Control Term Research Articles

Identification and prediction model of placenta-brain axis genes associated with neurodevelopmental delay in moderate and late preterm children

BackgroundModerate and late preterm (MLPT) birth accounts for the vast majority of preterm births, which is a global public health problem. The association between MLPT and neurobehavioral developmental delays in children and the underlying biological mechanisms need to be further revealed. The “placenta-brain axis” (PBA) provides a new perspective for gene regulation and risk prediction of neurodevelopmental delays in MLPT children.MethodsThe authors performed multivariate logistic regression models between MLPT and children’s neurodevelopmental outcomes, using data from 129 MLPT infants and 3136 full-term controls from the Ma’anshan Birth Cohort (MABC). Furthermore, the authors identified the abnormally regulated PBA-related genes in MLPT placenta by bioinformatics analysis of RNA-seq data and RT-qPCR verification on independent samples. Finally, the authors established the prediction model of neurodevelopmental delay in children with MLPT using multiple machine learning models.ResultsThe authors found an increased risk of neurodevelopmental delay in children with MLPT at 6 months, 18 months, and 48 months, especially in boys. Further verification showed that APOE and CST3 genes were significantly correlated with the developmental levels of gross-motor domain, fine-motor domain, and personal social domain in 6-month-old male MLPT children.ConclusionsThese findings suggested that there was a sex-specific association between MLPT and neurodevelopmental delays. Moreover, APOE and CST3 were identified as placental biomarkers. The results provided guidance for the etiology investigation, risk prediction, and early intervention of neurodevelopmental delays in children with MLPT.

Conserved Covarying Gut Microbial Network in Preterm Infants and Childhood Growth During the First 5 Years of Life: A Prospective Cohort Study

BackgroundLongitudinally conserved microbe-microbe interactions may provide insights to understand the complex dynamic system of early-life gut microbiota among preterm infants. ObjectivesWe aimed to profile the covarying network of gut microbiota among preterm infants and investigate its potential influence on host growth (2–5 y). MethodsWe collected time-series stool samples (n = 717 from children and n = 116 from mothers) among 51 preterm and 51 full-term infants from birth up to 5 y of age and among 53 mothers. The included infants underwent time-series measurements of early-life gut microbiota (0–5 y) and growth (2–5 y) from June 2014 to April 2017. The covarying taxa that exhibited consistent covariation from day 1 to year 5 were defined as conserved features in the development of gut microbiota. Childrens’ height-for-age z score (HAZ) and weight-for-age z score were calculated according to World Health Organization Child Growth Standards. ResultsWe observed distinct dynamic patterns of both microbial alpha and beta diversity comparing preterm infants with full-term controls during the very early stage (<3 mo). Moreover, we identified a covarying network containing 10 taxa as a conserved gut microbial feature of these preterm infants from birth to 5 y old. This covarying network was distinctive between preterm and full-term infants before 3 mo of age (P < 0.001) and tended to be similar as the infants grew up. Several covarying taxa of the network during early life (<3 mo) were associated with childhood growth (2–5 y) (eg, Clostridium_sensu_stricto_1 with HAZ, β = -0.32, q < 0.01), and the human milk feeding duration was a main modulating factor. ConclusionsPreterm born children possess conserved and distinct covarying microbiota during very early life, which may have a profound influence on their growth later in life.This trial was registered at clinicaltrials.gov as NCT03373721.

Late effects of prematurity: Psychiatric outcomes of 17-year-olds born very preterm.

