Ovarian Follicular Function Is Not Altered by SARS–CoV-2 Infection or BNT162b2 mRNA COVID-19 Vaccination

Y. Bentov; O. Beharier; A. Moav-Zafrir; M. Kabessa; M. Godin; C.S. Greenfield; M. Ketzinel-Gilad; E. Ash Broder; H.E.G. Holzer; D. Wolf; E. Oiknine-Djian; I. Barghouti; D. Goldman-Wohl; S. Yagel; A. Walfisch; A. Hersko Klement


Hum Reprod. 2021;36(9):2506-2513. 

In This Article

Abstract and Introduction


Study Question: Does the immune response to coronavirus disease 2019 (COVID-19) infection or the BNT162b2 mRNA vaccine involve the ovarian follicle, and does it affect its function?

Summary Answer: We were able to demonstrate anti-severe acute respiratory syndrome coronavirus 2 (SARS–CoV-2) IgG in follicular fluid (FF) from both infected and vaccinated IVF patients, with no evidence for compromised follicular function.

What is Known Already: No research data are available yet.

Study Design, Size, Duration: This is a cohort study, composed of 32 consecutive IVF patients, either infected with COVID-19, vaccinated or non-exposed, conducted between 1 February and 10 March 2021 in a single university hospital-based IVF clinic.

Participants/Materials, Setting, Methods: A consecutive sample of female consenting patients undergoing oocyte retrieval was recruited and assigned to one of the three study groups: recovering from confirmed COVID-19 (n = 9); vaccinated (n = 9); and uninfected, non-vaccinated controls (n = 14). Serum and FF samples were taken and analyzed for anti-COVID IgG as well as estrogen, progesterone and heparan sulfate proteoglycan 2 concentration, as well as the number and maturity of aspirated oocytes and day of trigger estrogen and progesterone measurements. Main outcome measures were follicular function, including steroidogenesis, follicular response to the LH/hCG trigger, and oocyte quality biomarkers.

Main Results and the Role of Chance: Both COVID-19 and the vaccine elicited anti-COVID IgG antibodies that were detected in the FF at levels proportional to the IgG serum concentration. No differences between the three groups were detected in any of the surrogate parameters for ovarian follicle quality.

Limitations, Reasons for Caution: This is a small study, comprising a mixed fertile and infertile population, and its conclusions should be supported and validated by larger studies.

Wider Implications of the Findings: This is the first study to examine the impact of SARS–Cov-2 infection and COVID-19 vaccination on ovarian function and these early findings suggest no measurable detrimental effect on function of the ovarian follicle.

Study Funding/Competing Interest(S): The study was funded out of an internal budget. There are no conflicts of interest for any of the authors.

Trial Registration Number: CinicalTrials.gov registry number NCT04822012.


Since emerging in the last months of 2019, over 127 000 000 individuals have contracted confirmed severe acute respiratory syndrome Coronavirus 2 (SARS–CoV-2) infection, and the documented death toll from coronavirus disease 2019 (COVID-19) had reached 2 788 639 individuals globally by the end of March 2021 (CDC, 2021). Jerusalem, the setting of the present study, has presented one of the highest incidence rates of COVID-19 in Israel (Abu Jabal et al., 2021).

Nationwide anti-COVID-19 vaccination began in Israel in December 2020, using the Pfizer—BioNtech vaccine (BNT162b2 mRNA; BioNTech SE, Rhineland-Palatinate, Germany). By the end of March 2021, 5 216 801 and 4 700 957 individuals received the first and second doses of the vaccine, representing 56.1% and 50.55% of Israel's population, respectively. Vaccination for individuals of reproductive age began in January 2021; by the end of March 2021, 72.3% and 61.3% of 20–29 year olds, 77.1% and 67.8% of 30–39 year olds, and 82% and 74.5% of 40–49 year olds had received the first and second doses of the vaccine, respectively: the highest proportions in the world (Abu Jabal et al., 2021).

Both the rapidly spreading disease and the vaccination campaign were associated with concerns regarding potential detrimental effects on future fertility (Jing et al., 2020; Blake Evans et al., 2021; Flynn et al., 2021). There is still a lack of real-world data to assist clinicians in counseling their IVF patients regarding the possible impact of recent recovery from COVID infection, or vaccination against it, on the potential for success of ART. While it has been suggested that COVID-19 might impact fertility, no studies, to the best of our knowledge, have proven a direct gonadal effect of either the disease or the vaccine (Frendo et al., 2003; Chen et al., 2008; Jing et al., 2020; Blake Evans et al., 2021).

We aimed to determine the impact of confirmed COVID-19 disease and/or immunization on human follicular function, by comparing follicular steroidogenesis, response to the LH/hCG trigger, and oocyte quality biomarker (heparan sulfate proteoglycan 2: HSPG2), in the aspirated follicular fluid (FF) of patients undergoing oocyte retrieval.