TSR19-001 - Detection of maternal colonisation with Group B Streptococcus in pregnancy by vaginal volatile organic compound analysis
Group B Streptococcus (GBS) is the most frequent cause of life threatening early onset infection in newborn infants in the UK, known as EOGBS disease. This infection can lead to sepsis, pneumonia, meningitis and death. GBS commonly colonises the gastrointestinal and genital tract of adults (1 in 5). It does not cause harm to the mother. The infection is acquired by a baby vertically though exposure to GBS from the vagina of a colonised mother. The optimal screening strategy to prevent EOGBS is uncertain, with a variety of practices worldwide. Administration of antibiotics to colonised women during labour reduces neonatal infection.The currently available tools to diagnose maternal colonisation with GBS can take days and are therefore not appropriate to be used acutely in labour. There is a need to develop an accurate point of care test for GBS colonisation which can be taken at the bedside and produce results within a few minutes. The detection of specific patterns of volatile organic compounds (VOCs) in urine, breath, sweat and faeces is a novel tool that has been developing over recents years for the detection of various diseases. Utilising instruments that detect VOCs mean that it is possible to obtain results within minutes of samples being taken. The objective of this study is to develop the use VOC detection technology in the rapid detection of maternal GBS colonisation.
TSR19-002 - Analysis of the endometrium to understand mechanisms of reproductive failure.
Miscarriage is a profoundly devastating experience and for many couples the level of grief is similar to that of stillbirth. Chromosomal errors in the embryo often account for sporadic (occasional) miscarriage but persistent defects in the lining of the womb (endometrium) lead to recurrent pregnancy loss. Because the endometrium is such a dynamic tissue that changes day-by-day, it has been challenging to identify the pathways that cause recurrent pregnancy loss. By unravelling the pathways that lead to abnormal embryo implantation, our research aims to (i) uncover biomarkers that can be used in the clinic to identify women at risk of miscarriage and to (ii) develop new preventative strategies to reduce the burden of recurrent miscarriage.
TSR19-003 - A Pilot Study into endometrial microbiome sampling and contamination
A Pilot Study into endometrial microbiome sampling and contamination
Research has shown that the balance of certain bacteria that colonise the lining of the womb might lead to miscarriage (1). These bacteria are known as the endometrial microbiota. This imbalance can lead to persistent inflammation, known as Chronic Endometritis (CE). Researchers have found that treatment with an antibiotic called doxycycline can resolve CE (2) and therefore might prevent miscarriage. To assess the microbiota, sampling of the endometrium is required. This is normally performed by passing a small tube called a pipelle, through the vagina and cervix to reach the womb, this tube might pick up bacteria on route which could contaminate the results. This has been a limiting factor for research into the endometrial microbiota, fueling speculation about the origin of bacteria detected. A Tao brush is an endometrial sampler that has a cover which protects the sampling device as it passes through the vagina and cervix, reducing the risk of contamination. It has additionally been shown to be better tolerated by patients (3). There is little evidence on the risk of and site of contamination using this form of sampling. This pilot study aims to assess this and guide further experimental and trial methodology in the field.
(1) Moreno I, Codoñer FM, Vilella F, Valbuena D, Martinez-Blanch JF, Jimenez-Almazán J, et al. Evidence that the endometrial microbiota has an effect on implantation success or failure. Am J Obstet Gynecol. 2016 Dec;215(6):684–703
(2) Kitaya K, Matsubayashi H, Takaya Y, Nishiyama R, Yamaguchi K, Takeuchi T, et al. Live birth rate following oral antibiotic treatment for chronic endometritis in infertile women with repeated implantation failure. Am J Reprod Immunol. 2017 Nov;78(5)
(3) Yang GC, Wan LS. Endometrial biopsy using the Tao Brush method. A study of 50 women in a general gynecologic practice. J Reprod Med. 2000 Feb;45(2):109–14
TSR19-004 - The phenotype and function of endometrial immune cells in recurrent pregnancy loss (RPL)
Throughout a woman’s menstrual cycle the endometrium (the lining of the uterus) undergoes dynamic cellular changes. For the establishment of pregnancy, precise cellular conditions are required; and in particular the maternal immune cells in the endometrium are modified to assist the process. Defects in immune cell adaptations are implicated in women who have recurrent pregnancy loss. In this study we wish to isolate immune cells from the endometrium, investigating their characteristics and functions. We will do this by processing the endometrial biopsy into a single cell suspension, characterising the genetic material or proteins that they express and performing assays to investigate the functions of the immune cells. Specifically we will be investigating T and B cells. The T regulatory subset is known to be critical for embryo implantation in mice but there is limited scientific data regarding their significance in humans. We will perform in vitro experiments determine if regulatory functions are altered in women with recurrent pregnancy loss compared to control women (using control samples obtained from a fertility clinic) and those with recurrent pregnancy loss. B cells make antibodies, as RPL is associated with autoimmunity for example the antiphospholipid syndrome, we wish to find out if the B cells are altered in the endometrium of women with RPL. Using samples recruited from the CERM trial (recruiting women with recurrent pregnancy loss) we will also be able to identify whether the type or function of these cells is related to the chance of a live birth in the next pregnancy.
