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1.  Maternal gestational vitamin D supplementation and offspring bone health: a multicentre randomised, double-blind, placebo-controlled trial (MAVIDOS) 
Background
Maternal vitamin D status has been associated with lower bone mass of the offspring in many, but not all, observational studies. However, proof that maternal vitamin D repletion during pregnancy improves offspring bone mass is lacking.
Methods
Between 06/10/2008 and 11/02/2014, we randomly assigned pregnant women with a serum 25-hydroxyvitamin D [25(OH)D] 25-100nmol/l at 12 weeks’ gestation to either 1000IU/day cholecalciferol or matched placebo from 14 weeks’ gestation until delivery. Serum 25(OH)D was measured at 14 and 34 weeks’ gestation. Neonatal whole body bone mineral, assessed within 2 weeks after birth (n=665) by dual-energy X-ray absorptiometry (DXA), was the primary outcome. Secondary pre-specified analyses explored interactions with study centre, maternal ethnicity, parity, compliance, protocol completion, baseline BMI, baseline 25(OH)D and change in 25(OH)D from 14 to 34 weeks; and offspring sex and season of birth.
Findings
We found no difference in neonatal whole body bone mineral content (BMC) of infants born to mothers randomised to 1000IU/day cholecalciferol compared with infants born to mothers randomised to placebo [61.6g (95%CI: 60.3, 62.8g) vs 60.5g (95%CI: 59.3, 61.7g) respectively, p=0.21].
Interpretation
Supplementation of mothers with 1000IU/day cholecalciferol during pregnancy did not lead to increased offspring whole body BMC compared with placebo.
doi:10.1016/S2213-8587(16)00044-9
PMCID: PMC4843969  PMID: 26944421
Vitamin D; cholecalciferol; supplementation; trial; osteoporosis; epidemiology; DXA; pregnancy; neonate
2.  Determinants of the Maternal 25-Hydroxyvitamin D Response to Vitamin D Supplementation During Pregnancy 
Context:
Current approaches to antenatal vitamin D supplementation do not account for interindividual differences in 25-hydroxyvitamin D (25(OH)D) response.
Objective:
We assessed which maternal and environmental characteristics were associated with 25(OH)D after supplementation with cholecalciferol.
Design:
Within-randomization-group analysis of participants in the Maternal Vitamin D Osteoporosis Study trial of vitamin D supplementation in pregnancy.
Setting:
Hospital antenatal clinics.
Participants:
A total of 829 pregnant women (422 placebo, 407 cholecalciferol). At 14 and 34 weeks of gestation, maternal anthropometry, health, and lifestyle were assessed and 25(OH)D measured. Compliance was determined using pill counts at 19 and 34 weeks.
Interventions:
1000 IU/d of cholecalciferol or matched placebo from 14 weeks of gestation until delivery.
Main Outcome Measure:
25(OH)D at 34 weeks, measured in a single batch (Diasorin Liaison).
Results:
25(OH)D at 34 weeks of gestation was higher in the women randomized to vitamin D (mean [SD], 67.7 [21.3] nmol/L) compared with placebo (43.1 [22.5] nmol/L; P < .001). In women randomized to cholecalciferol, higher pregnancy weight gain from 14 to 34 weeks of gestation (kg) (β = −0.81 [95% confidence interval −1.39, −0.22]), lower compliance with study medication (%) (β = −0.28 [−0.072, −0.48]), lower early pregnancy 25(OH)D (nmol/L) (β = 0.28 [0.16, 0.40]), and delivery in the winter vs the summer (β = −10.5 [−6.4, −14.6]) were independently associated with lower 25(OH)D at 34 weeks of gestation.
Conclusions:
Women who gained more weight during pregnancy had lower 25(OH)D in early pregnancy and delivered in winter achieved a lower 25(OH)D in late pregnancy when supplemented with 1000 IU/d cholecalciferol. Future studies should aim to determine appropriate doses to enable consistent repletion of 25(OH)D during pregnancy.
Within the treatment arm of the MAVIDOS RCT, poorer 25(OH)D response to 1000IU/d cholecalciferol was associated with lower initial 25(OH)D, greater pregnancy weight gain and delivery in winter.
doi:10.1210/jc.2016-2869
PMCID: PMC5155676  PMID: 27788053
3.  Tracking of 25-hydroxyvitamin D status during pregnancy: the importance of vitamin D supplementation 
Background
The role of maternal 25-hydroxyvitamin D [25(OH)D] in fetal development is uncertain and findings of observational studies are inconsistent. Most studies have assessed 25(OH)D only once in pregnancy, but the tracking of an individual’s 25(OH)D during pregnancy is unknown.
Objective
We determined the tracking of serum 25(OH)D from early to late pregnancy, and factors which influence this.
Design
The Southampton Women’s Survey is a prospective mother-offspring birth cohort study. Lifestyle, diet and 25(OH)D status were assessed at 11 and 34 weeks gestation. A Fourier transformation was used to model seasonal variation in 25(OH)D for early and late pregnancy, separately, and the difference between measured and seasonally modelled 25(OH)D calculated to generate a season-corrected 25(OH)D. Tracking was assessed using Pearson’s correlation coefficient, and multivariate linear regression used to determine factors associated with change in season-corrected 25(OH)D.
