Individual differences in cognitive ability and social behaviour are influenced by the variability in the structure and function of the limbic system. A strong heritability of the limbic cortex has been previously reported, but little is known about how genetic factors influence specific limbic networks. We used diffusion tensor imaging tractography to investigate heritability of different limbic tracts in 52 monozygotic and 34 dizygotic healthy adult twins. We explored the connections that contribute to the activity of three distinct functional limbic networks, namely the dorsal cingulum , the ventral cingulum and the fornix  and the uncinate fasciculus . Genetic and environmental variances were mapped for multiple tract-specific measures that reflect different aspects of the underlying anatomy. We report the highest heritability for the uncinate fasciculus, a tract that underpins emotion processing, semantic cognition, and social behaviour. High to moderate genetic and shared environmental effects were found for pathways important for social behaviour and memory, for example, fornix, dorsal and ventral cingulum. These findings indicate that within the limbic system inheritance of specific traits may rely on the anatomy of distinct networks and is higher for fronto-temporal pathways dedicated to complex social behaviour and emotional processing. Socio-emotional functioning and behaviour depend on the coordinated activity of the limbic system, composed of specific cortical and subcortical regions interconnected by white matter tracts  and dizygotic (DZ) twins raised in the same family. The heritability is reflected in the difference in correlations between MZ and DZ twins, because MZ twins share all their genetic sequence while DZ twins share approximately 50% of their genes. If MZ twins resemble each other more than DZ twins, the trait can be assumed to be heritable. Furthermore, using structural equation modelling (SEM) the phenotypic variance can be parsed into genetic and environmental components  , hippocampus (64–71%), and amygdala (55–71%)  tractography permit to reliably reconstruct and study specific white matter pathways neonates . PreviouTo the best of our knowledge, there is no DTI study that has explored heritability of limbic tracts in healthy adults using tractography. Here we used DTI tractography and univariate twin modelling to study the heritability of specific limbic pathways in healthy adults. We compared the dorsal cingulum , the ventral cingulum and the fornix  and the uncinate fasciculus  in 52 MZ and 34 DZ adult twins. The contributions of genes and environment were studied on multiple tract-specific measures including volume, fractional anisotropy and mean diffusivity that reflect different aspects of the underlying anatomy, microarchitecture, and biology.In this study, we included 86 healthy right-handed adult twins, 26 MZ and 17 DZ twin pairs, recruited from a volunteer twin register at the Institute of Psychiatry, Psychology and Neuroscience  and by national media advertisements. Mean age for MZ twins was 35.5 years (age range 21–56 years), and 42.5 years (age range 20–62 years) for DZ twins. All DZ twin pairs included in this study were same-sex pairs. Opposite-sex pairs were excluded to avoid inflation of heritability estimates due to an overall lower DZ correlation due to qualitative sex differences . Of the 2 applied along directions uniformly distributed in space.DTI data were acquired using a GE Signa 1.5-T LX MRI system  with maximum gradient amplitude of 40 mT/m and an acquisition sequence fully optimized for DTI and tractography of white matter. All images were acquired from the whole brain, with sections parallel to the anterior–posterior commissure line. Using a peripherally gated echo planar imaging pulse sequence, each DTI-MRI volume was acquired from 60 contiguous 2.5 mm thick slices with a field of view of 240 × 240 mm and an acquisition matrix size of 96 × 96 pixels, giving an isotropic voxel size of 2.5 mm × 2.5 mm × 2.5 mm. Echo time was 102 ms. Acquisitions were peripherally gated with an effective repetition time of 15 R–R intervals. At each location, 7 images were acquired without diffusion weighting, together with 64 images with a weighting of 1300 s/mmDiffusion data were analysed using ExploreDTI . FollowiThe tractography data were visualized using TrackVis  to perform the virtual dissection of white matter bundles.We used a two-regions of interest (ROI) approach to dissect the uncinate fasciculus, in line with the method previously described by our laboratory . The firWe used a one-ROI approach to dissect the fornix, as described previously by our laboratory . This chIn this study, we introduce a novel method for segmenting the cingulum bundle into its dorsal and ventral components, in contrast to the one-ROI approach for dissecting the whole cingulum bundle described previously by our group . Previout-tests and Levene’s test, respectively).For each limbic tract, namely fornix and bilateral dorsal cingulum, ventral cingulum, and uncinate fasciculus, the number of voxels touched by the tract streamlines was calculated as a surrogate measure of the tract volume (referred from now on as Volume), together with average tract-specific measures of FA and MD. We confirmed that these quantitative measures were normally distributed, and that there was homogeneity of means and variances across the measures (using paired A comparison of intra-class correlation coefficients (ICCs) of DTI measures in MZ and DZ twins provided initial descriptive statistics on the presence of genetic effects. An MZ ICC that is at least twice as large as a DZ ICC indicates that this measure is largely influenced by genetic factors. An MZ correlation larger than, but less than twice the DZ correlation, indicates the significant effect of shared environmental factors .A) effects, shared environmental (C) effects, environmental influences that make the twins more similar, and non-shared or specific environmental influences (E) that contribute to differences between the twins and also include a possible measurement error , with their 95% confidence intervals calculated and a series of nested models compared. A full ACE model was compared to the nested AE, CE and E models . However, in cases where effect sizes, sample sizes or trait prevalence are low, statistical power for univariate twin analyses can become an issue . Estimates are significant if the reported maximum likelihood 95% confidence intervals do not contain zero.Prior to quantitative genetic model fitting of the extracted diffusion measures from the limbic connections, age, sex and handedness were regressed out using SPSS, and residuals standardized for subsequent analysis. On that note, we have recently reported the absence of gender differences among the limbic tracts studied suggesting that this bias was unlikely to influence the findings , to provnt error . The proP < 0.05). This may suggest high genetic or shared environmental effects on the anatomy of the limbic tracts. The ICCs of the right MD in both ventral cingulum and fornix were high and significant in both MZ and DZ twins, suggesting presence of shared environmental effects. Representative examples of the anatomy of the four limbic tracts in MZ and DZ twin pairs are shown in The ICC results for FA, MD and volume measures extracted from four limbic tracts are shown in A), common environmental (C) and unique environmental (E) factors on the variability of the volume, FA and MD measures of the four limbic tracts (A) and shared environmental (C) effects were non-significant, but significant when tested together as familial effect (A + C)  accounted for 49% and 66% of variance in the left and right volume of dorsal cingulum, respectively, with significant familial effect present only in the left hemisphere (51%), and smaller insignificant familial effect (36%) in the right hemisphere where the E model was the best fit. In contrast to the volume, genetics (A) accounted for most of the variance in the right MD (73%), while significant familial effects (A + C) accounted for 62% of left MD. Heritability of FA was high and accounted for 56% and 45% of variance in the left and right hemisphere respectively  significantly explained most of the variance in FA and MD of the left ventral cingulum . In contrast, the variability in FA and MD in the right hemisphere was influenced mostly by the familial factors (A + C) (61–63%), and less so by specific environment (37–39%). Variability of the volume measures was to a similar degree determined by both familial and specific environmental factors independent of the hemisphere  of fornix. In contrast, familial effects had lower effect on the variability of FA and volume  .Table 3High genetic effects significantly accounted for most of the variability in the left FA (80%) and right MD (58%) of the uncinate fasciculus. It is important to note that the heritability of the right FA might be slightly inflated, because shared environmental factors might play a role as well in the 71% (ACE model was the best fit). Taken together, the familial effects explained 70–80% variability in the left, and 71–81% variability in the right hemisphere of MD and FA, respectively. Familial effects were also high for volume measures, accounting for 64% of the variance in the left, and 68% in the right hemisphere .Table 4In this study, we have used DTI tractography to investigate heritability of different limbic tracts important for memory and integrated socio-emotional processing. To our knowledge, this is the first twin study in healthy adults based on multiple tract-specific measures of the limbic system pathways.We observed the highest heritability for bilateral uncinate fasciculus, where genetic and/or familial factors explained 64–80% of variance in the microstructural measures of FA, MD and volume. This tract is the main connection of the temporo-amygdala-orbitofrontal network that supports emotion processing, semantic cognition and social behaviour. Previous literature suggests an increase of the genetic effect on the FA of the uncinate fasciculus over time, with low heritability observed in neonates  and ventral cingulum . The variability of the microstructure  of the left ventral cingulum is mostly explained by specific environmental effects  compared to the right ventral cingulum, whose microstructural variability is predominantly explained by familial effects . Previously, differences in heritability estimates were related to differences in white matter asymmetries . The onlTogether with the ventral cingulum, fornix is part of the hippocampal-diencephalic-retrosplenial network important for memory . Fornix The implications of these findings may be significant to our understanding of heritability of social and emotional processing in terms of personality and healthy adult cognition, as well as disordered functioning. Nowadays, DTI measures are starting to be used as phenotypes for genome-wide association and linkage studies (E). Furthermore, standard limitations of the classical twin study design should be taken into account, such as assumptions of equal environments between MZ and DZ twins  effects (C and A (genetic) effects in combination, when they were statistically significant together, and expressing them as ‘familial effects’  and dorsal cingulum  and a weaker but still high effect on the tracts that underpin memory, that is, left ventral cingulum and fornix . In the light of the differential role that these networks have with respect to social and cognitive functioning, these findings might have important translational implications.


