key: cord-1008435-j7cj8p3n
authors: Safrai, Myriam; Hertzberg, Shmuel; Imbar, Tal; Reubinoff, Benjamin; Dior, Uri; Ben-Meir, Assaf
title: The BNT162b2 mRNA Covid-19 vaccine does not impair sperm parameters
date: 2022-01-31
journal: Reprod Biomed Online
DOI: 10.1016/j.rbmo.2022.01.008
sha: 0c231b507c01b29199da4eac9c3e839fbae7925b
doc_id: 1008435
cord_uid: j7cj8p3n

Research Question We aimed to investigate the effect of the BNT162b2 COVID-19 vaccine on sperm parameters of patients with a normal and abnormal semen analysis. Design We collected data of male patients undergoing in vitro fertilization (IVF) treatment after vaccination completion between February and June 2021 (POST vaccine). For comparison, we reviewed records of the same patients before the vaccination (PRE vaccine) up to January 2017. Azoospermia patients were excluded. Sperm parameters were compared between PRE and POST vaccine groups. Each patient served as self-control. Results Seventy-two patients were included in the study (mean age 38.1±6.7 years), of whom 57 had a normal semen analysis. The mean time between the first vaccine and the POST vaccine sperm analysis was 66.3±44.0 days. The median [IQR] of the sperm parameters before and after the vaccination were: sperm volume before 3.0 [2.0-4.0] and after 3.0 [1.6-3.9] ml, p=0.02; sperm concentration: before 26.5 [14.0-64.7] and after 31.0 [14.2-80.0] 106/ml, p=0.35; and total motile count: before 33.7 [9.0-66.0] and after 29 [6.0-97.5] 106, p=0.96. Sub-group analyses were performed for patients with male infertility and patients with a normal semen analysis. Neither of the sub-groups showed significant changes post-vaccination. Conclusion Sperm parameters showed no significant changes following vaccination among men with a normal and abnormal semen analysis. Therefore, the BNT162b2 vaccine appears not to affect sperm parameters. The preliminary results are reassuring for the entire global population, currently undergoing intense vaccination campaigns against COVID-19.

A novel coronavirus emerged in December 2019 (Zhu et al., 2020) , causing severe acute respiratory syndrome coronavirus 2, termed SARS-CoV-2 or coronavirus disease 2019 . This pandemic illness spread to millions of people worldwide, causing severe disease and widespread death, with devastating medical, economic, and social consequences (Polack et al., 2020) . As a result, there were intense international efforts to rapidly develop a vaccine to eliminate or mitigate the effects of COVID-19. The BNT162b2 vaccine by BioNTech and Pfizer was one of the first vaccines that received emergency used authorization by the United States Food and Drug Administration and was shown to be highly effective in reducing infection rates and rates of severe illness (Dagan et al., 2021) . In a large trial, the two-dose regiment of BNT162b2 was assessed and found to confer 95% protection against SARS-CoV-2 in persons aged 16 and older (Dagan et al., 2021) . The vaccine's safety was assessed using self-reporting of local and systemic adverse events, the use of antipyretic or pain medication, and unsolicited serious adverse events, and a favorable safety profile was confirmed (Polack et al., 2020; Walsh et al., 2020) . Accordingly, mass vaccination campaigns have been carried out globally with the recommendation to vaccinate the entire population from 16 years old upwards (Dagan et al., 2021) .

Amongst the possible non-respiratory influences of COVID-19 is the effect of the virus on male fertility. Indeed, recent evidence suggests a substantial negative effect, as shown by histopathological examinations of autopsied testes post COVID-19 infection showing edema, congestion, inflammation, thinning, and injury of the seminiferous tubules Yang et al., 2020) . Nevertheless, the vaccination pace in many countries is slower than expected, partially due to public fear of possible adverse effects and the potentially negative long-term effect of the vaccine (Lo Re et al., 2021) . Despite no evidence of a negative effect on male or female fertility, as stressed by the Association of Reproductive and Clinical Scientists and the British Fertility Society (Web-1; Iacobucci, 2021), many people are still hesitant to receive the vaccine due to fertility concerns (Diaz et al., 2021) . Hence, this study aimed to investigate the effect of the BNT162b2 COVID-19 vaccine on sperm parameters among men, including men with fertility issues and impaired initial sperm parameters; We hypothesized that the vaccine would not affect sperm quality.

