Use of assisted reproduction in HIV- and hepatitis-infected couples

INTRODUCTION — A growing proportion of couples seeking fertility services have medical issues that need to be addressed. This topic will discuss fertility treatment for individuals chronically infected with HIV or hepatitis C virus, as these individuals can transmit the infection to an uninfected partner during the process of conception. Counseling these couples about the safest methods for avoiding viral transmission to their partner involves discussion of adoption, child-free living, and use of donor sperm, in addition to natural or assisted conception with their own gametes.

Recommendations for reducing the risk of viral transmission during fertility treatment have been published by the American Society for Reproductive Medicine (ASRM) [1]. The basic principles underlying these recommendations are:

●Reduce viral load in the infected partner(s).

●Reduce the noninfected partner's exposure and susceptibility to the infection.

●Discuss the available scientific evidence and risk reduction strategies with both the patient and partner to provide a basis for informed consent.

We are not able to make an absolute recommendation for the best procedure for helping serodiscordant couples conceive because there are inadequate data to prove that any technique is significantly safer than any other and choice of treatment is based upon available resources and results of standard infertility tests, which are also part of the decision-making process. We evaluate and treat these patients on a case-by-case basis, with the understanding that safer conception services are a critical component to the care of HIV-affected couples [2].

INFORMED CONSENT — The diagnosis; purpose of treatment; risks, benefits, alternatives to the suggested treatment; and the risks of no treatment must be discussed and documented.

Risks include:

●The transmission to partner (new virus or different strains of virus)

●Transmission to the child

●Side effects of infertility treatment on the underlying disease process

●Complications that pregnancy may cause to the patient's condition

●Psychosocial implications of the child acquiring the infection

●The parent(s) becoming unable to care for the child due to parental illness/death [3]

Benefits of assisted reproduction technology include:

●Decreasing the risk of transmission to the partner compared with unprotected intercourse

●Decreasing the possibility that the child will be infected

●Early intervention with prenatal/intrapartum treatment that can reduce transmission to the child

Finally, alternatives such as adoption, not having children, and donor sperm if the female is unaffected or surrogacy if the female is affected should be discussed [4].

HIV INFECTION — Increased longevity and quality of life have led HIV-infected individuals to think about long-term plans, such as childbearing. In a group of serodiscordant (male HIV-infected) opposite-sex couples, 70 percent of the couples expressed a desire to have children in the future if their fertility treatment was successful [5]. Predictors of couples' desires for additional children if fertility treatment was successful were: younger age, shorter relationship duration, being childless currently, and having the male partner diagnosis of HIV known prior to when the couple met. Thus, an understanding of overall fertility desires in this patient population is important, in combination with a discussion of various methods by which pregnancy can be achieved.

Men and women living with HIV may seek assistance in pregnancy planning so they can avoid unprotected intercourse with an uninfected partner when the couple is attempting to conceive. One survey reported that 12 percent of HIV serodiscordant couples concerned about transmission of HIV to their partner would still be willing to have unprotected timed intercourse if no other alternatives existed for achieving pregnancy [6]. Ideally, these couples should have an alternative to unprotected intercourse because even partners with undetectable plasma HIV levels can transmit HIV in semen, female genital secretions, and rectal secretions [7]. However, the risk of transmission appears to be very low when the HIV-infected partner is receiving maximally suppressive antiretroviral therapy [8,9]. (See 'Natural conception in serodiscordant couples' below.)

Factors affecting the risk and rate of male to female and female to male HIV transmission during sexual intercourse are discussed in detail separately. (See "The natural history and clinical features of HIV infection in adults and adolescents", section on 'Viral transmission'.)

Initial evaluation — Managing HIV-infected patients with childbearing desires involves a multidisciplinary approach, ideally including maternal-fetal medicine specialists, HIV/AIDS specialists, neonatologists, pediatricians, psychiatrists, social workers, and reproductive endocrinologists. A team of providers knowledgeable in this area should review each case, including the couple's ability to tolerate the fertility evaluation, treatment, and pregnancy.

Access to an institution that can care for pregnant patients with HIV and the child delivered under these circumstances is also a prerequisite to beginning fertility treatment. In addition, the program's staff should have training in how to process specimens and separate freezing facilities for gametes/embryos from HIV-infected clients. While the 2015 American Society for Reproductive Medicine committee opinion found "no ethical reason(s) to withhold fertility services," access to assisted reproductive technology services for HIV-infected individuals remains variable and appears to differ based on who makes the inquiry [10]. In a survey of 140 United States infertility clinics, when a clinician inquired about assisted reproductive technology services for an HIV-infected individual, 63 percent of clinics offered services to a couple with an HIV-infected man and HIV-uninfected woman; however, when the caller was identified as a patient, only 40 percent offered services [11]. Of the clinics not providing services to patient callers, only half (51 percent) referred patients to other clinics, which further demonstrates the need to overcome barriers of access to assisted reproductive technology in this population.

