Andrew K Wills

Association of maternal vitamin D status during pregnancy with bone-mineral content in offspring: a prospective cohort study

Summary Background Maternal vitamin D status in pregnancy is a suggested determinant of bone-mineral content (BMC) in offspring, but has been assessed in small studies. We investigated this association in a large prospective study. Methods Eligible participants were mother-and-singleton-offspring pairs who had participated in the Avon Longitudinal Study of Parents and Children, and in which the mother had recorded measurements of 25(OH)D concentration in pregnancy and the offspring had undergone dual-energy x-ray absorptiometry at age 9–10 years. 25(OH)D concentrations in pregnancy were assessed per 10·0 nmol/L and classified as sufficient (more than 50·00 nmol/L), insufficient (49·99–27·50 nmol/L), or deficient (lower than 27·50 nmol/L). Associations between maternal serum 25(OH)D concentrations and offspring total body less head (TBLH) and spinal BMC were assessed by trimester. Results 3960 mother-and-offspring pairs, mainly of white European origin, were assessed (TBLH BMC n=3960, spinal BMC n=3196). Mean offspring age was 9·9 years. 2644 (67%) mothers had sufficient, 1096 (28%) insufficient, and 220 (6%) deficient 25(OH)D concentrations in pregnancy, but TBLH and spinal BMC did not differ between offspring of mothers in the lower two groups versus sufficient 25(OH)D concentration. No associations with offspring BMC were found for any trimester, including the third trimester, which is thought to be most relevant (TBLH BMC confounder-adjusted mean difference −0·03 g per 10·0 nmol/L, 95% CI −1·71 to 1·65; spinal BMC 0·04 g per 10·0 nmol/L, 95% CI −0·12 to 0·21). Conclusions We found no relevant association between maternal vitamin D status in pregnancy and offspring BMC in late childhood. Funding UK Medical Research Council, Wellcome Trust, and University of Bristol.

Adult obesity susceptibility variants are associated with greater childhood weight gain and a faster tempo of growth: the 1946 British Birth Cohort Study

Background: Longitudinal growth associations with genetic variants identified for adult BMI may provide insights into the timing of obesity susceptibility. Objective: The objective was to explore associations of known BMI loci with measures of body size from birth to adulthood. Design: A total of 2537 individuals from a longitudinal British birth cohort were genotyped for 11 genetic variants robustly associated with adult BMI (in/near FTO, MC4R, TMEM18, GNPDA2, KCTD15, NEGR1, BDNF, ETV5, SEC16B, SH2B1, and MTCH2). We derived an obesity-risk-allele score, comprising the sum of BMI-increasing alleles in each individual, and examined this for an association with birth weight and repeated measures of weight, height, and BMI SD scores (SDS) at 11 time points between ages 2 and 53 y. Results: The obesity-risk-allele score showed borderline significant association with birth weight (0.019 SDS/allele; P = 0.05) and was more clearly associated with higher weight and BMI at all time points between ages 2 and 53 y; the strongest associations with weight occurred at ages 11 and 20 y (both 0.056 SDS/allele). In longitudinal analyses, the score was positively associated with weight gain only between birth and 11 y (0.003 SDS/allele per year; 95% CI: 0.001, 0.004; P = 0.001). The risk-allele score was associated with taller height at 7 y (0.031 SDS/allele; P = 0.002) and greater height gains between 2 and 7 y (0.007 SDS/allele per year; P < 0.001), but not with adult height (P = 0.5). Conclusions: The combined effect of adult obesity susceptibility variants on weight gain was confined to childhood. These variants conferred a faster tempo of height growth that was evident before the pubertal years.

