In utero exposure to endocrine disrupting chemicals, micro-RNA profiles, and fetal growth: a pilot study protocol.

Background: The developing fetus is particularly vulnerable to the effects of endocrine disrupting chemicals (EDCs). Molecular fingerprints of EDCs can be identified via microRNA (miRNA) expression profiles and may be etiologically implicated in the developmental origin of disease (DOHaD). Methods/design: This pilot study includes pregnant women at high risk (smoking at conception), and low risk (non-smoking at conception) for SGA birth (birthweight<10th percentile for gestational age). We have randomly selected 12 mothers (3 high-risk SGA birth, 3 low-risk SGA birth, 3 high-risk non-SGA birth, 3 low-risk non-SGA birth), with EDC measurements from gestational week 17. All offspring are female. We aim to test the stability of our samples (maternal serum, cord blood, placenta tissue), observe the differential expression of miRNA profiles over time (gestational weeks 17, 25, 33, 37, birth), and study the consistency between maternal EDC measures and miRNA expression profiles across our repeated measures. Expected impact of the study for Public Health: Results from this pilot study will inform the development of a larger cohort wide analysis, and will impact the current state of knowledge in the fields of public health, epigenetics, and the DOHaD.

Reduced white matter fractional anisotropy mediates cortical thickening in adults born preterm with very low birthweight.

Development of the cerebral cortex may be affected by aberrant white matter development. Preterm birth with very low birth weight (VLBW) has been associated with reduced fractional anisotropy of white matter and changes in cortical thickness and surface area. We use a new methodological approach to combine white and gray matter data and test the hypothesis that white matter injury is primary, and acts as a mediating factor for concomitant gray matter aberrations, in the developing VLBW brain. T1 and dMRI data were obtained from 47 young adults born preterm with VLBW and 73 term-born peers (mean age = 26). Cortical thickness was measured across the cortical mantle and compared between the groups, using the FreeSurfer software suite. White matter pathways were reconstructed with the TRACULA software and projected to their cortical end regions, where cortical thickness was averaged. In the VLBW group, cortical thickness was increased in anteromedial frontal, orbitofrontal, and occipital regions, and fractional anisotropy (FA) was reduced in frontal lobe pathways, indicating compromised white matter integrity. Statistical mediation analyses demonstrated that increased cortical thickness in the frontal regions was mediated by reduced FA in the corpus callosum forceps minor, consistent with the notion that white matter injury can disrupt frontal lobe cortical development. Combining statistical mediation analysis with pathway projection onto the cortical surface offers a powerful novel tool to investigate how cortical regions are differentially affected by white matter injury.

Is vaginal breech delivery associated with higher risk for perinatal death and cerebral palsy compared with vaginal cephalic birth? Registry-based cohort study in Norway.

OBJECTIVE: This paper aims to study if vaginal breech delivery is associated with increased risk for neonatal mortality (NNM) or cerebral palsy (CP) in Norway where vaginal delivery accounts for 1/3 of all breech deliveries. DESIGN: Cohort study using information from the national Medical BirthRegister and Cerebral Palsy Register. SETTING: Births in Norway 1999-2009. PARTICIPANTS: 520 047 term-born singletons without congenital malformations. MAIN OUTCOME MEASURES: NNM, CP and a composite outcome of these and death during birth. RESULTS: Compared with cephalic births, breech births had substantially increased risk for NNM but not for CP. Vaginal delivery was planned for 7917 of 16 700 fetuses in breech, while 5561 actually delivered vaginally. Among these, NNM was 0.9 per 1000 compared with 0.3 per 1000 in vaginal cephalic delivery, and 0.8 per 1000 in those actually born by caesarean delivery (CD) in breech. Compared with planned cephalic delivery, planned vaginal delivery was associated with excess risk for NNM (OR 2.4; 95% CI 1.2 to 4.9), while the OR associated with planned breech CD was 1.6 (95% CI 0.7 to 3.7). These risks were attenuated when NNM was substituted by the composite outcome. Vaginal breech delivery was not associated with excess risk for CP compared with vaginal cephalic delivery. CONCLUSION: Vaginal breech delivery, regardless of whether planned or actual, and actual breech CD were associated with excess risk for NNM compared with vaginal cephalic delivery, but not with CP. The risk for NNM and CP in planned breech CD did not differ significantly from planned vaginal cephalic delivery. However, the absolute risk for these outcomes was low, and taking into consideration potential long-term adverse consequences of CD for the child and later deliveries, we therefore conclude that vaginal breech delivery may be recommended, provided competent obstetric care and strict criteria for selection to vaginal delivery.

