Prescription of benzodiazepines, z-drugs, and gabapentinoids and mortality risk in people receiving opioid agonist treatment: Observational study based on the UK Clinical Practice Research Datalink and Office for National Statistics death records.

BACKGROUND: Patients with opioid dependency prescribed opioid agonist treatment (OAT) may also be prescribed sedative drugs. This may increase mortality risk but may also increase treatment duration, with overall benefit. We hypothesised that prescription of benzodiazepines in patients receiving OAT would increase risk of mortality overall, irrespective of any increased treatment duration. METHODS AND FINDINGS: Data on 12,118 patients aged 15-64 years prescribed OAT between 1998 and 2014 were extracted from the Clinical Practice Research Datalink. Data from the Office for National Statistics on whether patients had died and, if so, their cause of death were available for 7,016 of these patients. We identified episodes of prescription of benzodiazepines, z-drugs, and gabapentinoids and used linear regression and Cox proportional hazards models to assess the associations of co-prescription (prescribed during OAT and up to 12 months post-treatment) and concurrent prescription (prescribed during OAT) with treatment duration and mortality. We examined all-cause mortality (ACM), drug-related poisoning (DRP) mortality, and mortality not attributable to DRP (non-DRP). Models included potential confounding factors. In 36,126 person-years of follow-up there were 657 deaths and 29,540 OAT episodes, of which 42% involved benzodiazepine co-prescription and 29% concurrent prescription (for z-drugs these respective proportions were 20% and 11%, and for gabapentinoids 8% and 5%). Concurrent prescription of benzodiazepines was associated with increased duration of methadone treatment (adjusted mean duration of treatment episode 466 days [95% CI 450 to 483] compared to 286 days [95% CI 275 to 297]). Benzodiazepine co-prescription was associated with increased risk of DRP (adjusted HR 2.96 [95% CI 1.97 to 4.43], p < 0.001), with evidence of a dose-response effect, but showed little evidence of an association with non-DRP (adjusted HR 0.91 [95% CI 0.66 to 1.25], p = 0.549). Co-prescription of z-drugs showed evidence of an association with increased risk of DRP (adjusted HR 2.75 [95% CI 1.57 to 4.83], p < 0.001) but little evidence of an association with non-DRP (adjusted HR 0.79 [95% CI 0.49 to 1.28], p = 0.342). There was no evidence of an association of gabapentinoid co-prescription with DRP (HR 1.54 [95% CI 0.60 to 3.98], p = 0.373) but evidence of an association with increased non-DRP (HR 1.83 [95% CI 1.28 to 2.62], p = 0.001). Concurrent benzodiazepine prescription also increased mortality risk after consideration of duration of OAT (adjusted HR for DRP with benzodiazepine concurrent prescription 3.34 [95% CI 2.14 to 5.20], p < 0.001). The main limitation of this study is the possibility that unmeasured confounding factors led to an association between benzodiazepine prescription and DRP that is not causal. CONCLUSIONS: In this study, co-prescription of benzodiazepine was specifically associated with increased risk of DRP in opioid-dependent individuals. Co-prescription of z-drugs and gabapentinoids was also associated with increased mortality risk; however, for z-drugs there was no evidence for a dose-response effect on DRP, and for gabapentinoids the increased mortality risk was not specific to DRP. Concurrent prescription of benzodiazepine was associated with longer treatment but still increased risk of death overall. Clinicians should be cautious about prescribing benzodiazepines to opioid-dependent individuals.

Self-controlled case series studies: Just how rare does a rare non-recurrent outcome need to be?

The self-controlled case series method assumes that adverse outcomes arise according to a non-homogeneous Poisson process. This implies that it is applicable to independent recurrent outcomes. However, the self-controlled case series method may also be applied to unique, non-recurrent outcomes or first outcomes only, in the limit where these become rare. We investigate this rare outcome assumption when the self-controlled case series method is applied to non-recurrent outcomes. We study this requirement analytically and by simulation, and quantify what is meant by 'rare' in this context. In simulations we also apply the self-controlled risk interval design, a special case of the self-controlled case series design. To illustrate, we extract data on the incidence rate of some recurrent and non-recurrent outcomes within a defined study population to check whether outcomes are sufficiently rare for the rare outcome assumption to hold when applying the self-controlled case series method to first or unique outcomes. The main findings are that the relative bias should be no more than 5% when the cumulative incidence over total time observed is less than 0.1 per individual. Inclusion of age (or calendar time) effects will further reduce bias. Designs that begin observation with exposure maximise bias, whereas little or no bias will be apparent when there is no time trend in the distribution of exposures, or when exposure is central within time observed.

