The present study intended to characterize the profile of soluble immune mediators in serum samples and in the cerebrospinal fluid (CSF) microenvironment from parturients with acute and convalescent COVID-19 as compared to healthy controls (HC), during the circulation of B.1.1.28 and B.1.1.33 SARS-CoV-2 strains, which were identified during the initial spread of COVID-19 in Brazil. Data demonstrated increased levels of immune mediators in serum at acute infection with a clear waning during convalescent COVID-19. Conversely, a progressive increase of immune mediators was observed in CSF from acute infection towards convalescent COVID-19. Immune mediator signatures and integrative correlation circuits further confirmed these findings and supported the existence of dichotomic microenvironments in the serum and CSF compartments. While a waning of correlations involving pro-inflammatory cytokines with increased connectivity of regulatory cytokines was observed in serum samples from acute towards convalescent COVID-19, an increasing frequency of correlations mediated by pro-inflammatory cytokines with decreased connectivity of regulatory cytokine was the hallmark of CSF. Correlations analysis identified a set of molecules associated with the dichotomic crosstalk between serum and CSF compartments, including chemokines (CXCL8, CCL5, CXCL10) and regulatory cytokines (IL-4 and IL-9). These immune biomarkers may represent potential targets for therapeutic strategies in parturients with COVID-19. Together, these findings demonstrated the existence of a divergent landscape of soluble immune mediators in serum and CSF, emphasizing the relevance of understanding the systemic and compartmentalized immune response elicited by SARS-CoV-2 infection during pregnancy.