Sperm Parameters Before and After COVID-19 mRNA Vaccination | Urology | JAMA | JAMA Network
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Figure.  Waterfall Plot Showing Changes in Total Motile Sperm Count Parameters Within Participants Before and After COVID-19 Vaccination
Waterfall Plot Showing Changes in Total Motile Sperm Count Parameters Within Participants Before and After COVID-19 Vaccination

Each bar represents an individual participant.

Table.  Change in Semen Analysis Parameters Before and After COVID-19 Vaccination
Change in Semen Analysis Parameters Before and After COVID-19 Vaccination
1.
Szilagyi  PGTK, Thomas  K, Shah  MD,  et al.  National trends in the US public’s likelihood of getting a COVID-19 vaccine: April 1 to December 8, 2020.   JAMA. 2020;325(4):396-398. doi:10.1001/jama.2020.26419PubMedGoogle ScholarCrossref
2.
Berry  SD, Johnson  KS, Myles  L,  et al.  Lessons learned from frontline skilled nursing facility staff regarding COVID-19 vaccine hesitancy.   J Am Geriatr Soc. 2021;69(5):1140-1146. doi:10.1111/jgs.17136PubMedGoogle ScholarCrossref
3.
Best  JC, Kuchakulla  M, Khodamoradi  K,  et al.  Evaluation of SARS-CoV-2 in human semen and effect on total sperm number: a prospective observational study.   World J Mens Health. 2021;39(e12).PubMedGoogle Scholar
4.
Cooper  TG, Noonan  E, von Eckardstein  S,  et al.  World Health Organization reference values for human semen characteristics.   Hum Reprod Update. 2010;16(3):231-245. doi:10.1093/humupd/dmp048PubMedGoogle ScholarCrossref
5.
Keel  BA.  Within- and between-subject variation in semen parameters in infertile men and normal semen donors.   Fertil Steril. 2006;85(1):128-134. doi:10.1016/j.fertnstert.2005.06.048PubMedGoogle ScholarCrossref
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    4 Comments for this article
    EXPAND ALL
    What is the Value?
    Sergio Stone, M.D. | Retired. Former university professor
    Dear Sir/Madam: What is the value of publishing a "research paper" with predictable results? A one-sample baseline and a one-sample after vaccination sperm analysis could not have shown anything.
    CONFLICT OF INTEREST: None Reported
    "Not The Live Virus"
    Csaba Szinyei, Dr. rer. nat. | University of Muenster
    A virus is never a living organism. Please correct the text. Thank you!
    CONFLICT OF INTEREST: None Reported
    Questions About Methodology
    Serafeim Louk, PhD in Bioengineering | University of Geneva
    While I find this article insightful, I have some questions about the methodology.

    In the Methods section it is mentioned that “Wilcoxon rank sum test was used to compare pre- and postvaccination semen parameters”.

    The observations are from the same sample (paired), pre & post vaccination and thus, the Wilcoxon signed-rank test should have been used instead of the Wilcoxon rank sum test which is appropriate for independent observations. If this is the case, then this is extremely important as a) the statistical test is not correct, b) the p-values depend on the test, and c) all conclusions
    depend on the (wrongly estimated) p-values.

    Was the statistical test a Wilcoxon signed-rank test (paired samples) or a Wilcoxon rank sum test (for independent samples), as stated in the paper?

    CONFLICT OF INTEREST: None Reported
    READ MORE
    Study Design Does Not Consider Seasonality
    Vadim Zipunnikov, PhD | Johns Hopkins University
    The study hints an improvement in sperm quality after mRNA vaccination. However, the study didn't account for the seasonality in sperm quality which has been reported in the literature - particularly, in the context of this study, lower quality in winter, higher quality in spring. The baseline in the study was done "between December 17, 2020, and January 12, 2021. The study ended on April 24, 2021". So the baseline was done in the middle of winter, and the follow-up has been collected during Spring. I think having a control (unvaccinated) group would allow to estimate and account for the seasonal effect.
    CONFLICT OF INTEREST: None Reported
    READ MORE
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    Research Letter
    June 17, 2021

    Sperm Parameters Before and After COVID-19 mRNA Vaccination

    Author Affiliations
    • 1Department of Urology, University of Miami, Miami, Florida
    JAMA. 2021;326(3):273-274. doi:10.1001/jama.2021.9976

    Two mRNA vaccines, BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna), received Emergency Use Authorization from the US Food and Drug Administration. Despite high efficacy and few adverse events found in clinical trials, only 56% of individuals in the US reported wanting to receive the vaccine.1 One of the reasons for vaccine hesitancy is the potential negative effect on fertility.2 Because reproductive toxicity was not evaluated in the clinical trials and SARS-CoV-2 has been associated with decreases in sperm parameters,3 we assessed sperm parameters before and after mRNA vaccine administration.

    Methods

    This single-center prospective study at the University of Miami recruited healthy volunteers aged 18 to 50 years scheduled for mRNA COVID-19 vaccination through flyers posted throughout the university hospital and internal list-serve emails. The University of Miami institutional review board approved the study and written informed consent was obtained from all participants.

    Men were prescreened to ensure they had no underlying fertility issues. Those with COVID-19 symptoms or a positive test result within 90 days were excluded. Participants provided a semen sample after 2 to 7 days of abstinence, prior to receiving the first vaccine dose and approximately 70 days after the second. Semen analyses were performed by trained andrologists per World Health Organization guidelines and included semen volume, sperm concentration, sperm motility, and total motile sperm count (TMSC).4 Individuals with oligospermia (sperm concentration <15 million/mL) were included. After calculating data distribution on normality test, medians and interquartile ranges (IQRs) were reported for all variables. The Wilcoxon rank sum test was used to compare pre- and postvaccination semen parameters. Change in TMSC is presented graphically. Statistical analysis was performed with SPSS version 24 (IBM). A 2-tailed P < .05 was considered statistically significant.