Results
1753 women had 25(OH)D measured in both early and late pregnancy. There was a moderate correlation between season-corrected 25(OH)D measurements at 11 and 34 weeks gestation (r=0.53, p<0.0001, n=1753). Vitamin D supplementation was the strongest predictor of tracking: compared with women who never used supplements, discontinuing supplementation after 11 weeks was associated with reduction in season-corrected 25(OH)D (β=−7.3nmol/l, p<0.001), whereas commencing (β=12.6nmol/l, p<0.001) or continuing (β=6.6nmol/l, p<0.001) supplementation were associated with increases. Higher pregnancy weight gain was associated with reduction in season-corrected 25(OH)D (β=−0.4nmol/l per kg, p=0.015), whereas greater physical activity (β=0.4nmol/l per hour/week, p=0.011) was associated with increases.
Conclusions
There is moderate tracking of 25(OH)D status through pregnancy; factors such as vitamin D supplementation, weight gain and physical activity are associated with changes in season-corrected 25(OH)D from early to late gestation. These findings have implications for study design and analysis and approaches to intervention studies and clinical care.
doi:10.3945/ajcn.115.115295
PMCID: PMC4634223  PMID: 26399867
Moon; Crozier; Dennison; Davies; Robinson; Inskip; Godfrey; Cooper; Harvey
4.  Diet quality across early childhood and adiposity at 6 years: the Southampton Women’s Survey 
BACKGROUND
Poor diet quality in early childhood is inconsistently linked to obesity risk. Understanding may be limited by use of cross-sectional data, and use of body mass index (BMI) to define adiposity in childhood.
OBJECTIVE
To examine the effects of continued exposure to diets of varying quality across early childhood in relation to adiposity at 6 years.
METHODS
1018 children from a prospective UK birth cohort were studied. Diet was assessed using food frequency questionnaires when the children were aged 6 and 12 months, 3 and 6 years; diet quality was determined according to scores for a principal component analysis-defined dietary pattern at each age (characterized by frequent consumption of fruit, vegetables and fish). At each age children were allocated a value of 0/1/2 according to third of the distribution (bottom/middle/top) their diet quality score was in; values were summed to calculate an overall diet quality index (DQI) for early childhood (range 0–8). Obesity outcomes considered at 6 years were dual-energy X-ray absorptiometry-assessed fat mass and BMI.
RESULTS
107 (11%) children had a DQI=0, indicating a consistently low diet quality; 339 (33%), DQI=1–3; 378 (37%), DQI=4–6; 194 (19%), DQI=7–8. There was a strong association between lower DQI and higher fat mass z-score at 6 years that was robust to adjustment for confounders [fat mass SDs per 1-unit DQI increase: β=−0.05 (95% CI: −0.09, −0.01), P=0.01]. In comparison with children who had the highest diet quality (DQI=7–8), this amounted to a difference in fat mass of 14% (95% CI: 2%, 28%) at 6 years for children with the poorest diets (DQI=0). In contrast, no independent associations were observed between DQI and BMI.
CONCLUSIONS
Continued exposure to diets of low quality across early childhood is linked to adiposity at the age of 6 years.
doi:10.1038/ijo.2015.97
PMCID: PMC4597330  PMID: 26121960
Diet quality; adiposity; childhood
5.  Maternal Factors Are Associated with the Expression of Placental Genes Involved in Amino Acid Metabolism and Transport 
PLoS ONE  2015;10(12):e0143653.
Introduction
Maternal environment and lifestyle factors may modify placental function to match the mother’s capacity to support the demands of fetal growth. Much remains to be understood about maternal influences on placental metabolic and amino acid transporter gene expression. We investigated the influences of maternal lifestyle and body composition (e.g. fat and muscle content) on a selection of metabolic and amino acid transporter genes and their associations with fetal growth.
Methods
RNA was extracted from 102 term Southampton Women’s Survey placental samples. Expression of nine metabolic, seven exchange, eight accumulative and three facilitated transporter genes was analyzed using quantitative real-time PCR.
Results
Increased placental LAT2 (p = 0.01), y+LAT2 (p = 0.03), aspartate aminotransferase 2 (p = 0.02) and decreased aspartate aminotransferase 1 (p = 0.04) mRNA expression associated with pre-pregnancy maternal smoking. Placental mRNA expression of TAT1 (p = 0.01), ASCT1 (p = 0.03), mitochondrial branched chain aminotransferase (p = 0.02) and glutamine synthetase (p = 0.05) was positively associated with maternal strenuous exercise. Increased glutamine synthetase mRNA expression (r = 0.20, p = 0.05) associated with higher maternal diet quality (prudent dietary pattern) pre-pregnancy. Lower LAT4 (r = -0.25, p = 0.05) and aspartate aminotransferase 2 mRNA expression (r = -0.28, p = 0.01) associated with higher early pregnancy diet quality. Lower placental ASCT1 mRNA expression associated with measures of increased maternal fat mass, including pre-pregnancy BMI (r = -0.26, p = 0.01). Lower placental mRNA expression of alanine aminotransferase 2 associated with greater neonatal adiposity, for example neonatal subscapular skinfold thickness (r = -0.33, p = 0.001).
