Ovarian function after COVID-19: long-term effects and vaccine safety in ART patients.

Purpose This study aimed to evaluate the long-term impact of mild COVID-19 infection and COVID-19 vaccination on ovarian function in patients undergoing assisted reproductive technology (ART). Specifically, we assessed ovarian outcomes between 9 and 18 months post-infection and investigated the effects of COVID-19 vaccines (inactivated virus and adenovirus) on reproductive parameters.

The study included two objectives: (a) examining ovarian function in post-COVID-19 patients (9–18 months post-infection) compared to a control group and (b) comparing reproductive outcomes in vaccinated versus unvaccinated patients. According to the study objectives, ART patients were divided into the following groups: a control group (n = 30), a post-COVID-19 group (n = 55), an unvaccinated group (n = 70), and a vaccinated group (n = 55). Findings revealed a reduction in the number of retrieved and mature oocytes in patients over 36 years in the post-COVID-19 group. Lower IL-1β levels were found in follicular fluid (FF) of post-COVID-19 patients, while VEGF levels were reestablished between 9 and 18 months post-infection. Although cell migration was reduced in endothelial cells incubated with post-COVID-19 FF, angiogenic factor levels and DNA integrity remained stable. No significant differences in retrieved or mature oocytes were observed between vaccinated and unvaccinated patients.

VEGF levels and DNA integrity in FF from post-COVID-19 patients were normalized between 9 and 18 months post-infection. Additionally, COVID-19 vaccination did not negatively impact ovarian response in ART patients, supporting vaccine safety in reproductive contexts. Similar content being viewed by others Data availability Anonymized raw data will be provided upon request.

Strauss SA, Seo C, Carrier M, et al. From cellular function to global impact: the vascular perspective on COVID-19. Can J Surg. 2021;64:E289–97. Cao X. COVID-19: immunopathology and its implications for therapy. Nat Rev Immunol. 2020;20:269–70. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan China. Lancet. 2020;395:497–506. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181:271-280.e8. Reis FM, Bouissou DR, Pereira VM, et al. Angiotensin-(1–7), its receptor Mas, and the angiotensin-converting enzyme type 2 are expressed in the human ovary. Fertil Steril. 2011;95:176–81. Jing Y, Run-Qian L, Hao-Ran W, et al. Potential influence of COVID-19/ACE2 on the female reproductive system. Mol Hum Reprod. 2020;26:367–73. Mauvais-Jarvis F, Klein SL, Levin ER. Estradiol, progesterone, immunomodulation, and COVID-19 outcomes. Endocrinology. 2020;161:bqaa127. Herrero Y, Pascuali N, Velázquez C, et al. SARS-CoV-2 infection negatively affects ovarian function in ART patients. Biochim Biophys Acta Mol Basis Dis. 2022;1868:166295. Cherenack EM, Salazar AS, Nogueira NF, et al. Infection with SARS-CoV-2 is associated with menstrual irregularities among women of reproductive age. PLoS ONE. 2022;17:e0276131. Maham S, Yoon M-S. Clinical spectrum of long COVID: effects on female reproductive health. Viruses. 2024;16:1142. Zhang S, Wu Y, Mprah R, et al. COVID-19 and persistent symptoms: implications for polycystic ovary syndrome and its management. Front Endocrinol (Lausanne). 2024;15:1434331. Bianchi L, Gagliardi A, Landi C, et al. Protein pathways working in human follicular fluid: the future for tailored IVF? Expert Rev Mol Med. 2016;18:e9. Chen F, Spiessens C, D’Hooghe T, et al. Follicular fluid biomarkers for human in vitro fertilization outcome: proof of principle. Proteome Sci. 2016;14:17. Wu Y-T, Wu Y, Zhang J-Y, et al. Preliminary proteomic analysis on the alterations in follicular fluid proteins from women undergoing natural cycles or controlled ovarian hyperstimulation. J Assist Reprod Genet. 