Microstructural alterations in association tracts and language abilities in schoolchildren born very preterm and with poor fetal growth.

BACKGROUND: Prematurity and perinatal risk factors may influence white matter microstructure. In turn, these maturational changes may influence language development in this high-risk population of children. OBJECTIVE: To evaluate differences in the microstructure of association tracts between preterm and term children and between preterm children with appropriate growth and those with fetal growth restriction and to study whether the diffusion tensor metrics of these tracts correlate with language abilities in schoolchildren with no severe neurological impairment. MATERIALS AND METHODS: This study prospectively followed 56 very preterm children (mean gestational age: 28.7 weeks) and 21 age- and gender-matched term children who underwent diffusion tensor imaging at a mean age of 9 years. We used automated probabilistic tractography and measured fractional anisotropy in seven bilateral association tracts known to belong to the white matter language network. Both groups participated in language assessment using five standardised tests at the same age. RESULTS: Preterm children had lower fractional anisotropy in the right superior longitudinal fasciculus 1 compared to term children (P < 0.05). Preterm children with fetal growth restriction had lower fractional anisotropy in the left inferior longitudinal fasciculus compared to preterm children with appropriate fetal growth (P < 0.05). Fractional anisotropy in three dorsal tracts and in two dorsal and one ventral tract had a positive correlation with language assessments among preterm children and preterm children with fetal growth restriction, respectively (P < 0.05). CONCLUSION: There were some microstructural differences in language-related tracts between preterm and term children and between preterm children with appropriate and those with restricted fetal growth. Children with better language abilities had a higher fractional anisotropy in distinct white matter tracts.

Antenatal and neonatal risk factors in very preterm children were associated with language difficulties at 9 years of age.

AIM: This Finnish study compared language and reading abilities between schoolchildren born at a very low gestational age (VLGA) of <32 weeks and at term and analysed any associations between antenatal and neonatal risk factors and language skills in the VLGA group. METHODS: We prospectively followed 76 children born at a VLGA and 50 children born at term when they reached a mean age of 9.0 (8.1-10.0) years. They attended mainstream schools and had no severe neurosensory disabilities. Receptive language ability, rapid naming and word reading were evaluated using standardised tests. RESULTS: Children in the VLGA group had lower scores for receptive language abilities (median 55.0 vs. 57.0, p = 0.01) and word reading (mean 4.4 vs. 5.1, p = 0.03) than the children in the term group. In the VLGA group, foetal growth restriction was associated with lower scores for rapid naming, early intraventricular haemorrhage was associated with poor word reading and respiratory distress syndrome was associated with poor rapid naming (p < 0.05). CONCLUSION: Schoolchildren born at a VLGA had more difficulties with receptive language abilities and word reading than children born at term. Foetal growth restriction and early neonatal morbidities were associated with language difficulties.

HIDEA syndrome is caused by biallelic, pathogenic, rare or founder P4HTM variants impacting the active site or the overall stability of the P4H-TM protein.

HIDEA syndrome is caused by biallelic pathogenic variants in P4HTM. The phenotype is characterized by muscular and central hypotonia, hypoventilation including obstructive and central sleep apneas, intellectual disability, dysautonomia, epilepsy, eye abnormalities, and an increased tendency to develop respiratory distress during pneumonia. Here, we report six new patients with HIDEA syndrome caused by five different biallelic P4HTM variants, including three novel variants. We describe two Finnish enriched pathogenic P4HTM variants and demonstrate that these variants are embedded within founder haplotypes. We review the clinical data from all previously published patients with HIDEA and characterize all reported P4HTM pathogenic variants associated with HIDEA in silico. All known pathogenic variants in P4HTM result in either premature stop codons, an intragenic deletion, or amino acid changes that impact the active site or the overall stability of P4H-TM protein. In all cases, normal P4H-TM enzyme function is expected to be lost or severely decreased. This report expands knowledge of the genotypic and phenotypic spectrum of the disease.

Children born before 32 weeks of gestation displayed impaired reading fluency, comprehension and spelling skills at 9 years of age.

AIM: Our aim was to study whether prematurity, associated with prenatal and neonatal risk factors, affects specific literacy skills among school children born at a very low gestational age (VLGA) of <32 weeks. METHODS: The study group comprised 76 prospectively followed VLGA children born between November 1998 and November 2002 at Oulu University Hospital, Finland, and 51 term controls. The median gestational age of the VLGA children was 29.0 (24.1-31.9) weeks. All children were examined at a median age of 8.9 (8.0-9.9) years in Oulu between November 2007 and November 2011. Reading fluency, comprehension and spelling skills were evaluated using standardised tests for Finnish-speaking children. RESULTS: Very low gestational age children had significantly poorer test results in reading comprehension (median 6.9 vs 8.3, P = .014) and spelling (median 35.7 vs 38.0, P = .013) than term children. Furthermore, VLGA children more often performed below the 10th percentile normal values in spelling (P = .012) compared with term controls. Foetal growth restriction was associated with lower scoring in reading fluency (P = .023) and spelling (P = .004) among VLGA children. CONCLUSION: Very low gestational age school children performed poorer in reading comprehension and spelling than term children. In addition, poor foetal growth in VLGA children was associated with literacy problems.