Recent studies have noted differences in social acquiescence and interpersonal relations among adults born preterm or with very low birth weight compared to full term adults. In addition, birth weight has been observed to be negatively correlated with lie-scale scores in two studies. We attempted to replicate and extend these studies by examining young adult lie-scale scores in a Danish birth cohort.Weight, length and head circumference of 9125 children from the Copenhagen Perinatal Cohort were measured at birth and at 1, 3 and 6 years. A subsample comprising 1182 individuals participated in a follow-up at 20–34 years and was administered the Eysenck Personality Questionnaire (EPQ) which includes a lie-scale . Associations between lie-scale scores and weight, length and head circumference respectively were analysed by multiple linear regression adjusting for single-mother status, parity, mother’s age, father’s age, parental social status, age at EPQ measurement, intelligence, and adult size.Male infants with lower weight, length, and head-circumference at birth and the following three years grew up to have higher scores on the lie-scale as young adults. Most of these associations remained significant after adjustment for the included covariates. No associations were found for females. Analyses were also conducted with neuroticism, extraversion and psychoticism as outcome variables, but no significant associations were found for these traits after adjustment.The findings replicate and extend findings from previous studies suggesting that size at birth and during the first three years of life is significantly associated with social acquiescence in adult men. They highlight the potential influence of prenatal and early postnatal development on personality growth and development. Birth weight (kg), length (cm) and head circumference (cm) were measured immediately after birth by either a midwife or a nurse and again at 1, 3 and 6 years (Villumsen The adult follow-up took place when the participants were 20.3–34.5 years old (SD = 4.31). Among other measures, the comprehensive assessment included the following:Eysenck Personality Questionnaire (EPQ) developed in 1975 (Eysenck and Eysenck Weight (kg), length (cm), and head circumference (cm) were obtained as part of a comprehensive assessment of physical characteristics.The complete Wechsler’s Adult Intelligence Scale (WAIS) was administered Wechsler , and theThe missing data rate on weight, length, and head circumference between the ages of 0 and 6 years varied from 2.8% to 49.5% with missing data rates generally increasing with increasing age of the child. Participants with incomplete information on exposure variables were excluded from the analysis in which the particular exposure was analysed. T-tests were used to evaluate associations between birth weight and potential confounding factors and mediators Table .Table 1Estimates of the associations between weight, length, and head circumference during the first six years and personality traits in adulthood were computed by means of multiple linear regression models Rothman  adjustinTo evaluate the independent contribution of size at 1, 3 and 6 years, previous growth variables  were included as covariates in a separate analysis. In several other studies, intelligence in adulthood has been found to be associated with size at birth  and analysed using 40 imputed datasets Schafer . Adjusteas predictors of neuroticism, where the quadratic component explained 0.57% and 0.60% respectively).The assumption of normal distribution of residuals of the lie-scale score was evaluated graphically and only showed minor deviations which should not bias estimates or standard-errors , while it was -0.11 (p < 0.05) for length at 1 year Table . AdjustiFor males, inclusion of adult intelligence as covariate did not change the overall pattern of results, although weight, length, and head circumference at age 3 were no longer significantly associated with lie-scale scores. When adjusting for adult measures of weight and head-circumference, the estimates for weight at the ages of 1 and 3 years and head-circumference at birth and at 3 years increased. The estimates for length generally became smaller and non-significant when adjusting for adult height. Thus, it is possible that adult height may mediate the associations between early physical growth and size and adult personality. Imputing missing values did not change the adjusted estimates noteworthily.No significant associations with physical size were found for the lie-scale in women Table .extraversion, significant associations were found only for women with weight at 1 year  and 6 years , but after adjustment for previous growth these estimates became non-significant. For neuroticism, no significant associations were found for either men or women for any of the exposure variables. Associations with psychoticism were found only for women where weak associations were observed for birth weight and birth length. These associations, however, became non-significant after adjustment for covariates. (Data not shown). The lie-scale was significantly correlated with extraversion , psychoticism , and intelligence  (Data not shown).Extraversion, neuroticism and psychoticism showed few significant associations with weight, length and head circumference during the first six years: For Our analyses reveal associations between small size at birth, at 1 year and at 3 years of age, and a higher score on the EPQ lie-scale in adulthood. Male infants with lower weight, length, and head-circumference at birth and the following three years grew up to have higher scores on the lie-scale as young adults.The main advantage of this study is the prospective design including real-time documentation of weight, length and head-circumference repeated over a period of six years. Nevertheless, the frequency of missing data tended to be high especially for measures at the 3 and 6 year assessments. A further limitation of the study is that Type I error is a possibility, as we conducted tests on 12 measures of weight, length and head-circumference. However, the fact that the lie-scale was consistently associated with weight, length and head-circumference, in addition to the fact that none of the other EPQ scales showed significant associations, points towards a consistent pattern and thus a non-incidental finding.As in all observational studies, there may be unrecognized confounding factors associated with size and lie-scale scores. Single-mother status, parity, mother’s age, father’s age, parental social status, age at EPQ measurement, intelligence, and adult size were considered confounding or mediating factors in the linear regression models. However, there may be other unobserved confounding factors influencing both physical growth and brain development (see: “Interpretation of findings”). These factors were not included in the analyses as appropriate data were not available, and therefore we do not know the impact of these factors on the associations at hand.The most comparable findings from previous studies are: (1) The study by Allin et al.  who founOther studies support the two studies by pointing towards low birth weight or preterm birth as being associated with social acquiescence and interpersonal relations, such as difficulties in establishing social contacts  may contribute to size at birth and growth in childhood in addition to affecting the overall development of the brain and thereby the development of personality. Previous studies suggest that possible characteristics in the brain associated with lie-scale scores are striatal D2/3 receptor availability which in several studies have been shown to be negatively correlated with lie-scale scores (Egerton et al. The inverse association between size during the first three years and lie-scale scores in adulthood might be explained by several biological or psychological mechanisms. A psychological explanation is that the experience of being large or small is an important factor in the causal network leading to a high lie-scale score. A recent study found that babies down to the age of 8 months were able to perceive social dominance or hierarchy on the basis of mere physical size (Thomsen et al. Due to our insufficient knowledge of the traits assessed by the lie scale, the developmental trajectories of these traits and the factors influencing thems, it is not possible to reach conclusions concerning biological and psychological explanations, and the interpretation of the associations between early size and the traits assessed by the lie scale remains an open question.The results suggest that scores on the EPQ lie-scale are associated with weight, length, and head-circumference at birth and the following three years in men, while no significant associations were found for the lie-scale in women. Although the mechanisms underlying these associations remain largely unidentified, the findings highlight the potential influence of prenatal and early postnatal development on personality growth and development.As this is the first study to investigate scores on the lie-scale in relation to early physical growth and size, more research should be conducted in the area to elucidate the present findings. In particular, the psychological conceptualization of the lie-scale should be further evaluated in empirical studies, and in addition, further studies of possible confounding and mediating factors should be conducted to better evaluate the causal network leading to empirical associations between early physical growth and size and scores on the lie scale.