2015;32:417–27. Revelli A, Delle Piane L, Casano S, et al. Follicular fluid content and oocyte quality: from single biochemical markers to metabolomics. Reprod Biol Endocrinol. 2009;7:40. Guzmán A, Hernández-Coronado CG, Gutiérrez CG, et al. The vascular endothelial growth factor (VEGF) system as a key regulator of ovarian follicle angiogenesis and growth. Mol Reprod Dev. 2023;90:201–17. Abramovich D, Parborell F, Tesone M. Effect of a vascular endothelial growth factor (VEGF) inhibitory treatment on the folliculogenesis and ovarian apoptosis in gonadotropin-treated prepubertal rats. Biol Reprod. 2006;75:434–41. Parborell F, Abramovich D, Tesone M. Intrabursal administration of the antiangiopoietin 1 antibody produces a delay in rat follicular development associated with an increase in ovarian apoptosis mediated by changes in the expression of BCL2 related genes. Biol Reprod. 2008;78:506–13. Maisonpierre PC, Suri C, Jones PF, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science. 1997;277:55–60. Milostić-Srb A, Srb N, Talapko J, et al. The effect of COVID-19 and COVID-19 vaccination on assisted human reproduction outcomes: a systematic review and meta-analysis. Diseases. 2024;12:201. Ssentongo P, Ssentongo AE, Voleti N, et al. SARS-CoV-2 vaccine effectiveness against infection, symptomatic and severe COVID-19: a systematic review and meta-analysis. BMC Infect Dis. 2022;22:439. Zaçe D, La Gatta E, Petrella L, et al. The impact of COVID-19 vaccines on fertility-a systematic review and meta-analysis. Vaccine. 2022;40:6023–34. Aharon D, Lederman M, Ghofranian A, et al. In vitro fertilization and early pregnancy outcomes after coronavirus disease 2019 (COVID-19) vaccination. Obstet Gynecol. 2022;139:490–7. Aizer A, Noach-Hirsh M, Dratviman-Storobinsky O, et al. The effect of coronavirus disease 2019 immunity on frozen-thawed embryo transfer cycles outcome. Fertil Steril. 2022;117:974–9. Morris RS. SARS-CoV-2 spike protein seropositivity from vaccination or infection does not cause sterility. F S Rep. 2021;2:253–5. Odeh-Natour R, Shapira M, Estrada D, et al. Does mRNA SARS-CoV-2 vaccine in the follicular fluid impact follicle and oocyte performance in IVF treatments? Am J Reprod Immunol. 2022;87:e13530. Orvieto R, Noach-Hirsh M, Segev-Zahav A, et al. Does mRNA SARS-CoV-2 vaccine influence patients’ performance during IVF-ET cycle? Reprod Biol Endocrinol. 2021;19:69. Male V. Menstruation and COVID-19 vaccination. BMJ. 2022;376:o142. Rodríguez Quejada L, Toro Wills MF, Martínez-Ávila MC, et al. Menstrual cycle disturbances after COVID-19 vaccination. Womens Health (Lond). 2022;18:17455057221109376. Zhu S, Luan C, Zhang S, et al. Effect of SARS-CoV-2 infection and vaccine on ovarian reserve: a systematic review. Eur J Obstet Gynecol Reprod Biol. 2024;292:63–70. Albamonte M, Azás Y, González C, et al. Transient changes to the menstrual period in women from Argentina following COVID-19 vaccination. Mathews J Gynecol Obstet. 2022;6. https://doi.org/10.30654/MJGO.10019. Gori S, Soczewski E, Fernández L, et al. Decidualization process induces maternal monocytes to tolerogenic IL-10-producing dendritic cells (DC-10). Front Immunol. 2020;11:1571. Edgell CJ, McDonald CC, Graham JB. Permanent cell line expressing human factor VIII-related antigen established by hybridization. Proc Natl Acad Sci U S A. 1983;80:3734–7. Scotti L, Abramovich D, Pascuali N, et al. Involvement of the ANGPTs/Tie-2 system in ovarian hyperstimulation syndrome (OHSS). Mol Cell Endocrinol. 