To determine the relationship between maternal vitamin D status in pregnancy and body composition in the offspring.
Prospective mother-offspring cohort study.
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.
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.
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.
Background and objectives
Chronic widespread pain (CWP) is a common disorder affecting ∼10% of the general population and has an estimated heritability of 48–52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP.
We conducted a GWAS meta-analysis in 1308 female CWP cases and 5791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1480 CWP cases and 7989 controls. Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain.
The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of chaperonin-containing-TCP1-complex-5 gene (CCT5) and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (minor allele frequency=43%; OR=1.30, 95% CI 1.19 to 1.42, p=1.2×10−8). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.7×10−7) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95% CI 1.14 to 1.32, p=3.4×10−8, I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (p>7.7×10−4).
We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain.
Gene Polymorphism; Fibromyalgis/Pain Syndromes; Epidemiology
1) To assess change in confidence in having conversations that support parents with healthy eating and physical activity post-training. 2) To assess change in staff competence in using ‘open discovery’ questions (those generally beginning with “how” and “what” that help individuals reflect and identify barriers and solutions) post-training. 3) To examine the relationship between confidence and competence post-training.
A pre-post evaluation of ‘Healthy Conversation Skills’, a staff training intervention.
Sure Start Children’s Centres in Southampton, England.
A total of 145 staff working in Sure Start Children’s Centres completed the training, including playworkers (45%) and community development or family support workers (31%).
We observed an increase in median confidence rating for having conversations about healthy eating and physical activity (both p<0.001), and in using ‘open discovery’ questions (p<0.001) after staff attended the ‘Healthy Conversation Skills’ training. We also found a positive relationship between use of ‘open discovery’ questions and confidence in having conversations about healthy eating post-training (r=0.21, p=0.01), but a non-significant trend was observed for having conversations about physical activity (r=0.15, p=0.06).
The ‘Healthy Conversation Skills’ training has proved effective at increasing the confidence of staff working at Sure Start Children’s Centres to have more productive conversations with parents about healthy eating. Wider implementation of these skills may be a useful public health nutrition capacity building strategy to help community workers support families with young children to eat more healthy foods.
Natural experimental studies are often recommended as a way of understanding the health impact of policies and other large scale interventions. Although they have certain advantages over planned experiments, and may be the only option when it is impossible to manipulate exposure to the intervention, natural experimental studies are more susceptible to bias. This paper introduces new guidance from the Medical Research Council to help researchers and users, funders and publishers of research evidence make the best use of natural experimental approaches to evaluating population health interventions. The guidance emphasises that natural experiments can provide convincing evidence of impact even when effects are small or take time to appear. However, a good understanding is needed of the process determining exposure to the intervention, and careful choice and combination of methods, testing of assumptions and transparent reporting is vital. More could be learnt from natural experiments in future as experience of promising but lesser used methods accumulates.
Chronic widespread pain (CWP) is a common disorder affecting ~10% of the general population and has an estimated heritability of 48-52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP.
We conducted a GWAS meta-analysis in 1,308 female CWP cases and 5,791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1,480 CWP cases and 7,989 controls (P<1×10−5). Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain.
The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of CCT5 and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (MAF=43%; OR=1.30, 95%CI=1.19-1.42, P=1.2×10−8). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95%CI=1.10-1.24, P=4.7×10−7) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95%CI=1.14-1.32, P=3.4×10−8, I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (P>7.7×10−4).
We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain.
Gene Polymorphism; Fibromyalgia/Pain Syndromes; Epidemiology
Use of psychotropic drugs has been linked with an increased risk of fracture in older people, but there are indications that the conditions for which these drugs were prescribed may themselves influence fracture risk.
To investigate the relation between symptoms of anxiety and depression and risk of fracture in older people.
Prospective cohort study.
1087 men and 1050 women aged 59-73 years completed the Hospital Anxiety and Depression Scale (HADS). Data on incident fracture during an average follow-up period of 5.6 years was collected through interview and a postal questionnaire.