Very preterm (VPT) birth is a known early vulnerability factor, impacting both physical and mental health over the life-span. The additional burden of psychiatric illness in VPT adolescents is likely to adversely affect critical developmental tasks and personal, social and academic/vocational trajectories. Our aim was to examine the magnitude and extent of the risk of psychological burden by determining the prevalence of psychiatric disorders in our prospectively followed-up VPT and full-term (FT) control cohorts, in this period of developmental transition at age 17 years. Rates of psychiatric disorder in the VPT and FT control cohorts were ascertained at clinical interview of the adolescents and their care giver(s) by an adolescent psychiatrist. VPT birth was associated with a greater risk of generalised anxiety disorder (VPT vs. FT risk ratio (RR) 2.33; 95% confidence interval (CI): 1.16, 4.67, P = 0.02), as well as attentional problems (VPT vs. FT RR 3.46; 95% CI: 1.01, 11.88, P = 0.03). Although care givers of VPT adolescents reported many social and communication difficulties, and observation at clinical interview supported this, our data did not reach clinical threshold for group differences in autistic spectrum disorder. For all other psychiatric disorders, there was no difference between VPT and FT control adolescents. Our longitudinal cohort follow-up study examining the late effects of VPT birth has demonstrated increased rates of clinically significant psychiatric disorder in this period of important developmental transition. Families and health professionals need to be aware of the increased risk so they can monitor for symptoms and seek effective mental health treatments and support.

Altered gray-to-white matter tissue contrast in preterm-born adults.

To investigate cortical organization in brain magnetic resonance imaging (MRI) of preterm-born adults using percent contrast of gray-to-white matter signal intensities (GWPC), which is an in vivo proxy measure for cortical microstructure. Using structural MRI, we analyzed GWPC at different percentile fractions across the cortex (0%, 10%, 20%, 30%, 40%, 50%, and 60%) in a large and prospectively collected cohort of 86 very preterm-born (<32 weeks of gestation and/or birth weight <1500 g, VP/VLBW) adults and 103 full-term controls at 26 years of age. Cognitive performance was assessed by full-scale intelligence quotient (IQ) using the Wechsler Adult Intelligence Scale. GWPC was significantly decreased in VP/VLBW adults in frontal, parietal, and temporal associative cortices, predominantly in the right hemisphere. Differences were pronounced at 20%, 30%, and 40%, hence, in middle cortical layers. GWPC was significantly increased in right paracentral lobule in VP/VLBW adults. GWPC in frontal and temporal cortices was positively correlated with birth weight, and negatively with duration of ventilation (p < 0.05). Furthermore, GWPC in right paracentral lobule was negatively correlated with IQ (p < 0.05). Widespread aberrant gray-to-white matter contrast suggests lastingly altered cortical microstructure after preterm birth, mainly in middle cortical layers, with differential effects on associative and primary cortices.

Early biomarkers of neurodevelopmental disorders in preterm infants: protocol for a longitudinal cohort study

IntroductionPreterm (PT) infants are at high likelihood for poor neurodevelopmental outcomes, including autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD) and other neurodevelopmental disorders (NDDs), which could considerably impair the...

Five-to-Fifteen-Parental Perception of Developmental Profile from Age 5 to 8 Years in Children Born Very Preterm.

Children born very preterm have increased risk of developmental difficulties. We examined the parental perception of developmental profile of children born very preterm at 5 and 8 years by using the parental questionnaire Five-to-Fifteen (FTF) compared to full-term controls. We also studied the correlation between these age points. The study included 168 and 164 children born very preterm (gestational age < 32 weeks and/or birth weight ≤ 1500 g) and 151 and 131 full-term controls. The rate ratios (RR) were adjusted for sex and the father's educational level. At 5 and 8 years, children born very preterm were more likely to have higher scores (more difficulties) compared to controls in motor skills (RR = 2.3, CI 95% = 1.8-3.0 at 5 years and RR = 2.2, CI 95% = 1.7-2.9 at 8 years), executive function (1.7, 1.3-2.2 and 1.5, 1.2-2.0), perception (1.9, 1.4-2.5 and 1.9, 1.5-2.5), language (1.5, 1.1-1.9 and 2.2, 1.7-2.9), and social skills (1.4, 1.1-1.8 and 2.1, 1.6-2.7), and at 8 years in learning (1.9, 1.4-2.6) and memory (1.5, 1.2-2.0). There were moderate-to-strong correlations (r = 0.56-0.76, p < 0.001) in all domains between 5 and 8 years in children born very preterm. Our findings suggest that FTF might help to earlier identify children at the greatest risk of incurring developmental difficulties persisting to school-age.

The interrelatedness of cognitive abilities in very preterm and full-term born children at 5.5 years of age: a psychometric network analysis approach.

