Regional differences in the frequency of the c.985A>G ACADM mutation: findings from a meta-regression of genotyping and screening studies.

Several countries include medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, a rare autosomal recessive disease, in their newborn screening programmes despite prevalence uncertainty. We estimated the frequency of its most common mutation, c.985A>G, tested for regional differences and compared screening and genotype frequencies. We identified 43 studies reporting the frequency of c.985A>G over 10 million individuals, and pooled frequency data using a novel Bayesian approach. We found significant variation in the frequency of the mutation across regions supporting a reported founder effect. The proportion of c.985A>G homozygotes was highest in Western Europe with 4.1 (95%CI: 2.8-5.6) per 100,000 individuals, then the New World (3.2, 95%CI: 2.0-4.7), Southern (1.2, 95%CI: 0.6-2.0) and Eastern European regions (0.9, 95%CI: 0.5-1.7). No cases with the mutation were identified in Asian and Middle Eastern regions. Significant differences were found in some countries between the genotype and screening allele frequency of c.985A>G. Our predictions could inform the frequency of the mutation by region and our approach could apply to other genetic conditions.

Using cohort studies in lifecourse epidemiology.

The UK Medical Research Council (MRC) Population Health Sciences Research Network is a network of MRC research units and centres that aims to bring together and add value to existing MRC investment in public health, health services and epidemiological research. This symposium held in August 2011 at the World Congress of Epidemiology, Edinburgh, discussed a range of topics including methodology and analytical issues based on a number of examples of cohort studies within the context of lifecourse epidemiology.

Sex and ethnic differences in the waist circumference of 5-year-old children: findings from the Millennium Cohort Study.

We examined sex and ethnic differences in central fatness, as assessed by waist circumference measurements, in 13 590 Millennium Cohort Study 5-year-olds. Measurements were expressed as z-scores based on reference data from the British Standards Institute. The cohort, especially girls, had larger waist circumference measurements than the reference population. Black children had larger waist, and children from other minority ethnic groups had smaller waist than White children. Girls, and Black children, in the United Kingdom are at particular risk for central fatness. Further research is needed to clarify ethnic and other influences on fat distribution, and the health outcomes associated with central fatness.

Risk factors for rapid weight gain in preschool children: findings from a UK-wide prospective study.

OBJECTIVE: To examine risk factors for rapid weight gain between 3 and 5 years of age. DESIGN: Nationally representative prospective cohort study. PARTICIPANTS: A total of 11 653 preschool children participating in the UK Millennium Cohort Study, with anthropometry at 3 and 5 years. MEASUREMENTS: Weight gain z-scores were calculated from 3 to 5 years. Children in the top quarter of this distribution were classified as gaining weight rapidly. A total of 26 biological and early life, social, psychological, behavioural and environmental risk factors were examined. RESULTS: Among the participants, 13% of normal weight, 63% of overweight and 88% of obese 5-year olds had experienced rapid weight gain since 3 years of age. Six biological and early life factors and two social factors were found to be significantly associated with this growth pattern. In a mutually adjusted model, children were more likely to gain weight rapidly if they had a higher body mass index at age 3 (adjusted odds ratio: 1.27, 95% confidence interval: 1.23-1.32), if they were of Bangladeshi (adjusted odds ratio: 1.88, 95% confidence interval: 1.27-2.79) or black (adjusted odds ratio: 1.47, 95% confidence interval: 1.07-2.02) ethnicity, if their mother was overweight (adjusted odds ratio: 1.32, 95% confidence interval: 1.15-1.51) or had been overweight before pregnancy (adjusted odds ratio: 1.56, 95% confidence interval: 1.36-1.79), if their father was overweight (adjusted odds ratio: 1.56, 95% confidence interval: 1.34-1.81) or if their mother smoked during pregnancy (adjusted odds ratio:1.23, 95% confidence interval: 1.09-1.38). Children were also more likely to gain weight rapidly if others smoked in the same room (adjusted odds ratio: 1.31, 95% confidence interval: 1.16-1.49) or if they were a lone child in the household (adjusted odds ratio: 1.14, 95% confidence interval: 1.01-1.30). CONCLUSIONS: Factors operating during pregnancy and early life increase the risk of rapid weight gain in young children; thus, signalling the importance of obesity prevention programmes before and during pregnancy and for children at an early age. In particular, these programmes should address parental weight status and smoking habits, both modifiable risk factors.