HIV-infected couples seeking fertility treatment should undergo the following:

Medical assessment — The medical status of both partners should be evaluated, appropriate preventive therapies should be initiated, and any problems that can be treated should be addressed by their primary care provider and/or HIV specialist before initiating fertility therapy. An overview of the evaluation and management of HIV-infected adults can be found separately. (See "Primary care of adults with HIV".)

Antiretroviral therapy — Evaluating the need for antiretroviral and other medical therapies should be part of the initial assessment. Some issues that need to be addressed by the HIV/AIDS specialist are: Should the patient be started on antiretroviral therapy if he/she is not already taking these drugs? Is he/she on the optimum regimen? Should an HIV-uninfected female partner of an HIV-infected male receive prophylactic antiretroviral therapy during assisted reproductive technology?

In the United States, initiation of antiretroviral therapy is recommended for all HIV-infected individuals to reduce the risk of AIDS and non-AIDS morbidity and mortality [12]. Antiretroviral therapy may also be useful from a fertility, as well as a medical, perspective. Some experts believe it may improve the outcome of sperm washing/intrauterine insemination (IUI) (see below), while others do not [13,14].

Although routine semen analysis may not be significantly different between HIV-infected and uninfected males, as HIV infection progresses, semen parameters show decreased concentration, motility, and number of morphological normal sperm and increased round cells with more viscous semen [13]. There is likely a positive correlation between total sperm concentration and CD4 cell count [15]. A retrospective study describing observations from 10 years of experience providing fertility care to HIV-infected men reported 76 of 181 such men (42 percent) had an abnormal semen analysis with at least one parameter in the subfertile range [16]. In a retrospective case-control study of 770 men using highly active antiretroviral therapy (HAART), the median values of all semen parameters were statistically lower for HIV-1 infected individuals compared with the World Health Organization (WHO) 2010 reference group [17]. Semen analysis parameters below the 5^th percentile of the WHO reference group occurred for 26 percent of the group for volume, 32 percent for progressive motility, and 28 percent for normal morphology. Theories for sperm alterations include poor spermatogenesis, ejaculatory dysfunction, dysfunction of the prostate/seminal vesicles, increased reactive oxygen species, or Leydig cell dysfunction due to infected macrophage interaction with seminal epithelium degeneration.

Preconceptional evaluation and counseling — The couple should receive preconceptional evaluation and counseling. (See "The preconception office visit" and "Prenatal evaluation of women with HIV in resource-rich settings".)

Fertility assessment — Before undergoing time-consuming, expensive, and involved treatments such as IUI or in vitro fertilization (IVF), we assess factors that could affect outcomes, even if the HIV infected patient or their partner is not known to be infertile. This assessment includes:

●Semen analysis. Leukocytospermia should be evaluated. If present, it may increase the risk for transmission of HIV. Semen parameters affect the choice of treatment. (See "Approach to the male with infertility" and "Treatments for male infertility".)

●Assessment of ovulatory function and ovarian reserve. (See "Female infertility: Evaluation".)

●Assessment of fallopian tube patency. HIV-infected women are at risk of infertility from tubal disease, given the increased prevalence of other sexually transmitted infections in HIV-infected individuals [18]. However, if IVF is planned, tubal patency evaluation is not necessary.

●Assessment of the uterine cavity. Uterine evaluation is performed if clinically indicated. Hysterosalpingography, sonohysterography, or hysteroscopy is performed before IVF to ensure that there is no abnormality that might interfere with pregnancy, such as a submucous fibroid or uterine septum.

Female and male infertility factors are addressed, as appropriate.

HIV infection appears to impact fertility parameters in women and men. A review of age-specific fertility rates (ASFR) from demographic and health surveys revealed a decreasing fertility rate among HIV-infected women compared with HIV-uninfected women [19]. ASFR is calculated as the total number of births in the 36 months preceding the survey divided by the sum of woman-years at childbearing age during that 36 months multiplied by 1000 for every five-year bracket. The ASFR ratio (defined as a ratio of ASFRs of HIV-infected women divided by ASFRs of HIV-uninfected women) for each five-year bracket group from 15 to 49 years old was 1.2, 0.77, 0.71, 0.65, 0.59, 0.53, 0.47. In addition, a case-control study reported lower anti-Müllerian hormone levels for women with HIV compared with uninfected control women (3.0±2.8 versus 3.7±3.5 ng/mL, respectively) [20]. However, the clinical significance of this difference is not yet know. A different case-control study reported a lower clinical pregnancy rate per transfer, although the implantation and live birth rates per transfer were not significantly different between HIV-infected women compared with controls [21].