Very preterm (VP) birth is associated with a considerable risk for cognitive impairment, putting children at a disadvantage in academic and everyday life. Despite lower cognitive ability on the group level, there are large individual differences among VP born children. Contemporary theories define intelligence as a network of reciprocally connected cognitive abilities. Therefore, intelligence was studied as a network of interrelated abilities to provide insight into interindividual differences. We described and compared the network of cognitive abilities, including strength of interrelations between and the relative importance of abilities, of VP and full-term (FT) born children and VP children with below-average and average-high intelligence at 5.5 years. A total of 2,253 VP children from the EPIPAGE-2 cohort and 578 FT controls who participated in the 5.5-year-follow-up were eligible for inclusion. The WPPSI-IV was used to measure verbal comprehension, visuospatial abilities, fluid reasoning, working memory, and processing speed. Psychometric network analysis was applied to analyse the data. Cognitive abilities were densely and positively interconnected in all networks, but the strength of connections differed between networks. The cognitive network of VP children was more strongly interconnected than that of FT children. Furthermore, VP children with below average IQ had a more strongly connected network than VP children with average-high IQ. Contrary to our expectations, working memory had the least central role in all networks. In line with the ability differentiation hypothesis, children with higher levels of cognitive ability had a less interconnected and more specialised cognitive structure. Composite intelligence scores may therefore mask domain-specific deficits, particularly in children at risk for cognitive impairments (e.g., VP born children), even when general intelligence is unimpaired. In children with strongly and densely connected networks, domain-specific deficits may have a larger overall impact, resulting in lower intelligence levels.

Different aspects of visual perception are important for 12-year social functioning depending on gestational age.

Perceptual mechanisms in social functioning might promote interventions. We investigated relations between visual perception and social functioning, in preterm children. A prospective preterm cohort born in Uppsala County, Sweden, in 2004-2007 and 49 full-term controls were examined at 12 years. Aspects of visual perception, including static shapes, emotions, and time to detect biological motion, were related to social functioning and visual acuity. The preterm group comprised 25 extremely preterm children, EPT, born below 28 gestational weeks and 53 children born between 28-31 weeks. Preterm children had difficulties in perception of static shapes (p=0.004) and biological motion, p<0.001), but not in emotion perception, compared to controls. In the EPT children, poorer shape perception and lower scores on emotion perception were associated with more social problems (p=0.008) and lower visual acuity (p=0.004). Shape perception explained more variance in social functioning than emotion perception. In controls, fewer social problems were linked to faster biological motion perception (p=0.04). Static shape and biological motion perception was affected in the preterm groups. Biological motion perception was relevant for social functioning in full-term children. In EPT children, only shape perception was linked to social functioning, suggesting differential visual perception mechanisms for social deficits.

Disrupted resting-sate brain network dynamics in children born extremely preterm.

The developing brain has to adapt to environmental and intrinsic insults after extremely preterm (EPT) birth. Ongoing maturational processes maximize their fit to the environment and this can provide a substrate for neurodevelopmental failures. Resting-state functional magnetic resonance imaging was used to scan 33 children born EPT, at < 27weeks of gestational age, and 26 full-term controls at 10years of age. We studied the capability of a brain area to propagate neural information (intrinsic ignition) and its variability across time (node-metastability). This framework was computed for the dorsal attention network (DAN), frontoparietal, default-mode network (DMN), and the salience, limbic, visual, and somatosensory networks. The EPT group showed reduced intrinsic ignition in the DMN and DAN, compared with the controls, and reduced node-metastability in the DMN, DAN, and salience networks. Intrinsic ignition and node-metastability values correlated with cognitive performance at 12years of age in both groups, but only survived in the term group after adjustment. Preterm birth disturbed the signatures of functional brain organization at rest in 3 core high-order networks: DMN, salience, and DAN. Identifying vulnerable resting-state networks after EPT birth may lead to interventions that aim to rebalance brain function.

High rate of insecure attachment patterns in preterm infants at early school age.