Genome-wide association study of blood lead shows multiple associations near ALAD.

Exposure to high levels of environmental lead, or biomarker evidence of high body lead content, is associated with anaemia, developmental and neurological deficits in children, and increased mortality in adults. Adverse effects of lead still occur despite substantial reduction in environmental exposure. There is genetic variation between individuals in blood lead concentration but the polymorphisms contributing to this have not been defined. We measured blood or erythrocyte lead content, and carried out genome-wide association analysis, on population-based cohorts of adult volunteers from Australia and UK (N = 5433). Samples from Australia were collected in two studies, in 1993-1996 and 2002-2005 and from UK in 1991-1992. One locus, at ALAD on chromosome 9, showed consistent association with blood lead across countries and evidence for multiple independent allelic effects. The most significant single nucleotide polymorphism (SNP), rs1805313 (P = 3.91 × 10(-14) for lead concentration in a meta-analysis of all data), is known to have effects on ALAD expression in blood cells but other SNPs affecting ALAD expression did not affect blood lead. Variants at 12 other loci, including ABO, showed suggestive associations (5 × 10(-6) > P > 5 × 10(-8)). Identification of genetic polymorphisms affecting blood lead reinforces the view that genetic factors, as well as environmental ones, are important in determining blood lead levels. The ways in which ALAD variation affects lead uptake or distribution are still to be determined.

Association between maternal vitamin D status in pregnancy and neurodevelopmental outcomes in childhood: results from the Avon Longitudinal Study of Parents and Children (ALSPAC).

Seafood intake in pregnancy has been positively associated with childhood cognitive outcomes which could potentially relate to the high vitamin D content of oily fish. However, whether higher maternal vitamin D status (serum 25-hydroxyvitamin D (25(OH)D)) in pregnancy is associated with a reduced risk of offspring suboptimal neurodevelopmental outcomes is unclear. A total of 7065 mother-child pairs were studied from the Avon Longitudinal Study of Parents and Children cohort who had data for both serum total 25(OH)D concentration in pregnancy and at least one measure of offspring neurodevelopment (pre-school development at 6-42 months; 'Strengths and Difficulties Questionnaire' scores at 7 years; intelligence quotient (IQ) at 8 years; reading ability at 9 years). After adjustment for confounders, children of vitamin D-deficient mothers (<50·0 nmol/l) were more likely to have scores in the lowest quartile for gross-motor development at 30 months (OR 1·20; 95 % CI 1·03, 1·40), fine-motor development at 30 months (OR 1·23; 95 % CI 1·05, 1·44) and social development at 42 months (OR 1·20; 95 % CI 1·01, 1·41) than vitamin D-sufficient mothers (≥50·0 nmol/l). No associations were found with neurodevelopmental outcomes, including IQ, measured at older ages. However, our results suggest that deficient maternal vitamin D status in pregnancy may have adverse effects on some measures of motor and social development in children under 4 years. Prevention of vitamin D deficiency may be important for preventing suboptimal development in the first 4 years of life.

Prevalence and risk factors for reduced sound tolerance (hyperacusis) in children.

OBJECTIVE: To estimate the prevalence of reduced sound tolerance (hyperacusis) in a UK population of 11-year-old children and examine the association of early life and auditory risk factors with report of hyperacusis. DESIGN: A prospective UK population-based study. STUDY SAMPLE: A total of 7097 eleven-year-old children within the Avon longitudinal study of parents and children (ALSPAC) were asked about sound tolerance; hearing and middle-ear function was measured using audiometry, otoacoustic emissions, and tympanometry. Information on neonatal risk factors and socioeconomic factors were obtained through parental questionnaires. RESULTS: 3.7% (95% CI 3.25, 4.14) children reported hyperacusis. Hyperacusis report was less likely in females (adj OR 0.64, 95% CI 0.49, 0.85), and was more likely with higher maternal education level (adj OR 1.72, 95% CI 1.08, 2.72) and with readmission to hospital in first four weeks (adj OR 1.98, 95% CI 1.20, 3.25). Report of hyperacusis was associated with larger amplitude otoacoustic emissions but with no other auditory factors. CONCLUSIONS: The prevalence of hyperacusis in the population of 11-year-old UK children is estimated to be 3.7%. It is more common in boys.

