Variants of the EAAT2 Glutamate Transporter Gene Promoter Are Associated with Cerebral Palsy in Preterm Infants

© 2017, The Author(s). Preterm delivery is associated with neurodevelopmental impairment caused by environmental and genetic factors. Dysfunction of the excitatory amino acid transporter 2 (EAAT2) and the resultant impaired glutamate uptake can lead to neurological disorders. In this study, we investigated the role of single nucleotide polymorphisms (SNPs; g.-200CCloseSPigtSPiA and g.-181ACloseSPigtSPiC) in the EAAT2 promoter in susceptibility to brain injury and neurodisability in very preterm infants born at or before 32-week gestation. DNA isolated from newborns’ dried blood spots were used for pyrosequencing to detect both SNPs. Association between EAAT2 genotypes and cerebral palsy, cystic periventricular leukomalacia and a low developmental score was then assessed. The two SNPs were concordant in 89.4% of infants resulting in three common genotypes all carrying two C and two A alleles in different combinations. However, in 10.6% of cases, non-concordance was found, generating six additional rare genotypes. The A alleles at both loci appeared to be detrimental and consequently, the risk of developing cerebral palsy increased four- and sixfold for each additional detrimental allele at -200 and -181bp, respectively. The two SNPs altered the regulation of the EAAT2 promoter activity and glutamate homeostasis. This study highlights the significance of glutamate in the pathogenesis of preterm brain injury and subsequent development of cerebral palsy and neurodevelopmental disabilities. Furthermore, the described EAAT2 SNPs may be an early biomarker of vulnerability to neurodisability and may aid the development of targeted treatment strategies

Randomised trial of parental support for families with very preterm children

Aim-To test the effectiveness of a home based developmental education programme in very preterm children.Methods-A randomised controlled trial was conducted of developmental or social support intervention, started at discharge for up to 2 years, in 309 consecutive survivors of 32 weeks gestation or less, born to mothers resident in greater Bristol between December 1990 and July 1993. Home visits were made by research nurses trained in either Portage (a developmental education programme) or in non-directional counselling (Parent adviser scheme). Interventions were also provided to appropriate primary care and community support for disability. Griffiths Mental Development Scales were used to assess outcome at 2 years.Results-Mean (SEM) Griffiths quotients (GQ) were: Portage 96.8 (1.6); parent adviser 95.9 (1.6); preterm control 92.9 (2.0). Despite randomisation, social variables significantly confounded these results. Using Linear regression analysis, intervention was associated with improved scores: Portage: + 4.3 GQ points (95% CI 1.6 to 7.0); parent adviser: +3.4 GQ points (1.4 to 6.1). The effect of Portage was greatest in those children with birthweights <1250 g (+5.3 GQ points (0.2 to 10.4) and in those with an abnormal neonatal cerebral ultrasound scan (+7.3 GQ points (1.6 to 13.0).Conclusion-Primary analysis showed no developmental benefit from long term family support after preterm birth. Secondary analysis controlling for the presence of adverse social markers showed similar small advantage for both intervention groups. In the smallest infants and those with brain injuries, a structured developmental programme may offer advantage over social support intervention

Efficacy of preventative parenting interventions for parents of preterm infants on later child behavior: A systematic review and meta-analysis

© 2014 Michigan Association for Infant Mental Health. The aim of this systematic review was to determine the efficacy of parenting interventions for parents of preterm infants to improve child behavior. Randomized controlled trials (RCTs) of parenting interventions for parents of preterm infants were included. Searchers were conducted of PubMed from 1951 to April 2013, the Cumulative Index to Nursing and Allied Health Literature (CINAHL) from 1982 to April 2013, Scopus from 1966 to April 2013, PsycINFO from 1840 to April 2013, the Web of Science, and the Cochrane Library. Twelve RCTs were identified that assessed child behavior. Of these studies, only data from three were able to be pooled for meta-analysis: the Infant Health and Development Program (IHDP) at 3 years, the Mother-Infant Transaction Program (modified; MITP-M) at 5 years, and the Victorian Infant Brain Studies (VIBeS Plus) at 4 years. Outcome from this analysis revealed a small, but significant, effect on child behavior favoring the intervention (95% CI: 0.08-0.32; p = .001). There is evidence that preterm parenting interventions can improve child behavior. Streamlined interventions such as MITP-M and VIBeS Plus that have a strong focus on the mother-infant relationship may have greatest potential

Early developmental intervention programmes provided post hospital discharge to prevent motor and cognitive impairment in preterm infants

