of HIV RNA in seminal samples subjected to sperm washing in 11 European laboratories [81]. This study revealed the need to improve existing assays and suggested the opportunity of using of silica-based extraction.

In a manner similar to that reported above, major European centers offering ARTs to couples with HIV have now joined forces in two efforts aimed at addressing fertility in HIV-positive women. The first is an extended retrospective analysis of approximately 1000 assisted conception cycles performed in HIV-positive women with the aim of clarifying the still existing doubts regarding fertility profile and response to ART. The second is a prospective cohort study of different reproduction practices in couples affected by HIV. The main objective of this European database is to pool data to establish the safety and efficacy of the methods currently in use, to investigate the impact of antiretroviral medication on fertility in HIV-positive women and to study the desire for maternity and its impact on quality of life.

In conclusion, data regarding the fertility treatment of women with HIV are reassuring. However, these methods should be more widely available and accessible as a significant proportion of asymptomatic HIV-positive women have infertility issues and the demand for reproductive assistance in this population is rising.

Footnotes

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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Infertility Treatment for HIV-Positive Women

Abstract

Keywords

Desire for parenthood in HIV-positive women

Fertility in HIV-positive women

Impact of HIV infection on fertility

Genital tract infections in HIV-positive women

Clinical outcome with assisted reproduction treatment

Increased risks in pregnancy

Limiting the risks connected with assisted reproduction techniques

Risk of vertical transmission

Risk of contamination to other patients/tissues

Ethical & medico-legal aspects of offering treatment

Future perspective

Footnotes

References