A longitudinal study of associations between psychiatric symptoms and disorders and cerebral gray matter volumes in adolescents born very preterm.

BACKGROUND: Being born preterm with very low birthweight (VLBW ≤ 1500 g) poses a risk for cortical and subcortical gray matter (GM) abnormalities, as well as for having more psychiatric problems during childhood and adolescence than term-born individuals. The aim of this study was to investigate the relationship between cortical and subcortical GM volumes and the course of psychiatric disorders during adolescence in VLBW individuals. METHODS: We followed VLBW individuals and term-born controls (birth weight ≥10th percentile) from 15 (VLBW;controls n = 40;56) to 19 (n = 44;60) years of age. Of these, 30;37 individuals were examined longitudinally. Cortical and subcortical GM volumes were extracted from MRPRAGE images obtained with the same 1.5 T MRI scanner at both time points and analyzed at each time point with the longitudinal stream of the FreeSurfer software package 5.3.0. All participants underwent clinical interviews and were assessed for psychiatric symptoms and diagnosis (Schedule for Affective Disorders and Schizophrenia for School-age Children, Children's Global Assessment Scale, Attention-Deficit/Hyperactivity Disorder Rating Scale-IV). VLBW adolescents were divided into two groups according to diagnostic status from 15 to 19 years of age: persisting/developing psychiatric diagnosis or healthy/becoming healthy. RESULTS: Reduction in subcortical GM volume at 15 and 19 years, not including the thalamus, was limited to VLBW adolescents with persisting/developing diagnosis during adolescence, whereas VLBW adolescents in the healthy/becoming healthy group had similar subcortical GM volumes to controls. Moreover, across the entire VLBW group, poorer psychosocial functioning was predicted by smaller subcortical GM volumes at both time points and with reduced GM volume in the thalamus and the parietal and occipital cortex at 15 years. Inattention problems were predicted by smaller GM volumes in the parietal and occipital cortex. CONCLUSIONS: GM volume reductions in the parietal and occipital cortex as well as smaller thalamic and subcortical GM volumes were associated with the higher rates of psychiatric symptoms found across the entire VLBW group. Significantly smaller subcortical GM volumes in VLBW individuals compared with term-born peers might pose a risk for developing and maintaining psychiatric diagnoses during adolescence. Future research should explore the possible role of reduced cortical and subcortical GM volumes in the pathogenesis of psychiatric illness in VLBW adolescents.

Associations of Maternal Vitamin B12 Concentration in Pregnancy With the Risks of Preterm Birth and Low Birth Weight: A Systematic Review and Meta-Analysis of Individual Participant Data.

Vitamin B12 (hereafter referred to as B12) deficiency in pregnancy is prevalent and has been associated with both lower birth weight (birth weight <2,500 g) and preterm birth (length of gestation <37 weeks). Nevertheless, current evidence is contradictory. We performed a systematic review and a meta-analysis of individual participant data to evaluate the associations of maternal serum or plasma B12 concentrations in pregnancy with offspring birth weight and length of gestation. Twenty-two eligible studies were identified (11,993 observations). Eighteen studies were included in the meta-analysis (11,216 observations). No linear association was observed between maternal B12 levels in pregnancy and birth weight, but B12 deficiency (<148 pmol/L) was associated with a higher risk of low birth weight in newborns (adjusted risk ratio = 1.15, 95% confidence interval (CI): 1.01, 1.31). There was a linear association between maternal levels of B12 and preterm birth (per each 1-standard-deviation increase in B12, adjusted risk ratio = 0.89, 95% CI: 0.82, 0.97). Accordingly, B12 deficiency was associated with a higher risk of preterm birth (adjusted risk ratio = 1.21, 95% CI: 0.99, 1.49). This finding supports the need for randomized controlled trials of vitamin B12 supplementation in pregnancy.

Small Size at Birth or Abnormal Intrauterine Growth Trajectory: Which Matters More for Child Growth?