Compared to men with no or few symptoms of anxiety (score ≤7 on the HADS anxiety subscale), men with probable anxiety (score ≥11) had an increased risk of fracture: after adjustment for age and potential confounding factors, the odds ratio (OR) (95% confidence interval) was 4.03 (1.55, 10.5). Men with possible anxiety (score 8-10) did not have an increased risk of fracture: multivariate-adjusted OR was 1.04 (0.36, 3.03). There were no associations between levels of anxiety and fracture risk in women. Few men or women had probable depression at baseline (score ≥11 on the HADS depression subscale). Among men with possible depression (score 8-10) there was an increased risk of fracture that was of borderline significance: multivariate-adjusted OR 3.57 (0.99, 12.9). There was no association between possible depression and fracture risk in women.
High levels of anxiety in older men may increase their risk of fracture. Future research needs to replicate this finding in other populations and investigate the underlying mechanisms.
anxiety; depression; fracture
Osteoporotic fracture is associated with considerable morbidity and mortality in women throughout the world. However, significant variation in hip fracture rates among women from different nations have been observed, and are likely to represent a combination of real and apparent differences due to ascertainment bias. Higher rates are observed in Caucasian women, with lowest rates observed in black women and intermediate rates among Asian women. These differences are likely to represent a combination of genetic and environmental differences; for example, among European women, the highest fracture rates are observed in Scandinavian women where vitamin D insufficiency is common. In all groups, an expansion in absolute fracture numbers is anticipated due to demographic changes.
Osteoporosis; Fracture; Geographic; Variation; Women; Epidemiology
To study the effects of age and dose of selective serotonin reuptake inhibitors (SSRI), trycyclic antidepressants (TCA) and anxiolytics/sedatives on fracture risk.
Subjects and methods
Case control study. From the Danish National Health Service, we identified 124,655 fracture cases and 373,962 age- and gender-matched controls. Crude odds ratios (OR) were estimated, and propensity score adjustment was used to minimize confounding by indication.
A higher risk of fractures was associated with an increasing dose of anxiolytics and sedatives; the highest excess risk was present in the age stratum below 40 years of age (p<0.01), and thereafter the excess risk of fractures declined with age. For SSRI, a growing excess risk of fractures was seen with both increasing dose and age. Regarding TCA, no particular trend with age was present. However, an increasing risk of fractures was associated with increasing TCA dose in the age group above 60 years. Finally, for other antidepressants no particular trend with age or dose was observed. In our data, a hospital diagnosis of depression or manic-depression was associated with fewer fractures.
Caution should be shown upon prescription of SSRI to older subjects. A hospital diagnosis of depression or manic-depression and thus potentially more severe disease was not a risk factor for fractures.
Selective serotonin reuptake inhibitors; tricyclic antidepressants; antidepressant; fracture
Meta-analysis of case-control genome wide association studies (GWAS) for early onset and morbid obesity identified four variants in/near the PRL, PTER, MAF and NPC1 genes.
We aimed to validate association of these variants with obesity-related traits in population-based samples.
Genotypes and anthropometric traits were available in up to 31 083 adults from the Fenland, EPIC-Norfolk, Whitehall II, Ely and Hertfordshire studies and in 2 042 children and adolescents from the European Youth Heart Study. In each study, we tested associations of rs4712652 (near-PRL), rs10508503 (near-PTER), rs1424233 (near-MAF) and rs1805081 (NPC1), or proxy variants (r2>0.8), with the odds of being overweight and obese, as well as with BMI, percentage body fat (%BF) and waist circumference (WC). Associations were adjusted for sex, age and age2 in adults and for sex, age, age-group, country and maturity in children and adolescents. Summary statistics were combined using fixed effects meta-analysis methods.
