Distinct neural mechanisms underlying cognitive difficulties in preterm children born at different stages of prematurity

Children born very preterm (VPT) are at high-risk for altered brain development and impaired neurodevelopmental outcomes but are not well-studied before school-age. We investigated 64 four-year-olds: 37 VPT children [<32 weeks gestational age [GA]; 22 males; mean GA: 28.8 weeks ± 1.6], 25 full-term (FT) children (12 males), plus two VPT cases with ventriculomegaly and exceptionally resilient outcomes. All children underwent high-resolution structural magnetic resonance imaging and developmental assessments. Measures of brain volume, cortical thickness, and surface area were obtained. Children born VPT demonstrated reduced cerebral and cerebellar white matter volumes yet increased cerebral gray matter, temporal lobe, occipital lobe and ventricle volumes after adjusting for total brain volume. Cortical thickness was greater in the VPT children compared to FT children across all lobes. On developmental assessments, the VPT children scored lower on average than FT children while the two cases had intact cognitive abilities. In addition to larger ventricle volumes, the two cases had white matter and gray matter volumes within the ranges of the FT children. The VPT children displayed distinct differences in structural brain volumes at 4 years of age, consistent with delayed maturation. The cases with persistent ventriculomegaly and good cognitive outcomes displayed typical gray matter and increased white matter volumes, indicating a potential protective developmental phenomenon contributing to their intact cognitive abilities.

Very preterm (VPT) children (≤32 weeks) have school readiness difficulties across multiple domains, but routine follow-up is often limited. We assessed the performance of VPT children on the Before School Check (B4SC), a community-based screening programme of school readiness at 4 years of age. VPT children discharged from Wellington and Auckland Neonatal Intensive Care Units (2005-2009) were compared to a national control cohort born during the same period. Outcome measures included Parental Evaluation of Developmental Status (PEDS), parent and teacher versions of the Strengths and Difficulties Questionnaire (SDQ-P and SDQ-T) and vision and hearing screening, and were related to perinatal and demographic characteristics obtained from the Australia and New Zealand Neonatal Network database. Of 1105 VPT children, 920 were matched to the B4SC database, of whom 814 (88%) had one or more B4SC screening outcomes recorded. Compared with controls, VPT children were more likely to have abnormal PEDS (odds ratio (OR) = 1.79, 1.53-2.10), SDQ-P (OR = 1.82, 1.49-2.23), SDQ-T (OR = 1.51, 1.10-2.06), vision (OR = 2.00, 1.54-2.60) and hearing (OR = 1.95, 1.65-2.31) screen outcomes. While VPT children with an abnormal screen were more likely to be referred for further assessment, only 34%, 22%, 94% and 51% with abnormal PEDS, SDQ or vision and hearing screen, respectively, had evidence of appropriate referral. School readiness difficulties were significantly associated with birthweight z-score ≤ -1, vaginal delivery, significant cranial ultrasound abnormalities, younger maternal age, higher deprivation neighbourhood and ventilation ≥72 h. Community-based screening may be useful for identifying VPT children with school readiness difficulties, but low referral rates may limit the effectiveness of such programmes.

The effects of prematurity on hippocampal development through early childhood are largely unknown. The aims of this study were to (1) compare the shape of the very preterm (VPT) hippocampus to that of full-term (FT) children at 7 years of age, and determine if hippocampal shape is associated with memory and learning impairment in VPT children, (2) compare change in shape and volume of the hippocampi from term-equivalent to 7 years of age between VPT and FT children, and determine if development of the hippocampi over time predicts memory and learning impairment in VPT children. T1 and T2 magnetic resonance images were acquired at both term equivalent and 7 years of age in 125 VPT and 25 FT children. Hippocampi were manually segmented and shape was characterized by boundary point distribution models at both time-points. Memory and learning outcomes were measured at 7 years of age. The VPT group demonstrated less hippocampal infolding than the FT group at 7 years. Hippocampal growth between infancy and 7 years was less in the VPT compared with the FT group, but the change in shape was similar between groups. There was little evidence that the measures of hippocampal development were related to memory and learning impairments in the VPT group. This study suggests that the developmental trajectory of the human hippocampus is altered in VPT children, but this does not predict memory and learning impairment. Further research is required to elucidate the mechanisms for memory and learning difficulties in VPT children.