Life course body mass index and risk of knee osteoarthritis at the age of 53 years: evidence from the 1946 British birth cohort study

Introduction The authors examined how body mass index (BMI) across life is linked to the risk of midlife knee osteoarthritis (OA), testing whether prolonged exposure to high BMI or high BMI at a particular period has the greatest influence on the risk of knee OA. Methods A population-based British birth cohort of 3035 men and women underwent clinical examination for knee OA at age 53 years.Heights and weights were measured 10 times from 2 to 53 years. Analyses were stratified by gender and adjusted for occupation and activity levels. Results The prevalence of knee OA was higher in women than in men (12.9% (n=194) vs 7.4% (n=108)). In men, the association between BMI and later knee OA was evident at 20 years (p=0.038) and remained until 53 years (OR per z-score 1.38 (95% CI 1.11 to 1.71)). In women, there was evidence for an association at 15 years (p=0.003); at 53 years, the OR was 1.89 (95% CI 1.59 to 2.24) per z-score increase in BMI. Changes in BMI from childhood in women and from adolescence in men were also positively associated with knee OA. A structured modelling approach to disentange the way in which BMI is linked to knee OA suggested that prolonged exposure to high BMI throughout adulthood carried the highest risk and that there was no additional risk conferred from adolescence once adult BMI had been accounted for. Conclusion This study suggests that the risk of knee OA accumulates from exposure to a high BMI through adulthood.

Improving women's diet quality preconceptionally and during gestation: effects on birth weight and prevalence of low birth weight—a randomized controlled efficacy trial in India (Mumbai Maternal Nutrition Project)

Background: Low birth weight (LBW) is an important public health problem in undernourished populations. Objective: We tested whether improving womens dietary micronutrient quality before conception and throughout pregnancy increases birth weight in a high-risk Indian population. Design: The study was a nonblinded, individually randomized controlled trial. The intervention was a daily snack made from green leafy vegetables, fruit, and milk (treatment group) or low-micronutrient vegetables (potato and onion) (control group) from ≥90 d before pregnancy until delivery in addition to the usual diet. Treatment snacks contained 0.69 MJ of energy (controls: 0.37 MJ) and 10–23% of WHO Reference Nutrient Intakes of β-carotene, riboflavin, folate, vitamin B-12, calcium, and iron (controls: 0–7%). The primary outcome was birth weight. Results: Of 6513 women randomly assigned, 2291 women became pregnant, 1962 women delivered live singleton newborns, and 1360 newborns were measured. In an intention-to-treat analysis, there was no overall increase in birth weight in the treatment group (+26 g; 95% CI: −15, 68 g; P = 0.22). There was an interaction (P < 0.001) between the allocation group and maternal prepregnant body mass index (BMI; in kg/m2) [birth-weight effect: −23, +34, and +96 g in lowest (<18.6), middle (18.6–21.8), and highest (>21.8) thirds of BMI, respectively]. In 1094 newborns whose mothers started supplementation ≥90 d before pregnancy (per-protocol analysis), birth weight was higher in the treatment group (+48 g; 95% CI: 1, 96 g; P = 0.046). Again, the effect increased with maternal BMI (−8, +79, and +113 g; P-interaction = 0.001). There were similar results for LBW (intention-to-treat OR: 0.83; 95% CI: 0.66, 1.05; P = 0.10; per-protocol OR = 0.76; 95% CI: 0.59, 0.98; P = 0.03) but no effect on gestational age in either analysis. Conclusions: A daily snack providing additional green leafy vegetables, fruit, and milk before conception and throughout pregnancy had no overall effect on birth weight. Per-protocol and subgroup analyses indicated a possible increase in birth weight if the mother was supplemented ≥3 mo before conception and was not underweight. This trial was registered at www.controlled-trials.com/isrctn/ as ISRCTN62811278.