TSR19-005 - Mechanisms of Labour
Preterm birth, postpartum heamorrhage and dysfunctional labour remain serious obstetric complications that have profound consequences for mother and baby. Part of the reason we fail to treat these conditions effectively is that we do not yet fully understand how the uterus contracts. This research aims to understand how certain cells at the interface between the placenta and the uterus muscle are different in their molecular makeup. We will use new technology called single cell RNA sequencing to characterize these cells to understand how their activation leads to the stimulus of contractions.
TSR19-006 - Chronic endometritis and recurrent miscarriage- the underlying mechanisms. Mechanistic work associated with the CERM Trial
Recurrent miscarriage (RM) is a condition in which women suffer from two or more consecutive miscarriages. At present no cause for this is found in the majority of women. Chronic Endometritis (CE) is inflammation of the womb lining. It is thought this may be a cause of RM. The Chronic Endometritis and Recurrent Miscarriage (CERM) trial aims to assess if a short course of antibiotics to treat this can result in more pregnancies and births in affected women compared to treatment with a placebo. In order to be checked for CE women will undergo sampling of the womb lining. Some women will also have a repeat biopsy following treatment. This study will use any surplus part of the sample not required to diagnosis CE in order to better understand the condition and how it may be causing RM. This will include questions such as whether the presence or absence of CE or its treatment affects the numbers and type of immune cells, progenitor cells or blood vessel development within the womb lining. We will also attempt to better understand CD138, a marker of CE diagnosis, including the function of this protein in cells and what regulates it.
TSR19-007 - The chronic endometritis and recurrent miscarriage (CERM) trial – Microbiota Analysis
Recurrent miscarriage (RM) is condition that causes considerable distress to couples. In the majority of women no clear cause is identified. One suspected cause of RM is chronic endometritis (CE). This is inflammation of the womb lining. It is thought that in some cases, an imbalance in the types of bacteria present within the womb lining may cause CE. The chronic endometritis and recurrent miscarriage (CERM) trial aims to assess the effect of a course of antibiotics on women with CE and RM. As part of the CERM trial some patients will undergo sampling of the womb lining to determine the underlying balance of bacteria. This study looks to use those samples to understand the relationship between bacterial composition, CE and RM. It also looks to determine the effect that antibiotic treatment may be having on these relationships.
TSR19-008 - Use of novel volatile organic compound (VOC) analysis to accurately diagnose urinary tract infections in pregnancy
Urinary tract infections (UTIs) are common in pregnancy affecting up to one in ten women. Some of these women have symptoms to warn them but others do not. UTIs can lead to complications in pregnancy which can affect both the mother and the baby and therefore diagnosis in a timely fashion is important. The current rapid tests used in clinics are not very accurate to diagnose UTIs. Consequently, it is currently recommended that all women provide a urine sample when they book their pregnancy with their community midwife which is sent to the laboratory to be cultured. If bacteria grow additional tests are done to determine which antibiotics will be effective at treating that bacteria which has grown. This is a time consuming and expensive process which can lead to delays in starting treatment.
A new technology which mimics the human nose has been recently shown to accurately diagnose several human diseases including various infections. We want to ascertain if this technology which could be available as a bedside test can diagnose UTIs in pregnancy.
TSR19-009 - Investigating the relationship between differences in blood vessel growth in the placenta and placental dysfunction: a step towards personalised therapeutics?
There is currently no test that can accurately predict which pregnancies will go on to be affected by poor growth of a baby in the womb (fetal growth restriction), blood pressure problems in the mother (preeclampsia) or death of a baby before birth (stillbirth). Furthermore, once these problems are apparent, there are no available treatments which can improve the outcome of the pregnancy for mother and baby. Altered levels of hormones in the mother’s blood can sometimes be seen earlier in pregnancy, before these problems develop. Low placental growth factor (PlGF) is particularly exciting because a clinical test already exists for this. We hope to understand what low PlGF (and related hormones) tell us about how the placenta is working. This work will aid identification of at-risk pregnancies, may identify targets for development of personalised drug treatments to improve pregnancy outcomes and prevent harm for mother and baby.
