Low birth weight and accelerated infant growth have been identified as independent risk factors for childhood and adult obesity and cardiovascular disease. This led to the ‘Developmental Origins of Health and Disease’ (DOHaD) hypothesis, stating that environmental factors during pregnancy and early postnatal life affect disease risk in later life. There is growing evidence that perinatal factors may influence adult health through the programming of energy balance regulation, including sedentary behavior and physical activity. The present study focuses on the influence of birth weight and infant growth on physical fitness, physical activity and sedentary behavior in 8-9 year old children, as this might partly explain the higher obesity and cardiovascular risk associated with low birth weight and accelerated infant growth. In addition, this study provides the opportunity for a validation study of a linguistic and cross-cultural translated physical activity questionnaire compared to accelerometer data. This article describes the study protocol for this study.This is a study embedded in the Amsterdam Born Children and their Development (ABCD) birth cohort. In 200 children of Dutch ethnicity, physical fitness, physical activity and sedentary behavior were assessed at age 8-9. We measured aerobic fitness using the 20 meter multistage shuttle run test, and neuromuscular fitness using the standing broad jump and handgrip strength test. Sedentary behavior and physical activity levels were measured using accelerometry. All children also completed a translated physical activity questionnaire, the scores of which will be compared to accelerometry data to assess the construct validity of the questionnaire in Dutch school-aged children.This study will be the first population-based prospective cohort study to address the association of both prenatal and postnatal growth with physical fitness and objectively-assessed physical activity and sedentary behavior. This will contribute to a better understanding of the way perinatal growth relate to lifestyle and obesity in later life. The results may guide both future studies in the field of DOHaD, and public health strategies in the prevention of childhood obesity. In the 1980s Barker and Hall reported a series of studies regarding the association between low birth weight and death from coronary heart disease, suggesting that prenatal environmental factors are involved in the aetiology of adult-onset diseases . In the As the number of DOHaD related studies grew, several important additions and refinements to the hypothesis were made. First, an important feature of the epidemiological observations is that adult disease risk is continuous within the normal range of birth weight, rather than being a pathological feature which is expressed below a critical cut-off point . Second,Obesity plays a critical role in the association between perinatal growth and adult disease, often preceding insulin resistance, dyslipidemia, and hypertension in children and young adults . Given tPhysical activity (PA) and sedentary behavior are components of energy expenditure that vary considerably between persons as well as for a given person over time ,24. SedeBoth PA and sedentary behavior are of particular interest in the study of the developmental origins of energy balance regulation. Animal studies have shown that offspring of nutritionally impaired pregnancies are significantly less physically active than controls, and show increased sedentary behavior -28. ThesPhysical fitness is generally defined as the ability to perform sports or occupations, and is bidirectionally related to PA . As receThe current evidence suggests that physical fitness and PA may have a combined and accumulative effect on cardiometabolic health from an early age. Especially body fatness is inversely associated with fitness and PA levels . But impIn recent years, sedentary behavior has been identified as a distinct health risk factor. For example, sedentary behavior has been shown to be positively associated with an increased risk of type 2 diabetes, cancer, and all-cause and CVD mortality in adults -56. ThesBased on the aforementioned data, we hypothesize that low birth weight and accelerated infant growth is associated with lower levels of aerobic fitness, muscular strength and PA and more time spent on sedentary behavior in school aged children, contributing to the increased propensity to obesity and related diseases in later life. The hypothesized model is shown graphically in Figure This paper describes the rationale and design of a study aiming to examine the association of birth weight and infant growth trajectories with aerobic fitness, muscular strength and objectively assessed sedentary behavior and PA levels in 8-9 year old children. In order to assess whether an accurate assessment of regular PA can be obtained by self-report questionnaires in Dutch children, we will additionally validate a linguistic and cross-cultural translation of a commonly used PA questionnaire in 8-9 year old children. If validity of this questionnaire has been confirmed in our subgroup, we may use it to assess PA and sedentary behavior of our entire cohort in a future phase of the ABCD study. This article outlines the development of this PA questionnaire.The primary study objectives are to examine the association of birth weight and infant growth trajectories with (i) aerobic fitness assessed by the 20 meter multistage shuttle run test (20-m MSRT), (ii) muscular strength assessed by the standing broad jump (SBJ) and hand grip strength test, and (iii) physical activity levels and sedentary time assessed by accelerometry, at 8 to 9 years of age. We will control for potential confounders, such as maternal factors , maternal height, socio-economic status) and child factors , and test for possible effect modification by gender. (see Table This study is embedded in the Amsterdam Born Children and their Development (ABCD) study, a prospective birth cohort study aimed at the identification of prenatal and early life influences on health at birth and in later life. The project is carried out by a multidisciplinary team of researchers from the Public Health Service Amsterdam, the Academic Medical Center and VU University Medical Center.st week of life. Until the age of 4 years, height and weight measures of these children were routinely collected as part of regular preventive Child Health Care. These measurements took place during on average 14 regular follow-up moments and were performed by qualified nurses and physicians. Of the 6735 women who gave permission for follow-up of their child, 6575 mothers also consented to follow up of their child’s growth data.The design and conceptual framework of the overall ABCD-study has been previously described in detail . In summth birthday, 3321 children completed a ‘health check’. At the appointment for this health check we collected data on anthropometrics, blood pressure, heart rate variability, body composition and a capillary blood sample to determine lipid profile, glucose, insulin, C-peptide, HbA1c and albumin. In addition, parents completed questionnaires about the child’s health, development and behavior, family socio-demographics, maternal lifestyle and psychosocial conditions and family history of medical conditions.In 2008, around their 5The primary determinants in our study are birth weight and infant growth trajectories. Birth weight is hereby used as a surrogate marker for intrauterine growth, and an established index for the intrauterine environment.th percentile (-1.28 SD). Infant growth is expressed as the average standardized growth velocity, defined as the change in SD score between birth and 12 months. We will examine growth in weight-for-age, height-for-age and weight-for-height. We expect the association with the outcome measures to differ for each expression of growth, with the strongest association for weight-for-age. Accelerated growth is defined as >0.67 change in SD score. This 0.67 SD represents the distance between two adjacent growth lines on standard infant and childhood growth charts . The adopted definitions of low birth weight and accelerated infant growth are based on recommendations of Monteiro et al. [Birth weight is expressed as standard deviation (SD) score, adjusted for maternal height, weight, parity, ethnicity and fetal sex, in accordance with the recommendations of Gardosi . Low biro et al. , and in o et al. -65.The current study is conducted in a subgroup of the ABCD-birth cohort. At the time of the data collection, the children were 8 or 9 years of age. Children were eligible for this study if (i) they fully completed the ABCD age 5 health check and (ii) were of Dutch ethnicity (i.e. with both parents born in the Netherlands). This is to exclude confounding by ethnicity. Exclusion criteria were (i) a personal history of neurological, cardiovascular or metabolic disease, (ii) any musculoskeletal injury or disability or (iii) the use of any medication at the time of data collection.Based on the literature, we expected to find a difference between low birth weight and normal birth weight children of 1 stage on the 20-m MSRT, with a SD of 2 stages ,66, and To ensure an adequate number of children in each subgroup, we selected more children with low birth weight and/or accelerated growth than that would be selected by random sampling. This to ensure power of the study that may be lost in a more generalized sampling technique.A recruitment letter, explaining study objective and design in detail, was sent to all children´s parents. For the children, simplified written information was provided. Informed and written consent were obtained from parents before participation. The Amsterdam Medical Center’s Ethics Committee approved the study protocol, and all procedures were performed in accordance with the ethical standards of the Helsinki Declaration of 1975 as revised in 2008 .Three identical measurement periods were arranged two or three weeks apart. Each measurement period consisted of (A) the self-completion of a PA questionnaire, (B) a physical fitness test battery, and (C) wearing an accelerometer for 7 consecutive days.After written consent was obtained, a PA questionnaire was sent to the children by surface mail. The questionnaire was completed at home and handed back at the day of the physical fitness test battery. Responses were checked for completeness by staff.The PA questionnaire is a cross-cultural adaptation of the Physical Activity Questionnaire for Older Children (PAQ-C)  and the The PAQ-C is a 7-day self-reported recall instrument, developed to assess general levels of PA throughout the elementary school year for children approximately 8 to 14 years of age . It provThe PAQ-C is widely accepted -74 and rThe aim of the translation process was to develop a Dutch version of the PAQ-C that is conceptually equivalent but adapted to represent common Dutch physical activities. The translation process was carried out using a forward-backward translation technique -79. FirsA physical fitness test battery was developed using the evidence-based recommendations of the ALPHA health-related fitness test battery for children and adolescents  and the Height and weight were measured with the children dressed in light sportswear. Height was measured to the nearest millimetre using a Leicester portable height measure (Seca), and weight to the