In preterm infants, insecure attachment is associated with behavioural and emotional problems but data on attachment beyond toddler age are scarce. This study assessed attachment security at 6-8 years in very and moderate or late preterm infants. The results were compared to a non-clinical full-term sample. Attachment security of 38 very and 20 moderate or late preterm infants was assessed during a home visit with the German version of the Attachment Story Completion Task. Attachment patterns of 28 full-term controls were taken from a previous study. Primary outcomes were attachment security and attachment security score. Secondary outcomes for the preterm groups were infant behavioural problems, parental stress, perceived social support, maternal depressive symptoms, and infant development. Very preterm infants had the highest rate of insecure attachment (81%) compared to moderate or late preterm infants (60%) and full-term infants (47%); (p= 0.013). Attachment security scores differed significantly between very preterm and full-term infants (p= 0.001). Secondary outcomes were similar in very and moderate or late preterm cohorts. Prematurity was associated with an increased risk of insecure attachment at early school age. Interventions targeting attachment security are reasonable considering the high rate of behavioural problems following premature birth.

Relationship between Platelet-to-Lymphocyte Ratio and Lymphocyte-to-Monocyte Ratio with Spontaneous Preterm Birth: A Systematic Review and Meta-analysis.

Spontaneous preterm birth is one of the most common pregnancy complications in obstetric clinical practice, and its etiology is complex. The problems of low survival and high morbidity rates of premature infants need to be solved urgently. The platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR) are two novel biomarkers of inflammation, and several studies have linked PLR and LMR to spontaneous preterm birth. These systematic review and meta-analysis are aimed at analyzing the relationship between PLR and LMR in patients with spontaneous preterm birth to provide new ideas for the early prevention and treatment of spontaneous preterm births. Cochrane Library, EMBASE, PubMed, and China National Knowledge Infrastructure databases were inspected to gather PLR and LMR in patients with spontaneous preterm birth, all from the database to February 2022. Interstudy heterogeneity was evaluated using Cochran's Q test and I 2 statistic. Differences in PLR and LMR between patients with spontaneous preterm birth and full-term controls were evaluated by computing standardized mean differences and 95% confidence intervals. Publication bias and sensitivity analyses were also performed. Nine studies were included in the meta-analysis based on the inclusion and exclusion criteria. The meta-analysis showed that serum PLR values were remarkably larger for patients with spontaneous preterm birth than for full-term controls (SMD = 0.49, 95% CI: 0.13 to 0.84, P = 0.007), whereas the difference between serum LMR in patients with spontaneous preterm birth and full-term controls was not statistically significant (SMD: 0.35, 95% CI: -0.18, 0.88, P = 0.199). The results of Begg's and Egger's tests revealed that the publication bias of the meta-analysis was not significant. The outcomes of the sensitivity analysis showed that the individual studies did not influence the meta-analysis results. Current evidence shows that PLR is strongly associated with spontaneous preterm birth, whereas LMR is not. PLR has a certain clinical value in diagnosing and treating spontaneous preterm births, and our research will provide strong theoretical support for clinical work. In the future, it will be necessary to further explore the reasons for the increased PLR in the serum of patients with spontaneous preterm birth and other mechanisms inducing spontaneous preterm birth.

Corpus callosum structural characteristics in very preterm children and adolescents: Developmental trajectory and relationship to cognitive functioning

Previous studies suggest that structural alteration of the corpus callosum, i.e., the largest white matter commissural pathway, occurs after a preterm birth in the neonatal period and lasts across development. The present study aims to unravel corpus callosum structural characteristics across childhood and adolescence in very preterm (VPT) individuals, and their associations with general intellectual, executive and socio-emotional functioning. Neuropsychological assessments, T1-weighted and multi-shell diffusion MRI were collected in 79 VPT and 46 full term controls aged 6–14 years. Volumetric, diffusion tensor and neurite orientation dispersion and density imaging (NODDI) measures were extracted on 7 callosal portions using TractSeg. A multivariate data-driven approach (partial least squares correlation) and a cohort-based age normative modelling approach were used to explore associations between callosal characteristics and neuropsychological outcomes. The VPT and a full-term control groups showed similar trends of white-matter maturation over time, i.e., increase FA and reduced ODI, in all callosal segments, that was associated with increase in general intellectual functioning. However, using a cohort-based age-related normative modelling, findings show atypical pattern of callosal development in the VPT group, with reduced callosal maturation over time that was associated with poorer general intellectual and working memory functioning, as well as with lower gestational age.