Background: Infants born preterm are at increased risk of developing cognitive and motor impairment compared with infants born at term. Early developmental interventions have been provided in the clinical setting with the aim of improving overall functional outcomes for these infants. Long-term benefits of these programmes remain unclear. Objectives: Primary objective: To compare the effectiveness of early developmental intervention programmes provided post hospital discharge to prevent motor or cognitive impairment in preterm (< 37 weeks) infants versus standard medical follow-up of preterm infants at infancy (zero to < three years), preschool age (three to < five years), school age (five to < 18 years) and adulthood (≥ 18 years). Secondary objectives: To perform subgroup analyses to determine the following • Effects of gestational age, birth weight and brain injury (periventricular leukomalacia (PVL)/intraventricular haemorrhage (IVH)) on cognitive and motor outcomes when early intervention is compared with standard follow-up ∘ Gestational age: < 28 weeks, 28 to < 32 weeks, 32 to < 37 weeks.∘ Birth weight: < 1000 grams, 1000 to < 1500 grams, 1500 to < 2500 grams ∘ Brain injury: absence or presence of grade III or grade IV IVH or cystic PVL (or both) or an abnormal ultrasound/magnetic resonance image (MRI) before initiation of the intervention. • Effects of interventions started during inpatient stay with a post-discharge component versus standard follow-up care. • Effects of interventions focused on the parent-infant relationship, infant development or both compared with standard follow-up care. To perform sensitivity analysis to identify the following. • Effects on motor and cognitive impairment when early developmental interventions are provided within high-quality randomised trials with low risk of bias for sequence generation, allocation concealment, blinding of outcome measures and selective reporting bias.Search methods: The search strategy of the Cochrane Neonatal Review Group was used to identify randomised and quasi-randomised controlled trials of early developmental interventions provided post hospital discharge. Two review authors independently searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Advanced, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO and EMBASE (1966 to August 2015). Selection criteria: Studies included had to be randomised or quasi-randomised controlled trials of early developmental intervention programmes that began within the first 12 months of life for infants born before 37 weeks' gestational age. Interventions could commence on an inpatient basis but had to include a post-discharge component for inclusion in this review. Outcome measures were not prespecified, other than that they had to assess cognitive outcomes, motor outcomes or both. Rates of cerebral palsy were documented. Data collection and analysis: Two independent review authors extracted and entered data. Cognitive and motor outcomes were pooled by four age groups: infancy (zero to < three years), preschool age (three to < five years), school age (five to < 18 years) and adulthood (≥ 18 years). Meta-analysis using RevMan 5.1 was carried out to determine the effects of early developmental interventions at each age range. Subgroup analyses focused on gestational age, birth weight, brain injury, commencement of the intervention, focus of the intervention and study quality. Main results: Twenty-five studies met the inclusion criteria (3615 randomly assigned participants). Only 12 of these studies were randomised controlled trials with appropriate allocation concealment. Variability was evident with regard to focus and intensity of the intervention, participant characteristics and length of follow-up. Meta-analysis led to the conclusion that intervention improved cognitive outcomes at infancy (developmental quotient (DQ): standardised mean difference (SMD) 0.32 standard deviations (SDs), 95% confidence interval (CI) 0.16 to 0.47; P value < 0.001; 16 studies; 2372 participants) and at preschool age (intelligence quotient (IQ); SMD 0.43 SDs, 95% CI 0.32 to 0.54; P value < 0.001; eight studies; 1436 participants). However, this effect was not sustained at school age (IQ: SMD 0.18 SDs, 95% CI -0.08 to 0.43; P value = 0.17; five studies; 1372 participants). Heterogeneity between studies for cognitive outcomes at infancy and at school age was significant. With regards to motor outcomes, meta-analysis of 12 studies showed a significant effect in favour of early developmental interventions at infancy only; however, this effect was small (motor scale DQ: SMD 0.10 SDs, 95% CI 0.01 to 0.19; P value = 0.03; 12 studies; 1895 participants). No effect was noted on the rate of cerebral palsy among survivors (risk ratio (RR) 0.82, 95% CI 0.52 to 1.27; seven studies; 985 participants). Little evidence showed a positive effect on motor outcomes in the long term, but only five included studies reported outcomes at preschool age (n = 3) or at school age (n = 2). Authors' conclusions: Early intervention programmes for preterm infants have a positive influence on cognitive and motor outcomes during infancy, with cognitive benefits persisting into preschool age. A great deal of heterogeneity between studies was due to the variety of early developmental intervention programmes tested and to gestational ages of included preterm infants; thus, comparisons of intervention programmes were limited. Further research is needed to determine which early developmental interventions are most effective in improving cognitive and motor outcomes, and to discern the longer-term effects of these programmes