For HIV-infected men, semen testing (especially those using antiretroviral therapy) has revealed a lower ejaculate volume, decreased sperm motility, and increased abnormal sperm morphology compared with controls [22,23].

Counseling and evaluation — Patients receive counseling about the psychosocial factors involved in pursuing fertility treatment and are evaluated to make sure they understand and accept these risks. The exact method by which to conceive should be decided after careful discussion with HIV and reproductive specialists [24].

Optimal candidates for fertility services — Experts have suggested the following criteria to guide clinicians in selecting HIV infected patients who seek assistance with conception [25-27]:

●High motivation for childbearing

●Well-controlled HIV with a stable CD4 count

●Undetectable virus in the serum and the semen (<50 to 100 copies/mL)

●Antiretroviral medication adherence of >90 percent

HIV-infected male and HIV-uninfected female — The goal when the male is infected is to prevent transmission of infection to the female partner and the fetus. Options include use of donor sperm, IUI using prepared (washed) sperm from the infected male, or in vitro fertilization (with intracytoplasmic sperm injection [ICSI]) using prepared (washed) sperm from the infected male. The male partner should be receiving antiretroviral therapy and ideally demonstrate sustained suppression of plasma viral load below the limits of detection [28]. Oral periconception pre-exposure HIV prophylaxis (PrEP) is an option for the female partner.

Management of patients desiring natural conception is discussed elsewhere. (See 'Natural conception in serodiscordant couples' below.)

Donor insemination — The use of donor sperm from an HIV-uninfected man and IUI is the safest option for HIV-uninfected women who desire conception [28]. If the couple elects to use donor sperm, they should be informed that donor sperm samples are quarantined for at least 180 days (ie, six months) after the date of donation to allow testing and retesting of the donors for communicable diseases, such as HIV. Donor insemination is discussed in detail separately. (See "Donor insemination".)

IUI with processed sperm — For couples who do not wish to use donor sperm, sperm preparation techniques (ie, sperm washing) combined with IUI or IVF are options for limiting the risk of HIV transmission to the uninfected female partner. The rationale for this approach, even when there is no detectable virus in the male's serum, comes from data reporting that semen may contain a high viral load and transmission to a partner can occur [7]. The risk of female seroconversion is likely to be substantially reduced by utilizing medically assisted reproduction. In couples with a normal fertility evaluation, IUI with specially processed sperm is a safe and effective strategy [29,30]. Some specialists also treat the female partner with pre-exposure prophylaxis (PrEP) at the time of IUI with washed sperm. In a study of 11 serodiscordant couples who underwent 28 cycles of IUI using washed sperm combined with PrEP, six cycles resulted in pregnancy (fecundability rate of 21 percent), and all of the women remained HIV seronegative at six months of follow-up [31]. However, for couples in which the semen analysis is abnormal, IVF may be the best treatment option. (See "Treatments for male infertility".)

It has been suggested that HIV is carried in the seminal fluid and white blood cells and that spermatozoa do not carry the virus because they do not have the necessary viral receptors, but this is controversial. Most authorities believe that the sperm do not have HIV on their surface or in the cell. However, it is easy to contaminate a sperm preparation with microscopic quantities of semen. Sperm washing prior to IUI eliminates the round cells, seminal plasma, and the majority of immotile sperm. Sperm are isolated by sequential density gradient and swim-up techniques and are then tested by PCR assays for the presence of HIV RNA. Using this method of sperm preparation, less than 1 percent of sperm samples from HIV-infected men test positive (typically, these "positives" are "low level" positive tests).

A Cochrane Review noted, however, that there were no relevant clinical trials identified in the literature to determine the benefits and risks of sperm washing to prevent HIV transmission in the setting of attempted conception [32]. Our current information base is derived from observational studies which demonstrate a need for further research with a multicenter randomized trial in this area. As there have been no documented transmissions of HIV through any processing methods currently used, it is unclear how randomization to treatment other than sperm washing could ethically be performed.

The goal of IUI is to place "virus free" sperm into the uterine cavity near the time of ovulation. If PCR assays are negative for HIV, the sperm are transferred into the uterine cavity via a flexible catheter. Using this protocol over several thousand cycles, there has been a zero rate of seroconversion in female partners and no documented births of HIV-infected children [33].