To assess the relationship between clinically assessed Upper Motor Neuron (UMN) disease in Amyotrophic Lateral Sclerosis (ALS) and local diffusion alterations measured in the brain corticospinal tract (CST) by a tractography-driven template-space region-of-interest (ROI) analysis of Diffusion Tensor Imaging (DTI).This cross-sectional study included 34 patients with ALS, on whom DTI was performed. Clinical measures were separately obtained including the Penn UMN Score, a summary metric based upon standard clinical methods. After normalizing all DTI data to a population-specific template, tractography was performed to determine a region-of-interest (ROI) outlining the CST, in which average Mean Diffusivity (MD) and Fractional Anisotropy (FA) were estimated. Linear regression analyses were used to investigate associations of DTI metrics  with clinical measures , along with age, sex, handedness, and El Escorial category as covariates.For MD, the regression model was significant (p = 0.02), and the only significant predictors were the Penn UMN Score (p = 0.005) and age (p = 0.03). The FA regression model was also significant (p = 0.02); the only significant predictor was the Penn UMN Score (p = 0.003).Measured by the template-space ROI method, both MD and FA were linearly associated with the Penn UMN Score, supporting the hypothesis that DTI alterations reflect UMN pathology as assessed by the clinical examination. Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease of unknown cause, whose diagnosis requires evidence of both Upper Motor Neuron (UMN) and Lower Motor Neuron (LMN) involvement Studies correlating these DTI changes with clinical assessments of disease severity have been inconsistent. Some groups report correlation with clinical UMN metrics and other measures such as the Revised ALS Functional Rating Scale (ALSFRS-R) or duration of disease This study protocol was approved by the institutional review board of the University of Pennsylvania. Written informed consent was obtained from all subjects. All clinical investigation was conducted according to the principles expressed in the Declaration of Helsinki.Thirty-four patients with ALS were recruited for participation from consecutive new patients who presented at the ALS Association Center at Pennsylvania Hospital over a 2-year period, as well as 13 control subjects with no known neurologic disease. Each subject was classified using the Revised El Escorial criteria At each patient visit to the ALS Center, clinical metrics including the ALSFRS-R score and a summary score of UMN disease burden were recorded. The Penn UMN Score see  ranged fWe then modified these raw scores, depending upon the results of prior exam visits. At any single point in time, the reflex examination may have been confounded in the presence of advanced LMN disease, so that a previously abnormal reflex may have “pseudo-normalized” on later exams 2), followed by measurements along 30 non-collinear/non-coplanar directions isotropically distributed in space (b = 1000 s/mm2). Other parameters: TR = 6700 ms, TE = 85 ms, NEX = 3, FOV = 245×245 mm, matrix = 112×112, slice = 2.2 mm, gap 0 mm, voxel size 2.19×2.19×2.2 mm3, scan time 13 minutes. The time interval from the clinic visit to the DTI scan date varied from 57 days before to 43 days after the scan. A similar MRI scan was performed for each control subject, using the same scanner.At a separate visit, Diffusion Tensor Imaging of the brain was performed on a 3.0T whole-body scanner , using an 12-channel phased-array head coil, and a 30-direction single-shot spin-echo diffusion-weighted echo-planar sequence, GRAPPA acceleration of 3. The diffusion-sampling scheme consisted of four images with no weighting (b = 0 s/mmwww.nitrc.org/projects/dtitk) The DTI data on the 34 subjects with ALS were spatially normalized using a high-dimensional deformable registration algorithm that explicitly optimized tensor orientation for alignment of white matter structures, described in more detail elsewhere Fiber Assignment by Continuous Tracking) developed by Mori et al. www.mristudio.org). The CST was determined by the following procedure, as outlined by Wakana Deterministic fiber tractography was performed in the tensor template using the standard FACT method  were applied separately using either MD or FA, in the CST or in the forceps major, as the dependent variable, and using the Penn UMN Score, ALSFRS-R score, and duration of disease as independent variables, along with El Escorial category, age, sex, and handedness as covariates. Indicator (dummy) variables were used for the categorical data . Overall significance of a regression model was determined by a standard analysis-of-covariance. Separate analyses (“limited models”) were also performed excluding the Clinically Possible ALS patients, using either MD or FA in the CST as the dependent variable, and their respective significant predictor variables determined from the full model. All statistical analyses were performed using STATA 12.1 .There was a significant difference in both MD  and FA  measured in the CST, between ALS patients and controls.The scatterplots of the DTI metrics (MD and FA) measured in the CST and the clinical metrics  are summarized in a scatterplot matrix see . ApproxiPlease see For MD in the forceps major, the regression model was not significant .For FA in the CST, the regression model was also significant (p = 0.02). Again, the Penn UMN Score was a significant predictor (p = 0.003). The ALSFRS-R score and duration-of-disease were not significant predictors , nor were age (p = 0.20), handedness (p = 0.22), or sex (p = 0.25). Again, post-estimation analysis showed no significance among the 3 El Escorial categories (p = 0.99). Please see For FA in the forceps major, the regression model was not significant .DTI is a powerful non-invasive method to assess the integrity of white matter tracts of the upper motor neurons in ALS. In their seminal report, Ellis et al. found measurable MD increases and FA decreases in the corticospinal tracts (CST) of patients with ALS More recent reports using newer analysis methods have not clarified the relationship between DTI metrics and clinical measures of disease. One study using probabilistic tractography found no association between FA and rate of disease progression In this study, we found that both MD and FA, when measured throughout the CST using a DTI normalization algorithm, and appropriately controlled for covariates, showed significant linear associations with our clinically derived Penn UMN Score. This finding contrasted with prior reports, which had suggested that FA was a significant marker for disease severity, but not MD. Since both FA and MD were derived from the same set of three eigenvalues that diagonalized the tensor, our finding should not have been surprising. Indeed, a post-hoc analysis showed a high negative correlation between MD and FA (–0.80) in our study data, suggesting a strong interdependence between these two DTI measures. To avoid statistical problems with multiple comparisons, we chose to limit our analysis of DTI metrics to MD and FA, the two most commonly studied.Our study also found that the clinical metric that best related to DTI changes was the Penn UMN Score, not ALSFRS-R or duration of disease. The UMN score we described, which partially accommodated for a confounded UMN examination in the presence of possible LMN disease by incorporating prior visit data, probably represented an improvement over purely cross-sectional assessments of UMN disease, although it still would not correct for the confounding possibility of LMN degeneration at the initial time point. For ALSFRS-R, the poor contribution to the regression model was not surprising, since this score has been known to be affected by both UMN and LMN disease. The reason why our study failed to corroborate the previously suggested relationship between DTI metrics and duration of disease was not immediately apparent, but may have been due to inherent differences in the patient populations studied. Notably, the duration-of-disease predictor fell just short of significance (p = 0.09) in the full regression model for FA.The regression analyses also found that El Escorial category of the patient was not a significant contributor to either regression model. Furthermore, the Penn UMN score remained a significant predictor in the regressions even after excluding Clinically Possible ALS cases. These results suggest that all patients with ALS, regardless of the distribution of their clinical manifestations, share the same underlying relationship between UMN disease and DTI changes. Therefore, future research studying the utility of DTI as a biomarker in ALS may include patients in the Clinically Possible ALS category.Our method to measure the DTI metrics, using a high-dimensional algorithm to normalize the data into a common spatial frame, and template-space tractography to define the CST, had important advantages over methods used in other research articles. First, the method avoided user definition of ROIs, which not only would have been time-consuming, but also could have added error and bias. In contrast, using our method, once the CST was defined by tractography in template-space, subsequent measures for all subjects were performed using exactly the same, consistently defined, unbiased ROI. Indeed, prior studies using more variable ROIs to define the CST may have contained significant measurement error and/or bias, which may have obscured the true relationship between DTI metrics and clinical measures. Finally, our method also would be more suitable for any future large-scale studies, inasmuch as individual tractography or ROI definition need not be performed. All that said, adding a normalization step may have introduced additional pitfalls in the DTI analysis, as pointed out by Jones and Cercigagni We purposefully chose a large ROI encompassing both sides of the corticospinal tract to perform DTI measures in this study. Most importantly, this single summary metric of DTI abnormality avoided the multiple-comparison problem that would complicate voxel-based or tract-based methods, and therefore simplified the statistics, albeit at the expense of spatial selectivity. Previous studies have shown variable abnormalities throughout the CST . Therefore, we chose the large-ROI method in order to make it the most robust, capturing potential abnormalities throughout the corticospinal tract, while preserving power. As a further benefit, a single summary measure of DTI abnormality also would have more straightforward application as a diagnostic test, or as an endpoint in clinical trials.It is important to understand that the regression analysis performed in this study can only test for linear associations between the Penn UMN score  and DTI metrics in the CST (an MRI measure), but establishing this relationship does not imply causality. That is, while we did find that increasing clinical disease burden (i.e. higher Penn UMN scores) is associated with worsening DTI measures in the CST , we cannot conclude that worsening disease burden directly results in worsening DTI measures. This limitation is intrinsic to the design of our study.There were several other limitations to our study. While greater than others, the number of subjects in our study, 34, was not large. If multicenter trials are to be performed evaluating DTI as a biomarker in ALS, the clinical and DTI data should be acquired in a uniform manner in order to be compiled. The success of the Penn UMN Score indicates that a similarly comprehensive upper motor neuron exam should be performed and recorded as the optimal clinical measure for validation. Moreover, putative biomarkers should be specified at the outset so that they can be tested in a formal, prospective fashion. Another limitation to our study was the need to sum together all the components of the clinical exam and the DTI exam across body segments. It may be useful in the future to segment DTI metrics, not only left-vs.-right, but also by body part , and then correlate these with the clinical data. Finally, limitations of the diffusion tensor model do not allow full definition of the pyramidal tract by deterministic tractography, due to the “crossing fiber” problem. As a result, only a portion of the true pyramidal tract was in fact interrogated by our methods.One possible concern with our methods is the complexity added by the DTI normalization step, which theoretically could add error to the measures. However, the benefits of the DTI-TK normalization method likely outweigh this complexity and potential error, and the positive results of our manuscript do indicate that the method successfully allows meaningful DTI measurements that correspond to the clinical examination. Two important differences between the DTI-TK normalization algorithm and other methods are the tensor-based metric used by DTI-TK to drive the normalization, unlike the scalar metric of FA used by standard tract-based spatial statistics (TBSS), and the high number of degrees of freedom in the underlying transform used in DTI-TK, unlike the few degrees used by standard voxel-based morphometry (VBM). Given these differences, it is entire possible, though unproven, that the DTI-TK method significantly improved the registration, and this improvement enabled measurement of DTI metrics that could be related to the clinical examination. Indeed, one recent study that compared several methods At first glance, the use of the maximum prior reflex scores in calculation of the Penn UMN score may seem problematic; however, this modification to the Penn UMN reflex score was performed for an important reason. It is a known phenomenon that a patient’s reflex examination may artifactually “improve” over time in the presence of increasing lower motor neuron (LMN) degeneration – that is, a reflex that was previously hyperreflexic  may appear to normalize, and in cases of end-stage lower motor neuron disease, the reflex will abolish. This “improvement” does not reflect recovery of the UMN’s or decreased disease burden, but rather is an indication that there are not sufficient lower motor neurons remaining to generate a reflex. To correct for this artifact, the total UMN score was calculated from the maximum UMN score per segment during the course of the disease.In summary, we used an unbiased method to measure DTI abnormalities in the CST of patients with ALS, and found significant linear relationships with a clinically-assessed metric of UMN disease, but not with the ALSFRS-R score or duration of disease, when controlled for covariates including the El Escorial category. Contrasting with other reports, we found that both MD and FA showed significant linear relationships with UMN disease. This finding has important consequences for future studies using DTI as a biomarker of UMN disease burden, as both MD and FA should be studied.Figure S1Scatterplot matrix of DTI and clinical metrics. This figure shows a scatterplot matrix of the DTI metrics , and the clinical metrics . Linear associations are suggested between the DTI metrics and the Penn UMN Score, as well as ALSFRS-R score, but not the duration-of-disease. The asterisks (*) denote the significant relationships between MD and the Penn UMN Score (p = 0.005) and between FA and the Penn UMN Score (p = 0.003).(TIF)Click here for additional data file.