Conclusion
A number of maternal influences have been linked with outcomes in childhood, independently of neonatal size; our finding of associations between placental expression of transporter and metabolic genes and maternal smoking, physical activity and diet raises the possibility that their effects are mediated in part through alterations in placental function. The observed changes in placental gene expression in relation to modifiable maternal factors are important as they could form part of interventions aimed at maintaining a healthy lifestyle for the mother and for optimal fetal development.
doi:10.1371/journal.pone.0143653
PMCID: PMC4682815  PMID: 26657885
6.  Longitudinal changes in lean mass predict pQCT measures of tibial geometry and mineralisation at 6-7 years 
Bone  2015;75:105-110.
Background
Studies in childhood suggest that both body composition and early postnatal growth are associated with bone mineral density (BMD). However, little is known of the relationships between longitudinal changes in fat (FM) and lean mass (LM), and bone development in pre-pubertal children. We therefore investigated these associations in a population-based mother-offspring cohort, the Southampton Women’s Survey.
Methods
Total FM and LM were assessed at birth and 6-7 years of age by Dual-Energy X-ray Absorptiometry (DXA). At 6-7y, total cross-sectional area (CSA) and trabecular volumetric BMD (vBMD) at the 4% site (metaphysis) of the tibia was assessed using peripheral quantitative computed tomography [pQCT (Stratec XCT-2000)]. Total CSA, cortical CSA, cortical vBMD and strength-strain index (SSI) were measured at the 38% site (diaphysis). FM, LM and bone parameters were adjusted for age and sex and standardised to create within-cohort z-scores. Change in LM (ΔLM) or FM (ΔFM) was represented by change in z-score from birth to 7y and conditioned on the birth measurement. Linear regression was used to explore the associations between ΔLM or ΔFM and standardised pQCT outcomes, before and after mutual adjustment and for linear growth. The β-coefficient represents SD change in outcome per unit SD change in predictor.
Results
DXA at birth, in addition to both DXA and pQCT scans at 6-7y, were available for 200 children (48.5% male). ΔLM adjusted for ΔFM was positively associated with tibial total CSA at both the 4% (β=0.57SD/SD, p<0.001) and 38% sites (β=0.53SD/SD, p<0.001), cortical CSA (β=0.48SD/SD, p<0.001) and trabecular vBMD (β=0.30SD/SD, p<0.001), but not with cortical vBMD. These relationships persisted after adjustment for linear growth. In contrast, ΔFM adjusted for ΔLM was only associated with 38% total and cortical CSA, which became non-significant after adjustment for linear growth.
Conclusion
In this study, gain in childhood LM was positively associated with bone size and trabecular vBMD at 6-7 years of age. In contrast, no relationships between change in FM and bone were observed, suggesting that muscle growth, rather than accrual of fat mass, may be a more important determinant of childhood bone development.
doi:10.1016/j.bone.2015.02.015
PMCID: PMC4556067  PMID: 25703480
Osteoporosis; epidemiology; body composition; pQCT; growth; childhood
7.  Maternal vitamin D status in pregnancy is associated with adiposity in the offspring: prospective observational study 
Objective
To determine the relationship between maternal vitamin D status in pregnancy and body composition in the offspring.
Design
Prospective mother-offspring cohort study.
Setting
Southampton, UK.
Participants
977 pregnant women whose serum 25-hydroxyvitamin D concentration (25(OH)D) was measured in late pregnancy and their offspring, followed up within 3 weeks of birth, and at 4 and 6 years of age.
Main outcome measures
Offspring lean and fat mass assessed using Dual X-ray Absorptiometry.
Results
Median daily vitamin D intake (from food and supplements) in late pregnancy was 3.7μg/day (IQR 2.7 to 5.7). 22% of the women took vitamin D supplements in late pregnancy, but only 8.5% of the women complied with UK guidance to take 10μg per day. Median maternal serum 25(OH)D in late pregnancy was 62nmol/l (IQR 43-89); 35% of the women studied had values below 50 nmol/l. Lower vitamin D status was associated with lower fat mass in the offspring at birth, but with greater fat mass at 4 and 6 years. It was not associated with lean mass at any of the ages studied. The opposing associations seen between maternal 25(OH)D (SDs) and fat mass (SDs) in the offspring at birth and at 6 years were robust to adjustment for a range of confounding factors, including maternal BMI and weight gain in pregnancy (β (95% CI) 0.08 (0.02, 0.15) and −0.10 (−0.17, − 0.02 respectively). The key independent predictors of higher maternal vitamin D status were season of measurement and taking vitamin D in dietary supplements in late pregnancy.
Conclusion
These data suggest that insufficient maternal vitamin D status in pregnancy could result in programmed differences in offspring fat mass. The findings require replication but add to a growing evidence base for a role of vitamin D in the origins of adiposity.
doi:10.3945/ajcn.112.037473
PMCID: PMC4632192  PMID: 22623747
8.  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.
doi:10.3945/ajcn.114.094268
PMCID: PMC4307207  PMID: 25646335
adiposity; childhood obesity; early life; obesity; lifecourse; prevention
9.  Association of early childhood abdominal circumference and weight gain with blood pressure at 36 months of age: secondary analysis of data from a prospective cohort study 
BMJ Open  2014;4(7):e005412.
