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1.  Modifiable early-life risk factors for childhood adiposity and overweight: an analysis of their combined impact and potential for prevention1234 
Background: Early life may be a “critical period” when appetite and regulation of energy balance are programmed, with lifelong consequences for obesity risk. Insight into the potential impact of modifying early-life risk factors on later obesity can be gained by evaluating their combined effects.
Objective: The objective was to examine the relation between the number of early-life risk factors and obesity outcomes among children in a prospective birth cohort (Southampton Women's Survey).
Design: Five risk factors were defined: maternal obesity [prepregnant body mass index (BMI; in kg/m2) >30], excess gestational weight gain (Institute of Medicine, 2009), smoking during pregnancy, low maternal vitamin D status (<64 nmol/L), and short duration of breastfeeding (none or <1 mo). Obesity outcomes examined when the children were aged 4 and 6 y were BMI, dual-energy X-ray absorptiometry–assessed fat mass, overweight, or obesity (International Obesity Task Force). Data were available for 991 mother-child pairs, with children born between 1998 and 2003.
Results: Of the children, 148 (15%) had no early-life risk factors, 330 (33%) had 1, 296 (30%) had 2, 160 (16%) had 3, and 57 (6%) had 4 or 5. At both 4 and 6 y, there were positive graded associations between number of early-life risk factors and each obesity outcome (all P < 0.001). After taking account of confounders, the relative risk of being overweight or obese for children who had 4 or 5 risk factors was 3.99 (95% CI: 1.83, 8.67) at 4 y and 4.65 (95% CI: 2.29, 9.43) at 6 y compared with children who had none (both P < 0.001).
Conclusions: Having a greater number of early-life risk factors was associated with large differences in adiposity and risk of overweight and obesity in later childhood. These findings suggest that early intervention to change these modifiable risk factors could make a significant contribution to the prevention of childhood obesity.
PMCID: PMC4307207  PMID: 25646335
adiposity; childhood obesity; early life; obesity; lifecourse; prevention
2.  Childhood bone mineral content is associated with methylation status of the RXRA promoter at birth 
Maternal vitamin D deficiency has been associated with reduced offspring bone mineral accrual. Retinoid-X Receptor-alpha (RXRA) is an essential cofactor in the action of 1,25(OH)2-vitamin D, and RXRA methylation in umbilical cord DNA has been associated with later offspring adiposity. We tested the hypothesis that RXRA methylation in umbilical cord DNA collected at birth is associated with offspring skeletal development, assessed by dual-energy X-ray absorptiometry, in a population-based mother-offspring cohort (Southampton Women’s Survey). Relationships between maternal plasma 25(OH)-vitamin D concentrations and cord RXRA methylation were also investigated. In 230 children aged 4 years, higher % methylation at 4 out of 6 RXRA CpG sites measured was correlated with lower offspring % bone mineral content (%BMC) (β=−0.02 to −0.04%/SD, p=0.002 to 0.043) and BMC corrected for body size (β=−2.1 to −3.4g/SD, p=0.002 to 0.047), with a further site associated with %BMC only. Similar relationships for %BMC were observed in a second independent cohort (n=64). Maternal free 25(OH)-vitamin D index was negatively associated with methylation at one of these RXRA CpG sites (β=−3.3 SD/unit, p=0.03). In addition to the mechanistic insights afforded by associations between maternal free 25(OH)-vitamin D index, RXRA methylation in umbilical cord DNA, and childhood BMC, such epigenetic marks in early life might represent novel biomarkers for adverse bone outcomes in the offspring.
PMCID: PMC3836689  PMID: 23907847
Epigenetic; methylation; umbilical cord; RXRA; vitamin D; DXA
3.  Vitamin D supplementation in pregnancy: A systematic review 
It is unclear whether the current evidence base allows definite conclusions to be made regarding the optimal maternal circulating concentration of 25(OH)-vitamin D during pregnancy, and how this might best be achieved. CRD42011001426.