Diffusion tensor imaging in frontostriatal tracts is associated with executive functioning in very preterm children at 9 years of age.

BACKGROUND: Very preterm birth can disturb brain maturation and subject these high-risk children to neurocognitive difficulties later. OBJECTIVE: The aim of the study was to evaluate the impact of prematurity on microstructure of frontostriatal tracts in children with no severe neurologic impairment, and to study whether the diffusion tensor imaging metrics of frontostriatal tracts correlate to executive functioning. MATERIALS AND METHODS: The prospective cohort study comprised 54 very preterm children (mean gestational age 28.8 weeks) and 20 age- and gender-matched term children. None of the children had severe neurologic impairment. The children underwent diffusion tensor imaging and neuropsychological assessments at a mean age of 9 years. We measured quantitative diffusion tensor imaging metrics of frontostriatal tracts using probabilistic tractography. We also administered five subtests from the Developmental Neuropsychological Assessment, Second Edition, to evaluate executive functioning. RESULTS: Very preterm children had significantly higher fractional anisotropy and axial diffusivity values (P<0.05, corrected for multiple comparison) in dorsolateral prefrontal caudate and ventrolateral prefrontal caudate tracts as compared to term-born children. We found negative correlations between the diffusion tensor imaging metrics of frontostriatal tracts and inhibition functions (P<0.05, corrected for multiple comparison) in very preterm children. CONCLUSION: Prematurity has a long-term effect on frontostriatal white matter microstructure that might contribute to difficulties in executive functioning.

Very preterm children with fetal growth restriction demonstrated altered white matter maturation at nine years of age.

AIM: This study evaluated the role of preterm birth and fetal growth restriction on white matter maturation in schoolchildren without any severe neurodevelopmental impairment. METHODS: The study group comprised 56 very preterm children and 21 term children born between November 1998 and November 2002 at Oulu University Hospital, Finland. The mean gestational age of the preterm children was 28.7 (24.1-31.9) weeks. All children underwent diffusion tensor imaging at a mean age of 9.0 (8.6-9.6) years. Voxel-wise statistical analyses of the imaging data were carried out using tract-based spatial statistics. RESULTS: Preterm children with fetal growth restriction had lower fractional anisotropy and higher radial diffusivity than term controls (p < 0.05), bilaterally in several white matter areas. Preterm children without fetal growth restriction had higher mean diffusivity and axial diffusivity than term controls (p < 0.05) in analogous areas, but more asymmetrically. CONCLUSION: Preterm children had microstructural differences in white matter, compared to term-born children at a mean age of nine, and those with poor fetal growth showed widespread changes in white matter maturation compared to term-born children. Fetal growth and prematurity seemed to affect white matter maturation in a way that was still visible at that age.

Fetal hemodynamics and adverse outcome in primary school-aged children with fetal growth restriction: a prospective longitudinal study.

INTRODUCTION: Fetal growth restriction is associated with short-term and long-term mortality and morbidity. We hypothesized that adverse outcome in children with fetal growth restriction at primary school age is associated with fetoplacental circulatory abnormalities. MATERIAL AND METHODS: Comprehensive ultrasonographic assessment of fetoplacental hemodynamics was performed in 72 growth-restricted fetuses prenatally, and short-term outcome data were collected. At the median age of 9 years, mortality and morbidity were determined using medical charts and questionnaires. The impact of abnormal fetoplacental hemodynamics on mortality and morbidity with significant developmental disorders or delay were studied. RESULTS: Fetal growth restriction children with adverse long-term outcome were delivered earlier and with lower birthweights than were those with non-compromised outcome. Seventy percent of the fetal growth restriction group showed non-compromised long-term outcomes and participated in mainstream education at the appropriate age level. Absent/retrograde diastolic flow in the umbilical artery (p < 0.001), negative A-wave in the ductus venosus (p = 0.006), cardiomegaly (p = 0.02), hydrops (p = 0.006) and cardiovascular profile score <6 (p = 0.002) were associated with increased risk of adverse outcome. After adjustment for gestational age, these parameters demonstrated hazard ratios of 5.0-16.5 for adverse long-term outcome; increased systemic venous pulsatility and low cardiovascular profile score had the highest predictive power. CONCLUSIONS: Absent or reversed end-diastolic flow in the umbilical artery, reversed A-wave in the ductus venosus, cardiomegaly, hydrops, and low cardiovascular profile score are associated with adverse outcomes at primary school age in fetal growth restriction children. These fetal parameters play a significant role in the prediction of long-term outcomes for fetal growth restriction children.

Cerebral Palsy and Polymorphism of the Chemokine CCL18 in Very Preterm Children.