Genome-wide association study identifies loci affecting blood copper, selenium and zinc.

Genetic variation affecting absorption, distribution or excretion of essential trace elements may lead to health effects related to sub-clinical deficiency. We have tested for allelic effects of single-nucleotide polymorphisms (SNPs) on blood copper, selenium and zinc in a genome-wide association study using two adult cohorts from Australia and the UK. Participants were recruited in Australia from twins and their families and in the UK from pregnant women. We measured erythrocyte Cu, Se and Zn (Australian samples) or whole blood Se (UK samples) using inductively coupled plasma mass spectrometry. Genotyping was performed with Illumina chips and > 2.5 m SNPs were imputed from HapMap data. Genome-wide significant associations were found for each element. For Cu, there were two loci on chromosome 1 (most significant SNPs rs1175550, P = 5.03 × 10(-10), and rs2769264, P = 2.63 × 10(-20)); for Se, a locus on chromosome 5 was significant in both cohorts (combined P = 9.40 × 10(-28) at rs921943); and for Zn three loci on chromosomes 8, 15 and X showed significant results (rs1532423, P = 6.40 × 10(-12); rs2120019, P = 1.55 × 10(-18); and rs4826508, P = 1.40 × 10(-12), respectively). The Se locus covers three genes involved in metabolism of sulphur-containing amino acids and potentially of the analogous Se compounds; the chromosome 8 locus for Zn contains multiple genes for the Zn-containing enzyme carbonic anhydrase. Where potentially relevant genes were identified, they relate to metabolism of the element (Se) or to the presence at high concentration of a metal-containing protein (Cu).

Polyunsaturated fatty acid levels in blood during pregnancy, at birth and at 7 years: their associations with two common FADS2 polymorphisms.

Minor alleles of polymorphisms in the fatty acid desaturase (FADS) gene cluster have been associated with reduced desaturation of the precursor polyunsaturated fatty acids (FAs) in small studies. The effects of these polymorphisms during progressive developmental stages have not previously been reported. Data from blood samples for 4342 pregnant women, 3343 umbilical cords reflecting the newborn's blood supply and 5240 children aged 7 years were analysed to investigate the associations of polyunsaturated FAs with rs1535 and rs174575-two polymorphisms in the FADS2 gene. Strong positive associations were observed between the minor G allele for these two markers, especially rs1535, and the substrates linoleic (18:2n-6) and α-linolenic (18:3n-3) acid. Negative associations were observed for the more highly unsaturated FAs such as arachidonic acid (20:4n-6), timnodonic acid (EPA, 20:5n-3) and cervonic acid (DHA, 22:6n-3). Bivariable genetic associations using the mother and child genotypes suggested that the newborn metabolism had a greater capacity to synthesize the more highly unsaturated omega-6 FAs than the more highly unsaturated omega-3 FAs. Nevertheless, despite the immaturity of the neonate, there was evidence that synthesis of DHA was occurring. However, by 7 years, no associations were observed with the maternal genotype. This suggested that the children's FA levels were related only to their own metabolism with no apparent lasting influences of the in utero environment.

Effect of inadequate iodine status in UK pregnant women on cognitive outcomes in their children: results from the Avon Longitudinal Study of Parents and Children (ALSPAC).