Nevertheless, couples should be counseled that the risk of acquiring HIV from insemination with prepared (washed) sperm from an HIV-infected partner has not yet definitively been proven to be zero. We may be approaching assurance of a transmission rate of zero with the advent of nested PCR, which can detect a single HIV viral copy [34].

IVF with ICSI — Intrauterine insemination has been the traditional medical approach to achieving conception in discordant couples because of convenience and low cost. Since this approach still leaves the potential for thousands to millions of sperm and possible remnants of HIV from the seminal fluid to come into contact with the female partner, the use of IVF with ICSI has had growing appeal, even when there is no evidence of female or male infertility factors [35-43]. IVF with ICSI is used as a first-line approach when there are insufficient sperm for IUI or, theoretically, to reduce exposure to the virus.

The combination of sperm wash, nested PCR, and ICSI potentially has several advantages [44,45]:

●It provides the least sperm and seminal/prostatic secretion exposure (a single sperm for each oocyte)

●Sperm samples negative for disease are already available to the patient for future cycles if sperm are cryopreserved

●The sperm wash is performed prior to the cycle so cycles are not canceled because of a positive result on PCR testing

●There is no need to recover large numbers of sperm to achieve adequate pregnancy rates post wash (as in IUI)

●Pregnancy rates are more than three times higher than for IUI

●A higher pregnancy rate decreases the number of attempts and exposures

Pregnancy rates after ICSI in serodiscordant couples are similar to those in HIV-uninfected couples undergoing ICSI [16,33,44,46,47].

No seroconversions in over 700 cycles have been documented using the IVF with ICSI approach [33]. Nevertheless, as with IUI, prevention of HIV viral transmission cannot be guaranteed. Even though IVF with ICSI theoretically reduces the female's exposure to the virus, there are several reasons that it is not the standard technique for all HIV discordant couples. For example, pregnancies conceived by IVF are associated with increased risks of multiple gestations, congenital anomalies, preterm delivery, low birth weight, and the complications associated with these outcomes. (See "Assisted reproductive technology: Pregnancy and maternal outcomes".)

In addition, the process of IVF, which involves ovulation induction, egg retrieval, and embryo transfer, is not a risk-free surgical procedure and is costly. Potential complications include bleeding, infection, and damage to bowel, bladder, blood vessels, and other internal organs/structures (see "In vitro fertilization: Overview of clinical issues and questions"). Thus, although minimizing transmission of the virus is a major concern in decision-making with these couples, it is not the only concern.

There is a theoretical risk of HIV contamination of the oocyte or embryo during IVF procedures [48]. After IVF/ICSI because of paternal HIV infection, no births of HIV-infected children to uninfected mothers have been documented [33].

HIV-infected female and HIV-uninfected male — The goal in this situation is to prevent transmission of the virus to the male. For these couples, the safest form of conception is artificial insemination, including the option for the woman to self-inseminate with her partner's sperm during the periovulatory period [28]. A meta-analysis reported pregnancy rates are generally similar to those in HIV-uninfected couples undergoing IUI, but may be lower for assisted reproductive technology; however, this requires further study as multiple factors could account for the discrepancy [29]. The female partner should be receiving antiretroviral therapy. (See "Antiretroviral selection and management in pregnant individuals with HIV in resource-rich settings" and "Prenatal evaluation of women with HIV in resource-rich settings".)

Compared with HIV-uninfected women, HIV-infected women who discontinued contraception with the intent to conceive have decreased fecundity (defined as time to pregnancy in the 12 months following discontinuation of contraception); differences of 25 to 40 percent have been reported [49,50]. Management of patients desiring natural conception is discussed elsewhere. (See 'Natural conception in serodiscordant couples' below.)

IUI — IUI using the male partner's sperm will avoid exposure of the male to his partner's vaginal secretions. If IUI is unsuccessful or if there is severe male factor infertility, then IVF can be performed as per usual protocols. (See "Procedure for intrauterine insemination (IUI) using processed sperm".)

The following is a low cost, low resource alternative approach to IUI:

●The time of the luteinizing hormone (LH) surge, which signifies impending ovulation, is determined using an ovulation predictor kit

●When the LH surge is identified, the male ejaculates into a condom without spermicide

●A syringe (without a needle) is then used to aspirate the semen in the condom

●The syringe is inserted into the vagina and the semen is released near the cervix

IVF — Like IUI, use of IVF prevents contact of the HIV-uninfected male with the HIV-infected female. (See "In vitro fertilization: Overview of clinical issues and questions" and "Intracytoplasmic sperm injection".)

If IVF is performed, HIV-infected women may have a clinically varied response to ovarian hyperstimulation. One study reported that only the CD4 cell count of HIV-infected women had an effect on the occurrence of ovarian resistance to IVF stimulation medications and that increased amounts of gonadotropins were needed to result in ovarian hyperstimulation in HIV-infected women [51].

