The investigations for short and long term impacting on reproductive system of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are ongoing [1, 2]. As SARS- CoV-2 is likely to coexist with humans for a long time, infections may continue to occur frequently. Couples who are undergoing assisted reproductive technology (ART) therapy are also at constant risk of infection. There are concerns that the virus may adversely affect ART pregnancy and obstetric outcomes, including decreased live birth rates, increased rates of miscarriages, ectopic pregnancies, newborn malformation, and premature births.
The primary pathways which SARS-CoV-2 enters cells are through the angiotensin-converting enzyme 2 (ACE2) receptor and transmembrane protease serine 2 (TMPRSS2). Studies have identified significant ACE-2 expression in various cells, including coronary, Sertoli, interstitial, and testicular cells, particularly in sperm. This implies that cells or organs expressing high levels of ACE2 and TMPRSS2 are more vulnerable to viral invasion [3–5], suggesting that the testicles are susceptible to SARS-CoV-2 infection. Males with COVID-19 have shown evidence of SARS-CoV-2 in their testicles and semen, together with the presence of the SARS-CoV-2 spike protein [6–8]. This implies that the virus may affect sperm quality directly or indirectly, raising concerns about whether sperm can transmit the virus. Statistics show that human semen contains approximately 27 different viruses, all of which can induce viremia [9]. In addition, orchitis has been identified in the testicles of males with COVID-19 [10], indicating potential spread of SARS-CoV-2 through genital secretions and disruption of the normal structure of the male genital tract.
The vagina, uterus, ovaries, and fallopian tubes collectively form the normal female reproductive system, working together to control the release of female hormones and support follicular and embryonic development. Current evidence indicates high levels of ACE2 expression in the ovary, uterus, vagina, and placenta [11]. Based on this information, it is hypothesized that SARS-CoV-2 may impact the anatomy of the female reproductive system, resulting in infertility. In addition, ACE2 has been shown to govern the maturation of ovarian cells, ovarian development, and steroid synthesis. Furthermore, in vitro experiments have shown that viruses trigger follicular lesions [12]. Two (5.7%) SARS-CoV-2 RT-PCR-positive samples were found in 35 vaginal samples from COVID-19 positive patients, while ten reports of SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) positivity were identified in 80 swabs of the vagina from women with COVID-19 [13, 14]. The aforementioned findings suggest that SARS-CoV-2 infection may be detrimental to follicular development and female reproduction. However, SARS-CoV-2 has not been shown to negatively affect the therapeutic parameters of in vitro fertilization (IVF) or cause short-term pregnancy loss. Moreover, the treatment outcomes were unaffected despite alterations in post- exposure sperm concentrations [15]. These contentious statements may have arisen due to the limited number of samples and the breadth of the research. The physiological effects of SARS- CoV-2 on human fertility and assisted reproduction are not widely recognized, suggesting a lack of awareness regarding the virus's immediate consequences and potential harm to humans. Furthermore, several clinical cohort analyses have been conducted to elucidate the outcomes of infection. In our previous study, we've demonstrated that SARS-CoV-2 infection during ovarian stimulation does not significantly impact fresh IVF cycle outcomes and laboratory parameters [16], but the effect on FET cycles, especially with embryos generated from SARS- CoV-2 infection during COS, remains unclear. This is the first study looking into whether SARS-CoV-2 infection during COS affects the pregnancy and obstetric outcomes of FET.