Fertility considerations: The COVID-19 disease may have a more negative impact than the COVID-19 vaccine, especially among men
There is no current credible evidence to support that COVID-19 vaccines may impact fertility, however, there may be a negative impact of COVID-19 disease on male fertility.
Rachel E. Watsona, Taylor B. Nelson, D.O.b, Albert L. Hsu, M.D.c
- a University of Missouri School of Medicine Class of 2021; Columbia, Missouri; USA
- b Division of Infectious Diseases; Department of Medicine, University of Missouri-Columbia School of Medicine; Columbia, Missouri; USA.
- c Reproductive Medicine and Fertility Center, Department of Obstetrics, Gynecology and Women’s Health, University of Missouri-Columbia School of Medicine; Columbia, Missouri; USA.
The COVID-19 pandemic has manifested as twin public health and economic crises. With hundreds of millions of cases and millions of fatalities worldwide, the SARS-CoV-2 virus has drastically impacted lives across the globe. In December 2020, Pfizer and Moderna published encouraging results about their SARS-CoV-2 vaccines with 95% and 94.1% efficacy, respectively (1, 2). In February 2021, the US Food and Drug Administration (FDA) issued emergency use authorization for the Janssen (Johnson & Johnson) SARS-CoV-2 vaccine, with published results indicating 66% efficacy for a single-dose regimen (3). Unfortunately, vaccine distribution has been complicated. Many factors have become barriers to the thoughtful, orderly, and equitable distribution and administration of the COVID-19 vaccines, including limited and inconsistent vaccine supply, logistical hurdles in accessing underserved communities, and significant vaccine hesitancy and skepticism. Uniquely, public concerns on the alleged negative impact of the COVID-19 vaccines on female fertility have been particularly prominent on social media and other platforms.
Negative opinions about vaccines and immunizations certainly did not originate with the COVID-19 vaccines. The anti-vaccine movement is thriving and vocal online, with 31 million people following anti-vaccine groups on Facebook and 17 million people subscribing on YouTube (4). Vaccine misinformation and disinformation is often released on social media platforms, resulting in a frenzy of mistrust (5). Misinformation concerning the COVID-19 vaccine in the United States and other countries has resulted in decreased intention to receive the COVID-19 vaccine over time.
Misinformation/Disinformation: Alleged link between COVID-19 vaccine and infertility
Misinformation on the impact of the COVID-19 vaccine on female fertility appears to have originated on 1 December 2020, when Dr. Michael Yeadon, a physician and former chief scientist for allergy and respiratory therapy at Pfizer, and Dr. Med. Wolfgang Wodrag, a pulmonologist, filed a petition with the European Medicines Agency, calling for a halt in SARS-CoV-2 vaccine studies due to safety concerns, as well as concerns for female infertility (6). They stated that the vaccine could result in female infertility by inducing an autoimmune reaction against the syncytin-1 protein, which is involved in placenta formation. One article entitled “Head of Pfizer Research: Covid Vaccine is Female Sterilization” was shared thousands of times across various social media platforms (7). Despite efforts on the part of those social media platforms to remove or educate consumers on this disinformation, the widespread dissemination of this article, in conjunction with pre-existing negative opinions and fears about vaccines, have cemented this misinformation in the minds of many.
Both the Pfizer (BNT162b2) and Moderna (mRNA 1273) SARS-CoV-2 vaccines are messenger RNA (mRNA) vaccines (1,2), a novel vaccine platform using new technology. Such mRNA vaccines have been studied for many years in both infectious diseases and oncologic settings, but they have been implemented on a large scale for the first time during this pandemic. The Janssen vaccine is a recombinant adenovirus vector vaccine (3). Through different mechanisms, these three COVID-19 vaccines induce the body to generate antibodies against the spike protein of the SARS-CoV-2 virus. The SARS-CoV-2 spike (S) glycoprotein consists of 1273 amino acids, including two subunits (N-terminal S1 and C-terminal S2). The S1 subunit contains a receptor-binding domain (RBD) which facilitates SARS-CoV-2 viral binding to ACE-2 receptors; this RBD is the main target for neutralizing antibodies to prevent viral attachment (8).
Once an mRNA vaccine is administered, mRNA is delivered, coated in a lipid nanoparticle, to the cytoplasm of host cells. RNA is translated into the target protein, in this case the SARS-CoV-2 spike glycoprotein, which then promotes an immune response with neutralizing antibodies as well as cellular immunity. mRNA contained in the biodegradable lipid nanoparticle vector remains in the cytoplasm of cells where it degenerates quickly; it does not enter the nucleus and does not interact with or integrate into the recipient’s genome (9). This particular S glycoprotein is unique to SARS-CoV-2 and only a small portion of that protein is encoded by the mRNA vaccines. No other elements required for formation of a complete SARS-CoV-2 virion are present, and as such the vaccines induce immunity with no risk of SARS-CoV-2 infection (10).
