Julian Gardiner

Vitamin D and mortality: meta-analysis of individual participant data from a large consortium of cohort studies from Europe and the United States

Objective To investigate the association between serum 25-hydroxyvitamin D concentrations (25(OH)D) and mortality in a large consortium of cohort studies paying particular attention to potential age, sex, season, and country differences. Design Meta-analysis of individual participant data of eight prospective cohort studies from Europe and the US. Setting General population. Participants 26 018 men and women aged 50-79 years Main outcome measures All-cause, cardiovascular, and cancer mortality. Results 25(OH)D concentrations varied strongly by season (higher in summer), country (higher in US and northern Europe) and sex (higher in men), but no consistent trend with age was observed. During follow-up, 6695 study participants died, among whom 2624 died of cardiovascular diseases and 2227 died of cancer. For each cohort and analysis, 25(OH)D quintiles were defined with cohort and subgroup specific cut-off values. Comparing bottom versus top quintiles resulted in a pooled risk ratio of 1.57 (95% CI 1.36 to 1.81) for all-cause mortality. Risk ratios for cardiovascular mortality were similar in magnitude to that for all-cause mortality in subjects both with and without a history of cardiovascular disease at baseline. With respect to cancer mortality, an association was only observed among subjects with a history of cancer (risk ratio, 1.70 (1.00 to 2.88)). Analyses using all quintiles suggest curvilinear, inverse, dose-response curves for the aforementioned relationships. No strong age, sex, season, or country specific differences were detected. Heterogeneity was low in most meta-analyses. Conclusions Despite levels of 25(OH)D strongly varying with country, sex, and season, the association between 25(OH)D level and all-cause and cause-specific mortality was remarkably consistent. Results from a long term randomised controlled trial addressing longevity are being awaited before vitamin D supplementation can be recommended in most individuals with low 25(OH)D levels.

Cortisol Diurnal Rhythm and Stress Reactivity in Male Adolescents with Early-Onset or Adolescence-Onset Conduct Disorder

Background Previous studies have reported lower basal cortisol levels and reduced cortisol responses to stress in children and adolescents with conduct disorder (CD). It is not known whether these findings are specific to early-onset CD. This study investigated basal and stress-induced cortisol secretion in male participants with early-onset and adolescence-onset forms of CD. Methods Forty-two participants with early-onset CD, 28 with adolescence-onset CD, and 95 control subjects participated in the study. They collected saliva across the day to assess their cortisol awakening response and diurnal rhythm. Subsequently, salivary cortisol was measured before, during, and after a psychosocial stress procedure designed to elicit frustration. Cardiovascular activity and subjective mood states were also assessed during stress exposure. Results There were no group differences in morning cortisol levels or the size of the cortisol awakening response. Basal cortisol levels in the evening and at 11 am during the laboratory visit were higher in both CD subgroups relative to control subjects. In contrast, cortisol and cardiovascular responses to psychosocial stress were reduced in both CD subgroups compared with control subjects. All groups reported similar increases in negative mood states during stress. Conclusions Our findings suggest that group differences in cortisol secretion are most pronounced during stress exposure, when participants with CD show cortisol hyporeactivity compared with control subjects. There was no evidence for reduced basal cortisol secretion in participants with CD, but rather increased secretion at specific time points. The results do not support developmentally sensitive differences in cortisol secretion between CD subtypes.

The health and development of children born to older mothers in the United Kingdom: observational study using longitudinal cohort data

Objective To assess relations between children’s health and development and maternal age. Design Observational study of longitudinal cohorts. Setting Millennium Cohort Study (a random sample of UK children) and the National Evaluation of Sure Start study (a random sample of children in deprived areas in England), 2001 to 2007. Participants 31 257 children at age 9 months, 24 781 children at age 3 years, and 22 504 at age 5 years. Main outcome measures Childhood unintentional injuries and hospital admissions (aged 9 months, 3 years, and 5 years), immunisations (aged 9 months and 3 years), body mass index, language development, and difficulties with social development (aged 3 and 5 years). Results Associations were independent of personal and family characteristics and parity. The risk of children having unintentional injuries requiring medical attention or being admitted to hospital both declined with increasing maternal age. For example, at three years the risk of unintentional injuries declined from 36.6% for mothers aged 20 to 28.6% for mothers aged 40 and hospital admissions declined, respectively, from 27.1% to 21.6%. Immunisation rates at nine months increased with maternal age from 94.6% for mothers aged 20 to 98.1% for mothers aged 40. At three years, immunisation rates reached a maximum, at 81.3% for mothers aged 27, being lower for younger and older mothers. This was linked to rates for the combined measles, mumps, and rubella immunisation because excluding these resulted in no significant relation with maternal age. An increase in overweight children at ages 3 and 5 years associated with increasing maternal age was eliminated once maternal body mass index was included as a covariate. Language development was associated with improvements with increasing maternal age, with scores for children of mothers aged 20 being lower than those of children of mothers aged 40 by 0.21 to 0.22 standard deviations at ages 3 and 4 years. There were fewer social and emotional difficulties associated with increasing maternal age. Children of teenage mothers had more difficulties than children of mothers aged 40 (difference 0.28 SD at age 3 and 0.16 SD at age 5). Conclusion Increasing maternal age was associated with improved health and development for children up to 5 years of age.

