Brain Development In Preterm Infants Research Articles

Lactoferrin intake from maternal milk during the neonatal hospitalization and early brain development among preterm infants.

Lactoferrin is an immuno-modulatory nutrient in human milk that may be neuroprotective. In 36 infants born <32 weeks' gestation, we sampled human milk at 14 and 28 days of chronologic age and measured lactoferrin by electrochemiluminescence multiplex immunoassay. Using 3T quantitative brain magnetic resonance imaging scans obtained at term equivalent, we estimated total and regional brain volumes. We compared outcomes between infants exposed to low (bottom tertile, range 0.06-0.13 mg/mL) vs. high (top tertile, range 0.22-0.35 mg/mL) lactoferrin using median regression in models adjusted for gestational age, birth weight z-score, sex, and postmenstrual age. Compared to infants exposed to low lactoferrin, infants exposed to high lactoferrin had 43.9 cc (95% CI: 7.6, 80.4) larger total brain volume, 48.3 cc (95% CI: 12.1, 84.6) larger cortical gray matter, and 3.8 cc (95% CI: 0.7, 7.0) larger deep gray matter volume at term equivalent age. Other regional brain volumes were not statistically different between groups. Higher lactoferrin exposure during the neonatal hospitalization was associated with larger total brain and gray matter volumes, suggesting that lactoferrin may have potential as a dietary supplement to enhance brain growth in the neonatal intensive care unit setting. This study suggests that lactoferrin, a whey protein found in human milk, may be beneficial for preterm infant brain development, and therefore has potential as a dietary supplement in the neonatal intensive care unit setting.

Insulin-like growth factor 1 supplementation supports motor coordination and affects myelination in preterm pigs.

Preterm infants have increased risk of impaired neurodevelopment to which reduced systemic levels of insulin-like growth factor 1 (IGF-1) in the weeks after birth may play a role. Hence, we hypothesized that postnatal IGF-1 supplementation would improve brain development in preterm pigs, used as a model for preterm infants. Preterm pigs delivered by cesarean section received recombinant human IGF-1/IGF binding protein-3 complex (rhIGF-1/rhIGFBP-3, 2.25 mg/kg/day) or vehicle from birth to postnatal day 19. Motor function and cognition were assessed by monitoring of in-cage and open field activities, balance beam test, gait parameters, novel object recognition and operant conditioning tests. Collected brains were subject to magnetic resonance imaging (MRI), immunohistochemistry, gene expression analyses and protein synthesis measurements. The IGF-1 treatment increased cerebellar protein synthesis rates (both in vivo and ex vivo). Performance in the balance beam test was improved by IGF-1 but not in other neurofunctional tests. The treatment decreased total and relative caudate nucleus weights, without any effects to total brain weight or grey/white matter volumes. Supplementation with IGF-1 reduced myelination in caudate nucleus, cerebellum, and white matter regions and decreased hilar synapse formation, without effects to oligodendrocyte maturation or neuron differentiation. Gene expression analyses indicated enhanced maturation of the GABAergic system in the caudate nucleus (decreased NKCC1:KCC2 ratio) with limited effects in cerebellum or hippocampus. Supplemental IGF-1 during the first three weeks after preterm birth may support motor function by enhancing GABAergic maturation in the caudate nucleus, despite reduced myelination. Supplemental IGF-1 may support postnatal brain development in preterm infants, but more studies are required to identify optimal treatment regimens for subgroups of very or extremely preterm infants.

An Animal Model of Neonatal Intensive Care Unit Exposure to Light and Sound in the Preterm Infant.

According to the World Health Organization, ∼15 million children are born prematurely each year. Many of these infants end up spending days to weeks in a neonatal intensive care unit (NICU). Infants who are born prematurely are often exposed to noise and light levels that affect their auditory and visual development. Children often have long-term impairments in cognition, visuospatial processing, hearing, and language. We have developed a rodent model of NICU exposure to light and sound using the Mongolian gerbil (Meriones unguiculatus), which has a low-frequency human-like audiogram and is altricial. To simulate preterm infancy, the eyes and ears were opened prematurely, and animals were exposed to the NICU-like sensory environment throughout the gerbil's cortical critical period of auditory development. After the animals matured into adults, auditory perceptual testing was carried out followed by auditory brainstem response recordings and then histology to assess the white matter morphology of various brain regions. Compared to normal hearing control animals, NICU sensory-exposed animals had significant impairments in learning at later stages of training, increased auditory thresholds reflecting hearing loss, and smaller cerebellar white matter volumes. These have all been reported in longitudinal studies of preterm infants. These preliminary results suggest that this animal model could provide researchers with an ethical way to explore the effects of the sensory environment in the NICU on the preterm infant's brain development.