Aim/ Research Questions
What are the clinical criteria for vitamin D deficiency in pregnant women?What adverse maternal and neonatal health outcomes are associated with low maternal circulating 25(OH)-vitamin D?Does maternal supplementation with vitamin D in pregnancy lead to an improvement in these outcomes (including assessment of compliance and effectiveness)?What is the optimal type (D2 or D3), dose, regimen and route for vitamin D supplementation in pregnancy?Is supplementation with vitamin D in pregnancy likely to be cost-effective?
We performed systematic review and where possible combined study results using meta-analysis to estimate the combined effect size.
Major electronic databases were searched up to June 2012 covering both published and grey literature. Bibliographies of selected papers were hand-searched for additional references. Relevant authors were contacted for any unpublished findings and additional data if necessary.
Inclusion and exclusion criteria
Pregnant women or pregnant women and their offspring.
Either assessment of vitamin D status (dietary intake, sunlight exposure, circulating 25(OH)-vitamin D concentration) or supplementation of participants with vitamin D or vitamin D containing food e.g. oily fish.
Offspring: Birth weight, birth length, head circumference, bone mass, anthropometry and body composition, risk of asthma and atopy, small for gestational dates, preterm birth, type 1 diabetes, low birth weight, serum calcium concentration, blood pressure and rickets. Mother: Preeclampsia, gestational diabetes, risk of caesarean section and bacterial vaginosis.
76 studies were included. There was considerable heterogeneity between the studies and for most outcomes there was conflicting evidence.
The evidence base was insufficient to reliably answer question 1 in relation to biochemical or disease outcomes.
For questions 2 and 3, modest positive relationships were identified between maternal 25(OH)-vitamin D and 1) offspring birth weight in meta-analysis of 3 observational studies using log-transformed 25(OH)-vitamin D concentrations after adjustment for potential confounding factors (pooled regression coefficient 5.63g/10% change maternal 25(OH)D, 95% CI 1.11,10.16), but not in those 4 studies using natural units, or across intervention studies; 2) offspring cord blood or postnatal calcium concentrations in a meta-analysis of 6 intervention studies (all found to be at high risk of bias; mean difference 0.05mmol/l, 95% CI 0.02, 0.05); and 3) offspring bone mass in observational studies judged to be of good quality, but which did not permit meta-analysis.
The evidence base was insufficient to reliably answer questions 4 and 5.
Study methodology varied widely in terms of study design, population used, vitamin D status assessment, exposure measured and outcome definition.
The evidence base is currently insufficient to support definite clinical recommendations regarding vitamin D supplementation in pregnancy. Although there is modest evidence to support a relationship between maternal 25(OH)-vitamin D status and offspring birth weight, bone mass and serum calcium concentrations, these findings were limited by their observational nature (birth weight, bone mass) or risk of bias and low quality (calcium concentrations). High quality randomised trials are now required.
PMCID: PMC4124722  PMID: 25025896
5.  Programming of Osteoporosis and Impact on Osteoporosis Risk 
Osteoporosis is a skeletal disorder characterised by reduced bone quantity and quality and an increased susceptibility to fracture, and appears to be one of many chronic conditions that might be influenced by events early in life. Specifically, there is growing evidence of an interaction between the genome and the environment in the expression of the disease.
PMCID: PMC3732203  PMID: 23787708
osteoporosis; programming; bone; fracture; nutrition; cohort
6.  Objectively measured physical activity in four-year-old British children: a cross-sectional analysis of activity patterns segmented across the day 
Little is known about preschool-aged children’s levels of physical activity (PA) over the course of the day. Using time-stamped data, we describe the levels and patterns of PA in a population-based sample of four-year-old British children.
Within the Southampton Women’s Survey the PA levels of 593 4-year-old children (51% female) were measured using (Actiheart) accelerometry for up to 7 days. Three outcome measures: minutes spent sedentary (<20 cpm); in light (LPA: ≥20 – 399 cpm) and in moderate-to-vigorous activity (MVPA: ≥400 cpm) were derived. Average daily activity levels were calculated and then segmented across the day (morning, afternoon and evening). MVPA was log-transformed. Two-level random intercept models were used to analyse associations between activity level and temporal and demographic factors.
