BackgroundEpidemiologic evidence suggests that periconceptional maternal folate intake is associated with decreased risk for autism spectrum disorder (ASD), but the biochemical underpinnings of this relationship and direct maternal folate measurement have not been reported.ObjectiveTo examine the association between first trimester in utero maternal metabolic risk factors (including methyl donors and folate metabolites, markers of oxidative stress and inflammation, and maternal BMI) and risk of ASD at age 4–7years.MethodsUsing a case‐control design, we identified 44 four to seven year old children with an ADOS‐confirmed diagnosis of Autism Spectrum Disorder treated at Maine Medical Center Developmental Behavioral Pediatrics Clinic (Portland, ME). Archived maternal blood samples from the first trimester of pregnancy (11–13 weeks gestational age) were identified for these cases at the Foundation for Blood Research in Scarborough, ME. 44 control samples from the biorepository were identified based on five matching criteria (sex of child, maternal age, maternal smoking status, age of sample, gestational age of sample collection.) All samples were linked with birth certificate data to identify covariates. We measured unmetabolized folic acid (FA), 5‐methyl tetrahydrofolate (MTHF), vitamin B12, homocysteine and high Sensitivity C Reactive protein (CRP) from the samples. We examined the associations between these factors in pregnancy and diagnosis of ASD with logistic regression using SAS version 9.2.ResultsMaternal and infant characteristics for cases and controls are shown in table 1. Although in other cohorts maternal obesity has been associated with increased risk of ASD, maternal obesity was not associated with ASD diagnosis in our cohort, although our power for this comparison was low. As shown in table 2, maternal first trimester serum concentration of 5‐MTHF in the lower 2 tertiles (T1, T2) (compared to the highest tertile, T3) was associated with increased odds of ASD diagnosis in offspring [OR (95% CI) T1: 6.04 (1.25, 29.30) and T2: 7.10 (1.38, 36.46)]. Maternal CRP, FA, vitamin B12, and homocysteine were not significantly associated with risk of ASD (Table 2).ConclusionsLower first trimester serum maternal 5‐MTHF concentration was associated with increased risk of developing autism in offspring in an unadjusted analysis. Analysis of markers of oxidative stress and products of folate catabolism in these samples as well as adjustment for potential confounders is underway. If these findings are confirmed in larger cohorts, this may present an opportunity for prenatal intervention to reduce the risk for autism.Support or Funding InformationThe Alden Trust Characteristics of mother‐infant pairs of ASD cases and controls. Characteristic Cases (n= 44) Controls (n= 44) p n (%) Mother's BMI at blood draw <25 kg/m2 14 (32%) 17 (39%) 0.61 25–<30 kg/m2 12 (27%) 14 (32%) 30–<35kg/m2 7 (16%) 9 (20%) 35+ kg/m2 11 (25%) 4 (9%) Gestational age at birth <37 weeks 7 (16%) 6 (14%) 0.43 37–40 weeks 36 (82%) 33 (75%) >40 weeks 1 (2%) 5 (11%) Maternal tobacco use No 35 (81%) 36 (83%) 0.32 Yes 8 (19%) 7 (17%) Unknown 1 1 Gestational diabetes No 42 (95%) 43 (98%) 0.56 Yes 2 (5%) 1 (2%) Maternal Education HS or less 13 (30%) 11 (25%) 0.26 Some college or degree 22 (50%) 22 (50%) Post college 9 (20%) 11 (25%) Paternal Education HS or less 13 (52%) 8 (32%) 0.09 Some college or degree 4 (16%) 11 (44%) Post college 8 (32%) 6 (24%) Missing 18 16 Mother's Race/ethnicity Black 2 (5%) 0 (0%) White 40 (91%) 43 (98%) Asian 2 (5%) 1 (2%) Gestational Age at blood draw (wks) 11 12 (27%) 10 (23%) 0.57 12 18 (41%) 18 (41%) 13 14 (32%) 16 (36%) Year of blood draw 2008 9 (20%) 8 (18%) 0.90 2009 11 (25%) 12 (27%) 2010 16 (36%) 14 (32%) 2011 8 (18%) 10 (23%) Infant Male Sex 30 (68%) 30 (68%) 1.00 Odds ratios (OR) and 95% CIs for associations between first trimester maternal metabolic markers and ASD diagnosis at 4–7 years compared to controls. Maternal Metabolic Marker OR (95% CI) Unmetabolized Folic Acid (FA) nmol/L <0.293 1.06 (0.36, 3.13) 0.293–<1.89 1.28 (0.40, 4.08) 1.89+ 1.00 (Referent) Serum 5‐Methyl THF nmol/L <19.3 6.04 (1.25, 29.30) 19.3–<27.4 7.10 (1.38, 36.46) 27.4+ 1.00 (Referent) Serum Vitamin B12 pg/ml <450 0.74 (0.25, 2.18) 450–<702 0.72 (0.26,1.96) 702+ 1.00 (Referent) Homocysteine micromol/L <3.09 0.65 (0.22, 1.96) 3.09–<3.68 1.25 (0.41, 3.81) 3.68+ 1.00 (Referent) Serum High Sensitivity CReactive protein (CRP) mg/L <1.7 1.00 (Referent) 1.7–<7.2 0.84 (0.29, 2.47) 7.2+ 0.68 (0.20, 2.32)

