Observational Birth Cohort Study Research Articles

Association of Toll-like receptor 2 rs111200466 polymorphism with low serum levels of IL-33 in early childhood.

TLR2 is one of ten human TLRs which plays an important role in the recognition of pathogens and activation of the innate immunity via NF-κB pathway. NF-κB activation induces the expression of various pro-inflammatory genes. This study examines the effect of TLR2 polymorphisms on the production of blood pro-inflammatory cytokines in healthy Finnish children. One hundred forty-six children who participated in a prospective observational birth cohort study in Turku, Finland, were included. DNA samples were analysed by PCR-based sequencing for two common TLR2 polymorphisms (rs5743708 Arg753Gln; rs111200466 -196 to -174del). Serum concentrations of IL-33, IL-31, IL-17A and IL-17F were measured by multiplex immunoassay and sST2 by ELISA in children at the age of 13 months. Children with variant type of TLR2 rs111200466 (ins/del or del/del) had significantly lower level of serum IL-33 (median, 0.00 pg/mL; IQR 0.00 - 17.60) than those with ins/ins type of TLR2 (19.81 pg/mL; IQR 0.00 - 51.78) (P = 0.0001). Almost all study subjects had serum concentrations of IL-17A, IL-17F and IL-31 below the detection limit and therefore not included into the final analyses. No differences in levels of above four cytokines and sST2 were found between TLR2 rs5743708 genotypes (GG and GA). Our results indicated that the TLR2 rs111200466 deletion was associated with a low level of serum IL-33, suggesting that the polymorphism may impair the production of IL-33.

The burden of respiratory syncytial virus in healthy term-born infants in Europe: a prospective birth cohort study.

Respiratory syncytial virus (RSV) is a major cause of hospitalisation in infants. The burden of RSV infection in healthy term infants has not yet been established. Accurate health-care burden data in healthy infants are necessary to determine RSV immunisation policy when RSV immunisation becomes available. We performed a multicentre, prospective, observational birth cohort study in healthy term-born infants (≥37 weeks of gestation) in five sites located in different European countries to determine the health-care burden of RSV. The incidence of RSV-associated hospitalisations in the first year of life was determined by parental questionnaires and hospital chart reviews. We performed active RSV surveillance in a nested cohort to determine the incidence of medically attended RSV infections. The study is registered with ClinicalTrials.gov, NCT03627572. In total, 9154 infants born between July 1, 2017, and April 1, 2020, were followed up during the first year of life and 993 participated in the nested active surveillance cohort. The incidence of RSV-associated hospitalisations in the total cohort was 1·8% (95% CI 1·6-2·1). There were eight paediatric intensive care unit admissions, corresponding to 5·5% of 145 RSV-associated hospitalisations and 0·09% of the total cohort. Incidence of RSV infection in the active surveillance cohort confirmed by any diagnostic assay was 26·2% (24·0-28·6) and that of medically attended RSV infection was 14·1% (12·3-16·0). RSV-associated acute respiratory infection causes substantial morbidity, leading to the hospitalisation of one in every 56 healthy term-born infants in high-income settings. Immunisation of pregnant women or healthy term-born infants during their first winter season could have a major effect on the health-care burden caused by RSV infections. Innovative Medicines Initiative 2 Joint Undertaking, with support from the EU's Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations.

Bowel habits in healthy infants and the prevalence of functional constipation, infant colic and infant dyschezia.

During infancy bowel habits change. Most infants with gastrointestinal problems have a functional gastrointestinal disorder (FGID), a major reason for visiting paediatricians. This study aims to provide data on stool frequency and consistency during the first year, prevalence rates for functional constipation (FC) and to establish associations with relevant demographic data. The occurrence of infant colic (IC) and infant dyschezia (ID) was also reported. This prospective observational birth-cohort study enrolled 122 healthy full-term infants. Questionnaires were completed at 2 weeks and 2, 6 and 12months. Stool frequency decreased with age and consistency changed, with fewer runny stools. At 2 weeks, 24.3% had at least one of the studied FGID. FC was found in 2.6%-14.3% (up to 12months), IC was found in 4.9%-3.4% (up to 2 months) and ID in 22.1%-3.9% (up to 6 months). Infants with an FGID had a lower weight and more healthcare visits than infants without. Breastfeeding and a high percentage of runny stools at 2 weeks of age decreased the odds of developing FC. Data on bowel habits and the prevalence of FC, IC and ID are presented. FGID during infancy is common and affects children's well-being, while their families need support and advice.

Validation of a touchscreen assessment tool to screen for cognitive delay at 24 months.