BACKGROUND: As a component of thyroid hormones, iodine is essential for fetal brain development. Although the UK has long been considered iodine replete, increasing evidence suggests that it might now be mildly iodine deficient. We assessed whether mild iodine deficiency during early pregnancy was associated with an adverse effect on child cognitive development. METHODS: We analysed mother-child pairs from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort by measuring urinary iodine concentration (and creatinine to correct for urine volume) in stored samples from 1040 first-trimester pregnant women. We selected women on the basis of a singleton pregnancy and availability of both a urine sample from the first trimester (defined as ≤13 weeks' gestation; median 10 weeks [IQR 9-12]) and a measure of intelligence quotient (IQ) in the offspring at age 8 years. Women's results for iodine-to-creatinine ratio were dichotomised to less than 150 µg/g or 150 µg/g or more on the basis of WHO criteria for iodine deficiency or sufficiency in pregnancy. We assessed the association between maternal iodine status and child IQ at age 8 years and reading ability at age 9 years. We included 21 socioeconomic, parental, and child factors as confounders. FINDINGS: The group was classified as having mild-to-moderate iodine deficiency on the basis of a median urinary iodine concentration of 91·1 µg/L (IQR 53·8-143; iodine-to-creatinine ratio 110 µg/g, IQR 74-170). After adjustment for confounders, children of women with an iodine-to-creatinine ratio of less than 150 µg/g were more likely to have scores in the lowest quartile for verbal IQ (odds ratio 1·58, 95% CI 1·09-2·30; p=0·02), reading accuracy (1·69, 1·15-2·49; p=0·007), and reading comprehension (1·54, 1·06-2·23; p=0·02) than were those of mothers with ratios of 150 µg/g or more. When the less than 150 µg/g group was subdivided, scores worsened ongoing from 150 µg/g or more, to 50-150 µg/g, to less than 50 µg/g. INTERPRETATION: Our results show the importance of adequate iodine status during early gestation and emphasise the risk that iodine deficiency can pose to the developing infant, even in a country classified as only mildly iodine deficient. Iodine deficiency in pregnant women in the UK should be treated as an important public health issue that needs attention. FUNDING: None.

Umbilical cord PUFA are determined by maternal and child fatty acid desaturase (FADS) genetic variants in the Avon Longitudinal Study of Parents and Children (ALSPAC).

Fetal supply with long-chain PUFA (LC-PUFA) during pregnancy is important for brain growth and visual and cognitive development and is provided by materno-fetal placental transfer. We recently showed that maternal fatty acid desaturase (FADS) genotypes modulate the amounts of LC-PUFA in maternal blood. Whether FADS genotypes influence the amounts of umbilical cord fatty acids has not been investigated until now. The aim of the present study was to investigate the influence of maternal and child FADS genotypes on the amounts of LC-PUFA in umbilical cord venous plasma as an indicator of fetal fatty acid supply during pregnancy. A total of eleven cord plasma n-6 and n-3 fatty acids were analysed for association with seventeen FADS gene cluster SNP in over 2000 mothers and children from the Avon Longitudinal Study of Parents and Children. In a multivariable analysis, the maternal genotype effect was adjusted for the child genotype and vice versa to estimate which of the two has the stronger influence on cord plasma fatty acids. Both maternal and child FADS genotypes and haplotypes influenced amounts of cord plasma LC-PUFA and fatty acid ratios. Specifically, most analysed maternal SNP were associated with cord plasma levels of the precursor n-6 PUFA, whereas the child genotypes were mainly associated with more highly desaturated n-6 LC-PUFA. This first study on FADS genotypes and cord fatty acids suggests that fetal LC-PUFA status is determined to some extent by fetal fatty acid conversion. Associations of particular haplotypes suggest specific effects of SNP rs498793 and rs968567 on fatty acid metabolism.

Social and behavioural outcomes in children diagnosed with autism spectrum disorders: a longitudinal cohort study.

OBJECTIVE: To compare social and behavioural outcomes between children formally diagnosed with autism spectrum disorders (ASD) with those of children who displayed autistic traits at preschool age, but remained undiagnosed as teenagers. METHOD: A secondary analysis of data from a birth cohort study, the Avon Longitudinal Study of Parents and Children (N = 13,944), in SW England. Children clinically diagnosed with ASD were identified from their medical records (n = 71). A comparison group, who displayed autistic traits at age 3-4, but without ASD diagnosis were also identified (n = 142). Social and behavioural outcomes in adolescence were compared between the two groups. RESULTS: Children with ASD diagnoses were more impaired as teenagers that those in the comparison group on a range of measures of autistic-like behaviour. The developmental trajectory of prosocial behaviour showed that differences between the case and comparison groups increased dramatically in the preschool and early primary years, but that after 6 years the trajectories were similar. CONCLUSIONS: The divergence of the clinically diagnosed group and the nondiagnosed group in measures of autistic-like behaviour increased with age. This study provides evidence that it may be difficult to distinguish preschool age children who exhibit autistic-like symptoms but improve, from those who go on to develop lifelong impairment.

