SARS-CoV-2, fertility and assisted reproduction

Abstract

BACKGROUND In 2020, SARS-CoV-2 and the COVID-19 pandemic had a huge impact on the access to and provision of ART treatments. Gradually, knowledge of the virus and its transmission has become available, allowing ART activities to resume. Still, questions on the impact of the virus on human gametes and fertility remain. OBJECTIVE AND RATIONALE This article summarizes published data, aiming to clarify the impact of SARS-CoV-2 and the COVID-19 disease on human fertility and assisted reproduction, as well as the impact of vaccination, and from this, provide answers to questions that are relevant for people contemplating pregnancy and for health care professionals. SEARCH METHODS PUBMED/MEDLINE and the WHO COVID-19 database were searched from inception to 5 October 2022 with search terms focusing on ‘SARS-CoV-2’ and gametes, embryos, reproductive function, fertility and ART. Non-English studies and papers published prior to 2020 were excluded, as well as reviews and non-peer reviewed publications. Full papers were assessed for relevance and quality, where feasible. OUTCOMES From the 148 papers included, the following observations were made. The SARS-CoV-2-binding proteins, angiotensin-converting enzyme 2 (ACE2) and type II transmembrane serine protease (TMPRSS2), are expressed in the testis, but co-expression remains to be proven. There is some evidence of SARS-CoV-2 RNA in the ejaculate of COVID-19 patients with severe disease, but not in those with mild/moderate disease. SARS-CoV-2 infection can impair spermatogenesis, but this seems to resolve after one spermatogenic cycle. Testosterone levels seem to be lower during and after COVID-19, but long-term data are lacking; disease severity may be associated with testosterone levels. COVID-19 cannot be considered a sexually transmitted disease. There is no co-expression of ACE2 and TMPRSS2 in the myometrium, uterus, ovaries or fallopian tubes. Oocytes seem to have the receptors and protease machinery to be susceptible to SARS-CoV-2 infection; however, viral RNA in oocytes has not been detected so far. Women contemplating pregnancy following COVID-19 may benefit from screening for thyroid dysfunction. There is a possible (transient) impact of COVID-19 on menstrual patterns. Embryos, and particularly late blastocysts, seem to have the machinery to be susceptible to SARS-CoV-2 infection. Most studies have not reported a significant impact of COVID-19 on ovarian reserve, ovarian function or follicular fluid parameters. Previous asymptomatic or mild SARS-CoV-2 infection in females does not seem to negatively affect laboratory and clinical outcomes of ART. There are no data on the minimum required interval, if any, between COVID-19 recovery and ART. There is no evidence of a negative effect of SARS-CoV-2 vaccination on semen parameters or spermatogenesis, ovarian function, ovarian reserve or folliculogenesis. A transient effect on the menstrual cycle has been documented. Despite concerns, cross reactivity between anti-SARS-CoV-2 spike protein antibodies and Syncytin-1, an essential protein in human implantation, is absent. There is no influence of mRNA SARS-CoV-2 vaccine on patients’ performance during their immediate subsequent ART cycle. Pregnancy rates post-vaccination are similar to those in unvaccinated patients. WIDER IMPLICATIONS This review highlights existing knowledge on the impact of SARS-CoV-2 infection or COVID-19 on fertility and assisted reproduction, but also identifies gaps and offers suggestions for future research. The knowledge presented should help to provide evidence-based advice for practitioners and couples contemplating pregnancy alike, facilitating informed decision-making in an environment of significant emotional turmoil.

Association of SARS-CoV-2 Infection During Controlled Ovarian Stimulation With Oocyte- and Embryo-Related Outcomes

“…Angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine subtype 2 (TMPRSS2) are expressed in the reproduction system in both males and females 1 ; therefore, reproductive function is theoretically vulnerable to SARS-CoV-2 infection, and many studies 2,3 have explored the possible effect of SARS-CoV-2 infection on the human reproductive system. A recent review 4 summarized published data and clarified the effect of SARS-CoV-2 and COVID-19 on human fertility and assisted reproduction.…”

Effect of SARS-CoV-2 infection on IVF/ICSI-ET outcomes: A propensity score-matched cohort study

“…Several pathogens, such as hepatitis virus, human immunode ciency virus, and Zika virus [27], may have variable impacts on the physiopathology of the reproductive organs, leading to infertility or poor ART outcomes [28]. Therefore, when the new SARS-CoV-2 virus emerged and spread globally, researchers focused on the impact of infection with this virus on human reproduction and ART outcomes [5]. The effects of SARS-CoV-2 infection on the laboratory and clinical outcomes of ART have not yet been consistently documented in the literature [14,[29][30][31].…”

“…SARS-CoV-2 is still evolving [1], resulting in new cases and reinfections in the population [2][3][4]. As SARS-CoV-2 is a new virus, we still need to improve our understanding of it, especially its effects on human reproduction and assisted reproductive technology (ART) [5] Currently, it is believed that the SARS-CoV-2 virus damages cells or tissues by infecting and replicating in cells, which requires the expression of SARS-CoV-2 receptors, such as angiotensin converting enzyme 2 (ACE2), basigin (BSG), transmembrane serine protease 2 (TMPRSS2) and cathepsin L (CTSL) [6,7]. It is noteworthy that all the aforementioned viral receptor mRNAs are expressed in most of the human female reproductive tract, including the ovaries (including follicular granulosa cells) [8] and endometrium [9].…”

Causality between COVID‐19 and female reproductive function: A Mendelian randomization study

“…Recent studies have indicated that severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) Omicron sublineages, such as XBB.1, exhibit enhanced antibody evasion, presenting a significant challenge in the prevention and treatment of COVID‐19 1 . Furthermore, it is essential to understand the effect of COVID‐19 on the reproductive system because it affects fertility policies in multiple regions 2 …”

“…1 Furthermore, it is essential to understand the effect of COVID-19 on the reproductive system because it affects fertility policies in multiple regions. 2 Multiple studies have suggested that COVID-19 might influence female reproductive characteristics, including the menstrual cycle, ovarian reserve, and sex hormone levels. 3,4 Two observational studies reported that 28% and 16% of female patients with COVID-19 experienced irregular menstruation respectively, which was associated with disease severity.…”