Catharine R. Gale

Maternal vitamin D status during pregnancy and childhood bone mass at age 9 years: a longitudinal study.

BACKGROUND Vitamin D insufficiency is common in women of childbearing age and increasing evidence suggests that the risk of osteoporotic fracture in adulthood could be determined partly by environmental factors during intrauterine and early postnatal life. We investigated the effect of maternal vitamin D status during pregnancy on childhood skeletal growth. METHODS In a longitudinal study, we studied 198 children born in 1991-92 in a hospital in Southampton, UK; the body build, nutrition, and vitamin D status of their mothers had been characterised during pregnancy. The children were followed up at age 9 years to relate these maternal characteristics to their body size and bone mass. FINDINGS 49 (31%) mothers had insufficient and 28 (18%) had deficient circulating concentrations of 25(OH)-vitamin D during late pregnancy. Reduced concentration of 25(OH)-vitamin D in mothers during late pregnancy was associated with reduced whole-body (r=0.21, p=0.0088) and lumbar-spine (r=0.17, p=0.03) bone-mineral content in children at age 9 years. Both the estimated exposure to ultraviolet B radiation during late pregnancy and the maternal use of vitamin D supplements predicted maternal 25(OH)-vitamin D concentration (p<0.0001 and p=0.0110, respectively) and childhood bone mass (p=0.0267). Reduced concentration of umbilical-venous calcium also predicted reduced childhood bone mass (p=0.0286). INTERPRETATION Maternal vitamin D insufficiency is common during pregnancy and is associated with reduced bone-mineral accrual in the offspring during childhood; this association is mediated partly through the concentration of umbilical venous calcium. Vitamin D supplementation of pregnant women, especially during winter months, could lead to longlasting reductions in the risk of osteoporotic fracture in their offspring.

Epigenetic Gene Promoter Methylation at Birth Is Associated With Child’s Later Adiposity

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.

Maternal vitamin D status during pregnancy and child outcomes.

Objective:To investigate whether exposure to high maternal concentrations of 25(OH)-vitamin D in pregnancy poses any risk to the child.Design:Prospective study.Setting:Princess Anne Maternity Hospital, Southampton, UK.Subjects:A group of 596 pregnant women were recruited. A total of 466 (78%) children were examined at birth, 440 (74%) at age 9 months and 178 (30%) at age 9 years.Methods:Maternal 25 (OH)-vitamin D concentrations were measured in late pregnancy. Anthropometry of the child was recorded at birth, 9 months and 9 years. At 9 months, atopic eczema was assessed. At 9 years, children had an echocardiogram and a dual energy x-ray absorptiometry scan, blood pressure, arterial compliance and carotid intima-media thickness were measured and intelligence and psychological function assessed.Results:There were no associations between maternal 25(OH)-vitamin D concentrations and the childs body size or measures of the childs intelligence, psychological health or cardiovascular system. Children whose mothers had a 25(OH)-vitamin D concentration in pregnancy >75 nmol/l had an increased risk of eczema on examination at 9 months (OR 3.26, 95% CI 1.15–9.29, P=0.025) and asthma at age 9 years (OR 5.40, 95% CI, 1.09–26.65, P=0.038) compared to children whose mothers had a concentration of <30 nmol/l.Conclusion:Exposure to maternal concentrations of 25(OH)-vitamin D in pregnancy in excess of 75 nmol/l does not appear to influence the childs intelligence, psychological health or cardiovascular system; there could be an increased risk of atopic disorders, but this needs confirmation in other studies.Sponsorship:The study was supported by the Medical Research Council and WellChild (previously known as Children Nationwide).

Prevention of age related macular degeneration

Papers p 11 Age related macular degeneration may be recognised in its early stages by the appearance of drusen and pigment change within the retina, but it produces few symptoms. Progression of age related macular degeneration can result in irreversible visual loss and is the commonest cause of blindness in the Western world. New treatments such as photodynamic therapy and macular surgery may limit the extent of visual loss and in a few cases even restore sight.1 But in contrast with cataract surgery, outcomes are unpredictable and the treatment is burdensome for patients and carries massive resource implications for healthcare providers. The prospect of prevention is thus very appealing from the public health perspective, not to mention that of the patient who may be at risk of losing the ability to recognise faces, read a newspaper, or to live independently. Increasing evidence suggests that cumulative oxidative damage increases risk of age related macular degeneration.2 But evidence from trials and reviews suggests that the antioxidant vitamin E, used alone, does not seem to have a protective effect against age related macular degeneration. …

Vitamin C and risk of death from stroke and coronary heart disease in cohort of elderly people