Considerable debate surrounds the influence media have on first-time pregnant women. Much of the academic literature discusses the influence of  television, which often portrays birth as risky, dramatic and painful and there is evidence that this has a negative effect on childbirth in society, through the increasing anticipation of negative outcomes. It is suggested that women seek out such programmes to help understand what could happen during the birth because there is a cultural void. However the impact that has on normal birth has not been explored.A scoping review relating to the representation of childbirth in the mass media, particularly on television.Three key themes emerged: (a) medicalisation of childbirth; (b) women using media to learn about childbirth; and (c) birth as a missing everyday life event.Media appear to influence how women engage with childbirth. The dramatic television portrayal of birth may perpetuate the medicalisation of childbirth, and last, but not least, portrayals of normal birth are often missing in the popular media. Hence midwives need to engage with television producers to improve the representation of midwifery and maternity in the media. Considerable debate surrounds the influence media has on people’s perceptions and expectations of birth . A commoMany high-income countries experience rising rates of childbirth intervention, without much evidence that such interventions lead to improvements in maternal or newborn outcomes . Unnecesst century learn about childbirth through television, as previous generations did, perhaps to a lesser extent, from childbirth manuals [One Born Every Minute, A Baby Story, Call the Midwife, Pramface Babies, Underage and Pregnant and 16 and Pregnant. The media-effects theory has long been regarded as too simplistic [.The literature suggests that many women in the 21 manuals . Unfortu manuals . Thus womplistic . Halloramplistic .Women are exposed to a number of different viewpoints on and perceptions of childbirth that include: 1) an often stereotypical sensationalised version of the birthing process in the media; 2) stories from friends and relatives; 3) antenatal information provided by midwives, doctors, and other childbirth educators; and 4) personal experiences of giving birth. While we might be critical of women seeking out programmes that depict inaccurate representations of childbirth, we need to remember that media representations are for most women the only opportunity to see a birth .Reality television often presents birth as unpredictable and potentially dangerous, pointing to a steady stream of programmes depicting hypertension, postpartum bleeding, cervical cancer, mothers in preterm labour and diabetes . The medThe paper was designed to determine the gaps in the literature around media and childbirth.Scoping reviews map relevant literature in the field of interest , includiMidwives (RCM)’, ‘Maternity & Infant Care’, ‘Media, Culture & Society’ and BMC Pregnancy & Childbirth.The following electronic databases were searched Medline, Pubmed, NHS Evidence, Academic Search Complete, MIDIRS, Education Research Complete, CINAHL Plus, Scopus, Intute, Zetoc and Web of Knowledge. Databases were searched from their starting date until summer 2014. The following journals were hand-searched, ‘Databases were searched using the key terms; ‘media representations’, ‘media influence’, ‘media effects’, ‘childbirth’, ‘labour/labor’. ‘The results of searching electronic databases are measured in terms of yield, recall and precision . Howeverpublished in English;included research ;contained portrayals of childbirth and/or labour in the media.A total of 4,014 publications were identified and the titles and abstracts (where available) of the identified publications were screened and included if they met the following inclusion criteria: -Figure n = 17) and the UK (n = 10), with four from Canada, three from Australia, and one each from New Zealand and Poland.The review comprises twelve qualitative and five quantitative published research studies, three unpublished research pieces and 18 elements of grey literature. The latter includes 13 papers from professional journals, two conference proceedings, two on-line discussion fora and one book chapter. Table The key themes were: 1) medicalisation of childbirth, which includes birth being depicted as risky and dangerous and hence something to fear; 2) media the dominant way for women to learn about childbirth, despite the representations being mostly negative; and 3) birth being missing as a normal “everyday” life event. These three themes are presented under the key media groupings of television, print media, new media, and books: old media. The literature revealed a difference in the way that childbirth is depicted in different countries. From the North-American perspective, medicalised childbirth is seen as the only option for mothers-to-be. In the UK, however, this discourse is only starting to emerge . The keyth century doctors began to displace midwives as the primary provider of maternity care [th century in the US. Resulting in the idea that “Giving birth made a woman a mother … a good mother had to learn about mothering from authoritative sources” . Wources”  to save them and their babies, and hence accept medical control and interventions , 41. Bakquires’ .As women turn to television to learn how others feel and cope with childbirth, birth is no longer a natural experience that women own, rather generations of women have never seen a real-life birth before they themselves experience it . This maWhat is underreported in the literature is the role newspapers and magazines play in the childbirth experience. Bor found that positive newspaper reports of the first television portrayal of pregnancy in the ‘I Love Lucy’ sitcom in the 1950s, influenced positive audience reception to pregnancy being portrayed on television .The Daily Express’ headline ‘Terror of giving birth in Britain today’, The Times’ headline, ‘Childbirth is about pain’ and The Independent’s story on the ‘conveyor belt of childbirth’ [. While she did not conduct primary research, she highlighted that such sensationalistic headlines could influence women to avoid seeking a midwife, and instead choose a medicalised birth [. A recent review of British newspapers highlights a distorted view of birth focusing on risk, which, MacLean argues, prompts a vicious cycle of intervention that starts with fear [Robotham commented anecdotally on UK newspaper headlines such as ldbirth’ . While sed birth . A recenith fear .Two print-media-based studies were reported in Australia , 45. The‘regardless of an individual woman’s situation, the experiences of pregnancy and childbirth engender expectations, desires and concerns; thus women seek advice, guidance and care from others with experience and knowledge of the contingencies of these processes’ .‘Social messages support the view that birth needs to be medicalised and depersonalized  and these social messages about birth also condition women’s views and beliefs. Therefore interventions in promoting normal birth need to focus on women’s personal lifestyles and wishes as well as on the wider social context of birth and on what needs to be changed in this context to make normal birth possible’ .‘an important event in a woman’s life when she needs to be introspective, focused completely on the labour process and on ensuring her baby’s safe passage into the world’ . . ‘an impThis moral ideal of a ‘good’ mother dictates that it is important to be seen both online and offline as doing one’s pregnancy ‘right’, and that ‘love, tenderness and care’ are the driving factors .‘by reaching out for the latest findings and most helpful information available’  as their prime source of information about birth [Moffat showed how discourses around childbirth and the media that mothers seek out for information have changed over the last 30 years . Books wilable’ . ut birth . Therefout birth .Much of the literature in this scoping review fell into a category of media-effects research that suggests that audiences do not critically engage . This ‘h‘different people use the same media in different ways and for different purposes, making it likely that a newspaper will have different effects on different people. People have a well-developed capacity to suppress, forget, distort or misinterpret messages to fit their view of the world’ [The research conducted thus far fails to take into consideration that the relationship between cause and effect is not one way. There are many external influences that need to be considered: socioeconomic and environmental factors, fear of childbirth and lack of first-hand knowledge of childbirth. Media representations of childbirth and labour merely reflect the ideologies of society. Ideology refers to an integrated set of frames of reference through which we sees the world and to which all of us adjust our actions . Ideologe world’ .The debates about media portrayal link to the two paradigms of childbirth: the ‘social’ or ‘midwifery’ and the ‘medical’ model , 58. ProMedia representations often portray technology and interventions as contributing to the medical profession’s success in reducing the risk and uncertainty associated with childbirth . The pro‘blame culture’ that propagates the medical model [Call the Midwife, and more recently advisor on a midwifery television drama in Bangladesh [.It is important to take into consideration the societal ideological viewpoints of childbirth and labour, for instance, in the US, the predominant approach is the medical model; whilst in the UK both models have currency although the medical model is dominant. Some argue that UK midwives are working in a al model . Changinngladesh .‘high rates of straightforward birth with guaranteed midwifery support throughout labour and a low need to admit babies to special care baby units’ and want good postnatal and breastfeeding support; thus, suggesting that a medicalised childbirth on television, might not carry over into real life scourse’ . This discourse’ , 22. Durscourse’ section’ . Fear survention , 38, 62.et al. concur that childbirth in Australia has also been portrayed on television as frightening, overrepresenting deaths and dramatic life-threatening complications [Casualty and Holby City, learnt that there were nurse and medical advisers, but midwifery input was lacking [Handfield ications . It coul lacking . This re‘reflect on ways they themselves must conform to the cultural institutions that surround them. People must submit themselves to the power carried within prescriptions to think and behave in normalized and normalizing ways’ [.This review has shown that depictions of childbirth and labour indicate that women face social anxieties around their pregnancy. By watching reality television to gain an understanding of what childbirth might be like, viewers must: ng ways’ , p 194.The most commonly watched shows tend to dramatize pregnancy and birth and over represent obstetric complications and the need for interventions . Women wTelevision can act as a bridge when a life change or transition is occurring, alleviating women’s social anxieties about childbirth . HoweverUnderlying all of this is the societal discourse that suggests that it is safer for women to participate in medicalised childbirth, rather than risk a midwife-led birth (in US) or labouring/ birthing at home (in UK). To offset the encroachment of the medicalised model of childbirth, midwives must watch reality and fictional television where childbirth is the focus to be in a position to alleviate fears and answer questions posed by pregnant women. Secondly, midwives and childbirth educators must engage with media producers to create more realistic portrayals of childbirth and labour.This review searched and assessed the literature on the effects of the media on childbirth perceptions. The evidence of media influence generally was of low quality. This scoping review only used a selection of the poorly graded evidence to illustrate the key issues. In brief, Consequently many assertions put forward in the academic literature about media influence on perceptions of childbirth are unproven since few studies have measured the impact that such representations have on women and health professionals.This review offers insight into current research on the portrayal of childbirth in the media and identifies where gaps exist. It is important to look from an ideological perspective, taking into account issues such as ethnicity, gender and socioeconomic status; none of which were mentioned or considered in the literature included in this scoping review. Future research needs to explore women’s understandings of normal versus risky childbirth, independent of what they watch on television, or what they seek out on the Internet or read in newspapers or magazines. Further research needs to be conducted on where women are getting their information about childbirth and labour. With newer online platforms  growing rapidly, it is important that researchers understand the role social networking now plays in a woman’s decisions about pregnancy. However as the recent study by Maclean highlighted; UK newspapers have an interest in horror stories and a tendency to suggest that an absence of obstetricians is dangerous, something that she has termed a ‘hierarchy of safety’ . As prin


