The Ex-Preterm Infant in Childhood (EPIC) Study

Around 5 million babies are born prematurely (before 37 weeks of pregnancy) worldwide every year. Due to significant advances in neonatal care over the last twenty years most of these babies survive. It was previously believed that the principal risks to long-term health from being born preterm was from delayed development and learning difficulties. However, it is now increasingly being shown that preterm babies are also at higher risk of diseases like high blood pressure and diabetes in later life. The reasons for this are not known. I propose that this may be because preterm babies store fat differently to term babies. It has previously been shown that babies and young adults born preterm have more fat in their abdomen and liver but it has not been shown that these differences persist in the same individuals from infancy through into childhood and adult life. Having more fat in your abdomen and liver is linked to diabetes and high blood pressure in later life. There are however, no studies that have followed preterm and term babies from infancy into childhood. This is one of the main purposes of my study. My research will lead to further understanding of how preterm birth might affect long term health and is an important step to identifying options to improve outcomes in future.

I plan to investigate two different aspects of body fat in preterm and term children; the way that fat is distributed, particularly in the abdomen and around the liver and the activity of a special type of fat called Brown Adipose Tissue (BAT). Most types of fat store energy but BAT is different because when it is active it burns calories to generate heat. BAT is likely to be important in stopping people from becoming obese, but very little is known about how much and how active it is in children. Differences in the way that fat is stored cannot be picked up by measuring height and weight. Measuring body fat accurately requires advanced methods such as Magnetic Resonance imaging and thermal imaging. Magnetic Resonance imaging uses a large magnetic field to generate images. It is a very safe, painless and radiation-free method to measure the amount and distribution of fat. Thermal imaging is also very safe and involves the detection of heat energy to produce a picture.

I will invite children who had a magnetic resonance imaging scan performed in infancy to measure their body fat, to take part in my new study. These children are now between 6-9 years old. To measure the activity of BAT, children will sit in front of a special infrared camera that detects heat while wearing a sleeve over one arm that slightly cools body temperature. Reducing body temperature slightly kick-starts BAT activity and helps the machine to detect it accurately. As the amount of exercise can affect body fat, it is important to take this into account. Children will be asked to wear an accelerometer over the course of three days. This is a bit like a fitness tracker but is worn on the chest instead of the wrist. It detects movement and heart rate and will tell us if children born preterm tend to be less active than children born at term which might contribute to the differences in body fat. The study will only require children to visit the hospital once and the appointment will take no more than two-three hours. The overwhelming majority parents of children who took part in the first study have said they are happy for them to participate again and 30 children have already done so.

Background: Preterm birth is associated in epidemiological studies with adverse cardiometabolic health in later life. The mechanism for this is unknown. Altered adiposity, primarily increased internal abdominal adipose tissue (IAAT), has been observed in cross sectional studies of preterm infants at term age and young adults born preterm. I hypothesise that IAAT tracks from birth to adulthood, conferring a lifelong risk of poor cardiometabolic health.

Aim: I will test the primary hypothesis that the pattern of increased IAAT observed in preterm infants (at term equivalent age) in comparison with full-term infants, is detectable in the same children when investigated in childhood.

Research objectives: to characterise the adiposity of preterm and term born children using the following investigative techniques:
1) Magnetic Resonance Imaging (MRI) to quantify whole body adipose tissue and discrete adipose tissue compartments, hepatic lipid content and the supra-clavicular fat fraction of Brown Adipose Tissue (BAT)
2) Infrared thermography (thermal imaging) to measure the activity of Brown Adipose Tissue (BAT) following application of a cold stimulus

Sample size: I will recruit 110 children (preterm=55) to enable a minimum difference of 0.045l in IAAT to be detected between the two groups. I will capture objective data on physical activity, energy expenditure and measure blood pressure. Children recruited will be drawn from a cohort of preterm and term born children who all underwent whole body MRI scans to measure adipose tissue distribution in infancy.

Scientific and medical opportunities: Whole body MRI is considered the gold standard approach to quantifying adipose tissue quantity and distribution. This study will follow-up a cohort of preterm and term born infants through childhood to assess if differences in adipose tissue distribution persist, which potentially underlies the increased risk of cardiometabolic disease in young adults born preterm.

My research aims to have personal, societal and academic impact.

Personal impact: This fellowship will contribute materially towards the training and experience I need to develop a successful career in academic neonatology. I will acquire skills in imaging techniques suitable for children, data handling, statistical analysis, presentations and publications, managing a large cohort of children and communicating, involving and engaging with them and their parents. Strong patient-public involvement is crucial to the success of clinical research. My study will establish a pool of over 100 children and their families who are interested in clinical research. Additional personal impact will arise as I plan to involve the cohort in co-design future studies. My planned research also integrates closely with the wider programme of my host institution's research group and the goals of other research groups around the world. These aim to identify the causal mechanisms that underlie the well-established greater susceptibility to cardio-metabolic disease of individuals born preterm in comparison with those born at full-term, and identify and test interventions to attenuate these risks. The collaborations I will build during this fellowship will assist me in transitioning towards becoming an independent researcher.

Societal impact: My engagement with parents and collaboration with Bliss, the national charity for sick and preterm babies, will have broader societal impact. Communicating the nature and value of research, and its findings, are important societal aspects of science. My research will add to understanding of how best to communicate the life-long risks of preterm birth with sensitivity and clarity. I will seek to explain the importance of medical follow-up studies, and the value of patient involvement in longitudinal research to children and young adults born preterm and their families. My wider societal engagement events for children and families in west London will bring to life how research can improve child health. I will highlight how all children (including those born term) can be involved in research, and the benefits to them of taking part. This will improve design of, and recruitment for, future research studies at Imperial, as well as enhance engagement with the public more generally.

Academic impact: There are to my best knowledge very few studies globally, such as Growing up in Singapore and the Pune Maternal Nutrition Study, that are evaluating longitudinal birth cohorts in relation to early developmental origins of cardio-metabolic disease, and none that is specifically focussing on preterm risks. Preterm longitudinal studies to-date have largely concentrated on neurodevelopmental outcomes and epidemiological observations. The Guangzhou Preterm Birth Cohort Study is a new cohort currently recruiting that will carry out body composition assessment using the indirect method, Dual Energy X-Ray Absorptiometry at ages 3, 6, 12 and 18 years in preterm children. The outcomes of my study will thus make a small but important and novel contribution to this scientific area. Additionally, my study will assist in validating the work on thermal imaging, and brown adipose tissue content and activity, pioneered by Professor Budge's group in Nottingham.

My study will benefit academic and industry researchers in related fields by providing tested imaging protocols for use in child populations. My work will be of particular use in research on body composition, obesity and metabolic complications in children. By study end, I will have established a large cohort of preterm and term children on whom detailed clinical and body composition data are available. This will be a unique international resource, available on request in accordance with institutional processes. I will ask all participants if I might contact them about future studies to add to our research database of infants, children and young adults.