To validate a touchscreen assessment as a screening tool for mild cognitive delay in typically developing children aged 24 months. Secondary analysis of data was completed from an observational birth cohort study (The Cork Nutrition & Microbiome Maternal-Infant Cohort Study [COMBINE]), with children born between 2015 and 2017. Outcome data were collected at 24 months of age, at the INFANT Research Centre, Ireland. Outcomes were the Bayley Scales of Infant and Toddler Development, Third Edition cognitive composite score and a language-free, touchscreen-based cognitive measure (Babyscreen). A total of 101 children (47 females, 54 males) aged 24 months (mean=24.25, SD=0.22) were included. Cognitive composite scores correlated with the total number of Babyscreen tasks completed, with moderate concurrent validity (r=0.358, p < 0.001). Children with cognitive composite scores lower than 90 (1 SD below the mean, defined as mild cognitive delay) had lower mean Babyscreen scores than those with cognitive scores equal to or greater than 90 (8.50 [SD=4.89] vs 12.61 [SD=3.68], p=0.001). The area under the receiver operating characteristic curve for the prediction of a cognitive composite score less than 90 was 0.75 (95% confidence interval=0.59-0.91; p=0.006). Babyscreen scores less than 7 were equivalent to less than the 10th centile and identified children with mild cognitive delay with 50% sensitivity and 93% specificity. Our 15-minute, language-free touchscreen tool could reasonably identify mild cognitive delay among typically developing children.

Relationship between Animal Sourced Food Consumption and Early Childhood Development Outcomes.

Early-childhood development (ECD) is an important determinant of a child’s cognitive ability, learning, productivity, and lifetime earnings. Animal-sourced food (ASF), which is a rich source of high-quality protein and micronutrients, has been linked with ECD outcomes. This study investigates the relationship between the number, frequency, and cumulative consumption of ASF at 6, 9, 12, and 18 months of age and ECD outcomes at 24 months of age, controlling for physical growth. The study uses data collected from 701 mother−child pairs from an observational birth cohort study carried out in Banke, Nepal. ECD outcomes were assessed through a standardized ages and stages questionnaire (ASQ-3) tool. Separate multivariable ordinary least squares regression models were used to test for associations. Significant positive association was seen between total ASQ-3 score at 24 months of age and any ASF consumption at 18 months (β = 8.98, p-value < 0.01), controlling for growth outcomes. The study findings highlight the positive contribution and the accumulating benefit of consistent ASF consumption on ECD outcomes. This study recommends support and promotion of ASF intake among young children in Nepal through policy and programming actions relevant to female education; nutrition knowledge; quality ASF production; improved market access; cold storage; and poverty reduction.

Effect of perinatal factors on neonatal thyroid stimulating hormone

Background: Congenital Hypothyroidism (CH) is a common cause of mental retardation. Its incidence varies in different parts of the world from 1:4000 to 1:2000. Objective: To study effect of perinatal factors on heel prick blood TSH levels and to find incidence of congenital hypothyroidism. Study Design: Prospective Observational birth cohort study. Method: Heel prick blood samples of total 3151babies, 1673 (53.1%) males and 1478 (46.9%) females was taken on special graded filter paper within 48 hours of life and screened by fluoroimmunometric assay. Babies with TSH value more than 9µU/ml were recalled at 5 to 7 days of life for repeat sample of T3, T4, TSH. Babies with low T4 less than 7 µgm/dl and TSH more than 20 µU/ml were labelled as congenital hypothyroidism. The effect of perinatal factors was analyzed statistically. Result: In our study, thyroid screening in two third of neonates was done at 12 to 24 hours of age. Median (IQR) TSH of 3151 neonates was 3(1.4-5.5) µU/ml. TSH level was significantly low in neonates with sampling at age of >24 hours. Recall rate in our study was 7.6% (238 cases) and 2 neonates were diagnosed as congenital hypothyroidism. Neonates with assisted deliveries showed a higher median (IQR) TSH level 5.3(3-9.1µU/ml) as compared to normal vaginal deliveries and lower segment caesarean section. This was statistically significant (p

Nothing about us, without us: is for us

BackgroundPublic Participation Involvement Engagement (PPIE) is now strongly encouraged across health policy and research. Coproduction, although linked to PPIE is a way of working that can be applied to work collaboratively with participants in health. However, a lack of definition which leads to interchangeable terminology, limited guidance and examples of good practice on how to facilitate the process impedes progress. The Born in Bradford (BiB) research programme consists of a family of observational and longitudinal birth cohort studies (Raynor et al. in BMC Public Health 8:1–13, 2008; Dickerson et al. in BMC Public Health 16(1):1–14, 2016) which include participants from multi-ethnic and socially diverse backgrounds (Uphoff et al. in Int J Equity Health 12:1–12, 2013).MethodsThis paper aims to highlight our approach to PPIE and coproduction methodologies, to provide an outline of the methods we have utilised to work collaboratively with our cohort populations from diverse communities and how we have managed to overcome challenges to achieve successful PPIE.A secondary aim of this paper is to demonstrate the value of PPIE and coproduction and how it can enhance research. Some examples from recent years are provided to demonstrate how useful the approach has been for BiB community engagement and community participation. In addition, we discuss the methods we have used and how this methodology has now been embedded into protocol and practice in our research.ResultsSuccessful and productive PPIE and coproduction occur where stakeholders are taken on board and realise the impact that their involvement can have in terms of policy design and delivery.ConclusionsThe involvement of participants and the community in research about them becomes more credible when equal partnerships are formed and they are involved in the whole process leading to community ownership of research. Hence, nothing about us, without us—is for us.

