SARS-CoV-2 and its repercussive effect on reproductive health: recent trends

Since the global COVID-19 outbreak, approximately 241 million confirmed cases and 4.9 million deaths have been reported by the WHO in 2 years [1]. Infertility affects 48 million couples and 186 million individuals worldwide [2], with millions of couples seeking services for assisted reproduction globally. A Cochrane Gynecology and Fertility Group review on COVID-19 fertility and pregnancy including 192 studies on pregnant and nonpregnant women with COVID-19 reported that a greater amount of pregnant and recently pregnant women required intensive care treatment for COVID-19. Furthermore, pregnant women with COVID-19 were more likely to deliver a preterm infant, and such infants were likely to receive neonatal care [3]. In addition, the review indicated that the updated joint statement of global societies for assisted reproductive technology such as the European Society of Human Reproduction and Embryology (ESHRE), the American Society for Reproductive Medicine (ASRM) and the International Federation of Fertility Societies (IFFS), dated 9 February 2021, conveyed that universal recommendations are not possible during the billowing waves of COVID-19 across nations, due to fewer data being available to make staunch recommendations.

These societies recommended putting off pregnancy until steps are undertaken to reduce the risk of COVID-19 including the availability of vaccines and prenatal care, getting a COVID-19 vaccination at the earliest possibility, seeking out local public health infrastructure for antenatal and delivery care and appropriately managing patients with acute and severe COVID-19 infections. Pregnant women are recommended to follow preventive strategies such as wearing masks, washing hands and maintaining a social distance and to delay COVID-19 vaccination until after pregnancy. Some organizations proposed that pregnant women should be vaccinated cautiously. However, COVID-19 vaccinations are being administered to pregnant women with a high risk of infection in countries such as the USA, despite universal recommendations not yet being available. Furthermore, they indicated that the choice of vaccination depends on each individual but is strongly recommended in both pregnant and nonpregnant women [4]. The statement provides suggestions for women but not for men undergoing assisted reproductive healthcare.

The ESHRE has released a standalone statement for accessing healthcare by segregating services on the basis of a triage questionnaire. They indicated continuing services for COVID-19-negative patients but postponing services for COVID-19-positive patients until they test negative and collectively questioning patients who have undergone COVID-19 treatment during follow-up. The staff should be monitored for their vaccination status; if they are vaccinated, they can directly start to work, whereas those who are not vaccinated must be tested for SARS-CoV-2 infection every 2 weeks. If staff are found to be COVID-19 positive, they should be quarantined until they receive a negative result, whereas staff members with negative results can continue to work [5]. The same strategy has been recommended by all other societies.

Review on effects of COVID-19 infection in male reproductive system

In a recent review published in Fertility and Sterility, the authors discussed the effects of SARS-CoV-2 and COVID-19 on male reproduction. They hypothesized that COVID-19 infection is mostly spread to the male reproductive tract through blood and highlighted that 5% of patients with severe COVID-19 were young men. Moreover, men developed severe COVID-19 infection because of the higher expression of viral entry receptors such as ACE2 and TMPRSS-2 in male-specific organs. Innate immune responses in women resulted in them having a less severe disease [6]. In a Letter to the Editor published in Journal of Andrology in August 2021, the author indicated that leukocyte infiltration was observed in the semen of individuals during early infection, which indirectly emphasized the severity of infection in men. Moreover, sperm DNA fragmentation had a prominent role in SARS-CoV-2 infection [7]. Erbay et al. analyzed semen samples collected from 69 centers and observed significant decreases in sperm motility and vitality [8]. Yao et al. detected the presence of SARS-CoV-2 in the male reproductive tract and examined the semen quality and pathological characteristics of the testis in patients with COVID-19. They found substantial SARS-CoV-2 infection in the reproductive tract in patients with severe COVID-19. Furthermore, they indicated that SARS-CoV-2 infection may be present in the reproductive tract for approximately 2 weeks and that the destruction of the testes may occur in the middle stage of infection depending on its severity, even in the absence of the virus in the testes [9]. Selvaraj et al. demonstrated that a defect in steroidogenesis in the testis can lead to the abnormal levels of hormones such as testosterone, follicle-stimulating hormone and luteinizing hormone in patients with SARS-CoV-2, whereas increases in the levels of follicle stimulating hormone and luteinizing hormone indicate testicular damage [10].

