Cell-free fetal DNA and spontaneous preterm birth

Abstract

Inflammation is known to play a key role in preterm and term parturition. Cell-free fetal DNA (cff-DNA) is present in the maternal circulation and increases with gestational age and some pregnancy complications (e.g. preterm birth, preeclampsia). Microbial DNA and adult cell-free DNA can be pro-inflammatory through DNA-sensing mechanisms such as Toll-like receptor 9 and the Stimulator of Interferon Genes (STING) pathway. However, the pro-inflammatory properties of cff-DNA, and the possible effects of this on pregnancy and parturition are unknown. Clinical studies have quantified cff-DNA levels in the maternal circulation in women who deliver preterm and women who deliver at term and show an association between preterm labor and higher cff-DNA levels in the 2nd, 3rd trimester and at onset of preterm birth symptoms. Together with potential pro-inflammatory properties of cff-DNA, this rise suggests a potential mechanistic role in the pathogenesis of spontaneous preterm birth. In this review, we discuss the evidence linking cff-DNA to adverse pregnancy outcomes, including preterm birth, obtained from preclinical and clinical studies.

Figure 1

DNA sensing through STING and TLR9. (1) DNA enters the cells through a variety of mechanisms, including interactions with C1q, antimicrobial peptides (AMPs) and receptor for advanced glycation end-products (RAGE). (2) This DNA can then be sensed by binding to STING directly or by firstly biding to cyclic GMP-AMP synthase (cGAS). STING activation produces type 1 interferons through transcription factor interferon receptor factor 3 (IRF3) and, to a lesser extent, pro-inflammatory cytokines via activation of NF-κB. (3) TLR9 is found in the endosome and unmethylated DNA (CpG) or DNA with a modified back bone are typical ligands. TLR9 activation produces type 1 interferons and pro-inflammatory cytokines through IRF7 and NF-κB. (4) Pro-inflammatory cytokines are hypothesized to elicit a potent inflammatory response that can lead to the parturition cascade. (5) Type 1 interferons are known to play a role in inflammation and immunomodulation.