Serological Markers of Malaria Exposure and Immunity in Pregnancy in Endemic Settings: A Critical Integrative Review

Abstract

Malaria in pregnancy presents a distinctive immunological problem: women who have acquired substantial clinical immunity through years of exposure may become newly susceptible to placental infection, while antibodies generated during successive pregnancies can reduce parasite sequestration and its consequences. Serology therefore offers a potentially valuable means of reconstructing exposure, characterising pregnancy-specific immunity, identifying women at elevated risk, and evaluating interventions. Yet the interpretation of serological markers is complicated by antigenic diversity, assay format, gestational timing, gravidity, concurrent parasitaemia, transmission intensity, preventive treatment, human immunodeficiency virus infection, and the imperfect correspondence between antibody quantity and protective function. This critical narrative review evaluates evidence on pregnancy-specific and species-inclusive serological markers in malaria-endemic settings. Literature was selected through live searches of accessible biomedical sources, supplemented by citation tracking and verification of bibliographic metadata and Digital Object Identifiers. The strongest mechanistic and epidemiological evidence concerns antibodies to the Plasmodium falciparum erythrocyte membrane protein 1 variant VAR2CSA, especially native infected-erythrocyte surface recognition, binding-inhibitory activity, breadth, avidity, and cytophilic immunoglobulin G subclass responses. Nevertheless, elevated VAR2CSA reactivity frequently marks recent or cumulative infection as strongly as it marks protection, and associations with placental infection, maternal anaemia, preterm birth, or low birth weight vary by antigen construct, sampling time, study design, and adjustment for exposure. Antibodies to non-pregnancy-specific blood-stage antigens can improve estimates of background transmission but generally lack specificity for placental malaria. Evidence for Plasmodium vivax is expanding, including Duffy binding protein, merozoite, and variant interspersed repeat antigens, but remains less mature and more geographically restricted. No single serological measurement reliably separates exposure from effective immunity. The most defensible direction is a longitudinal, multi-antigen and multi-functional framework that integrates pregnancy-specific responses with infection detection, clinical covariates, and calibrated transmission models. Standardised antigen panels, reference reagents, harmonised functional assays, and prospective validation are required before serology can support individual risk stratification or routine antenatal decision-making.