The Janssen COVID-19 vaccine (Ad26.COV2.S) is a recombinant, replication-incompetent adenovirus vector vaccine, using technology that has been studied since the 1970s and utilized in vaccines for other illnesses including Ebola, Zika, influenza, and malaria (11). The DNA of inactivated adenovirus 26 is modified by incorporating the gene for the SARS-CoV-2 spike protein; when this vaccine is administered, the modified adenovirus enters the body’s cells to release its viral DNA. The adenovirus itself is inactivated and cannot replicate to cause illness, but the presence of spike protein DNA induces the recipient’s immune system to produce antibodies as well as induce cellular immunity against SARS-CoV-2 spike protein (12). Drs. Yeadon and Wodrag raised concern about the apparent homology between this viral spike glycoprotein and syncytin-1, a cell-cell fusion protein which is critical for placental development; they further allege that antibodies against the COVID-19 spike glycoprotein could cross-react with syncytin-1, potentially leading to anti-placental antibodies and female infertility. However, the SARS-CoV-2 spike protein and syncytin-1 protein actually have no significant sequence homology, and Dr. Yeadon later clarified that his claim was based on a tiny and limited sequence of five amino acids, four of which are reportedly shared between the 538-amino acid syncytin-1 protein and the 1273-amino acid SARS-CoV-2 spike protein (13).
No evidence for any effects on fertility with vaccine administration have been reported from Pfizer, Moderna, or Janssen (1,2,3,14). At this time, there is no long-term data regarding the COVID-19 vaccines, and so it is essential to educate the public that there is no current evidence, nor any valid theories to suggest any credible risk of male or female infertility with COVID-19 vaccine administration. The American Society for Reproductive Medicine (ASRM) also specifically states that the mRNA vaccines “are not thought to cause an increased risk of infertility, first or second trimester loss, stillbirth, or congenital anomalies (15).” The CDC also states that “there is no evidence suggesting that fertility problems are a side effect of ANY vaccine (16). Several clinical trials are now underway to assess the efficacy and side effects of the COVID-19 vaccines on women who are pregnant or breastfeeding; data on fertility impacts will likely take months and years to emerge.
Potential Impact of COVID-19 Disease on Male Reproductive Health and Fertility
In contrast, there may be a negative impact of COVID-19 disease on testicular function, sperm production, and male fertility. We performed a systematic review of 3 large databases (PubMed, Scopus, CINAHL) on “COVID-19 vaccine and fertility” and “COVID-19 disease and infertility” with 185 unique article abstracts found. No evidence of any connection between COVID-19 vaccines and male infertility was found, but there were 50 reviews, 17 commentaries/letters to editors, and 9 original articles on how COVID-19 disease could possibly impact male fertility.
As noted above, the angiotensin-converting enzyme 2 (ACE-2) is a receptor that the SARS-CoV-2 spike protein utilizes to enter host cells, and ACE-2 has particularly high expression in spermatogonia and Leydig and Sertoli cells, and low expression in early spermatocytes, late spermatocytes, and spermatids. ACE-2-positive spermatogonia cells express genes that are important for virus reproduction and transmission, which suggests that SARS-CoV-2 infection may negatively impact spermatogenesis (17). Several studies have also sought to evaluate the presence of SARS-CoV-2 in semen following COVID-19 infection (18-22). Several studies have evaluated semen samples from men with current or past COVID-19 infections (18-20); one review noted the presence of SARS-CoV-2 virus in six out of a total of 160 semen samples (4 from men in the acute phase of the infection, 2 from men in the recovery phase) (19), while Li et al. identified the virus in 6/38 participants (20). Achua et al. found that 3/6 postmortem testicular samples had abnormal spermatogenesis; this study also showed a direct association between the level of ACE2 and impaired spermatogenesis (21). One systematic review noted “SARS-CoV-2 RNA in 98% (293/299) of seminal fluid samples, 16/17 testicular biopsies, and all 89 prostatic fluid samples (22).” There are also numerous reports of male COVID-19 patients with testicular pain/discomfort, orchitis, and/or epididymitis (18).
