The long term goal of our research group is to reduce perinatal morbidity and mortality related to preterm birth (PTB) by reducing the incidence of PTB as well as improving the outcomes of babies born preterm. The group is multidisciplinary and centred around an important collaboration between Professor Donald Peebles (Maternal and Fetal Medicine, Institute for Women’s Health) and Professor Nigel Klein (Infection and Immunity, Great Ormond Street Institute of Child Health).
Preterm birth is the culmination of a number of different pathways that can interact to further increase risk. To achieve our long term goal we have focused on two of the main causes of PTB – infection and inflammation, both as a cause of PTB, but also because of its deleterious effect on the developing fetus, and placental dysfunction leading to severe fetal growth restriction; we estimate that up to 70% of PTBs will be covered by these 2 causes. Placental gene therapy is at the centre of an EU funded research project - EVERREST (see Prenatal Gene and Cell Therapy).
Professor Donald Peebles - Group lead
Dr Anna David – Reader, lead for the PTB clinic at UCLH
Dr Simon Waddington – Reader in gene transfer technology, UCL
Dr Catherine James – Wellcome Trust/Wellbeing of Women Research Training Fellowship
Dr Natalie Suff – Wellbeing of Women Research Training Fellowship
Dr Jane Currie – Wellbeing of Women/British Maternal Fetal Medicine Society funded Entry Level Fellowship
The cervix separates the vagina from the inside of the uterus (see figure). Our research has shown that even using sensitive molecular tests it is not possible to detect bacteria in the placenta of women delivered by planned caesarean. We also know that the vagina, like the mouth, contains an abundant bacterial community. Our hypothesis is therefore that the cervix acts as a barrier that prevents bacteria from ascending from vagina to uterine cavity during pregnancy; we are investigating the possibility that in some women this “barrier function” will be impaired, allowing bacteria to enter the uterus and trigger PTB. There are a number of components that contribute to cervical immunity. Mucins are large mucosa- associated glycoproteins that line the endocervical canal; they provide a scaffold that binds cationic anti-microbial proteins (AMPs), such as Human b Defensins, Elafin and SLPI that have a combination of immune modulating and bactericidal properties. In addition, cervical mucus contains leukocytes that form part of the mothers innate immune response. Our research focusses on factors that could alter cervical immunity such as cervical structure and length (measured by ultrasound), maternal and fetal genotype, exposure to viral infection and hormones such as progesterone. Improved understanding of these mechanisms is an essential first step in designing tests to identify women at high risk of PTB early in pregnancy, enabling clinicians to decide which treatment strategy is most appropriate for an individual woman and finally, to discover new methods to prevent PTB.
The role of bacteria
Using sensitive molecular techniques we demonstrated that bacterial DNA could be identified in membranes and placenta from over 80% of spontaneous preterm births. More recently we have used high throughput multiplexed sequencing approaches to identify the vaginal, oral and placental microbiomes of women following term and preterm delivery. This work strongly suggests that bacteria within the uterine cavity are responsible for PTB in a large proportion of cases. However, further research is needed to determine to what degree the composition of the microbiome itself contributes to the failure of cervical immunity or whether the problem lies solely at the level of the cervix, with an imperfect barrier allowing easy entry of bacteria from the normal microbiome.
The goal of much PTB related research has been to delay PTB so that delivery occurs at a later gestation than would otherwise have occurred. It remains unclear as to whether this strategy actually improves neonatal outcomes and is safe. Prolonged exposure to bacterial products and the resulting wave of inflammation- related molecules such as cytokines has been shown to cause lung and brain injury in both animal and human studies. An important focus of our research is therefore to understand the key pathways by which PTB and its prevention affects neonatal outcome. Working in collaboration with Professors Marlow and Robertson we propose combining in-depth characterisation of fetal inflammation/infection at birth with investigation of neonatal immune function and neurological outcomes, measured using MRI and state of the art neuropsychological assessment. We will use these data to determine the effect of strategies to delay/prevent PTB on neonatal outcome and to stratify postnatal interventions to improve their efficacy.
Improving the care of women at increased risk of PTB
Prof Anna David leads the Preterm Birth Clinic at UCLH. As the second largest prematurity clinic in the UK, it cares for approximately 350 women per year with risk factors for PTB, of whom about 50% have consented to participate in one or more research studies. These include studies to develop new tests to predict PTB such as salivary progesterone as a marker for recurrent preterm birth, and quantitative fetal fibronectin, a protein detectable in the cervicovaginal fluid that is released weeks before women go into spontaneous labour. The clinic benefits from the help of a team of 3 midwives funded to do research who recruit women to national research studies to improve outcomes related to PTB. Working in collaboration with Professor James Malone-Lee (UCL Division of Medicine) we are investigating subclinical urinary tract infection in high risk women and women with abdominal pain presenting to acute obstetric triage.
Preventing iatrogenic PPROM
Iatrogenic pre-term premature rupture of the fetal membranes (PPROM) and subsequent PTB also occurs commonly after amniocentesis and fetoscopic surgery, interventional fetal therapies that are increasingly used in fetal medicine. Healing of the amniotic membrane is poor making attempts to seal the defect using collagen plugs or blood patches ineffective. The mechanisms which promote fetal membrane healing are poorly understood. Recent research in collaboration with Queen Mary University of London (Dr Tina Chowdhury) has demonstrated the importance of Cx43, a stretch-sensitive protein which influences inflammation and the healing response. Modulating Cx43 expression to alter healing of the amniotic membrane is now being investigated as a potential therapy.
Public engagement/research agenda setting
The involvement of patients in designing research pathways has huge benefits in achieving successful outcomes and is an important aspect of our research. Dr David and Dr James are members of the steering group for the Preterm Birth Priority Setting Partnership, James Lind Alliance. In conjunction with families with experience of PTB and organisations representing them this group have identified and prioritised the top 15 research questions of which the top is “Which interventions are most effective to predict or prevent preterm birth?” (see Duley ref – Key Publications)
Current Grant Funds
A David (PI) Purchase of Olympus CX41 microscope for point-of-care urinalysis in pregnancy. Elizabeth Garrett Anderson Hospital Appeal Trust. £2,928 (2014)
C James (D Peebles primary supervisor) Maternal innate immune genotype and preterm birth risk. Elizabeth Garrett Anderson Hospital Appeal Trust. £10,000 (2014)
A David (PI). Role of connexin 43: Putative factor which affects fetal membrane healing and tissue strength”. Rosetrees Trust Project Grant. £29,775 (2014-2017).
Wellbeing of Women ELS Jane Currie (A David primary supervisor) “Do women presenting with abdominal pain and negative urine dipstick tests in pregnancy have subclinical urinary tract infection?” £19,765 (2014-2016)
Wellbeing of Women RTF Natalie Suff. (D Peebles primary supervisor) Augmentation of cervical antimicrobials to prevent preterm labour. £200,000 (2014-2017)
BMFMS Bursary Catherine James. Subclinical urinary tract infection in women at increased risk of Preterm Birth. £4960 (2013)
Wellcome Trust / Wellbeing of Women RTF Catherine James. (D Peebles Primary Supervisor) The role of cervical innate immunity in preterm birth. £278,903 (2011-2015)
N Klein (PI), D Peebles. An investigation of the role of maternal immune regulation in bacterial accumulation leading to preterm birth. Action Medical Research £119 332 (2011-2013)
Julietta Patnick (PI) D Peebles P Brocklehurst, P Sasieni, A Castanon, N Singh, P Walker. Risk of preterm delivery after excision of the cervical transformation zone NIHR RfPB £154,153 (2011-2013)