AimTo compare the impact of low-grade haemorrhage on neurocognitive function in 16-year-old adolescents born preterm, by grade of intraventricular haemorrhage, and term controls.MethodsWe evaluated 338 preterm adolescents (birth weight 600-1250g) for intelligence, executive function and memory tasks. Eleven had grade 3-4 haemorrhage, 44 had grade 2, 31 had grade 1, and 251 had no haemorrhage. Group comparisons were made with 102 term age-matched controls, and regression models used to identify the risk that low-grade haemorrhage posed for cognitive, executive function and memory deficits.ResultsPreterm adolescents with grade 2 haemorrhage had higher deficit rates of verbal intelligence, receptive vocabulary, phonemic fluency, cognitive flexibility and phonological fluency than preterm adolescents with grade 1 or no haemorrhage, compared with term controls. After excluding preterm adolescents with both grade 2 haemorrhage and cystic periventricular leukomalacia, those with isolated grade 2 haemorrhage remained at greater risk of cognitive and executive function deficits than term controls and of cognitive deficits than preterm adolescents with no haemorrhage.ConclusionOur findings suggest that preterm adolescents born in the early 1990s with isolated grade 2 haemorrhage are at increased risk of learning challenges, including cognitive and executive function deficits.

CONTEXTLower neurocognitive development scores at age 2 yr have been reported in association with euthyroid hypothyroxinemia during early pregnancy.OBJECTIVEThe objective of this study was to further explore this association with euthyroid hypothyroxinemia during early pregnancy.DESIGNThis was an observational, nested case-control study.SETTINGThe study was conducted at physician offices and prenatal clinics throughout Maine.STUDY SUBJECTSBetween May 2004 and March 2006, TSH was measured in 5734 women in conjunction with second-trimester Down syndrome screening. After completion of pregnancy, free T(4) was measured in stored second-trimester sera from euthyroid women (TSH 0.1-3.5 mIU/ml; n = 5560). Women with free T(4) at the third centile or less (n = 99) were matched with women whose free T(4) was at the 10th to the 90th centile (n = 99).INTERVENTIONSThere were no interventions.MAIN OUTCOME MEASUREBayley Scales of Infant Development (BSID III) were administered to the 198 offspring at age 2 yr. Scores for cognitive, language, and motor development were compared between matched pairs of offspring from the two groups before and after correcting for relevant variables.RESULTSUnadjusted BSID-III scores (cognitive, language, and motor) were lower by about 3% at age 2 yr among offspring of 98 hypothyroxinemic women (cases), reaching borderline significance for cognitive and motor scores. After adjustment for gestational age, the child's age at testing, maternal weight, and education, all differences diminished and became nonsignificant. Scores less than 85 were more frequent among case children but did not reach statistical significance (P = 0.14).CONCLUSIONSIsolated hypothyroxinemia during the second trimester is not associated with significantly lower BSID-III scores at age 2 yr, compared with scores for offspring of matched euthyroxinemic women.

Computational thinking (CT) has been described as the use of abstraction, automation, and analysis in problem-solving [3]. We examine how these ways of thinking take shape for middle and high school youth in a set of NSF-supported programs. We discuss opportunities and challenges in both in-school and after-school contexts. Based on these observations, we present a "use-modify-create" framework, representing three phases of students' cognitive and practical activity in computational thinking. We recommend continued investment in the development of CT-rich learning environments, in educators who can facilitate their use, and in research on the broader value of computational thinking.

