Placental malaria has a profound effect on the fetal immune system, and differential alterations of innate immune responses by prenatal malaria exposure categories may drive heterogeneity to clinical malaria susceptibility during the first year of life, according to a study recently published in BMC Medicine.

Infants in endemic countries continue to be born to mothers with placental malaria, which will likely increase the child’s risk for malaria infection in early childhood, despite widespread implementation of strategies to prevent malaria during pregnancy. The association between placental malaria and risk for malaria infection during infancy is not well understood, but it has been correlated with changes in malaria-specific fetal immunity. More specifically, maternal peripheral and placental infections during pregnancy have an impact on cord blood cytokine responses to toll-like receptor (TLR) agonists and time and type of malaria exposure can skew cytokine responses toward a regulatory/tolerogenic or a proinflammatory profile. 

The clinical relevance of TLR-mediated immune responses in the susceptibility to malaria has been reported mainly for TLR3, TLR7/8, and TLR9 in African children. Therefore, this study examined the impact of 4 types of prenatal malaria exposure (maternal peripheral infection and placental acute, chronic, and past infections) on both spontaneous and TLR-mediated cytokine production in cord blood and how these innate immune responses modulate the risk for malaria during the first year of life.

A birth cohort study was conducted of 313 mother-child pairs from within the COSMIC clinical trial ( identifier: NCT01941264), which assessed malaria interventions during pregnancy in Burkina Faso. Both malaria infections during pregnancy and infants’ clinical malaria episodes detected during the first year of life were recorded. Supernatant concentrations of 30 cytokines, chemokines, and growth factors induced by stimulation of cord blood with agonists TLRs 3, 7/8, and 9 were measured. Crude concentrations and rations of TLR-mediated cytokine responses relative to background control were analyzed.

Results showed that the spontaneous cytokine, chemokine, and growth factor production were all significantly lower in samples from exposed vs non-exposed infants. However, cord blood cells from mothers with previous placental malaria were found to be hyperresponsive compared with those without evidence of prenatal exposure, following TLR7/8 stimulation. Further, both spontaneous responses and responses following TLR stimulation were identified to be associated with differential malaria risk in infancy. Certain biomarker levels were significantly modified depending on prenatal malaria exposure category and were independent predictors of either malaria risk (granulocyte-colony stimulating factor TLR7/8 crude) or protection (IL-12 TLR7/8 ratio and interferon gamma-induced protein-10 TLR3 crude, interleukin 1 receptor agonist TLR7/8 ratio) during the first year of life. Various prenatal malaria exposure categories demonstrated different effects on innate immune responses of the newborn at birth, which may contribute to variation between individual malaria susceptibility during the first year of life.

Related Articles

Overall, the study authors concluded that, “The differential alteration of TLR-mediated immune responses by [prenatal malaria exposure] categories may have profound implications on immune response to other infections as well as to vaccines formulated with TLR-based adjuvants in infants prenatally exposed to malaria.”


Natama HM, Moncunill G, Rovira-Vallbona E, et al. Modulation of innate immune responses at birth by prenatal malaria exposure and association with malaria risk during the first year of life. BMC Med. 2018;16(1):198.