TSR20-001 - Stillbirth prevention by combating placental rejection
The placenta (afterbirth) is the organ which connects the growing baby to the mother’s womb. It allows nutrients and oxygen to be transferred from the mother, and is essential for the baby’s survival and development. The placenta shares half of its genetic make-up with the mother, and half the father. Normally, this would trigger the mother’s immune system, but in healthy pregnancy the placenta is protected. In a condition known as CHI (Chronic Histiocytic Intervillositis), it appears that this protection fails and the mother’s immune cells attack the placenta and damage it. If severe, this can cause miscarriage or stillbirth. Although rare, CHI often returns in following pregnancies, with no confirmed way to manage or prevent it. Currently, it is unclear what causes CHI, but there are similarities to the way a transplanted organ is rejected. Our study aims to better describe the mother’s immune response in CHI-affected pregnancies, and how it brings about stillbirth. We believe that tests used in transplant biology to find a suitable organ donor, may also be applied in pregnancy; identifying women who will get CHI (perhaps even before they’re pregnant) and likely treatments which will prevent or manage its effects on the unborn baby.
TSR20-002 - A novel tocolytic to treat preterm labour.
Preterm birth, postpartum heamorrhage and dysfunctional labour remain serious obstetric complications that have profound consequences for mother and baby. Part of the reason we fail to treat these conditions effectively is that we do not yet fully understand how the uterus contracts and have few drug options to manipulate how the uterus contracts. This research is a partnership with an international pharmaceutical company to develop a new drug to inhibit uterine contractions as a tocolytic treatment for preterm birth
TSR20-003 - The role of uterine natural killer cells in the endometrium
The roleThe human endometrium undergoes cyclic transformation and regeneration as part of a women menstrual cycle. There are many different types of cells within the endometrium that contribute to this process, including immune cells. The major immune cell population is uterine natural killer cells (uNKs), which peak at time of embryo implantation. The transformation of the endometrium in each cycle is characterized by the emergence of two difference populations of endometrial cells. That being mature cells and stressed/senescent cells. Senescent cells have important biological functions at time of implantation by secreting signals to attract embryos. However, sustained secretions may increase cellular senescence in neighboring cells leading to excessive stress and tissue damage. Conditions that are not conducive to pregnancy. uNKs are the gate-keepers of endometrial senescence, targeting and eliminating stressed cells, thereby rejuvenating tissue for pregnancy. We currently do not understand what effect embryo have on the ability of natural killer cells to eliminate cellular senescence. We aim to isolate uNKs from whole endometrial biopsies and investigate their function in response to embryonic signals collected from media in which they are grown for IVF treatment. We envisage this research will provide therapeutic avenues to enhance uNK function and improve reproductive outcomes of uterine natural killer cells in the endometrium
TSR20-004 - Dietary constituents as pregnancy therapeutics: can dietary nitrate improve vascular function and growth in fetal growth restriction?
Fetal growth restriction (FGR) occurs when a baby’s growth in the womb is slowed or halted, and affects ~5% of all pregnancies. FGR increases the risk of stillbirth, and FGR babies are at greater risk of developing high blood pressure and diabetes in adult life. In many FGR cases, blood flow across the placenta is impaired, reducing oxygen and nutrient delivery to the fetus. Nitric oxide is a small molecule produced throughout the body that causes blood vessels to dilate, and is critically involved in maintaining blood flow across the placenta in pregnancy. Recently, it has been shown that nitrate, a compound found abundantly in the diet and predominantly in green leafy vegetables and beetroot, can be activated in the body to increase nitric oxide levels. Our studies aim to determine whether increasing dietary nitrate during pregnancy, through supplementation with beetroot juice, might improve blood flow to the baby and hence increase fetal growth in pregnancies complicated by FGR. In addition, we are investigating whether the processes that activate dietary nitrate are altered in placentas of FGR pregnancies compared to those where the baby has grown normally.
TSR20-005 - Assessing endometrial receptivity and inter-cycle displacement of the Window of Implantation by gene expression analysis
Successful pregnancy depends on the synchronous processes of healthy embryo development and endometrial preparation. It has been shown that up to 40% of infertile patients seeking treatment through assisted reproductive technologies display abnormal endometrial preparation and show a displaced window of implantation (WOI), the brief timespan in the menstrual cycle during which the endometrium is receptive to an implanting embryo. A shift in the WOI may lead to mistimed embryo transfer, lower implantation rates and reduced reproductive success.
Accurate determination of endometrial receptivity based on molecular markers allows IVF clinicians the opportunity to adjust the embryo transfer timelines to accommodate displacement in the window of implantation. Evidence suggests that accurate assessment of receptive preparation in a given cycle can be leveraged in subsequent cycles to define an optimal transfer window.
This study aims to analyze inter-cycle consistency of WOI displacement to determine the utility of endometrial receptivity testing.