Small size at birth is linked with lifelong adverse health implications. However, small size is only a proxy for the pathological process of interest, intrauterine growth restriction. We examined the extent to which information on intrauterine growth patterns improved prediction of childhood anthropometry, above and beyond birth weight alone. We obtained fetal weights estimated via serial ultrasound for 478 children in the Scandinavian Successive Small-for-Gestational-Age Births Study (1986-1988). Size at birth was classified using birth weight-for-gestational-age z scores and conditional fetal growth z scores (reflecting growth between 25 weeks' gestation and birth) using internal references. Conditional z scores were also expressed as residuals of birth weight z scores. Growth measures were linked with age-5-years anthropometric characteristics using linear regression. In univariable analyses, conditional fetal growth z scores were positively associated with z scores for child height, body mass index, total skinfold thickness, and head circumference (ß = 0.24 (95% confidence interval (CI): 0.18, 0.31), ß = 0.16 (95% CI: 0.09, 0.23), ß = 0.08 (95% CI: 0.01, 0.16), and ß = 0.37 (95% CI: 0.22, 0.52), respectively). However, conditional z scores were highly correlated with birth weight z scores (r = 0.9), and residuals explained minimal additional variation in anthropometric factors (null coefficients; adjusted R(2) increases < 0.01). Information on the intrauterine trajectory through which birth weight was attained provided little additional insight into child growth beyond that obtained from absolute size at birth.

Mental health and cerebellar volume during adolescence in very-low-birth-weight infants: a longitudinal study.

BACKGROUND: Preterm birth at very low birth weight (VLBW) poses a risk for cerebellar abnormalities and increased psychiatric morbidity compared with reference populations. We aimed to study cerebellar volumes (grey and white matter; GM, WM) and mental health in VLBW individuals and controls at 15 and 19 years of age, as well as changes between the two time points. METHODS: Forty VLBW (≤1500 g) and 56 control adolescents were included in the study at 15 years of age, and 44 VLBW and 60 control adolescents at 19 years of age. We had longitudinal data for 30 VLBW participants and for 37 controls. Clinical diagnoses were assessed following the schedule for affective disorders and schizophrenia for school-age children (KSADS). Psychiatric symptoms and function were further investigated with the Achenbach System of Empirically Based Assessment (ASEBA), ADHD Rating Scale-IV and the children's global assessment scale (CGAS). An automatic segmentation of cerebellar GM and WM volumes was performed in FreeSurfer. The MRI scans were obtained on the same 1.5T scanner at both ages. RESULTS: The VLBW group had higher rates of psychiatric disorders at both ages. Cerebellar growth trajectories did not differ between VLBW adolescents and controls, regardless of psychiatric status. However, VLBW adolescents who had a psychiatric diagnosis at both ages or developed a psychiatric disorder from 15 to 19 years had maintained smaller cerebellar WM and GM volumes than controls and also smaller volumes than VLWB adolescents who were or became healthy in this period. Moreover, there were no differences in cerebellar WM and GM volumes between controls and those VLBW who were healthy or became healthy. In the VLBW group, cerebellar WM and GM volumes correlated positively with psycho-social function at both 15 and 19 years of age, and smaller GM volumes were associated with inattention at 15 years. CONCLUSIONS: Smaller cerebellar volume in adolescents born very preterm and with VLBW may be a biomarker of increased risk of psychiatric problems in young adulthood.

Executive function relates to surface area of frontal and temporal cortex in very-low-birth-weight late teenagers.

BACKGROUND: Being born with very low birth weight (VLBW; birth weight (BW) ≤1500 g) is associated with increased risk of maldevelopment of the immature brain which may affect neurological functioning. Deficits in attention and executive function problems have been reported in VLBW survivors compared with healthy subjects. AIMS: The aim of this study was to evaluate attention and executive functions and to relate the clinical test results to cortical morphometry findings in VLBW young adults compared with term-born controls. STUDY DESIGN: Prospective follow-up study of three year cohorts of VLBW and control children from birth to adulthood. OUTCOME MEASURES: A comprehensive neuropsychological test battery was administered to 55 VLBW subjects born preterm (mean BW: 1217 g) and 81 term-born controls (mean BW: 3707 g) at age 19-20. Cerebral MRI was successfully obtained in 46 VLBW subjects and 61 controls. The FreeSurfer software package was applied for the cortical analyses based on T1-weighted MRI images. RESULTS: The VLBW group obtained inferior scores on 15 of the 29 neuropsychological measures assessing attention and executive function and on both the attention and executive function domain scores. We found positive correlations between the executive function domain score and cortical surface area, especially in the antero-medial frontal and the temporal lobes of the brain in the VLBW group. CONCLUSION: Young adults born with VLBW show deficits in attention and executive function compared with controls. The executive problems were related to smaller cortical surface area in brain regions known to be involved in higher order cognitive functioning.