    Results

    Between December 17, 2020, and January 12, 2021, 45 men volunteered (median age, 28 years [IQR, 25-31]); follow-up samples were obtained at a median of 75 days (IQR, 70-86) after the second dose. The study ended on April 24, 2021. Baseline samples were obtained after a median abstinence period of 2.8 days (IQR, 2-3) and follow-up samples after a median of 3 days (IQR, 3-4). Of the 45 men, 21 (46.7%) received BNT162b2 and 24 (53.3%) received mRNA-1273. Baseline median sperm concentration and TMSC were 26 million/mL (IQR, 19.5-34) and 36 million (IQR, 18-51), respectively. After the second vaccine dose, the median sperm concentration significantly increased to 30 million/mL (IQR, 21.5-40.5; P = .02) and the median TMSC to 44 million (IQR, 27.5-98; P = .001). Semen volume and sperm motility also significantly increased (Table).

    Eight of the 45 men were oligospermic before the vaccine (median concentration, 8.5 million/mL [IQR, 5.1-12]). Of these 8, 7 men had increased sperm concentration to normozoospermic range at follow-up (median concentration, 22 million/mL [IQR, 17-25.5]), and 1 man remained oligospermic. No man became azoospermic after the vaccine.

    The waterfall plot shows the within-participant change in TMSC from baseline (range, −22 million to 93 million) for each man (Figure).

    Discussion

    In this study of sperm parameters before and after 2 doses of a COVID-19 mRNA vaccine, there were no significant decreases in any sperm parameter among this small cohort of healthy men. Because the vaccines contain mRNA and not the live virus, it is unlikely that the vaccine would affect sperm parameters. While these results showed statistically significant increases in all sperm parameters, the magnitude of change is within normal individual variation and may be influenced by regression to the mean.5 Additionally, the increase may be due to the increased abstinence time before the second sample. Men with oligospermia did not experience further decline.

    The limitations of the study include the small number of men enrolled; limited generalizability beyond young, healthy men; short follow-up; and lack of a control group. In addition, while semen analysis is the foundation of male fertility evaluation, it is an imperfect predictor of fertility potential. Despite this, the study’s time frame encompasses the full life cycle of sperm.

    Section Editor: Jody W. Zylke, MD, Deputy Editor.
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    Article Information

    Corresponding Author: Ranjith Ramasamy, MD, Department of Urology, University of Miami Miller School of Medicine, 1120 NW 14th St, 15th Fl, Miami, FL 33136 (ramasamy@miami.edu).

    Accepted for Publication: June 1, 2021.

    Published Online: June 17, 2021. doi:10.1001/jama.2021.9976

    Author Contributions: Dr Ramasamy and Mr Gonzalez had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Gonzalez, Nassau, Ory, Ramasamy.

    Acquisition, analysis, or interpretation of data: Gonzalez, Nassau, Khodamoradi, Ibrahim, Blachman-Braun.

    Drafting of the manuscript: Gonzalez, Nassau, Khodamoradi, Blachman-Braun, Ory.

    Critical revision of the manuscript for important intellectual content: Gonzalez, Nassau, Ibrahim, Blachman-Braun, Ory, Ramasamy.

    Statistical analysis: Blachman-Braun, Ramasamy.

    Administrative, technical, or material support: Gonzalez, Nassau, Khodamoradi, Ibrahim.

    Supervision: Nassau, Ibrahim, Ory, Ramasamy.

    Conflict of Interest Disclosures: None reported.

    Additional Contributions: We thank Iakov Efimenko, BSc, Justin Dubin, MD, and Manuel Molina, MD (all with University of Miami Department of Urology), for assistance with recruitment and institutional review board preparation, as well as Ali Tourchi, MD (University of Arkansas for Medical Sciences Department of Urology), for developing the concept of the study. None were compensated for their contributions.

    References
    1.
    Szilagyi  PGTK, Thomas  K, Shah  MD,  et al.  National trends in the US public’s likelihood of getting a COVID-19 vaccine: April 1 to December 8, 2020.   JAMA. 2020;325(4):396-398. doi:10.1001/jama.2020.26419PubMedGoogle ScholarCrossref
    2.
    Berry  SD, Johnson  KS, Myles  L,  et al.  Lessons learned from frontline skilled nursing facility staff regarding COVID-19 vaccine hesitancy.   J Am Geriatr Soc. 2021;69(5):1140-1146. doi:10.1111/jgs.17136PubMedGoogle ScholarCrossref
    3.
    Best  JC, Kuchakulla  M, Khodamoradi  K,  et al.  Evaluation of SARS-CoV-2 in human semen and effect on total sperm number: a prospective observational study.   World J Mens Health. 2021;39(e12).PubMedGoogle Scholar
    4.
    Cooper  TG, Noonan  E, von Eckardstein  S,  et al.  World Health Organization reference values for human semen characteristics.   Hum Reprod Update. 2010;16(3):231-245. doi:10.1093/humupd/dmp048PubMedGoogle ScholarCrossref
    5.
    Keel  BA.  Within- and between-subject variation in semen parameters in infertile men and normal semen donors.   Fertil Steril. 2006;85(1):128-134. doi:10.1016/j.fertnstert.2005.06.048PubMedGoogle ScholarCrossref
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