Reluctance of women and men of fertility age to receive a new vaccine is common, especially due to uncertainty regarding its possible long-term effects and when a new vaccine, such as the mRNA COVID-19, is produced and approved emergently [16]. Yet, lack of knowledge or misleading information may cause uncertainty. Thus, it is essential to evaluate the safety of the COVID-19 mRNA vaccine regarding fertility and sterility.

The current study did not find any differences in fertility treatment or obstetric outcomes between women who were vaccinated and those who were not. In addition, no differences were found among patients before and after receiving the vaccine.

Our results support those of Bentov et al. who showed that neither COVID-19 infection, the BNT162b2 mRNA vaccine, nor the immune response, resulted in any measurable detrimental effects on IVF treatment and outcome parameters [17]. Moreover, Orvieto et al. showed that the mRNA SARS-CoV-2 vaccine did not affect patient performance or ovarian reserve in the immediate, subsequent IVF cycle [13]. Aharon et al. reported similar results [12]. However, it is important to mention that the authors did not conduct serology tests to exclude unvaccinated patients who might have been exposed to the virus.

A study of frozen embryo transfer cycles compared implantation rates among women who were SARS-CoV-2 vaccine seropositive, infection seropositive or seronegative. No difference was found in serum-documented hCG implantation rates or sustained implantation rates among the 3 groups [18]. We also evaluated pregnancy rates between vaccinated and unvaccinated/uninfected patients. Although we found a trend toward a higher pregnancy rate, this was not sustained in multivariant regression.

The lack of negative effects of the vaccine may be related to its biological activity, as it is composed of nucleoside-modified RNA (modRNA) [19] encoding the SARS-CoV-2 full-length spike, modified by two proline mutations. mRNA-based therapy avoids deleterious side effects (which include integration into chromosomes) that limit clinical application of most virus- and DNA-based vectors [20]. Other mRNA-based vaccines that have been investigated primarily with animals, including influenza A virus [21], rabies virus [22], HIV-1 [23], and Ebola virus [24], also showed efficacy of the mRNA vaccines combined with safety data.

The current study found no differences between semen analysis among vaccinated and unvaccinated men. Orvietto et al. also did not find any differences in semen volume, sperm concentration, sperm %, and pre-wash TMC, based on vaccine status [13]. This may be explained by the biological activity of the vaccine, as mentioned above [20]. In addition, spermatogenesis takes 74 days and another 12–21 days to be transported through the epididymis to the ejaculatory ducts [25]. Thus, the specific semen analysis examined may have represented sperm parameters before exposure to the vaccine.

This study supports the approach of major professional associations. The most recent SRM, ACOG and SMFM Joint Statement notes that medical experts continue to assert that COVID-19 vaccines do not affect fertility [26].

When evaluating IgG serology titers, the only effect on fertility outcomes that we found was a positive relation between progesterone levels on the day of triggering and IgG titer. Bentov et al. also found that serum progesterone was lower in the non-exposed group compared to the exposed group [17]. Progesterone is known to be involved in the immune response. Progesterone receptors are expressed in most immune cells, including epithelial cells, macrophages, dendrites, lymphocytes, mast cells, and eosinophils, and help modulate the immune response to pathogens [27]. Moreover, women are known to have higher levels of estrogen and progesterone, which have been shown to modulate a more robust immune response [27]. During the COVID-19 pandemic, this study suggested giving hormone replacement therapy, including estrogen and progesterone, to older patients based on the evidence that sex hormone levels can influence immune system function [28]. Accordingly, it may be suggested that the higher immune response in some women may have triggered activation of progesterone as an immune system modulator. Further studies are needed to evaluate this issue.

The strengths of this study relate to the prospective evaluation of the important question regarding whether mRNA COVID-19 vaccination affects fertility treatments. Evaluation of the serologic titer was also very important. Moreover, we evaluated treatment measures, pregnancy and obstetric outcomes and semen analyses. It was also important that we evaluated the serologic status of each patient to exclude exposed, unvaccinated patients; rendering our analyses more accurate and precise. Therefore, to avoid selection bias, it was essential to exclude these individuals when analyzing the unvaccinated population. However, this study was limited by its relatively small sample size. In addition, it is essential to evaluate long-term pregnancy outcomes, congenital malformations. Future, larger studies will be needed to validate our observations and to maintain longer follow-up of these patients.