Associations between neurological examination at term-equivalent age and cerebral hemodynamics and oxygen metabolism in infants born preterm.

Infants born at 29-36 weeks gestational age (GA) are at risk of experiencing neurodevelopmental challenges. We hypothesize that cerebral hemodynamics and oxygen metabolism measured by bedside optical brain monitoring are potential biomarkers of brain development and are associated with neurological examination at term-equivalent age (TEA). Preterm infants (N = 133) born 29-36 weeks GA and admitted in the neonatal intensive care unit were enrolled in this prospective cohort study. Combined frequency-domain near infrared spectroscopy (FDNIRS) and diffuse correlation spectroscopy (DCS) were used from birth to TEA to measure cerebral hemoglobin oxygen saturation and an index of microvascular cerebral blood flow (CBF i ) along with peripheral arterial oxygen saturation (SpO2). In combination with hemoglobin concentration in the blood, these parameters were used to derive cerebral oxygen extraction fraction (OEF) and an index of cerebral oxygen metabolism (CMRO2i ). The Amiel-Tison and Gosselin Neurological Assessment was performed at TEA. Linear regression models were used to assess the associations between changes in FDNIRS-DCS parameters from birth to TEA and GA at birth. Logistic regression models were used to assess the associations between changes in FDNIRS-DCS parameters from birth to TEA and neurological examination at TEA. Steeper increases in CBF i (p < 0.0001) and CMRO2i (p = 0.0003) were associated with higher GA at birth. Changes in OEF, CBF i , and CMRO2i from birth to TEA were not associated with neurological examination at TEA. In this population, cerebral FDNIRS-DCS parameters were not associated with neurological examination at TEA. Larger increases in CBF i and CMRO2i from birth to TEA were associated with higher GA. Non-invasive bedside FDNIRS-DCS monitoring provides cerebral hemodynamic and metabolic parameters that may complement neurological examination to assess brain development in preterm infants.

Prenatal consequences of ­congenital heart disease on brain development

In fetuses with complex congenital heart disease (CHD), impaired brain growth and brain development starts in utero. A complex interplay between heart, brain, body and placenta takes place in the second and third trimesters of pregnancy. Altered fetal cardiovascular hemodynamics due to differnt types of CHD lead to altered cerebral, body and placental perfusion, all factors contributing to maturational delay of body and brain development. Impaired cerebral perfusion, oxygenation and nutritive energy supply affects brain growth and leads to a brain developmental delay of 3–4 weeks until birth. Comparable to the altered brain development in preterm infants, similar pathogenic mechanisms lead to an encephalopathy of CHD on a micro- and macrostructural level. After birth palliative or corrective cardiac surgery is needed, which further contributes to the brain maturational delay with consequences on the neurodevelopmental outcome.

DNA methylation in relation to gestational age and brain dysmaturation in preterm infants.

Preterm birth is associated with dysconnectivity of structural brain networks and is a leading cause of neurocognitive impairment in childhood. Variation in DNA methylation is associated with early exposure to extrauterine life but there has been little research exploring its relationship with brain development. Using genome-wide DNA methylation data from the saliva of 258 neonates, we investigated the impact of gestational age on the methylome and performed functional analysis to identify enriched gene sets from probes that contributed to differentially methylated probes or regions. We tested the hypothesis that variation in DNA methylation could underpin the association between low gestational age at birth and atypical brain development by linking differentially methylated probes with measures of white matter connectivity derived from diffusion MRI metrics: peak width skeletonized mean diffusivity, peak width skeletonized fractional anisotropy and peak width skeletonized neurite density index. Gestational age at birth was associated with widespread differential methylation at term equivalent age, with genome-wide significant associations observed for 8870 CpG probes (P < 3.6 × 10−8) and 1767 differentially methylated regions. Functional analysis identified 14 enriched gene ontology terms pertaining to cell–cell contacts and cell–extracellular matrix contacts. Principal component analysis of probes with genome-wide significance revealed a first principal component that explained 23.5% of the variance in DNA methylation, and this was negatively associated with gestational age at birth. The first principal component was associated with peak width of skeletonized mean diffusivity (β = 0.349, P = 8.37 × 10−10) and peak width skeletonized neurite density index (β = 0.364, P = 4.15 × 10−5), but not with peak width skeletonized fraction anisotropy (β = −0.035, P = 0.510); these relationships mirrored the imaging metrics’ associations with gestational age at birth. Low gestational age at birth has a profound and widely distributed effect on the neonatal saliva methylome that is apparent at term equivalent age. Enriched gene ontology terms related to cell–cell contacts reveal pathways that could mediate the effect of early life environmental exposures on development. Finally, associations between differential DNA methylation and image markers of white matter tract microstructure suggest that variation in DNA methylation may provide a link between preterm birth and the dysconnectivity of developing brain networks that characterizes atypical brain development in preterm infants.