Objectives
To assess whether changes in measures of fat distribution and body size during early life are associated with blood pressure at 36 months of age.
Design
Analysis of data collected from a prospective cohort study.
Setting
Community-based investigation in Southampton, UK.
Participants
761 children with valid blood pressure measurements, born to women participating in the Southampton Women’s Survey.
Primary and secondary outcome measures
Anthropometric measurements were collected at 0, 6, 12, 24 and 36 months and conditional changes between the time points calculated. Blood pressure was measured at 36 months. Factors possibly influencing the blood pressure were assessed using linear regression. All independent variables of interest and confounding variables were included in stepwise multiple regression to identify the model that best predicted blood pressure at 36 months.
Results
Greater conditional gains in abdominal circumference (AC) between 0–6 and 24–36 months were associated with higher systolic and diastolic blood pressures at 36 months (p<0.001). Subscapular skinfold and height gains were weakly associated with higher blood pressures, while greater weight gains between 0–6, 12–24 and 24–36 months were more strongly associated, but the dominant influences were AC gains, particularly from 0–6 to 24–36 months. Thus one SD score increases in AC between 0–6 and 24–36 months were associated with 1.59 mm Hg (95% CI 0.97 to 2.21) and 1.84 mm Hg (1.24 to 2.46) higher systolic blood pressures, respectively, and 1.04 mm Hg (0.57 to 1.51) and 1.02 mm Hg (0.56, 1.48) higher diastolic pressures, respectively.
Conclusions
Conditional gains in abdominal circumference, particularly within 6 months of birth and in the year preceding measurement, were more positively associated with blood pressure at 36 months than gains in other anthropometric measures. Above-average AC gains in early childhood may contribute to adult hypertension and increased cardiovascular disease risk.
doi:10.1136/bmjopen-2014-005412
PMCID: PMC4091398  PMID: 24993768
EPIDEMIOLOGY
11.  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.
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1038/pr.2013.119
PMCID: PMC3797011  PMID: 23857297
12.  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.
doi:10.1359/jbmr.091022
PMCID: PMC3793299  PMID: 20437610
EPIDEMIOLOGY; OSTEOPOROSIS; PROGRAMMING; DEVELOPMENTAL ORIGINS
13.  Patterns of fetal and infant growth are related to atopy and wheezing disorders at age 3 years 
Thorax  2010;65(12):1099-1106.
Background
Little is known about whether patterns of growth are associated with altered respiratory and immune development. This study relates prenatal and infant growth patterns to wheeze and atopy at age 3 years
Methods
Birth weight and length were measured in 1548 children born at term. Conditional fetal head and abdominal circumference growth velocities were calculated from antenatal ultrasound measurements. Conditional postnatal growth velocities were calculated from infant weight, length and adiposity data. .Measures of size and conditional growth were related to parentally-reported infant and early childhood wheeze and to atopic status at age 3.
Results
Atopy risk increased by 46% per standard deviation (SD) increase in abdominal circumference growth velocity from 11-19 weeks’ gestation but by 20% per SD decrease in abdominal growth velocity from 19-34 weeks (p=0.007 and p=0.011). Atopic wheeze risk increased by 20% per SD decrease in 19-34 week abdominal growth (p=0.046). Non-atopic wheeze risk increased by 10% per SD decrease in 11-19 week head circumference growth. Greater relative infant weight and adiposity gains were associated with both atopic and non-atopic wheeze.
Conclusions
Rapid growth during 11-19 weeks’ gestation followed by growth faltering is associated with atopy, suggesting that influences affecting fetal growth may also alter immune development. A lower early fetal growth trajectory is associated with non-atopic wheeze, possibly reflecting an association with smaller airways. An association between postnatal adiposity gain and wheeze may partly reflect prenatal influences that cause fetal growth to falter but are then followed by postnatal adiposity gain.
doi:10.1136/thx.2010.134742
PMCID: PMC3685135  PMID: 20956394
asthma; preschool-wheeze; allergic sensitisation; growth; nutrition
14.  Correction of unexpected distributions of P values from analysis of whole genome arrays by rectifying violation of statistical assumptions 
BMC Genomics  2013;14:161.
Background
Statistical analysis of genome-wide microarrays can result in many thousands of identical statistical tests being performed as each probe is tested for an association with a phenotype of interest. If there were no association between any of the probes and the phenotype, the distribution of P values obtained from statistical tests would resemble a Uniform distribution. If a selection of probes were significantly associated with the phenotype we would expect to observe P values for these probes of less than the designated significance level, alpha, resulting in more P values of less than alpha than expected by chance.
Results
In data from a whole genome methylation promoter array we unexpectedly observed P value distributions where there were fewer P values less than alpha than would be expected by chance. Our data suggest that a possible reason for this is a violation of the statistical assumptions required for these tests arising from heteroskedasticity. A simple but statistically sound remedy (a heteroskedasticity–consistent covariance matrix estimator to calculate standard errors of regression coefficients that are robust to heteroskedasticity) rectified this violation and resulted in meaningful P value distributions.