nearest 100 gram using a Marsden weighing scale, model MS-4102.Blood pressure was measured two times on the right arm in a sitting position after a few minutes rest. If the difference between the measurements was more than 10 mmHg for either systolic or diastolic pressure, a third measurement was obtained. The device used was the Omron 705 IT  with an appropriate sized cuff. Outcome measures were systolic pressure (SP), diastolic pressure (DP), and mean arterial pressure (MAP), all expressed in mmHg. MAP was calculated using the following equation: MAP = DP + 1/3 (SP-DP) .With the standing broad jump (SBJ) and hand grip strength test we assessed explosive muscle strength and maximum muscle strength, respectively.In the SBJ test, the child attempts to jump as far as possible with feet together. From a starting position immediately behind a line with feet slightly apart, the child jumps using both feet with take-off and landing, swinging the arms and bending the knees to provide forward drive. The distance was measured from the take-off line to the point where the back of the heel nearest to the take-off line lands, and reported in centimetres. The test was repeated twice, and the best score retained.Hand grip strength was measured using a hand dynamometer, with the scores recorded in kilograms (kg). The reported precision is 0.5 kg. The test was performed twice , with the dynamometer adjusted to the age- and gender-specific optimal grip span, as this seems the most appropriate protocol to evaluate maximal hand grip strength in children .2 = 0.83–0.86), as well as with upper body muscular strength tests (R2 = 0.7-0.9) [2 = 0.70) [The SBJ test seems to be the most valid test assessing lower body muscular strength compared to other muscular strength tests , showing the highest associations with isokinetic parameters . In addi0.7-0.9) . Millike = 0.70) .-1 (2.4 m • s-1), increasing by 0.5 km • h-1 (0.1 m • s-1) with each stage thereafter (one stage takes one minute). Children were instructed to run in a straight line, to pivot and turn on completing a shuttle, and to pace themselves in accordance with the beeps. The test ended when the child failed to reach the end line concurrent with the beeps on two consecutive occasions. The children were verbally encouraged by the researchers to run for as long as possible throughout the course of the test. The last completed half-stage of the 20-m MSRT was recorded and used as a valid proxy for aerobic fitness [We measured aerobic fitness using the 20 meter multistage shuttle run test (20-m MSRT); a simple non-invasive, valid and reliable field test providing an estimate of maximal cardiorespiratory capacity . The tes fitness ,88.The 20-m MSRT has several advantages over other field tests, such as tests that cover as much distance as possible in a set time , or testAccelerometers have shown to provide reliable estimates of overall PA, sedentary behavior and PA-related energy expenditure among children ,94. In tResearchers distributed the accelerometers face-to-face at the end of the physical fitness test battery. Information about accelerometer use was given to the children and parents orally. Researchers placed the accelerometer to the children’s waist using an elastic waistband, and they told the children not to remove the device for 7 days except during sleeping, swimming and bathing. Additionally, children and parents received a brochure with information about accelerometer use and a compliance log. Children had to self-complete this compliance log for the duration of the accelerometer data collection, as this is an effective, low cost method to increase compliance . Each daThe accelerometer signal is summarized over a user-defined period of time, called epoch, into what are called counts. The higher the number of counts, the higher the intensity of PA. As children tend to have short bursts of PA , we seleData will be presented as means ± SD for continuous variables, and as percentages for categorical variables.For every primary outcome, its association with standardized birth weight and infant growth will be assessed using multivariable linear regression analysis. First, birth weights and infant growth trajectories will be dichotomized as normal vs. low birth weight and normal vs. accelerated infant growth, respectively, and analyzed together in a linear regression analysis to account for mutual interference. To assess whether the effect of low birth weight and accelerated infant growth exceeds the sum of each exposure separately, we will subsequently add an interaction term of birth weight with infant growth to the model. A p-value less than 0.10 for the interaction term is considered indicative of effect modification, after which a subgroup analysis will be performed with the children divided into four subgroups .A scatterplot will be employed to identify potential linear associations of either birth weight or infant growth with the outcome variable. If the scatterplot suggests a linear association of either birth weight or infant growth with the outcome, we will additionally run the analysis with the respective dichotomized variable replaced by its continuous equivalent.The model will be adjusted for potential confounding, by addition of the potential confounders group-wise in a multivariable linear regression analysis. The first group of potential confounders are subject-specific variables , the second are family-specific variables , maternal age, maternal height, maternal pre-pregnancy BMI). Effect modification by gender will be evaluated by addition of an interaction term of gender with either birth weight or infant growth.To assess the construct validity of the modified PA questionnaire, PAQ-C summary scores will be examined as originally constructed (the average of the nine questions) . PearsonAlthough low birth weight and accelerated infant growth have been consistently linked to childhood and adult obesity ,15, the To our knowledge, this study is the first prospective cohort study addressing the association of both birth weight and infant growth with objectively assessed PA and sedentary behavior, aerobic fitness and muscular strength in later childhood. A major strength of this study is that it is conducted within the framework of the ABCD study, a prospective cohort study with extensive data on birth outcome, growth patterns, and lifestyle factors, amongst others. This provides the opportunity to control for a broad range of potential confounders, like BMI, gestational age, Apgar score, maternal age, maternal pre-pregnancy BMI, and socio-economic status. All these variables are prospectively collected and assessed during the course of the ABCD study .A limitation of this study is that only children of Dutch ethnicity are included, to exclude confounding by ethnicity. As there are known ethnic differences in both obesity risk ,105 and th percentile is used to identify intrauterine growth retardation [In this study design, and in many others, birth weight below the 10ardation . Howeverardation , and theardation . On the ardation , may parardation . In factardation ,9,111. IWhile the significance of infant growth in the predisposition to adult disease has extensive support from observational studies, it is not clear whether the detrimental adult outcomes (obesity and cardiovascular disease) are related to a specific time window. Different studies vary widely in definition and duration of accelerated growth, with the period of growth evaluated being as short as 1 week  up to thThere are consistent relations between PA and fitness status in adults and children . PhysicaIf the present study indeed shows that physical fitness, PA and sedentary behavior are significantly associated with birth weight and infant growth, further assessment of the potential mechanisms underlying these associations is required. For example, animal studies provide evidence that sympathetic nervous system (SNS) function is likely to be involved in the developmental origins of later obesity risk. Perinatal insults have been reported to alter SNS development, which may persist throughout life . In humaIn conclusion, this study examines developmentally-induced variations in physical fitness, PA and sedentary behavior in children aged 8-9 years and contributes to an improved understanding of the perinatal influences on energy balance regulation. This knowledge may guide future studies in the field of developmental origins of obesity and related diseases. In addition, the results might initiate preventive public health strategies, as the early promotion of an active lifestyle may be an effective and efficient way to attenuate later disease risk in low birth weight and infant growth accelerated children.ABCD: Amsterdam born children and their development; BMI: Body mass index; CLASS: Children’s leisure activities study survey; c.p.m.: Counts per minute; DOHaD: Developmental origins of health and disease; DP: Diastolic pressure; kg: Kilograms; MAP: Mean arterial pressure; MET: Metabolic equivalent units; MVPA: Moderate to vigorous physical activity; PA: Physical activity; PAQ-C: Physical activity questionnaire for older children; SBJ: Standing broad jump; SD: Standard deviation; SNS: Sympathetic nervous system; SP: Systolic pressure; 20-m MSRT: 20 meter multistage shuttle run test.The authors declare that they have no competing interests.AD: Conception and design of study. Drafting the article and revision on critically important intellectual content. Final approval of the manuscript version to be published. MC: Conception and design of study. Drafting the article and revision on critically important intellectual content. Final approval of the manuscript version to be published. TV: Conception and design of study. Establishing and coordinating the ABCD-birth cohort. Drafting the article and revision on critically important intellectual content. Final approval of the manuscript version to be published. RG: Conception and design of study. Establishing the ABCD-birth cohort. Drafting the article and revision on critically important intellectual content. Final approval of the manuscript version to be published. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2431/13/102/prepubPA Questionnaire. Physical Activity Questionnaire. Physical Activity Questionnaire as used in the study, based on the Physical Activity Questionnaire for Older Children (PAQ-C) and Children’s Leisure Activities Study Survey (CLASS), cross-culturally adapted to represent common Dutch physical activities.Click here for file


