Despite significant advances in assisted reproductive technologies, most IVF cycles will not result in a pregnancy – indeed up to 10% of couples undergoing IVF will experience repeated implantation failure (repeated IVF failure following multiple good quality embryo transfers) or recurrent early pregnancy loss. Unfortunately, for many couples experiencing repeated implantation failure there is no definitive diagnosis and no cure, causing significant distress. An important process in the preparation of the uterus for a healthy pregnancy is ‘decidualization’ or the differentiation of uterine cells. Decidualization is an important physiological mechanism by which maternal immune tolerance towards the fetus is established, however the mechanism by which decidualization alters uterine immune cells is unknown. Impaired decidualization is associated with pregnancy disorders including repeated implantation failure, recurrent early pregnancy loss and preeclampsia.
This project aimed to 1. Understand how uterine decidualization would affect immune cells within the uterus; and 2. Understand how drug treatments commonly given during early pregnancy affect uterine decidualization.
Aim 1. To investigate how decidualization may regulate maternal immune tolerance, decidual secretion of microRNAs was investigated. microRNAs are tiny pieces of RNA which when secreted by one cell, have the capability to alter the function of another cell. It was hypothesized that decidual secreted microRNAs may alter the function of immune cells within the uterus. It was identified that decidualization repressed uterine stromal cell production of a specific set of microRNAs which have been shown to regulate immune cell function. As repeated early pregnancy loss is attributed to a pro-inflammatory uterine environment, it was investigated whether these microRNAs were dysregulated in women with a history of repeated early pregnancy loss. Two microRNAs which fail to be repressed by decidualization in the uterus of women with a history of recurrent early pregnancy loss were identified. The function of these microRNAs in the uterus are now being investigated. Profilin-1, a protein target of one of these microRNAs, was identified to play an important role in inhibiting macrophage production of pro-inflammatory cytokines (TNFa and IL1b), supporting the hypothesis that impaired decidualization results in a pro-inflammatory uterine environment. This project has identified novel biomarkers of impaired uterine decidualization in women with recurrent early pregnancy loss and will enable the development of new treatments to improve pregnancy outcomes.
Aim 2. Prednisolone is a glucocorticoid commonly prescribed (off-label) to women trying to conceive who have repeated implantation failure and early pregnancy loss. It is prescribed to reduce the numbers of a specific type of uterine immune cell (Natural Killer), however the effect of prednisolone on other cells within the uterus is unknown. In vitro experiments were conducted to investigate the effect of prednisolone on decidualization of uterine stromal cells. It was found that interactions between decidual and fetal cells in vitro were altered by prednisolone and prednisolone production of proteins previously associated with preeclampsia. Recent large, population-based studies have identified a link between prednisolone use during early pregnancy and preeclampsia: the study has identified that prednisolone may have effects on the uterus during early pregnancy which alter decidualization in a manner that predisposes the pregnancy to preeclampsia.