Rubella seroprevalence in pregnant women in North Thames: estimates based on newborn screening samples.

OBJECTIVES: Routine screening for rubella susceptibility is recommended in the UK so that women found to be susceptible can be offered immunization in the post partum period. We demonstrate the use of newborn dried blood spot samples linked to routine vital statistics datasets to monitor rubella susceptibility in pregnant women and to investigate maternal characteristics as determinants of rubella seronegativity. SETTING: North Thames region of England (including large parts of inner London). METHODS: Maternally acquired rubella IgG antibody levels were measured in 18882 newborn screening blood spot samples. Latent class regression finite mixture models were used to classify samples as seronegative to rubella. Data on maternal country of birth were available through linkage to birth registration data. RESULTS: An estimated 2.7% (95% CI 2.4%-3.0%) of newly delivered women in North Thames were found to be seronegative. Mothers born abroad, particularly in Sub-Saharan Africa and South Asia, were more likely to be seronegative than UK-born mothers, with adjusted odds ratios of 4.2 (95% CI 3.1-5.6) and 5.0 (3.8-6.5), respectively. Mothers under 20 years were more likely to be seronegative than those aged 30 to 34. CONCLUSION: Our findings highlight the need for vaccination to be targeted specifically at migrant women and their families to ensure that they are protected from rubella in pregnancy and its serious consequences.

Effects of infant feeding practice on weight gain from birth to 3 years.

OBJECTIVE: The influence of infant feeding practices on weight gain during childhood remains unresolved, with few studies adjusting appropriately for confounding factors. This study examined the effect of breastfeeding initiation, breastfeeding duration and age at introduction of solid foods on weight gain from birth to 3 years. DESIGN: Nationally representative prospective study. SETTING: England, Wales, Scotland and Northern Ireland. PARTICIPANTS: 10,533 3-year-old children from the UK Millennium Cohort Study. MAIN OUTCOME MEASURE: Conditional weight gain z-scores from birth to 3 years (adjusted for birthweight); multiple linear regression analyses were conducted to examine the impact of infant feeding practices on this measure after adjustment for confounding factors. RESULTS: Breastfeeding initiation and breastfeeding duration were significantly associated with weight gain from birth to 3 years. Infants receiving no breast milk grew faster than those whose mothers initiated breastfeeding (adjusted regression coefficient (difference in z-scores) 0.06, 95% CI 0.02 to 0.09), as did those breastfed for less than 4 months (0.05, 95% CI 0.01 to 0.09) versus those breastfed 4 months or longer. Early introduction of solids was not associated with faster weight gain after adjustment for height z-score at 3 years (-0.01, 95% CI -0.04 to 0.03). CONCLUSIONS: Initiating and prolonging breastfeeding may reduce excess weight gain by preschool age. Association of the early introduction of solids with rapid weight gain during early childhood is mediated through childhood stature. Although effects sizes are small, at a population level they are of public health importance as these risk factors are potentially modifiable. Strategies to support mothers to follow internationally recommended infant feeding practices are required.

Newborn screening for medium chain acyl CoA dehydrogenase deficiency.

Medium chain acyl CoA dehydrogenase deficiency (MCADD) is an uncommon inborn error of fatty acid oxidation that is a preventable cause of morbidity and mortality. Newborn screening for MCADD has been introduced in many centres worldwide and in this review we outline what the clinician needs to know. In most screening programmes a positive screening test has a high predictive value, but the diagnosis should always be confirmed independently. The basic treatment is dietary: avoid fasting and ensure a high carbohydrate intake during any illness. Careful attention to detail is essential as the long term outcome is only as good as the frontline clinical management.

Feasibility of collecting oral fluid samples in the home setting to determine seroprevalence of infections in a large-scale cohort of preschool-aged children.

