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

Lead Research Organisation: University of Edinburgh
Department Name: MRC Centre for Reproductive Health

Abstract

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.

Technical Summary

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.

Publications

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Austin T (2024) Neonatal brain magnetic resonance imaging: clinical indications, acquisition and reporting. in Archives of disease in childhood. Fetal and neonatal edition

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Batty GD (2023) Systemic inflammation and subsequent risk of amyotrophic lateral sclerosis: prospective cohort study. in medRxiv : the preprint server for health sciences

 
Title Animation 
Description Co-design with parents a 5-minute animation designed to support recruitment to PRENCOG 
Type Of Art Film/Video/Animation 
Year Produced 2024 
Impact Favourable participant feedback 
URL https://media.ed.ac.uk/media/Prencog_Neonatal/1_9llqdgsd
 
Title Animation 
Description Co-designd with parents an animation designed to explain to child participants data collection at 5 years of age. 
Type Of Art Film/Video/Animation 
Year Produced 2024 
Impact Favourable feedback 
URL https://media.ed.ac.uk/media/PRENCOG_5%20YEAR%20OLD%20APPOINTMENT_ANIMATION/1_akzmmsc4
 
Title Mapping Development After Preterm Birth 
Description Images representing Theirworld Edinburgh Birth Cohort infants born at specific gestational ages were created from numeric data points from study participants. The visuals convey three ideas: the breadth of prematurity among participants, how individual contributions from neonates help form the big picture, and the power of anonymised data to facilitate neonatal research. The artwork was created by Dr Lorena Jiménez Sánchez, who works with TEBC families and is an early career researcher in child development at the University of Edinburgh. 
Type Of Art Artwork 
Year Produced 2023 
Impact The artwork is exhibited at the University of Edinburgh. 
 
Description Neonatal brain magnetic resonance imaging: clinical indications, acquisition and reporting
Geographic Reach National 
Policy Influence Type Contribution to new or improved professional practice
 
Description Witness to House of Lords select committee
Geographic Reach National 
Policy Influence Type Contribution to a national consultation/review
URL https://committees.parliament.uk/committee/701/preterm-birth-committee
 
Description Acute High Dose Melatonin for Encephalopathy of the Newborn (ACUMEN):Phase I Study
Amount £5,211,597 (GBP)
Funding ID MR/X030067/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2023 
End 09/2026
 
Description Theirworld Edinburgh Birth Cohort
Amount £300,000 (GBP)
Organisation Theirworld 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2026 
End 03/2028
 
Description Theirworld Edinburgh Birth Cohort
Amount £131,897 (GBP)
Organisation Theirworld 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2025 
End 03/2026
 
Description Theirworld Edinburgh Birth Cohort
Amount £127,304 (GBP)
Organisation Theirworld 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2024 
End 03/2025
 
Title Code for integrating neonatal MRI and neonatal microbiome data 
Description Code used for the data analysis in: Vaher K, Cabez MB, Parga PL, Binkowska J, van Beveren GJ, Odendaal ML, Sullivan G, Stoye DQ, Corrigan A, Quigley AJ, Thrippleton MJ, Bastin ME, Bogaert D, Boardman JP. The neonatal gut microbiota: A role in the encephalopathy of prematurity. Cell Rep Med. 2024 Dec 17;5(12):101845. doi: 10.1016/j.xcrm.2024.101845. Epub 2024 Dec 4. PMID: 39637857. 
Type Of Material Improvements to research infrastructure 
Year Produced 2024 
Provided To Others? Yes  
Impact None as yet. 
URL https://git.ecdf.ed.ac.uk/jbrl/neonatal-microbiota-and-brain-dysmaturation
 
Title Scripts for analysing Neonatal Magnetisation transfer imaging (MTsat) data 
Description A cardinal feature of the encephalopathy of prematurity is dysmaturation of developing white matter and subsequent hypomyelination. Magnetisation transfer imaging (MTI) offers surrogate markers for myelination, including magnetisation transfer ratio (MTR) and magnetisation transfer saturation (MTsat). Using data from 105 neonates, we characterise MTR and MTsat in the developing brain and investigate how these markers are affected by gestational age at scan and preterm birth. We explore correlations of the two measures with fractional anisotropy (FA), radial diffusivity (RD) and T1w/T2w ratio which are commonly used markers of white matter integrity in early life. We used two complementary analysis methods: voxel-wise analysis across the white matter skeleton, and tract-of-interest analysis across 16 major white matter tracts. We found that MTR and MTsat positively correlate with gestational age at scan. Preterm infants at term-equivalent age had lower values of MTsat in the genu and splenium of the corpus callosum, while MTR was higher in central white matter regions, the corticospinal tract and the uncinate fasciculus. Correlations of MTI metrics with other MRI parameters revealed that there were moderate positive correlations between T1w/T2w and MTsat and MTR at voxel level, but at tract level FA had stronger positive correlations with these metrics. RD had the strongest correlations with MTI metrics, particularly with MTsat in major white matter tracts. The observed changes in MTI metrics are consistent with an increase in myelin density during early postnatal life, and lower myelination and cellular/axonal density in preterm infants at term-equivalent age compared to term controls. Furthermore, correlations between MTI-derived features and conventional measures from diffusion MRI provide new understanding about the contribution of myelination to non-specific imaging metrics that are often used to characterise early brain development. 
Type Of Material Improvements to research infrastructure 
Year Produced 2023 
Provided To Others? Yes  
Impact A novel method for myelin sensitive imaging of the developing human brain. 
URL https://git.ecdf.ed.ac.uk/jbrl/neonatal-mtsat
 
