For most mothers, awaiting the arrival of their baby is a safe and successful process, but we know that adverse outcomes can unexpectedly complicate one in five pregnancies. These outcomes include preterm (early, premature) birth, pre-eclampsia (high blood pressure), and low birthweight (growth restriction). Alone, or in combination, they may have serious consequences for the mother and/or her baby. Importantly, they are the leading causes of neonatal brain injury and later childhood disability (both cognitive and motor, ranging from poor academic achievement through to cerebral palsy).
Predicting which mothers are at risk and implementing preventive strategies would be ideal. However, identifying at-risk-mothers-to-be is difficult. To that extent, understanding of the underlying pathophysiology would enable targeted preventive solutions, but also lead to the generation of predictive tests and lead to successful change in the clinical setting.
Since 2007, and with the support of Cerebra, the Cerebra Perinatal Research Centre based at the University of Leeds has been engaged with identifying and disseminating effective and preventive strategies for adverse outcomes in pregnancy, through a research process that is outward-facing, collaborative, and transitional. They have established a research centre which has informed clinical practice, inspired multi-professional teaching and led to a reduction in one of the key adverse outcomes, preterm birth (over the period of Cerebra’s funding of the centre, this work has led to a fall in premature birth rates, with almost 350 fewer babies each year being born too soon).
The Cerebra Perinatal Research Centre conducts a varied programme of research that aims to prevent neonatal brain injury and childhood disability. The main focuses of the centre are four interrelated research themes that are summarised below.
1. Fetomaternal interface: Characterising normal and abnormal placental structure and function.
A healthy placenta is the key to an uncomplicated pregnancy, but our understanding of its structure and function remains limited. Each placenta reflects the environment its baby shared and, as such, has the potential to shed light on the causes of adverse pregnancy outcome. At present assessment of placental structure is confined to microscopic inspection. This yields a large amount of descriptive and qualitative information, but is limited in its ability to quantify abnormalities seen. By implementing innovative technology, researchers at the Cerebra Perinatal Research Centre have pushed these boundaries. Full thickness placental sections are stained, scanned and later reconstructed digitally. This allows targeted, large areas of the placenta to be surveyed with a view to make more accurate assessments. Furthermore, by using this digital platform the group is also able to capture sequential sections of the placenta tissue, virtually reassemble them and establish a 3D image, thus undertaking a comprehensive analysis of healthy and diseased placenta and compare for structural anomalies.
2. Early circulatory markers of pregnancy complications: Developing predictive strategies
The ability to predict at an early stage of pregnancy which expectant mothers would encounter complications later would allow intervention and preventing them from occurring. Such discovery research would also reveal new avenues for future exploration and enhance understanding of the mechanisms of both pregnancy complications and brain injury. To that extent the Leeds team is part of a worldwide collaboration: the Screening for Pregnancy Endpoints (SCOPE) biobank, which took over five years to complete. The wealth and depth of this biobank has been realised through over 100 SCOPE consortium-approved studies and has already led to 30 peer-reviewed publications. Most importantly it has led to the identification of PIGF (placental growth factor) as being the most important biomarker in the prediction of pre-eclampsia (high blood pressure during pregnancy). The group will continue to examine the role of potential biomarkers focusing on cell-free nucleic acids (microRNA and DNA) as markers of disease, due to their relative stability compared to many proteins. To that extent the centre has initiated the creation of a further local biobank the 1000 Women Study (an NIHR portfolio study) which will be used both in terms of establishing novel predictive tests, but also evaluate the reliability of those proposed elsewhere.
3. Maternal, fetal and neonatal immune function: Control, modulation and prevention of postnatal brain injury
The group has long had an interest in the role of immune system dysfunctions in the onset of major adverse pregnancy outcomes and the relationship between this and subsequent neonatal brain injury. Their focus has been on the major groups of cells involved in maternal immune defence, particularly macrophages, as it is becoming clear that these respond and behave differently in the mother and her baby, that they have different consequences dependent on their location, and that they were amenable to modulation. Researchers in the centre have developed and refined in vitro cell models to compare maternal and fetal/neonatal macrophage function. The group also carried out experiments to evaluate and characterise the effects these macrophages have on developing neurones, changes which may have long-lasting consequences. Scientists in the Cerebra Perinatal Research Centre hope that a better understanding of prenatal immune function, and how this evolves through advancing gestational age, birth and during early postnatal development, will also offer much needed insight into how brain development is affected by inflammation, and the ways in which the maternal, fetal and neonatal inflammatory/immune responses can be modulated and extrapolated to the clinical setting.
4. Systems biology: Towards the identification of novel therapeutic targets
The biological systems underlying pregnancy complications are complex, diverse and frequently interrelated. There are limitations of examining pathways and molecular interactions in isolation from each other, rather than considering the wider picture. To that extent the Cerebra Perinatal Research Centre is now implementing as systems biology approach to define the biological networks that characterise normal pregnancy and early neonatal life.
Supported by partnerships with Harvard Medical School and the newly established MRC-funded Medical Bioinformatics Centre recently awarded to the University of Leeds, the group has been able to create frameworks of interactions and identify key targets for novel therapeutic interventions (by applying mathematical formulas/algorithms and probability to represent complex biological functions).
The main objective of the Cerebra Perinatal Research Centre is to make a difference in the lives of expectant mothers and their children. Through collaborative, global, translational research they have made important advances in this aim, improving the prediction of mums at risk of early delivery and preventing it from happening, thus reducing the incidence and burden of brain injury acquired as a consequence of pregnancy complications.
To that extent, the centre’s research has always concentrated on ensuring effective clinical practice. Without successful implementation of research findings there will be no reduction in the numbers of babies born at risk of brain injury and later disability. Their work so far, focusing on preterm birth, has led to a sustained reduction in prematurity in Leeds and the expansion of the preterm prevention service at Leeds Teaching Hospitals Trust. They now have a tertiary service that runs two clinics each week for women at risk of preterm birth, and which receives referrals from all of Yorkshire and other centres within the North of England.
The group have always had several research students assisting on existing projects or initiating pilot studies. These include both undergraduate (BSc) and postgraduate (MD and PhD) students. It is these students that will ensure this work continues to influence practice and shape policy in the years ahead.
The next six years
Cerebra are delighted to be in a position to provide the core funding for the Cerebra Perinatal Research Centre at the University of Leeds for a further 6 years (between 2014 and 2019) to continue the innovative and translational work they do in the area of brain injury acquired through adverse pregnancy outcomes.