Background: Exposure to inorganic arsenic (iAs) from drinking water is a global public health problem, yet much remains unknown about the extent of exposure in susceptible populations.Objectives: We aimed to establish the Biomarkers of Exposure to ARsenic (BEAR) prospective pregnancy cohort in Gómez Palacio, Mexico, to better understand the effects of iAs exposure on pregnant women and their children.Methods: Two hundred pregnant women were recruited for this study. Concentrations of iAs in drinking water (DW-iAs) and maternal urinary concentrations of iAs and its monomethylated and dimethylated metabolites  were determined. Birth outcomes were analyzed for their relationship to DW-iAs and to the concentrations and proportions of maternal urinary arsenicals.Results: DW-iAs for the study subjects ranged from < 0.5 to 236 μg As/L. More than half of the women (53%) had DW-iAs that exceeded the World Health Organization’s recommended guideline of 10 μg As/L. DW-iAs was significantly associated with the sum of the urinary arsenicals (U-tAs). Maternal urinary concentrations of MMAs were negatively associated with newborn birth weight and gestational age. Maternal urinary concentrations of iAs were associated with lower mean gestational age and newborn length.Conclusions: Biomonitoring results demonstrate that pregnant women in Gómez Palacio are exposed to potentially harmful levels of DW-iAs. The data support a relationship between iAs metabolism in pregnant women and adverse birth outcomes. The results underscore the risks associated with iAs exposure in vulnerable populations.http://dx.doi.org/10.1289/ehp.1307476Citation: Laine JE, Bailey KA, Rubio-Andrade M, Olshan AF, Smeester L, Drobná Z, Herring AH, Stýblo M, García-Vargas GG, Fry RC. 2015. Maternal arsenic exposure, arsenic methylation efficiency, and birth outcomes in the Biomarkers of Exposure to ARsenic (BEAR) pregnancy cohort in Mexico. Environ Health Perspect 123:186–192;  The World Health Organization (WHO) has established guidelines suggesting that levels of arsenic (As) in drinking water should not exceed 10 μg/L . Severalin utero or in early childhood has been associated with multiple adverse health outcomes, including both cancer and noncancer end points, later in life (Exposure to elevated levels of inorganic arsenic (iAs) in drinking water is a major public health concern because iAs has been linked with numerous adverse health outcomes . The det in life . The bio in life .III), arsenate (iAsV), monomethylarsonous acid (MMAIII), monomethylarsonic acid (MMAV), dimethylarsinous acid (DMAIII), and dimethylarsinic acid (DMAV)  . Generald (DMAV) , 2002. Id (DMAV) . Becaused (DMAV) . High urd (DMAV) . It is kd (DMAV) . HoweverWe set out to understand the effects of iAs exposure and iAs metabolism during pregnancy on maternal/fetal health, with the ultimate aim of increasing awareness and reducing exposures to iAs. To this end, we established the Biomarkers of Exposure to ARsenic (BEAR) prospective pregnancy cohort. Women recruited to participate in the BEAR project reside in the Gómez Palacio area, which is located in the state of Durango in the Lagunera region of Northern Mexico. It is believed that > 450,000 people are exposed to levels of iAs in drinking water that exceed 50 μg/L in Mexico, including residents of Lagunera and Durango . MultiplStudy design. BEAR participants, adult women, were recruited during the time frame of August 2011 through March 2012 at the General Hospital of Gómez Palacio. Recruitment took place before delivery, usually within 24 hr of birth. The mean gestational age at birth was 39 weeks . All procedures associated with this study were approved by the institutional review boards of Universidad Juarez del Estado de Durango (UJED), Gómez Palacio, Durango, Mexico, and the University of North Carolina at Chapel Hill (UNC-Chapel Hill). For each woman participation requirements at the time of recruitment included a) 1 year minimum residence in the Gómez Palacio region, which included urban locations of Gómez Palacio and surrounding rural locations, b) confirmation of a pregnancy without complications such as eclampsia or preeclampsia, and c) good overall health status . A total of 221 women were approached for the study. Of those, 93% (n = 206) provided informed consent for participation in the study. Six women were not included in the study as a result of confirmation of a twin pregnancy  or sample collection failure . A social worker administered questionnaires to the study participants to collect the following information: age, education, occupation, time living at residence, smoking status and alcoholic beverage consumption during pregnancy (both defined as yes or no and frequency), daily prenatal supplement intake (yes or no), residence location , seafood consumption (yes or no), source and daily consumption of drinking and cooking water, and source of bathing water. In addition, information on previous pregnancy outcomes including number of pregnancies and number of previous pregnancy losses was gathered from questionnaires. Information on birth outcomes/measures including newborn birth weight, newborn length, gestational age, head circumference, placental weight, and 5-min Appearance, Pulse, Grimace, Activity, Respiration (APGAR) score was gathered at time of delivery by the physician . Maternal spot urine samples were collected at the hospital before birth, immediately transferred to cryovials, and placed in liquid nitrogen. Aliquots of urine samples were shipped on dry ice to UNC-Chapel Hill and immediately stored at –80°C. It was not possible to inform the women of the levels of iAs in their drinking water during their pregnancies because these results were not available before the birth of their children. However, the women were informed within 3 months of delivery.Detection of arsenic in drinking water and urine. The concentrations of iAs in drinking water  were measured at UJED, Mexico, using hydride generation–atomic absorption spectrometry (HG-AAS) supported by a FIAS-100 flow injection accessory system as described previously  of each urine sample was measured using a handheld refractometer . To account for differences in water intake/differential hydration, concentrations of U-iAs, U-MMAs, and U-DMAs in each urine sample were adjusted using the following equation: iAs × (mean SG – 1)/ as previously described . UrinaryStatistical analysis. Data were analyzed using the statistical package SAS 9.3 . Arsenical concentrations in drinking water and urine that were below their respective LODs were assigned a value equal to the LOD divided by the square root of 2. To determine the efficiency of iAs metabolism, the proportion of total urinary As comprising the individual arsenicals iAs, MMAs, and DMAs  was calculated for each study subject. A Spearman rank correlation was calculated to quantify the relationship between DW-iAs and U-tAs.t-test. Age- and education-based comparisons of levels of DW-iAs and U-tAS were analyzed using a Kruskal–Wallis test and analysis of variance, respectively.Differences in DW-iAs were analyzed based on maternal characteristics . The nonparametric Wilcoxon rank sum test was used because of the failure of DW-iAs to achieve normality in transformations. Differences in log-transformed U-tAs were analyzed based on maternal characteristics using Student’s two-sample a priori status as known confounders using a directed acyclic graph (DAG). Additionally, if covariates changed the estimate by at least 10%, they were included in the model. Model 1 included the following covariates: maternal age at delivery (as a continuous variable), education level as a measure for socioeconomic status (SES) , smoking status (dichotomized as yes/no), and alcoholic beverage consumption during pregnancy (dichotomized as yes/no). Gestational age was not included in model 1 because of its potential role as a mediator of birth weight that can result in biased estimates  and birth outcomes (modeled as continuous variables). Regression assumptions of linearity and the homogeneity of residuals were evaluated by examination of appropriate residual plots. Covariates were selected if associated with both exposure and outcome or based on their stimates . Model 2Maternal and newborn characteristics. All maternal and birth characteristics are presented in p = 0.0003) higher birth weight  relative to females . Among newborns, 2% were LBW, 14% were SGA, and ~ 10% were LGA. The average placental weight was 648 g. The newborns had an average crown to heel length of 50 cm, an average head circumference of 35 cm, and an average APGAR score of 9 . Of the newborns, 104 (52%) were male and 96 (48%) were female. The average weight of the newborns was 3,339 g (SD ± 500 g); males had a significantly (ore of 9 .Levels of iAs in drinking-water and urinary samples. Levels of iAs in study subjects’ drinking water ranged from below the LOD (0.46 μg As/L) to 236.0 μg As/L  (μg As/L) . Of the μg As/L) .r = 0.51, p < 0.0001) . Across the entire cohort, there was a significant positive relationship between U-tAs and DW-iAs ( 0.0001) . The una 0.0001) . The mea 0.0001) . This co 0.0001) .p < 0.0001) for those women who reportedly drank and cooked with municipally supplied water   than for those who reportedly drank and cooked with bottled water  . Similarly, U-tAs levels were higher in women who reportedly drank and cooked with municipally supplied water  than in those who drank and cooked with bottled water  . There were no statistically significant differences in U-tAs , U-iAs, or U-MMAs (data not shown) between the women who reported consuming seafood versus those who did not; however, women who consumed seafood had higher mean levels of U-DMAs than those who did not . There was no statistical difference in U-tAs associated with a woman’s age; however, women with less than a high school education had significantly higher (p = 0.0173) U-tAs  than women with a high school education , college , and greater than college education . There was no statistical difference in U-tAs based on residence status , smoking