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

Recurrent pregnancy loss is associated with a pro-senescent decidual response during the peri-implantation window

During the implantation window, the endometrium becomes poised to transition to a pregnant state, a process driven by differentiation of stromal cells into decidual cells (DC). Perturbations in this process, termed decidualization, leads to breakdown of the feto-maternal interface and miscarriage, but the underlying mechanisms are poorly understood. Here, we reconstructed the decidual pathway at single-cell level in vitro and demonstrate that stromal cells first mount an acute stress response before emerging as DC or senescent DC (snDC). In the absence of immune cell-mediated clearance of snDC, secondary senescence transforms DC into progesterone-resistant cells that abundantly express extracellular matrix remodelling factors. Additional single-cell analysis of midluteal endometrium identified DIO2 and SCARA5 as marker genes of a diverging decidual response in vivo. Finally, we report a conspicuous link between a pro-senescent decidual response in peri-implantation endometrium and recurrent pregnancy loss, suggesting that pre-pregnancy screening and intervention may reduce the burden of miscarriage

Progress of the ALIFE2 study : a dynamic road towards more evidence

Investigator-initiated studies are invaluable, especially in fields that are not particularly of interest for the pharmaceutical industry because they are either less profitable or concern special patient groups such as pregnant women. However, designing, conducting, and completing an investigator-initiated randomised controlled trial is challenging. Patients and physicians' preferences, ethics requirements, (international) legislation and funding are all areas where such challenges are encountered. The Anticoagulants for LIving FEtuses (ALIFE)2 study (NTR3361) is an example of an investigator initiated international multicenter trial that progresses slowly, at least initially, as many challenges had to be overcome. Here, we discuss the challenges we faced during the course of the ALIFE2 study up till now and we explain how some of these challenges can be tackled or even avoided

The glycosyltransferase EOGT regulates adropin expression in decidualizing human endometrium

In pregnancy, resistance of endometrial decidual cells to stress signals is critical for the integrity of the feto-maternal interface and, by extension, survival of the conceptus. O-GlcNAcylation is an essential post-translational modification that links glucose sensing to cellular stress resistance. Unexpectedly, decidualization of primary endometrial stromal cells (EnSCs) was associated with a 60% reduction in O-GlcNAc modified proteins, reflecting downregulation of the enzyme that adds O-GlcNAc to substrates (O-GlcNAc transferase, OGT) but not the enzyme that removes the modification (O-GlcNAcase, OGA). Notably, EOGT, an endoplasmic reticulum-specific O-GlcNAc transferase that modifies a limited number of secreted and membrane proteins, was markedly induced in differentiating EnSCs. Knockdown of EOGT perturbed a network of decidual genes involved in multiple cellular functions. The most downregulated gene upon EOGT knockdown in decidualizing cells was ENHO, which encodes adropin, a metabolic hormone involved in energy homeostasis and glucose and fatty acid metabolism. Analysis of mid-luteal endometrial biopsies revealed an inverse correlation between endometrial EOGT and ENHO expression and body mass index. Taken together, our findings reveal that obesity impairs the EOGT-adropin axis in decidual cells, which in turn points towards a novel mechanistic link between metabolic disorders and adverse pregnancy outcome. [Abstract copyright: Copyright © 2017 Endocrine Society.

The challenges managing pregnancies with suspected fetal macrosomia : a mixed methods evaluation

Objectives Macrosomic and large for gestational age (LGA) fetuses are at increased risk of shoulder dystocia and associated complications. The aim of this thesis was to explore the specific challenges when managing these pregnancies. The objectives were to investigate the predictive value of diagnostic tools, explore decision-making for birth interventions, investigate the quality of information available, synthesise the findings and make recommendations for practice. Methods A mixed methods approach was taken mirroring a woman’s journey from diagnosis to birth. The accuracy of ultrasound to detect LGA using a customised standard was investigated in a retrospective cohort study. A systematic review of multivariable prediction models for macrosomia / LGA was conducted to assess if they improved detection. Qualitative interviews with obstetricians were undertaken to explore how they made decisions about birth in pregnancies with suspected macrosomia / LGA. Finally, a systematic review of the online health information on induction of labour was performed. The results from the thesis were synthesised using the extended Pillar Integration Process. Results Three key themes were identified which make managing pregnancies with suspected macrosomia / LGA challenging. 1. Variation in practice due to varying definitions of macrosomia / LGA, conflicting national guidance and reports, organisational culture, personal experience, and defensive medical practice. 2. Diagnostic and therapeutic uncertainty making obstetricians balance unknown risks when recommending birth options for women. 3. Challenges communicating risk and facilitating shared decision-making in the context of uncertainty when there is a finite time resource available and the health information available to women varies in quality. Conclusions The findings highlight the need for standardisation of care, the need for better diagnostic testing, and the need to start a process to provide standardised information about risk to women to facilitate shared decision-making when managing pregnancies with suspected fetal macrosomia / LGA

Online health information on induction of labour : A systematic review and quality assessment study

Objectives Many women will seek information online about induction of labour. However, the quality of the available information varies greatly and there are no regulations regarding the content that is published. Our objective was to systematically evaluate the quality of online health information on induction of labour. Study Design We established a bespoke search strategy with our public and patient representative using common induction of labour search terms. In January 2021 we used the metasearch engines Dogpile, Duckduckgo and Ecosia to identify relevant websites and additional searches were undertaken using different google platforms. We included all open access websites in English which provided specific advice to women on induction of labour. We assessed the quality of the websites for their credibility, accuracy, readability, and content quality in duplicate. The websites were compared according to their source of funding, target user and whether they were pregnancy specific websites or generic. There was no funding for this project. Results We screened 2875 websites from the searches. 221 websites were included out of which only 45 (20%) were pregnancy specific and 109 (50%) had governmental funding. Generic websites had higher credibility (median 6.0 vs 5.5; p = 0.031), accuracy (median 10.75 vs 9.5; p = 0.042) and quality scores (median 45.0 vs 40.0; p = 0.036) than pregnancy specific ones. Those with governmental funding had higher quality scores than commercially funded ones for credibility (median 6.5 vs 5.5; p = 0.002), accuracy (median 13.5 vs 9.0; p < 0.000), readability (72.2 vs 61.2; p = 0.001) and quality (51.0 vs 38.5; p=<0.000). Conclusions The quality of online health information on induction of labour is varied. Governmental websites seem to offer better quality information to pregnant women awaiting induction of labour

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.