Body mass index, occupational activity, and leisure-time physical activity: an exploration of risk factors and modifiers for knee osteoarthritis in the 1946 British birth cohort

BackgroundKnee osteoarthritis (kOA) risk is increased by obesity and physical activities (PA) which mechanically stress the joint. We examined the associations of midlife kOA with body mass index (BMI) and activity exposure across adult life and their interaction.MethodsData are from a UK birth cohort of 2597 participants with a clinical assessment for kOA at age 53. At ages 36, 43 and 53 BMI (kg/m2), self-reported leisure-time PA, and occupational activity (kneeling/squatting; lifting; climbing; sitting; assigned using a job-exposure matrix) were ascertained. Associations were explored using the multiplicative logistic model.ResultsBMI was strongly and positively associated with kOA in men and women. Men and women in manual occupations also had greater odds of kOA; there was a weak suggestion that kOA risk was higher among men exposed to lifting or kneeling at work. For men, the only evidence of a multiplicative interaction between BMI and activities was for lifting (p = 0.01) at age 43; BMI conferred higher kOA risk among those most-likely to lift at work (OR per increase in BMI z-score: 3.55, 95% CI: 1.72-7.33). For women, the only evidence of an interaction was between BMI and leisure-time PA (p = 0.005) at age 43; BMI conferred higher kOA risk among those at higher PA levels (OR per increase in BMI z-score: 1.59, 95% CI: 1.26-2.00 in inactive; 1.70, 95% CI: 1.14-2.55 (less-active); and 4.44; 95% CI: 2.26-8.36 (most-active).ConclusionsAt the very least, our study suggests that more active individuals (at work and in leisure) may see a greater reduction in risk of kOA from avoiding a high BMI than those less active.

Maternal 25-hydroxyvitamin D and its association with childhood atopic outcomes and lung function

It has been suggested that maternal vitamin D status in pregnancy influences the risk of asthma and atopy in the offspring. The epidemiological evidence to support these claims is conflicting and may reflect chance findings and differences in how vitamin D was assessed.

Associations between the Pubertal Timing-Related Variant in LIN28B and BMI Vary Across the Life Course

CONTEXT The common C allele of rs314276 in LIN28B has been robustly associated with earlier age at menarche in girls and associated with earlier timing of other pubertal traits in both sexes. OBJECTIVE Our objective was to explore the associations between rs314276, as a marker of earlier pubertal timing, and body mass index (BMI), weight, and height across the life course. METHODS The rs314276 in LIN28B was genotyped in 1242 men and 1209 women born in 1946 and participating in the Medical Research Council National Survey of Health and Development. Birth weight was recorded, and height and weight were measured or self-reported repeatedly at 11 time points between ages 2 and 53 yr. Polynomial mixed models were used to test whether additive genetic associations with sd scores (SDS) for BMI and height changed with age between 0 and 53 yr. RESULTS Longitudinal analyses revealed age-dependent associations between rs314276 genotype and BMI (P < 0.001 for genotype-by-age(2) interaction) and body weight (P < 0.001 for genotype-by-age(2) interaction) in women, but not in men. In women only, the C allele at rs314276 was associated with higher BMI SDS from ages 15-43 yr. In contrast, C allele associations with shorter height SDS were apparent in both men and women and did not vary with age. CONCLUSION A common genetic variant in LIN28B that confers earlier puberty was associated with a prolonged increase in BMI during adolescence and early to mid-adulthood in women only. Such genetic associations may provide insights into the direct effects of pubertal timing on obesity risk.

Physical Activity Across Adulthood in Relation to Fat and Lean Body Mass in Early Old Age: Findings From the Medical Research Council National Survey of Health and Development, 1946–2010

Fat and lean body mass have important implications for health and physical functioning in older age, and physical activity is purported to be an important modifiable determinant. However, our evidence-based understanding of its role is limited. We examined the associations of physical activity, assessed both by self-report (using data on leisure time physical activity (LTPA) collected on 4 occasions over a 28-year period) and objectively (using 5-day heart rate and movement monitoring), with fat and lean mass at ages 60–64 years in 1,162 British participants from the Medical Research Council National Survey of Health and Development in 1946–2010. Higher objectively assessed physical activity energy expenditure (PAEE) at ages 60–64 years was associated with lower fat mass and android (abdominal):gynoid (hip) fat ratio (mean differences in fat mass per 1–standard deviation increase in PAEE were −0.79 kg/m1.2 in men (95% confidence interval: −1.08, −0.50) and −1.79 kg/m1.2 (95% confidence interval: −2.15, −1.42) in women). After adjustment for fat mass, higher PAEE was associated with higher appendicular lean mass. Both light and moderate-to-vigorous intensities of activity were associated with fat mass, and the latter was associated with lean mass. More frequent LTPA across adulthood was associated with lower fat mass (in women only) and higher appendicular lean mass (in both sexes, after adjustment for fat mass). These results support the promotion of LTPA across adulthood, as well as both light and moderate-to-vigorous intensities of activity among older adults.