This study was carried out in a large tertiary center. We assessed the impact of the BNT162b2 mRNA Covid-19 Vaccine, a nucleoside-modified RNA vaccine developed by BioNTech and Pfizer. Our medical center is a university hospital with an in vitro fertilization (IVF) unit, which runs an average of 1000 fresh IVF cycles per year. Data was collected from patients in the IVF unit between February 2 and June 21, 2021, after the vaccinations became available for the population aged 16 and older. To isolate the vaccine's effect and avoid confounding, patients with prior infection by COVID-19 were excluded from the study. Patients with azoospermia or who had not completed 2 doses of vaccination were excluded too from our study. Sperm parameters of patients who had received two doses of the BNT162b2 vaccine were collected (POST-vaccine) and compared to the same patient's retrospective data before vaccination (PREvaccine) using the hospital's electronic database. Retrospective data were collected up to January 1, 2017, before vaccination was available and electronic data were available in our system. Only patients with two available full semen analyses before the vaccine were included in the PREvaccine group to ensure accurate pre-vaccine information. To minimize bias, each patient served as self-control before and after vaccination. None of the patients were prescribed medications aiming to improve sperm analyses, during the study time frame.

Data obtained included patient demographics (age), indication for IVF treatment (i.e., women/male factor, unexplained infertility, fertility preservation and need for pre-implantation genetic diagnosis (PGD)), sperm parameters (volume, concentration, and motility), and the time since the first dose of vaccine. The second vaccine dose was given as recommended, 21 days after the first dose (Dagan et al., 2021; Walsh et al., 2020) . Male factor was defined as one or more sperm abnormality (volume, concentration, or motility) as per the WHO criteria (Cooper et al., 2010) in at least 2 available semen analyses performed at least 6 weeks apart. Sperm analyses were performed according to the WHO laboratory manual (WHO, 2010) and was processed and examined by an experienced technician. A small drop of sperm was transferred to the center of a Makler counting chamber (Sefi Medical Instruments, Israel) reusable sperm counting chamber and analyzed under a 400X microscope. This number represented the concentration in millions per mL.

The primary outcome was the difference in sperm parameters between the pre and postvaccination groups. Sub-group analyses were performed for patients with male infertility and patients with normal sperm analysis results undergoing IVF for indications other than male infertility. The vaccination rate among the male population undergoing IVF treatment was also assessed.

Statistical analysis: Patient characteristics are described as proportions for categorical variables, median and interquartile range (IQR). The significance of the differences between the PRE and POST vaccine groups was assessed using the Wilcoxon-Rank Test. To assess the impact of the BNT162b2 vaccine based on the initial sperm parameters, sub-group analyses were performed for patients with male infertility, as well as for patients with a normal semen analysis. A twosided P-value < 0.05 indicated statistical significance. The data were analyzed using Software Package for Statistics and Simulation (IBM SPSS version 25, IBM Corp, Armonk, NY).

Ethics approval: Approval was obtained from our medical center's institutional review board (IRB) [0092-21-HMO]. The requirement for written informed consent was waived by the IRB.

During the study period, 200 men were treated in our IVF unit. Most of them (56%) had completed the two doses of the BNT162b2 vaccine. Almost twenty-five percent (n=49) had a prior history of SARS-CoV-2 infection, while 75 % (n=151) were eligible for vaccination. In this subgroup of men who were eligible for vaccination, 75% (n=111) had completed the two vaccine doses, 2% (n=3) had received only one dose, and 25% (n=37) were not vaccinated for COVID-