Abstract Objectives: To determine whether vitamin C status, as measured by dietary intake and plasma ascorbic acid concentration, is related to mortality from stroke and coronary heart disease in people aged 65 and over. Design: A 20 year follow up study of a cohort of randomly selected elderly people living in the community who had taken part in the 1973-4 Department of Health and Social Security nutritional survey and for whom dietary and other data had been recorded. Setting: Eight areas in Britain (five in England, two in Scotland, and one in Wales). Subjects: 730 men and women who had completed a seven day dietary record and who had no history or symptoms of stroke, cerebral arteriosclerosis, or coronary heart disease when examined by a geriatrician in 1973-4. Results: Mortality from stroke was highest in those with the lowest vitamin C status. Those in the highest third of the distribution of vitamin C intake had a relative risk of 0.5 (95% confidence interval 0.3 to 0.8) compared with those in the lowest third, after adjustment for age, sex, and established cardiovascular risk factors. The relation between vitamin C intake and stroke was independent of social class and other dietary variables. A similar gradient in risk was present for plasma ascorbic acid concentrations. No association was found between vitamin C status and risk of death from coronary heart disease. Conclusion: In elderly people vitamin C concentration, whether measured by dietary intake or plasma concentration of ascorbic acid, is strongly related to subsequent risk of death from stroke but not from coronary heart disease. Key messages Key messages Vitamin C is the most important dietary antioxidant in terms of intake Both dietary intake of vitamin C and plasma ascorbate concentrations were related to risk of death from stroke (but not from coronary heart disease) in 730 elderly people studied prospectively Vitamin C status was as strong a predictor of death from stroke as diastolic blood pressure Antioxidant vitamins are potentially important in the prevention of cerebrovascular disease

Objective measures of physical capability and subsequent health: a systematic review

Background: measures of physical capability may be predictive of subsequent health, but existing published studies have not been systematically reviewed. We hypothesised that weaker grip strength, slower walking speed and chair rising and shorter standing balance time, in community-dwelling populations, would be associated with higher subsequent risk of fracture, cognitive outcomes, cardiovascular disease, hospitalisation and institutionalisation. Methods: studies were identified through systematic searches of the electronic databases MEDLINE and EMBASE (to May 2009). Reference lists of eligible papers were also manually searched. Results: twenty-four papers had examined the associations between at least one physical capability measure and one of the outcomes. As the physical capability measures and outcomes had been assessed and categorised in different ways in different studies, and there were differences in the potential confounding factors taken into account, this made it impossible to pool results. There were more studies examining fractures than other outcomes, and grip strength and walking speed were the most commonly examined capability measures. Most studies found that weaker grip strength and slower walking speed were associated with increased risk of future fractures and cognitive decline, but residual confounding may explain results in some studies. Associations between physical capability levels and the other specified outcomes have not been tested widely. Conclusions: there is some evidence to suggest that objective measures of physical capability may be predictors of subsequent health in older community-dwelling populations. Most hypothesised associations have not been studied sufficiently to draw definitive conclusions suggesting the need for further research.

Cognitive impairment and mortality in a cohort of elderly people

Abstract Objectives: To investigate the relation between cognitive function and cause specific mortality in people aged 65 and over. Design: A 20 year follow up study of a cohort of randomly selected elderly people living in the community who in 1973-4 had taken part in a nutritional survey funded by the Department of Health and Social Security. Setting: Eight areas in Britain (five in England, two in Scotland, and one in Wales). Subjects: 921 men and women whose cognitive function was assessed by a geriatrician in 1973-4 and for whom data on health, socioeconomic circumstances, and diet had been recorded. Results: Cognitive impairment was associated with increased mortality, in particular death from ischaemic stroke. Those who scored 7 or less on the Hodkinson mental test had a relative risk of dying from stroke of 2.8 (95% confidence interval 1.4 to 5.5), compared with those who gained the maximum score (10), after adjustment for age, sex, blood pressure, serum cholesterol concentration, and vitamin C intake. These associations were independent of illness or social class. At the time of the nutritional survey, cognitive function was poorest in those with the lowest vitamin C status, whether measured by dietary intake or plasma ascorbic acid concentration. The relation between vitamin C status and cognitive function was independent of age, illness, social class, or other dietary variables. Conclusion: The relation between cognitive function and risk of death from stroke suggests that cerebrovascular disease is an important cause of declining cognitive function. Vitamin C status may be a determinant of cognitive function in elderly people through its effect on atherogenesis. A high vitamin C intake may protect against both cognitive impairment and cerebrovascular disease. Key messages Key messages In this prospective study of 921 elderly people cognitive impairment was a strong predictor of death from ischaemic stroke Low vitamin C intake and low plasma ascorbate concentrations were also important risk factors for death from stroke Cognitive performance was poorest in people with the lowest vitamin C status A high vitamin C intake may protect against both cognitive impairment and cerebrovascular disease

