In the present study, we found that endometrial IDO expression was positively associated with more live birth among women during their first IVF treatment, after adjusting for important confounders. Our results suggest that IDO might play a functional role in predicting live birth among women in their first IVF treatment.
A successful pregnancy depends on the regulation of maternal immune system at the maternal-fetal interface to enable a functional placenta to develop. Thus, the semiallogenic fetus is tolerated by the mother and protected by a very efficient process of immune tolerance during the entire process. Since Munn et al. [10] formulated the hypothesis that the expression of IDO at the maternal-fetal interface could prevent immunological rejection of the fetal allograft, there have been many studies on the physiological significance of IDO in human pregnancy. The role of IFO in regulating maternal-fetal tolerance is attributed to its immunosuppressive properties, which are based on inhibition of T cell proliferation through deletion of the essential amino acid tryptophan since T cells exhibit a tryptophan-sensitive G1 cell cycle arrest [16]. Our previous study showed that the expression level of IDO was downregulated in RM patients compared with controls, suggesting an important role of IDO in the maintenance of normal pregnancy [14]. Furthermore, the production of IFN-γ, which is an important and potent stimulator of IDO expression, is found to be significantly decreased in RM patients, which may lead to the reduction in IDO and its activity [17]. Previous studies have demonstrated a link between IDO and preeclampsia [15]. IDO expression was significantly downregulated in preeclampsia placenta, and the reduction in IDO expression was associated with the severity of maternal hypertension and proteinuria. Thus, IDO may play an important role in maintaining a healthy pregnancy.
In our study, endometrial IDO expression starts in the mid-luteal phase around the time when embryo implantation is expected. Thus, this early IDO expression at maternal-fetal interface may be considered as preparation of the endometrium for maternal establishment for fetal tolerance and the regulation of trophoblast invasion.
It is unclear why we failed to see any relationship between IDO expression levels and clinical pregnancy and miscarriage rates. This result can be partially explained by the recent postulation that the first trimester of pregnancy is associated with inflammation, which is required for blastocyst implantation [18]. Pregnancy can be divided into three distinct immunological processes characterized by different biological processes. During the first stage, the blastocyst has to break through the epithelial lining of the uterus and damage the endometrial tissue in order to implant; then the trophoblast must replace the endothelium and vascular smooth muscle of the maternal blood vessels to secure an adequate placental-fetal blood supply. Thus, the first trimester of pregnancy can be viewed as a pro-inflammatory phase. Consistently, higher IDO expression was not associated with higher clinical pregnancy rate and lower miscarriage rate in our study.
Although we have concluded that endometrial IDO expression was positively correlated with live birth in infertile patients seeking IVF-ET treatment, several limitations should be further considered. First, this is a retrospective study, so a well-designed randomized controlled study should be conducted to verify these results. Second, our study did not include frozen-thawed ET cycles, which may induce some unknown bias. Third, well-designed clinical studies are warranted to elucidate the pathogenesis of IDO expression and its subsequent effects on IVF success.
In conclusion, our data suggest that an elevated level of endometrial IDO expression is associated with an increased rate of live birth in IVF treatment. The endometrial IDO expression may also be a new therapeutic target for better IVF treatment, however, further large prospective study are required to verify this hypothesis.