ESHRE guideline: medically assisted reproduction in patients with a viral infection/disease.

STUDY QUESTION: What is the recommended management for medically assisted reproduction (MAR) in patients with a viral infection or disease, based on the best available evidence in the literature? SUMMARY ANSWER: The ESHRE guideline on MAR in patients with a viral infection/disease makes 78 recommendations on prevention of horizontal and vertical transmission before, during and after MAR, and the impact on its outcomes, and these also include recommendations regarding laboratory safety on the processing and storage of gametes and embryos testing positive for viral infections. WHAT IS KNOWN ALREADY: The development of new and improved anti-viral medications has resulted in improved life expectancy and quality of life for patients with viral infections/diseases. Patients of reproductive age are increasingly exploring their options for family creation. STUDY DESIGN SIZE DURATION: The guideline was developed according to the structured methodology for the development of ESHRE guidelines. After the formulation of nine key questions for six viruses (hepatitis B virus, hepatitis C virus, human immunodeficiency virus, human papilloma virus, human T-lymphotropic virus I/II and Zika virus) by a group of experts, literature searches and assessments were performed. Papers published up to 2 November 2020 and written in English were included in the review. Evidence was analyzed by female, male or couple testing positive for the virus. PARTICIPANTS/MATERIALS SETTING METHODS: Based on the collected evidence, recommendations were formulated and discussed until consensus was reached within the guideline group. There were 61 key questions to be answered by the guideline development group (GDG), of which 12 were answered as narrative questions and 49 as PICO (Patient, Intervention, Comparison, Outcome) questions. A stakeholder review was organized after the finalization of the draft. The final version was approved by the GDG and the ESHRE Executive Committee. MAIN RESULTS AND THE ROLE OF CHANCE: This guideline aims to help providers meet a growing demand for guidance on the management of patients with a viral infection/disease presenting in the fertility clinic.The guideline makes 78 recommendations on prevention of viral transmission before and during MAR, and interventions to reduce/avoid vertical transmission to the newborn. Preferred MAR treatments and interventions are described together with the effect of viral infections on outcomes. The GDG formulated 44 evidence-based recommendations-of which 37 were formulated as strong recommendations and 7 as weak-33 good practice points (GPP) and one research only recommendation. Of the evidence-based recommendations, none were supported by high-quality evidence, two by moderate-quality evidence, 15 by low-quality evidence and 27 by very low-quality evidence. To support future research in the field of MAR in patients with a viral infection/disease, a list of research recommendations is provided. LIMITATIONS REASONS FOR CAUTION: Most interventions included are not well-studied in patients with a viral infection/disease. For a large proportion of interventions, evidence was very limited and of very low quality. More evidence is required for these interventions, especially in the field of human papilloma virus (HPV). Such future studies may require the current recommendations to be revised. WIDER IMPLICATIONS OF THE FINDINGS: The guideline provides clinicians with clear advice on best practice in MAR for patients with a viral infection/disease, based on the best evidence currently available. In addition, a list of research recommendations is provided to stimulate further studies in the field. STUDY FUNDING/COMPETING INTERESTS: The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the dissemination of the guideline. The guideline group members did not receive any financial incentives, all work was provided voluntarily. A.D. reports research fees from Ferring and Merck, consulting fees from Ferring, outside the submitted work. C.P. reports speakers fees from Merck and MSD outside the submitted work. K.T. reports speakers fees from Cooper Surgical and Ferring and consultancy fees as member of the advisory board BioTeam of Ferring, outside the submitted work. The other authors have no conflicts of interest to declare. DISCLAIMER: This guideline represents the views of ESHRE, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant ESHRE stakeholders has been obtained. Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgment to each individual presentation, nor variations based on locality and facility type. ESHRE makes no warranty, express or implied, regarding the clinical practice guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose. (Full disclaimer available at  www.eshre.eu/guidelines.).

Consensus statement: Supporting Safer Conception and Pregnancy For Men And Women Living with and Affected by HIV.