Children were active for 67% (mean 568.5 SD 79.5 minutes) of their daily registered time on average, with 88% of active time spent in LPA. All children met current UK guidelines of 180 minutes of daily activity. There were no differences in children’s average daily levels of sedentary activity and LPA by temporal and demographic factors: differences did emerge when activity was segmented across the day. Sex differences were largest in the morning, with girls being more sedentary, spending fewer minutes in LPA and 18% less time in MVPA than boys. Children were more sedentary and less active (LPA and MVPA) in the morning if they attended childcare full-time compared to part-time, and on weekend mornings compared to weekdays. The reverse was true for weekend afternoons and evenings. Children with more educated mothers were less active in the evenings. Children were less sedentary and did more MVPA on summer evenings compared to winter evenings.
Preschool-aged children meet current physical activity guidelines, but with the majority of their active time spent in LPA, investigation of the importance of activity intensity in younger children is needed. Activity levels over the day differed by demographic and temporal factors, highlighting the need to consider temporality in future interventions. Increasing girls’ morning activity and providing opportunities for daytime activity in winter months may be worthwhile.
PMCID: PMC3896827  PMID: 24405936
7.  Fetal and infant growth predict hip geometry at six years old: Findings from the Southampton Women’s Survey 
Pediatric research  2013;74(4):450-456.
We investigated relationships between early growth and proximal femoral geometry at age six years in a prospective population-based cohort, the Southampton Women’s Survey.
In 493 mother-offspring pairs we assessed linear size (individual measure dependent on developmental stage) using high-resolution ultrasound at 11, 19 and 34 weeks gestation (femur length) and at birth, 1, 2, 3, 4 and 6 years (crown-heel length/height). Standard deviation (SD)-scores were created and conditional regression modelling generated mutually independent growth variables. Children underwent hip DXA (Dual X-ray absorptiometry) at 6 years (Hologic Discovery, Hologic Inc., MA); hip structure analysis software yielded measures of geometry and strength.
There were strong associations between early linear growth and femoral neck section modulus (Z) at 6 years, with the strongest relationships observed for femur growth from 19-34 weeks gestation (β=0.26 cm3/SD, p<0.0001), and for height growth from birth to 1 year (β=0.25 cm3/SD, p<0.0001) and 1-2 years (β=0.33 cm3/SD, p<0.0001), with progressively weaker relationships over years 3 (β=0.23 cm3/SD, p=0.0002) and 4 (β=0.10 cm3/SD, p=0.18).
These results demonstrate that growth before age 3 years predicts proximal femoral geometry at six years old. The data suggest critical periods in which there is capacity for long term influence on the later skeletal growth trajectory.
PMCID: PMC3797011  PMID: 23857297
8.  Different Indices of Fetal Growth Predict Bone Size and Volumetric Density at 4 Years of Age 
We have demonstrated previously that higher birth weight is associated with greater peak and later-life bone mineral content and that maternal body build, diet, and lifestyle influence prenatal bone mineral accrual. To examine prenatal influences on bone health further, we related ultrasound measures of fetal growth to childhood bone size and density. We derived Z-scores for fetal femur length and abdominal circumference and conditional growth velocity from 19 to 34 weeks’ gestation from ultrasound measurements in participants in the Southampton Women’s Survey. A total of 380 of the offspring underwent dual-energy X-ray absorptiometry (DXA) at age 4 years [whole body minus head bone area (BA), bone mineral content (BMC), areal bone mineral density (aBMD), and estimated volumetric BMD (vBMD)]. Volumetric bone mineral density was estimated using BMC adjusted for BA, height, and weight. A higher velocity of 19- to 34-week fetal femur growth was strongly associated with greater childhood skeletal size (BA: r = 0.30, p < .0001) but not with volumetric density (vBMD: r = 0.03, p = .51). Conversely, a higher velocity of 19- to 34-week fetal abdominal growth was associated with greater childhood volumetric density (vBMD: r = 0.15, p = .004) but not with skeletal size (BA: r = 0.06, p = .21). Both fetal measurements were positively associated with BMC and aBMD, indices influenced by both size and density. The velocity of fetal femur length growth from 19 to 34 weeks’ gestation predicted childhood skeletal size at age 4 years, whereas the velocity of abdominal growth (a measure of liver volume and adiposity) predicted volumetric density. These results suggest a discordance between influences on skeletal size and volumetric density.