It is not clear if HIV infection impacts the outcome of assisted reproductive technology, particularly IVF. In a systematic review of 10 studies including 342 HIV-infected women, ovarian stimulation cancellation rates were higher and pregnancy rates were lower for HIV-infected women compared with non-infected women [52]. However, small sample sizes and heterogeneity of study designs prevented meta-analysis of the data. Prospective data are necessary to understand the impact of HIV infection on the outcome of assisted reproductive technology.

Multiple gestations are more problematic for HIV-infected women because these pregnancies are at higher risk of preterm delivery. Prematurity, related to multiple gestation and possibly to antiretroviral therapy (particularly those containing protease inhibitors), together with obstetrical complications increase the risk of maternal-to-fetal HIV transmission [53]. For these reasons, single embryo transfer is desirable in this population (especially in women <40 year old) [54]. (See "Strategies to control the rate of high order multiple gestation".)

Natural conception in serodiscordant couples — Although successful antiretroviral therapy of the infected partner dramatically reduces the rate of HIV transmission in serodiscordant couples, it is uncertain if it can completely eliminate the risk [55,56]. Additionally, transmission can occur despite antiretroviral use when infected individuals have not achieved viral suppression on therapy. Moreover, two out of three HIV-affected couples experience subfertility and may benefit from early recognition of fertility factors [57]. Because of these uncertainties, it is prudent to continue to recommend safe sex practices (ie, condom use) and use of assisted reproduction techniques until more information on optimal management of these couples is available [28]. The risk of sexual transmission of HIV is discussed in detail elsewhere. (See "HIV infection: Risk factors and prevention strategies", section on 'Treatment as prevention' and "HIV infection: Risk factors and prevention strategies", section on 'Sexual transmission risk factors'.)

For serodiscordant couples who desire pregnancy, several steps can be taken prior to attempting conception to reduce the risk of HIV transmission to the uninfected partner [28]:

●Both partners should be screened and treated for genital tract infections.

●The HIV-infected partner should be receiving combination antiretroviral therapy and demonstrate sustained suppression of plasma viral load below the limits of detection.

●PrEP for the HIV-uninfected partner may further reduce the risk of sexual transmission [28,58,59]. The benefit of PrEP for the HIV-uninfected partner in addition to suppression of viral load to below the detectable limit in the HIV-infected partner is not known. The use of peri-conception PrEP and subsequent continued use during pregnancy is acceptable and feasible to those desiring pregnancy. It offers autonomy as a use-controlled prevention technique in the peri-conception time frame for both women and men [60].

Beyond optimal medical suppression of the HIV-infected partner, serodiscordant couples should time unprotected intercourse to coincide with ovulation to maximize the chance of pregnancy and minimize the number of exposed sexual events [61]. In a case series of 46 couples, in whom the HIV-infected male partner was on optimal suppressive therapy for at least six months, the cumulative pregnancy rate was 66 percent after five attempts, and no seroconversions occurred [62]. Thirty-seven of the women were treated with two-dose pre-exposure tenofovir prophylaxis; nine of the women declined because they felt the risk of viral transmission was low. In general practice, if pregnancy is not achieved after three months of attempting for natural conception, then consideration of further evaluation and treatment should be considered.

Timed intercourse also appears beneficial for couples in whom the HIV-infected partner may have a detectable viral load. One study of HIV-uninfected women who had timed intercourse with HIV-infected partners (whose CD4 counts ranged from 7 to 1273/microL; viral loads were not available) reported that 4 of 92 (4.3 percent) seroconverted [63]. No seroconversions occurred within the first three months following conception, but two women seroconverted in the third trimester and two seroconverted postpartum. All four seroconversions occurred in couples reporting inconsistent condom use.

Seroconcordant couples — If both partners are infected, the couple may be concerned about acquiring a new viral strain of the disease from their partner. It has been hypothesized that assisted reproductive technology may be useful in these couples to decrease the risk of transmitting a different or mutated strain to the partner. If a female partner has a unique viral mutation, then IUI would reduce the risk of transmission to the male partner. If the male partner has the unique mutation, then sperm washing or donor insemination may be used to reduce the female's risk of acquiring the mutated virus.

However, most couples do not know the subtype of HIV that they carry. Moreover, there are no data to document the magnitude and clinical implications of transmission of genotypically divergent strains through sexual intercourse or assisted reproductive technology between HIV-infected, subtype discordant partners. Thus, these issues are of theoretical interest, but do not influence assisted reproductive technology treatment recommendations at this time. Most such couples attempt to conceive naturally. If infertility issues arise, they are addressed in the same way as in uninfected couples.

