The effect of immunomodulators in recurrent pregnancy loss

Recurrent pregnancy loss (RPL) is a complex, multifaceted condition affecting 1-5% of couples attempting to conceive, imposing significant psychological, clinical, and economic burdens on healthcare systems globally. Despite advancements in reproductive medicine, significant gaps remain in the ongoing research to develop effective diagnosis tools and interventions, leaving many RPL cases unexplained and difficult to manage. Research has consistently suggested that disruptions in the decidualisation of human endometrial stromal cells (hESCs) and overactivated immune responses contribute to implantation and pregnancy failure. With this inflammatory signature being common in RPL patients, drugs that modulate or suppress the immune system have been proposed as potential therapies to decrease the likelihood of a miscarriage. This thesis aims to explore the current evidence on immunomodulators used in the treatment of RPL and assess their efficacies through a systematic review. With a varying number of RCTs available for each intervention, the results of the meta-analysis showed that only steroids appear to have a significant benefit on live birth rate, whereas for intravenous immunoglobulin (IVIG), granulocyte colony stimulating factor (G-CSF), intralipid, and hydroxychloroquine (HCQ) there was significant uncertainty in the findings. This thesis also includes further exploration of intralipid and hydroxychloroquine (HCQ), two drugs for which there is the least amount of evidence as concluded in the systematic review. This study explores how these two immunomodulators may affect decidualisation and inflammatory cytokine expression by hESCs. Stromal cell lines derived from control and RPL patients were cultured, treated, and assessed for morphological changes and decidual marker secretion. Key findings include increased expression of MCP-1 in response to intralipid and significant monocyte migration when cultured with treated-stromal cells. Although there is a lack of high-quality evidence for the use of intralipid in RPL, these results highlight the potential benefit of intralipid treatment by increasing endometrial receptivity, by way of early recruitment of monocytes and immune tolerance, in subgroups of immunology-mediated RPL cases.