INFLUENCE OF UNFRACTIONATED AND LOW-MOLECULAR-WEIGHT HEPARIN ON DNA METHYLATION OF LEUKOCYTES IN WOMEN WITH GENITAL INFECTIONS AND MISCARRIAGE

Abstract

This study investigated the impact of unfractionated heparin (UFH) and low- molecular-weight heparin (LMWH) on leukocyte DNA methylation in women with genital infections and a history of early pregnancy loss. The findings demonstrated that women with genital infections and early miscarriages who did not receive preconception therapy (comparison group) exhibited a distinct pathological profile. Compared to the control group (women with genital infections andfull- term pregnancies), this profile was characterized by marked proteolytic activity—reflected in significantly elevated matrix metalloproteinase (MMP) levels and decreased tissue inhibitors of metalloproteinases (TIMPs)—as well as by a progressive hypermethylation phenotype. The latter included significantly increased DNMT1 activity and elevated levels of global DNA methylation (5- methyl-2'-deoxycytidine), both of which intensified during gestation. Additionally, a pronounced immune imbalance was observed, with persistently elevated pro-inflammatory cytokines (TNF-a, IL- 1P) and suppressed anti-inflammatory IL-10 levels at all assessed time points. In women who received LMWH (clexane) in the preconception period, a non-significant but observable reduction in DNMT1 activity was noted by week 12, along with a modest decrease in global DNA methylation compared to the untreated comparison group. Both baseline and gestational increases in methylation markers were numerically lower in this group. IL-10 levels demonstrated more stable dynamics, with no significant reduction over time. TNF-a concentrations were lower than in the comparison group but remained higher than in the UFH group. In the UFH group, a more pronounced reduction in DNMT1 activity was observed by week 12, with a significantly lower baseline level compared to the comparison group. Global DNA methylation levels also showed a notable decline by week 12, with lower initial concentrations and a less pronounced gestational increase than in the untreated group. Circulating IL-10 levels in this group decreased significantly during pregnancy, while TNF-a concentrations were lower than both the comparison group and the LMWH group.