Prophylactic Low-Dose Paracetamol Administration for Ductal Closure and Microstructural Brain Development in Preterm Infants

Introduction: Prophylactic low-dose paracetamol administration is used to induce closure of the ductus arteriosus. Effects on the neurological outcome in preterm infants remain unknown. We compared microstructural brain development in very preterm infants with and without exposure to prophylactic paracetamol by using MR-based diffusion tensor imaging. Materials and Methods: Infants aged <32 gestational weeks born between October 2014 and December 2018 received prophylactic paracetamol (10 mg/kg intravenously every 8 h until echocardiography after at least 72 h) and form the paracetamol group; infants born between February 2011 and September 2014 form the control group. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) at term-equivalent age were measured in 14 defined cerebral regions and compared between the groups. Results: Included in the study were 340 infants, of whom 217 received prophylactic paracetamol, and 123 formed the control group. The paracetamol group showed significantly higher FA values and lower ADC values in the splenium of the corpus callosum, as well as higher FA values in the pons bilaterally, the left middle cerebellar peduncle, the right occipital white matter, and the right posterior limb of the internal capsule (p ≤ 0.02). Conclusion: The perceived safety of prenatal paracetamol exposure has been questioned in recent years. We found no impairment on microstructural maturation processes in the brain of preterm infants at term-equivalent age following early paracetamol administration. The clinical relevance of these imaging findings has to be determined in long-term follow-up studies on neurodevelopmental outcome.

Music Enhances Brain Development in Premature Infants: A Literature Review

Preterm infants have a high risk of neurodevelopmental problem with a decrease of functional capacity of brain network. Without early intervention, it will develop as long-lasting brain network deficiency. We examine the studies of music effect on early life of preterm infants in neonatal intensive care units (NICU). It founds that music has a positive correlation with brain development in preterm infants. The preterm infants exposed with repetitive music as NICU environment enrichment have a chance to develop brain as good as the term infants and have long-lasting beneficial effects on brain development.

Exclusive breastfeeding and its impact on neurodevelopment

Many advantages have been reported among the various studies in the literature about the efficacy of breastfeeding on brain development, which is mainly attributable to the abundant presence of the bioactive compounds and the essential fatty acids in breast milk. Moreover, it has been proven that breastfeeding enhanced long-term outcomes in children. In this context, arachidonic acid and docosahexaenoic acid are two fatty acids that were previously reported to be associated with the developmental outcomes of the retina, nerve cells and brain. Both of these amino acids have also been found in breast milk, and they are not present in other milk formulas as cow’s milk which is usually administered to newborns. In the present literature review, we aim to discuss the impact of exclusive breastfeeding on neurodevelopment. The findings from various studies indicate the strong effect of breastfeeding on the neurodevelopmental outcomes as compared to the administration of other milk formulas. Another finding from previous literature, the favorable events that are obtained from breastfeeding were also found to be sustained to the school-age of these children. On the other hand, evidence regarding the efficacy of breastfeeding on brain development in preterm infants is still poor. As a result, further studies are needed to furtherly validate this point. The main mechanisms by which favorable neurodevelopmental outcomes are obtained following breastfeeding are the nutritional values that are found within the breast milk along with the physical interactions between the mothers and infants during breastfeeding.

NutriBrain: protocol for a randomised, double-blind, controlled trial to evaluate the effects of a nutritional product on brain integrity in preterm infants

