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1.  Validation of novel wheeze phenotypes using longitudinal airway function and atopic sensitisation data in the first 6 years of life: Evidence from the Southampton Women’s Survey. 
Pediatric pulmonology  2013;48(7):683-692.
Background
In 1995 the Tucson Children’s Respiratory Study (TCRS) identified clinically distinct phenotypes amongst early wheezers; the Avon Longitudinal Study of Parents And Children (ALSPAC) has recently re-examined these.
Objectives
To validate statistically derived ALSPAC phenotypes in the Southampton Women’s Survey (SWS) using infant and 6 year lung function, and allergic sensitisation at 1, 3 and 6 years, comparing these with TCRS phenotypes.
Methods
Complete 6 year follow-up data were available for 926 children, selected from 1973 infants born to 12,579 women characterised pre-conception. 95 children had V’maxFRC and FEV0.4 measured age 5-14 weeks using rapid compression/raised volume techniques. At 6 years we performed spirometry (n=791), fractional exhaled nitric oxide (FeNO, n=589) and methacholine challenge (n=234). Skin prick testing was performed at 12m, 3 and 6 years (n=1494, 1255, 699, respectively). Using wheeze status questionnaire data at 6m, 12m, 2, 3 and 6 years we classified children into TCRS (never, transient early, persistent, late-onset) and ALSPAC based groups (never, early, transient, intermediate-onset, late-onset, persistent).
Results
Amongst ALSPAC groups, persistent and late-onset wheeze were associated with atopy at 3 and 6 years, whilst intermediate-onset wheeze showed earlier atopic association at 1 year; all three were associated with FeNO at 6 years. Persistent wheezers had lower infant (V’maxFRC p<0.05) and 6 year lung function (FEV1, FEV1/FVC and FEF25-75, p<0.05), whilst late and intermediate-onset wheezers showed no lung function deficits. Transient wheezers were non-atopic but showed persistent lung function deficits (V’maxFRC in infancy, FEV1 and FEF25-75 at 6 years, all p<0.05). Those who wheezed only in the first year (early phenotype) showed no lung function deficits. No associations were seen with 6 years bronchial hyper-responsiveness or infancy FEV0.4.
Conclusion
SWS cohort data validates the statistically derived ALSPAC 6-class model. In particular, lung function and atopy successfully differentiate persistent, late-onset and intermediate-onset wheeze, whilst the Tucson ‘transient early’ wheeze phenotype can be sub-classified into groups that reflect early lung function. Since the 4-class model fails to adequately differentiate phenotypes based on lung function and atopy, we propose that strong consideration be given to using the 6-class paradigm for longitudinal outcome work in wheezing with onset in early life.
doi:10.1002/ppul.22766
PMCID: PMC3689612  PMID: 23401430
Wheeze; asthma; phenotype; lung function; cohort; atopy
2.  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
3.  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
4.  THE RELATIONSHIP BETWEEN MATERNAL ADIPOSITY AND INFANT WEIGHT GAIN AND CHILDHOOD WHEEZE AND ATOPY 
Thorax  2013;68(4):372-379.
Background
Obesity and asthma have increased in westernised countries. Maternal obesity may increase childhood asthma risk. If this relation is causal it may be mediated through factors associated with maternal adiposity, such as fetal development, pregnancy complications or infant adiposity. We investigated the relationships of maternal BMI and fat mass with childhood wheeze and examined the influences of infant weight gain and childhood obesity.
Methods
Maternal pre-pregnancy BMI and estimated fat mass (from skinfold thicknesses) were related to asthma, wheeze and atopy in 940 children. Transient or persistent/late wheeze was classified using questionnaire data collected at ages 6, 12, 24 and 36 months and 6 years. At 6 years, skin prick testing was conducted and exhaled nitric oxide and spirometry measured. Infant adiposity gain was calculated from skinfold thickness at birth and 6 months.
Results
Greater maternal BMI and fat mass were associated with increased childhood wheeze (RR 1.08 per 5 kg m−2, p=0.006; RR 1.09 per 10 kg, p=0.003); these reflected associations with transient wheeze (RR 1.11, p=0.003; RR 1.13, p=0.002, respectively) but not with persistent wheeze or asthma. Infant adiposity gain was associated with persistent wheeze but not significantly. Adjusting for infant adiposity gain or BMI at 3 or 6 years did not reduce the association between maternal adiposity and transient wheeze. Maternal adiposity was not associated with offspring atopy, exhaled nitric oxide, or spirometry.
Discussion
Greater maternal adiposity is associated with transient wheeze but not asthma or atopy, suggesting effects upon airway structure/function but not allergic predisposition.
doi:10.1136/thoraxjnl-2012-202556
PMCID: PMC3661999  PMID: 23291350
adiposity; body mass index; obesity; asthma; allergic sensitisation
5.  Physical activity intensity, sedentary time, and body composition in preschoolers123 
Background
Detailed associations between physical activity (PA) subcomponents, sedentary time, and body composition in preschoolers remain unclear.
