Does the DPP4 inhibitor sitagliptin increase the endometrial mesenchymal stem cell count in those with recurrent pregnancy loss?

Abstract

Introduction: Miscarriage is the most common complication of pregnancy. It is estimated that approximately 1% of women suffer three or more consecutive miscarriages. Chromosomal abnormalities are the most common cause of first trimester miscarriage. Maternal medical conditions such as uncontrolled diabetes, thyroid disease, thrombophilia’s, infection and immunological disorders have all been implicated as a cause for recurrent pregnancy loss (RPL). Other important risk factors include advanced maternal age and lifestyle factors such as stress, smoking, alcohol intake and body mass index. Research conducted at Warwick Medical School recently discovered that RPL is associated with stem cell deficiency as well as enhanced cellular senescence and disordered inflammation of the endometrium. Stem cell recruitment normally occurs in response to menstruation, childbirth, miscarriage and curettage of the uterus. The process of stem cell recruitment may be deficient in those with RPL but has been shown in animal studies to be enhanced with DPP4 inhibitors. Hypothesis: We hypothesised that DPP4 inhibition with Sitagliptin given prior to conception will increase the endometrial mesenchymal stem cell (eMSC) count during menstruation. Methods/Design: The SIMPLANT study (Sitagliptin for IMPLANTation) was a double blind randomised feasibility study conducted at University Hospital Coventry and Warwickshire. The study was aimed at women aged 18 – 42 with 3 or more miscarriages. Participants were randomised to one of two groups; an endometrial scratch and 100mg Sitagliptin taken once daily for 3 months or an endometrial scratch and placebo taken once daily for 3 months. Group allocation was unknown at the time of analysis and so have been labelled as Group 0 and Group 1. Our primary outcome measure was the eMSC count after 3 months of Sitagliptin versus 3 months of placebo, measured using a clonogenic assay. Results: The results of this feasibility study showed no significant difference in the final eMSC count between the two treatment groups. The study was acceptable to participants and very few side effects to study medication experienced. The study has shown a significant increase in the eMSC count in one treatment group (Group1) 12 when the baseline eMSC count was compared to the eMSC count after 3 months. Conclusion: Our results have shown that the eMSC count after 3 months of treatment of Sitagliptin was not significantly different to the eMSC count after 3 months of placebo. Significant confounding and limiting factors within this feasibility study design have been discussed. Results have shown that we may be able to increase the eMSC count in certain patients which should in turn improve decidualisation of the endometrium and the environment for implantation; however much further work is required before investigating this