Preterm birth as a determinant of neurodevelopment and cognition in children: mechanisms and causal evidence

Globally, 15 million infants are born preterm (less than 37 weeks of gestation) each year. Survival rates for infants born too soon or too small have improved dramatically over the past two decades, but brain injury among survivors has not. Consequently, preterm birth is a leading cause of developmental and learning problems in childhood. As survivors of modern intensive care have begun to reach adulthood, it is clear that the legacy of preterm birth can affect the life course. Cerebral palsy, autism, attention deficit hyperactivity disorder, low IQ, memory problems, language and social difficulties, depression, and schizophrenia are all more common in people who were born early.

Importantly, there are no effective treatments for promoting brain health after preterm birth. One of the biggest challenges facing perinatal medicine is to find new ways to reduce brain injury and improve life-long outcomes. In this project, we aim to discover which parental/infant factors influence the brain development of preterm infants, and how those factors become biologically 'embedded' in the brain.

To do this, we will study a large UK-wide population to determine which aspects of being born preterm impact neurodevelopment and ability at school age, and whether a person's socioeconomic circumstances modify these impacts. This will help us define the relative importance of a range of risk/resilience factors to real-world neurodevelopmental outcomes and school performance.

We will use sophisticated brain scans (MRI) to define changes in brain growth that commonly affect premature babies and will use these to investigate how premature birth causes altered brain development. We will investigate whether the perinatal stress environment (hypothalamic-pituitary-adrenal axis activity) and/or markers of low-level chronic systemic inflammation (DNA methylation signatures) link risk factors with brain changes on MRI.

To understand how prematurity affects cognition, we will study the brains of 5-year-olds who were born preterm and a comparator group of children born at term using functional MRI. In this technique, children view movie scenes whilst in the MRI scanner, and brain systems that activate in response to cognitive tasks such as social thinking, attention and memory, are revealed. We expect this analysis to determine whether brain networks that underpin specific cognitive abilities are altered in preterm children and whether cognitive capacities are underpinned by alterations in specific or more general cognitive processes. For example, children born preterm often have social difficulties at school age but it is unknown whether this is due to difficulties in reasoning about other people, or because of more general difficulties with language or attention that make social interactions challenging. Functional MRI will help us to tease apart these alternative accounts, which is a necessary first step for designing targeted cognitive training interventions.

In summary, this programme of work will explain why some premature children develop brain injury while others are resilient. It could pave the way to new therapies that promote healthy brain growth and long-term outcomes because the stress response and immune systems are modifiable, and mechanistic understanding of cognitive deficits is essential for developing rational cognitive training strategies.

Preterm birth (delivery at less than 37 weeks of gestation) affects around 11% of births, globally, and is a leading cause of neurodevelopmental and cognitive impairment with impacts that extend across the life course. We aim to identify the physiological axes that embed biological, psychosocial and socioeconomic preterm birth-associated risk factors in abnormal brain development. We will use epidemiological, neuroinformatic and experimental medicine approaches, and focus on neuroendocrine stress and immune activation. We have two key goals that are addressable now due to recent advances in population-level neonatal data availability and perinatal phenotyping technologies. The first is to determine the weighted contributions of socioeconomic and medical exposures to neurodevelopment and educational attainment in a contemporary UK population of children born preterm. The second is to elucidate the pathways that link multi-dimensional exposures with abnormal brain development by analysing HPA axis activity, immune dysregulation indexed by DNAm proxies of low-level systemic chronic inflammation, and neuroimaging within a prediction framework. We will characterise brain development in terms of connectome complexity, brain age and markers of myelination, and we will use these together with functional MRI to investigate neural substrates of cognitive impairment and reserve in childhood. We will work with survivors and parents with lived experience of preterm birth to ensure our research questions are relevant and to disseminate our findings. Our ambition is to identify targets within neuroendocrine stress and immune pathways that lead to atypical brain development in preterm infants, paving the way for novel neuroprotective intervention and cognitive training strategies.