Given the unique role of the corticotrophin-releasing hormone (CRH) system in human fetal development, the aim of our study was to estimate the association of birth weight with DNA sequence variation in three maternal genes involved in regulating CRH production, bioavailability and action: CRH, CRH-Binding Protein (CRH-BP), and CRH type 1 receptor (CRH-R1), respectively, in three racial groups .Our study was carried out on a population-based sample of 575 mother–child dyads. We resequenced the three genes in mouse–human hybrid somatic cell lines and selected SNPs for genotyping.A significant association was observed in each race between birth weight and maternal CRH-BP SNP genotypes. Estimates of linkage disequilibrium and haplotypes established three common haplotypes marked by the rs1053989 SNP in all three races. This SNP predicted significant birth weight variation after adjustment for gestational age, maternal BMI, parity, and smoking. African American and Hispanic mothers carrying the A allele had infants whose birth weight was on average 254 and 302 grams, respectively, less than infants having C/C mothers. Non-Hispanic White mothers homozygous for the A allele had infants who were on average 148 grams less than those infants having A/C and C/C mothers.The magnitudes of the estimates of the birth weight effects are comparable to the combined effects of multiple SNPs reported in a recent meta-analysis of 6 GWAS studies and is quantitatively larger than that associated with maternal cigarette smoking. This effect was persistent across subpopulations that vary with respect to ancestry and environment. The contribution of genetic and environmental determinants to variation in birth weight is an area of considerable on-going interest and investigation. The association of pathophysiological fetal growth, as reflected by extremes of the birth weight distribution  and large-for-gestational age (LGA) births), with high perinatal morbidity and mortality has long been established While much effort has been committed to the identification and management of pathologically inadequate or pathologically excessive fetal growth, less effort has been committed to evaluating the determinants of normal variation in fetal growth and birth weight. Furthermore, current limitations in knowledge about factors influencing variation in fetal growth make it difficult to accurately distinguish the optimally grown from the sub- or supra-optimally grown infant Birth weight, the phenotype representing the culmination of fetal growth, is a complex, multi-factorial trait regulated by the interplay of maternal and fetal genes and intrauterine physiology . Relatively little information, however, is currently available about the genetic loci that explain variation in birth weight. Studies using animal models have provided important insights regarding the genetic and environmental determinants of birth weight including the role of imprinted genes CRH is the key regulator of the hypothalamic-pituitary-adrenal axis. It is primarily secreted centrally (in the brain) and exerts major effects on growth, reproduction, immunity, thyroid function and metabolism In human pregnancy CRH is primarily produced in the decidua, fetal membranes and placenta In humans, placental CRH is known to play an important role in outcomes related to the length of human gestation and timing of onset of parturition Given the importance of elucidating the determinants of birth weight and the potentially unique role of the CRH system in human fetal growth and development, we carried out the study reported here to estimate the association of variation in birth weight with DNA sequence variation in gene regions coding for the three key genes regulating CRH production, bioavailability and action , respectively There are significant differences among racial/ethnic groups for average birth weight Because an important goal of clinical research is to identify measures of risk before, or during pregnancy, we elected here to investigate the utility of the maternal genotype in explaining variation in birth weight. We treated birth weight as a quantitative trait in order to evaluate the determinants of normal, physiological fetal growth. In addition to the dominant effect of gestational age at birth, the pursuit of defining the agents that influence fetal growth has identified a significant contribution of a subset of predictors of birth weight that include sex of the child and maternal BMI, race/ethnicity, parity, obstetric risk and smoking Does the CRH pathway-related genetic information explain variation in birth weight after accounting for the effects of other established risk factors/determinants of birth weight?Is there CRH-pathway related genetic information that explains variation in birth weight across the three major racial/ethnic groups in the U.S.?Participants in our study were recruited at two study sites in Southern California  and one study site in Pennsylvania . All participants in the current study participated in one or more clinical studies of pregnancy outcomes. These study protocols included multiple, serial assessments of biomedical, biological, psychosocial, and behavioral processes in pregnancy. Women <18 years, with multiple gestation, cord, placental, or uterine anomalies, fetal congenital malformations and those whose pregnancies ended in a spontaneous abortion were ineligible for the study. Beyond study design, we also restricted the final study dataset to only include Blacks, Hispanics, and Whites; and removed births <168 days (24 weeks) gestation. Race/ethnicity was determined by self-report using the Office of Management and Budget 1997 Revisions to the Standards for the Classification of Federal Data on Race and Ethnicity . The characteristics of the samples ascertained for each racial group are presented in All methods and procedures included in the current study were approved by the UC Irvine Institutional Review Board, the Cedars-Sinai Medical Center Institutional Review Board, and the Magee Women’s Hospital Institutional Review Board. All participants provided written informed consent. This consent procedure was approved by the institutional review boards of the participating institutions.Information on birth weight was abstracted from the delivery medical record. For all participants, gestational age was determined by best obstetric estimate with a combination of last menstrual period and early uterine size, and was confirmed by obstetric ultrasonographic biometry using standard clinical criteria Participants attended multiple, serial study visits during pregnancy. Study assessments included structured psychosocial and medical interviews, questionnaires, fetal biometry ultrasound, and the collection of venous blood, saliva and urine. Maternal venous blood was collected in Paxgene blood DNA tubes and samples were stored at −80°C until DNA extraction.We resequenced the three key genes from the CRH pathway  in mouse-human hybrid somatic cell lines constructed from individuals representing three major American ethnic groups including 20 Africans, 19 Hispanics, and 20 Whites SNP allele frequencies were estimated using the gene counting method and linkage disequilibrium between each pair of SNPs was defined by the formula presented by Weir A description of the mothers and infants included in our study is presented in As depicted in Estimates of the contribution of variation in sex of child and characteristics of the mother in determining variation in birth weight are presented in To provide a comprehensive survey of genetic variation in the three genes  we selected because they are involved in regulating the CRH pathway, we resequenced cell lines derived from 20 Blacks, 19 Hispanics, and 20 Whites representative of the three racial/ethnic groups included in our study. The results of the analyses to evaluate the contribution of SNP variation to explaining birth weight variation beyond the traditional risk factors are presented in On the basis of the results of the analyses presented in The A allele explains a large and statistically significant dominant effect on the decrease in birth weight in Blacks  and Hispanics  and a recessive effect in Whites . Those Black and Hispanic mothers carrying the A allele had infants whose birth weight was on average 254 and 302 grams, respectively, less than infants having C/C mothers. Those White mothers homozygous for the A allele had infants who were on average 148 grams less than those infants having A/C and C/C mothers. The relative frequency of the A allele in Black mothers was significantly greater than in Hispanic and White mothers . Black mIn our study of the relation between birth weight and sequence variation in the CRH family of genes, we found that variation in the 3′ untranslated region (UTR) of the CRH-BP gene, marked by SNP rs1053989, explained a significant amount of variation in birth weight in Whites, Hispanics and Blacks. The influence of sequence variation in the CRH-BP gene on birth weight in our study is similar in magnitude to the reported influence of cigarette smoking LKR1 and CCNL1, and rs9883204 in ADCY5)With respect to previous explorations of the genetic contribution to birth weight, Freathy et al conducted a meta-analysis of six genome-wide association studies of newborn genotype and identified two loci C/A A) that must be perfectly complementary for binding of microRNAs with recognition sites in 3′ UTRs of targeted genes. This evolutionarily conserved microRNA is encoded within intron 16 of the gene for sterol-responsive element-binding protein 2 transcription factor (SREBP2 on chromosome 22) that regulates cholesterol homeostasis. Previous functional studies have shown that miR33a regulates expression of genes in cellular pathways of cholesterol transport, including ABCA1 (ATP binding cassette transporter) and the lysosomal transporter protein NPC1  The biological mechanisms linking CRH-BP to fetal growth and birth weight are unknown. In human pregnancy, maternal CRH is related to offspring birth weight and fat mass This finding raises the opportunity for future study, and, possibly, patient care advances. Our data do not permit insight into the relative contribution of CRH-BP sequence variation to the various components of newborn weight such as skeletal, lean and fat mass. Further study of the body composition of newborns and the influence of genotype will serve to further dissect biological mechanism of influence. The contribution of sequence variation in the CRH-BP gene to physiologic and pathologic variation in the growth of the human fetus ought to be assessed prospectively in a population of women with rigorously ascertained environmental contributors to birth weight. Our finding also raises the possibility that sequence variation in CRH-BP might influence the clinical ability of assessment of fetal growth to distinguish the fetus with pathologic growth from the fetus with physiological growth restriction/impairment. Observational and randomized trials are warranted to evaluate the clinical utility of birth weight customization models that include genotype to distinguish newborns at risk for adverse outcome from those not at risk for adverse outcome. Current strategies show promise in this regard but are limited by their inability to explain sufficient physiological variation in birth weight. This is particularly an issue in attempts to identify the small-for-gestational-age and large-for-gestational-age newborns at risk for adverse outcome Figure S1Map of the Corticotrophin Releasing Hormone Binding Protein (CRH-BP) Gene – 5g11.2–13.3.(TIF)Click here for additional data file.Figure S2Map of the Corticotrophin Releasing Hormone (CRH) Gene – 8q13.(TIF)Click here for additional data file.Figure S3Map of the Corticotrophin Releasing Hormone Receptor 1 (CRH-R1) 17q12–q22 (1 of 2).(TIF)Click here for additional data file.Figure S4Map of the Corticotrophin Releasing Hormone Receptor 1 (CRH-R1) 17q12–q22 (2 of 2).(TIF)Click here for additional data file.Table S1CRH-BP Gene.(DOC)Click here for additional data file.Table S2CRH Gene.(DOC)Click here for additional data file.Table S3CRH-R1 Gene.(DOC)Click here for additional data file.Supporting Information S1Statistical Methods.(DOC)Click here for additional data file.