We had 80% power to detect ORs of 1.046 to 1.092 for overweight and 1.067 to 1.136 for obesity. Variants near PRL, PTER and MAF were not associated with the odds of being overweight or obese, or with BMI, %BF or WC after meta-analysis (P > 0.15). The NPC1 variant rs1805081 showed some evidence of association with %BF (beta=0.013 SD/allele, P =0.040), but not with any of the remaining obesity-related traits (P >0.3).
Overall, these variants, which were identified in a GWAS for early onset and morbid obesity, do not seem to influence obesity-related traits in the general population.
Obesity-susceptibility loci; genome-wide association; morbid; early-onset; anthropometric traits; children and adolescents; population-based
Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood1. Previous genome-wide association studies identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes, and a second variant, near CCNL1, with no obvious link to adult traits2. In an expanded genome-wide association meta-analysis and follow-up study (up to 69,308 individuals of European descent from 43 studies), we have now extended the number of genome-wide significant loci to seven, accounting for a similar proportion of variance to maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes; ADRB1 with adult blood pressure; and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
Studies exploring the relationship between prenatal vitamin D exposure and childhood asthma have yielded conflicting results. Higher vitamin D intake during pregnancy has been shown to lower the risk of childhood wheeze, yet a study of maternal late-pregnancy serum 25-hydroxyvitamin D suggested higher serum concentrations may be associated with increased childhood asthma.
To assess the relationship between mothers’ serum 25-hydroxyvitamin D status and asthma and wheeze phenotypes in their children at age 6 years. Secondly, to explore the relationship between maternal 25-hydroxyvitamin D status and objective measures of childhood atopy and lung function.
Serum 25-hydroxyvitamin D was measured at 34 weeks’ gestation in the mothers of 860 children born at term. Wheeze was classified as either transient or persistent/late using questionnaire data collated from 6, 12, 24 and 36 months and 6 years. At 6 years spirometry was performed and atopic status was determined by skin prick testing, exhaled nitric oxide was measured in 451 and bronchial hyperresponsiveness in 216 children.
There were no significant associations between maternal late-pregnancy 25-hydroxyvitamin D status and either asthma or wheeze at age 6 years. Maternal vitamin D status was not associated with transient or persistent/late wheeze; no significant association was found between persistent/late wheeze when subdivided according to atopic status. No associations were found with skin sensitisation or lung function.
This study provides no evidence that exposure to higher concentrations of 25-hydroxyvitamin D in maternal serum during late pregnancy increases the risk of childhood asthma, wheeze or atopy.
asthma epidemiology; asthma; paediatric asthma
Effective communication is necessary for good relationships between healthcare practitioners and clients. This study examined barriers and facilitators to implementing new communication skills.
One hundred and one Sure Start Children’s Centre staff attended one of 13 follow-up workshops to reflect on the use of new skills following a training course in communication, reflection and problem-solving. Barriers and facilitators were assessed with an adapted Problematic Experiences of Therapy scale (PETS). Staff reported frequency of skill use, and described what made it more difficult or easier to use the skills.
The PETS indicated that staff had confidence in using the skills, but felt there were practical barriers to using them, such as lack of time. Skills were used less often when staff perceived parents not to be engaging with them (rs=−0.42, p<.001), when staff felt less confident to use the skills (rs =−0.37, p<.001), and when there were more practical barriers (rs =−0.37, p<.001). In support of findings from the PETS, content analysis of free text responses suggested that the main barrier was a perceived lack of time to implement new skills. Facilitators included seeing the benefits of using the skills, finding opportunities and having good relationships with parents.