BackgroundThe gut microbiota and the brain are connected through different mechanisms. Bacterial colonisation of the gut plays a substantial role in normal brain development, providing opportunities for nutritional neuroprotective interventions that target the gut microbiome. Preterm infants are at risk for brain injury, especially white matter injury, mediated by inflammation and infection. Probiotics, prebiotics and L-glutamine are nutritional components that have individually already demonstrated beneficial effects in preterm infants, mostly by reducing infections or modulating the inflammatory response. The NutriBrain study aims to evaluate the benefits of a combination of probiotics, prebiotics and L-glutamine on white matter microstructure integrity (i.e., development of white matter tracts) at term equivalent age in very and extremely preterm born infants.MethodsThis study is a double-blind, randomised, controlled, parallel-group, single-center study. Eighty-eight infants born between 24 + 0 and < 30 + 0 weeks gestational age and less than 72 h old will be randomised after parental informed consent to receive either active study product or placebo. Active study product consists of a combination of Bifidobacterium breve M-16V, short-chain galacto-oligosaccharides, long-chain fructo-oligosaccharides and L-glutamine and will be given enterally in addition to regular infant feeding from 48 to 72 h after birth until 36 weeks postmenstrual age. The primary study outcome of white matter microstructure integrity will be measured as fractional anisotropy, assessed using magnetic resonance diffusion tensor imaging at term equivalent age and analysed using Tract-Based Spatial Statistics. Secondary outcomes are white matter injury, brain tissue volumes and cortical morphology, serious neonatal infections, serum inflammatory markers and neurodevelopmental outcome.DiscussionThis study will be the first to evaluate the effect of a combination of probiotics, prebiotics and L-glutamine on brain development in preterm infants. It may give new insights in the development and function of the gut microbiota and immune system in relation to brain development and provide a new, safe treatment possibility to improve brain development in the care for preterm infants.Trial registrationISRCTN, ISRCTN96620855. Date assigned: 10/10/2017.

Effects of in-hospital breast feeding on brain function development in preterm infants in China: study protocol for a prospective longitudinal cohort study

IntroductionDue to immature brain development, preterm infants are more likely to develop neurological developmental defects compared with full-term infants. Most preterm infants without neurodevelopmental damage can eventually reach the same...

Quiet Sleep Organization of Very Preterm Infants Is Correlated With Postnatal Maturation.

Background: Sleep is an important determinant of brain development in preterm infants. Its temporal organization varies with gestational age (GA) and post-menstrual age (PMA) but little is known about how sleep develops in very preterm infants. The objective was to study the correlation between the temporal organization of quiet sleep (QS) and maturation in premature infants without severe complications during their neonatal hospitalization.Methods: Percentage of time spent in QS and average duration of time intervals (ADI) spent in QS were analyzed from a cohort of newborns with no severe complications included in the Digi-NewB prospective, multicentric, observational study in 2017–19. Three groups were analyzed according to GA: Group 1 (27–30 weeks), Group 2 (33–37 weeks), Group 3 (>39 weeks). Two 8-h video recordings were acquired in groups 1 and 2: after birth (T1) and before discharge from hospital (T2). The annotation of the QS phases was performed by analyzing video recordings together with heart rate and respiratory traces thanks to a dedicated software tool of visualization and annotation of multimodal long-time recordings, with a double expert reading. Results are expressed as median (interquartile range, IQR). Correlations were analyzed using a linear mixed model.Results: Five newborns were studied in each group (160 h of recording). Median time spent in QS increased from 13.0% [IQR: 13–20] to 28.8% [IQR: 27–30] and from 17.0% [IQR: 15–21] to 29.6% [IQR: 29.5–31.5] in Group 1 and 2, respectively. Median ADI increased from 54 [IQR: 53–54] to 288 s [IQR: 279–428] and from 90 [IQR: 84–96] to 258 s [IQR: 168–312] in Group 1 and 2. Both groups reach values similar to that of group 3, respectively 28.2% [IQR: 24.5–31.3] and 270 s [IQR: 210–402]. The correlation between PMA and time spent in QS or ADI were, respectively 0.73 (p < 10−4) and 0.46 (p = 0.06). Multilinear analysis using temporal organization of QS gave an accurate estimate of PMA (r2 = 0.87, p < 0.001).Conclusion: The temporal organization of QS is correlated with PMA in newborns without severe complication. An automated standardized continuous behavioral quantification of QS could be interesting to monitor during the hospitalization stay in neonatal units.

Invited Review: Factors associated with atypical brain development in preterm infants: insights from magnetic resonance imaging.