Safer conception interventions reduce HIV incidence while supporting the reproductive goals of people living with or affected by HIV. We developed a consensus statement to address demand, summarize science, identify information gaps, outline research and policy priorities, and advocate for safer conception services. This statement emerged from a process incorporating consultation from meetings, literature, and key stakeholders. Three co-authors developed an outline which was discussed and modified with co-authors, working group members, and additional clinical, policy, and community experts in safer conception, HIV, and fertility. Co-authors and working group members developed and approved the final manuscript. Consensus across themes of demand, safer conception strategies, and implementation were identified. There is demand for safer conception services. Access is limited by stigma towards PLWH having children and limits to provider knowledge. Efficacy, effectiveness, safety, and acceptability data support a range of safer conception strategies including ART, PrEP, limiting condomless sex to peak fertility, home insemination, male circumcision, STI treatment, couples-based HIV testing, semen processing, and fertility care. Lack of guidelines and training limit implementation. Key outstanding questions within each theme are identified. Consumer demand, scientific data, and global goals to reduce HIV incidence support safer conception service implementation. We recommend that providers offer services to HIV-affected men and women, and program administrators integrate safer conception care into HIV and reproductive health programs. Answers to outstanding questions will refine services but should not hinder steps to empower people to adopt safer conception strategies to meet reproductive goals.

Effectiveness of semen washing to prevent human immunodeficiency virus (HIV) transmission and assist pregnancy in HIV-discordant couples: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the effectiveness of semen washing in human immunodeficiency virus (HIV)-discordant couples in which the male partner is infected. DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Forty single-arm open-label studies among HIV-discordant couples that underwent intrauterine insemination (IUI) or in vitro fertilization (IVF) with or without intracytoplasmic sperm injection (ICSI) using washed semen. INTERVENTION(S): Semen washing followed by IUI, IVF, or IVF/ICSI. PRIMARY OUTCOME: HIV transmission to HIV-uninfected women; secondary outcomes: HIV transmission to newborns and proportion of couples achieving a clinical pregnancy. RESULT(S): No HIV transmission occurred in 11,585 cycles of assisted reproduction with the use of washed semen among 3,994 women. Among the subset of HIV-infected men without plasma viral suppression at the time of semen washing, no HIV seroconversions occurred among 1,023 women after 2,863 cycles of assisted reproduction with the use of washed semen. Studies that measured HIV transmission to infants reported no cases of vertical transmission. Overall, 56.3% of couples (2,357/4,184) achieved a clinical pregnancy with the use of washed semen. CONCLUSION(S): Semen washing appears to significantly reduce the risk of transmission in HIV-discordant couples desiring children, regardless of viral suppression in the male partner. There are no randomized controlled studies or studies from low-income countries, especially those with a large burden of HIV. Continued development of lower-cost semen washing and assisted reproduction technologies is needed. Integration of semen washing into HIV prevention interventions could help to further reduce the spread of HIV.

Safe conception for HIV-discordant couples: insemination with processed semen from the HIV-infected partner.

OBJECTIVE: The objective of the study was to evaluate the safety of semen washing with intrauterine insemination (SW-IUI) for achieving pregnancy when the man is human immunodeficiency virus (HIV) infected and the woman is HIV negative. STUDY DESIGN: We conducted a retrospective analysis of 635 HIV-discordant couples enrolled in a SW-IUI program and followed up 367 Italian women. We computed pregnancy, live birth, and multiple delivery rates and assessed the women's postinsemination HIV status. RESULTS: The retrospective analysis included 635 couples (2113 SW-IUI cycles): 41% of the women (95% confidence interval [CI], 37-45%) had a live birth (per-cycle live birth rate 13%; 95% CI, 11-14%). HIV status after SW-IUI was negative when available but unknown for 26% of the women: missing HIV status was not associated with correlates of HIV risk. The follow-up study included 367 couples (1365 cycles): 47% of the women (95% CI, 42-52%) had a live birth (per-cycle rate 14%; 95% CI, 12-16%). Ascertainment of postinsemination HIV status was complete and confirmed no HIV transmission attributable to SW-IUI. The upper 95% confidence limit of the HIV transmission rate was 1.8 per 1000 cycles in the retrospective analysis and 2.7 per 1000 cycles in the follow-up study. CONCLUSION: SW-IUI appears to be a safe and effective method for achieving pregnancy in HIV-discordant couples in which the man is HIV infected.