PMCID: PMC3793299  PMID: 20437610
9.  Maternal awareness of young children’s physical activity: levels and cross-sectional correlates of overestimation 
BMC Public Health  2013;13:924.
Factors associated with parental awareness of children’s physical activity (PA) levels have not been explored in preschool-aged children. This paper investigates maternal awareness of preschool-aged children’s PA levels and determined correlates associated with maternal overestimation of PA.
Data from the Southampton Women’s Survey, a UK population-based study, were collected March 2006 through June 2009. Daily minutes of moderate-to-vigorous PA (MVPA) were derived using accelerometry in 478 4-year-old children. Mothers who were realistic or overestimated their child’s PA were identified. Log-binomial regression was used to analyse correlates of maternal overestimation of PA levels in children whose mothers perceived them to be active (n = 438).
40.8% of children were classified as inactive: 89.7% of these were perceived to be active by their mothers (over-estimators). These mothers were more likely to think their child sometimes lacked skills required to be physically active (RR (95% CI) = 1.29(1.03-1.63)) and their child was more likely to attend nursery full-time (RR = 1.53(1.14-2.04)). They were less likely to have older children at home (RR = 0.71(0.56-0.90)).
Almost 90% of mothers of inactive preschool-aged children perceive their child to be active. Nursery-school attendance and having older siblings at home may be important to consider when designing behavioural interventions to increase PA in preschool children.
PMCID: PMC3852941  PMID: 24090173
Physical activity; Awareness; Preschool children
10.  Physical activity intensity, sedentary time, and body composition in preschoolers123 
Detailed associations between physical activity (PA) subcomponents, sedentary time, and body composition in preschoolers remain unclear.
We examined the magnitude of associations between objectively measured PA subcomponents and sedentary time with body composition in 4-y-old children.
We conducted a cross-sectional study in 398 preschool children recruited from the Southampton Women’s Survey. PA was measured by using accelerometry, and body composition was measured by using dual-energy X-ray absorptiometry. Associations between light physical activity, moderate physical activity (MPA), vigorous physical activity (VPA), and moderate-to-vigorous physical activity (MVPA) intensity; sedentary time; and body composition were analyzed by using repeated-measures linear regression with adjustment for age, sex, birth weight, maternal education, maternal BMI, smoking during pregnancy, and sleep duration. Sedentary time and PA were also mutually adjusted for one another to determine whether they were independently related to adiposity.
VPA was the only intensity of PA to exhibit strong inverse associations with both total adiposity [P < 0.001 for percentage of body fat and fat mass index (FMI)] and abdominal adiposity (P = 0.002 for trunk FMI). MVPA was inversely associated with total adiposity (P = 0.018 for percentage of body fat; P = 0.022 for FMI) but only because of the contribution of VPA, because MPA was unrelated to fatness (P ≥ 0.077). No associations were shown between the time spent sedentary and body composition (P ≥ 0.11).
In preschoolers, the time spent in VPA is strongly and independently associated with lower adiposity. In contrast, the time spent sedentary and in low-to-moderate–intensity PA was unrelated to adiposity. These results indicate that efforts to challenge pediatric obesity may benefit from prioritizing VPA.
PMCID: PMC3785144  PMID: 23553158
12.  Maternal late-pregnancy serum 25-hydroxyvitamin D in relation to childhood wheeze and atopic outcomes 
Thorax  2012;67(11):950-956.
Studies exploring the relationship between prenatal vitamin D exposure and childhood asthma have yielded conflicting results. Higher vitamin D intake during pregnancy has been shown to lower the risk of childhood wheeze, yet a study of maternal late-pregnancy serum 25-hydroxyvitamin D suggested higher serum concentrations may be associated with increased childhood asthma.
To assess the relationship between mothers’ serum 25-hydroxyvitamin D status and asthma and wheeze phenotypes in their children at age 6 years. Secondly, to explore the relationship between maternal 25-hydroxyvitamin D status and objective measures of childhood atopy and lung function.
Serum 25-hydroxyvitamin D was measured at 34 weeks’ gestation in the mothers of 860 children born at term. Wheeze was classified as either transient or persistent/late using questionnaire data collated from 6, 12, 24 and 36 months and 6 years. At 6 years spirometry was performed and atopic status was determined by skin prick testing, exhaled nitric oxide was measured in 451 and bronchial hyperresponsiveness in 216 children.