Title Theirworld Edinburgh Birth Cohort (TEBC) 
Description A prospective, longitudinal cohort study of preterm and term infants which aims to investigate neuroanatomic variation and adverse outcomes associated with preterm birth, using brain using MRI linked to biosamples and clinical, environmental and neuropsychological data. Includes datasets linked to published manuscripts using TEBC data. Users may request access to a copy of the data by contacting the Principal Investigator or Data Manager named on this page. 
Type Of Material Database/Collection of data 
Year Produced 2022 
Provided To Others? Yes  
Impact None yet. 
URL https://www.research.ed.ac.uk/en/datasets/e65499db-2263-4d3c-9335-55ae6d49af2b
 
Description Early brain development in children born to depressed mothers in high- and low-income settings 
Organisation University of Cape Town
Country South Africa 
Sector Academic/University 
PI Contribution The collaboration is based on data sharing of derived brain MRI and collateral data acquired in Edinburgh and shared with colleagues in Cape Town
Collaborator Contribution The Cape Town team will deliver a novel data analysis.
Impact Psychiatry, paediactrics
Start Year 2024
 
Description Harmonizing multisite neonatal diffusion-weighted brain MRI data for developmental neuroscience 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of neonatal MRI data and human resource for data analysis.
Collaborator Contribution Provision of neonatal MRI dataset
Impact Bonthrone AF, Blesa Cábez M, Edwards AD, Hajnal JV, Counsell SJ, Boardman JP. Harmonizing multisite neonatal diffusion-weighted brain MRI data for developmental neuroscience. Dev Cogn Neurosci. 2025 Jan;71:101488. doi: 10.1016/j.dcn.2024.101488. Epub 2024 Dec 8. PMID: 39662239; PMCID: PMC11683243.
Start Year 2023
 
Description Interview for national news 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Following a press release by University of Edinburgh, a clinical research fellow gave an interview for Scottish Television (STV) News about a research output (McKinnon et al JAMA Network Open 2023). A piece on the same output was also published in a national newspaper following the press release.
Year(s) Of Engagement Activity 2023
 
Description Laboratory visits by Members of the Scottish Parliament 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact In 2024-5, James Boardman hosted health spokespersons/leaders of all the main political parties at Holyrood to discuss ways to translate research into policy to improve maternal and child health. The visits were supported by Professor David Argyle, Vice-Principal and Head of the College of Medicine and Veterinary Medicine at the University of Edinburgh.

The series of visitors were Dame Jackie Baillie MSP, (Scottish Labour), Jenni Minto MSP (SNP), Alex Cole-Hamilton MSP (Scottish Liberal Democrats), Annie
Wells MSP (Scottish Conservatives), and Gillian Mackay MSP (Scottish Greens).
Year(s) Of Engagement Activity 2024,2025
 
Description Patient group workshop 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Study participants or study members
Results and Impact Convened a parent group to co-design research questions and all participant facing materials related to the award. This included creation of two animations designed to support recruitment and retention:

https://media.ed.ac.uk/media/Prencog_Neonatal/1_9llqdgsd
https://media.ed.ac.uk/media/PRENCOG_5%20YEAR%20OLD%20APPOINTMENT_ANIMATION/1_akzmmsc4
Year(s) Of Engagement Activity 2023
URL https://www.ed.ac.uk/centre-reproductive-health/prencog
 
Description Public lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Boardman gave a the Edinburgh Neuroscience Public Christmas Lecture at the Edinburgh Art School. Title: Born Small and Vulnerable, Shining a Light on the Lives of People Born Too Soon or Too Small.
Year(s) Of Engagement Activity 2024
 
Description Witness to House of Lords select committee on preterm birth 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Boardman gave evidence about research priorities in preterm birth to a House of Lords select committee on 4th March 2024. The PRENCOG study was discussed during the session. It was live-streamed on parliament TV.
Year(s) Of Engagement Activity 2024
URL https://committees.parliament.uk/committee/701/preterm-birth-committee