Preterm birth (PTB) is a leading cause of neurodevelopmental and neurocognitive impairment in childhood and is closely associated with psychiatric disease. The biological and environmental factors that confer risk and resilience for healthy brain development and long‐term outcome after PTB are uncertain, which presents challenges for risk stratification and for the discovery and evaluation of neuroprotective strategies. Neonatal magnetic resonance imaging reveals a signature of PTB that includes dysconnectivity of neural networks and atypical development of cortical and deep grey matter structures. Here we provide a brief review of perinatal factors that are associated with the MRI signature of PTB. We consider maternal and foetal factors including chorioamnionitis, foetal growth restriction, socioeconomic deprivation and prenatal alcohol, drug and stress exposures; and neonatal factors including co‐morbidities of PTB, nutrition, pain and medication during neonatal intensive care and variation conferred by the genome/epigenome. Association studies offer the first insights into pathways to adversity and resilience after PTB. Future challenges are to analyse quantitative brain MRI data with collateral biological and environmental data in study designs that support causal inference, and ultimately to use the output of such analyses to stratify infants for clinical trials of therapies designed to improve outcome.

Book Review: Manuela Filippa, Pierre Kuhn, &amp; Björn Westrup. Early vocal contact and preterm infant brain development: Bridging the gaps between research and practice

Book Review: Manuela Filippa, Pierre Kuhn, &amp; Björn Westrup. <i>Early vocal contact and preterm infant brain development: Bridging the gaps between research and practice</i>

Decomposition of a Multiscale Entropy Tensor for Sleep Stage Identification in Preterm Infants

Established sleep cycling is one of the main hallmarks of early brain development in preterm infants, therefore, automated classification of the sleep stages in preterm infants can be used to assess the neonate’s cerebral maturation. Tensor algebra is a powerful tool to analyze multidimensional data and has proven successful in many applications. In this paper, a novel unsupervised algorithm to identify neonatal sleep stages based on the decomposition of a multiscale entropy tensor is presented. The method relies on the difference in electroencephalography(EEG) complexity between the neonatal sleep stages and is evaluated on a dataset of 97 EEG recordings. An average sensitivity, specificity, accuracy and area under the receiver operating characteristic curve of 0.80, 0.79, 0.79 and 0.87 was obtained if the rank of the tensor decomposition is selected based on the age of the infant.

Early vocal contact and music in the NICU: new insights into preventive interventions.

It is now clearly established that the environment and the sensory stimuli, particularly during the perinatal period, have an impact on infant's development. During the last trimester of gestation, activity-dependent plasticity shapes the fetal brain, and prematurity has been shown to alter the typical developmental trajectories. In this delicate period, preventive interventions aiming at modulating these developmental trajectories through activity-inducing interventions are currently underway to be tested. The purpose of this review paper is to describe the potentialities of early vocal contact and music on the preterm infant's brain development, and their potential beneficial effect on early development. Scientific evidence supports a behavioral orientation of the newborn to organized sounds, such as those of voice and music, and recent neuroimaging studies further confirm full cerebral processing of music as multisensory stimuli. However, the impact of long-term effects of music exposure and early vocal contact on preterm infants' long-term neurodevelopment needs be further investigated. To conclude, it is necessary to establish the neuroscientific bases of the early perception and the long-term effects of music and early vocal contact on the premature newborns' development. Scientific projects are currently on the way to fill this gap in knowledge.

NICU Diet, Physical Growth and Nutrient Accretion, and Preterm Infant Brain Development.

Half of very preterm infants experience neurodevelopmental impairments after NICU discharge. These adverse outcomes result in part from abnormal brain development and injury that occur during the NICU hospitalization. Although many factors influence infant brain development, nutritional determinants are of particular interest because they are highly modifiable within clinical care. Physical growth of preterm infants in the NICU continues to lag behind the reference fetus, suggesting reduced nutrient accretion during a critical period for brain development. Nutrient accretion is driven by intake of specific nutrients such as macro- and micronutrients as well as non-nutritional factors such as systemic inflammation. Most often, anthropometric indicators, such as weight, length, and head circumference, are used as proxies for nutrient accretion. A limitation of weight is that it does not differentiate the healthy growth of specific organs and tissues from excess fat accumulation. Body length provides information about skeletal growth, and linear growth stunting predicts neurodevelopmental impairment. Head circumference is only a crude proxy for brain size. More recently, application of new technologies such as air displacement plethysmography and magnetic resonance imaging has allowed the direct estimation of lean tissue accretion and brain growth in the NICU. These newer techniques can facilitate research to improve our understanding of the links among the NICU diet, inflammation, physical growth, and brain development. These new measures may also be relevant within clinical care to identify infants who may benefit from specific interventions to enhance nutrient accretion and brain development.

Connection between gut microbiome and brain development in preterm infants.