Other studies suggest that disruption of the hypothalamic-pituitary-testicular axis, oxidative stress, and hypogonadism in men may occur after COVID-19 infection. SARS-CoV-2 has been identified in brain and glial cells, and neurons also express ACE-2 receptors, indicating that they may be viral targets. This raises the concern that COVID-19 might negatively impact fertility through disruption of the hypothalamic-pituitary-gonadal axis and thereby alter hormone levels necessary for normal sperm production (23-25). Li et al. performed autopsies on testicular and epididymal specimens in patients with COVID-19 and found interstitial edema, congestion, and red blood cell exudation, thinning of seminiferous tubules, increased apoptosis, and increased concentrations of CD3+ and CD68+ (23). Others have found that semen from COVID-19 patients showed oligozoospermia (39.1%) and increased leukocytes (60.9%), and theorized that this could be caused by an immune response within the testes and autoimmune orchitis (24). Oxidative stress has also been theorized as a potential mechanism for male infertility due to COVID-19. SARS-CoV-2 may activate inflammatory pathways to induced oxidative stress, which may alter sperm function and morphology, causing apoptosis of spermatozoa (25). Achua et al (21) found COVID-19 in postmortem testicular autopsies; one testicular biopsy of a living male patient who had COVID-19 showed “interstitial macrophage and leukocyte infiltration,” as well as an association between increased ACE-2 levels and impaired spermatogenesis. Studies have also evaluated the impact of COVID-19 on male sex hormones. One found that follicle stimulating hormone: luteinizing hormone (LH) and testosterone (T): LH ratios were significantly decreased in the COVID-19 group compared to healthy controls, while another found decreases in T and increases in LH (18). It is unclear the impact that these changes in hormone ratios may have on male fertility, and further research is ongoing, to fully understand the impact of COVID-19 disease and the COVID-19 vaccines on male fertility. Similar to the ASRM statement on female fertility and the COVID-19 vaccines above, the Society for Male Reproduction and Urology (SMRU) and the Society for the Study of Male Reproduction (SSMR) have similarly issued a joint statement that “COVID-19 vaccines should be offered to men desiring fertility, similar to men not desiring fertility, when they meet criteria for vaccination.” (26)
Extensive research has shown that many therapeutics (hydroxychloroquine, ivermectin, azithyromycin, tocilizumab and other interleukin-6 inhibitors, bamlanivumab and other monoclonal antibodies, and convalescent plasma, among others) that have been studied for severe COVID-19 disease are variable in their efficacy, at best. Indeed, it is likely that we will emerge from the COVID-19 pandemic by way of successful mass vaccinations to achieve herd immunity, rather than through effective anti-viral therapy for severe disease. As we have previously published, “misinformation is a powerfully destructive force in this era of global communication, when one false idea can spread instantly to many vulnerable ears (27).” This concept remains critically important, and clinicians should be involved in combating misinformation by educating about known vaccine side effects, including providing reassurance about the lack of any substantive evidence or theories for infertility associated with COVID-19 vaccines. It is also important to educate about the limited evidence for impaired male reproductive health and fertility from COVID-19 infection.
Throughout the course of this pandemic, the limits of both our technology and our scientific knowledge have required us as healthcare providers to remain humble and transparent. As readers of this article are likely aware, infertility is defined as the inability to conceive after 12 months of regular, unprotected heterosexual intercourse. By this definition, the SARS-CoV-2 virus simply hasn’t been around long enough to give us sufficient information about its possible impacts on male and female infertility. Of note, one pre-COVID study showed evidence of an increased odds of preterm birth and pregnancy loss when mothers or fathers received intensive care during the preconception period (28). Human reproduction is extremely complex, and the potential systemic and downstream effects of COVID-19 disease on male and female infertility remains to be elucidated. Aggregating the myriad allegations of infertility associated with the COVID-19 pandemic, the best current evidence suggests that men should receive the COVID-19 vaccine to prevent the potential risks to male reproductive health and male fertility with actual COVID-19 disease; further, there is no evidence and no credible theoretical underpinnings to link the COVID-19 vaccine with female infertility.
- Polack FP, Thomas SJ, Kitchin N, et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 2020;383(27):2603-2615.
- Baden LR, El Sahly HM, Essink B, et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med. 2021;384(5):403-416.
- Oliver SE, Gargano JW, Scobie H, et al. The Advisory Committee on Immunization Practices’ Interim Recommendation for Use of Janssen COVID-19 Vaccine - United States, February 2021. MMWR Morb Mortal WWkly Rep 2021;10:329-332. DOI: http://dx.doi.org/10.15585/mmwar.mm7009e4
- Burki T. The online anti-vaccine movement in the age of COVID-19. The Lancet Digital Health. https://doi.org/10.1016/S2589-7500(20)30227-2. Published October 1, 2020. Accessed February 4, 2021.
