Elaine Avshman

Purpose. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious and infectious disease that has rapidly spread worldwide.¹ As of September 2021, more than 125,000 cases of SARS-CoV-2 have been reported in pregnant women.¹ Pregnant women are more likely to develop severe symptoms, as they are prone to immunosuppression and are at increased risk for respiratory infections.¹ Severe SARS-CoV-2 infection can result in a cytokine storm, characterized by the release of several interleukines.² Interleukin-6 (IL-6) in particular, is associated with the most adverse clinical outcomes.² Recent studies suggest that viral infections in pregnant women have been strongly associated with changes in brain development due to IL-6.³ Studies have documented a correlation between the maternal immune response and development of neuropsychiatric disorders in infants.³ The effects of SARS-CoV-2 on the neurodevelopment of offspring is a current and important area of research.³ Methods.  A literature review was performed to explore the impact of IL-6 on the development of the fetal brain. Overall, studies in animal models were more commonly found than studies in human populations. The literature review identified studies on both the effects of prenatal exposure as well as knockout of IL-6 on neurodevelopmental and behavioral changes in offspring.⁵ Results. The presence of cytokines were found in all three compartments of the maternal-fetal interface, including the uterus, fetal circulation, and fetal brain.⁴ Finding of cytokines in these compartments suggests potential ability of cytokine transmission from mother to offspring.⁴ However, receptors for SARS-CoV-2 were also found in placenta⁶, supporting the possibility that SARS-CoV-2 itself can be transmitted to the fetus. Comparable studies injected maternal rodent models with IL-6 and demonstrated increased levels of IL-6 in offspring compared to the control group.⁷ Analysis also revealed that prenatal IL-6 exposure resulted in higher rates of anxiety-like behaviors, decreased social interaction, and increased marble burying in the experimental group.⁷ Changes in neuronal migration, synaptic pruning, synaptogenesis, and myelination were also observed.⁷ Another study, also in a rodent model, showed that neuron survival was reduced by 14-21% in the group with higher levels of IL-6.⁸ Conversely, genetic knockout of IL-6 resulted in a reduction in the maternal immune response and prevention of behavioral abnormalities and brain neuropathologies in offspring.⁵ Conclusion. Current research shows that the elevation of IL-6 in the maternal-fetal interface consistently has an adverse effect on fetal neurodevelopment. Though research on the effects of SARS-CoV-2 on fetal brain development is limited, data showing that this virus results in placental elevation of IL-6 advances a rationale for therapies aimed at controlling the maternal interleukin response during an infection.⁹

1. ​​Salem D, Katranji F, Bakdash T. COVID-19 infection in pregnant women: Review of maternal and fetal outcomes. Int J Gynaecol Obstet. 2021;152(3):291-298. doi:10.1002/ijgo.13533
2. Nile SH, Nile A, Qiu J, Li L, Jia X, Kai G. COVID-19: Pathogenesis, cytokine storm and therapeutic potential of interferons. Cytokine Growth Factor Rev. 2020;53:66-70. doi:10.1016/j.cytogfr.2020.05.002
3. Figueiredo CP, Fontes-Dantas FL, da Poian AT, Clarke JR. SARS-CoV-2-associated cytokine storm during pregnancy as a possible risk factor for neuropsychiatric disorder development in post-pandemic infants. Neuropharmacology. 2021;201:108841. doi:10.1016/j.neuropharm.2021.108841
4. Dammann, O., Leviton, A. Maternal Intrauterine Infection, Cytokines, and Brain Damage in the Preterm Newborn. Pediatr Res 42, 1–8 (1997). doi.org/10.1203/00006450-199707000-00001
5. Wu WL, Hsiao EY, Yan Z, Mazmanian SK, Patterson PH. The placental interleukin-6 signaling controls fetal brain development and behavior. Brain Behav Immun. 2017;62:11-23. doi:10.1016/j.bbi.2016.11.007
6. Diriba K, Awulachew E, Getu E. The effect of coronavirus infection (SARS-CoV-2, MERS-CoV, and SARS-CoV) during pregnancy and the possibility of vertical maternal-fetal transmission: a systematic review and meta-analysis. Eur J Med Res. 2020;25(1):39. Published 2020 Sep 4. doi:10.1186/s40001-020-00439-w
7. Rose DR, Careaga M, Van de Water J, McAllister K, Bauman MD, Ashwood P. Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation. Brain Behav Immun. 2017;63:60-70. doi:10.1016/j.bbi.2016.11.020
8. Smith SE, Li J, Garbett K, Mirnics K, Patterson PH. Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci. 2007;27(40):10695-10702. doi:10.1523/JNEUROSCI.2178-07.2007
9. Copaescu A, Smibert O, Gibson A, Phillips EJ, Trubiano JA. The role of IL-6 and other mediators in the cytokine storm associated with SARS-CoV-2 infection. J Allergy Clin Immunol. 2020;146(3):518-534.e1. doi:10.1016/j.jaci.2020.07.001