Assisted reproduction in COVID-19 season: Expend the fear
Singh Rajender, Ph.D.
Male Reproductive Biology Laboratory, Central Drug Research Institute
COVID-19 is infecting and killing millions of people worldwide. Specialists in every medical field are concerned about the penetrance of the virus in specific organs. Accordingly, its transmission in addition to the nasopharyngeal route has raised apprehensions. With regard to reproduction, transmission of the virus holds a very important place and the disquiet that it can result in infection to the fetus in addition to its transmission to the female partner looms large (1,2). The much-awaited first study on semen samples was conducted in China (2). In this study, 15.8% (6 out of 38) COVID-19 patients were found to have the virus in the semen samples, of which 10.5% (4 out of 38) were in the acute phase and 5.26% (2 out of 38) were in the clinical recovery phase of the COVID-19 disease (2). This study made headlines on various media platforms across the world, suggesting that reproduction in COVID-19 pandemic could result in sexual transmission of the virus not only between sexual partners but also to the fetus. This has also resulted in the reduction of IVF cycles taken in the last six months (3).
While the fear of sexual transmission of the virus was up in the air, another study refuted the claims regarding its presence in the semen samples. Pan et al, did not detect SARS-CoV-2 in the semen samples of 34 COVID-19 patients after a median of 31 days (4). While six patients were reported to have scrotal discomfort, none of the patients tested positive for SARS-CoV-2 in the semen samples. This study provided contrasting data regarding the presence of the virus in the semen samples, easing concerns about planning an assisted reproduction cycle in the COVID-19 pandemic season. In both these studies, it was not described if the semen samples were processed before RT-PCR testing. We assume that native semen samples were used for RNA extraction followed by RT-PCR. However, the immediate question ‘should assisted reproduction take a backseat in the COVID-19 pandemic season?’ still remained unanswered.
While no study has analyzed the presence of SARS-CoV-2 in the testis, an important investigation on SARS-CoV (coronavirus pandemic 2002-2003) reported that SARS-CoV was not found in the testis, though the immune response in the host resulted in a significant damage to the testicular tissue (5). Similarly, SARS-CoV-2 is likely to affect the testicular function and fertility, but no study has investigated its presence in the testis or germ cells. Further, none of the above studies analyzed the impact of SARS-CoV-2 on fertility or semen parameters. COVID-19 is highly likely to affect fertility because of various factors discussed by us recently (6). However, the impact of infection on semen parameters remained to be assessed until recently.
Now with more negative reports transpiring, the possibility of the presence of virus in the semen samples appears brink. A third study by Holtmann et al. 2020 showed the absence of the virus by RT-PCR after analysis of eighteen semen samples from recovered men obtained 8–54 days after absence of symptoms, 14 from control subjects, and 2 from patients with an active COVID-19 infection (7). The study found that while moderate viral infection could affect semen paramters, there was no evidence of its presence in semen and hence its sexual transmission. This is the first study showing an actual impact of the SARS-CoV-2 infection on semen parameters. Another recent study analyzed SARS-CoV-2 in semen samples obtained from nine Italian males (8). It was found that despite prolonged nasopharyngeal swab positivity, the virus could not be detected in the semen samples. These studies have largely cleared the air with respect to the presence of the virus in the semen samples.
SARS-CoV-2 is thus highly unlikely to be present in the semen samples. Even if the SARS-CoV-2 could be present in a rare case, its source is unlikely to be testicular. It remains a remote possibility for transmission of the virus by the accessory glands’ secretions or because of the presence of a higher numbers of leukocytes in the semen samples. Irrespective of the source, the chances of the presence of virus in the semen are brink, and if at all detected, the likely percentage of the cases having the virus in semen is likely to be negligible. Irrespective of its source, the presence of virus in the germ cells is not a biological plausibility and it was shown by studies on SARS-CoV and recent studies on SARS-CoV-2. At the most, certain cases with high leukocyte counts could be considered for performing a test for the presence of virus in the semen samples.