- Vaccine Misinformation Guide (Dec 2020) at https://vaccinemisinformation.guide
- “Head of Pfizer Research: Covid Vaccine is Female Sterilization.” December 6, 2020. At http://archive.is/q5ENl
- “Covid-19 vaccine not shown to cause female sterilization.” December 9, 2020. At https://factcheck.afp.com/covid-19-vaccine-not-shown-cause-female-sterilization
- GA Poland, et al. SARS_CoV-2 immunity: review and applications to phase 3 vaccine candidates. Published online 20 Oct 2020. The Lancet
- Park KS, Sun X, Aikins ME, Moon JJ. Non-viral COVID-19 vaccine delivery systems. Adv Drug Deliv Rev. 2021;169:137-151.
- Maruggi G, Zhang C, Li J, Ulmer JB, Yu D. mRNA as a Transformative Technology for Vaccine Development to Control Infectious Diseases. Mol Ther. 2019;27(4):757-772.
- “Understanding and Explaining Viral Vector COVID-19 vaccines,” by CDC.gov, at <https://www.cdc.gov/vaccines/covid-19/hcp/viral-vector-vaccine-basics.html>.
- Livingston EH, Malani PN, Creech CB. The Johnson & Johnson Vaccine for COVID-19. Published online March 01, 2021. doi:10.1001/jama.2021.2927
- “There is no risk of infertility from COVID-19 vaccines due to cross reactivity with placenta proteins, as SARS-CoV-2 and placenta proteins are different.” December 10, 2020. at https://healthfeedback.org/claimreview/there-is-no-risk-of-or-infertility-from-covid-19-vaccines-as-sars-cov-2-proteins-and-placenta-proteins-are-different/
- US Food and Drug Administration (FDA). Fact sheet for healthcare providers administering vaccine: Emergency Use Authorization (EUA) of the Janssen COVID-19 vaccine to prevent coronavirus disease 2019 (COVID-19). https://www.fda.gov/media/146304/download. Updated February 27, 2021.
- “ASRM Issues Statement on COVID-19 Vaccines, Joins Other OB/GYN Groups on Community-Wide Statement.” December 16, 2020 by the American Society for Reproductive Medicine at https://www.asrm.org/news-and-publications/news-and-research/press-releases-and-bulletins/asrm-issues-statement-on-covid-19-vaccines-joins-other-obgyn-groups-on-community-wide-statement/
- Myths and Facts about COVID-19 vaccines by CDC.gov, at <https://www.cdc.gov/coronavirus/2019-ncov/vaccines/facts.html>.
- Wang Z, Xu X. scRNA-seq Profiling of Human Testes Reveals the Presence of the ACE2 Receptor, A Target for SARS-CoV-2 Infection in Spermatogonia, Leydig and Sertoli Cells. Cells. 2020;9(4). doi:3390/cells9040920
- Madjunkov M, Dviri M, Librach C. A comprehensive review of the impact of COVID-19 on human reproductive biology, assisted reproduction care and pregnancy: a Canadian perspective. J Ovarian Res. 2020;13(1):140.
- Gonzalez DC, Khodamoradi K, Pai R, et al. A Systematic Review on the Investigation of SARS-CoV-2 in Semen. Res Rep Urol. 2020;12:615-621.
- 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.
- Achua JK, Chu KY, Ibrahim E, et al. Histopathology and Ultrastructural Findings of Fatal COVID-19 Infections on Testis. World J Mens Health. 2021;39(1):65-74.
- Tur-Kaspa I, Tur-Kaspa T, Hildebrand G, Cohen D. COVID-19 May Affect Male Fertility but is Not Sexually Transmitted: A Systematic Review. Fertil Steril Rev. 2021 Feb 3. doi: 10.1016/j.xfnr.2021.01.002. Epub ahead of print. PMID: 33558864; PMCID: PMC7857030.
- Li H, Xiao X, Zhang J, et al. Impaired spermatogenesis in COVID-19 patients. EClinicalMedicine. 2020;28:100604.
- Vishvkarma R, Rajender S. Could SARS-CoV-2 affect male fertility? Andrologia. 2020;52(9):e13712.
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- “Joint Statement Regarding COVID-19 Vaccine in Men Desiring Fertility from the Society for Male Reproduction and Urology (SMRU) and the Society for the Study of Male Reproduction (SSMR)” at: https://www.asrm.org/news-and-publications/covid-19/statements/joint-statement-regarding-covid-19-vaccine-in-men-desiring-fertility-from-the-society-for-male-reproduction-and-urology-smru-and-the-society-for-the-study-of-male-reproduction-ssmr/
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- Kasman AM, Bhambhvani HP, Li S, et al. Reproductive sequelae of parental severe illness before the pandemic: implications for the COVID-19 pandemic. Fertil Steril. 2020;114(6):1242-1249.