Background: In late October 2003, a series of wildfires exposed urban populations in Southern California to elevated levels of air pollution over several weeks. Previous research suggests that short-term hospital admissions for respiratory outcomes increased specifically as a result of these fires.Objective: We assessed the impact of a wildfire event during pregnancy on birth weight among term infants.n = 886,034), we compared birth weights from pregnancies that took place entirely before or after the wildfire event  with those where wildfires occurred during the first , second , or third  trimester. The trimester-specific effects of wildfire exposure were estimated using a fixed-effects regression model with several maternal characteristics included as covariates.Methods: Using records for singleton term births delivered to mothers residing in California’s South Coast Air Basin (SoCAB) during 2001–2005 : –11.8, –2.2] when the wildfire occurred during the third trimester, 9.7 g lower when it occurred during the second trimester , and 3.3 g lower when it occurred during the first trimester .in utero. The extent and increasing frequency of wildfire events may have implications for infant health and development.Conclusions: Pregnancy during the 2003 Southern California wildfires was associated with slightly reduced average birth weight among infants exposed  We excluded preterm births (< 37 weeks gestation), post-term births (> 42 weeks gestation), and births with a reported birth weight < 1 kg or > 6 kg, yielding a total of 886,034 births for our analysis. Gestational ages were based on the number of days since the mother’s reported last menstrual period (LMP).The SoCAB, which forms the geographic basis for our study population, includes the entirety of Orange County as well as populous areas within Los Angeles, San Bernardino, and Riverside counties. This air basin was chosen as the boundary for the study on the basis of satellite images of the fires; it is partially bounded by mountains that trap air pollution in the absence of wind . The SoCExposure assessment. On the basis of reports from the California Department of Forestry and Fire Protection  were delivered before 21 October 2003 and could not have been exposed in utero. An additional 256,094 births were assigned an LMP later than 10 November 2003, and were also classified as unexposed. All remaining births  were classified as exposed on the basis of temporal overlap between the wildfire exposure window and gestational intervals.otection  and inspotection , we defi10 measures during the fires of < 40 µg/m3 were classified as low exposure, and tracts with average daily levels > 40 µg/m3 were classified as high exposure. This cut point split the PM10 monitors in the SoCAB in half, with 36% of births that gestated during the fires occurring in high exposure census tracts.Our primary analysis used this temporal contrast as the basis for exposure assessment. However, we also conducted a sensitivity analysis in which we examined spatial contrasts based on proximity of maternal residence census tracts to air monitors. Tracts closer to monitors with average PMCovariates and primary model. We fit the data to a linear fixed-effects model (Equation 1) with birth weight (iy) as a continuous outcome and ijx as an indicator of exposure for birth i in trimester j. For our primary analysis, we defined ix as a categorical variable with four levels: exposed in trimester 1; exposed in trimester 2; exposed in trimester 3; or unexposed (iz) associated with birth weight and included terms based on the date of the LMP (it) to control for seasonality and trend.nexposed . We defii =y β0 + β1xi1 + β2xi2 + β3xi3 + ηi´z + f(it) + εi [1]Our analysis was limited by the availability of information on administrative birth records. Among the variables included on these forms, we adjusted for maternal characteristics  and characteristics of the birth itself  known to have a substantial influence on birth weight. These variables may have confounding potential, or play a role in explaining variation even in the absence of a confounding effect. We included parity of the mother with three levels: first live birth (reference), second live birth, or third or more live births. We coded gestational age (weeks since LMP) as 37 (reference), 38, 39, 40, 41, or 42 weeks. As a proxy for socioeconomic status, we coded maternal education with four levels: less than a high school education; completed high school or equivalent (reference); 1–3 years of postsecondary education; and ≥ 4 years of postsecondary education. We coded maternal race/ethnicity as non-Hispanic white (reference); Hispanic of any race; non-Hispanic black; non-Hispanic Asian; and unknown/multiple/other. We also included fetal sex with male as the referent category.f(it) as a combination of a linear secular trend based on the date of the last menstrual period for birth i (it) and categorical indicator terms for the season of birth (in quartiles): Q1 , Q2 (April–June), Q3 (July–September), or Q4 (October–December):To account for secular trend and seasonal effects, we parameterized f(it) = βtrend(it) + βQ2IQ2 + βQ3IQ3 + βQ4IQ4 [2]Sensitivity analyses. In addition to our primary analyses, we conducted three sensitivity analyses. In the first, we dichotomized the population according to whether the maternal residence census tract was closer to a PM10 monitor active during the fire period with an average PM10 measure > 40 μg/m3, or closer to a PM10 monitor with a lower average PM10 during the fire period. In the second, because of the association between season and trimester of exposure (f(it) as a smooth, periodic, sinusoidal function of time known as the cosinor [http://dx.doi.org/10.1289/ehp.1104515)]. In the third, because accounts differ concerning the length of the wildfire event, we reduced the length of the wildfire event to peak exposure periods of 2 weeks or 1 week instead of 3 (keeping the starting date unchanged) and reassigned exposures accordingly.exposure , we instStatistical software. We used R version 2.14.0 and the stats::lm function for model fitting. To fit the cosinor-based seasonal model, we used the season package, version 0.2–6 .n = 747,590) were unexposed in utero. Of the 138,444 exposed, 28.0%  were exposed in the third trimester, 28.5%  were exposed in the second trimester, and 43.5%  were exposed in the first trimester , followed by non-Hispanic white (22.0%), non-Hispanic Asian or Pacific Islander (11.3%), and non-Hispanic black (5.9%) mothers. Most infants were delivered to mothers 18–34 years of age (76.1%), with 20.8% delivered to mothers 35–50 years of age and 3.1% delivered to mothers 15–18 years of age. Approximately one-third of mothers had less than a high school education (32.1%), whereas 28.4% had completed a high school degree or equivalent, 18.1% had 1–3 years of postsecondary education, and 21.4% had ≥ 4 years of postsecondary education.http://dx.doi.org/10.1289/ehp.1104515).We did not observe substantive differences between the exposed and unexposed with respect to measured covariates, except for season of birth . Effect Estimated effects of wildfire exposure. Adjusted models revealed that mean birth weight was 6.1 g lower  among infants exposed in utero during any trimester compared with unexposed infants . Among those exposed in the third trimester, we observed a reduction of 7.0 g . The largest estimated effect was observed in the second trimester, with a reduction of 9.7 g . Among infants exposed in the first trimester, we also estimated a decline in mean birth weight but it was not statistically significant   . Both un10 during the wildfire event, the estimated decrement in birth weight associated with pregnancy (any trimester) during the event was 6.6 g . In tracts more proximal to monitors with average PM10 levels < 40 μg/m3, the estimated decrement in birth weight associated with pregnancy during the event was 5.9 g . These estimates were not discernibly different from each other .Among births in census tracts proximal to monitors with higher average PMSeasonality and trend. Over the entire period, 2001–2005, we found a secular decline in mean birth weight of 6.9 g/year  . Those conceived in Q3 (July–September) had the highest estimated mean weight at birth, 11.9 g  more than infants conceived in Q1 (January–March), the referent time period. Infants conceived in Q1 weighed the least.http://dx.doi.org/10.1289/ehp.1104515)].When we conducted a sensitivity analysis, using an alternate model with seasonal effects parameterized as a cosinor, the magnitude of the seasonal effect was comparable , as was the relative timing  of highest birth weight, with the maximum occurring on 4 August  . As such, it is readily interpretable, and it has been widely applied to the analysis of seasonal and circadian rhythms  in seasonal variation was similar to the difference between the minimum and maximum seasonal coefficients from the model using indicator terms (11.9 g). The phase was also consistent with the primary model’s seasons of lowest and highest average birth weight .Other potential confounders. We adjusted for several individual-level covariates known to be associated with birth weight, but data on other potential confounders were not available. For example, maternal smoking is not reported on most California birth records, and its inclusion in our study may have changed our results. However, recent studies suggest that although smoking during pregnancy has a large effect on birth weight, in studies of ambient air pollution it does not significantly confound the association between ambient air pollution exposure and adverse perinatal outcomes such as infant mortality and preterm birth , including background pollution could induce confounding just as including seasonality can. Without access to detailed measurements of both fractions, we elected to consider a strictly temporal contrast, reserving spatiotemporal refinements of exposure for future work.Previous studies that have attempted to isolate the contribution of wildfire-generated smoke have also compared health effects to a reference period e.g., . HoweverThis study indicates that maternal exposure to wildfire events may result in modestly lower infant birth weight. A small decline in birth weight is unlikely to have clinical relevance for individual infants, and there is debate about whether a small shift in the population distribution of birth weight has broader health implications e.g., . Althoug(152 KB) PDFClick here for additional data file.