Contribution of genetic factors to high rates of neonatal hyperbilirubinaemia on the Thailand-Myanmar border.

Very high unconjugated bilirubin plasma concentrations in neonates (neonatal hyperbilirubinaemia; NH) may cause neurologic damage (kernicterus). Both increased red blood cell turn-over and immaturity of hepatic glucuronidation contribute to neonatal hyperbilirubinaemia. The incidence of NH requiring phototherapy during the first week of life on the Thailand-Myanmar border is high (approximately 25%). On the Thailand-Myanmar border we investigated the contribution of genetic risk factors to high bilirubin levels in the first month of life in 1596 neonates enrolled in a prospective observational birth cohort study. Lower gestational age (<38 weeks), mutations in the genes encoding glucose-6-phosphate dehydrogenase (G6PD) and uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A1 were identified as the main independent risk factors for NH in the first week, and for prolonged jaundice in the first month of life. Population attributable risks (PAR%) were 61.7% for lower gestational age, 22.9% for hemi or homozygous and 9.9% for heterozygous G6PD deficiency respectively, and 6.3% for UGT1A1*6 homozygosity. In neonates with an estimated gestational age ≥ 38 weeks, G6PD mutations contributed PARs of 38.1% and 23.6% for "early" (≤ 48 hours) and "late" (49-168 hours) NH respectively. For late NH, the PAR for UGT1A1*6 homozygosity was 7.7%. Maternal excess weight was also a significant risk factor for "early" NH while maternal mutations on the beta-globin gene, prolonged rupture of membranes, large haematomas and neonatal sepsis were risk factors for "late" NH. For prolonged jaundice during the first month of life, G6PD mutations and UGT1A1*6 mutation, together with lower gestational age at birth and presence of haematoma were significant risk factors. In this population, genetic factors contribute considerably to the high risk of NH. Diagnostic tools to identify G6PD deficiency at birth would facilitate early recognition of high risk cases.

Neurocognitive outcomes in Malawian children exposed to malaria during pregnancy: An observational birth cohort study.

BackgroundAnnually 125 million pregnancies are at risk of malaria infection. However, the impact of exposure to malaria in pregnancy on neurodevelopment in children is not well understood. We hypothesized that malaria in pregnancy and associated maternal immune activation result in neurodevelopmental delay in exposed offspring.Methods and findingsBetween April 2014 and April 2015, we followed 421 Malawian mother–baby dyads (median [IQR] maternal age: 21 [19, 28] years) who were previously enrolled (median [IQR] gestational age at enrollment: 19.7 [17.9, 22.1] weeks) in a randomized controlled malaria prevention trial with 5 or 6 scheduled assessments of antenatal malaria infection by PCR. Children were evaluated at 12, 18, and/or 24 months of age with cognitive tests previously validated in Malawi: the Malawi Developmental Assessment Tool (MDAT) and the MacArthur–Bates Communicative Development Inventories (MCAB-CDI). We assessed the impact of antenatal malaria (n [%] positive: 240 [57.3]), placental malaria (n [%] positive: 112 [29.6]), and maternal immune activation on neurocognitive development in children. Linear mixed-effects analysis showed that children exposed to antenatal malaria between 33 and 37 weeks gestation had delayed language development across the 2-year follow-up, as measured by MCAB-CDI (adjusted beta estimate [95% CI], −7.53 [−13.04, −2.02], p = 0.008). Maternal immune activation, characterized by increased maternal sTNFRII concentration, between 33 and 37 weeks was associated with lower MCAB-CDI language score (adjusted beta estimate [95% CI], −8.57 [−13.09, −4.06], p < 0.001). Main limitations of this study include a relatively short length of follow-up and a potential for residual confounding that is characteristic of observational studies.ConclusionsThis mother–baby cohort presents evidence of a relationship between malaria in pregnancy and neurodevelopmental delay in offspring. Malaria in pregnancy may be a modifiable risk factor for neurodevelopmental injury independent of birth weight or prematurity. Successful interventions to prevent malaria during pregnancy may reduce the risk of neurocognitive delay in children.