There were no significant associations between maternal late-pregnancy 25-hydroxyvitamin D status and either asthma or wheeze at age 6 years. Maternal vitamin D status was not associated with transient or persistent/late wheeze; no significant association was found between persistent/late wheeze when subdivided according to atopic status. No associations were found with skin sensitisation or lung function.
This study provides no evidence that exposure to higher concentrations of 25-hydroxyvitamin D in maternal serum during late pregnancy increases the risk of childhood asthma, wheeze or atopy.
PMCID: PMC3679514  PMID: 22707522
asthma epidemiology; asthma; paediatric asthma
13.  MAVIDOS Maternal Vitamin D Osteoporosis Study: study protocol for a randomized controlled trial. The MAVIDOS Study Group 
Trials  2012;13:13.
MAVIDOS is a randomised, double-blind, placebo-controlled trial (ISRCTN82927713, registered 2008 Apr 11), funded by Arthritis Research UK, MRC, Bupa Foundation and NIHR.
Osteoporosis is a major public health problem as a result of associated fragility fractures. Skeletal strength increases from birth to a peak in early adulthood. This peak predicts osteoporosis risk in later life. Vitamin D insufficiency in pregnancy is common (31% in a recent Southampton cohort) and predicts reduced bone mass in the offspring. In this study we aim to test whether offspring of mothers supplemented with vitamin D in pregnancy have higher bone mass at birth than those whose mothers were not supplemented.
Women have their vitamin D status assessed after ultrasound scanning in the twelfth week of pregnancy at 3 trial centres (Southampton, Sheffield, Oxford). Women with circulating 25(OH)-vitamin D levels 25-100 nmol/l are randomised in a double-blind design to either oral vitamin D supplement (1000 IU cholecalciferol/day, n = 477) or placebo at 14 weeks (n = 477). Questionnaire data include parity, sunlight exposure, dietary information, and cigarette and alcohol consumption. At 19 and 34 weeks maternal anthropometry is assessed and blood samples taken to measure 25(OH)-vitamin D, PTH and biochemistry. At delivery venous umbilical cord blood is collected, together with umbilical cord and placental tissue. The babies undergo DXA assessment of bone mass within the first 14 days after birth, with the primary outcome being whole body bone mineral content adjusted for gestational age and age. Children are then followed up with yearly assessment of health, diet, physical activity and anthropometric measures, with repeat assessment of bone mass by DXA at age 4 years.
As far as we are aware, this randomised trial is one of the first ever tests of the early life origins hypothesis in human participants and has the potential to inform public health policy regarding vitamin D supplementation in pregnancy. It will also provide a valuable resource in which to study the influence of maternal vitamin D status on other childhood outcomes such as glucose tolerance, blood pressure, cardiovascular function, IQ and immunology.
PMCID: PMC3395865  PMID: 22314083
Vitamin D; cholecalciferol; supplementation; trial; osteoporosis; DXA; pregnancy; neonate
14.  Validation of a maternal questionnaire on correlates of physical activity in preschool children 
Valid measures of physical activity correlates in preschool children are lacking. This study aimed to assess the validity, factor structure and internal consistency of a maternal questionnaire on potential correlates of four-year-old children's physical activity.
The questionnaire was designed to measure the following constructs: child personal factors; parental support and self-efficacy for providing support; parental rules and restrictions; maternal attitudes and perceptions; maternal behaviour; barriers to physical activity; and the home and local environments. Two separate studies were conducted. Study I included 24 mothers of four-year-old children who completed the questionnaire then participated in a telephone interview covering similar items to the questionnaire. To assess validity, the agreement between interview and questionnaire responses was assessed using Cohen's kappa and percentage agreement. Study II involved 398 mothers of four-year-old children participating in the Southampton Women's Survey. In this study, principal components analysis was used to explore the factor structure of the questionnaire to aid future analyses with these data. The internal consistency of the factors identified was assessed using Cronbach's alpha.