Migrant studies in multiple sclerosis

To re-evaluate how migrant studies contribute to our understanding of the epidemiology and aetiology of multiple sclerosis, we undertook a systematic review of all relevant studies published in English language journals, comparing rates of multiple sclerosis in migrant populations with those in the host country and in the country of origin. Interpretation of migrant studies is difficult. Migrants are seldom representative of the country of origin, tending to be younger, healthier and of higher socioeconomic status. Data quality may be poor, and lack of age-standardisation can mislead when rates are compared. Nevertheless, two consistent patterns can be discerned in these studies of the effect of migration on risk of multiple sclerosis. Migrants who move from an area where the disease is common to an area where it is rarer show a decrease in rate of disease. By contrast, people who migrate in the opposite direction tend to retain the low risk of their country of origin. Results from the few studies which have examined the effect of age at migration on risk of multiple sclerosis suggest that an individuals risk of the disease is largely established during the first two decades of life. Risk of multiple sclerosis can change rapidly between generations: although migrants from low risk countries to high risk countries retain their low risk, their children have a risk of multiple sclerosis that approaches that of the host country. Migrant studies add little to our understanding of the genetics of multiple sclerosis but they emphasise the importance of environmental factors. We discuss several possible interpretations of the patterns seen in migrant studies, including the hypothesis that multiple sclerosis is a sequel to delayed exposure to a common infectious agent. One candidate for such an infectious agent is Epstein-Barr virus.

Influence of individual and combined health behaviors on total and cause-specific mortality in men and women: The United Kingdom Health and Lifestyle Survey

BACKGROUND Physical activity, diet, smoking, and alcohol consumption have been shown to be related to mortality. We examined prospectively the individual and combined influence of these risk factors on total and cause-specific mortality. METHODS The prospective cohort study included 4886 individuals at least 18 years old from a United Kingdom-wide population in 1984 to 1985. A health behavior score was calculated, allocating 1 point for each poor behavior: smoking; fruits and vegetables consumed less than 3 times daily; less than 2 hours physical activity per week; and weekly consumption of more than 14 units of alcohol (in women) and more than 21 units (in men) (range of points, 0-4). We examined the relationship between health behaviors and mortality using Cox models and compared it with the mortality risk associated with aging. RESULTS During a mean follow-up period of 20 years, 1080 participants died, 431 from cardiovascular diseases, 318 from cancer, and 331 from other causes. Adjusted hazard ratios and 95% confidence intervals (CIs) for total mortality associated with 1, 2, 3, and 4 poor health behaviors compared with those with none were 1.85 (95% CI, 1.28-2.68), 2.23 (95% CI, 1.55-3.20), 2.76 (95% CI, 1.91-3.99), and 3.49 (95% CI, 2.31-5.26), respectively (P value for trend, <.001). The effect of combined health behaviors was strongest for other deaths and weakest for cancer mortality. Those with 4 compared with those with no poor health behaviors had an all-cause mortality risk equivalent to being 12 years older. CONCLUSION The combined effect of poor health behaviors on mortality was substantial, indicating that modest, but sustained, improvements to diet and lifestyle could have significant public health benefits.

The influence of head growth in fetal life, infancy, and childhood on intelligence at the ages of 4 and 8 years

OBJECTIVE. We investigated the effects of head growth prenatally, during infancy, and during later periods of development on cognitive function at the ages of 4 and 8 years. METHODS. We studied 633 term-born children from the Avon Longitudinal Study of Parents and Children cohort whose head circumference was measured at birth and at regular intervals thereafter. Their cognitive function was assessed with the Wechsler Preschool and Primary Scale of Intelligence at the age of 4 years and with the Wechsler Intelligence Scale for Children at the age of 8 years. Linear regression analysis was used to calculate postnatal head growth between successive time points, conditional on previous size, and to examine the relationship between head growth during different periods of development and later IQ. RESULTS. When the influence of head growth was distinguished for different periods, only prenatal growth and growth during infancy were associated with subsequent IQ. At 4 years, after adjustment for parental characteristics, full-scale IQ increased an average of 2.41 points for each 1-SD increase in head circumference at birth and 1.97 points for each 1-SD increase in head growth during infancy, conditional on head size at birth. At 8 years, head circumference at birth was no longer associated with IQ, but head growth during infancy remained a significant predictor, with full-scale IQ increasing an average of 1.56 points for each 1-SD increase in growth. CONCLUSION. The brain volume a child achieves by the age of 1 year helps determine later intelligence. Growth in brain volume after infancy may not compensate for poorer earlier growth.