Cortical trajectories during adolescence in preterm born teenagers with very low birthweight.

While cross-sectional neuroimaging studies on cortical development predict reductions in cortical volume (surface area and thickness) during adolescence, this is the first study to undertake a longitudinal assessment of cortical surface area changes across the continuous cortical surface during this period. We studied the developmental dynamics of cortical surface area and thickness in adolescents and young adults (aged 15-20) born with very low birth weight (VLBW; <1500 g) as well as in term-born controls. Previous studies have demonstrated brain structural abnormalities in cortical morphology, as well as long-term motor, cognitive and behavioral impairments, in adolescents and young adults with VLBW, but the developmental dynamics throughout adolescence have not been fully explored. T1-weighted MRI scans from 51 VLBW (27 scanned twice) and 79 term-born adolescents (37 scanned twice) were used to reconstruct the cortical surface and produce longitudinal estimates of cortical surface area and cortical thickness. Linear mixed model analyses were performed, and the main effects of time and group, as well as time × group interaction effects, were investigated. In both groups, cortical surface area decreased up to 5% in some regions, and cortical thickness up to 8%, over the five-year period. The most affected regions were located on the lateral aspect of the hemispheres, in posterior temporal, parietal and to some extent frontal regions. There was no significant interaction between time and group for either morphometry variable. In conclusion, cortical thickness decreases from 15 to 20 years of age, in a similar fashion in the clinical and control groups. Moreover, we show for the first time that developmental trajectories of cortical surface area in preterm and term-born adolescents do not diverge during adolescence.

Folic acid supplementation in early pregnancy and the risk of preeclampsia, small for gestational age offspring and preterm delivery.

OBJECTIVE: To assess whether folic acid intake during the first trimester of pregnancy is related to pregnancy outcomes preeclampsia, low birth weight or preterm birth. STUDY DESIGN: Prospective cohort study of 3647 women who were followed from the first trimester of pregnancy. Detailed information on quantity of folic acid intake before and during the first three months of pregnancy was recorded. Pregnancy outcome data were abstracted from obstetric records. RESULTS: Lean mothers who used folic acid supplementation the month before pregnancy had a 40% reduced risk of developing preeclampsia. The adjusted odds ratio (OR) with 95% confidence intervals (95%CI) for preeclampsia in lean mothers (BMI<25) who used folic acid supplements the month before pregnancy was 0.6 (95% CI 0.4-1.0). Obese mothers who used folic acid supplementation in the first trimester had an increased, but not statistically significant risk for preterm birth (adjusted OR 1.9 with 95% CI 0.9-4.0). There were no significant associations between folic acid supplementation and low birth weight. CONCLUSION: Our study supports a possible protective effect of folate intake in early pregnancy on preeclampsia in lean mothers. There was no support for any beneficial effect of folic acid use on preterm birth or low birth weight, and we found no evidence of any harmful effects of folate use for the outcomes included in our study.

Fetal growth, cognitive function, and brain volumes in childhood and adolescence.

OBJECTIVE: To evaluate the association between fetal growth pattern and cognitive function at 5 and 9 years and regional brain volumes at 15 years. METHODS: Eighty-three term-born small-for-gestational-age (SGA) neonates and 105 non-SGA neonates in a control group were available for follow-up. Based on serial fetal ultrasound measurements from gestational weeks 25-37, SGA neonates were classified with fetal growth restriction (n=13) or non-fetal growth restriction (n=36). Cognitive function was assessed at 5 and 9 years, and brain volumes were estimated with cerebral magnetic resonance imaging at 15 years. RESULTS: Small-for-gestational-age children had lower performance intelligence quotient at 5 years compared with those in a control group (107.3 compared with 112.5, P<.05). Although there were no differences between the SGA non-fetal growth restriction and control groups, the SGA fetal growth restriction group had significantly lower performance intelligence quotient at 5 years (103.5 compared with 112.5, P<.05) and 9 years (96.2 compared with 107.5, P<.05) compared with those in the control group. There were some brain volume differences at 15 years between SGA children and those in the control group, but after adjustment for total intracranial volume, age at examination, and sex, there were only significant differences between the SGA fetal growth restriction and control groups for thalamic (17.4 compared with 18.6 cm, P<.01) and cerebellar white matter volumes (21.5 compared with 24.3 cm, P<.01). CONCLUSION: Small-for-gestational-age children had lower intelligence quotient scores at 5 and 9 years and smaller brain volumes at 15 years compared with those in the control group, but these findings were only found in those with fetal growth restriction, indicating a possible relationship to decelerated fetal growth. LEVEL OF EVIDENCE: II.

