The Role of the Endocannabinoid System in Preterm Birth

Preterm labour (PTL) is a serious and costly obstetric complication affecting ~10% of all pregnancies, is difficult to predict and so difficult to prevent. Previous studies have demonstrated that the concentration of the endocannabinoid (eCB), N-arachidonylethanolamine (AEA) increases, in the plasma, whilst levels of its hydrolysing enzyme, fatty acid amide hydrolase (FAAH) decrease in the blood cells of women at risk of PTL. This project re-examined plasma concentrations of AEA and two other eCBs; N-oleoylethanolamine (OEA) and N-palmityolethanolamine (PEA), in women at high-risk for PTL. Expression studies of the enzymes that regulate eCB concentrations (FAAH and N-acyl-phosphatidylethanolamine-specific phospholipase D (NAPE-PLD)), and the receptors to which they bind (cannabinoid receptors 1 and 2 (CB1 and CB2)), were performed on labour affected and unaffected placentae and fetal membranes taken at term and preterm and related to the expression of progesterone receptor (PR) isoforms. The data showed that a plasma AEA concentration of >1.095 nM had a specificity of 87.1 %, sensitivity of 25.9 %, NPV of 70.2 % and PPV of 61.2 %) to predict PTL. Furthermore, the gestational age at delivery and the number of days remaining in the pregnancy could also be determined by the AEA concentration. Similar to that for AEA, plasma OEA concentration predicted parturition up to eight weeks before it occurred, through a process that involved decreased placental CB1 expression and increased placental CB2 expression, with higher CB2 expression in the FM, especially in prematurity. This was associated with decreased PR expression during PTL in the placenta and choriodecidua, with the PR-C isoform being the dominant isoform involved in pPROM. In conclusion, plasma AEA predicts PTL in asymptomatic “high-risk” women. The interaction of the endocannabinoid system with PR expression in the placenta and FM, suggest not only its involvement in parturition, but also suggests a novel mechanism for preterm labour.