Adverse birth outcomes such as low birth weight and premature birth have been previously linked with exposure to ambient air pollution. Most studies relied on a limited number of monitors in the region of interest, which can introduce exposure error or restrict the analysis to persons living near a monitor, which reduces sample size and generalizability and may create selection bias.2.5) levels during pregnancy in Massachusetts for a 9-year period (2000–2008). Building on a novel method we developed for predicting daily PM2.5 at the spatial resolution of a 10x10km grid across New-England, we estimated the average exposure during 30 and 90 days prior to birth as well as the full pregnancy period for each mother. We used linear and logistic mixed models to estimate the association between PM2.5 exposure and birth weight (among full term births) and PM2.5 exposure and preterm birth adjusting for infant sex, maternal age, maternal race, mean income, maternal education level, prenatal care, gestational age, maternal smoking, percent of open space near mothers residence, average traffic density and mothers health.We evaluated the relationship between premature birth and birth weight with exposure to ambient particulate matter  = −21.10, -6.05] in birth weight after controlling for other factors, including traffic exposure. The odds ratio for a premature birth was 1.06  = 1.01–1.13) for each 10 μg/m3 increase of PM2.5 exposure during the entire pregnancy period.Birth weight was negatively associated with PM2.5 during the last month of pregnancy contributes to risks for lower birth weight and preterm birth in infants.The presented study suggests that exposure to PM Recent epidemiological studies have established the association between maternal exposure to air pollution and adverse pregnancy outcomes -10. The Low or reduced birth weight (LBW) is an important predictor of children’s health and is associated with higher risk of infant and childhood mortality  and coroInterpretations of studies are complicated since LBW  represents a heterogeneous group of outcomes with different pathogenic mechanisms. Some infants have LBW as a result of PTB (less than 37 completed weeks of gestation at delivery), while others are a result of intrauterine growth restriction- IUGR . Some maternal prenatal determinants may be associated with an increased risk of LBW through effects on the length of gestation alone , others through effects on intrauterine fetal growth alone , and some possibly through effects on both PTB and IUGR . Where air pollution falls in this spectrum is not fully resolved.2.5 have typically used available monitors in the study area. PM2.5 concentrations vary spatially within the study domain and thus using only available monitors introduces exposure error and likely biases the effect estimates downward ,. During the analysis, multicollinearity and normality were evaluated, and no issues were uncovered (tolerance > 0.4).where Descriptive statistics are presented in Table 3 increase of PM2.5 exposure during the last 30 days prior to delivery was associated with a decrease of 8.80 g  in birth weight. A 10 μg/m3 increase of PM2.5 exposure during the last 90 days prior to delivery was associated with a decrease of 9.20 g  in birth weight. Finally, a 10 μg/m3 increase of PM2.5 exposure during the entire pregnancy was associated with a decrease of 13.80 g  in birth weight.Table 3 increase of PM2.5 exposure during the full pregnancy. Other exposure periods were non-significant.The odds ratio for a premature birth was 1.06 [95% confidence interval (CI) = 1.01–1.13] for each 10 μg/m2.5 model but were essentially identical across all 3 averaging times.In addition, all other covariates acted as expected (see Appendix 1). For example cigarette use both pre pregnancy and during pregnancy also decrease birth weight significantly  (see Appendix 1). These results are for the full birth PMFactors affecting birth weight for all singleton live births in Eastern Massachusetts between 2000–2008.2.5 exposure on birth outcomes in a study of singleton births in seven Massachusetts counties between 2000 and 2008. Using a model based on satellite remote sensing we were able to assign exposure to all subjects, regardless of the distance between a participant’s residence and the closest PM2.5 monitor. We found a consistent effect of exposure to PM2.5 on birth weight for infants who were born full term, and an elevated risk of preterm delivery after adjusting for other potential risk factors such as previous and current mother’s health conditions, socioeconomic factors and physical environment risk factors. Importantly, this association remained after controlling for traffic density within 100 meters of the residence and open space. Combined with the fact that the satellite grid is too coarse to capture local effects of high traffic on a nearby road, this suggests that the PM2.5 results we report here are due predominantly to non-primary traffic particles, and that the traffic density variable captures the additional impact of traffic pollution. In Massachusetts during these years, such non primary particle exposures were mostly sulfates, from coal burning power plants, and transported secondary organic aerosols, which are generated from a variety of sources including traffic in upwind locations.We examined the effects of PM2.5 we can assign daily PM2.5 exposure to the entire study population, avoiding selection bias that would yield a non-representative sample. In addition we account for small area measures of potential confounders at a 10x10km spatial resolution, thus minimizing exposure error.A key feature of the presented study compared to previous epidemiologic studies showing associations between air pollution and birth weight ,29,30 is2.5 on birth weight and its determinants is still very limited. Fine particulate matter may affect birth weight through direct or indirect means. Some studies have shown that PM2.5 is associated with a number of cardiovascular and respiratory related outcomes both in adults and children [2.5 during pregnancy could indirectly affect fetal health by adversely affecting the health of the mother. Since PM2.5 has been associated with arterial narrowing [Knowledge of the exact impact of PMchildren -33. Matearrowing ,35, incrarrowing -39, and arrowing , this exarrowing .2.5[Our results are in agreement with the previous studies which analyzed the effect of exposure to PM2.5,29 and a2.5 is relatively homogeneous spatially [2.5, with the local traffic contribution captures by that separate covariate. Moreover this coarse resolution, combined with our use of a local traffic exposure variable allow us to focus on the effects of regional pollutants in this study. Another limitation of using a fixed 10x10km grid is the Modifiable areal unit problem (MAUP) which refers to the problem of information loss due to data aggregation [A major limitation of the present study is the spatial resolution of 10X10 km. While estimation conducted at a finer spatial resolution is preferable, PMpatially , and so regation , althougregation  which isAs satellite remote sensing evolves and progresses, higher spatial resolution data (e.g 3x3km and 1x1 km) should become available in the next two years, which will further reduce exposure error. Such increased resolution should enable us to more precisely estimate daily exposures and how these vary across spatial locations.2.5 during pregnancy contributes to the risk of preterm birth and lower birth weight in infants.In summary, the presented study suggests that exposure to PMThe authors declare that they have no competing interests.IK was the principal investigator responsible for design, conduct, analysis, interpretation of data and writing the manuscript. SJM was responsible for all GIS and spatial analysis work. WLR was responsible for design, data management and analysis. BAC participated as statistician and in the compilation and interpretation of the data and JS made contributions to conception, design, analysis of data and drafting the manuscript. All authors read and approved the final manuscript.