Of note, one study of 85 HIV-infected couples undergoing assisted reproductive technology reported lower ongoing pregnancy rates when both partners were seropositive [64]. A subsequent retrospective case-control study also described poor IVF pregnancy outcome for seroconcordant couples, with only one delivery occurring out of 33 IVF cycles [65].These findings may have been related to a very high rate of age-related cycle cancellations, previous history of advanced AIDS disease (which may affect fertility), or to chance.

Legal and ethical issues — The general consensus in the medical [66,67] and legal [68] communities caring for individuals infected with HIV is that these individuals should be counseled and offered access to infertility treatment or treatment to decrease the risk of infection in an uninfected partner when the couple is attempting to conceive.

Physicians should have the right to assist infertility patients with HIV in their reproductive goals without blame if a child is affected [69]. After appropriate evaluation, however, some patients may not be candidates for assisted reproductive technology and the physician is not legally bound to provide treatment.

In couples with HIV/AIDS, assistance in conceiving children is supported by the following [66]:

●The prognosis of patients with HIV has markedly improved with antiretroviral therapy allowing HIV-infected patients to be considered along a continuum of chronic disease. (See "The natural history and clinical features of HIV infection in adults and adolescents".)

●Perinatal transmission has decreased significantly with medical interventions. (See "Prenatal evaluation of women with HIV in resource-rich settings" and "Antiretroviral selection and management in pregnant individuals with HIV in resource-rich settings".)

●Assisted reproductive technology appears to allow HIV discordant couples to decrease the risk of viral transmission to the unaffected partner.

On the other hand, opponents to offering infertility treatment to these individuals make the following points [67]:

●The parental prognosis is uncertain; it may not be in the best interest of the child to be born to a parent who may not be available to provide long-term care for that child.

●There is a risk of the child acquiring HIV from the parent. This risk is lower than before medical and surgical interventions to prevent perinatal transmission were instituted, but it is not zero.

●The toxicity and risk of antiretroviral therapy are thought to be minimal, but these issues have not been completely elucidated. (See "Antiretroviral selection and management in pregnant individuals with HIV in resource-rich settings".)

●Theoretically, development of drug resistance may be increased by giving prophylactic regimens of antiretroviral agents to prevent perinatal transmission to many women who would not be considered for drug therapy in the absence of pregnancy.

Legal issues — Bragdon versus Abbott and the American Disabilities Act (ADA) suggest that individuals with HIV can be classified as disabled and are entitled to medical care unless there is objective scientific evidence available that a "significant risk" with the proposed treatment is present [70,71]. Under the ADA, "no individual shall be discriminated against on the basis of disability in the full and equal enjoyment of … accommodations of any place of public accommodation" which includes the "professional office of a health care provider." Handling specimens from HIV-infected patients does pose a risk to the health and safety of others, but this risk can be reduced or eliminated by universal precautions and separated storage facilities. Therefore, HIV-infected status is not enough to justify withholding infertility treatment.

Harm may also be thought of in the terms of "wrongful birth" and "wrongful life." Wrongful life occurs when the child claims that negligence has occurred and that no life would be superior to the current life [4]. Wrongful life is similar to the ethical principle of nonmaleficence (first do no harm). Parents may claim wrongful birth against a health care professional who does not fully inform them of the possibility that the mother may have a child with a disease. This underscores the importance of an extensive informed consent process that allows for patient autonomy in the decision to proceed with treatment with the understanding of the possibility of transmission of HIV to the child. If both partners are infected, then reasonable life expectancy for at least one partner should be documented [25] and the welfare of the child should be considered [72].

Ethical issues — The American College of Obstetricians and Gynecologists Ethics Committee has stated that there is an ethical obligation to provide assisted reproductive technology to couples where one or both partners are infected with HIV while respecting both the patient's autonomy and fetal beneficence [67].

The Ethics Committee of the American Society for Reproductive Medicine (ASRM) has indicated that health care professionals may be legally and ethically obligated to provide requested assistance with reproduction. This committee opinion on HIV and infertility treatment notes that there is no ethical reason to withhold fertility services to HIV-infected individuals, and clinics without sufficient resources to provide care should refer patients to appropriate providers who can offer management options [10].

In 2010, the California Department of Public health mandated that all fertility centers provide appropriate fertility interventions to HIV infected individuals seeking infertility care, or refer the couple to a center that offers such services.