Brain morphometry and cognition in young adults born small for gestational age at term.

OBJECTIVES: To examine brain volumes and cortical surface area and thickness and to relate these brain measures to cognitive function in young adults born small for gestational age (SGA) at term compared with non-SGA control patients. STUDY DESIGN: This population-based follow-up study at age 20 years included 58 term-born SGA (birth weight <10th percentile, mean: 2915 g) and 81 non-SGA controls (birth weight ≥ 10th percentile, mean: 3707 g). Brain volumes and cortical surface area and thickness were investigated with magnetic resonance imaging, which was successfully obtained in 47 SGA patients and 61 control patients. Cognitive function was assessed using the Wechsler Adult Intelligence Scale, 3rd edition. A subgroup analysis was performed in the SGA group among subjects diagnosed with fetal growth restriction (FGR) based on repeated fetal ultrasound measurements. RESULTS: The SGA group showed regional reductions in cortical surface area, particularly in the frontal, parietal, and temporal lobes. Total brain volume, cortical gray matter, cerebral white matter, and putamen volumes were reduced in the SGA group compared with control patients, but there were no differences in specific subcortical brain structure volumes when correcting for intracranial volume. Reductions were most pronounced among SGA subjects with FGR. No associations were found between brain measures and IQ measures in either group. CONCLUSION: Young adults born SGA at term show a global reduction in brain volume as well as regional reductions in cortical surface area. We speculate whether these reductions may be confined to those exposed to FGR. None of the brain measures correlated with cognition.

Neuropsychological deficits in young adults born small-for-gestational age (SGA) at term.

Reduced IQ, learning difficulties and poor school performance have been reported in small-for-gestational-age (SGA) subjects. However, few studies include a comprehensive neuropsychological assessment. Our aim was to study neuropsychological functioning in young adults born SGA at term. A comprehensive neuropsychological test battery was administered to 58 SGA subjects (birth weight <10th centile) born at term, and 81 term non-SGA controls (birth weight ≥10th centile). The SGA group obtained significantly (p < .01) lower scores on the attention, executive and memory domains compared to non-SGA controls and showed higher risk of obtaining scores below -1.5 SD on the memory domain (odds ratio = 13.3, 95% confidence interval: 1.57, 112.47). At a subtest level, the SGA group obtained lower scores on most neuropsychological tests, with significant differences on 6 of 46 measures: the Trail Making Test 3 (letter sequencing), the Wechsler Memory Scale mental control and the auditory immediate memory scale, the Design Fluency, the Stroop 3 (inhibition) and the Visual Motor Integration (VMI) motor coordination subtest. Young adults born SGA score more poorly on neuropsychological tests compared with non-SGA controls. Differences were modest, with more significant differences in the memory domain.

Effect of fructose-reduced diet in patients with irritable bowel syndrome, and its correlation to a standard fructose breath test.

OBJECTIVES: To perform a validation of dairy registrations for use as diagnostic tool in IBS and fructose malabsorption (FM). To investigate the precision of the fructose breath test (FBT) as compared with symptom score reduction on fructose-reduced diet (FRD) in a cohort of patients with Rome II defined irritable bowel syndrome (IBS). DESIGN: IBS patients diagnosed according to the Rome II criteria and with no organic gastrointestinal disease were enrolled. The patients were randomized in an open study design with a 2 week run-in on IBS diet, followed by 4 weeks w/wo additional FRD. FBT was performed in all patients. Dairy registrations of stool frequency and consistency as well as abdominal pain/discomfort and bloating on a visual analog scale (VAS) were performed during the whole study. RESULTS: A total of 182 subjects performed the study according to protocol (88 FRD, 94 controls). The VAS symptom registration performed well in validation procedures, whereas stool data showed less impressive characteristics. FRD improved symptom scores (abdominal pain/discomfort and bloating) significantly whereas no changes were observed in the control group. The effect of FRD on the stool frequency was modest but no effect was observed on the stool consistency. The FBT did not discriminate between patients with and without effect of FRD, and even in the group with a negative FBT significant improvement of symptom scores was observed. CONCLUSION: VAS measures yield reliable symptom evaluation in dairy registrations of IBS. FRD improves symptom scores in IBS patients independent of results from the FBT.

