Introduction
Preterm delivery is a persisting problem of modern neonatal medicine. Despite the continued development of neonatal support, due to the frequent occurrence of preterm birth (PTB), neonatal outcomes are still unsatisfactory1. PTB occurs in 5-9% in Europe, 12-14% in the United States, and around 18% in Africa and Asia2; it leads to critical medical conditions of the fetuses, the psychological distress of the parents, and significant economic losses as each of these newborns require exceptional medical support.
Preterm babies are vulnerable because of the high incidence of respiratory distress (93% of infants), retinopathy of prematurity (59%), patent ductus arteriosus (46%), bronchopulmonary dysplasia (42%), late-onset sepsis (36%), necrotizing enterocolitis (11%), grade III or higher (7-9%) intraventricular hemorrhage, periventricular leukomalacia (3%), according to a report from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network on very low birth weight (less than 1500 g)3.
There are several hypotheses on why PTB occurs. The factors which seem to play a role include preterm hypothalamic–pituitary–adrenal axis stimulation connected with a stress reaction, preterm placental abruption, pathological uterine expansion, and resulting preterm rupture of the membranes, as well as an inflammatory response in the urogenital tract4,5.
The inflammatory effect is one of the mechanisms of PTB and term delivery. A higher concentration of the inflammatory cytokines was found in the amniotic fluid after delivery6,7. Raba et al., in their study, observed that inflammatory cytokines played a crucial role in over 80% of PTB cases, especially in deliveries before 30. hbd8. Preterm prelabour rupture of the membranes might also be caused by an infection of the amniotic sac. Vagina’s bacterial flora plays an important role, as the presence of Ureaplasma urealyticum, Mycoplasma hominis, and Chlamydia trachomatis predisposes to PTB9,10.
The endocannabinoid signaling system (ECS) includes the endocannabinoid receptor type 1 (CB1) and type 2 (CB2) as well as endogenous ligand (arachidonoylethanolamide and 2-arachidonoyl glycerol) for the cannabinoid receptors11. Low levels of anandamide help support the pregnancy, however, if its level becomes too high, it can lead to miscarriages12. One of the best-known exogenous activators of CB1 and CB2 is Δ9-tetrahydrocannabinol (THC), found in Cannabis sativa (marijuana), which is often used as a psychoactive agent13. Signaling pathways mediated by the cannabinoid receptors (CB) may affect cell proliferation, differentiation, and apoptosis in animal and human cells14,15.
CB1 is encoded by the CNR1 gene and is found mainly in the central nervous system and the heart, liver, uterus, testes, and the small intestine16,17. CB1 receptor also has alternative splice variant forms - endocannabinoid receptor type 1a (CB1a) and endocannabinoid receptor type 1b (CB1b). Both isoforms are encoded by the gene CNR1 and are found in the brain, similarly to CB118,19. The CB2, encoded by CNR2 is expressed in T and B lymphocytes as well as macrophages and hematopoietic cells, brain, and other peripheral tissues, where it modulates the immune response16,17 .
CB is involved in both male and female reproductive systems13. In the female reproductive system, the CB receptors are located in the oviduct, uterus, embryo14. ECS plays a significant role in oogenesis regulation, embryo development, embryo transport, implantation, and placental development. ECS is also involved in the maintenance of pregnancy and in childbirth14. Many studies show that the ECS affects pregnancy outcomes, but the precise role of the endocannabinoid receptor is still unknown.
The objective of the study was the investigation of the relationship between the expression of the cannabinoid receptors within the placenta after delivery and the problem of preterm delivery.