Kappa scores showed 30% of items to have moderate agreement or above, 23% to have fair agreement and 47% to have slight or poor agreement. However, 89% of items had fair agreement as assessed by percentage agreement (≥ 66%). Limited variation in responses to variables is likely to have contributed to some of the low kappa values. Six questions had a low kappa and low percentage agreement (defined as poor validity); these included questions from the child personal factors, maternal self-efficacy, rules and restrictions, and local environment domains. The principal components analysis identified eleven factors and found several variables to stand alone. Eight of the composite factors identified had acceptable internal consistency (α ≥ 0.60) and three fell just short of achieving this (0.60 > α > 0.50).
Overall, this maternal questionnaire had reasonable validity and internal consistency for assessing potential correlates of physical activity in young children. With minor revision, this could be a useful tool for future research in this area. This, in turn, will aid the development of interventions to promote physical activity in this age group.
PMCID: PMC2791748  PMID: 19954524
15.  Maternal vitamin D status during pregnancy and child outcomes 
To investigate whether exposure to high maternal concentrations of 25(OH)-vitamin D in pregnancy poses any risk to the child.
Prospective study.
Princess Anne Maternity Hospital, Southampton, UK.
596 pregnant women were recruited. 466 (78%) children were examined at birth, 440 (74%) at age 9 months and 178 (30%) at age 9 years.
Maternal (OH)-vitamin D concentrations were measured in late pregnancy. Anthropometry of the child was recorded at birth, 9 months and 9 years. At 9 months, atopic eczema was assessed. At 9 years, children had an echocardiogram and a DXA scan, blood pressure, arterial compliance and carotid intima-media thickness were measured and intelligence and psychological function assessed.
There were no associations between maternal 25(OH)-vitamin D concentrations and the child's body size or measures of the child's intelligence, psychological health or cardiovascular system. Children whose mothers' concentration of 25(OH)-vitamin D in pregnancy was >75 nmol/l had an increased risk of eczema on examination at 9 months (OR 3.26, 95% CI 1.15-9.29, p=0.025) and asthma at age 9 years (OR 5.40, 95% CI, 1.09-26.65, p=0.038) compared to children whose mothers' concentration was <30 nmol/l.
Exposure to maternal concentrations of 25(OH)-vitamin D in pregnancy in excess of 75 nmol/l does not appear to influence the child's intelligence, psychological health or cardiovascular system; there could be an increased risk of atopic disorders, but this needs confirmation in other studies.
PMCID: PMC2629513  PMID: 17311057
pregnancy; diet; vitamin D; infant; child
16.  Risk of fracture after bariatric surgery in the United Kingdom: population based, retrospective cohort study  
Objectives To estimate fracture risk in patients receiving bariatric surgery versus matched controls.
Design Population based, retrospective cohort study.
Setting Use of records from the United Kingdom General Practice Research Database, now known as the Clinical Practice Research Datalink (from January 1987 to December 2010).
Participants Patients with a body mass index of at least 30, with a record of bariatric surgery (n=2079), and matched controls without a record (n=10 442). Each bariatric surgery patient was matched to up to six controls by age, sex, practice, year, and body mass index. Patients were followed from the date of bariatric surgery for the occurrence of any fracture. We used time dependent Cox regression to calculate relative rates of fracture, adjusted for disease and previous drug treatment, and time-interaction terms to evaluate fracture timing patterns.
Main outcome measure Relative rates of any, osteoporotic, and non-osteoporotic fractures.
Results Mean follow-up time was 2.2 years. Overall, there was no significantly increased risk of fracture in patients who underwent bariatric surgery, compared with controls (8.8 v 8.2 per 1000 person years; adjusted relative risk 0.89, 95% confidence interval 0.60 to 1.33). Bariatric surgery also did not affect risk of osteoporotic and non-osteoporotic fractures. However, we saw a trend towards an increased fracture risk after three to five years following surgery, as well as in patients who had a greater decrease in body mass index after surgery, but this was not significant.
Conclusion Bariatric surgery does not have a significant effect on the risk of fracture. For the first few years after surgery, these results are reassuring for patients undergoing such operations, but do not exclude a more protracted adverse influence on skeletal health in the longer term.
PMCID: PMC3413006  PMID: 22867649

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