Understanding the range of barriers and facilitators to implementation is essential when developing training to facilitate on-going support and sustain skill use. Special attention should be given to exploring trainees’ perceptions of time, in order to be able to address this significant barrier to skill implementation. Staff training requires a multifaceted approach to address the range of perceived barriers.
barriers; communication; epidemiology; Sure Start; training
Gene–lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-g glucose challenge are used to diagnose diabetes and are associated with both genetic and lifestyle factors. However, whether these factors interact to determine 2-h glucose levels is unknown. We meta-analyzed single nucleotide polymorphism (SNP) × BMI and SNP × physical activity (PA) interaction regression models for five SNPs previously associated with 2-h glucose levels from up to 22 studies comprising 54,884 individuals without diabetes. PA levels were dichotomized, with individuals below the first quintile classified as inactive (20%) and the remainder as active (80%). BMI was considered a continuous trait. Inactive individuals had higher 2-h glucose levels than active individuals (β = 0.22 mmol/L [95% CI 0.13–0.31], P = 1.63 × 10−6). All SNPs were associated with 2-h glucose (β = 0.06–0.12 mmol/allele, P ≤ 1.53 × 10−7), but no significant interactions were found with PA (P > 0.18) or BMI (P ≥ 0.04). In this large study of gene–lifestyle interaction, we observed no interactions between genetic and lifestyle factors, both of which were associated with 2-h glucose. It is perhaps unlikely that top loci from genome-wide association studies will exhibit strong subgroup-specific effects, and may not, therefore, make the best candidates for the study of interactions.
A number of studies suggest that breastfeeding has beneficial effects on adult cardiovascular risk factors in adulthood, although the mechanisms involved are unknown. One possible explanation is that adults who were breastfed differ in their health behaviours. In a historical cohort, adult health behaviours were examined in relation to type of milk feeding in infancy. From 1931-1939, records were kept on all infants born in Hertfordshire, UK. Their type of milk feeding was summarised as breastfed only, breast & bottle-fed, or bottle-fed only. Information about adult health behaviours was collected from 3217 of these men and women when they were aged 59-73 years. Diet was assessed by administered food frequency questionnaire; the key dietary pattern was a ‘prudent’ pattern, that described compliance with ‘healthy’ eating recommendations. 60% of the men and women were breastfed, 31% were breast & bottle-fed, 9% were bottle-fed. Type of milk feeding did not differ according to social class at birth, and was not related to social class attained in adult life. There were no differences in smoking status, alcohol intake or reported physical activity according to type of milk feeding, but there were differences in the participants’ dietary patterns. In a multivariate model that included gender and infant weight gain, there were independent associations between type of feeding and prudent diet scores in adult life (P=0.009), such that higher scores were associated with being breast fed. These data support experimental findings that suggest that early dietary exposures can have lifelong influences on food choice.
Breastfeeding; food choice; dietary patterns; health behaviours
Strontium ranelate is currently used for osteoporosis. The international, double-blind, randomised, placebo-controlled Strontium ranelate Efficacy in Knee OsteoarthrItis triAl evaluated its effect on radiological progression of knee osteoarthritis.
Patients with knee osteoarthritis (Kellgren and Lawrence grade 2 or 3, and joint space width (JSW) 2.5–5 mm) were randomly allocated to strontium ranelate 1 g/day (n=558), 2 g/day (n=566) or placebo (n=559). The primary endpoint was radiographical change in JSW (medial tibiofemoral compartment) over 3 years versus placebo. Secondary endpoints included radiological progression, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and knee pain. The trial is registered (ISRCTN41323372).
The intention-to-treat population included 1371 patients. Treatment with strontium ranelate was associated with smaller degradations in JSW than placebo (1 g/day: −0.23 (SD 0.56) mm; 2 g/day: −0.27 (SD 0.63) mm; placebo: −0.37 (SD 0.59) mm); treatment-placebo differences were 0.14 (SE 0.04), 95% CI 0.05 to 0.23, p<0.001 for 1 g/day and 0.10 (SE 0.04), 95% CI 0.02 to 0.19, p=0.018 for 2 g/day. Fewer radiological progressors were observed with strontium ranelate (p<0.001 and p=0.012 for 1 and 2 g/day). There were greater reductions in total WOMAC score (p=0.045), pain subscore (p=0.028), physical function subscore (p=0.099) and knee pain (p=0.065) with strontium ranelate 2 g/day. Strontium ranelate was well tolerated.