Sleep and 24-hour rhythm characteristics in preschool children born very preterm and full term.

Sleep impacts the quality of life and is associated with cardiometabolic and neurocognitive outcomes. Little is known about the sleep of preterm-born children at preschool age. We, therefore, studied sleep and 24-hour rhythms of preschool children born very preterm compared with full-term children. This was a prospective cohort study comparing sleep quality and quantity of children born very preterm (gestational age [GA] < 30 weeks) with full-term children at the (corrected) age of 3 years, using (1) 2 parent-reported questionnaires (Brief Infant Sleep Questionnaire and The Munich Chronotype Questionnaire) and (2) at least 3 days of triaxial wrist actigraphy combined with sleep diary. We performed regression analyses with adjustment for sex (corrected), age, and birth weight standard deviation (SD) score. Ninety-seven very-preterm-born (median GA 27+5; interquartile range 26 + 3;29 + 0 weeks) and 92 full-term children (GA 39 + 3; 38 + 4;40 + 4 weeks) were included. Sleep problems and other reported sleep parameters were not different between groups. As measured with actigraphy, sleep and 24-hour rhythm were similar between groups, except for very-preterm born children waking up 21 minutes (4;38) minutes later than full-term children (adjusted P = .001). Based on parent reports and actigraphy, very-preterm-born children sleep quite similar to full-term controls at the corrected age of 3 years. Reported sleep problems were not different between groups. Actigraphy data suggest that preterm-born children may wake up later than children born full term. Further studies are needed to explore how sleep relates to cardiometabolic and neurodevelopmental outcomes after preterm birth and whether early interventions are useful to optimize 24-hour rhythm and sleep. Bijlsma A, Beunders VAA, Dorrepaal DJ, etal. Sleep and 24-hour rhythm characteristics in preschool children born very preterm and full term. J Clin Sleep Med. 2023;19(4):685-693.

Elevated insulin growth factor-1 in dentate gyrus induces cognitive deficits in pre-term newborns.

Prematurely born infants are deprived of maternal hormones and cared for in the stressful environment of Neonatal Intensive Care Units (NICUs). They suffer from long-lasting deficits in learning and memory. Here, we show that prematurity and associated neonatal stress disrupt dentate gyrus (DG) development and induce long-term cognitive deficits and that these effects are mediated by insulin growth factor-1 (IGF1). Nonmaternal care of premature rabbits increased the number of granule cells and interneurons and reduced neurogenesis, suggesting accelerated premature maturation of DG. However, the density of glutamatergic synapses, mature dendritic spines, and synaptic transmission were reduced in preterm kits compared with full-term controls, indicating that premature synaptic maturation was abnormal. These findings were consistent with cognitive deficits observed in premature rabbits and appeared to be driven by transcriptomic changes in the granule cells. Preterm kits displayed reduced weight, elevated serum cortisol and growth hormone, and higher IGF1 expression in the liver and DG relative to full-term controls. Importantly, blocking IGF-1 receptor in premature kits restored cognitive deficits, increased the density of glutamatergic puncta, and rescued NR2B and PSD95 levels in the DG. Hence, IGF1 inhibition alleviates prematurity-induced cognitive dysfunction and synaptic changes in the DG through modulation of NR2B and PSD95. The study identifies a novel strategy to potentially rescue DG maldevelopment and cognitive dysfunction in premature infants under stress in NICUs.

Placental telomere length shortening is not associated with severe preeclampsia but the gestational age.