Infertility treatment for HIV-positive women.

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.

Safe conception for HIV discordant couples through sperm-washing: experience and perceptions of patients in Milan, Italy.

Our research explored the reproductive desires of HIV-negative women and their HIV-positive partners who underwent assisted conception based on sperm-washing and intrauterine insemination in Italy. Twenty-two semi-structured interviews were conducted with former patients (6 women, 5 men and 11 couples). Desire for children, perceived risk from treatment and acceptability of the insemination technique were some of the issues explored. Participants had the treatment for a mean duration of 3.5 years, with a mean number of cycles of 5.3. They were highly motivated to conceive a biological child to bring purpose to their lives, and strongly desired options to conceive safely. Most rejected spontaneous conception. Those who successfully conceived reported a positive impact on their quality of life, fulfilling their desire to be parents and restoring their sense of "normalcy". Participants strongly supported extending assisted conception services to all HIV negative women living with HIV positive partners who wished to become pregnant and felt that withholding such treatment was not ethically justified. They perceived assisted conception services to be a safe and effective alternative to spontaneous conception, and felt that society has a moral obligation to provide such services.

Safety and efficacy of sperm washing in HIV-1-serodiscordant couples where the male is infected: results from the European CREAThE network.

OBJECTIVE: To examine the safety and effectiveness of assisted reproduction using sperm washing for HIV-1-serodiscordant couples wishing to procreate where the male partner is infected. DESIGN AND METHODS: A retrospective multicentre study at eight centres adhering on the European network CREAThE and involving 1036 serodiscordant couples wishing to procreate. Sperm washing was used to obtain motile spermatozoa for 3390 assisted reproduction cycles (2840 intrauterine inseminations, 107 in-vitro fertilizations, 394 intra-cytoplasmic sperm injections and 49 frozen embryo transfers). An HIV test was performed in female partners at least 6 months after assisted reproduction attempt. The outcome measures recorded were number of assisted reproduction cycles, pregnancy outcome and HIV test on women post-treatment. RESULTS: A total of 580 pregnancies were obtained from 3315 cycles. Pregnancy outcome was unknown in 47 cases. The 533 pregnancies resulted in 410 deliveries and 463 live births. The result of female HIV testing after assisted reproduction was known in 967 out of 1036 woman (7.1% lost to follow-up). All tests recorded were negative. The calculated probability of contamination was equal to zero (95% confidence interval, 0-0.09%). CONCLUSION: This first multicentre retrospective study of assisted reproduction following sperm washing demonstrates the method to be effective and to significantly reduce HIV-1 transmission risk to the uninfected female partner. These results support the view that assisted reproduction with sperm washing could not be denied to serodiscordant couples in developed countries and, where possible, could perhaps be integrated into a global public health initiative against HIV in developing countries.

Multicenter quality control of the detection of HIV-1 genome in semen before medically assisted procreation.

Couples in whom the man is HIV-1-positive may use medically assisted procreation in order to conceive a child without contaminating the female partner. But, before medically assisted procreation, the semen has to be processed to exclude HIV and tested for HIV nucleic acid before and after processing. The performance was evaluated of the technical protocols used to detect and quantify HIV-1 in 11 centers providing medically assisted procreation for couples with HIV-1 infected men by testing panels of seminal plasma and cells containing HIV-1 RNA and/or DNA. The performance of these tests varied due to the different assays used. False positive results were obtained in 14-19% of cases. The sensitivity for RNA detection in seminal plasma was 500-1,000 RNA copies/ml, over 500 RNA copies/10(6) cells in semen cells, and for DNA detection in semen cells 50-500 DNA copies/10(6) cells. The use of silica-based extraction seemed to increase the assay performance, whereas the use of internal controls to detect PCR inhibitor did not. This first quality control highlights the need for technical improvements of the assays to detect and quantify HIV in semen fractions and for regular evaluation of their performance.

Sperm washing, use of HAART and role of elective Caesarean section.