It is noteworthy that the preparation of the semen samples for IVF consists of a number of preparations before use. The washing is generally undertaken in 2-3 steps and this would not leave any virus particle attached to sperm. This further reduces the possibility of sexual transmission to be considered in the clinical practice. This is why assisted reproduction need not take a back seat amid COVID-19 pandemic. Infertility is a serious personal, psychological and societal problem. While several critical illnesses may need attention even during the COVID-19 pandemic, infertility treatment cannot be ignored or delayed. A delay in the treatment could leave several infertile individuals in a more despaired state, including faster deterioration of semen quality, limiting further possibility of assisted reproduction using their own sperm. It has been seen that stress makes a vicious cycle with infertility and individuals undergoing infertility care are already under significant stress. Further delay in the availability of treatment could incite deeper stress clock and render them more prone to losing their remote fertility. In infertile individuals, a delay of 6 months to 2 years could take a significant toll as the clock in these individuals is ticking faster in comparison to all others.
Reproduction is at the core of the survival of a species. Given that spermatogenesis is at the core of reproduction, testicular privilege to contain the entry of viruses and other infectious agents adds to the robustness of the reproductive system. It is because of the tight regulation in these tiny organs that we often talk about the infections of accessory glands in infertility without infection right inside the testicular compartments. It is not just about the presence of various receptors in the testis, further layers that provide immunological privilege to these special organs make penetration impossible. High vulnerability of the testis to various infections would have rendered the species prone to extinction by new challenging infections that may evolve and swipe a species. While the overall health state of an individual, overtly spillage of the immune response to distant organs, and the impact on the hypothalamic-pituitary-gonadal axis render the reproductive organs vulnerable to the indirect effects of COVID-19, a direct access to the virus in the organs no less critical than the vital organs could not be considered by the nature.
Acknowledgement: The author would like to gratefully acknowledge the Council of Scientific and Industrial Research (CSIR), Govt. of India, for funding under MLP2021.
- Vivanti AJ, Vauloup-Fellous C, Prevot S. et al.Transplacental transmission of SARS-CoV-2 infection. Nat Commun11, 3572 (2020). https://doi.org/10.1038/s41467-020-17436-6
- Li D, Jin M, Bao P, Zhao W, Zhang S. Clinical Characteristics and Results of Semen Tests Among Men With Coronavirus Disease 2019. JAMA Netw Open. 2020;3(5):e208292. Published 2020 May 1. doi:10.1001/jamanetworkopen.2020.8292
- Alviggi C, Esteves SC, Orvieto R, et al. COVID-19 and assisted reproductive technology services: repercussions for patients and proposal for individualized clinical management. Reprod Biol Endocrinol. 2020;18(1):45. Published 2020 May 13. doi:10.1186/s12958-020-00605-z.
- Pan F, Xiao X, Guo J, et al. No evidence of severe acute respiratory syndrome-coronavirus 2 in semen of males recovering from coronavirus disease 2019. Fertil Steril. 2020;113(6):1135-1139. doi:10.1016/j.fertnstert.2020.04.024
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- Holtmann N, Edimiris P, Andree M, et al. Assessment of SARS-CoV-2 in human semen-a cohort study. Fertil Steril. 2020;114(2):233-238. doi:10.1016/j.fertnstert.2020.05.028
- Vishvkarma R, Rajender S. Could SARS-CoV-2 affect male fertility? [published online ahead of print, 2020 Jun 23]. Andrologia. 2020;e13712. doi:10.1111/and.13712
- Pavone, C., Giammanco, G.M., Baiamonte, D. et al.Italian males recovering from mild COVID-19 show no evidence of SARS-CoV-2 in semen despite prolonged nasopharyngeal swab positivity. Int J Impot Res(2020). https://doi.org/10.1038/s41443-020-00344-0