Female Reproductive Health in SARS-CoV-2 Pandemic Era

Document Type : Review Article


1 Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran

2 Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran

3 Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Iran, Tehran

4 Institute for Regenerative Medicine, Sechenov University, Moscow, Russia

5 Department of Reproductive Biotechnology, Reproductive Biomedicine Research Centre, Royan Institute for Biotechnology, ACECR, Isfahan, Iran


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic struck global health systems with overgrowing demands in many fields of health care; yet, reproductive care, particularly pregnancy care remains a special focus of interest. Pregnancy is a major physiologic change that alters temporarily normal function of many organs, and specifically the immune system. Therefore, pregnant women are more susceptible to respiratory pathogens compared to the others. The current pandemic may have serious consequences on pregnancy whether directly or indirectly. In the present review, direct and indirect possible adverse effects of SARS-CoV-2 infection on female reproductive system by focusing on pregnancy and delivery has been discussed in details. In addition, the pregnancy consequences and whether maternal infection can affect infants were deliberated. The adverse impact of luck down and related psychological complications and obesity on pregnant women were discussed as well. Finally, the effects of SARS-CoV-2 vaccination on maternal health and pregnancy outcome was analyzed.


  1. World Health Organization. Maintaining essential health services: operational guidance for the COVID-19 context. Available from: https://apps.who.int/iris/rest/bitstreams/1279080/retrieve (04 Aug 2021).
  2. Pazos M, Sperling RS, Moran TM, Kraus TA. The influence of pregnancy on systemic immunity. Immunol Res. 2012; 54(1-3): 254-261.
  3. Soma-Pillay P, Nelson-Piercy C, Tolppanen H, Mebazaa A. Physiological changes in pregnancy. Cardiovasc J Afr. 2016; 27(2): 89-94.
  4. Herr D, Bekes I, Wulff C. Local renin-angiotensin system in the reproductive system. Front Endocrinol (Lausanne). 2013; 4: 150.
  5. Cui D, Liu Y, Jiang X, Ding C, Poon LC, Wang H, et al. Single-cell RNA expression profiling of SARS-CoV-2-related ACE2 and TMPRSS2 in human trophectoderm and placenta. Ultrasound Obstet Gynecol. 2021; 57(2): 248-256.
  6. Chadchan SB, Popli P, Maurya VK, Kommagani R. The SARSCoV-2 receptor, angiotensin-converting enzyme 2, is required for human endometrial stromal cell decidualization. Biol Reprod. 2021; 104(2): 336-343.
  7. Yan L, Yang M, Guo H, Yang L, Wu J, Li R, et al. Single-cell RNASeq profiling of human preimplantation embryos and embryonic stem cells. Nat Struct Mol Biol. 2013; 20(9): 1131-1139.
  8. Stanley KE, Thomas E, Leaver M, Wells D. Coronavirus disease-19 and fertility: viral host entry protein expression in male and female reproductive tissues. Fertil Steril. 2020; 114(1): 33-43.
  9. Reis FM, Bouissou DR, Pereira VM, Camargos AF, dos Reis AM, Santos RA. Angiotensin-(1-7), its receptor Mas, and the angiotensin-converting enzyme type 2 are expressed in the human ovary. Fertil Steril. 2011; 95(1): 176-181.
  10. Cavallo IK, Dela Cruz C, Oliveira ML, Del Puerto HL, Dias JA, Lobach VN, et al. Angiotensin-(1–7) in human follicular fluid correlates with oocyte maturation. Hum Reprod. 2017; 32(6): 1318-1324.
  11. Pan PP, Zhan QT, Le F, Zheng YM, Jin F. Angiotensin-converting enzymes play a dominant role in fertility. Int J Mol Sci. 2013; 14(10): 21071-21086.
  12. Honorato-Sampaio K, Pereira VM, Santos RAS, Reis AM. Evidence that angiotensin-(1–7) is an intermediate of gonadotrophininduced oocyte maturation in the rat preovulatory follicle. Exp Physiol. 2012; 97(5): 642-650.
  13. Barreta MH, Gasperin BG, Ferreira R, Rovani M, Pereira GR, Bohrer RC, et al. The components of the angiotensin-(1-7) system are differentially expressed during follicular wave in cattle. J Renin Angiotensin Aldosterone Syst. 2015; 16(2): 275-283.
  14. Hezavehei M, Shokoohian B, Nasr-Esfahani MH, Shpichka A, Timashev P, Shahverdi AH, et al. Possible male reproduction complications after coronavirus pandemic. Cell J. 2021; 23(4): 382-388.