BACKGROUND:Very preterm adolescents display persistent deficits in neuropsychological functions.OBJECTIVE:To compare cognitive and language outcomes at 16 years and cognitive and receptive vocabulary trajectories throughout school years between very preterm and term children and to determine child and family factors associated with better developmental trajectories.DESIGN AND METHODS:At 8, 12, and 16 years, 322 very preterm children with birth weights of 1250 g or less and 41 term children had cognitive and language testing. Hierarchical growth-curve modeling was used to delineate the differences in cognitive and receptive vocabulary development between participants. Cluster analyses allowed for the characterization of very preterm children with different patterns of cognitive and receptive vocabulary development.RESULTS:At 16 years, very preterm adolescents had deficits in general cognition and higher-order language skills (phonological awareness and phonemic decoding) compared with term peers. Although the between-group difference in cognitive scores remained stable from 8 to 16 years, very preterm children demonstrated catch-up gains in receptive vocabulary during the same period. Moreover, subgroups of very preterm children displayed developmental trajectories in cognition similar to term children (55% on the vocabulary and 46% on the block-design subtests). These children had lower rates of neurosensory impairment and mothers with higher education and were from an ethnic nonminority.CONCLUSIONS:Significant catch-up in receptive vocabulary is observed by the age of 16 years among very preterm children compared to term peers. The absence of neurosensory impairment and residing in a favorable socioeconomic milieu are associated with the most optimal developmental trajectories.

BACKGROUND: Many preterm children display school difficulties, which may be mediated by impairment in executive function and memory. OBJECTIVE: To evaluate executive and memory function among adolescents born preterm compared with term controls at 16 years. METHODS: A total of 337 of 437 (77%) adolescents born in 1989 to 1992 with a birth weight < 1250 g and 102 term controls were assessed with a battery of executive function and memory tasks. Multiple regression analyses were used to compare groups and to identify associations between selected factors and outcomes among preterm subjects. RESULTS: Adolescents born preterm, compared with term controls, showed deficits in executive function in the order of 0.4 to 0.6 SD on tasks of verbal fluency, inhibition, cognitive flexibility, planning/organization, and working memory as well as verbal and visuospatial memory. After exclusion of adolescents with neurosensory disabilities and full-scale IQ < 70, significant group differences persisted on most tests. Preterm subjects, compared with term controls, were at increased risk of exhibiting problems related to executive dysfunction, as measured with the Behavior Rating Inventory of Executive Function, on the Metacognition Index (odds ratio [OR]: 2.5 [95% confidence interval (CI): 1.2–5.1]) and the Global Executive Composite (OR: 4.2 [95% CI: 1.6–10.9]), but not on the Behavioral Regulation index (OR: 1.5 [95% CI: 0.7–3.5]). Among adolescents born preterm, severe brain injury on neonatal ultrasound and lower maternal education were the most consistent factors associated with poor outcomes. CONCLUSIONS: Even after exclusion of preterm subjects with significant disabilities, adolescents born preterm in the early 1990s were at increased risk of deficits in executive function and memory.

Maine’s one-to-one laptop program provides an ideal opportunity to explore conditions that optimize teacher integration of technology-focused curriculum into the classroom. EcoScienceWorks (ESW) is an ecology curriculum that includes targeted simulations and a code block programming challenge developed through an NSF-ITEST grant. The project was designed as a collaboration that included simulation software developers; middle school science teachers; the Maine laptop program; environmental educators; an external evaluator; and a lead organization experienced in teacher guided curriculum development. Thus, each of the elements of TPACK (technology, pedagogy, and content knowledge) worked together to produce the final ecology simulation-centered curriculum. In 2008–2009, the ESW curriculum became available statewide through the Maine laptop program. Partner teachers have transitioned their classrooms to more learning-centered environments through the use of technology and have become teacher leaders. The collaborative approach to technology focused curriculum development used in this project is a model for TPACK professional development.

Objective: To assess the blood pressure of former preterm and term matched adolescent controls and to identify risk factors associated with blood pressure at 16 years.Design: Observational cohort study. Secondary analysis of a randomized clinical trial.Setting: Three academic centres participating in the Multicenter Indomethacin IVH Prevention Trial.Participants: A total of 296 children born in 1989-1992 with birth weights 600 to <1250 g who participated in the Multicenter Indomethacin IVH Prevention Trial and 95 term controls were evaluated at 16 years.Main outcome measures: Blood pressure and predictors of blood pressure.Results: The adjusted mean difference in blood pressure for preterm adolescents was 5.1 mm Hg; p = 0.002 for systolic and 2.1 mm Hg; p = 0.027 for diastolic blood pressure. Among preterms, the primary predictors of increased systolic blood pressure were weight gain velocity between birth and 36 months (b = 8.54, p < 0.001), pre-eclampsia (b = 5.67, p = 0.020), non-white race (b = 3.77, p = 0.04) and male gender (b = 5.09). Predictors of diastolic blood pressure were weight gain velocity between birth and 36 months (b = 4.69, p = 0.001), brain injury (b = 6.51, p = 0.002) and male gender (b = -2.4, p = 0.02).Conclusions: Early programming secondary to increased early weight gain velocity, intrauterine stress and neonatal brain injury may all contribute to risk of increased blood pressure among former preterm adolescents.

