COVID-19 Infection and Subfertility: A Subtle and Debatable Complication

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INFECTIOUS DISEASE

Medical writer: Christy Leung | Last updated: 16 January 2023 | In: COVID-19, SARS-CoV2, Gynaecology, Infectious Disease

Article Keywords

reproductive health, antivirals, fertility, COVID-19, SARS-CoV-2, gynaecology

While much has been discussed about maternal-foetal wellbeing in pregnant women with coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)’s influence on the female and male reproductive systems is less well studied. This article explores any plausible association between COVID-19 infection and subfertility, here defined as the failure to conceive for a prolonged period of time, without a strict cut-off point.¹

In order to assess male fertility, two semen samples are required for analysis of sperm cell count, motility, and morphology, along with sperm DNA intactness.^2,3 Acute COVID-19 infection triggers mass release of pro-inflammatory cytokines and oxidative stress, predisposing to sperm DNA fragmentation^4,5; particularly in patients with fever, high scrotal temperature causes reduced sperm count and motility, in positive correlation with the duration of fever.^6,7Both phenomena are believed to resolve with time, the latter specifically after two to three months post-infection.⁵ While antioxidants such as Vitamin C theoretically act against the oxidative stress from COVID-19 infection⁸, its effect against oxidative stress-induced sperm DNA fragmentation is yet awaiting scientific proof.⁸

Anti-viral agents such as lopinavir/ritonavir, nirmatrelvir/ritonavir and ribavirin are mostly used pro re nata in patients with COVID-19.⁹ Antivirals may — apart from the sperm count reduction due to the SARS-CoV-2 infection itself — also negatively affect sperm quality. Ribavirin is known to trigger sperm DNA fragmentation, a significant cause for subfertility³; male patients with prior antiviral use should therefore be counselled that conception is unlikely in the first six months after antiviral treatment, even via in vitro fertilisation.^3,6 Murine studies suggest ritonavir may reduce sperm motility and viability¹⁰, while the effect of lopinavir or nirmatrelvir on male fertility has not been studied to date.

Infection with COVID-19 may also cause female-factor subfertility, although to a smaller extent compared to that in males and supported by less consistent study outcomes.¹¹ The viral entry point, the angiotensin converting enzyme (ACE)2 receptors, are present in tissues of the ovary and endometrium.¹² SARS-CoV-2 infection downregulates ACE2, triggering local hyperinflammation and subsequent immune-mediated damage.¹³ One study suggested this may reduce oocyte quantity.¹¹ In fact, ACE2 is a key contributor in the female reproductive cycle, promoting follicular maturation for ovulation and supporting the corpus luteum in progesterone secretion¹¹; with its downregulation, the success rates of ovulation and implantation will decrease. Last but not least, alterations in subjects’ menstrual cycles, which are classically interpreted as fertility indicators¹⁴, were reported by Carp-Veliscu et al.¹¹ Such cycle alterations may be influenced by other factors like psychological stress and therefore are not fully attributable to COVID-19 infection.^11,14

While COVID-19 infections cannot be completely prevented, COVID-19 vaccination can provide up to 90% protection against symptomatic infection and adverse outcomes¹⁵, implying the lower likelihood of requiring medical intervention, including the need for antiviral use. Contrary to fever caused by COVID-19 infection, vaccine-induced fever will not affect sperm count.⁷ Individuals, especially in those of reproductive age and regardless of gender, can therefore be well assured that the COVID-19 vaccination will not affect fertility.¹⁶

Reference

Gnoth C, et al. Hum Reprod. 2005;20(5):1144-7.

Kumar N & Singh AK. J Hum Reprod Sci. 2015;8(4):191-6.

González-Marín C, et al. Int J Mol Sci. 2012;13(11):14026-52.

Akhigbe RE, et al. Front Reprod Health. 2022;4:782915.

Shcherbitskaia AD, et al. Int J Mol Sci. 2022;23(17):10060.

Malki MI. Medicine. 2022;101(27):e29401.

Carlsen E, et al. Hum Reprod. 2003;18(10):2089-92.

Sengupta P, et al. Physiol Res. 2022;71(1):47-54.

Ali MJ, et al. Front Med. 2020. doi:10.3389/fmed.2020.00480.

Jung EJ, et al. Reprod Toxicol. 2022;114:1-6.

Carp-Veliscu A, et al. Int J Environ Res Public Health. 2022;19:984.

Sharp GC, et al. Int J Epidemiol. 2022;51(3):691-700.

Ni W, et al. Crit Care. 2020;24:422.

Ozimek N, et al. J Womens Health (Larchmt). 2022. doi:10.1089/jwh.2021.0158.

McMenamin ME, et al. Lancet Infect Dis. 2022;22(10):1435-43.

American Society for Reproductive Medicine. Available online. https://www.asrm.org/news-and-publications/covid-19/covid-19-press-releases-and-announcements/asrm-smfm-acog-issue-joint-statement-medical-experts-continue-to-assert-that-covid-vaccines-do-not-impact-fertility/. Last accessed: 30 December 2022.

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Disclaimer

This article is not medical advice. Patients should seek personal assessment by a licenced specialist. Physicians are recommended to read the full publication(s) as cited in the article before making medical decisions. This article does not supersede nor replace the published article(s).