Early school-based learning difficulties in children born very preterm

Impaired cerebellar development is an important determinant of adverse motor and cognitive outcomes in very preterm (VPT) infants. However, longitudinal MRI studies investigating cerebellar maturation from birth through childhood and associated neurodevelopmental outcomes are lacking. We aimed to compare cerebellar volume and growth from term-equivalent age (TEA) to 7years between VPT (< 30weeks' gestation or < 1250g) and full-term children; and to assess the association between these measures, perinatal factors, and 7-year outcomes in VPT children, and whether these relationships varied by sex. In a prospective cohort study of 224 VPT and 46 full-term infants, cerebellar volumes were measured on MRI at TEA and 7years. Useable data at either time-point were collected for 207 VPT and 43 full-term children. Cerebellar growth from TEA to 7years was compared between VPT and full-term children. Associations with perinatal factors and 7-year outcomes were investigated in VPT children. VPT children had smaller TEA and 7-year volumes and reduced growth. Perinatal factors were associated with smaller cerebellar volume and growth between TEA and 7years, namely, postnatal corticosteroids for TEA volume, and female sex, earlier birth gestation, white and deep nuclear gray matter injury for 7-year volume and growth. Smaller TEA and 7-year volumes, and reduced growth were associated with poorer 7-year IQ, language, and motor function, with differential relationships observed for male and female children. Our findings indicate that cerebellar growth from TEA to 7years is impaired in VPT children and relates to early perinatal factors and 7-year outcomes.

Previous research has shown that the quality of mother-child interactions between pre-term children and their mothers tends to be poorer than that of full-term children and their mothers (Forcada-Guex, Pierrehumbert, Borghini, Moessinger & Muller-Nix, 2006). Mothers of pre-term children are less responsive and more intrusive in interactions with their children than mothers of full-term children (Forcada-Guex et al., 2006; Ionio, Lista, Mascheroni, Olivari, Confalonieri, Mastrangelo, Brazzoduro, Balestriero, Banfi, Bonanomi, Bova, Castoldi, Colombo, Introvini & Scelsa, 2017; Laing, McMahon, Ungerer, Taylor, Badawi & Spence, 2010). The current research explored differences between mothers of pre-term and full-term children in terms of interactive beliefs and style, and the potential for language development to be differentially predicted by maternal interactive beliefs and styles in pre-term versus full-term children. Independent t-tests were conducted to compare pre-term and full-term groups in relation to the measures of maternal interactive beliefs and styles. A series of multiple regression analyses were then performed separately for each group to examine the shared and unique contributions of maternal interactive beliefs and styles on full-term versus pre-term children's language development. The results showed that mothers of pre-term children were more intrusive-directive than mothers of full-term children; in contrast, mothers of full-term children were more responsive and supportive-directive in interactions with their children. Moreover, predictors of language development were different in full-term versus pre-term children; in full-term children, maternal supportive beliefs and responsiveness were significant predictors of language development evaluated by both the Bayley Scales of Infant and Toddler Development and the MacArthur Communicative Development Inventory; in the pre-term group, maternal supportive and directive beliefs, as well as supportive and intrusive directiveness, were significant predictors, with the latter being negatively associated with language development indicators. This research can shed light on how to prevent language delay in children and improve mother-child interactions that contribute to language development, which may in turn improve language development in vulnerable children, children born pre-term in particular.