Dysbiosis of the gut microbiome in preterm infants predisposes the neonate to various major morbidities including neonatal necrotizing enterocolitis and sepsis in the neonatal intensive care unit, and adverse neurological outcomes later in life. There are parallel early developmental windows for the gut microbiota and the nervous system during prenatal to postnatal of life. Therefore, preterm infants represent a unique population in which optimization of initial colonization and microbiota development can affect brain development and enhance neurological outcomes. In this review, we will first discuss the factors affecting the assembly of neonatal gut microbiota and the contribution of dysbiosis in preterm infants to neuroinflammation and neurodevelopmental disorders. We then will discuss the emerging pathways connecting the gut microbiome and brain development. Further we will discuss the significance of current models for alteration of the gut microbiome (including humanized gnotobiotic models and exposure to antibiotics) to brain development and functions. Understanding the role of early optimization of the microbiome in brain development is of paramount importance for developing microbiome-targeted therapies and protecting infants from prematurity-related neurodevelopmental diseases.

Nurturing the preterm infant brain: leveraging neuroplasticity to improve neurobehavioral outcomes.

An intrinsic feature of the developing brain is high susceptibility to environmental influence-known as plasticity. Research indicates cascading disruption to neurological development following preterm (PT) birth; yet, the interactive effects of PT birth and plasticity remain unclear. It is possible that, with regard to neuropsychological outcomes in the PT population, plasticity is a double-edged sword. On one side, high plasticity of rapidly developing neural tissue makes the PT brain more vulnerable to injury resulting from events, including inflammation, hypoxia, and ischemia. On the other side, plasticity may be a mechanism through which positive experience can normalize neurological development for PT children. Much of the available literature on PT neurological development is clinically weighted and focused on diagnostic utility for predicting long-term outcomes. Although diagnostic utility is valuable, research establishing neuroprotective factors is equally beneficial. This review will: (1) detail specific mechanisms through which plasticity is adaptive or maladaptive depending on the experience; (2) integrate research from neuroimaging, intervention, and clinical science fields in a summary of findings suggesting inherent plasticity of the PT brain as a mechanism to improve child outcomes; and (3) summarize how responsive caregiving experiences situate parents as agents of change in normalizing PT infant brain development.

Early life predictors of brain development at term-equivalent age in infants born across the gestational age spectrum

BackgroundIt is well established that preterm infants have altered brain development compared with full-term (FT; ≥37 weeks' gestational age [GA]) infants, however the perinatal factors associated with brain development in preterm infants have not been fully elucidated. In particular, perinatal predictors of brain development may differ between very preterm infants (VP; <32 weeks' GA) and infants born moderate (MP; 32–33 weeks' GA) and late (LP; 34–36 weeks' GA) preterm, but this has not been studied. This study aimed to investigate the effects of early life predictors on brain volume and microstructure at term-equivalent age (TEA; 38–44 weeks), and whether these effects differ for GA groups (VP, MP, LP or FT). MethodsStructural images from 328 infants (91 VP, 63 MP, 104 LP and 70 FT) were segmented into white matter, cortical grey matter, cerebrospinal fluid, subcortical grey matter, brainstem and cerebellum. Cortical grey matter and white matter images were analysed using voxel-based morphometry. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) images from 361 infants (92 VP, 69 MP, 120 LP and 80 FT) were analysed using Tract-Based Spatial Statistics. Relationships between early life predictors (birthweight standard deviation score [BWSDS], multiple birth, sex, postnatal growth and social risk) and global brain volumes were analysed using linear regressions. Relationships between early life predictors and regional brain volumes and diffusion measures were analysed using voxelwise non-parametric permutation testing. ResultsMale sex was associated with higher global volumes of all tissues and higher regional volumes throughout much of the cortical grey matter and white matter, particularly in the FT group. Male sex was also associated with lower FA and higher AD, RD and MD in the optic radiation, external and internal capsules and corona radiata, and these associations were generally similar between GA groups. Higher BWSDS was associated with higher global volumes of all tissues and higher regional volumes in much of the cortical grey matter and white matter in all GA groups, as well as higher FA and lower RD and MD in many major tracts (corpus callosum, optic radiation, internal and external capsules and corona radiata), particularly in the MP and LP groups. Multiple birth and social risk also showed associations with global and regional volumes and regional diffusion values which varied by GA group, but these associations were not independent of the other early life predictors. Postnatal growth was not associated with brain volumes or diffusion values. ConclusionEarly life predictors of brain volumes and microstructure at TEA include sex, BWSDS, multiple birth and social risk, which have different effects based on GA group at birth. This study improves knowledge of the perinatal factors associated with brain abnormalities in infants born across the prematurity spectrum.