Oral fluid is a non-invasive biological sample, which can be returned by post, making it suitable for large-scale epidemiological studies in children. We report our experience of oral fluid collection from 14 373 preschool-aged children in the UK Millennium Cohort Study. Samples were collected by mothers in the home setting following the guidance of trained interviewers, and posted to the laboratory. Samples were received from 11 698 children (81.4%). Children whose mothers were of Black Caribbean ethnicity and who lived in non-English-speaking households were less likely to provide a sample, and those with a maternal history of asthma more likely to provide a sample [adjusted risk ratio (95% CI) 0.85 (0.73-0.98), 0.87 (0.77-0.98) and 1.03 (1.00-1.05) respectively]. Collection of oral fluid samples is feasible and acceptable in large-scale child cohort studies. Formal interpreter support may be required to increase participation rates in surveys that collect biological samples from ethnic minorities.

Ethnicity of children with homozygous c.985A>G medium-chain acyl-CoA dehydrogenase deficiency: findings from screening approximately 1.1 million newborn infants.

OBJECTIVES: It has been suggested that homozygous c.985A>G medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a disease of White ethnic origin but little is known regarding its ethnic distribution. We estimated ethnic-specific homozygous c.985A>G MCADD birth prevalence from a large-scale UK newborn screening study. METHODS: Homozygous c.985A>G MCADD cases were ascertained in six English newborn screening centres between 1 March 2004 and 28 February 2007 by screening approximately 1.1 million newborns using tandem mass spectrometry analysis of underivatised blood spot samples to quantitate octanoylcarnitine (C8). Follow-up biochemistry and mutation analyses for cases (mean triplicate C8 value >/=0.5 micromol/L) were reviewed to confirm diagnosis. Ethnicity was ascertained from clinician report and denominators from 2001 UK Census estimates of ethnic group of children less than one year. RESULTS: Sixty-four infants were c.985A>G MCADD homozygotes (overall prevalence 5.8 per 100,000 live births; 95% CI 4.4-7.2). Sixty (93%) were White, two (3%) were mixed/other and two were of unknown ethnic origin. No Asian or Black homozygotes were identified. Proportions of White, mixed/other, Asian and Black births in screening regions were estimated, yielding homozygous c.985A>G MCADD birth prevalence of 6.9 per 100,000 (95% CI 5.2-8.8) in White, and 95% CI estimates of 0-2.7 per 100,000 in Asian and 0-5.8 in Black populations. The c.985A>G carrier frequency in the White group was estimated at one in 65 (95% CI 1/74, 1/61) under Hardy-Weinberg conditions. CONCLUSION: c.985A>G homozygous MCADD is not found in Black and Asian ethnic groups that have been screened at birth in England. This is consistent with the earlier published observations suggesting that MCADD due to the c.985A>G mutation is a disease of White ethnic origin.

Analysis of rubella antibody distribution from newborn dried blood spots using finite mixture models.

Eluted dried blood spot specimens from newborn screening, collected in 2004 in North Thames and anonymously linked to birth registration data, were tested for maternally acquired rubella IgG antibody as a proxy for maternal antibody concentration using an enzyme-linked immunosorbent assay. Finite mixture regression models were fitted to the antibody concentrations from 1964 specimens. The Bayesian Information Criterion (BIC) was used as a model selection criterion to avoid over-fitting the number of mixture model components. This allowed investigation of the independent effect of maternal age and maternal country of birth on rubella antibody concentration without dichotomizing the outcome variable using cut-off values set a priori. Mixture models are a highly useful method of analysis in seroprevalence studies of vaccine-preventable infections in which preset cut-off values may overestimate the size of the seronegative population.

The birth prevalence of PKU in populations of European, South Asian and sub-Saharan African ancestry living in South East England.

Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism (OMIM 261600). Treatment with a low-phenylalanine diet following early ascertainment by newborn screening prevents impaired cognitive development, the major disease phenotype in PKU. The overall birth prevalence of PKU in European, Chinese and Korean populations is approximately 1/10,000. Since the human PAH locus contains PKU-causing alleles and polymorphic core haplotypes that describe and corroborate an out-of-Africa range expansion in modern human populations, it is of interest to know the prevalence of PKU in different ethnic groups with diverse geographical origin. We estimated PKU prevalence in South East England, where a sizeable proportion of the population are of Sub-Saharan African or South Asian ancestry. Over the period 1994 to 2004 167 children were diagnosed with PKU. Using birth registration and census data to derive denominators, PKU birth prevalence per 10,000 live births (95% Bayesian credible intervals) was estimated to be 1.14 (0.96-1.33) among white, 0.11 (0.02-0.37) among black, and 0.29 (0.10-0.63) among Asian ethnic groups. This suggests that PKU is up to an order of magnitude less prevalent in populations with Sub-Saharan African and South Asian ancestry that have migrated to the UK.

Regional differences in overweight: an effect of people or place?

OBJECTIVE: To examine UK country and English regional differences in childhood overweight (including obesity) at 3 years and determine whether any differences persist after adjustment for individual risk factors. DESIGN: Nationally representative prospective study. SETTING: England, Wales, Scotland and Northern Ireland. PARTICIPANTS: 13 194 singleton children from the UK Millennium Cohort Study with height and weight data at age 3 years. MAIN OUTCOME MEASURE: Overweight (including obesity) was defined according to the International Obesity TaskForce cut-offs for body mass index, which are age and sex specific. RESULTS: At 3 years of age, 23% (3102) of children were overweight or obese. In univariable analyses, children from Northern Ireland (odds ratio 1.30, 95% confidence interval 1.14 to 1.48) and Wales (1.26, 1.11 to 1.44) were more likely to be overweight than children from England. There were no differences in overweight between children from Scotland and England. Within England, children from the East (0.71, 0.57 to 0.88) and South East regions (0.82, 0.68 to 0.99) were less likely to be overweight than children from London. There were no differences in overweight between children from other English regions and children from London. These differences were maintained after adjustment for individual socio-demographic characteristics and other risk factors for overweight. CONCLUSIONS: UK country and English regional differences in early childhood overweight are independent of individual risk factors. This suggests a role for policies to support environmental changes that remove barriers to physical activity or healthy eating in young children.

Agreement of rubella IgG antibody measured in serum and dried blood spots using two commercial enzyme-linked immunosorbent assays.

Cases of congenital rubella are now rare in the United Kingdom. However, in certain areas such as London, where a significant proportion of pregnant women has been born abroad and uptake of trivalent measles-mumps-rubella (MMR) vaccination is low, the risk of a rubella outbreak remains. Prior to carrying out a seroprevalence study using rubella IgG antibody in newborn dried blood spots as an indirect marker of maternal immunity, rubella IgG antibody concentrations in serum and dried blood spot samples were investigated. Anonymous paired serum-dried blood spot samples left over from occupational health screening were tested for rubella IgG antibody by two commercially available enzyme-linked immunosorbent assays (ELISAs) (Dade Behring, Marburg, Germany, and Diesse, Siena, Italy). Agreement between serum samples and dried blood spot samples was high for both assays. There were no significant differences in antibody concentrations in paired samples, as 67 of 73 samples tested with the Diesse ELISA (91.8%), and 76 out of 79 samples tested with the Dade Behring ELISA (96.2%) were within two standard deviations of the mean difference. Commercial ELISAs are an appropriate test for seroprevalence surveys based on rubella IgG in dried blood spot samples.

Is infant growth changing?

Weight gain between birth and 9 months of 12 903 term Millennium Cohort Study infants was investigated in order to determine differences according to sex, ethnicity and country of birth. The standardised weights and weight gains were also compared with a cohort of mainly white infants born 10 years earlier to determine whether weight gain has changed over the last decade. There were significant differences between ethnic groups, with black infants showing the largest weight gain and Asians the smallest. White boys born in England and Scotland grew relatively faster than girls, but there were no significant gender differences among the other ethnic groups or among infants born in Ireland and Wales. There was very little difference in weight gain between white English Millennium cohort infants and the earlier cohort, suggesting that the current epidemic of childhood obesity starts after 9 months of age.