Social and demographic factors that influence the diagnosis of autistic spectrum disorders.

PURPOSE: Recent studies in epidemiology have highlighted the existence of children with autistic difficulties who remain undiagnosed. Other studies have identified 'access barriers' to clinics which include factors mediated by parents as well as health and education services. The purpose of this study was to examine whether social and demographic factors play a role in receiving a diagnosis of autistic spectrum disorder (ASD) independently of symptom severity. METHODS: Retrospective secondary analysis of a longitudinal UK cohort study, namely, the Avon Longitudinal Study of Parents and Children (ALSPAC). RESULTS: With the severity of autistic traits held constant, boys were more likely to receive an ASD diagnosis than girls. Younger mothers and mothers of first-born children were significantly less likely to have children diagnosed with ASD. Maternal depression before and around the time of their children's autistic difficulties was associated with lack of diagnosis. CONCLUSIONS: The study provides evidence that social as well as biological factors can influence whether children are brought to the clinic.

Prevalence and risk factors for mild and high-frequency bilateral sensorineural hearing loss at age 11 years old: a UK prospective cohort study.

OBJECTIVE: This study aimed to assess prevalence and risk factors for mild/high-frequency bilateral sensorineural hearing loss within a UK population of children at age 11 years. DESIGN: Prospective birth cohort study. STUDY SAMPLE: Repeat hearing thresholds were measured in 5032 children, as part of the Avon Longitudinal Study of Parents and Children (ALSPAC) at age 7, 9, and 11 years. Pregnancy, birth, and early medical history were obtained prospectively through parental questionnaires and medical records. RESULTS: Twenty children had mild and seven had high-frequency bilateral sensorineural hearing loss, giving a combined prevalence of 0.5% (95% CI 0.4-0.8%). These children were more likely than the rest of the study sample to have been admitted to hospital at 6-18 months (OR 2.7, 95% CI 1.00-7.30). Parents of these children were more likely to have suspected a hearing problem when the children were 3 years old (OR 2.4, 95% CI 1.05-5.60). CONCLUSIONS: This is the first UK prospective cohort study to investigate the prevalence of mild and high-frequency hearing loss. This study, which has the advantage of a large sample size and repeat hearing measures over a four year period, reports lower prevalence values than US cross-sectional studies.

Genetic variation in polyunsaturated fatty acid metabolism and its potential relevance for human development and health.

Blood and tissue contents of polyunsaturated fatty acid (PUFA) and long-chain PUFA (LC-PUFA) are related to numerous health outcomes including cardiovascular health, allergies, mental health and cognitive development. Evidence has accumulated to show that in addition to diet, common polymorphisms in the fatty acid desaturase (FADS) gene cluster have very marked effects on human PUFA and LC-PUFA status. Recent results suggest that in addition to fatty acid desaturase 1 and fatty acid desaturase 2, the gene product of fatty acid desaturase 3 is associated with desaturating activity. New data have become available to show that FADS single nucleotide polymorphisms (SNPs) also modulate docosahexaenoic acid status in pregnancy as well as LC-PUFA levels in children and in human milk. There are indications that FADS SNPs modulate the risk for allergic disorders and eczema, and the effect of breastfeeding on later cognitive development. Mechanisms by which FADS SNPs modulate PUFA levels in blood, breast milk and tissues should be explored further. More studies are required to explore the effects of FADS gene variants in populations with different ethnic backgrounds, lifestyles and dietary habits, and to investigate in greater depth the interaction of gene variants, diet and clinical end points, including immune response and developmental outcomes. Analyses of FADS gene variants should be included into all sizeable cohort and intervention studies addressing biological effects of PUFA and LC-PUFA in order to consider these important confounders, and to enhance study sensitivity and precision.

Identification of children with the same level of impairment as children on the autistic spectrum, and analysis of their service use.