Variations in telomere length (TL) have been associated with aging, stress, and many diseases. Placenta TL is an essential molecular component influencing the outcome of birth. Previous investigations into the relationship between placenta TL and preeclampsia (PE) have produced conflicting findings. We conducted a retrospective case-control analysis in this study to address the disparity. We used placenta samples from 224 births received from Hawaii Biorepository (HiBR) between 2006 and 2013, comprising 129 healthy full-term controls and 95 severe PE samples. The average absolute placental TL was calculated using the quantitative polymerase chain reaction (qPCR) technique. We utilized multiple linear regressions to associate placental TL with severe PE and other demographic, clinical and physiological data. The outcome demonstrates that the placental TL of severe PE cases did not significantly differ from that of healthy controls. Instead, there is a strong correlation between gestational age and placenta TL shortening. Placental TL also exhibits racial differences: (1) Latino moms' TL is significantly longer than non-Latino mothers' (p=0.009). (2) Caucasian patients with severe PE have shorter TL than non-Caucasian patients (p=0.0037). This work puts the long-standing question of whether severe PE influences placental TL to rest. Placental TL is not related to severe PE but is negatively associated with gestational age and is also affected by race.

Aberrant allometric scaling of cortical folding in preterm-born adults.

A universal allometric scaling law has been proposed to describe cortical folding of the mammalian brain as a function of the product of cortical surface area and the square root of cortical thickness across different mammalian species, including humans. Since these cortical properties are vulnerable to developmental disturbances caused by preterm birth in humans and since these alterations are related to cognitive impairments, we tested (i) whether cortical folding in preterm-born adults follows this cortical scaling law and (ii) the functional relevance of potential scaling aberrances. We analysed the cortical scaling relationship in a large and prospectively collected cohort of 91 very premature-born adults (<32 weeks of gestation and/or birthweight <1500 g, very preterm and/or very low birth weight) and 105 full-term controls at 26 years of age based on the total surface area, exposed surface area and average cortical thickness measured with structural magnetic resonance imaging and surface-based morphometry. We found that the slope of the log-transformed cortical scaling relationship was significantly altered in adults (very preterm and/or very low birth weight: 1.24, full-term: 1.14, P = 0.018). More specifically, the slope was significantly altered in male adults (very preterm and/or very low birth weight: 1.24, full-term: 1.00, P = 0.031), while there was no significant difference in the slope of female adults (very preterm and/or very low birth weight: 1.27, full-term: 1.12, P = 0.225). Furthermore, offset was significantly lower compared with full-term controls in both male (very preterm and/or very low birth weight: -0.546, full-term: -0.538, P = 0.001) and female adults (very preterm and/or very low birth weight: -0.545, full-term: -0.538, P = 0.023), indicating a systematic shift of the regression line after preterm birth. Gestational age had a significant effect on the slope in very preterm and/or very low birth weight adults and more specifically in male very preterm and/or very low birth weight adults, indicating that the difference in slope is specifically related to preterm birth. The shape or tension term of the scaling law had no significant effect on cognitive performance, while the size of the cortex did. Results demonstrate altered scaling of cortical surface and cortical thickness in very premature-born adults. Data suggest altered mechanical forces acting on the cortex after preterm birth.

Pulmonary function in school-age children following intravitreal injection of bevacizumab for retinopathy of prematurity

The effect of anti-vascular endothelial growth factor on neonatal lung development was inconclusive. To evaluate pulmonary function in school-age children who have received intravitreal bevacizumab (IVB) for retinopathy of prematurity (ROP), this study included 118 school-aged children who were grouped into three groups: full-term control children (group 1), preterm children who had not received IVB treatment (group 2) and preterm children with ROP who had received IVB treatment (group 3). Pulmonary function was measured by spirometry and impulse oscillometry. Pulmonary function was significantly better in group 1 than in groups 2 and 3 (all p < 0.05 in forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), forced expiratory flow between 25 and 75% of FVC (FEF25–75), and respiratory resistance at 5 Hz and difference between respiratory resistance at 5 and 20 Hz (R5-R20). There were no statistically significant differences between group 2 and group 3 in all pulmonary function parameters, including FVC, FEV1, ratio of FEV1 to FVC, FEF25-75, R5, R20, R5–R20, and respiratory reactance at 5 Hz. In conclusion, our study revealed that preterm infants receiving IVB for ROP had comparable pulmonary function at school age to their preterm peers who had not received IVB treatment.

The risk of serious bacterial infections among young ex-premature infants with fever.