Newborn screening for congenital heart defects: a systematic review and cost-effectiveness analysis.

OBJECTIVES: To provide evidence to inform policy decisions about the most appropriate newborn screening strategy for congenital heart defects, identifying priorities for future research that might reduce important uncertainties in the evidence base for such decisions. DATA SOURCES: Electronic databases. Groups of parents and health professionals. REVIEW METHODS: A systematic review of the published medical literature concerning outcomes for children with congenital heart defects was carried out. A decision analytic model was developed to assess the cost-effectiveness of alternative screening strategies for congenital heart defects relevant to the UK. A further study was then carried out using a self-administered anonymous questionnaire to explore the perspectives of parents and health professionals towards the quality of life of children with congenital heart defects. The findings from a structured review of the medical literature regarding parental experiences were linked with those from a focus group of parents of children with congenital heart defects. RESULTS: Current newborn screening policy comprises a clinical examination at birth and 6 weeks, with specific cardiac investigations for specified high-risk children. Routine data are lacking, but under half of affected babies, not previously identified antenatally or because of symptoms, are identified by current newborn screening. There is evidence that screen-positive infants do not receive timely management. Pulse oximetry and echocardiography, in addition to clinical examination, are alternative newborn screening strategies but their cost-effectiveness has not been adequately evaluated in a UK setting. In a population of 100,000 live-born infants, the model predicts 121 infants with life-threatening congenital heart defects undiagnosed at screening, of whom 82 (68%) and 83 (69%) are detected by pulse oximetry and screening echocardiography, respectively, but only 39 (32%) by clinical examination alone. Of these, 71, 71 and 34, respectively, receive a timely diagnosis. The model predicts 46 (0.5%) false-positive screening diagnoses per 100,000 infants with clinical examination, 1168 (1.3%) with pulse oximetry and 4857 (5.4%) with screening echocardiography. The latter includes infants with clinically non-significant defects. Total programme costs are predicted of pound 300,000 for clinical examination, pound 480,000 for pulse oximetry and pound 3.54 million for screening echocardiography. The additional cost per additional timely diagnosis of life-threatening congenital heart defects ranges from pound 4900 for pulse oximetry to pound 4.5 million for screening echocardiography. Including clinically significant congenital heart defects gives an additional cost per additional diagnosis of pound 1500 for pulse oximetry and pound 36,000 for screening echocardiography. Key determinants for cost-effectiveness are detection rates for pulse oximetry and screening echocardiography. Parents and health professionals place similar values on the quality of life outcomes of children with congenital heart defects and both are more averse to neurological than to cardiac disability. Adverse psychosocial effects for parents are focused around poor management and/or false test results. CONCLUSIONS: Early detection through newborn screening potentially can improve the outcome of congenital heart defects; however the current programme performs poorly, and lacks monitoring of quality assurance, performance management and longer term outcomes. Pulse oximetry is a promising alternative newborn screening strategy but further evaluation is needed to obtain more precise estimates of test performance and to inform optimal timing, diagnostic and management strategies. Although screening echocardiography is associated with the highest detection rate, it is the most costly strategy and has a 5% false-positive rate. Improving antenatal detection of congenital heart defects increases the cost per timely postnatal diagnosis afforded by any newborn screening strategy but does not alter the relative effects of the strategies. An improvement of timely management of screen positive infants is essential. Further research is required to refine the detection rate and other aspects of pulse oximetry, to evaluate antenatal screening strategies more directly, and to investigate the psychosocial effects of newborn screening for congenital heart defects.

The hip trial: psychosocial consequences for mothers of using ultrasound to manage infants with developmental hip dysplasia.