Perineal injury is a serious complication of vaginal delivery that has a severe impact on the quality of life of healthy women. The prevalence of perineal injuries among women who give birth in hospital has increased over the last decade, while it is lower among women who give birth at home. The aim of this study was to describe the practice of midwives in home birth settings with the focus on the occurrence of perineal injuries.Twenty midwives who had assisted home births for between one and 29 years were interviewed using an interview guide. The midwives also had experience of working in a hospital delivery ward. All the interviews were tape-recorded and transcribed. Content analysis was used.The overall theme was "No rushing and tearing about", describing the midwives' focus on the natural process taking its time. The subcategories 1) preparing for the birth; 2) going along with the physiological process; 3) creating a sense of security; 4) the critical moment and 5) midwifery skills illuminate the management of labor as experienced by the midwives when assisting births at home.Midwives who assist women who give birth at home take many things into account in order to minimize the risk of complications during birth. Protection of the woman's perineum is an act of awareness that is not limited to the actual moment of the pushing phase but starts earlier, along with the communication between the midwife and the woman. Perineal injuries and anal sphincter ruptures are serious complications of vaginal delivery. Most common consequences of perineal injury are pain and incontinence, which affect the quality of life of healthy women . Other cRisk factors for anal sphincter rupture during delivery are described as nulliparity, high birth weight of the child, instrumental deliveries, episiotomy, adverse birth position, maternal age and epidural analgesia ,5. WomenLower frequency of perineal injuries and anal sphincter ruptures has been reported from studies of planned home births internationally -12. A SwEvidence indicates that the prevalence of perineal trauma is lower among women giving birth at home assisted by a midwife. It is not clear whether this has to do with differences in midwifery practice or other factors. There is a need to understand more about midwifery practice in home births settings in order to gain knowledge on how to protect women from perineal injuries.A qualitative approach, using open-ended qualitative interviews, was applied in this study. Individual interviews were conducted with twenty midwives in 2009. Information regarding the study was presented on the website "Föda hemma" (Giving birth at home) hosted by a network of midwives assisting women in home deliveries. Midwives interested in participating were contacted, informed about the purpose of the study and invited to take part. Eleven midwives first gave their consent to participate and another nine midwives were contacted through these eleven midwives and invited to be individually interviewed. The interviews took place in the participants' homes or at their workplace. The time taken for the interviews was between 30 and 75 minutes. All interviews were tape-recorded with the permission of the participants. Interview guidelines with open-ended questions were developed prior to the study  that you use in order to prevent perineal injuries? • What do you think is the explanation for lower frequency of perineal injuries in home birth settings? Is there anything else that you consider significant for giving birth with an intact perineum?Click here for file


Concern about the completeness of comorbidity information in hospital records has been raised as a limitation of using hospital discharge data for research. The aim of this study is to assess the impact of additional comorbidity information from prior hospital admissions on estimation of prevalence and modelling of risk factors for obstetric haemorrhage.A range of chronic disease prevalence for 53,438 women who had their first birth in New South Wales (NSW), Australia, 2005-2006, were ascertained for up to five years prior to the birth admission  and obstetric haemorrhage was identified from maternal hospital records for 2005 and 2006.The ascertainment of chronic disease prevalence increased with increasing length of lookback. However, the rate of the increase was slower after 2 to 3 years than for the more recent periods. The effect size of chronic diseases on obstetric haemorrhage risk decreased with the increased case ascertainment associated with longer lookback. Furthermore, longer lookback did not improve the predictive capacity (C-statistic: 0.624) of a model that was based only on the birth admission records.Longer ascertainment periods resulted in improved identification of chronic disease history among pregnant women, but the additional information from prior admissions did little to improve the modelling of risk factors for obstetric haemorrhage. The use of population health data for health and health outcomes research is increasing. These routinely collected data may be administrative, surveillance, registry or vital statistics collections and have the common feature of including information on an entire population. However, concerns about the completeness of comorbidity information in the admission of interest (index record) have been raised as a limitation of using hospital discharge data for research . One reaUsing a longer lookback period for ascertaining a condition is likely to result in a higher proportion of subjects with the condition, but the effect of the condition may be reduced because the severity of the condition can vary depending on how recently it was identified . Few stuWorldwide, obstetric haemorrhage is a leading cause of maternal mortality and accounts for about 25% of all maternal deaths . IncreasIn the State of New South Wales (NSW), Australia, comprehensively linked perinatal population data were available from 1 July, 2000 to 31 December, 2006. Details of the record linkage were reported in a previous study . For theThe NSW Admitted Patient Data Collection  covers every inpatient admission in NSW, and includes demographic and episode-related data. Data from the medical records are coded according to the tenth revision of the International Classification of Diseases Australian Modification ICD-10-AM) and the affiliated Australian Classification of Health Interventions . Up to 20-AM and We selected chronic diseases including cardiac diseases, chronic renal disease, asthma/chronic obstructive pulmonary disease (COPD), psychiatric disorders, pre-existing hypertension, pre-existing diabetes, thyroid disorders and autoimmune diseases, for the study. The autoimmune diseases include Crohn's disease, ulcerative colitis, lupus, idiopathic, thrombocytopenic purpura, multiple sclerosis, psoriasis, autoimmune thyroiditis, rheumatoid diseases, Coeliac disease, vasculitis, pernicious anemia, myasthenia gravis, autoimmune hepatitis, ankylosing spondylitis, polymyositis and primary biliary cirrhosis. There is some evidence suggesting increased risk of obstetric haemorrhage associated with cardiac disease, pre-existing hypertension, asthma and thyroid disorders ,16-18. BThe ICD-10-AM diagnosis and affiliated procedure codes for these chronic diseases are presented in Table In this study, obstetric haemorrhage (refer to as 'haemorrhage') was identified from maternal hospital records for the birth admission and any associated transfer to another hospital prior to discharge home. A case of haemorrhage was determined if a record had any diagnosis code for postpartum haemorrhage (O72), intrapartum haemorrhage (O67), placenta previa with haemorrhage (O44.1), antepartum haemorrhage (O46.0), morbidly adherent placenta (O43.2), transfusion (Z51.3) or acute post-haemorrhage anaemia (D62); any procedure code for transfusions  or in case of vaginal birth any procedure code for manual removal of placenta (90482-00 or 90483-00).st day of pregnancy, '2 years' - from day 0 back to 2 years, '3 years' - from day 0 back to 3 years, '4 years' - from day 0 back to 4 years and '5 years' - from day 0 back to 5 years. The first day of pregnancy was estimated by baby's date of birth minus 7 × gestation age (ranged from 18 to 44 weeks) that was recorded in the birth record. Potential risk factors for obstetric haemorrhage such as type of hospital, baby's gender, birth weight, multiple birth, gestational age, maternal age and combination of onset of labour and mode of delivery were obtained from the birth record where they are reliably reported [The proportion of women with the selected chronic disease was calculated for different lengths of lookback, with the longer lookback periods including all conditions reported in the shorter periods: 'Birth' - at birth admission (day 0), 'Pregnancy' - from day 0 back to the estimated 1reported .P < 0.05, two-sided). The capacity of a model to predict haemorrhage was evaluated