Background and ObjectivesTo determine the rate of serious-bacterial-infections (SBI) in young ex-premature infants with fever, and to develop a risk-stratification algorithm for these patients.MethodsA retrospective cohort study including all infants who presented to the pediatric emergency department (ED) of a tertiary-care university-hospital between 2010 and 2020 with fever (≥38°C), were born prematurely (<37-weeks), had post-conception age of <52-weeks, and had available blood, urine, or CSF cultures. The rates of SBI by age-of-birth and age-at-visit were calculated and compared to a cohort of matched full-term controls.ResultsThe study included a total of 290 ex-premature cases and 290 full-term controls. There were 11 cases (3.8%) with an invasive bacterial infection (IBI) of either bacteremia, meningitis or both and only six controls (2.1%) with IBI (p = 0.32). Over 28-days chronologic-age, there were 10 (3.6%) IBIs among cases and no IBIs among the controls (p = 0.02). There were eight (3%) cases and three (1%) controls with IBI who were well-appearing on physical examination (p = 0.19). All eight well-appearing ex-premature infants were under 60-days adjusted-age, seven of whom (88%) were also under 28-days adjusted-age. There were 28 (10.6%) cases and 34 (12%) controls with urinary tract infection (UTI) (p = 0.5). Among cases under 60-days adjusted-age, urinalysis was not reliable to exclude UTI (50% negative).ConclusionsWell-appearing ex-preterm infants have a significant risk for IBI until the adjusted age of 28-days and for UTI until the adjusted age of 60-days. Further studies are needed to evaluate the approach to fever in this unique population.

Effect of foveal morphology on visual acuity in 4–6-year-old children with retinopathy of prematurity: a J-CREST study

Laser therapy is the most effective treatment considered for retinopathy of prematurity (ROP). We compared the foveal morphology of the retina in eyes with a history of ROP to that of full-term children. This cross-sectional comparative study included 74 patients with a history of ROP, aged 4–6 years. Among them, 41 underwent laser treatment for ROP. The clinical findings and retinal morphology in these patients were compared to that of 33 patients who had spontaneous ROP regression and 30 age-matched full-term controls. All the patients with ROP had 20/40 or better best-corrected visual acuity (BCVA). The foveal thickness was significantly thicker in laser-treated ROP eyes than in regressed ROP eyes and controls. The outer nuclear layer was significantly thicker, and the inner segment (IS) of the photoreceptors and the inner retinal layer were significantly thicker in the laser-treated ROP eyes than that in the control eyes. In the patients with ROP and controls, better BCVA was associated positively with deeper foveal depression, which was associated with a later gestational age. Our results suggest that prematurity and laser treatment affect the foveal morphology and BCVA.

Structural impact of arrested foveal development in children born extremely preterm without ROP at 6.5 years of age

ObjectivesTo characterize changes of foveal topography and microstructure of persisting foveal immaturity at 6.5 years of age in children born extremely preterm without retinopathy of prematurity (EPT-NoROP).MethodsImages from previous optical coherence tomography examinations of 37 EPT-NoROP and 92 control eyes were selected from a regional cohort of the EXPRESS (Extremely Preterm Infants in Sweden) study. Thickness of ganglion cell + inner plexiform layer (GCL+), outer nuclear layer (ONL), retinal thickness (RT) at the foveal centre (FC), foveal depth (FD) and RT at the foveal rim were evaluated.ResultsLayer thickness of GCL+, ONL and RT was increased at FC in the EPT-NoROP group. More than two-thirds had thickness values above the control limit (control mean +2 SD) at FC (GCL + 68%, ONL 76%, and RT 68%), and 50% had reduced FD compared to controls. All parameters showed a high correlation within the EPT-NoROP group, whereas no or weaker correlation was seen in control eyes. The EPT-NoROP sub-groups, divided based on the control limit, did not differ in terms of associated factors such as gestational age, birth weight, visual acuity, and refraction.ConclusionsExtreme prematurity without impact of ROP is associated with increased GCL + , ONL, and RT thickness at FC as well as reduced FD compared to full-term controls at age 6.5. This indicates that prematurity per se may have a profound effect on foveal anatomical maturation during the first months after birth. Our results suggest RT at FC to be a simple and useful measure of foveal anatomical immaturity.