BACKGROUND: The hip trial aimed to assess clinical effectiveness, economic and psychosocial costs, and benefits of ultrasound imaging (US) compared with conventional clinical assessment alone to guide the management of infants with neonatal hip instability. OBJECTIVE: To report on psychosocial consequences for mothers and the developing mother-child relationship of US, and associations between abduction splinting and maternal psychosocial distress. DESIGN: Multicentre randomised controlled trial. SETTING: Thirty three hospitals in the United Kingdom and Ireland. PARTICIPANTS, INTERVENTIONS: A total of 629 infants with neonatal hip instability randomised to US examination or clinical assessment alone before treatment decision. Questionnaires were completed by 561 (89%) mothers at 8 weeks and 494 (79%) at 1 year. MAIN OUTCOME MEASURES: Anxiety, postnatal depression, parenting stress assessed by standardised questionnaires. Maternal concerns about hip problems were assessed using the Infant hip worries inventory. RESULTS: At 8 weeks, there were no differences between US and non-US groups of the trial in maternal anxiety (mean difference (MD) -1.2, 95% confidence interval (CI) -3.2 to 0.8), depression (MD 0.0, 95% CI -0.7 to 0.8), parenting stress (MD -1.2, 95% CI -2.8 to 0.4), or other measures. The same pattern was evident at 1 year. In an explanatory analysis, early splinting was associated with increased anxiety at 8 weeks (MD 3.8, 95% CI 1.7 to 5.9) and increased level of hip worries at 8 weeks (MD 6.8, 95% CI 5.6 to 7.9) and 1 year (MD 1.3, 95% CI 0.3 to 2.4). CONCLUSIONS: Although early splinting is associated with maternal anxieties, US is not associated with any increase or reduction in psychosocial effects on mothers. Together with the clinical findings, this suggests that the use of US allows reduction in splinting rates without increased risk of adverse clinical or psychosocial outcomes.

Disclosing to parents newborn carrier status identified by routine blood spot screening.

BACKGROUND: Newborn blood spot screening programmes are designed to detect serious conditions affecting individuals, where early treatment can improve health. It is suggested that screening can improve the experience of diagnosis for parents. For example, without newborn screening, when a child with cystic fibrosis becomes symptomatic a period of uncertainty can arise prior to diagnosis. These potential advantages of screening need to be weighed against potential disadvantages of screening at individual and population levels. Some newborn screening programmes inadvertently identify newborn infants who, although not affected by the condition, carry a gene for it and can pass on that gene to their children; these are 'genetic carriers'. Knowledge of newborn carrier status can lead to: testing of parents and family members, and concern about possible affected future siblings should both parents be identified as carriers; the possibility of such testing revealing the putative father is not the biological father; concern about the child's future reproductive choices; and unjustified anxiety about the health of the carrier newborn. There is an urgent need to develop clear guidance as to how to respond, with advances in technology fuelling the expansion of newborn blood spot screening and raised expectations of informed consent and disclosing test results. Depending on the condition for which screening is offered, options include: employing tests that do not identify carrier status, if available; identifying acceptable ways of disclosing carrier status; or identifying acceptable ways of not disclosing carrier status. These options are illustrated by screening programmes for sickle cell disorders and cystic fibrosis. Currently, there are no screening tests available for sickle cell disorders that do not identify carrier status. For cystic fibrosis, the policy choice is between an extended period of testing, and a screening result that is available sooner for most newborns, but inadvertently identifies carrier babies. OBJECTIVES: The aim of this review was to assess the impact of disclosing to parents newborn carrier status inadvertently identified by routine newborn blood spot screening. SEARCH STRATEGY: We searched for reports addressing disclosing newborn carrier status to parents following newborn screening for sickle cell disorders and cystic fibrosis in: commercially available electronic databases (October 2002), specialist registers, online journals, online abstracts and conference abstracts. We also scanned the reference lists of included papers. SELECTION CRITERIA: Studies addressing the impact of disclosing carrier status using a soundly controlled trial or randomised controlled trial. DATA COLLECTION AND ANALYSIS: Two researchers independently scanned titles and abstracts for relevance using the pre-specified inclusion criteria. Full reports of selected citations were then located and screened again for relevance by two researchers independently. At each stage, results were compared and discrepancies resolved by discussion. MAIN RESULTS: We found no controlled trials about disclosing carrier status. REVIEWERS' CONCLUSIONS: There is a need to develop and evaluate the effects of interventions to support the disclosure of carrier status to parents following newborn screening.