BACKGROUND: Data from epidemiology have consistently highlighted a disparity between the true prevalence of childhood psychiatric disorders and their recognition as defined by receiving a clinical diagnosis. Few studies have looked specifically at the level of unidentified autistic spectrum disorder (ASD) in the population. METHOD: Logistic regression was used to determine the behavioural traits associated with receiving a diagnosis of ASD using data from the Avon Longitudinal Study of Parents and Children (ALSPAC). A composite score was derived to measure levels of autistic traits; undiagnosed children with scores matching those diagnosed with ASD were identified. Levels of educational provision beyond that provided by standard schooling were examined. RESULTS: Fifty-five percent of children with autistic traits at the same levels as those who had an autism diagnosis had not been identified as needing extra support from education or specialised health services. Of those who were identified as having special needs, 37.5% had been formally diagnosed with an ASD. For children with impairment at the same level as that associated with Asperger's syndrome, 57% had no special provision at school, and were not accessing specialised health services. Twenty-six percent of those who did have special provision at school had an ASD diagnosis. CONCLUSIONS: The results suggest that there may be a substantial proportion of children on the autistic spectrum who are never identified by services.

Influences on child fruit and vegetable intake: sociodemographic, parental and child factors in a longitudinal cohort study.

OBJECTIVE: To examine the sociodemographic, parental and child factors that predict fruit and vegetable consumption in 7-year-old children. DESIGN: Diet was assessed using three 1d unweighed food diaries. The child's daily fruit and vegetable consumption was calculated by summing the weight of each type of fruit, fruit juice and vegetable consumed. The various others factors measured were assessed by a questionnaire at different time points. SETTING: The Avon Longitudinal Study of Parents and Children (ALSPAC). SUBJECTS: A total of 7285 children aged 7 years residing in the south-west of England during 1999-2000. RESULTS: Median daily fruit and vegetable consumption (201 g) was below the recommendations for this age group (320 g). Girls ate more fruit and vegetables per unit energy (30.3 g/MJ) than boys (26.7 g/MJ; P =< 0.001). The predictors of fruit and vegetable consumption were mostly similar. Fruit and vegetable consumption was associated with maternal consumption, maternal education status and parental rules about serving fruit/vegetables every day, food expenditure per person and whether the child was choosy about food. Vegetable consumption was also associated with the other characteristics of the child, such as whether the child enjoyed food and whether the child tried a variety of foods. CONCLUSIONS: Children are not eating recommended amounts of fruit and vegetables, particularly boys. Consumption of fruit and vegetables appears to be influenced by parental rules about daily consumption and parental consumption and by the child's choosiness. Parent's actions could influence this. These findings may prove useful for those planning healthy eating campaigns for children.

High levels of depressive symptoms in pregnancy with low omega-3 fatty acid intake from fish.

BACKGROUND: Depression during pregnancy has adverse consequences for both mother and child. Although common in western countries, depression appears to be virtually absent in countries with high seafood intake. We test the hypothesis that low seafood intake during pregnancy is associated with increased prevalence of depressive symptoms. METHODS: This study used data prospectively collected from women participating in the Avon Longitudinal Study of Parents and Children in the period 1991-1992. At 32 weeks' gestation, the mother completed a questionnaire that included symptoms of depression and a food frequency questionnaire from which the amount of omega-3 fatty acids from fish was calculated. Statistical analysis took social and lifestyle factors into account. RESULTS: Unadjusted and adjusted analyses showed lower maternal intake of omega-3 from seafood was associated with high levels of depressive symptoms. Compared with women consuming more than 1.5 g omega-3 from seafood per week, those consuming none were more likely to have high levels of depressive symptoms at 32 weeks' gestation (adjusted odds ratios = 1.54; 95% confidence interval = 1.25-1.89). CONCLUSIONS: These observational data support an association between low omega-3 intake from seafood and increased risk of high levels of depressive symptoms during pregnancy. Eating seafood during pregnancy may have beneficial effects on mental well-being.

Selective drop-out in longitudinal studies and non-biased prediction of behaviour disorders.

BACKGROUND: Participant drop-out occurs in all longitudinal studies, and if systematic, may lead to selection biases and erroneous conclusions being drawn from a study. AIMS: We investigated whether drop out in the Avon Longitudinal Study of Parents And Children (ALSPAC) was systematic or random, and if systematic, whether it had an impact on the prediction of disruptive behaviour disorders. METHOD: Teacher reports of disruptive behaviour among currently participating, previously participating and never participating children aged 8 years in the ALSPAC longitudinal study were collected. Data on family factors were obtained in pregnancy. Simulations were conducted to explain the impact of selective drop-out on the strength of prediction. RESULTS: Drop out from the ALSPAC cohort was systematic and children who dropped out were more likely to suffer from disruptive behaviour disorder. Systematic participant drop-out according to the family variables, however, did not alter the association between family factors obtained in pregnancy and disruptive behaviour disorder at 8 years of age. CONCLUSIONS: Cohort studies are prone to selective drop-out and are likely to underestimate the prevalence of psychiatric disorder. This empirical study and the simulations confirm that the validity of regression models is only marginally affected despite range restrictions after selective drop-out.