status, nor alcohol consumption (data not shown).DW-iAs and U-tAs levels were analyzed in relation to demographic characteristics. Most women (55%) reported that their primary drinking- and cooking-water source was from the tap . DW-iAs was higher  adjusted for maternal age, education, smoking, and alcohol consumption, where all measured relationships represent analysis for a 1-unit change in exposure measures in association with birth outcomes/measures. DW-iAs, U-tAs, U-DMAs, and percent iAs (%iAs) were not significantly associated with any of the birth outcomes . There was no significant association between U-iAs and birth weight, head circumference, placental weight, and APGAR score.There was a significant negative relationship between U-iAs and mean gestational age, with an estimated decrease of 0.069 weeks in gestational age for every 1-unit change in U-iAs [95% confidence interval (CI): –0.13, –0.0043, p = 0.02) and mean birth weight (grams) . There were no significant associations between U-MMAs and mean head circumference, placental weight, and APGAR score. There was a significant negative relationship between %MMAs and mean birth weight, with an estimated 24-g decrease in birth weight for every unit increase in %MMAs . There was no significant association with %MMAs and mean head circumference or APGAR score. Placental weight (grams) was also negatively associated with %MMAs  and positively associated with %DMAs .There was a significant negative association between U-MMAs and both mean gestational age (weeks)  (model 3) showed consistent directions and significance of associations between exposure and metabolism indicators and birth outcomes, as observed with model 1 . Maternal urinary means of iAs and urinary arsenical proportions were not statistically different (p < 0.05) based on the sex of the infant (data not shown).Gestational age was included in model 2 for comparative purposes . The inclusion of gestational age did influence the estimates, in general reducing the magnitude of the relationships observed in model 1. It is important to consider, however, the potential role of gestational age as a mediator of birth outcomes. A sensitivity analysis that excluded seafood consumers  showed no significant associations. Interestingly, there were significant relationships between levels and proportions of iAs, MMAs, and DMAs in maternal urine and selected birth outcomes. Specifically increases in U-iAs were associated with a lower means in gestational age and newborn length. Increases in U-MMAs were associated with a lower mean gestational age and birth weight. Similarly, increases in %MMAs were negatively associated with both lower mean placental weight and birth weight, with an estimated approximately 24-g decrease per unit increase in %MMAs. As total amounts of urinary arsenic as well as DMAs can be attributed in part to seafood consumption , a sensiIII  relative to the proportions generally observed in exposed populations around the world, with observed ranges of approximately 10–20% for iAs, 10–20% for MMAs, and 60–80% for DMAs . U-tAs aIII , 2009.An inverse relationship between DW-iAs and birth weight has been observed previously  as well Although the data in the present study suggest an association between maternal methylation of iAs and infant birth weight, gestational age, and newborn length, this study is not without limitations. In addition to iAs exposure and metabolism, other factors that may influence birth outcomes include coexposure to other contaminants, gestational age, and maternal genotype. Additionally, residual confounding may remain based on maternal SES and potentially dietary sources of iAs. Together these complex factors may influence the relationships between iAs exposure during pregnancy and newborn health outcomes, and should be examined in larger cohort studies. It will be important in future research to examine the links between early-life exposure to iAs and postnatal development in the children through prospective analysis. Taken together, these data will enable a better understanding of the etiology of poorer birth outcomes associated with iAs exposure in early life.This study suggests three major findings. First, more than half of the drinking-water samples tested in Gómez Palacio exceeded the WHO’s guidelines for acceptable limits of iAs in drinking water, indicating that women drinking municipal water are at risk for elevated exposure to iAs. Second, biomonitoring data confirmed that many pregnant women had elevated levels of iAs in their urine. Third, individual differences in iAs metabolism in pregnant women were associated with birth outcomes. Specifically, elevated levels and proportions of MMAs in maternal urine were negatively associated with birth weight and gestational age, and urinary iAs was negatively associated with gestational age and newborn length. Given that these exposures to elevated iAs are occurring during pregnancy, there may also be concerns about later-life health effects for the children of the cohort. The results of this study suggest that a follow-up examination of the impacts of iAs exposure on the health of the women and their children is warranted.(1.6 MB) PDFClick here for additional data file.


Low Birth Weight (LBW) is a surrogate for fetal undernutrition and is associated with impaired nephron development in utero. In this study, we investigate whether having been born LBW and/or small for gestational age (SGA) predict progression to ESRD in IgA nephropathy (IgAN) patients.Retrospective registry-based cohort study.th percentile) and/or SGA  by Cox regression statistics.The Medical Birth Registry has recorded all births since 1967 and the Norwegian Renal Registry has recorded all patients with ESRD since 1980. Based on data from the Norwegian Kidney Biopsy Registry we included all patients diagnosed with IgAN in Norway from 1988–2013. These registries were linked and we analysed risk of progression to ESRD associated with LBW  of 2.0  for the total cohort, 2.2 (1.1–4.4) for males and 1.3 (0.30–5.8) for females. Corresponding HRs for SGA were 2.2 (1.1–4.2), 2.7 (1.4–5.5) and 0.8 (0.10–5.9). Further analyses showed that as compared to patients with neither LBW nor SGA, patients with either SGA or LBW did not have significantly increased risks (HRs of 1.3–1.4) but patients who were both LBW and SGA had an increased risk (HR 3.2 (1.5–6.8).Mean duration of follow-up only 10 years and maximum age only 46 years.Among IgAN patients, LBW and/or SGA was associated with increased risk for progression to ESRD, the association was stronger in males. Brenner hypothesized in 1988 that adverse intrauterine environment, for example due to placental insufficiency or maternal malnutrition, was associated with impaired nephron development and increased risk of hypertension and progressive kidney disease in adult life,3, increIgA nephropathy (IgAN) is the most frequently occurring primary idiopathic glomerulonephritis worldwide –17. The In the present study we used data from Norwegian Registries and analyzed whether adverse birth-weight related variables are associated with development of end-stage renal disease (ESRD) in patients diagnosed with IgAN in Norway in the period 1988–2013. We first analyzed whether LBW predicted progression to ESRD, but also analyzed the effects of SGA and preterm birth, and combinations of these factors. Our main hypothesis was that LBW and SGA predict progression to ESRD, in line with the Brenner hypothesis.Since 1967, the Medical Birth Registry of Norway has registered extensive medical data on all births in Norway  . The forWe included all patients diagnosed with IgA nephropathy in the Norwegian Kidney Biopsy Registry between 1988 and 2013 and who were born in Norway after 1967 and had their birth data registered in the Medical Birth Registry. The study was approved by the Regional Ethics Committee of Norway. Patient records/information was anonymized and de-identified prior to analysis. This investigation abides to Declaration of Helsinki.th percentile for gender . Based on total data from the Medical Birth Registry, different cut-offs were tested in separate analyses . From 1967 through 1998, gestational age was based on the last menstrual period and from 1999 onward on routine ultrasonographic examination in gestational weeks 17 through 20. Preterm birth was defined as a gestational age less than 37 weeks. Based on national data on birth weight, gestational week, gender and plurality, a z-score denoting standard deviation from mean of birth weight for each week of gestational age was calculated for each patient by the Medical Birth Registry . Identical analysis for the combined effect of preterm birth and/or SGA did on the other hand show a stronger effect of SGA in preterm as compared to term births (10.8 (2.6–45) vs 1.9 (0.93–3.1) (results not shown).In this comprehensive, registry-based study, we have shown that LBW was significantly associated with increased risk of progression to ESRD in IgAN. Having been born SGA, indicating intrauterine growth restriction, was also associated with ESRD. These effects were significant in the total cohort and in males, but we could not find evidence of increased risk in females. Further analyses showed that patients with combined LBW and SGA have significantly increased risk of developing ESRD as compared to patients with only one of the markers. After adjustments for eGFR at time of diagnosis, the birth weight related variables were no longer associated with progression to ESRD.As described in the introduction, previous studies have shown associations between birth-weight related variables and increased risk for all-cause ESRD in the total population ,36,37. IDuring nephrogenesis, week 9 to 36 in utero, the number of formed nephrons correlates with increase in fetal weight. LBW is the most accessible marker of adverse intrauterine environment , birth wIn this current study, SGA was on the other hand associated with slightly higher hazard ratio than LBW. The finding that SGA might be a strong risk marker have been indicated by previous studies demonstrating increased risk for development of renal disease and hypertension ,50, loweIn the paragraph above we discussed how a lower number of nephrons could represent a lower reserve capacity and predispose to progressive renal disease. It is however also possible that intrauterine nutritional imbalances could program immunological function or risk that may persist throughout life . PreviouAdjusted analysis showed that the association between LBW/SGA and progression to ESRD was lost after adjustments for eGFR. The most likely explanation for this is that eGFR is a much stronger risk factor for ESRD than LBW or SGA. It might however also imply that reduced GFR itself may be a consequence of being born SGA or LBW . In the We observed that the association between LBW and increased risk of ESRD was significant and strong in males but not in females. Globally, gender distribution in IgA nephropathy varies widely in different populations with more preponderance towards male gender ranging from a male: female ratio of less than 2:1 in Japan  to 6:1 iThe strengths of the present study are that the study is registry based with complete national inclusion, have prospective registration of birth weight related variables, investigates a clinically useful condition (IgAN) and has a clinically relevant and reliable end point (ESRD). A weakness was that data on death was not available for the cohort and patients could not be censored for death. Another weakness is that ESRD is a rare outcome and usually takes considerable time to develop, number of patients with endpoints were therefore low in some subgroups. As an inclusion criterion of the study was being born after 1967, we were only able to include a relatively young cohort of IgAN patients (mean age at biopsy was 24 years). Previous studies have shown that for IgAN patients younger than 60 years and elevated serum creatinine level > 2.0 mg/dl, young age correlated with poor prognosis 73]..73].Another limitation is that we did not have information regarding the treatment the patients received, most patients were however treated by nephrologists and received standard international care with angiotensin inhibition for those with either high blood pressure or proteinuria since the 1990’s, steroid treatment have been increasingly used since the early 2000’s for those with proteinuria above 1 gr/24h and preserved kidney function after a trial period with angiotensin inhibition.In conclusion, the present study has shown that birth-weight related variables were associated with risk for developing ESRD, the association was stronger in male patients who were the predominant gender of this cohort . Both LBW and SGA were important risk markers, but the combination of these were especially important. Our results support the Brenner hypothesis. Future studies should investigate further the importance of SGA vs LBW and whether these markers are associated with altered renal morphology and risk of progression to ESRD also in other kidney diseases.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.