using the area under the receiver-operating characteristic (ROC) curve (C-statistic), with values of 1.0 representing perfect ability and 0.5 indicating no better ability than chance. For comparing correlated C-statistics, we used %roc SAS® macro [Logistic regression was employed to determine the effect size (odds ratio) of a potential risk factor on haemorrhage after adjusting for maternal age. In the selection of independent risk factors, age was always retained in the model and a backwards elimination approach was used to progressively remove the least significant term until all terms remaining were significant (S® macro  (a nonpaS® macro ).Of 55,002 women with a first birth from 1 July 2005 through 31 December 2006, 53,438 (97.2%) linked to a birth admission record and were included in the study , chronic renal disease  and psychiatric disorders   and psychiatric disorders  were independent risk factors for haemorrhage using the birth admission records. These results were adjusted for type of hospital, baby's gender, birth weight, multiple birth, gestational age, maternal age and combination of onset of labor and mode of delivery (Table P > 0.29), and the C-statistic remained about the same (0.624) for models using hospital records from lookback periods of 'Pregnancy', '2 years', '3 years', '4 years' and '5 years'. This was also the case when comparing to a model that included two variables (i.e. one for the birth admission and the other for the lookback period) for each of the two chronic diseases . Both additional variables were not statistically significant in the model (both P > 0.71).In multivariate analysis, only chronic renal disease  was under-estimated. This is likely to be related to the fact that hospital data only identifies diseases/conditions that require hospitalisation or that affect a hospital admission. Although lookback over 5 years increased the identification of asthma from 0.9% to 2.4%, this still represents poor identification of women with asthma. The National Health Survey 2004-05 reported that 13.5% of Australian women aged 15 to 45 years had asthma and 3% of the population had COPD (emphysema and/or bronchitis) . SimilarWith regard to predictive ability, information from prior hospital admissions might not improve the capacity of a predictive model if it were simply used to increase the number of cases with a condition. In a study of 61,815 patients, Kim and Ahn  also repOn the other hand, Zhang et al.  found inWith regard to effect estimation, increasing the number of cases with a disease/condition by using information from prior hospital admissions could produce an effect size smaller than that estimated using only the index record (i.e. only severe or active cases). In this study we found that the more remote (in time) that hospitalisations with chronic disease were reported, the smaller the effect the disease had on haemorrhage. One explanation for this could be that conditions that were ascertained from previous hospital records might have been treated and well controlled or be less severe than conditions identified from the index records. The effect of a risk factor on a particular outcome is likely to be dependent not only on the risk factor but also its severity, and a more severe instance is more likely to be ascertained in recent records than in older records . Not mucChronic renal disease (via anemia) and psychiatric disorders (via medication) may place women at increased risk of obstetric haemorrhage . PregnanA five-year ascertainment period for a chronic disease improves estimation of the population prevalence in a young and generally healthy population if the disease required treatment in hospital. On the other hand, diseases that do not require hospitalisation or cases with no obvious symptoms or in subclinical categories would usually not be picked up using longitudinally linked hospital records. In the case of haemorrhage prediction, comorbidity information from prior hospital admissions did little to improve the haemorrhage modelling. For estimating the effect size of a risk factor, the most appropriate lookback period should be determined by the study objective.The authors declare that they have no competing interests.JSC performed the statistical analysis and drafted the manuscript. CLR and JBF conceived of the study, participated in its design and revised it critically for important intellectual content. JMS contributed to the study design, statistical analysis and interpretation of the results. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2288/11/68/prepub


Maxillary dentigerous cysts although uncommon need to be considered in the differential diagnosis in children with painless facial swelling. We present a case of dentigerous cyst associated with maxillary deciduous canine and maxillary premolars manifesting as a unilateral swelling in canine region of the face. A ten-year-old boy came to oral and maxillofacial surgery unit with a painless left facial swelling. The local dentist had prescribed antibiotics for treatment for the facial swelling, but the swelling did not subside, and the parents brought the child to our unit in Zliten Dental College. After clinical examination and imaging, the diagnosis of dentigerous cyst was made. Caldwell-Luc approach was done, the cyst was enucleated, and primary closure was done. The patient was followed up for a period of two years and there was no evidence of any recurrence. Cysts of the jaw usually present as asymptomatic swellings of the mandible and midface region. A dentigerous cyst is one that encloses the crown of an unerupted tooth by expansion of its follicle and is attached to its neck. In maxillary dentigerous cysts involving the canine region, extension into the maxillary sinus or to the orbital floor may be noted as seen in our case. Most dentigerous cysts are asymptomatic, and they are usually observed as an incidental finding on radiography. These cysts attain a large size with resorption of the roots of teeth till they manifest clinically or become evident radiographically. Treatment includes enucleation of the cyst with the removal of the unerupted tooth. Marsupialization is occasionally done with very large cyst to decompress the cyst. Prognosis is excellent with enucleation and recurrence is rare if the cysts is completely removed.A 10-year-old boy presented to our unit with the chief complaint of left facial swelling . A sevenDentigerous cyst is classified as a developmental cyst by the World Health Organization. The highest incidence of dentigerous cysts occurs during the second and third decade of life. The mandibular third molar and maxillary canines are involved most frequently. A greater incidence in males has been noted, with a ratio of 1.6 : 1 reported. They are the second most common type of odontogenic cyst and the most common developmental cyst of the jaws. In children from 2 to 14 years of age, dentigerous cysts account for 49% of intraosseous cystic lesions, with eruption cysts, odontogenic keratocysts, and radicular cysts accounting for more than 10% each. Approximately 24% of all true cysts in the jaw are dentigerous cysts . Like otBecause they are typically asymptomatic, dentigerous cysts are usually diagnosed on routine dental radiographs. The diagnosis of dentigerous cyst is based on a combination of radiographic and histological features. We took orthopantomogram, paranasal sinus view, and intraoral periapical radiographs for our case. Radiographically, a dentigerous cyst is presented as a well defined unilocular or occasionally multilocular radiolucency with corticating margins in association with the crown of an unerupted tooth. These cysts range in size from several millimeters to several centimeters, where they may compromise jaw bone integrity and produce facial asymmetry . In the Dentigerous cysts are frequently treated surgically, either by enucleation or marsupialisation. Following enucleation of the cyst and extraction of the unerupted tooth, the prognosis is excellent and recurrence is rarely observed after a complete removal. Surgical enucleation combined with the Caldwell-Luc approach followed by primary closure is recommended in treatment of the large maxillary sinus cyst as marsupialisation of these cysts towards the oral cavity will consequently create an oroantral fistula . In our Our patient presented with a painless left facial swelling. Over a period of several weeks, the lesion expanded and caused left facial deformity. Additional imaging and histological examination confirmed the diagnosis of dentigerous associated with a canine and first premolar tooth. Although dentigerous cysts are more often found in the mandible, they may occur in the maxilla and rarely may infiltrate the floor of the orbit as seen in our case. Caldwell-Luc approach and enucleation of the cyst have been the mainstay of maxillary sinus surgery over the past century and still prove to be the method of choice.