  15. Hu B, Huang S, Yin L. The cytokine storm and COVID-19. J Med Virol. 2021; 93(1): 250-256.
  16. Mokhtari S, Mahdavi AH, Hajian M, Kowsar R, Varnosfaderani SR, Nasr-Esfahani MH. The attenuation of the toxic effects of LPS on mouse pre-implantation development by alpha-lipoic acid. Theriogenology. 2020; 143: 139-47.
  17. Han H, Ma Q, Li C, Liu R, Zhao L, Wang W, et al. Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Emerg Microbes Infect. 2020; 9(1): 1123-1130.
  18. Ramezankhani R, Solhi R, Memarnejadian A, Nami F, Hashemian SM, Tricot T, et al. Therapeutic modalities and novel approaches in regenerative medicine for COVID-19. Int J Antimicrob Agents. 2020; 56(6): 106208.
  19. Dhar SK, Vishnupriyan K, Damodar S, Gujar S, Das M. IL-6 and IL-10 as predictors of disease severity in COVID-19 patients: results from meta-analysis and regression. Heliyon. 2021; 7(2): e06155.
  20. Popadic V, Klasnja S, Milic N, Rajovic N, Aleksic A, Milenkovic M, et al. Predictors of mortality in critically Ill COVID-19 patients demanding high oxygen flow: a thin line between inflammation, cytokine storm, and coagulopathy. Oxid Med Cell Longev. 2021; 2021: 6648199.
  21. Hashemian SMR, Aliannejad R, Zarrabi M, Soleimani M, Vosough M, Hosseini SE, et al. Mesenchymal stem cells derived from perinatal tissues for treatment of critically ill COVID-19-induced ARDS patients: a case series. Stem Cell Res Ther. 2021; 12(1): 91.
  22. Moghadam F, Hajian M, Varnosfaderani SR, Jafarpour F, Esfahani MHN. Effect of rosiglitazone on developmental competence of mouse embryos treated with lipopolysaccharide. Theriogenology. 2021; 161: 57-64.
  23. Liao Q, Cowling BJ, Lam WWT, Ng DMW, Fielding R. Anxiety, worry and cognitive risk estimate in relation to protective behaviors during the 2009 influenza A/H1N1 pandemic in Hong Kong: ten cross-sectional surveys. BMC Infect Dis. 2014; 14: 169.
  24. Fan FC, Zhang SY, Cheng Y. Incidence of psychological illness after coronavirus outbreak: a meta-analysis study. J Epidemiol Community Health. 2021; 75(9): 836-842.
  25. Salari N, Hosseinian-Far A, Jalali R, Vaisi-Raygani A, Rasoulpoor S, Mohammadi M, et al. Prevalence of stress, anxiety, depression among the general population during the COVID-19 pandemic: a systematic review and meta-analysis. Global Health. 2020; 16(1): 57.
  26. Rooney KL, Domar AD. The relationship between stress and infertility. Dialogues Clin Neurosci. 2018; 20(1): 41-47.
  27. Palomba S, Daolio J, Romeo S, Battaglia FA, Marci R, La Sala GB. Lifestyle and fertility: the influence of stress and quality of life on female fertility. Reprod Biol Endocrinol. 2018; 16(1): 113.
  28. Prasad S, Tiwari M, Pandey AN, Shrivastav TG, Chaube SK. Impact of stress on oocyte quality and reproductive outcome. J Biomed Sci. 2016; 23: 36.
  29. Parker VJ, Douglas AJ. Stress in early pregnancy: maternal neuro-endocrine-immune responses and effects. J Reprod Immunol. 2010; 85(1): 86-92.
  30. Stavridou A, Kapsali E, Panagouli E, Thirios A, Polychronis K, Bacopoulou F, et al. Obesity in children and adolescents during COVID-19 pandemic. Children (Basel). 2021; 8(2): 135.
  31. Nelson SM, Fleming R. Obesity and reproduction: impact and interventions. Curr Opin Obstet Gynecol. 2007; 19(4): 384-389.
  32. Vousden N, Bunch K, Morris E, Simpson N, Gale C, O’Brien P, et al. The incidence, characteristics and outcomes of pregnant women hospitalized with symptomatic and asymptomatic SARS-CoV-2 infection in the UK from March to September 2020: a national cohort study using the UK Obstetric Surveillance System (UKOSS). PLoS One. 2021; 16(5): e0251123.
  33. How can obesity affect a pregnancy? Available from: https://www.acog.org/womens-health/faqs/obesity-and-pregnancy (04 Aug 2021).
  34. Crovetto F, Crispi F, Llurba E, Pascal R, Larroya M, Trilla C, et al. Impact of SARS-CoV-2 infection on pregnancy outcomes: a population-based study. Clin Infect Dis. 2021; ciab104.
  35. Cribiù FM, Erra R, Pugni L, Rubio-Perez C, Alonso L, Simonetti S, et al. Severe SARS-CoV-2 placenta infection can impact neonatal outcome in the absence of vertical transmission. J Clin Invest. 2021; 131(6): e145427.
