INTRODUCTION: Spontaneous preterm birth (sPTB), which predominantly presents as 
spontaneous preterm labor (sPTL) or prelabor premature rupture of membranes 
(PPROM), is a syndrome that accounts for 5-10% of live births annually. The 
long-term morbidity in surviving preterm infants is significantly higher than 
that in full-term neonates. The causes of sPTB are complex and not fully 
understood. Human placenta, the maternal and fetal interface, is an 
environmental core of fetal intrauterine life, mediates fetal oxygen exchange, 
nutrient uptake, and waste elimination and functions as an immune-defense organ. 
In this study, the molecular signature of preterm birth placenta was assessed 
and compared to full-term placenta by proteomic profiling.
MATERIALS AND METHODS: Four groups of fetal membranes (the amniochorionic 
membranes), with five cases in each group in the discovery study and 30 cases in 
each group for validation, were included: groups A: sPTL; B: PPROM; C: full-term 
birth (FTB); and D: full-term premature rupture of membrane (PROM). Fetal 
membranes were dissected and used for proteome quantification study. Maxquant 
and Perseus were used for protein quantitation and statistical analysis. Both 
fetal membranes and placental villi samples were used to validate proteomic 
discovery.
RESULTS: Proteomics analysis of fetal membranes identified 2,800 proteins across 
four groups. Sixty-two proteins show statistical differences between the preterm 
and full-term groups. Among these differentially expressed proteins are (1) 
proteins involved in inflammation (HPGD), T cell activation (PTPRC), macrophage 
activation (CAPG, CD14, and CD163), (2) cell adhesion (ICAM and ITGAM), (3) 
proteolysis (CTSG, ELANE, and MMP9), (4) antioxidant (MPO), (5) extracellular 
matrix (ECM) proteins (APMAP, COL4A1, LAMA2, LMNB1, LMNB2, FBLN2, and CSRP1) and 
(6) metabolism of glycolysis (PKM and ADPGK), fatty acid synthesis (ACOX1 and 
ACSL3), and energy biosynthesis (ATP6AP1 and CYBB).
CONCLUSION: Our molecular signature study of preterm fetal membranes revealed 
inflammation as a major event, which is inconsistent with previous findings. 
Proteolysis may play an important role in fetal membrane rupture. Extracellular 
matrix s have been altered in preterm fetal membranes due to proteolysis. 
Metabolism was also altered in preterm fetal membranes. The molecular changes in 
the fetal membranes provided a significant molecular signature for PPROM in 
preterm syndrome.