How many subjects are needed in a longitudinal birth cohort study?

One of the first decisions that needs to be taken when planning a birth cohort concerns the size of the study. This in turn will depend on the research questions to be answered and thence whether environmental exposures and outcomes are measured on a continuum or as dichotomous variables. Here we describe ways in which different birth cohorts have addressed this issue and explore the advantages of smaller detailed studies over larger less-detailed studies.

Growth and body composition in children who are picky eaters: a longitudinal view.

BACKGROUND/OBJECTIVES: Picky eating may be associated with higher risk of being underweight and poor growth over time or conversely, being overweight. Our aim was to investigate if children identified as picky eaters showed differences in height, weight and body composition from their non-picky peers. SUBJECTS/METHODS: Picky eaters were identified in the Avon Longitudinal Study of Parents and Children cohort at 3 years of age. Height and weight were measured on seven occasions (age 7-17 years). Body composition was measured on five occasions by dual-energy x-ray absorptiometry (age 9-17 years). Participants were classified as thin/normal/overweight or obese at each age point using body mass index (BMI) classifications. Data were analysed with adjusted multiple regression analysis and mixed-design repeated measures ANOVA. RESULTS: There was a main effect of being a picky child on height and weight (and on BMI and lean mass index (LMI) in boys) (lower in the picky children, all p ≤ 0.044), but not on percentage body fat or fat mass index (and not on BMI and LMI in girls) (all p > 0.2). The mean heights, weights and BMIs of picky eaters were consistently above the 50th centiles of reference growth charts. More than two-thirds of picky eaters were not thin at any age point. However, being a picky eater was predictive of being thin at a few age points. CONCLUSIONS: The growth trajectories of children who were picky eaters were reassuring. The prevalence of thinness amongst some picky eaters is notable, suggesting that some children may need specific early identification, intervention and growth surveillance.

Maternal seafood consumption in pregnancy and neurodevelopmental outcomes in childhood (ALSPAC study): an observational cohort study.

BACKGROUND: Seafood is the predominant source of omega-3 fatty acids, which are essential for optimum neural development. However, in the USA, women are advised to limit their seafood intake during pregnancy to 340 g per week. We used the Avon Longitudinal Study of Parents and Children (ALSPAC) to assess the possible benefits and hazards to a child's development of different levels of maternal seafood intake during pregnancy. METHODS: 11,875 pregnant women completed a food frequency questionnaire assessing seafood consumption at 32 weeks' gestation. Multivariable logistic regression models including 28 potential confounders assessing social disadvantage, perinatal, and dietary items were used to compare developmental, behavioural, and cognitive outcomes of the children from age 6 months to 8 years in women consuming none, some (1-340 g per week), and >340 g per week. FINDINGS: After adjustment, maternal seafood intake during pregnancy of less than 340 g per week was associated with increased risk of their children being in the lowest quartile for verbal intelligence quotient (IQ) (no seafood consumption, odds ratio [OR] 1.48, 95% CI 1.16-1.90; some, 1.09, 0.92-1.29; overall trend, p=0.004), compared with mothers who consumed more than 340 g per week. Low maternal seafood intake was also associated with increased risk of suboptimum outcomes for prosocial behaviour, fine motor, communication, and social development scores. For each outcome measure, the lower the intake of seafood during pregnancy, the higher the risk of suboptimum developmental outcome. INTERPRETATION: Maternal seafood consumption of less than 340 g per week in pregnancy did not protect children from adverse outcomes; rather, we recorded beneficial effects on child development with maternal seafood intakes of more than 340 g per week, suggesting that advice to limit seafood consumption could actually be detrimental. These results show that risks from the loss of nutrients were greater than the risks of harm from exposure to trace contaminants in 340 g seafood eaten weekly.