BACKGROUND: Prematurity and hereditary factors predispose to cerebral palsy (CP). Previously, low cord blood levels of the anti-inflammatory chemokine CCL18 have been found to be associated with risk of CP in preterm children. OBJECTIVES: To investigate the association between single nucleotide polymorphisms (SNPs) in CCL18 and susceptibility to CP, as well as the association between the SNPs and cord blood levels of CCL18. METHODS: The original population comprised very-low-gestational-age (VLGA; <32 weeks) children from northern and central Finland (25 cases, 195 controls). Five CCL18 SNPs were genotyped and examined for associations with CP and cord blood CCL18. The replication population comprised Caucasian VLGA children from southern Finland and Canada (23 cases, 248 controls). RESULTS: In the original population, SNP rs2735835 was associated with CP; the minor allele A was underrepresented in cases compared to controls (OR = 0.42, 95% CI: 0.21-0.83, p = 0.01). This association remained significant after adjustment for multiple testing and risk factors of CP, and after combining the original and replication populations (OR = 0.52, 95% CI: 0.33-0.83, p = 0.005). Intraventricular hemorrhage (IVH) additively predicted CP. The Rs2015086 genotype was modestly associated with CCL18 concentration. CONCLUSIONS: A common CCL18 polymorphism together with IVH had an additive influence on CP susceptibility. Developmentally regulated CCL18, confined to primates, may be involved in the complex sequence of events leading to brain injury and predisposition to CP phenotype.

Very preterm birth and foetal growth restriction are associated with specific cognitive deficits in children attending mainstream school.

AIM: This study investigated the association of prenatal and neonatal factors with cognitive outcomes in schoolchildren born very preterm without impairments at the age of nine. METHODS: We recruited a prospective regional cohort of 154 very low gestational age (VLGA) children of <32 weeks and 90 term-born comparison children born between November 1998 and November 2002 at Oulu University Hospital, Finland. Cognitive outcome was assessed using an inclusive neuropsychological test repertoire at the age of nine. RESULTS: The final study group comprised 77 VLGA children without cerebral palsy or any cognitive impairment and 27 term-born children. VLGA was associated with a 1.5-point [95% confidence interval (CI) 0.6-2.3] reduction in visuospatial-sensorimotor processing and a 1.2-point (95% CI 0.5-1.9) reduction in attention-executive functions scores. Foetal growth restriction (FGR) was the only clinical risk factor that was associated with cognitive outcome. Children with FGR had a significant decrease in language (1.7 points, 95% CI 0.50-3.0) and memory-learning (1.6 points, 95% CI 0.4-2.8) scores. CONCLUSION: Children born very preterm without impairments had poorer performance in specific neurocognitive skills than term-born children. FGR was an independent risk factor for compromised neurocognitive outcome in VLGA children and predicted difficulties in language, memory and learning.

Perinatal immunoproteins predict the risk of cerebral palsy in preterm children.

OBJECTIVE: To investigate whether blood cytokines during the perinatal period predict the risk of cerebral palsy (CP) in preterm infants. METHODS: This prospective cohort study comprised 169 children born before 32 weeks of gestation. Cord blood was drawn at birth, and 109 cytokines were analyzed using microarrays. Eleven cytokines were further measured from both cord and peripheral blood on days 1 and 7. Cerebral palsy was confirmed at 5 years of age. RESULTS: Cerebral palsy was diagnosed in 19 children. Five clusters of cord blood cytokines were scored using factor analysis. According to logistic regression analysis, the scores of factors 1 and 2 independently predicted the risk of CP. These cytokines included several growth factors and chemokines, and they all tended to be higher in children with CP than in children without CP. Inflammatory cytokine levels were associated with CP risk on days 1 and 7 after birth. CONCLUSION: The high blood concentrations of various cytokines during the perinatal period may relate to CP, and these cytokines may influence the pathways leading to early insult in the central nervous system. The risk profile of inflammatory cytokines is different at birth than during the first week after birth.

Chemokine CCL18 predicts intraventricular hemorrhage in very preterm infants.

BACKGROUND: Intraventricular hemorrhage (IVH) in very preterm infants is a common disease associated with long-term consequences. Risk factors of IVH remain to be further defined. AIMS: To determine whether specific immunoproteins at birth predict the risk of IVH and whether their receptors are localized at the bleeding site. METHODS: A prospective cohort consisted of 163 infants born before 32 weeks of gestation. Altogether 107 cord blood immunoproteins and 12 cytokines from peripheral blood obtained 1 and 7 days after birth were analyzed. Serial brain ultrasounds were assessed. Immunohistochemistry of a chemokine receptor from 14 autopsies was studied. RESULTS: Low levels of cord chemokine CCL18 (chemokine (C-C motif) ligand 18) robustly predicted the risk of IVH grade II-IV when ante- and neonatal risk factors were considered. Cord CCL18 increased from 32 weeks to term. During the first week after very preterm birth CCL18 increased as the risk of new IVH cases decreased. CCL18 receptor, CCR3, was detectable in choroid plexus, periventricular capillary endothelium, ependymal cells, and in germinal matrix. CONCLUSION: Low cord blood CCL18 is an independent risk factor of IVH. CCL18 may inhibit signal transduction of its receptor in periventricular cells. Defining the function and regulation of CCL18 may help to decrease the risk of IVH.