Treatment with strontium ranelate 1 and 2 g/day is associated with a significant effect on structure in patients with knee osteoarthritis, and a beneficial effect on symptoms for strontium ranelate 2 g/day.
Knee Osteoarthritis; Osteoarthritis; Outcomes research
To derive a simple score for estimating the long-term risk of osteoporotic and hip fracture in individual patients with MS.
Using the UK General Practice Research Database linked to the National Hospital Registry (1997–2008), we identified patients with incident MS (n = 5,494). They were matched 1:6 by year of birth, sex, and practice with patients without MS (control subjects). Cox proportional hazards models were used to calculate the long-term risk of osteoporotic and hip fracture. We fitted the regression model with general and specific risk factors, and the final Cox model was converted into integer risk scores.
In comparison with the FRAX calculator, our risk score contains several new risk factors that have been linked with fracture, which include MS, use of antidepressants, use of anticonvulsants, history of falling, and history of fatigue. We estimated the 5- and 10-year risks of osteoporotic and hip fracture in relation to the risk score. The C-statistic was moderate (0.67) for the prediction of osteoporotic fracture and excellent (0.89) for the prediction of hip fracture.
This is the first clinical risk score for fracture risk estimation involving MS as a risk factor.
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.
B-vitamin intake; folate status; postpartum depression
Bone mineral density (BMD) is the most important predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and East Asian ancestry. We tested the top-associated BMD markers for replication in 50,933 independent subjects and for risk of low-trauma fracture in 31,016 cases and 102,444 controls. We identified 56 loci (32 novel)associated with BMD atgenome-wide significant level (P<5×10−8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal-stem-cell differentiation, endochondral ossification and the Wnt signalling pathways. However, we also discovered loci containing genes not known to play a role in bone biology. Fourteen BMD loci were also associated with fracture risk (P<5×10−4, Bonferroni corrected), of which six reached P<5×10−8 including: 18p11.21 (C18orf19), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
Experts disagree about the optimal classification of upper limb disorders (ULDs). To explore whether differential response to treatments offers a basis for choosing between case definitions, we analysed previously published research.
We screened 183 randomised controlled trials (RCTs) of treatments for ULDs, identified from the bibliographies of 10 Cochrane reviews, four other systematic reviews, and a search in Medline, Embase, and Google Scholar to June 2010. From these, we selected RCTs which allowed estimates of benefit (expressed as relative risks (RRs)) for >1 case definition to be compared when other variables (treatment, comparison group, follow-up time, outcome measure) were effectively held constant. Comparisons of RRs for paired case definitions were summarised by their ratios, with the RR for the simpler and broader definition as the denominator.
Two RCT reports allowed within-trial comparison of RRs and thirteen others allowed between-trial comparisons. Together these provided 17 ratios of RRs (five for shoulder treatments, 12 for elbow treatments, none for wrist/hand treatments). The median ratio of RRs was 1.0 (range 0.3 to 1.7; interquartile range 0.6 to 1.3).
Although the evidence base is limited, our findings suggest that for musculoskeletal disorders of the shoulder and elbow, clinicians in primary care will often do best to apply simpler and broader case definitions. Researchers should routinely publish secondary analyses for subgroups of patients by different diagnostic features at trial entry, to expand the evidence base on optimal case definitions for patient management.
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.
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.