OBJECTIVE:To study maternal obesity as a risk factor for preterm delivery. METHODS:Maine State Birth Records Database from 1996 through 2006 was evaluated to investigate obese pregnant women compared with normal weight women regarding risk for preterm delivery. Multiple risk factors and outcomes were studied in univariable and multivariable models. RESULTS:Among 58,112 pregnant women, 8% (n = 4653) gave birth to preterm infants. Univariable analyses revealed a relationship between obesity and increased risk of prematurity. In multivariable regressions, the most important intermediate variable appears to be gestational hypertension/preeclampsia. CONCLUSIONS:As maternal body mass index increases in pregnancy, the risk of preterm delivery and other maternal complications increases. The obesity-prematurity relationship is complex, with hypertensive disorders of pregnancy playing a crucial role. More detailed analyses of causal pathways are warranted.

Spatial literacy is a new frontier in K-12 education. This article describes a place-based introductory GIS/GPS middle school curriculum unit in which students used measuring tools, GPS units, and My World GIS software to collect physical and spatial data of trees to create a schoolyard tree inventory. Maine students completed omemory mapso of their schoolyards as a pre/post exercise assessment. A statistically significant increase in students' spatial awareness was documented. A technology-based curriculum can significantly increase students' spatial awareness especially in a place and context relevant to each student.

Objectives: To evaluate whether obesity is associated with changes in pro-inflammatory and immunomodulatory cytokines in pregnancy. Methods: We performed a cross-sectional study using maternal serum from the early second trimester to examine biomarkers associated with inflammation in relation to maternal body mass index (n=80 total). Results: Leptin and high sensitivity C-reactive protein were significantly different between groups and increased with increasing body mass index. MCP-1 was significantly increased in the morbidly obese mothers. Interleukin-2 exhibited a U-shaped relationship with body mass index; transforming growth factor-β1 demonstrated a nonsignificant negative trend with body mass index; and the levels of hepatocyte growth factor and tumor necrosis factor-α did not differ appreciably between groups. Conclusions: Maternal obesity in pregnancy is associated with changes in cytokines, protein hormones and acute phase proteins in the second trimester, with an increase in MCP-1 in the morbid obesity category, and an increase in Leptin and hsCRP with increasing BMI category.

OBJECTIVES: The goal was to examine whether indomethacin use, gender, neonatal, and sociodemographic factors predict patterns of receptive language development from 3 to 12 years of age in preterm children. METHODS: A total of 355 children born in 1989–1992 with birth weights of 600 to 1250 g were evaluated at 3, 4.5, 6, 8, and 12 years with the Peabody Picture Vocabulary Test-Revised. Hierarchical growth modeling was used to explore differences in language trajectories. RESULTS: From 3 to 12 years, preterm children displayed catch-up gains on the Peabody Picture Vocabulary Test-Revised. Preterm children started with an average standardized score of 84.1 at 3 years and gained 1.2 points per year across the age period studied. Growth-curve analyses of Peabody Picture Vocabulary Test-Revised raw scores revealed an indomethacin-gender effect on initial scores at 3 years, with preterm boys assigned randomly to receive indomethacin scoring, on average, 4.2 points higher than placebo-treated boys. However, the velocity of receptive vocabulary development from 3 to 12 years did not differ for the treatment groups. Children with severe brain injury demonstrated slower gains in skills over time, compared with those who did not suffer severe brain injury. Significant differences in language trajectories were predicted by maternal education and minority status. CONCLUSION: Although indomethacin yielded an initial benefit for preterm boys, this intervention did not alter the developmental trajectory of receptive language scores. Severe brain injury leads to long-term sequelae in language development, whereas a socioeconomically advantaged environment supports better language development among preterm children.