It has been suggested that periodontitis is associated with systemic alterations such as adverse pregnancy outcomes. However, some conflicting results have been reported. This study was conducted to determine the association between periodontitis and preterm birth (PTB), low birth weight (LBW) to obtain information which is necessary for the planning of preventive programs of periodontal disease for pregnant women in this area.This case-control study was performed on 264 mothers. The index used to determine oral hygiene and periodontal diseases is Community Periodontal Index Treatment Needs (CPITN).The mothers in the sample group with single delivery delivered 8 times low birth weight infants more than the mothers in the control group with single delivery. And also the mothers in the sample group with multiple deliveries; delivered 10 times low birth weight infants and 8 times premature infant more than the mothers in the control group.More studies should be carried out in through preventing and treating periodontal diseases, expenses incurred due to preterm labor and low birth weight decrease and the society will witness fewer mental problems suffered by such children as they grow up. So we can emphasize the importance of periodontal care in prenatal health programs. And we may suggest that a special program of periodontal disease prevention for pregnant women is very necessary. Preterm infants are born prior to completion of 37 weeks of gestation . An estiPregnancy is considered as one of complex physical and physiological changes that have significant impact on almost every organ system of the body. In the oral cavity, various pathologies have been reported among pregnant women .Periodontal disease is known as one of the most common chronic diseases with infectious origin in humans . It causDuring pregnancy, 4 major hormones including Estrogen, Progesterone, HCG and HCS are produced in large amounts. Most of the time, increase of these hormones may bring some changes in gingiva. Results of clinical studies prove that 30% to 100% of pregnant women suffer from gingivitis . CurrentMost of these studies were conducted in developed countries in spite of the fact that the vast majority of low birth weight babies are born in developing countries. To our knowledge, this association was not explored among Iranian women. The majority of women in Iran is of similar ethnic background, nonsmokers, nonalcoholic drinkers, and has only one sexual partner all through their life. Such characteristics were found to be associated with PLBW. Therefore, this study was conducted to assess the association between the severity and extent of maternal periodontal disease and PLBW delivery among women in the Qazvin. This study was carried out to investigate the impact of mother’s periodontal infections on the condition of the neonatal.This case–control study was conducted among women who gave birth at Kosar Teaching Hospital in the Qazvin, Iran over a period of 6 months. The study was approved by the Research Committee of the Qazvin University of Medical Sciences.Four hundred six pregnant mothers were included. Those who had a history of spontaneous abortion, used antibiotics within the last three months of pregnancy and those afflicted with diabetes or hypertension and those addicted to cigarettes were excluded from the samples. The remained patient included 264 pregnant mothers. The index used to assess periodontal health was CPITN .The same examiner collected all data based on three criteria including examination, observation and questionnaire from all participants. Mothers were divided into two groups, those found in need of treatment (case group) and those who were healthy (control group). Each of these two groups were further divided into two subgroups based on gravidity, hence those who were giving birth to their first child were put in the same group and others were put in another group (each group contained 64 subjects). The group members were of the same age group and there was no significant difference among them regarding their education, job, and domicile. Mothers’ excess weights were the same in all groups. Height at birth was normal in all newborns both in case and in control groups and there was no significant difference in the circumferences of their heads. Pregnant women of both case and control groups were examined to find out whether they were in need of periodontal treatment (TN). None of the members of the multiparity and primiparity subgroups categorized under control group were in (no) need of periodontal treatment (TN=0). However, 58% of women in the primiparity subgroup categorized under case group proved to be in need of learning personal oral health to control dental plaque (TN=1) and 39% were in need of learning oral health principles and they also needed instructions to be provided by experts on methods of removing plaque and abolishing factors that retain plaque (TN=2). Moreover, 3% of these women required more complicated treatments such as oral surgeries (TN=3).As to CPITN index, 58% of women included in the primiparity subgroup categorized under case group, were of code 1, and 27% were of code 2, 12% were of code 3 and 3% were of code 4. In multiparity subgroup categorized under case group, 24% were of code 1, 52% were of code 2, 15% were of code 3 and 9% were of code 4.Data was entered using the Epi Info computer program after which it was transferred to the SPSS, version 15, and program for analysis. Univariate analyses were performed by use of Chi-Square test and T-test was used wherever appropriate.Nine percent of mothers had babies with weights less than 2500gr at birth (LBW). 21% of mothers included in primiparity subgroup categorized under case group had babies with low weight at birth which reveals a significant difference .In multiparity subgroup/control group, 3% of mothers had babies with low weight at birth, while18% of mothers included in multiparity subgroup categorized under case group had babies with low weight at birth, and this reveals a significant difference.In primiparity subgroup categorized under control group, all mothers gave birth to babies after 37 weeks or more, however, in primiparity subgroup categorized under case group,12% of mothers had a pregnancy period of less than 37 and this shows a significant difference. In multiparity subgroup categorized under control group, 3% of women had pregnancy period of less than 32 weeks, however, in multiparity subgroup categorized under case group, 24% of mothers had pregnancy period of less than 37, which reveals a significant difference .The majority of the studies suggest that periodontal disease is associated with increased risk of various adverse pregnancy outcomes such as preterm birth and low birth weight. Infants are born preterm at less than 37 weeks’ gestational age .According to the findings, we can conclude that the frequency of low birth weight in newborns of women who were giving birth to their first child and were afflicted with periodontal diseases were 2.3 times more than that of those newborns whose mothers were in periodontal health. This is somehow in disagreement with the findings of Offenbacher and those of Ketz because these authors believe that risk of preterm labor in mothers afflicted with periodontal diseases is six times more than that of healthy mothers . On the As to the term of pregnancy, we can conclude that the frequency of preterm labor is 12 times more in women afflicted with periodontal diseases who are giving birth to their first child (pregnancy lasts for less than 37 weeks). Taking the study results into account, it can be concluded that term of pregnancy is significantly different between the primiparity subgroups categorized under case and control groups and this confirms the results achieved by Afenbakher, Ketz and Davenport. According to The present study demonstrated a 42.22% prevalence of CPITN score 3, corresponding to shallow pockets. Miyazaki et al. reported 31% of the pregnant women in a Japanese population had periodontal pockets of 4 or 5 mm, results similar to the data in the present work .Generally speaking, the more intensive the periodontal disease is, the more probable preterm labor and low birth weight will be and a reverse relationship exists between the average birth weight and the intensity of periodontal infections.Ideally, women should begin their pregnancy without periodontal infections, and they should be educated and motivated to maintain a high level of oral hygiene prior to and throughout pregnancy. However, if a periodontal infection is diagnosed at any time during pregnancy, the treatment should be administered as soon as possible in order to reduce the risk of PT/LBW.Health authorities should strengthen the implementation of community- based oral disease prevention and health promotion programmes. More importance must be given to oral health care center in family planning centers .More studies should be carried out in through preventing and treating periodontal diseases, expenses incurred due to preterm labor and low birth weight decrease and the society will witness fewer mental problems suffered by such children as they grow up. So we can emphasize the importance of periodontal care in prenatal health programs. Future research should focus on large-scale longitudinal studies, as well as interventional studies, to better prove a causal relationship and determine if periodontal treatment or prevention reduces the risk for adverse pregnancy outcomes.RecommendationsAdditional epidemiological studies are needed including a larger number and wider spectrum of participants from different hospitals in different areas.Future studies in which the direct measurement of specific periodontal pathogens in the fetal environment and the measurement of the resulting inflammatory mediator levels are made would be helpful in either approving or disapproving the hypothesis.The use of clinical attachment level and gingival crevicular fluid as a clinical parameter.The use of the Decayed, Missing, or Filled Teeth Index (DMFT) as an extra measure to indicate the total number of decayed, missing, or filled teeth as a result of dental caries.Further studies are needed to address the question whether pre-term births can be reduced by treating the periodontal disease.