The use of thiazolidinediones (TZDs) has been associated with an increased fracture risk. In addition, type 2 diabetes mellitus (T2DM) has been linked with fracture. We evaluated to what extent the association between TZD use and fracture risk is related to the drug or to the underlying disease. We conducted a population-based cohort study using the Danish National Health Registers (1996–2007), which link pharmacy data to the national hospital registry. Oral antidiabetic users (n = 180,049) were matched 1:3 by year of birth and sex to nonusers. Cox proportional hazards models were used to estimate hazard ratios (HRs) of fracture. Time-dependent adjustments were made for age, comorbidity, and drug use. We created a proxy indicator for the severity of disease. The first stage was defined as current use of either a biguanide or a sulfonyluerum, the second stage as current use of a biguanide and a sulfonyluerum at the same time, the third stage as patients using TZDs, and the fourth stage as patients using insulin. The risk of osteoporotic fracture was increased 1.3-fold for stages 3 and 4 compared with controls. Risk with current TZD use (stage 3 HR = 1.27, 95 % CI 1.06–1.52) and risk with current use of insulin (stage 4 HR = 1.25, 95 % CI 1.20–1.31) were similar. In the first (HR = 1.15, 95 % CI 1.13–1.18) and second (HR = 1.00, 95 % CI 0.96–1.04) stages risks were lower. Risk of osteoporotic fracture was similar for TZD users and insulin users. When studying fracture risk with TZDs, the underlying T2DM should be taken into account.
Thiazolidinedione; Type 2 diabetes mellitus; Fracture risk; Osteoporosis
Prevention of age-related losses in muscle mass and strength is key to protecting physical capability in older age and enabling independent living. To develop preventive strategies, a better understanding is needed of the lifestyle factors that influence sarcopenia and the mechanisms involved. Existing evidence indicates the potential importance of diets of adequate quality, to ensure sufficient intakes of protein, vitamin D, and antioxidant nutrients. Although much of this evidence is observational, the prevalence of low nutrient intakes and poor status among older adults make this a current concern. However, as muscle mass and strength in later life are a reflection of both the rate of muscle loss and the peak attained in early life, efforts to prevent sarcopenia also need to consider diet across the lifecourse and the potential effectiveness of early interventions. Optimising diet and nutrition throughout life may be key to preventing sarcopenia and promoting physical capability in older age.
MAVIDOS is a randomised, double-blind, placebo-controlled trial (ISRCTN82927713, registered 2008 Apr 11), funded by Arthritis Research UK, MRC, Bupa Foundation and NIHR.
Osteoporosis is a major public health problem as a result of associated fragility fractures. Skeletal strength increases from birth to a peak in early adulthood. This peak predicts osteoporosis risk in later life. Vitamin D insufficiency in pregnancy is common (31% in a recent Southampton cohort) and predicts reduced bone mass in the offspring. In this study we aim to test whether offspring of mothers supplemented with vitamin D in pregnancy have higher bone mass at birth than those whose mothers were not supplemented.
Women have their vitamin D status assessed after ultrasound scanning in the twelfth week of pregnancy at 3 trial centres (Southampton, Sheffield, Oxford). Women with circulating 25(OH)-vitamin D levels 25-100 nmol/l are randomised in a double-blind design to either oral vitamin D supplement (1000 IU cholecalciferol/day, n = 477) or placebo at 14 weeks (n = 477). Questionnaire data include parity, sunlight exposure, dietary information, and cigarette and alcohol consumption. At 19 and 34 weeks maternal anthropometry is assessed and blood samples taken to measure 25(OH)-vitamin D, PTH and biochemistry. At delivery venous umbilical cord blood is collected, together with umbilical cord and placental tissue. The babies undergo DXA assessment of bone mass within the first 14 days after birth, with the primary outcome being whole body bone mineral content adjusted for gestational age and age. Children are then followed up with yearly assessment of health, diet, physical activity and anthropometric measures, with repeat assessment of bone mass by DXA at age 4 years.
As far as we are aware, this randomised trial is one of the first ever tests of the early life origins hypothesis in human participants and has the potential to inform public health policy regarding vitamin D supplementation in pregnancy. It will also provide a valuable resource in which to study the influence of maternal vitamin D status on other childhood outcomes such as glucose tolerance, blood pressure, cardiovascular function, IQ and immunology.
Vitamin D; cholecalciferol; supplementation; trial; osteoporosis; DXA; pregnancy; neonate