The Effects of Exercise for the Prevention of Overuse Anterior Knee Pain A Randomized Controlled Trial

Background: Anterior knee pain (AKP) is the most common activity-related injury of the knee. The authors investigated the effect of an exercise intervention on the incidence of AKP in UK army recruits undergoing a 14-week physically arduous training program. Hypothesis: Modifying military training to include targeted preventative exercises may reduce the incidence of AKP in a young recruit population. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: A single-blind cluster randomized controlled trial was performed in 39 male and 11 female training groups (median age: 19.7 years; interquartile range, 17-25) undergoing phase 1 of army recruit training. Each group was randomly assigned to either an intervention (n = 759) or control (n = 743) protocol. The intervention consisted of 4 strengthening and 4 stretching exercises completed during supervised physical training lessons (7 per week). The control group followed the existing training syllabus warm-up exercises. The primary outcome was a diagnosis of AKP during the 14-week training program. Results: Forty-six participants (3.1%; 95% confidence interval [CI], 2.3-4.1) were diagnosed with AKP. There were 36 (4.8%; 95%CI, 3.5-6.7) new cases of AKP in the control group and 10 (1.3%; 0.7-2.4) in the intervention group. There was a 75% reduction in AKP risk in the intervention group (unadjusted hazard ratio = 0.25; 95% CI, 0.13-0.52; P < .001). Three participants (0.4%) from the intervention group were discharged from the military for medical reasons compared to 25 (3.4%) in the control group. Conclusion: A simple set of lower limb stretching and strengthening exercises resulted in a substantial and safe reduction in the incidence of AKP in a young military population undertaking a physical conditioning program. Such exercises could also be beneficial for preventing this common injury among nonmilitary participants in recreational physical activity.

Effect of physiological doses of oral vitamin B12 on plasma homocysteine – A randomized, placebo-controlled, double-blind trial in India

Background/Objectives:Vitamin B12 (B12) deficiency is common in Indians and a major contributor to hyperhomocysteinemia, which may influence fetal growth, risk of type II diabetes and cardiovascular disease. The purpose of this paper was to study the effect of physiological doses of B12 and folic acid on plasma total homocysteine (tHcy) concentration.Subjects/Methods:A cluster randomized, placebo-controlled, double-blind, 2 × 3 factorial trial, using the family as the randomization unit. B12 was given as 2 or 10 μg capsules, with or without 200 μg folic acid, forming six groups (B0F0, B2F0, B10F0, B0F200, B2F200 and B10F200). Plasma tHcy concentration was measured before and after 4 and 12 months of supplementation.Results:From 119 families in the Pune Maternal Nutrition Study, 300 individuals were randomized. There was no interaction between B12 and folic acid (P=0.14) in relation to tHcy concentration change and their effects were analyzed separately: B0 vs. B2 vs. B10; and F0 vs. F200. At 12 months, tHcy concentration reduced by a mean 5.9 (95% CI: −7.8, −4.1) μmol/l in B2, and by 7.1 (95% CI: −8.9, −5.4) μmol/l in B10, compared to nonsignificant rise of 1.2 (95% CI: −0.5, 2.9) μmol/l in B0. B2 and B10 did not differ significantly. In F200, tHcy concentration decreased by 4.8 (95% CI: −6.3, −3.3) μmol/l compared to 2.8 (95% CI: −4.3, −1.2) μmol/l in F0.Conclusion:Daily oral supplementation with physiological doses of B12 is an effective community intervention to reduce tHcy. Folic acid (200 μg per day) showed no additional benefit, neither had any unfavorable effects.