2013;365:223–30. Scotti L, Parborell F, Irusta G, et al. Platelet-derived growth factor BB and DD and angiopoietin1 are altered in follicular fluid from polycystic ovary syndrome patients. Mol Reprod Dev. 2014;81:748–56. Scotti L, Abramovich D, Pascuali N, et al. Inhibition of angiopoietin-1 (ANGPT1) affects vascular integrity in ovarian hyperstimulation syndrome (OHSS). Reprod Fertil Dev. 2016;28:690–9. Scotti L, Di Pietro M, Pascuali N, et al. Sphingosine-1-phosphate restores endothelial barrier integrity in ovarian hyperstimulation syndrome. Mol Hum Reprod. 2016;22:852–66. Rogakou EP, Pilch DR, Orr AH, et al. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem. 1998;273:5858–68. Sedelnikova OA, Horikawa I, Zimonjic DB, et al. Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks. Nat Cell Biol. 2004;6:168–70. Dutta S, Sengupta P. SARS-CoV-2 and male infertility: possible multifaceted pathology. Reprod Sci. 2021;28:23–6. Stanley KE, Thomas E, Leaver M, et al. Coronavirus disease-19 and fertility: viral host entry protein expression in male and female reproductive tissues. Fertil Steril. 2020;114:33–43. Bentov Y, Beharier O, Moav-Zafrir A, et al. Ovarian follicular function is not altered by SARS-CoV-2 infection or BNT162b2 mRNA COVID-19 vaccination. Hum Reprod. 2021;36:2506–13. Bowman CJ, Bouressam M, Campion SN, et al. Lack of effects on female fertility and prenatal and postnatal offspring development in rats with BNT162b2, a mRNA-based COVID-19 vaccine. Reprod Toxicol. 2021;103:28–35. BioNTech SE. A phase 3 study to evaluate the safety, tolerability, and immunogenicity of multiple production lots and dose levels of BNT162b2 RNA-based COVID-19 vaccines against COVID-19 in healthy participants. trials.gov. Noha M Hammad, MD, Principal investigator, Zagazig University. Safety and immunogenicity of Oxford AstraZeneca vaccine against COVID-19 infection. Strategies for combining the first component of Sputnik V with other adenoviral or mrna-based vaccines. Funding This research received financing from Ferring Covid-19 Investigational Grant (2020); National Agency for Scientific and Technological Promotion (ANPCyT) (PICT 1603–2017); Ministry of Science, Technology, and Innovation; and the Baron and Williams Foundations, Argentina. Author information Authors and Affiliations Contributions Conceptualization: D.A., F.P.; data curation: Y.H., L.S., C.V., V.H., I.Z., M.L., F.V., F.N., and G.M.; formal analysis: Y.H., L.S., C.V., V.H., F.V., M.L., and G.M.; investigation: Y.H., L.S., and V.H.; methodology: K.Z., A.K., P.W., and M.Z.; project administration: D.A. and F.P.; supervision: N.P.; validation: K.Z., A.K., and M.K.; writing—original draft: Y.H., L.S., and F.P.; writing—review and editing: Y.H., L.S., N.P., D.A., and F.P. All authors have read and approved the final manuscript. Corresponding author Ethics declarations Ethics approval and consent to participate This study was approved by the Ethics Committee of Dr. Enrique T. Segura (IByME-CONICET) (protocol no. 2850). A written informed consent was obtained from all patients. Conflict of interest The authors declare no competing interests. Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Herrero, Y., Velazquez, C., Pascuali, N. et al. Ovarian function after COVID-19: long-term effects and vaccine safety in ART patients. J Assist Reprod Genet 42, 563–576 (2025). https://doi.org/10.1007/s10815-025-03403-x Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s10815-025-03403-x