Maternal Prepregnancy BMI and Child Cognition: A Longitudinal Cohort Study

OBJECTIVE: To examine the association between maternal prepregnancy BMI and cognitive performance in children at 5 and 7 years of age. METHODS: This is a secondary analysis of data from the Millennium Cohort Study, a prospective population based cohort of 19 517 children in the United Kingdom. Standardized cognitive assessments of children, involving components of the British Ability Scales, second edition and a number skills test, were performed at 5 and 7 years of age. Principal components analysis was used to identify a general cognitive ability factor (g) from individual test scores. Maternal prepregnancy BMI was retrospectively self-reported when children were 9 months old. Mixed-effects linear regression models were fitted, controlling for multiple socio-demographic factors, child’s birth weight, child’s BMI, maternal smoking, and maternal diabetes. Complete data were available for 11 025 children at 5 years, and 9882 children at 7 years. RESULTS: Maternal prepregnancy BMI was negatively associated with children’s cognitive performance (g) at age 5 (P = .0069) and age 7 (P < .0001). The overall effect size was modest: a 10-point increase in maternal BMI was associated with a decrease in cognitive performance of ∼1/10th of an SD at age 7. CONCLUSIONS: Maternal prepregnancy BMI is negatively associated with children’s cognitive performance, even after adjusting for multiple socio-demographic confounders and children’s BMI. The relationship appears to become stronger as children get older, although the overall effect size is modest. In utero fetal programming or residual confounding may explain these findings.

Neuropsychological attention deficits in tuberous sclerosis complex (TSC)

Tuberous sclerosis complex (TSC) (OMIM191100) is a genetic disorder with multi‐system involvement including neurodevelopmental manifestations. There is great interest in understanding the pathogenetic mechanisms underlying these neurobehavioral and neurocognitive manifestations. However, there are still significant gaps in knowledge about the exact neuropsychiatric phenotypes observed in TSC. Here we report on the first systematic evaluation of neuropsychological attentional skills in a population‐derived sample of children and adolescents with TSC. The study showed that, even when age, gender, IQ, and intra‐familial clustering were controlled for, the TSC group had significantly lower scores than their unaffected siblings on a range of neuropsychological attentional tasks, and that they had significantly more neuropsychological attention deficits. Eighteen of the 20 children (90%) showed deficits on one or more attentional tasks, with dual task performance most consistently impaired (85%) and visual selective attention a relative strength. Active seizures and anti‐epilepsy medication did not influence attentional profiles. Furthermore, parent rating of attention‐related behaviors were not able to identify children at risk of neuropsychological deficits. The findings suggest that clinical neuropsychological evaluation of attentional skills should be performed in children and adolescents with TSC even when they have normal global intellectual abilities, no seizures, and no disruptive behaviors. Results suggest that the mechanisms underlying these deficits may include contributions from structural, seizure‐related and molecular factors.

The parenting of preschool children by older mothers in the United Kingdom

The parenting literature has focused on teenage motherhood but less is known about older mothers. In industrialized societies more women are giving birth later in life. The study examined whether there are any age trends in the use of discipline, home organization, provision of learning opportunities, maternal responsivity and mother child relationships treating maternal age at birth as a continuous construct. The sample was from two national UK cohorts with common assessments at three years (N = 24,610). Withholding treats or attention as discipline and parent/child conflict decreased as maternal age increased. Harsh discipline such as smacking was low for teenage mothers, highest in the mid-twenties after which it declined. Household chaos decreased with maternal age up to age 30 after which it was likely to be higher. Positive and responsive parenting generally increased with maternal age up to about age 40 after which it plateaued. Thus overall, while older motherhood is associated with medical risks for mother and child it should not present problems in relation to parenting during the preschool years.

Serum folate, vitamin B-12 and cognitive function in middle and older age: The HAPIEE study