As discussed above, opponents to providing assisted reproductive technology to HIV serodiscordant or seroconcordant couples have cited the seriousness of the disease, the availability of reproductive alternatives, and the best interests of the child [73]. These arguments have been refuted, based on the following principles:

●Autonomy – Autonomy reflects the choice of the patient, after all information is provided, to continue with infertility treatment despite one or both partners being HIV-infected. When considering HIV, it is helpful to point out other disease processes for which we do not deny access to infertility evaluation/treatment. Many couples with autosomal recessive diseases, such as cystic fibrosis and Tay-Sachs, have a 25 percent chance of transmitting the disease to their child. These diseases may also lead to child mortality, but have a higher risk of transmission than HIV, and yet we allow these couples to proceed with infertility treatment after appropriate genetic counseling. Moreover, women with chronic diseases such as diabetes and heart disease, where the pregnancy may have an effect on the mother's health, are not prohibited from engaging in infertility treatment [37].

●Beneficence – Beneficence is the health care provider's obligation to promote the health of his/her patients. Physicians can help patients decrease the transmission of HIV virus to their partner and can assist in providing a couple the psychological well-being that comes from the joy of having a genetically related child. The benefit of a supportive medical environment may encourage a woman to obtain medical and prenatal care and take precautions to prevent transmission to her child.

●Justice – The principle of justice refers to the battle between the right to reproduce and the possibility of an affected infant who may suffer and whose care has economic and social implications for the society in which he lives [25]. Physicians cannot claim to be simply the "technical agents" who perform the procedures to achieve conception without acknowledging the risk of transmission of HIV to the child. The risk is best justified by the low rate of perinatal transmission (less than 2 percent with appropriate precautions), which is lower than the general population risk of congenital malformations of medical, surgical, or cosmetic significance (3 to 5 percent).

HEPATITIS C — Many of the same principles discussed above also apply to couples discordant for other chronic, potentially serious infections where horizontal and vertical transmission can occur. Hepatitis C (HCV) is an example; among men chronically infected with HCV who have given three or more semen samples, approximately 50 percent of semen samples contain HCV RNA [74]. Thus, the potential exists for transmission to the female partner and fetus, and this risk should be discussed with these couples.

Factors affecting the risk and rate of male to female and female to male hepatitis C transmission are discussed in detail separately. (See "Epidemiology and transmission of hepatitis C virus infection", section on 'Sexual transmission'.)

The American Society for Reproductive Medicine (ASRM) has published recommendations on reproductive issues in women and men with hepatitis [1,75]. The medical status of both partners should be evaluated, appropriate preventive therapies should be initiated, and any problems that can be treated should be addressed by their primary care provider and/or infectious disease specialist before initiating fertility therapy. (See "Epidemiology and transmission of hepatitis C virus infection" and "Overview of the management of chronic hepatitis C virus infection".)

Counseling and evaluation of couples in which one partner is HCV infected should include [75]:

●Confirm HCV status with RIBA and obtain viral titers

●Test partner for HCV status

●Vaccinate patient and partner against HAV and HBV, if nonimmune

●Check HIV status

●Obtain liver function tests and gastroenterology consult

Treatment for hepatitis C should be considered prior to fertility treatment to decrease viral load [76]. The disadvantage of this approach is that the initial length of treatment is approximately 48 weeks and then pregnancy should be avoided from six months after completion of the treatment (for either partner who underwent treatment) because significant teratogenic effects at low doses of ribavirin have been consistently observed in animal studies [1,75].

Fertility potential should be evaluated, as discussed above for HIV-infected patients. (See 'Initial evaluation' above.)

HCV-infected male and HCV-uninfected female — As with HIV infected men, couples in whom the male partner is HCV-infected may undergo donor insemination, IUI with prepared sperm (washed), or IVF with or without ICSI with prepared (washed) sperm.

Density gradient centrifugation and sperm washing is performed followed by reverse transcription and nested PCR to confirm absence of virus [34]. Of note, HCV associated with cryopreserved semen or embryos can survive exposure to liquid nitrogen [75].

IVF with ICSI using washed sperm has been used successfully as a means of decreasing the risk of male to female HCV transmission, similar to the situation when the male is HIV-infected [44,45]. One group has questioned the need for ICSI in these couples and the need for testing seminal plasma for HCV RNA [74]. They feel semen treated with density-gradient separation and successive sperm washings essentially eliminate the risk of HCV transmission, suggesting that ICSI (with frozen sperm from the semen sample that underwent PCR evaluation) is unnecessary. This opinion is based on their experience with 58 serodiscordant couples who underwent assisted reproductive technology and produced 28 newborns, all of whom tested negative for HCV RNA in blood. Others have also found that 0 percent of semen samples contain HCV RNA after density gradient preparation [77].