Objective
We examined the magnitude of associations between objectively measured PA subcomponents and sedentary time with body composition in 4-y-old children.
Design
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.
Results
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).
Conclusions
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.
doi:10.3945/ajcn.112.045088
PMCID: PMC3785144  PMID: 23553158
6.  Correlates of Light and Moderate-to-Vigorous Objectively Measured Physical Activity in Four-Year-Old Children 
PLoS ONE  2013;8(9):e74934.
Background
Correlates of physical activity (PA) are hypothesized to be context and behaviour specific, but there is limited evidence of this in young children. The aim of the current study is to investigate associations between personal, social and environmental factors and objectively measured light and moderate-to-vigorous PA (LPA and MVPA, respectively) in four-year-old children.
Methods
Cross-sectional data were used from the Southampton Women’s Survey, a UK population-based longitudinal study. Four-year old children (n = 487, 47.0% male) had valid PA data assessed using accelerometry (Actiheart) and exposure data collected with a validated maternal questionnaire (including data on child personality, family demographics, maternal behaviour, rules and restrictions, and perceived local environment). Linear regression modelling was used to analyse associations with LPA and MVPA separately, interactions with sex were explored.
Results
LPA minutes were greater in children whose mothers reported more PA (vs. inactive: regression coefficient±standard error: 6.70±2.94 minutes), and without other children in the neighbourhood to play with (−6.33±2.44). MVPA minutes were greater in children with older siblings (vs. none: 5.81±2.80) and those whose mothers used active transport for short trips (vs. inactive: 6.24±2.95). Children accumulated more MVPA in spring (vs. winter: 9.50±4.03) and, in boys only, less MVPA with availability of other children in the neighbourhood (−3.98±1.70).
Discussion
Young children’s LPA and MVPA have differing associations with a number of social and environmental variables. Interventions targeting PA promotion in young children outside of formal care settings should consider including intensity specific factors.
doi:10.1371/journal.pone.0074934
PMCID: PMC3764204  PMID: 24040365
8.  Monitoring head size and growth using the new UK-World Health Organization growth standard 
Archives of disease in childhood  2011;96(4):386-388.
In order to assess the extent to which children in the United Kingdom (UK) will follow the UK-WHO head circumference standard, we used head circumference data from the Southampton Women’s Survey (SWS; n=3159) and the Avon Longitudinal Study of Parents and Children (ALSPAC; n=15,208) in children age 0-36 months, converted into z-scores using both the UK-WHO or UK1990 references. Rapid head growth was defined as crossing upwards through 2 major centile bands (1.33 SD). The UK-WHO standard identified many more infants with heads above the 98th centile compared to the UK1990 reference (UK-WHO 6% to 16% of infants at various ages, UK1990 1% to 4%). Rapid head growth in the first 6 to 9 months was also much more common using the UK-WHO standard (UK-WHO: 14.6% to 15.3%; UK1990: 4.8% to 5.1%). Practitioners should be aware of these findings to avoid unnecessary referrals.
doi:10.1136/adc.2010.200030
PMCID: PMC3685130  PMID: 21285227
ALSPAC; head circumference; growth charts; macrocephaly; microcephaly; hydrocephalus
9.  The long term effects of prenatal development on growth and metabolism 
Seminars in reproductive medicine  2011;29(3):257-265.
People who were small at birth and had poor infant growth have an increased risk of adult cardiovascular disease, osteoporosis and type 2 diabetes, particularly if their restricted early growth is followed by increased childhood weight gain. These relations extend across the normal range of birth size in a graded manner, so reduced size is not a prerequisite. In addition larger birth size is associated with risks of obesity and type 2 diabetes. The associations appear to reflect developmental plastic responses made by the fetus and infant based on cues about the environment, influenced by maternal characteristics including diet, body composition, stress and exercise levels. These responses involve epigenetic processes which modify the offspring’s phenotype. Vulnerability to ill-health results if the environment in infancy, childhood and later life is mismatched to the phenotype induced in development, informed by the developmental cues. This mismatch may arise through unbalanced diet or body composition of the mother, or change in lifestyle factors between generations. These insights offer new possibilities for early diagnosis and prevention of chronic disease.
doi:10.1055/s-0031-1275518
PMCID: PMC3685133  PMID: 21769765
Nutrition; fetal growth; metabolic disease; epigenetics
11.  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
12.  Maternal late-pregnancy serum 25-hydroxyvitamin D in relation to childhood wheeze and atopic outcomes 
Thorax  2012;67(11):950-956.
Background
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.
