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

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

Impact of sitagliptin on endometrial mesenchymal stem-like progenitor cells : a randomised, double-blind placebo-controlled feasibility trial

Background: Recurrent pregnancy loss (RPL) is associated with the loss of endometrial mesenchymal stem-like progenitor cells (eMSC). DPP4 inhibitors may increase homing and engraftment of bone marrow-derived cells to sites of tissue injury. Here, we evaluated the effect of the DPP4 inhibitor sitagliptin on eMSC in women with RPL, determined the impact on endometrial decidualization, and assessed the feasibility of a full-scale clinical trial. Methods: A double-blind, randomised, placebo-controlled feasibility trial on women aged 18 to 42 years with a history of 3 or more miscarriages, regular menstrual cycles, and no contraindications to sitagliptin. Thirty-eight subjects were randomised to either 100 mg sitagliptin daily for 3 consecutive cycles or identical placebo capsules. Computer generated, permuted block randomisation was used to allocate treatment packs. Colony forming unit (CFU) assays were used to quantify eMSC in midluteal endometrial biopsies. The primary outcome measure was CFU counts. Secondary outcome measures were endometrial thickness, study acceptability, and first pregnancy outcome within 12 months following the study. Tissue samples were subjected to explorative investigations. Findings: CFU counts following sitagliptin were higher compared to placebo only when adjusted for baseline CFU counts and age (RR: 1.52, 95% CI: 1.32–1.75, P<0.01). The change in CFU count was 1.68 in the sitagliptin group and 1.08 in the placebo group. Trial recruitment, acceptability, and drug compliance were high. There were no serious adverse events. Explorative investigations showed that sitagliptin inhibits the expression of DIO2, a marker gene of senescent decidual cells. Interpretation: Sitagliptin increases eMSCs and decreases decidual senescence. A large-scale clinical trial evaluating the impact of preconception sitagliptin treatment on pregnancy outcome in RPL is feasible and warranted. Funding: Tommy's Baby Charity. Clinical trial registration: EU Clinical Trials Register no. 2016-001120-54

Heparin for women with recurrent miscarriage and inherited thrombophilia (ALIFE2) : an international open-label, randomised controlled trial

Anticoagulant therapy might reduce the number of miscarriages and adverse pregnancy outcomes in women with recurrent pregnancy loss and inherited thrombophilia. We aimed to assess use of low-molecular-weight heparin (LMWH) versus standard care in this population. The ALIFE2 trial was an international open-label, randomised controlled trial undertaken in hospitals in the UK (n=26), the Netherlands (n=10), the USA (n=2), Belgium (n=1), and Slovenia (n=1). Women aged 18-42 years who had two or more pregnancy losses and confirmed inherited thrombophilia, and who were trying to conceive or were already pregnant (≤7 weeks' gestation), were eligible for inclusion. Women were randomly assigned (1:1) to use low-dose LMWH or not (alongside standard care in both groups) once they had a positive urine pregnancy test. LMWH was started at or before 7 weeks' gestation and continued until the end of pregnancy. The primary outcome measure was livebirth rate, assessed in all women with available data. Safety outcomes included bleeding episodes, thrombocytopenia, and skin reactions, and were assessed in all randomly assigned women who reported a safety event. The trial was registered within the Dutch Trial Register (NTR3361) and EudraCT (UK: 2015-002357-35). Between Aug 1, 2012, and Jan 30, 2021, 10 625 women were assessed for eligibility, 428 were registered, and 326 conceived and were randomly assigned (164 to LMWH and 162 to standard care). 116 (72%) of 162 women with primary outcome data in the LMWH group and 112 (71%) of 158 in the standard care group had livebirths (adjusted odds ratio 1·08, 95% CI 0·65 to 1·78; absolute risk difference, 0·7%, 95% CI -9·2% to 10·6%). 39 (24%) of 164 women in the LMWH group and 37 (23%) of 162 women in the standard care group reported adverse events. LMWH did not result in higher livebirth rates in women who had two or more pregnancy losses and confirmed inherited thrombophilia. We do not advise use of LMWH in women with recurrent pregnancy loss and inherited thrombophilia, and we advise against screening for inherited thrombophilia in women with recurrent pregnancy loss. National Institute for Health and Care Research and the Netherlands Organization for Health Research and Development. [Abstract copyright: Copyright © 2023 Elsevier Ltd. All rights reserved.