  36. Rizzo G, Mappa I, Maqina P, Bitsadze V, Khizroeva J, Makatsarya A, et al. Effect of SARS-CoV-2 infection during the second half of pregnancy on fetal growth and hemodynamics: a prospective study. Acta Obstet Gynecol Scand. 2021; 100(6): 1034-1039.
  37. Hcini N, Maamri F, Picone O, Carod JF, Lambert V, Mathieu M, et al. Maternal, fetal and neonatal outcomes of large series of SARS-CoV-2 positive pregnancies in peripartum period: a single-center prospective comparative study. Eur J Obstet Gynecol Reprod Biol. 2021; 257: 11-18.
  38. Khalil A, Von Dadelszen P, Draycott T, Ugwumadu A, O’Brien P, Magee L. Change in the incidence of stillbirth and preterm delivery during the COVID-19 pandemic. JAMA. 2020; 324(7): 705-756.
  39. Zambrano LD, Ellington S, Strid P, Galang RR, Oduyebo T, Tong VT, et al. Update: characteristics of symptomatic women of reproductive age with laboratory-confirmed SARS-CoV-2 infection by pregnancy status—United States, January 22–October 3, 2020. MMWR Morb Mortal Wkly Rep. 2020; 69(44): 1641-1647.
  40. Della Gatta AN, Rizzo R, Pilu G, Simonazzi G. Coronavirus disease 2019 during pregnancy: a systematic review of reported cases. Am J Obstet Gynecol. 2020; 223(1): 36-41.
  41. Zhu H, Wang L, Fang C, Peng S, Zhang L, Chang G, et al. Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia. Transl Pediatr. 2020; 9(1): 51-60.
  42. Flannery DD, Gouma S, Dhudasia MB, Mukhopadhyay S, Pfeifer MR, Woodford EC, et al. Assessment of maternal and neonatal cord blood SARS-CoV-2 antibodies and placental transfer ratios. JAMA Pediatr. 2021; 175(6): 594-600.
  43. Chen H, Guo J, Wang C, Luo F, Yu X, Zhang W, et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records. Lancet. 2020; 395(10226): 809-815.
  44. Halici-Ozturk F, Ocal FD, Aydin S, Tanacan A, Ayhan SG, Altinboga O, et al. Investigating the risk of maternal-fetal transmission of SARS-CoV-2 in early pregnancy. Placenta. 2021; 106: 25-29.
  45. Xiong X, Wei H, Zhang Z, Chang J, Ma X, Gao X, et al. Vaginal delivery report of a healthy neonate born to a convalescent mother with COVID-19. J Med Virol. 2020; 92(9): 1657-1659.
  46. Sungnak W, Huang N, Bécavin C, Berg M, HCA Lung Biological Network. SARS-CoV-2 entry genes are most highly expressed in nasal goblet and ciliated cells within human airways. arXiv. 2003; 06122.
  47. Salvatore CM, Han JY, Acker KP, Tiwari P, Jin J, Brandler M, et al. Neonatal management and outcomes during the COVID-19 pandemic: an observation cohort study. Lancet Child Adolesc Health. 2020; 4(10): 721-727.
  48. Rebutini PZ, Zanchettin AC, Stonoga ETS, Prá DMM, de Oliveira ALP, Dezidério FdS, et al. Association between COVID-19 pregnant women symptoms severity and placental morphologic features. Front Immunol. 2021; 12: 685919.
  49. Toto V, Tosi D, De Vitis LA, Marconi AM, Bulfamante G. Finding of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) within placental tissue 11 weeks after maternal infection. Arch Pathol Lab Med. 2021; 145(8): 920-921.
  50. Shende P, Gaikwad P, Gandhewar M, Ukey P, Bhide A, Patel V, et al. Persistence of SARS-CoV-2 in the first trimester placenta leading to transplacental transmission and fetal demise from an asymptomatic mother. Hum Reprod. 2021; 36(4): 899-906.
  51. Vivanti AJ, Vauloup-Fellous C, Prevot S, Zupan V, Suffee C, Do Cao J, et al. Transplacental transmission of SARS-CoV-2 infection. Nat Commun. 2020; 11(1): 3572.
  52. Zeng H, Xu C, Fan J, Tang Y, Deng Q, Zhang W, et al. Antibodies in infants born to mothers with COVID-19 pneumonia. JAMA. 2020; 323(18): 1848-1849.
  53. Dong L, Tian J, He S, Zhu C, Wang J, Liu C, et al. Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn. JAMA. 2020; 323(18): 1846-1848.
  54. Croen LA, Qian Y, Ashwood P, Zerbo O, Schendel D, Pinto-Martin J, et al. Infection and fever in pregnancy and autism spectrum disorders: findings from the study to explore early development. Autism Res. 2019; 12(10): 1551-1561.
  55. Jones KL, Croen LA, Yoshida CK, Heuer L, Hansen R, Zerbo O, et al. Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation. Mol Psychiatry. 2017; 22(2): 273-279.
  56. Shimabukuro TT, Kim SY, Myers TR, Moro PL, Oduyebo T, Panagiotakopoulos L, et al. Preliminary findings of mRNA Covid-19 vaccine safety in pregnant persons. N Engl J Med. 2021; 384(24): 2273-2282.