OBJECTIVES. Our goals were to compare cognitive, language, behavioral, and educational outcomes of preterm children to term controls and to evaluate the impact of neonatal brain injury, indomethacin, and environmental risk factors on intellectual function at 12 years of age.METHODS. A total of 375 children born in 1989–1992 with birth weights of 600 to 1250 g enrolled in the Indomethacin Intraventricular Hemorrhage Prevention Trial and 111 controls were evaluated. Neuropsychometric testing, neurologic examination, and interviews on educational needs were completed. Severe brain injury was defined as the presence of grade 3 to 4 indomethacin intraventricular hemorrhage, periventricular leukomalacia, or severe ventriculomegaly on cranial ultrasound.RESULTS. On the Wechsler Scales of Intelligence for Children, the preterm cohort obtained a full-scale IQ of 87.9 ± 18.3, verbal IQ of 90.8 ± 18.9, and performance IQ of 86.8 ± 17.9. Preterm children obtained scores 6 to 14 points lower than term controls on all psychometric tests after adjustment for sociodemographic factors. On the Clinical Evaluation of Language Fundamentals (test of basic language skills), 22% to 24% of preterm children scored in the abnormal ranges (<70) as opposed to 2% to 4% of controls. Preterm children with and without brain injury required more school services (76% and 44% vs 16%), and support in reading (44% and 28% vs 9%), writing (44% and 20% vs 4%), and mathematics (47% and 30% vs 6%) compared with controls. Preterm children also displayed more behavior problems than their term counterparts. Severe neonatal brain injury was the strongest predictor of poor intelligence. Antenatal steroids, higher maternal education, and 2-parent family were associated with better cognition, whereas minority status incurred a disadvantage. Indomethacin did not affect intellectual function among preterm children.CONCLUSIONS. Preterm children born in the early 1990s, especially those with severe brain injury, demonstrate serious deficits in their neuropsychological profile, which translates into increased use of school services at 12 years.

Alpha-fetoprotein (AFP) testing has been employed since the 1970s to screen pregnant women for the presence of open neural tube defects in the fetus (Brock et al., 1974). Along with fetal neural tube defects, several other conditions are known to affect the maternal serum alpha-fetoprotein (MSAFP) value including multiple gestation, maternal race, bleeding during pregnancy, and the presence of other fetal anomalies such as gastroschisis and omphalocele. At least 11% of pregnant women in the United States smoke during their pregnancy (Morbidity and Mortality Weekly Report, 2004); actual rates are likely even higher than this due to maternal under-reporting of smoking during pregnancy (England et al., 2007). Our objective was to determine whether maternal smoking during pregnancy is associated with increased falsepositive rates for MSAFP screening [i.e. MSAFP values greater than or equal to 2.0 or 2.5 multiples of the median (MoM)].

Objectives To use functional magnetic resonance imaging (fMRI) to test the hypothesis that subjects who were born prematurely develop alternative systems for processing language.Study design Subjects who were born prematurely (n = 14; 600-1250 g birthweight) without neonatal brain injury and 10 matched term control subjects were examined with a fMRI passive listening task of language, the Clinical Evaluation of Language Fundamentals (CELF) and portions of the Comprehensive Test of Phonological Processing (CTOPP). The fMRI task was evaluated for both phonologic and semantic processing.Results Although there were differences in CELF scores between the subjects born prematurely and control subjects, there were no significant differences in the CTOPP measures in the 2 groups. fMRI studies demonstrated that the groups differentially engaged neural systems known to process language. Children born at tern were significantly more likely to activate systems for the semantic processing of language, whereas subjects born prematurely preferentially engaged regions that subserve phonology.

BACKGROUND:Previous studies have demonstrated that indomethacin lowers the incidence and decreases the severity of intraventricular hemorrhage, as well as improves the cognitive outcome, in prematurely born male infants. OBJECTIVE:The purpose of this work was to use functional magnetic resonance imaging to test the hypothesis that neonatal indomethacin treatment would differentially affect brain activation across genders in school-aged, prematurely born children during performance of a language task. METHODS:Forty-seven prematurely born children (600-1250-g birth weight) and 24 matched term control subjects were evaluated using a functional magnetic resonance imaging passive language task and neurodevelopmental assessments that included the Wechsler Intelligence Scale for Children-III and the Peabody Picture Vocabulary Test-Revised. Neural activity was assessed during both phonologic and semantic processing in the functional magnetic resonance imaging protocol. RESULTS:Neurodevelopmental assessments demonstrated significant differences in full-scale, verbal, and performance intelligence quotient, as well as Peabody Picture Vocabulary Test scores, between the preterm and term control subjects. Rates of perinatal complications did not differ significantly across preterm treatment groups, but male preterm subjects randomly assigned to saline tended to have lower Peabody Picture Vocabulary Test-Revised scores than did all of the other preterm groups. During phonological processing, a significant treatment-by-gender effect was demonstrated in 3 brain regions: the left inferior parietal lobule, the left inferior frontal gyrus (Broca's area), and the right dorsolateral prefrontal cortex. CONCLUSIONS:These data demonstrate a differential effect of indomethacin administration early in postnatal life on the subsequent development of neural systems that subserve language functioning in these male and female preterm infants.