In their Review, Nassau et al. reported that the androgen receptor produces more TMPRSS-2 receptors that bind to the spike protein of SARS-CoV-2; hence, men are more susceptible to COVID-19 infection compared with women. Moreover, the authors reported that the therapeutic and causative effects of SARS-CoV-2 infection on the baseline testosterone level remain unclear. The presence of the virus in the penile shaft for up to 7 months can damage the cavernosal epithelium and cause erectile dysfunction because the cavernosal epithelium possesses TMPRSS-2 and ACE2 receptors. However, viral particles were absent in the prostate and seminal vesicles. Inflammation was noted in the testicles possibly due to the invasion of viral particles in the seminiferous tubules through blood where they resulted in spermatogenesis dysfunction and inflammation. These findings indicated that the virus can damage the testis–blood barrier and negatively affect male fertility. The authors concluded that COVID-19 infection can exert a temporary adverse effect on spermatogenesis and recommended that patients should resume their treatment 3 months after COVID-19 infection when spermatogenesis resumes normally [11].

Review on effects of COVID-19 in female reproductive system

A systematic review and meta-analysis investigating the effect of COVID-19 on female fertility reported that SARS-CoV-2 binds to the female reproductive tract through the ACE2 receptor, affecting the ovarian reserve and reducing the ova quality because of the presence of a high number of ACE2 receptors in the ovaries [12]. Virant-Klun and Strle indicated that SARS-CoV-2 may infect oocytes in patients with severe SARS-CoV-2 infection and affected the developing embryo in vitro or in utero, as determined through the transcriptomic and proteomic analysis of the human ovum. ACE2 and Basigin or CD147 (BSG) factors may act as the carriers of infection according to a hypothetical model [13]. Weatherbee et al. reported that ACE2, TMPRSS-2, BSG, NRP1 and CTSL factors, that are mainly expressed in the tri-semester, may act as a host for SARS-CoV-2 infection that can be spread through blood vessels supplying to the embryo, leading to miscarriage [14]. Rajput et al. examined ACE2, BSG (CD147), TMPRSS-2 and Cathepsin L factors and reported that follicular cells were not susceptible to SARS-CoV-2, whereas metaphase-II oocytes, zygotes and blastocysts expressed ACE2 and TMPRSS-2 proteins, and thus may be susceptible to SARS-CoV-2 infection; however, their underlying mechanism remains unclear [15]. Barragan et al. examined the aspirated ovum samples of two patients with SARS-CoV-2 infection through qPCR analysis and did not detect SARS-CoV-2 RNA in the samples [16]. Ateyo et al. reported that SARS-CoV-2 antibodies were not transferred across the placenta; the antibodies that were transferred had significantly lower functional titers and activity than did maternal plasma. This effect was noted in the third trimester. SARS-CoV-2 infection induced IgG and FCGR3A expression in the placenta, which, in turn, enhanced the immunity of the fetus [17].

Collective commentary for the investigations listed & future studies

All the reviews and studies conducted thus far to investigate the effect of SARS-CoV-2 infection on reproductive health have some limitations. Hence, due to these limitations, universal assisted-reproduction societies would find it difficult to release updated regulations for patients undergoing services in assisted reproductive technology (ART) clinics. Various organs of the male reproductive system, including semen, were observed to be adversely affected by the SARS-CoV-2 virus. However, studies examining semen quality are limited and were not performed on a large scale. The long-term effects of COVID-19 infection on semen quality and organs have not yet been studied. Large-scale studies should be conducted to investigate the effects of COVID-19 infection on hormone levels. Similarly, the effect of SARS-CoV-2 virus on female reproductive organs including the ovarian reserve must be studied. The viral load in the female reproductive organs might be dependent on the severity of SARS-CoV-2 infection, as observed in the male reproductive system; however, more studies on this topic are warranted. All the organs of the female reproductive system including the developing fetus may provide anchorage to infection due to factors that elicit the attachment of the S protein of SARS-CoV-2 virus. The recommendations proposed by the ESHRE regarding the segregation of patients and staff based on COVID-19 testing should be followed by all ART centers globally irrespective of the cost factor involved in testing. Studies involving the vaccination of pregnant women should be performed as early as possible because both the mother and fetus are at risk in the event of infection. A study on the immunological aspect of SARS-CoV-2 infection in the third trimester may lead to the development of safer vaccines for pregnant women.

Large-scale studies on both male and female reproductive systems should be conducted to elucidate the underlying mechanisms and investigate the effect of SARS-CoV-2 infection during and after infection. Routine testing for COVID-19 should be performed for patients and staff in settings providing ART treatment if they are not vaccinated. Large-scale studies must be conducted to determine if the RNA of the virus is transmitted when performing in vitro fertilization/intracytoplasmic sperm injection in an infected individual, considering the possibility of vertical transfer. Drugs that can prevent testicular damage and viral entry into reproductive organs must be evaluated. Moreover, studies should examine damage to reproductive organs and develop intervention strategies to alleviate these damages after COVID-19 infection. These are the future subjects of research concerning SARS-CoV-2 infection in reproductive organs.