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1136/thoraxjnl-2012-201888
PMCID: PMC3679514  PMID: 22707522
asthma epidemiology; asthma; paediatric asthma
13.  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
14.  Postpartum depressive symptoms: the B-vitamin link 
Objective This study examined longitudinal relationships between maternal red-cell folate status and dietary intakes of vitamins B6, B12 and folate before and during pregnancy and subsequent postpartum depressive symptoms.
Study design and setting Within a cohort study of women aged 20–34 years (the Southampton Women's Survey) dietary data were obtained before pregnancy and at 11 and 34 weeks' gestation. Red-cell folate was measured before pregnancy and at 11 weeks' gestation. We derived relative risks of postpartum depressive symptoms using an Edinburgh Postnatal Depression Scale (EPDS) score of ≥ 13 administered from 6 months to 1 year postpartum.
Results No significant differences were found between those with postpartum depressive symptoms (n = 905) and those without (n = 1951) in relation to red-cell folate concentration or dietary intake of folate, vitamin B12 and vitamin B6, before or during pregnancy. A prior history of mental illness (relative risk (RR) 1.83; 95% confidence interval (CI) 1.53–2.19) was associated with postpartum depressive symptoms, and women who breastfed until 6 months were less likely to experience postpartum depressive symptoms (RR 0.68; 95% CI 0.55–0.84).
Conclusion This study suggests that folate status and dietary folate, B6 and B12 intakes before and during pregnancy are not associated with postpartum depressive symptoms. A history of mental illness, however, was a strong risk factor.
PMCID: PMC3487611  PMID: 23277793
B-vitamin intake; folate status; postpartum depression
15.  Maternal Plasma Phosphatidylcholine Fatty Acids and Atopy and Wheeze in the Offspring at Age of 6 Years 
Variation in exposure to polyunsaturated fatty acids (PUFAs) might influence the development of atopy, asthma, and wheeze. This study aimed to determine whether differences in PUFA concentrations in maternal plasma phosphatidylcholine are associated with the risk of childhood wheeze or atopy. For 865 term-born children, we measured phosphatidylcholine fatty acid composition in maternal plasma collected at 34 weeks' gestation. Wheezing was classified using questionnaires at 6, 12, 24, and 36 months and 6 years. At age of 6 years, the children underwent skin prick testing, fractional exhaled nitric oxide (FENO) measurement, and spirometry. Maternal n-6 fatty acids and the ratio of n-3 to n-6 fatty acids were not associated with childhood wheeze. However, higher maternal eicosapentaenoic acid, docosahexaenoic acid, and total n-3 fatty acids were associated with reduced risk of non-atopic persistent/late wheeze (RR 0.57, 0.67 and 0.69, resp. P = 0.01, 0.015, and 0.021, resp.). Maternal arachidonic acid was positively associated with FENO (P = 0.024). A higher ratio of linoleic acid to its unsaturated metabolic products was associated with reduced risk of skin sensitisation (RR 0.82, P = 0.013). These associations provide some support for the hypothesis that variation in exposure to n-6 and n-3 fatty acids during pregnancy influences the risk of childhood wheeze and atopy.
doi:10.1155/2012/474613
PMCID: PMC3463812  PMID: 23049600
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.  Validation of a maternal questionnaire on correlates of physical activity in preschool children 
Background
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1186/1479-5868-6-81
PMCID: PMC2791748  PMID: 19954524
25.  Pathways of disadvantage and smoking careers: evidence and policy implications 
Journal of Epidemiology and Community Health  2006;60(Suppl 2):ii7-ii12.
Objectives
To investigate in older industrialised societies (a) how social disadvantage contributes to smoking risk among women (b) the role of social and economic policies in reducing disadvantage and moderating wider inequalities in life chances and living standards.
Methods
Review and analysis of (a) the effects of disadvantage in childhood and into adulthood on women's smoking status in early adulthood (b) policy impacts on the social exposures associated with high smoking risk.
Main results
(a) Smoking status—ever smoking, current smoking, heavy smoking, and cessation—is influenced not only by current circumstances but by longer term biographies of disadvantage (b) social and economic policies shape key social predictors of women's smoking status, including childhood circumstances, educational levels and adult circumstances, and moderate inequalities in the distribution of these dimensions of life chances and living standards. Together, the two sets of findings argue for a policy toolkit that acts on the distal determinants of smoking, with interventions targeting the conditions in which future and current smokers live.
Conclusions
An approach to tobacco control is advocated that combines changing smoking habits with reducing inequalities in the social trajectories in which they are embedded. Policies to level up opportunities and living standards across the lifecourse should be championed as part of an equity oriented approach to reducing the disease burden of cigarette smoking.
doi:10.1136/jech.2005.045583
PMCID: PMC2491894  PMID: 17708005
women; smoking; disadvantage; social policies; social inequalities

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