Peripheral and local immune responses in pregnancy and preterm birth

Abstract

Preterm birth (PTB) affects 11% of pregnancies worldwide and the leading cause is infection and inflammation. The maternal immune system undergoes temporal adaptions during healthy pregnancy, but how this may be altered in PTB remains largely unexplored. The vaginal microbial composition influences pregnancy outcome, although the mechanism of microbial-driven PTB is not well understood.

This thesis explores if there are peripheral and local immune signatures in women who undergo microbial-driven PTB. The key aims were to describe 1) changes in the maternal immune response in healthy pregnancy and spontaneous PTB, 2) alterations in the immune response to cervical shortening and cervical cerclage and 3) differences in the immune response to the vaginal microbial composition in term and preterm pregnancies.

Temporal adaptations in the peripheral immune response were similar in term and preterm pregnancies and were not directly impacted by the vaginal microbiota. Activation of the local innate and adaptive immune response were seen in cervical shortening, and in a proportion of women who delivered preterm. Lactobacillus iners and diverse microbial composition were associated with increases in local mediators of microbial recognition, complement and pro-inflammatory cytokines. This response was augmented in those who delivered preterm, suggestive of a dysregulated immune response. In contrast, cervical shortening and PTB in the presence of Lactobacillus crispatus was not associated with activation of the innate or adaptive immune response, therefore were likely to be driven by alternative causes. Placement of a Mersilene cerclage led to an augmented immune response and was associated with higher PTB rates compared to Nylon, and therefore should not be used.

Microbial-driven PTB involves microbial recognition and activation of the complement cascade, leading to a pro-inflammatory local immune milieu. This opens the door for the development of immune modulators, complement inhibitors and probiotics to mitigate the risk of microbial driven PTB.