Biological processes, including sleep, the hypothalamic-pituitary-adrenocortical (HPA) axis, and the autonomic nervous system (ANS), play an important role in positive development across the life-span. They are highly susceptible to early life experiences such as very preterm (VP) birth and to concurrent environmental factors such as parental sleep. Yet, research examining sleep, HPA axis activity, and ANS functioning in children and adolescents is rare. Therefore, the goal of this cumulative dissertation containing three studies is (a) to extend knowledge of the interplay between sleep, HPA axis activity, and ANS functioning during childhood and adolescence, (b) to examine the role of VP birth in these biological processes, and (c) to test whether parental insomnia symptoms are related to their children’s sleep as well as to parental perception of children’s sleep-related behavior. The samples included in the studies of this dissertation derived from the second wave of the Basel Study of Preterm Children investigating VP and full-term (FT) children and adolescents. Findings from Study 1 (Maurer et al., 2016) showed an association between elevated post-awakening HPA axis activity and a later sleep onset time, shorter sleep duration, and shorter rapid eye movement latency across the whole sample. Additionally, Study 2 (Urfer-Maurer et al., 2018) showed that predominant sympathetic activity of the ANS at rest and during different sleep stages was related to increased post-awakening HPA axis activity across the whole sample. Further, Study 1 showed that VP children had an earlier sleep onset time and lower HPA axis activity compared to FT children. Mediation analyses showed that earlier sleep onset time partially accounted for lower post-awakening HPA axis activity in VP children. Moreover, Study 2 showed that VP children had a dominance of parasympathetic over sympathetic activity of the ANS when awake and during stage 2 sleep. The results of Study 3 (Urfer-Maurer et al., 2017) revealed that maternal but not paternal insomnia symptoms were related to less restorative sleep in children. Finally, parental insomnia symptoms were related to parents’ reports of their children’s sleep-related behavior, and maternal insomnia symptoms were additionally related to paternal reports of sleep-related behavior in children. Findings of the present dissertation highlight the important role VP birth plays in altered development of biological processes, especially HPA axis activity during childhood and adolescence. Additionally, they emphasize that parental sleep difficulties may affect the sleep of their own children as well as how they perceive their children’s sleep. This dissertation outlines the practical implications of these results for the design of new treatments to foster positive development associated with sleep, HPA axis activity, and ANS functioning.

With improvements in the infant survival rates for high-risk pregnancies, the prevalence of short stature in children born prematurely and small for gestational age (SGA) has also increased. The aim of this study was to compare the effectiveness of recombinant human growth hormone (rhGH) therapy for preterm and full-term SGA children with short stature. This study included 114 children born SGA (40 preterm and 74 term), who showed no catch-up growth by age 4 years and had undergone rhGH therapy for at least one year. The clinical parameters were reviewed retrospectively. The mean height standard deviation scores (SDSs) for preterm and full-term SGA children at the start of rhGH therapy were -2.97±0.85 and -2.46±0.54, respectively. The mean duration of treatment was 3.3±1.9 years for preterm SGA children and 3.3±1.6 years for full-term SGA children. The height SDS increased to -1.13±0.96 in preterm children and -0.77±0.59 in full-term children by the fourth year of treatment. Full-term SGA children responded better to rhGH therapy than preterm children in the first year of therapy (P=0.03). Serum insulin-like growth factor 1 and insulin-like growth factor binding protein 3 levels significantly increased after the start of rhGH therapy (P<0.001). rhGH therapy significantly improved height SDS in both preterm and full-term SGA children, emphasizing the key role of this intervention for managing short stature in children born SGA, regardless of gestational age.

HighlightsExecutive functions (EFs) at ages 4, 5, and 8 and their relationship with reading abilities at age 9 were studied in 111 low-risk preterm children across three gestational age (GA) groups and 34 full-term children. No significant differences in EFs or reading abilities were found between GA groups. Linear regression analyses revealed that memory predicted lower-level reading processes (such as letter names or word reading), while higher-level reading processes (grammatical structures, sentence comprehension, and text comprehension) were affected by higher-order EFs, such as cognitive flexibility or planning.These findings suggest that low-risk preterm children exhibit similar developmental trajectories in EFs and reading skills as full-term peers and highlight the role of EFs in supporting several components of reading.What are the main findings?No significant difference was found between full-term and low-risk preterm children in their executive functions and their reading skills. Executive functions were assessed using cognitive and behavioral scale measures taken at different ages (4, 5, and 8 years), while reading skills were assessed at 9 years of age.Executive functions have a low-to-moderate predictive effect on reading skills. The effects of the different executive functions vary depending on the reading process. Verbal and non-verbal working memory had a positive significant effect on decoding skills. Cognitive flexibility and planning, as well as inhibitory control, showed positive effects on reading comprehension skills.What is the implication of the main finding?There are differences between low-risk and high-risk preterm children in their competencies in reading and in executive functions. It is important to specify the type of population studied.Early assessment of executive functions is relevant given the long-lasting effects of executive functions on reading.Background/Objectives. Previous research with extremely and very preterm children indicates that these children obtain significantly lower results in executive functions (EFs) and in reading skills than full-term (FT) children. The comparison results do not seem to be so clear when other PT children in lower-risk conditions are studied. Many studies with typically developing and preterm (PT) children indicate that reading ability is determined, in part, by EFs. Therefore, the study of EFs and reading and their relationships in low-risk PT children is pertinent. Methods. In the present study, 111 PT children, classified into three groups with different ranges of gestational age (GA), and one group of 34 FT children participated in a longitudinal study, carried out from 4 to 9 years of age. The results obtained from the four groups in different EFs measured at 4, 5, and 8 years of age, and in reading skills at 9 years of age were compared. The possible effects of EFs on reading skills were studied through multiple linear regression analyses. Results. The results obtained indicate that no significant difference was found between FT children and any of the GA groups of PT children, either in EFs or reading skills. The effect of EFs on reading skills was low to moderate. Verbal and non-verbal working memory had a positive significant effect on decoding skills (letter names, same–different, and word reading), but not on reading comprehension processes. Higher-order EFs (cognitive flexibility and planning), as well as inhibitory control, showed positive effects on reading comprehension skills. The effects of the different EFs varied depending on the reading process. Conclusions. In conclusion, low-risk PT children do not differ from FT children in their competence in EFs or reading skills. There are long-lasting effects of EFs, measured several years before, on reading skills measured at 9 years of age.