Birthweight and gestational age are associated with socioeconomic deprivation, but the evidence in relation to temporal changes in these associations is sparse. We investigated changes in the associations between socioeconomic status (SES) and birthweight and gestational age in Newcastle upon Tyne, North of England, during 1961–2000.We used population-based data from hospital neonatal records on all singleton births to mothers resident in Newcastle . We used linear regression to analyse the associations between neighbourhood SES and birthweight over the entire 40-year period and by decade, and logistic regression for associations with low birthweight (LBW) and preterm birth, adjusting for potential confounders.There was a significant interaction between SES and decade of birth for birthweight (p = 0.028) and preterm birth (p < 0.001). Socioeconomic gradients were similar in each decade for birthweight outcomes, but for preterm birth, socioeconomic disparities were more evident in the later decades . In each decade, there was a significant decrease in birthweight adjusted for gestational age for the most deprived compared to the least deprived SES group , while there was a significant increase in birthweight in each SES group over time.Socioeconomic inequalities did not narrow over the four decades for birthweight and widened for preterm birth. Mean birthweight adjusted for gestational age increased in all socioeconomic groups, suggesting an overall increase in fetal growth. Birthweight and gestational age are major determinants of perinatal and infant mortality ,2, with The well-established associations of adverse perinatal outcomes, such as LBW and preterm birth, with socioeconomic deprivation ,15-19 arThis population-based study aims to investigate decadal changes in birthweight and gestational age in relation to area-based socioeconomic status (SES) in Newcastle upon Tyne, UK, from 1961 to 2000. Compared to studies from larger areas over shorter periods -27, thishttp://www.newcastle.gov.uk/your-council/statistics-and-census-information/population-past-estimates-and-trends). Newcastle has transformed from a city with heavy industry and coal production in the early 1960s to a city with a predominantly service-based economy by 2000. The population structure of the region is characterised by a low percentage of ethnic minorities (2%) [This population-based study included all singleton births to mothers resident in Newcastle upon Tyne, North of England, from 1961 to 2000  , and a ries (2%) . A majories (2%) , with daies (2%) . Brieflyies (2%) , from biWe defined LBW as a birthweight less than 2500 g; gestational age as time between the woman’s last normal menstrual period (LMP) and date of delivery; preterm birth as birth at less than 37 completed weeks of gestation. For consistency across the study period, and meaningful comparison of preterm birth and low birthweight rates between the decades, we excluded stillbirths at <28 completed weeks of gestation, even for births from October 1992 when the legal cut-off in gestational age for stillbirth was changed to 24 completed weeks in England and Wales. Births with a birthweight <500 g were also excluded if gestational age was unknown.The Townsend Deprivation Score (TDS), an area-based measure of material deprivation incorporating the proportion of home ownership, car ownership, unemployment and overcrowding, was calculated at the enumeration district (ED) level using data from the 1971 (for 1961–76), 1981 (for 1977–1986) and 1991 (for 1987–1996) UK Census Surveys. ED is the finest geographical scale of census area (approximately 450 people in 200 households) in England and Wales for which census data were available. We identified EDs from the maternal residential postcode at birth  or grid reference . We used the 2001 Census data for births between 1997 and 2000 to calculate TDS which were available at the Census ward level  rather than ED level. We used TDS quartiles for this analysis, Q1 representing those resident in wards assumed to be the least deprived to Q4 representing those assumed to be most deprived. Since there can be considerable change in SES from one decade to the other , we calcThere were 131,044 singleton births within the study area between 1961 and 2000; birthweight was available for 118,450 (90.4%) and gestational age for 116,185 (88.7%) births. Data on birthweight and gestational age were missing mainly for home births in the earlier period of the study as it was not recorded in birth ledgers. Information was also available on maternal residential address including postcode, maternal age, parity, TDS and infant sex. Infant sex was available for 131,033 births (>99.9%), maternal age, parity and TDS were available for 118,027 (90.1%), 118,371 (90.3%) and 128,459 (98.0%) births respectively. Multivariable models used 113,182 births for birthweight and 113,431 for gestational age outcomes.th, 50th and 75th percentile cut-offs) and decades of birth  were also fitted as categorical variables in the models. We chose to use decade of birth rather than individual years to avoid noise due to annual fluctuations in outcomes and to link in with the use of census data. A product term was used to examine whether there was an interaction between TDS quartiles and decade of birth in the adjusted model for each outcome. We also carried out separate analyses by decade. STATA, version 10.1  was used for statistical analyses.We calculated mean birthweight and the proportions of LBW and preterm birth for each TDS quartile and plotted the trends. We used five-year moving averages to smooth the trends as there was considerable annual variation in each of the outcomes. In multivariable analyses, we fitted linear regression models to birthweight and logistic regression models to the dichotomous outcomes, LBW and preterm birth. We report regression coefficients for linear regression and odds ratios (ORs) for logistic regression with corresponding 95% confidence intervals (95% CI). Maternal age, parity and infant sex were included as categorical variables in the model with maternal age as five year groups  and parity as primipara, one, two, three and ≥ four. TDS quartiles  to use the hospital neonatal records for 1961–1992. We also received ethical and Caldicott approval to use the birth records for 1993–2002 to extend the PAMPER birth record database. For this sub-analysis we used anonymised data only.For the entire study period, there was a clear socioeconomic gradient with a higher risk of reduced birthweight –103, –87), LBW  and preterm birth  for the most deprived compared to the least deprived TDS quartile.Overall, mean birthweight increased from 3227 g in 1961 to 3333 g in 2000 . The percentage of LBW and preterm birth for each TDS quartile by decade are shown in Table There was a significant interaction between TDS quartile and decade of birth for birthweight p = 0.028) but not for LBW (p = 0.277). Table 8 but notTable This long-term population-based study from a relatively small conurbation with a stable population reports a clear socioeconomic gradient for continuous birthweight, LBW and preterm birth, with the higher risk of reduced birthweight, LBW and preterm birth in more deprived groups compared to the least deprived group using an area level deprivation measure. Over the four decades, mean birthweight increased and the percentage of LBW decreased across all deprivation groups. However, the percentage of preterm birth decreased in the least deprived groups and increased for the most deprived groups, thereby widening the gap between the most affluent and most deprived groups. There was a significant interaction between area deprivation and decade of birth for birthweight and preterm birth, while for LBW the SES gradients remained relatively smaller. In each SES group mean birthweight adjusted for gestational age  increased over time with a simultaneous decrease in the proportion of LBW, suggesting a possible increase in fetal growth across all TDS groups.th century, showed that the SES gap was either relatively stable or, similar to other health outcomes [The findings of this study are consistent with those in similar studies across larger geographic areas in the United States, Canada, Europe, which report socioeconomic disparity for birthweight outcomes ,18,25 anoutcomes , was widoutcomes . Our NewSocioeconomic inequality in birthweight is shown to be mediated by factors which can directly affect fetal growth, such as fetal exposure to maternal smoking . The intThe above mediators of the association of SES with fetal growth are less important for preterm birth. A systematic review showed that maternal anthropometric features such as BMI, pre-pregnancy weight and maternal height were poor predictors of preterm delivery . CigaretThe recent trend in increasing proportion of preterm birth observed in many countries may have resulted in part from more frequent obstetric interventions in compromised pregnancies at an earlier gestation as a result of improved survival of preterm babies. In this study, there was an increase in caesarean section from 1961 to 2000 , but theThis study has a number of strengths which have been described in detail elsewhere . The valIn this study we used an area-based composite scoring method to identify the neighbourhood SES of the postcode area and assigned the same status to all mother/infant pairs residing within that postcode. Previous UK studies of birthweight outcomes showed that area-based TDS, as a proxy measure of SES, was a reliable alternative to individual measures . Area deOne of the study limitations was lack of data on maternal smoking, an important determinant of fetal growth, which did not allow us to examine the direct contribution of smoking to the association of SES with LBW and preterm birth. Information on some maternal anthropometric characteristics such as height, BMI or pre-pregnancy weight, which may have mediated the association between area-based deprivation and birthweight, but not preterm birth , was alsThe study confirmed the role of socioeconomic inequalities on birthweight, LBW and preterm birth. The gap between the most and least deprived groups did not narrow for birthweight outcomes and widened for preterm birth over the four decades. These findings deserve due attention from a public health perspective. Further monitoring of changes in the association between SES and birth outcomes at the population level is important for prioritising public health interventions. Future studies are encouraged to use individual-level information on factors mediating the effects of socioeconomic inequality on birth outcomes to quantify their direct contribution and to determine the main target groups for interventions.BMI: Body mass index; CI: Confidence interval; ED: Enumeration district; LBW: Low birthweight; LMP: Last menstrual period; OR: Odds ratio; PAMPER: Particulate Matter and Perinatal Events Research; SD: Standard deviation; SES: Socioeconomic status; TDS: Townsend deprivation score.The authors declare that they have no competing interests.SVG, JR, MSP, LP and TPM contributed to the conception and design of the study, RG carried out the statistical analysis and SVG drafted the manuscript. All authors participated in the interpretation of the results, reviewed the paper for important intellectual content and read and approved the final version of the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/13/345/prepubMean (SD) maternal age (years) by decade of birth and by area deprivation group .Click here for file