A flow chart describing the study's patient inclusion protocol is shown in Figure 1 . The final cohort included a total of 72 men; their demographic data and indications for undergoing IVF are shown in Table 1 . When considering their original sperm parameters; 57 patients had a normal semen analysis, and 23 patients underwent IVF due to male factor issues. Of the latter, 8 were excluded due to azoospermia. The median (IQR) interval between the first vaccine dose and the second sperm analysis (POST vaccine group) was 71.0 (40.5-104.8) days. Table 2 . Except sperm volume, none of the parameters differed significantly after vaccination resulting in a volume of (0.3 (2.0-4.0) ml vs. 3.0 (1.6-3.9), p=0.02), a sperm concertation of (26.5 (14.0-64.7) 10 6 /ml vs. 31.0 (14.2-80.0), p= 0.35) and a TMC of 33.7 (9.0-66.0) 10 6 vs. 29 (6.0-97.5=)10 6 , p=0.96), in the PRE and POST vaccination groups respectively (median (IQR). There were also no significant differences in the sub-group analyses of patients with male infertility and with a normal semen analysis. All the sperm parameters for normospermic patients (n=57) and infertile patients (n=15) were similar in the PRE and POST groups (Table 2 ).

The main finding of our study is that the BNT162b2 vaccine does not affect sperm parameters. This was found to be true both for normospermic males and for those with abnormal sperm.

Two recent studies showed no significant decrease in any sperm parameter following vaccination (Gonzalez et al., 2021; Lifshitz et al., 2021) . Our group of patients, who are already facing fertility challenges, may be especially hesitant to receive the COVID-19 vaccine. Our results are therefore encouraging and may counteract the fears of many to receiving the vaccine. Moreover, given the potential negative effect of COVID-19 infection on male fertility Yang et al., 2020) , vaccination against COVID-19 may even prevent many infertility cases. Of note, while the change in sperm volume between before and after the vaccination was statistically significant, as the median volume has not changed and as total motile sperm count (TMC) did not differ between before and after the vaccination, we believe that this finding is not clinically relevant.

Our study has several limitations. The main one is the retrospective data collection of the sperm parameters of the pre-vaccine group. However, we included only patients with 2 available full semen analyses before the vaccine, allowing for accurate pre-vaccine information. Another limitation of the study is the relatively long interval between the pre and post vaccination semen analyses. While each patient had 2 semen analyses prior to the vaccination, it is still possible that semen characteristics have changed over time. Additionally, the methodology where each patient served as his own self-control strengthens the results and provides reliable answers to the questions raised regarding the effects of BNT162b2 vaccination on sperm parameters. As spermatogenesis takes approximately 3 months, our study was able to assess only the short-term effect of the vaccine; there is still a possibility of later sequala. Moreover, data regarding pregnancy outcomes were not available. Nevertheless, we believe that our findings will reassure and encourage vaccination among the young population.

The BNT162b2 vaccine was launched only months ago, and worldwide vaccination is still ongoing, with health organizations strongly advocating for the public to receive the vaccine. In our study sample, only 58 % of the men who applied for IVF were vaccinated against SARS-CoV-2. A much lower rate than the national average of 71-85 % for the age group 20-49 years (Web-2), possibly due to concerns of young men regarding adverse effects of the vaccine on their fertility. Furthermore, a recent study has shown that COVID-19 vaccine hesitancy is directly linked to increased internet search queries for side effects on fertility (Diaz et al., 2021) . Therefore, our results of no change in sperm parameters following vaccination among men with normal and abnormal semen analysis can reassure the young male population being vaccinated worldwide that their fears are unfounded.

Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Semen volume ( 

World Health Organization reference values for human semen characteristics * ‡

BNT162b2 mRNA Covid-19 vaccine in a nationwide mass vaccination setting

COVID-19 vaccine hesitancy linked to increased internet search queries for side effects on fertility potential in the initial rollout phase following Emergency Use Authorization

Covid-19 vaccines and fertility

Sperm Parameters Before and After COVID-19 mRNA Vaccination

Covid-19: No evidence that vaccines can affect fertility, says new guidance

Does mRNA SARS-CoV-2 vaccine detrimentally affect male fertility, as reflected by semen analysis?

Global covid-19 vaccine rollout and safety surveillance-how to keep pace

Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine

Safety and immunogenicity of two RNA-based Covid-19 vaccine candidates

WHO laboratory manual for the examination and processing of human semen

Pathological Findings in the Testes of COVID-19 Patients: Clinical Implications

A Novel Coronavirus from Patients with Pneumonia in China