Conclusions
The statistical analysis of ‘omics data requires careful handling, especially in the choice of statistical test. To obtain meaningful results it is essential that the assumptions behind these tests are carefully examined and any violations rectified where possible, or a more appropriate statistical test chosen.
doi:10.1186/1471-2164-14-161
PMCID: PMC3610227  PMID: 23496791
P values; Distributions; Statistical analysis; Statistical assumptions; Whole genome methylation promoter arrays; Epigenome
15.  Fetal Liver Blood Flow Distribution: Role in Human Developmental Strategy to Prioritize Fat Deposition versus Brain Development 
PLoS ONE  2012;7(8):e41759.
Among primates, human neonates have the largest brains but also the highest proportion of body fat. If placental nutrient supply is limited, the fetus faces a dilemma: should resources be allocated to brain growth, or to fat deposition for use as a potential postnatal energy reserve? We hypothesised that resolving this dilemma operates at the level of umbilical blood distribution entering the fetal liver. In 381 uncomplicated pregnancies in third trimester, we measured blood flow perfusing the fetal liver, or bypassing it via the ductus venosus to supply the brain and heart using ultrasound techniques. Across the range of fetal growth and independent of the mother's adiposity and parity, greater liver blood flow was associated with greater offspring fat mass measured by dual-energy X-ray absorptiometry, both in the infant at birth (r = 0.43, P<0.001) and at age 4 years (r = 0.16, P = 0.02). In contrast, smaller placentas less able to meet fetal demand for essential nutrients were associated with a brain-sparing flow pattern (r = 0.17, p = 0.02). This flow pattern was also associated with a higher degree of shunting through ductus venosus (P = 0.04). We propose that humans evolved a developmental strategy to prioritize nutrient allocation for prenatal fat deposition when the supply of conditionally essential nutrients requiring hepatic inter-conversion is limited, switching resource allocation to favour the brain if the supply of essential nutrients is limited. Facilitated placental transfer mechanisms for glucose and other nutrients evolved in environments less affluent than those now prevalent in developed populations, and we propose that in circumstances of maternal adiposity and nutrient excess these mechanisms now also lead to prenatal fat deposition. Prenatal developmental influences play important roles in the human propensity to deposit fat.
doi:10.1371/journal.pone.0041759
PMCID: PMC3425554  PMID: 22927915
16.  Epigenetic Gene Promoter Methylation at Birth Is Associated With Child’s Later Adiposity 
Diabetes  2011;60(5):1528-1534.
OBJECTIVE
Fixed genomic variation explains only a small proportion of the risk of adiposity. In animal models, maternal diet alters offspring body composition, accompanied by epigenetic changes in metabolic control genes. Little is known about whether such processes operate in humans.
RESEARCH DESIGN AND METHODS
Using Sequenom MassARRAY we measured the methylation status of 68 CpGs 5′ from five candidate genes in umbilical cord tissue DNA from healthy neonates. Methylation varied greatly at particular CpGs: for 31 CpGs with median methylation ≥5% and a 5–95% range ≥10%, we related methylation status to maternal pregnancy diet and to child’s adiposity at age 9 years. Replication was sought in a second independent cohort.
RESULTS
In cohort 1, retinoid X receptor-α (RXRA) chr9:136355885+ and endothelial nitric oxide synthase (eNOS) chr7:150315553+ methylation had independent associations with sex-adjusted childhood fat mass (exponentiated regression coefficient [β] 17% per SD change in methylation [95% CI 4–31], P = 0.009, n = 64, and β = 20% [9–32], P < 0.001, n = 66, respectively) and %fat mass (β = 10% [1–19], P = 0.023, n = 64 and β =12% [4–20], P = 0.002, n = 66, respectively). Regression analyses including sex and neonatal epigenetic marks explained >25% of the variance in childhood adiposity. Higher methylation of RXRA chr9:136355885+, but not of eNOS chr7:150315553+, was associated with lower maternal carbohydrate intake in early pregnancy, previously linked with higher neonatal adiposity in this population. In cohort 2, cord eNOS chr7:150315553+ methylation showed no association with adiposity, but RXRA chr9:136355885+ methylation showed similar associations with fat mass and %fat mass (β = 6% [2–10] and β = 4% [1–7], respectively, both P = 0.002, n = 239).
CONCLUSIONS
Our findings suggest a substantial component of metabolic disease risk has a prenatal developmental basis. Perinatal epigenetic analysis may have utility in identifying individual vulnerability to later obesity and metabolic disease.
doi:10.2337/db10-0979
PMCID: PMC3115550  PMID: 21471513
17.  Epigenetic gene promoter methylation at birth is associated with child’s later adiposity 
Diabetes  2011;60(5):1528-1534.
Objective
Fixed genomic variation explains only a small proportion of the risk of adiposity. In animal models, maternal diet alters offspring body composition, accompanied by epigenetic changes in metabolic control genes. Little is known about whether such processes operate in humans.