Associations between parental and offspring size at birth are well established, but the relative importance of parental growth at different ages as predictors of offspring birthweight is less certain. Here we model parental birthweight and postnatal conditional growth in specific age periods as predictors of offspring birthweight.We analyzed data from 3,392 adults participating in four prospective birth cohorts and 5,506 of their offspring.There was no significant heterogeneity by study site or offspring sex. 1SD increase in maternal birthweight was associated with offspring birthweight increases of 102 g, 1SD in maternal length growth 0–2 year with 46 g, and 1SD in maternal height growth Mid-childhood (MC)-adulthood with 27 g. Maternal relative weight measures were associated with 24 g offspring birth weight increases (2 year- MC) and 49 g for MC-adulthood period but not with earlier relative weight 0–2 year. For fathers, birthweight, and linear/length growth from 0–2 year were associated with increases of 57 and 56 g in offspring birthweight, respectively but not thereafter.Maternal and paternal birthweight and growth from birth to 2 year each predict offspring birthweight. Maternal growth from MC-adulthood, relative weight from 2-MC and MC-adulthood also predict offspring birthweight. These findings suggest that shared genes and/or adequate nutrition during early life for both parents may confer benefits to the next generation, and highlight the importance of maternal height and weight prior to conception. The stronger matrilineal than patrilineal relationships with offspring birth weight are consistent with the hypothesis that improving the early growth conditions of young females can improve birth outcomes in the next generation. Am. J. Hum. Biol. 27:99–105, 2015. © 2014 The Authors American Journal of Human Biology Published by Wiley Periodicals, Inc. Poor nutrition in early life may influence fetal and infant growth of future generations via genetic, epigenetic, physiological, and other mechanisms. Improved nutrition prior to age 2 year has been linked to taller adult stature, improved cognitive and school performance and in males, only, increased economic productivity and earnings  with offspring birth size, with most but not all finding evidence for stronger matrilineal than patrilineal inheritance of birthweight, BW . The authors reported that mothers who gained weight faster than the population mean from birth to 20 months, but not from 20 months to 42 months, had heavier firstborn babies. In contrast, paternal weight gain at these ages was unrelated to offspring BW.Here we build upon past work in this area by including three cohorts in addition to the Pelotas cohort and by examining all births, not just first-borns, while also including measures of growth in height and weight from birth through adulthood. Specifically, we assess the relative importance of parental birthweight and growth during different growth intervals from birth to adulthood as predictors of offspring birthweight in four cohorts from low and middle income countries (LMICs).The data for this study come from 4 of the 5 birth cohorts that participate in the Consortium on Health Orientated Research in Transitional Societies (COHORTS)  ≤2SD cut-off at 2 year  heights and weights were measured at variable ages due to site-specific differences in data collection schedules. It was at 4 years in Brazil, Guatemala and India, and 8.5 years in the Philippines. We used Offspring birth weights were reported by the parent, except in Guatemala where they were obtained by measurement for births before 1999 and by recall later , parental birth order (categorized into firstborns and non-firstborns), maternal age at delivery of offspring (categorized as <18y or ≥18y), type of nutrition supplementation received in Guatemala, and offspring sex. Parental early childhood SES was represented by father's income in Brazil, father's occupation and mother's education in India, and by asset scores, derived from principal component analyses (PCA) of household items for all other sites. As the parents in the Guatemala cohort had participated as children in a nutrition supplementation trial that improved linear growth . Hundred and seven (1.9%) pairs were excluded because the child was not a singleton.The primary inclusion criterion for the analytic study sample was availability of birthweight for the parent and the child  from birth through adulthood , we used mixed regression modelling to nest births within each parent as random intercepts. The classical sandwich estimator  was found for any of the models. We therefore carried out pooled analysis with adjustment for site and offspring sex as fixed effects.Descriptive characteristics are presented as means (SD) for continuous variables and as percentages for categorical variables. We estimated associations of parental birthweight and conditional heights and relative weights with offspring birthweight, separately for mothers and fathers, using mixed linear models adjusted for parental level covariates, offspring sex and study site as fixed effects. As we found significant intra family clustering of offspring birthweights (intra cluster correlations (ICC) = 28.7–40.5%, We examined the associations of parental birthweight and childhood conditional linear growth with offspring LBW status. We used generalized linear mixed models (GLMM) to estimate the prevalence ratios (PR) of LBW adjusted for random effects with parental childhood conditional growth variables as the chief model predictors. Similarly, we related parental childhood stunting with offspring LBW status in a separate mixed logit model. Since prevalence estimates of LBW and parental childhood stunting were not low (13–84%), PR (95% CI) with robust variance  were considered to be more precise measures of association and were used instead of odds ratios.All parental conditional variable derivation were based on birthweight rather than birthlength (unavailable for Brazil). The results of a sensitivity analysis showed very similar estimates using either birthlength or birthweight for the 3 cohorts that had both length and birthweight. Also, sensitivity analyses indicated no significant differences in results using growth measures obtained at 8.5 year (Philippines) vs. those obtained at 4 year (other 3 sites), as previously reported  in India and was not included in the analysis. We conducted sensitivity analyses by first converting continuous gestational ages (GA) in Guatemala and the Philippines to categorical variables in order to carry out a pooled analysis with India. The results of this pooled analysis involving the three sites with GA were very similar to the main analyses with all four sites but not controlled for gestational age.P-values <0.05 were considered statistically significant. All analyses were conducted with PC-SAS version 9.3 , and R  with maternal birthweight, 45.5 g (95% CI: 20.8–70.3) with length growth 0–2 year, and 27.3 g (95% C: 3.5–51.1) with height growth MC-Adulthood.Paternal birthweight and conditional linear/length growth 0–2 year were associated with 57.3 g (95% C: 25.9–88.6), and 55.5 g (95% C: 20.8–90.3) increases in offspring birthweight, respectively; there were no associations with 2 year-MC or MC-adulthood. There were significant associations between maternal relative weight for 2 year-MC  and MC – adulthood  and offspring birthweight. There were no significant associations with offspring birthweight for any of the paternal relative weight measures  of offspring LBW status are shown in Table.Associations between parental linear growth after age 2 year and offspring birthweight were of lower magnitude than for parental birthweight and linear growth from 0 to 2 year. Early growth failure leading to stunting is a marker of systemic dysfunction caused by societal, household, and individual factors that ultimately lead to poor diets and infection. Linear growth failure occurs during a sensitive phase of child development, from conception to 2 year, and co-occurs with poor growth and development in other organ systems. Hoddinott et al.  reportedThe pattern of relationships with conditional relative weight gain differs from that for linear growth. Father's conditional relative weight gain was not related with offspring birthweight and in mothers, coefficients are larger for later compared to earlier changes. Of note is the importance of relative weight gain from MC to adulthood, which reflects acquisition of both lean and fat mass independent of height and thus larger offspring birthweight (a coefficient of 49 g/1 SD change). This potential benefit, however, has to be balanced with the increased risks of maternal obesity and chronic diseases that are associated with relative weight at this period  models that controlled for any potential intra family correlations in birthweight  was unavailable for Brazil. Sensitivity analyses indicated similar results in pooled models with categorized GA  vs. all four sites pooled without adjustment for GA. Even though we adjusted for several confounding factors, residual confounding still remains a possibility. Finally, since the parental cohorts married mostly spouses from outside the cohorts, we had few couples who were both cohort members. This precluded many types of analyses that would have been useful in teasing apart paternal and maternal influences.Parental birth weight and linear growth from birth to 2 years, but not later, and maternal conditional relative weight  from 2 year through adulthood, are associated with offspring birth weight These findings suggest the importance of adequate nutrition during pregnancy and the first 2 year of life for both parents as well as the role of preconception body composition in mothers. Other mechanisms, such as shared genes, environment, and epigenetic changes, may also contribute to associations between parental growth and offspring birthweight.