The preterm cervix reveals a transcriptomic signature in the presence of premature pre-labor rupture of membranes

BACKGROUND: Premature Pre-labor Rupture of Fetal Membranes (PPROM) accounts for 30% of all premature births and is associated with detrimental long-term infant outcomes. Premature cervical remodeling, facilitated by matrix metalloproteinases (MMPs), may trigger rupture at the zone of the fetal membranes overlying the cervix. The similarities and differences underlying cervical remodeling in PPROM and spontaneous preterm labor with intact membranes (PTL) are unexplored.

OBJECTIVES: We aimed a) to perform the first transcriptomic assessment of the preterm human cervix to identify differences between PPROM and PTL and b) to compare the enzymatic activities of MMP-2 and 9 between PPROM and PTL.

STUDY DESIGN: Cervical biopsies were collected following PTL (n=6) and PPROM (n=5). Biopsies were also collected from reference groups at term labor (TL; n=12) or term not labor (TNL; n=5). The Illumina HT-12 v4.0 BeadChips microarray was utilized and a novel network graph approach determined the specificity of changes between PPROM and PTL. qRT-PCR and Western blotting confirmed the microarray findings. Immunofluorescence was employed for localization studies and gelatin zymography to assess MMP activity.

RESULTS: PRAM1, FGD3 and CEACAM3 were significantly higher whereas NDRG2 lower in the PPROM cervix when compared to the cervix in PTL, TL and TNL. PRAM1 and CEACAM3 were localized to immune cells at the cervical stroma and NDRG2 and FGD3 were localized to cervical myofibroblasts. The activity of MMP-9 was higher (1.22±4.403 fold, p<0.05) in the cervix in PPROM compared to PTL.

CONCLUSIONS: We identified four novel proteins with a potential role in the regulation of cervical remodeling leading to PPROM. Our findings contribute to the studies dissecting the mechanisms underlying PPROM and inspire further investigations towards the development of PPROM therapeutics.