Research Design and Methods
Using Sequenom MassARRAY we measured the methylation status of 68 CpGs 5′ from five candidate genes in umbilical cord tissue DNA from healthy neonates. Methylation varied greatly at particular CpGs: for 31 CpGs with median methylation ≥5% and a 5-95% range ≥10% we related methylation status to maternal pregnancy diet and to child’s adiposity at age 9 years. Replication was sought in a second independent cohort.
Results
In cohort 1, RXRA chr9:136355885+ and eNOS chr7:150315553+ methylation had independent associations with sex-adjusted childhood fat mass (exponentiated regression coefficient (β) 17% per standard deviation change in methylation (95% confidence interval (CI) 4 to 31%), P=0.009, n=64 and β=20% (9 to 32%), P<0.001, n=66, respectively) and %fat mass (β=10% (1 to 19%), P=0.023, n=64 and β=12% (4 to 20%), P=0.002, n=66, respectively). Regression analyses including sex and neonatal epigenetic marks explained >25% of the variance in childhood adiposity. Higher methylation of RXRA chr9:136355885+, but not of eNOS chr7:150315553+, was associated with lower maternal carbohydrate intake in early pregnancy, previously linked with higher neonatal adiposity in this population. In cohort 2, cord eNOS chr7:150315553+ methylation showed no association with adiposity, but RXRA chr9:136355885+ methylation showed similar associations with fat mass and %fat mass (β=6% (2 to 10%) and β=4% (1 to 7%), respectively, both P=0.002, n=239).
Conclusions
Our findings suggest a substantial component of metabolic disease risk has a prenatal developmental basis. Perinatal epigenetic analysis may have utility in identifying individual vulnerability to later obesity and metabolic disease.
doi:10.2337/db10-0979
PMCID: PMC3115550  PMID: 21471513
18.  Dietary patterns change little from before to during pregnancy1 
The Journal of nutrition  2009;139(10):1956-1963.
Principal component analysis is a popular method of dietary patterns analysis, but our understanding of its use to describe changes in dietary patterns over time is limited. We assessed the diets of 12,572 non-pregnant women aged 20-34 from Southampton, UK using a food frequency questionnaire, of whom 2,270 and 2,649 became pregnant and provided complete dietary data in early and late pregnancy respectively. Intakes of white bread, breakfast cereals, cakes and biscuits, processed meat, crisps, fruit and fruit juices, sweet spreads, confectionery, hot chocolate drinks, puddings, cream, milk, cheese, full-fat spread, cooking fats and salad oils, red meat and soft drinks increased in pregnancy. Intakes of rice and pasta, liver and kidney, vegetables, nuts, diet cola, tea and coffee, boiled potatoes and crackers decreased in pregnancy. Principal component analysis at each time point produced two consistent dietary patterns, labeled ‘prudent’ and ‘high-energy’. At each time point in pregnancy, and for both the prudent and high-energy patterns, we derived two dietary pattern scores for each woman: a ‘natural’ score, based on the pattern defined at that time point, and an ‘applied’ score, based on the pattern defined before pregnancy. Applied scores are preferred to natural scores to characterize changes in dietary patterns over time because the scale of measurement remains constant. Using applied scores there was a very small mean decrease in prudent diet score in pregnancy, and a very small mean increase in high-energy diet score in late pregnancy, indicating little overall change in dietary patterns in pregnancy.
doi:10.3945/jn.109.109579
PMCID: PMC3113465  PMID: 19710161
Diet; Dietary patterns; Pregnancy; Principal component analysis
19.  Weight gain in pregnancy and childhood body composition: findings from the Southampton Women’s Survey 
Background
Intrauterine life may be a critical period for the programming of later obesity, but there is conflicting evidence about whether pregnancy weight gain is an important determinant of offspring adiposity.
Objective
The purpose of this study was to examine the relationship of pregnancy weight gain with neonatal and childhood body composition.
Design
The participants (n=948) were children born to women in the Southampton Women’s Survey who had dual-energy x-ray absorptiometry measurements of body composition at birth, 4 or 6 years. Pregnancy weight gain was derived from the mothers’ measured weights before pregnancy and at 34 weeks gestation, analyzed using 2009 Institute of Medicine (IOM) categories (inadequate, adequate or excessive), and as a continuous measure.
Results
Almost half (49%) the children were born to women who gained excessive weight in pregnancy. In comparison with children born to women with adequate weight gain, they had a greater fat mass in the neonatal period (0.17 SD (95% CI 0.02, 0.32), P=0.03), at 4 years (0.17 SD (0.00, 0.34), P=0.05) and at 6 years (0.30 SD (0.11, 0.49), P=0.002). Greater pregnancy weight gain, as a continuous measure, was associated with greater neonatal fat mass (0.10 SD per 5kg weight gain (0.04, 0.15), P=0.0004) and, weakly, with fat mass at 6 years (0.07 SD per 5kg (0.00, 0.14), P=0.05), but not at 4 years (0.02 SD per 5kg (−0.04, 0.08), P=0.55).