PURPOSE OF REVIEW: Today, 50% of people living with HIV are women and most have been sexually infected. Highly active antiretroviral therapy (HAART) reduces the rates of both sexual and vertical infection, but maximum protection is achieved with sperm washing and elective Caesarean section. RECENT FINDINGS: Men taking HAART have lower seminal concentration of HIV, and sexual transmission may be reduced. However, a certain percentage of aviraemic men retain viral presence in semen, and unprotected intercourse to achieve fertilization must be discouraged as it carries the risk of sexual transmission of the virus. HIV-discordant couples should be informed that sperm washing can remove HIV from semen, allowing conception without the risk of infection for the seronegative female and eventually the child. In HIV-positive women, perinatal transmission of HIV can be curtailed to less than 2% by using HAART to decrease maternal viral load and offering prenatal preexposure prophylaxis of the fetus, and elective Caesarean section. Each intervention carries specific risks and benefits. The contribution of each preventive arm in achieving fetal protection can only be crudely measured and optimal obstetric management must involve discussion with the pregnant woman of the pros and cons of each strategy. SUMMARY: In HIV-positive men taking HAART, seminal viral load is decreased but not eliminated and fertilization should be achieved through sperm washing to offer maximum protection for the uninfected female. Pregnant HIV-positive women on antiretroviral medication have a reduced risk of transmitting the virus, but should still be counselled about the possibility to further limit the chances of infecting their infant through elective Caesarean section.

HIV and pregnancy: is the outlook for mother and baby transformed?

PURPOSE OF REVIEW: Advances in antiretroviral regimens and specific obstetrical procedures have enabled HIV-positive women to have children, with a very low risk of transmitting the infection to the infant and with improved chances of seeing their children reach adulthood. New studies have given providers of care better information on how to assist women with HIV who want to have a child in the safest possible way. RECENT FINDINGS: Highly active antiretroviral therapy can effectively control viral replication and reduce the risk of vertical transmission. The benefit of treatment for the mother and the infant must be balanced against any negative effects on pregnancy, the embryo and the fetus. Potential long-term consequences of prenatal exposure to potent compounds should also be considered and monitored. The evidence suggests that even in women with undetectable viral load, Caesarean section reduces vertical transmission to the same degree as documented previously for all women. Although the absolute risk reduction is very low, no study can show whether or not this is statistically significant and therefore women should be helped to make their individual choice. Mothers with HIV should not breastfeed in countries where formula milk is easily available, however highly active antiretroviral therapy administered to mothers or infants may reduce the risk of postnatal HIV transmission. SUMMARY: Counselling and assistance to conceive, modification of the therapeutic regimens and options about delivery have changed dramatically since the beginning of the HIV epidemic. Nowadays, women with HIV, similarly to uninfected women, can discuss with their doctors which therapeutic and treatment options would best fit their expectations of care.

HIV and reproduction.

PURPOSE OF REVIEW: Three quarters of individuals infected with HIV are in their reproductive years and can expect an almost normal life expectancy under antiretroviral treatment. Many of them want to have a child and reproductive counselling and care can offer a sharp reduction in both sexual and vertical transmission rates. RECENT FINDINGS: Most couples with HIV are formed by an infected man and an uninfected woman; in this setting, semen washing coupled with reproductive technology can be applied to eliminate the risk of sexual transmission of the virus. Semen washing is a processing method which reduces both HIV RNA and DNA to undetectable amounts. In couples in which only the woman is infected, self-insemination might be indicated. When both partners are carrying HIV, semen washing can be used in couples with different viral strains. HIV can be vertically transmitted and the risk of infection for the infant can be decreased to approximately 1% by reducing maternal viral load, elective caesarean section and avoidance of breastfeeding. In pregnancy the efficacy of antiretroviral treatment should be balanced against the possibility of embryonic or fetal toxicity. Caesarean section, performed electively, has proven its protective efficacy, without significant maternal morbidity. Its role should now be reassessed in mothers with undetectable viral load. Breastfeeding, discouraged to avoid postnatal transmission, might be possible in the future, with antiretroviral therapy capable of suppressing viral excretion in maternal milk. SUMMARY: Semen washing, reproductive technology, antiretroviral therapy and obstetrical care can work in sequence to allow safe reproduction in couples infected with HIV.