HCV-infected female and HCV-uninfected male — Serodiscordant couples in whom the female partner is HCV-infected are candidates for IUI therapy to decrease the risk of female to male HCV transmission. (See "Procedure for intrauterine insemination (IUI) using processed sperm".)

In HCV-infected women undergoing IVF for treatment of infertility, significantly increased gonadotropin doses, decreased ovarian response, and more cycle cancellations can be expected [78]. In a study that evaluated three cohort groups, anti-Müllerian hormone levels of HCV-infected women were lower than those of controls (1.8±2.0 versus 2.5±1.9 ng/mL) and had an increased likelihood of being in the undetectable range (<0.16 ng/mL; odds ratio 11.625, 95% CI 2.651-50.970) [79]. In addition, HCV-infected women had increased rates of infertility, miscarriage, premature birth, gestation diabetes, and preeclampsia as well as reduced rates of live birth. Treatment with antiviral therapy that resulted in a sustained virologic response was associated with a reduced rate of miscarriage.

The risk of vertical transmission correlates with maternal viral burden. The risk of transmission was 36 percent when HCV RNA titers were greater ≥1 million copies/mL and 0 when titers were ≤10,000 copies/mL. There is a 5 to 10 percent risk of transmission with unknown viral titers [75].

HEPATITIS B — Sexual transmission of hepatitis B between serodiscordant couples can be prevented by vaccination of the seronegative spouse. After vaccination, natural conception can be attempted. Assisted reproductive technology is reserved for treatment of infertility. (See "Epidemiology, transmission, and prevention of hepatitis B virus infection".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Female infertility".)

SUMMARY AND RECOMMENDATIONS

●Serodiscordant couples are evaluated and managed on a case-by-case basis. There are inadequate data to prove that any management approach is significantly safer than any other. In addition, choice of treatment is based upon the available resources and results of standard infertility tests, which are also part of the decision making process. (See 'Introduction' above.)

●Increased longevity and quality of life have led HIV-infected individuals to think about childbearing and to seek assistance in conceiving so that they may avoid placing their partner at risk of infection or potentially acquiring a new viral strain of the disease. (See 'HIV infection' above.)

●The general consensus in the legal and medical community is that couples or individuals who are HIV-infected should be counseled and offered access to infertility treatment or treatment to decrease the risk of infection in an uninfected partner when the couple is attempting to conceive. (See 'Legal and ethical issues' above.)

●HIV-infected patients seeking assisted reproduction services should have high motivation for childbearing, well-controlled HIV with a stable CD4 count, undetectable virus in the serum and the semen (<50 to 100 copies/mL), and antiretroviral medication adherence of >90 percent. (See 'Optimal candidates for fertility services' above.)

●When the female is HIV-uninfected and the male is HIV-infected, the risk of male to female transmission is likely to be substantially reduced by utilizing medically assisted reproduction. In women with a normal fertility evaluation, we suggest intrauterine insemination (IUI) with doubly processed sperm as first-line therapy (Grade 2C). If unsuccessful or for couples with a known female factor infertility diagnosis, in vitro fertilization with intracytoplasmic sperm injection can be performed. Donor sperm is an additional option. (See 'HIV-infected male and HIV-uninfected female' above.)

●When the female is HIV-infected and the male is HIV-uninfected, intrauterine insemination using the male partner's sperm will avoid female to male transmission from unprotected intercourse. In women with a normal fertility evaluation, we suggest intrauterine insemination (IUI) as first-line therapy (Grade 2C). If IUI is unsuccessful or if there is severe male factor infertility, in-vitro fertilization or donor sperm insemination can be performed as per usual protocols. (See 'HIV-infected male and HIV-uninfected female' above.)

●Successful antiretroviral therapy for the HIV-infected partner, and potentially periconceptional pre-exposure HIV prophylaxis (PrEP) for the uninfected partner, are important interventions to prevent HIV transmission in serodiscordant couples desiring natural conception. In addition to optimal medical management, serodiscordant couples should time unprotected intercourse to coincide with ovulation to maximize the chance of pregnancy and minimize the number of exposed sexual events. (See 'Natural conception in serodiscordant couples' above.)

●When the female is HCV-uninfected and the male is HCV-infected, similar principles to HIV serodiscordant couples apply. We suggest IUI with specially processed sperm (Grade 2C). IVF (with or without ICSI) and donor sperm are other options, depending on patient-specific factors. (See 'Hepatitis C' above and 'HCV-infected male and HCV-uninfected female' above.)

●When the female is HCV-infected and the male is HCV-uninfected, IUI therapy will decrease the risk of transmission to the male partner. IVF or donor sperm can be utilized when indicated. (See 'HCV-infected female and HCV-uninfected male' above.)