Conclusions
Appropriate pregnancy weight gain, as defined by 2009 IOM recommendations, is linked to lower levels of adiposity in the offspring.
doi:10.3945/ajcn.2009.29128
PMCID: PMC3091013  PMID: 20375187
20.  Dietary patterns in pregnant women: a comparison of food frequency questionnaires and four-day prospective diaries 
The British journal of nutrition  2007;99(4):869-875.
There is growing interest in the use of dietary patterns as measures of exposure in studies of diet-disease relationships. However, relatively little is known about the impact of the type of dietary assessment method on the patterns observed. Using food frequency questionnaire (FFQ) and food diary data collected from 585 women in early pregnancy we used principal component analysis to define dietary patterns. The first pattern was very similar in both datasets and was termed the ‘prudent’ diet. The second pattern, whilst comparable for the FFQ and food diaries, showed greater variation in coefficients than the prudent pattern; it was termed the ‘Western’ diet. Differences between the FFQ and diary scores were calculated for each woman for both the prudent and Western diet patterns. 95% of the differences in the prudent diet score lay within ±1.58 standard deviations of the mean, and 95% of the differences in the Western diet scores lay within ±2.22 standard deviations of the mean. Pearson’s correlation coefficients were 0.67 (P < 0.001) for the prudent diet score and 0.35 (P < 0.001) for the Western diet score. The agreement between the FFQ and diary scores was lowest amongst respondents who were younger, had lower educational attainment and whose diaries were coded as ‘poor, probably incomplete’, although these effects were small. The first two dietary patterns identified in this cohort of pregnant women appear to be defined similarly by both FFQ and diary data, suggesting that FFQ data provide useful information on dietary patterns.
doi:10.1017/S0007114507831746
PMCID: PMC3091014  PMID: 18005481
Dietary patterns; principal component analysis; food frequency questionnaire
21.  Do women change their health behaviours in pregnancy? Findings from the Southampton Women’s Survey 
SUMMARY
A woman’s lifestyle choices before and during pregnancy have important implications for her unborn child, but information on behaviour can be unreliable when data are collected retrospectively. In particular there are no large longitudinal datasets that include information collected prospectively before pregnancy to allow accurate description of changes in behaviour into pregnancy.
The Southampton Women’s Survey is a longitudinal study of women in Southampton, UK, characterised when they were not pregnant and again during pregnancy. The objective of the analyses presented here is to describe the degree to which women comply with diet and lifestyle recommendations before and during pregnancy, and changes between these time points.
The analyses are based on 1490 women who delivered between 1998 and 2003 and who provided information before pregnancy and at 11 and 34 weeks gestation. At each time point a trained research nurse ascertained smoking status and assessed food and drink consumption using a food frequency questionnaire. We derived the proportions of women who complied with recommendations not to smoke, to eat five portions of fruit and vegetables per day and to drink no more than four units of alcohol per week and 300mg of caffeine per day.
There was a notable reduction in smoking when women became pregnant; before pregnancy 27% of women smoked, whereas in early pregnancy 15% smoked. Similarly there were significant reductions in alcohol consumption and intake of caffeinated drinks; before pregnancy 54% of women drank more than 4 units of alcohol per week and 39% had estimated intakes of caffeine in drinks of more than 300mg per day, whereas comparable figures for early pregnancy were 10% and 16% respectively. However, there was little change in fruit and vegetable intake; the percentages of women who did not achieve the recommendation to eat at least five portions of fruit and vegetables per week were 47% before pregnancy and 46% in early pregnancy. Younger women and those with fewer educational qualifications were less likely to comply with public health recommendations. 81% of women in early pregnancy complied with at least three of the recommendations. Although there is encouraging evidence of changed health behaviours in pregnancy, young women and those with few educational qualifications may particularly benefit from targeted health initiatives.
doi:10.1111/j.1365-3016.2009.01036.x
PMCID: PMC3091015  PMID: 19689495
Pregnancy; smoking; alcohol drinking; fruit and vegetables; caffeinated drinks
22.  Development of a 20-item food frequency questionnaire to assess a ‘prudent’ dietary pattern amongst young women in Southampton 
Objective
To develop a short food frequency questionnaire (FFQ) that can be used amongst young women in Southampton to assess compliance with a prudent dietary pattern characterised by high consumption of wholemeal bread, fruit and vegetables, and low consumption of sugar, white bread, and red and processed meat.
Methods
Diet was assessed using a 100-item interviewer-administered FFQ in 6,129 non-pregnant women aged 20-34 years. 94 of these women were re-interviewed two years later using the same FFQ. Subsequently diet was assessed in 378 women attending SureStart Children’s Centres in the Nutrition and Well-being Study using a 20-item FFQ. The 20 foods included were those that characterised the prudent dietary pattern.
Results
The 20-item prudent diet score was highly correlated with the full 100-item score (r=0.94) in the Southampton Women’s Survey. Both scores were correlated with red blood cell folate (r=0.28 for the 100-item score and r=0.25 for the 20-item score). Amongst the women re-interviewed after two years, the change in prudent diet score was correlated with change in red cell folate for both the 20-item (rS=0.31) and 100-item scores (rS=0.32). In the Nutrition and Well-being Study a strong association between the 20-item prudent diet score and educational attainment (r=0.41) was observed, similar to that seen in the Southampton Women’s Survey (r=0.47).