More than meets the eye: Longitudinal visual system neurodevelopment in very preterm children and anophthalmia

Higher prevalence of autism in Taiwanese children born prematurely: A nationwide population-based study

Relation between birth status and attachment security

Very preterm (VPT) children are at risk for speech and language problems throughout school age. However, little is known about early speech sound production in these children. This study aims to present a detailed description of early speech sound production and its trajectories in VPT children from 2 to 4 years of age. In addition, this study aimed to determine if early speech sound production is associated with speech production and expressive language function at 4 years of age. In 63 VPT children (< 32 weeks of gestation, 41 boys, mean gestational age = 28.8 weeks, mean birth weight = 1,135 g), speech sound production was assessed by naturalistic speech analysis at 2 years of corrected age and speech and language function by standardized tests at 4 years of age. Speech sound production was found to be abnormal in 49% of the VPT children at 2 years of age and in 19% at 4 years of age. Four different speech production trajectories from 2 to 4 years of age could be identified: a normal trajectory, an abnormal trajectory, a catch-up trajectory, and a growing-into-deficit trajectory. Early speech production, defined by the number of acquired consonants at 2 years of age, significantly predicted the word production score at 4 years of age and the sentence production score at 4 years of age. Compared to the general population, an alarmingly high proportion of VPT children showed speech production problems at 2 years of age. About half of these children showed persistent speech problems at 4 years of age. Moreover, these problems were associated with expressive language problems at the age of 4 years. https://doi.org/10.23641/asha.19310822.

To evaluate the morphology of lamina cribrosa (LC) in preterm school-aged children. A study of 120 eyes from 120 patients, including 42 full-term children (control group), 41 preterm children without retinopathy of prematurity (ROP), 16 children with ROP treated with intravitreal bevacizumab (IVB), and 21 children with ROP treated with laser. Five parameters of LC were measured by optical coherence tomography, including Bruch's membrane opening (BMO) diameter, minimum rim width (MRW), LC depth, prelaminar tissue (PLT) thickness, and LC curvature index (LCCI). The PLT thickness increased with age in full-term and preterm children (β = 30.1, P = 0.003 and β = 19.6, P < 0.001, respectively). LC depth and LCCI showed no differences between full-term and preterm children. Worse refractive errors in preterm children were associated with greater MRW and PLT thickness (β = -17.1, P = 0.001 and β = -5.7, P = 0.03, respectively). However, this relationship was not found in full-term children. Laser-treated children had greater MRW, PLT, temporal peripapillary retinal nerve fibre layer, and foveal thickness than full-term or other preterm children (all P < 0.05). Prematurity and ROP treatment may have an impact on the structural development of the LC. Refractive status plays a vital role in the LC structure of preterm children. This highlights the refractive errors of preterm children at school age that merit greater attention.

Structural covariance networks relate to the severity of epilepsy with focal-onset seizures