Cortical surface area and IQ in very-low-birth-weight (VLBW) young adults.

INTRODUCTION: Quantitative MRI measurements have revealed abnormalities in cortical development in children born preterm with very-low-birth-weight (VLBW). These children also have increased risk of cognitive deficits that persist into adulthood. The aim of this study was to investigate cortical surface area in VLBW young adults at age 19 compared with controls and to see whether surface area change was associated with cognitive function in the VLBW group. METHODS: Thirty-eight VLBW (BW ≤ 1500 g) and 59 control participants were included in the study. Cognitive function was assessed by Wechsler Adult Intelligence Scale (WAIS)-III. The MRI scanning was performed at 1.5 T, and for the morphometric analyses of cortical surface area the FreeSurfer software was used. RESULTS: Reduction in cortical surface area was seen in ventrolateral prefrontal, temporal and parietal regions in the VLBW group. Intelligence quotient (IQ) scores were reduced and correlated with surface area reduction in superior and inferior frontal gyri, and in medial temporal and occipital regions in the VLBW group. Brodmann areas (BAs) included in the group differences and in the IQ correlation in the VLBW group were located to the inferior frontal gyrus (BA 11, 12, 44, 45, 47), isthmus (BA 25), the superior parietal (BA 7), the inferior temporal (BA 20) and the parahippocampal gyri (BA 28, 34, 35, 36, 37). The IQ indices that made the largest contribution to the associations between IQ and surface areal change in the VLBW group were the Working Memory and the Processing Speed indices. CONCLUSIONS: Our study indicates that permanent deviations in cortical surface area still present in adulthood may explain the increased prevalence of cognitive impairments in preterm born VLBW individuals.

Small for gestational age and intrauterine growth restriction decreases cognitive function in young adults.

OBJECTIVE: To examine the effect on adult cognitive function of being born small for gestational age (SGA), and to evaluate whether cognitive function is related to intrauterine growth restriction (IUGR). STUDY DESIGN: Fifty-nine SGA subjects (birth weight <10th percentile) and 81 controls (birth weight ≥10th percentile) born at term underwent cognitive assessment with the Wechsler Adult Intelligence Scale-Third Edition at age 19-20 years. Repeated ultrasound measures of fetal growth were available for weeks 25, 33, and 37 in a subgroup of 29 SGA subjects and 75 control subjects, and these were data used to dichotomize the 29 SGA subjects into those with IUGR and those without IUGR. IUGR was defined as growth deviating more than -2 SD from the mean value of the control group. The effect of maternal smoking during pregnancy was considered as well. Group differences were analyzed using a general linear model, controlling for sex and socioeconomic status. RESULTS: The SGA group had lower full IQ scores than the control group (mean difference, -6.3; 95% CI, -2.8 to -9.7; P = .001), including lower scores on 6 of the Wechsler Adult Intelligence Scale-Third Edition subtests. In the SGA subgroup with repeated ultrasound measures, 6 of 29 subjects (21%) had IUGR, and these subjects also had a lower IQ compared with controls (mean difference, -14.0; 95% CI: -4.8 to -23.3; P = .003). Maternal smoking during pregnancy was related to lower IQ in the control group but not in the SGA group, independent of IUGR or non-IUGR status. CONCLUSION: IQ scores were lower in young adults born SGA compared with controls. Our analysis suggest that this outcome is related to IUGR.

Cortical thickness and cognition in very-low-birth-weight late teenagers.