Conclusions
The prudent diet pattern describes a robust axis of variation in diet. A 20-item FFQ based on the foods that characterise the prudent diet pattern has clear advantages in terms of time and resources, and is a helpful tool to characterise the diets of young women in Southampton.
doi:10.1038/ejcn.2009.114
PMCID: PMC3091018  PMID: 19756032
Food frequency questionnaire; Principal component analysis
23.  Dietary patterns in the Southampton Women’s Survey 
European journal of clinical nutrition  2006;60(12):1391-1399.
Objective
Dietary pattern analysis is receiving increasing attention as a means of summarising the multi-dimensional nature of dietary data. This research aims to compare principal component analysis and cluster analysis using dietary data collected from young women in the UK.
Design
Diet was assessed using a 100-item interviewer-administered food frequency questionnaire. Principal component analysis and cluster analysis were used to examine dietary patterns.
Setting
Southampton, UK.
Subjects
6125 non-pregnant women aged 20 to 34 years
Results
Principal component analysis identified two important patterns: a ‘prudent’ diet, and a ‘high-energy’ diet. Cluster analysis defined two clusters, a ‘more healthy’ and a ‘less healthy’ cluster. There was a strong association between the prudent diet score and the two clusters, such that the mean prudent diet score in the less healthy cluster was −0.73 standard deviations and in the more healthy cluster was +0.83 standard deviations; the difference in the high-energy diet score between the two clusters was considerably smaller.
Conclusions
Both approaches revealed a similar dietary pattern. The continuous nature of the outcome of principal component analysis was considered to be advantageous compared with the dichotomy identified using cluster analysis.
doi:10.1038/sj.ejcn.1602469
PMCID: PMC3091020  PMID: 16804555
Dietary patterns; Principal component analysis; Cluster analysis
24.  Women’s compliance with nutrition and lifestyle recommendations before pregnancy: general population cohort study 
Objective To examine the extent to which women planning a pregnancy comply with recommendations for nutrition and lifestyle.
Design Prospective cohort study.
Setting Southampton, United Kingdom.
Participants 12 445 non-pregnant women aged 20-34 recruited to the Southampton Women’s Survey through general practices, 238 of whom became pregnant within three months of being interviewed.
Main outcome measures Folic acid supplement intake, alcohol consumption, smoking, diet, and physical activity before pregnancy.
Results The 238 women who became pregnant within three months of the interview were only marginally more likely to comply with recommendations for those planning a pregnancy than those who did not become pregnant in this period. Among those who became pregnant, 2.9% (95% confidence interval 1.2% to 6.0%) were taking 400 μg or more of folic acid supplements a day and drinking four or fewer units of alcohol a week, compared with 0.66% (0.52% to 0.82%) of those who did not become pregnant. 74% of those who became pregnant were non-smokers compared with 69% of those who did not become pregnant (P=0.08). Women in both groups were equally likely to consume five or more portions of fruit and vegetables a day (53% in each group, P=1.0), but only 57% of those who became pregnant had taken any strenuous exercise in the past three months compared with 64% in those who did not become pregnant (P=0.03).
Conclusion Only a small proportion of women planning a pregnancy follow the recommendations for nutrition and lifestyle. Greater publicity for the recommendations is needed, but as many pregnancies are unplanned, improved nutrition and lifestyles of women of childbearing age is also required.
doi:10.1136/bmj.b481
PMCID: PMC2643441  PMID: 19213768
25.  Women’s compliance with nutrition and lifestyle recommendations before pregnancy: general population cohort study 
The BMJ  2009;338:b481.
Objective To examine the extent to which women planning a pregnancy comply with recommendations for nutrition and lifestyle.
Design Prospective cohort study.
Setting Southampton, United Kingdom.
Participants 12 445 non-pregnant women aged 20-34 recruited to the Southampton Women’s Survey through general practices, 238 of whom became pregnant within three months of being interviewed.
Main outcome measures Folic acid supplement intake, alcohol consumption, smoking, diet, and physical activity before pregnancy.
Results The 238 women who became pregnant within three months of the interview were only marginally more likely to comply with recommendations for those planning a pregnancy than those who did not become pregnant in this period. Among those who became pregnant, 2.9% (95% confidence interval 1.2% to 6.0%) were taking 400 μg or more of folic acid supplements a day and drinking four or fewer units of alcohol a week, compared with 0.66% (0.52% to 0.82%) of those who did not become pregnant. 74% of those who became pregnant were non-smokers compared with 69% of those who did not become pregnant (P=0.08). Women in both groups were equally likely to consume five or more portions of fruit and vegetables a day (53% in each group, P=1.0), but only 57% of those who became pregnant had taken any strenuous exercise in the past three months compared with 64% in those who did not become pregnant (P=0.03).
Conclusion Only a small proportion of women planning a pregnancy follow the recommendations for nutrition and lifestyle. Greater publicity for the recommendations is needed, but as many pregnancies are unplanned, improved nutrition and lifestyles of women of childbearing age is also required.
doi:10.1136/bmj.b481
PMCID: PMC2643441  PMID: 19213768

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