Background Nutrient status of B vitamins, particularly folate and vitamin B-12, may be related to cognitive ageing but epidemiological evidence remains inconclusive. Objective The aim of this study was to estimate the association of serum folate and vitamin B-12 concentrations with cognitive function in middle-aged and older adults from three Central and Eastern European populations. Methods Men and women aged 45–69 at baseline participating in the Health, Alcohol and Psychosocial factors in Eastern Europe (HAPIEE) study were recruited in Krakow (Poland), Kaunas (Lithuania) and six urban centres in the Czech Republic. Tests of immediate and delayed recall, verbal fluency and letter search were administered at baseline and repeated in 2006–2008. Serum concentrations of biomarkers at baseline were measured in a sub-sample of participants. Associations of vitamin quartiles with baseline (n = 4166) and follow-up (n = 2739) cognitive domain-specific z-scores were estimated using multiple linear regression. Results After adjusting for confounders, folate was positively associated with letter search and vitamin B-12 with word recall in cross-sectional analyses. In prospective analyses, participants in the highest quartile of folate had higher verbal fluency (p < 0.01) and immediate recall (p < 0.05) scores compared to those in the bottom quartile. In addition, participants in the highest quartile of vitamin B-12 had significantly higher verbal fluency scores (β = 0.12; 95% CI = 0.02, 0.21). Conclusions Folate and vitamin B-12 were positively associated with performance in some but not all cognitive domains in older Central and Eastern Europeans. These findings do not lend unequivocal support to potential importance of folate and vitamin B-12 status for cognitive function in older age. Long-term longitudinal studies and randomised trials are required before drawing conclusions on the role of these vitamins in cognitive decline.

The Role of Care-seeking Delays in Intrauterine Fetal Deaths among ‘Near-miss’ Women in Herat, Afghanistan

BACKGROUND Many pregnant women in resource-poor countries seek care only after developing severe complications during childbirth at home and often reach health facilities in moribund conditions. The objectives were to (i) investigate the association between care-seeking duration and fetal survival at admission; and (ii) assess the significance of care-seeking duration in relation to other determinants. METHODS Data were analysed for 266 women who were pregnant with a singleton and admitted in life-threatening conditions to the maternity ward of Herat Regional Hospital in Afghanistan from February 2007 to January 2008. Information about the womens care-seeking durations, social and financial resources, reproductive factors, household economic status and household types were collected during interviews with the women and their husbands. Information about fetal heartbeats at admission was extracted from the womens medical records. RESULTS Fifty-four per cent of the women had a decision delay lasting 3 h or more; 69% had a transport delay lasting 3 h or more. Multivariable logistic regression analyses suggest that a decision delay lasting an hour or more increased the odds of fetal death by 6.6 (95% confidence interval [CI] 1.6, 26.3) compared with a delay less than 1 h. A womans lack of financial autonomy and a distance from her natal home increased the odds of fetal death by 3.1 [95% CI 1.1, 8.4] and 2.5 [95% CI 1.0, 6.3] respectively. CONCLUSION An integrated approach to improving fetal and maternal health from pre-pregnancy through childbirth (including increasing womens social and financial resources) is crucial particularly where senior family members act as gatekeepers to womens access to health care.

Paternal Age, Paternal Presence and Children's Health: An Observational Study.

In an observational study of 31,257 children we investigated the effects of paternal age at the time of the child’s birth, paternal absence and non-biological fathers on children’s health. Results are per 5 year change in paternal age. Older fathers were associated with lower rates of unintentional injuries, odds ratio (OR)=0.966, P=0.0027. There was a quadratic association between paternal age and risk of hospital admission, β=0.0121, P=0.0109, with minimum risk at paternal age 37.7. Absent fathers were associated with increased risk of hospital admission, OR=1.19, P<10−3, lower rates of complete immunizations to 9 months, OR=0.562, P<10−3, higher Strength and Difficulties Questionnaire (SDQ) difficulties scores: β=0.304, P=0.0024 (3 year olds), β=0.697, P<10−3 (5 year olds). Non-biological fathers were associated with increased risk of unintentional injury, OR=1.16, P=0.0319 and hospital admission, OR=1.26, P=0.0166; lower rates of complete immunizations to 9 months, OR=0.343, P=0.0309 and higher SDQ difficulties scores: β=0.908, P<10−3.

Educational Progress of Looked-After Children in England: A Study Using Group Trajectory Analysis

An investigation using group trajectory analysis of care environment and other factors affecting the educational progress of looked-after children in England. BACKGROUND: Looked-after children in local authority care are among the most disadvantaged, and measures of their well-being, including educational outcomes, are poorer than other children’s. METHODS: The study sample consisted of all children in England born in academic years 1993 to 1994 through 1997 to 1998 who were in local authority care at any point during the academic years 2005 to 2006 through 2012 to 2013 and for whom results of national tests in literacy and numeracy were available at ages 7, 11, and 16 (N = 47 500). RESULTS: Group trajectory analysis of children’s educational progress identified 5 trajectory groups: low achievement, late improvement, late decline, predominant, and high achievement. Being looked after earlier was associated with a higher probability of following a high achievement trajectory and a lower probability of following a late decline trajectory. For children first looked after between ages 7 and 16, having a longer total time looked after by age 16 was associated with a higher probability of following a high achievement trajectory. For children with poor outcomes at ages 7 and 11, being looked after by age 16 was associated with an increased chance of educational improvement by age 16. CONCLUSIONS: This study provides evidence that early entry into care can reduce the risk of poor educational outcomes. It also establishes group trajectory analysis as an effective method for analyzing the educational progress of looked-after children, with the particular strength that it allows factors associated with a late decline or improvement in educational progress to be identified.