BACKGROUND: Preterm born children with very low birth weight (VLBW: bw ≤ 1500 g) have an increased risk of perinatal brain injury which may influence the subsequent maturation of grey and white matter. Aberrant cortical development may have implications for future cognitive functioning. AIMS: The aim of this study was to measure deviations in cortical thickness and to investigate the relationship between cortical thickness, perinatal variables and IQ measurements in VLBW late teenagers compared with term-born controls. STUDY DESIGN: Prospective follow-up study of three year cohorts of children from birth to early adulthood. SUBJECT: Forty-seven VLBW and 61 term born controls were examined at ages 18-21. OUTCOME MEASURES: Cognitive function was assessed with the WAIS-III, measuring full IQ and IQ indices. We applied an automated method to reconstruct the cortical surface based on T1-weighted MRI images using the FreeSurfer software. RESULTS: We found widespread areas of thinner cerebral cortex in the left parietal and temporal lobes and thicker cortex in frontal areas bilaterally in the VLBW group compared to controls. There were positive correlations between IQ and cortical thickness in areas in ventro-lateral frontal, parietal and temporal lobes in the VLBW group. The most pronounced cortical changes were seen in the VLBW subjects with the lowest birth weight and gestational age, and in those with IQ below 89. CONCLUSION: Persistent cortical deviations seen in VLBW late teenagers are associated with immaturity at birth and level of cognitive functioning.

Metformin's effect on first-year weight gain: a follow-up study.

BACKGROUND: The impact of metformin medication in pregnant women with polycystic ovary syndrome on weight gain during pregnancy and after delivery and the impact on growth of the offspring are essentially unexplored. METHODS: This is a follow-up study of a randomized controlled trial (The Metformin treatment in pregnant PCOS women study), conducted in 11 secondary care centers. Women with PCOS were randomized to metformin (2000 mg daily) or placebo from first trimester to delivery. Questionnaires were sent to 256 participants 1 year postpartum. Maternal weight development in pregnancy and the first year after delivery and offspring anthropometry at birth and weight 1 year postpartum were registered. RESULTS: Women randomized to metformin gained less weight during pregnancy compared with those in the placebo group. In the newborns, there was no difference between the 2 groups in weight or length. One year postpartum, women who used metformin in pregnancy lost less weight and their infants were heavier than those in the placebo group (10.2 ± 1.2 kg vs 9.7 ± 1.1 kg, P = .003). CONCLUSIONS: Women randomized to metformin were heavier in the first trimester, gained less weight in pregnancy, and lost less weight in the first year postpartum compared with women randomized to placebo. Children exposed to metformin weighed more at 1 year of age.

Being born small for gestational age reduces white matter integrity in adulthood: a prospective cohort study.

BACKGROUND: Being born small for gestational age (SGA) (birth weight <10th percentile) is connected to decreased white matter (WM) integrity in newborns and increased prevalence of psychiatric symptoms in adulthood. The aims of this study were to investigate whether being born SGA at term affects WM integrity in young adulthood and to explore possible relationships between fractional anisotropy (FA) and pre- and perinatal factors and cognitive and psychiatric outcomes in adulthood in SGA and controls. METHODS: Diffusion tensor imaging and tract-based spatial statistics were conducted to test for voxelwise differences in FA in SGAs (n = 46) and controls (n = 57) at 18-22 y. RESULTS: As compared with controls SGAs had reduced FA in ventral association tracts and internal/external capsules. In the SGAs, no relationship was found between FA and intrauterine head growth in the third trimester, although total intelligence quotient was negatively correlated to FA. In controls, a positive correlation was found between FA and brain growth in the third trimester and maternal smoking. No relationship was found between FA and psychiatric measures in SGAs or controls. CONCLUSION: These results demonstrate that being born SGA leads to reduced WM integrity in adulthood, and suggest that different factors modulate the development of WM in SGA and control groups.

Folic acid supplementation in early pregnancy and asthma in children aged 6 years.

OBJECTIVE: The objective of the study was to assess whether folic acid intake during the first trimester of pregnancy is related to asthma in the offspring by the age of 6 years. STUDY DESIGN: This was a prospective cohort study of 1499 women who were followed up from the first trimester of pregnancy. Their children were followed up until they were 6 years old. RESULTS: Fifty-one percent of the women used folic acid in the month before conception and 88% in the third month of pregnancy. The adjusted odds ratio for asthma per 100 µm increase in the average daily intake of folic acid was 0.98 (95% confidence interval, 0.93-1.04). For categories of daily folate intake, there was no evidence of associations with childhood asthma or evidence of any dose response relation for any time period (all P(trend) > .05). CONCLUSION: Our results do not support any association of folic acid supplementation in pregnancy and asthma risk in offspring by age 6 years.