The High-Risk Type 1 Diabetes HLA-DR and HLA-DQ Polymorphisms Are Differentially Associated With Growth and IGF-I Levels in Infancy: The Cambridge Baby Growth Study.

This study explored the link between HLA polymorphisms that predispose to type 1 diabetes and birth size, infancy growth, and/or circulating IGF-I in a general population-based birth cohort. The Cambridge Baby Growth Study is a prospective observational birth cohort study that recruited 2,229 newborns for follow-up in infancy. Of these, 612 children had DNA available for genotyping single nucleotide polymorphisms in the HLA region that capture the highest risk of type 1 diabetes: rs17426593 for DR4, rs2187668 for DR3, and rs7454108 for DQ8. Multivariate linear regression models at critical ages (cross-sectional) and mixed-effects models (longitudinal) were performed under additive genetic effects to test for associations between HLA polymorphisms and infancy weight, length, skinfold thickness (indicator of adiposity), and concentrations of IGF-I and IGF-binding protein-3 (IGFBP-3). In longitudinal models, the minor allele of rs2187668 tagging DR3 was associated with faster linear growth (P = 0.007), which was more pronounced in boys (P = 3 × 10-7) than girls (P = 0.07), and was also associated with increasing IGF-I (P = 0.002) and IGFBP-3 (P = 0.003) concentrations in infancy. Cross-sectionally, the minor alleles of rs7454108 tagging DQ8 and rs17426593 tagging DR4 were associated with lower IGF-I concentrations at age 12 months (P = 0.003) and greater skinfold thickness at age 24 months (P = 0.003), respectively. The variable associations of DR4, DR3, and DQ8 alleles with growth measures and IGF-I levels in infants from the general population could explain the heterogeneous growth trajectories observed in genetically at-risk cohorts. These findings could suggest distinct mechanisms involving endocrine pathways related to the HLA-conferred type 1 diabetes risk.

Prevalence and early-life risk factors of school-age allergic multimorbidity: The EuroPrevall-iFAAM birth cohort.

BackgroundCoexistence of childhood asthma, eczema and allergic rhinitis is higher than can be expected by chance, suggesting a common mechanism. Data on allergic multimorbidity from a pan‐European, population‐based birth cohort study have been lacking. This study compares the prevalence and early‐life risk factors of these diseases in European primary school children.MethodsIn the prospective multicentre observational EuroPrevall‐iFAAM birth cohort study, we used standardized questionnaires on sociodemographics, medical history, parental allergies and lifestyle, and environmental exposures at birth, 12 and 24 months. At primary school age, parents answered ISAAC‐based questions on current asthma, rhinitis and eczema. Allergic multimorbidity was defined as the coexistence of at least two of these.ResultsFrom 10,563 children recruited at birth in 8 study centres, we included data from 5,572 children (mean age 8.2 years; 51.8% boys). Prevalence estimates were as follows: asthma, 8.1%; allergic rhinitis, 13.3%; and eczema, 12.0%. Allergic multimorbidity was seen in 7.0% of the whole cohort, ranging from 1.2% (Athens, Greece) to 10.9% (Madrid, Spain). Risk factors for allergic multimorbidity, identified with AICc, included family‐allergy‐score, odds ratio (OR) 1.50 (95% CI 1.32–1.70) per standard deviation; early‐life allergy symptoms, OR 2.72 (2.34–3.16) for each symptom; and caesarean birth, OR 1.35 (1.04–1.76). Female gender, OR 0.72 (0.58–0.90); older siblings, OR 0.79 (0.63–0.99); and day care, OR 0.81 (0.63–1.06) were protective factors.ConclusionAllergic multimorbidity should be regarded as an important chronic childhood disease in Europe. Some of the associated early‐life factors are modifiable and may be considered for prevention strategies.

Prenatal lead exposure: associations with growth and anthropometry in early childhood in a UK observational birth cohort study

Background:Lead is a neurotoxic metal that crosses the placenta freely. It has adverse effects on a range of birth outcomes. The few studies reporting on the associations of prenatal exposure to lead and child growth have had conflicting results. This study aimed to examine the effect of prenatal exposure to lead on children’s growth from 4 to 61 months of age.Methods:Pregnant women were enrolled in the UK Avon Longitudinal Study of Parents and Children (ALSPAC). Whole blood samples for pregnancies with a live birth were analysed for lead (n=4140). A 10% subsample of the offspring cohort (Children in Focus) were invited to clinics at 10 time points (4–61 months) at which anthropometric measurements were carried out; z-scores for height, weight and BMI were calculated using the 1990 British Growth Reference Standards. Associations between prenatal log10-lead concentrations and z-scores and other anthropometric measures were modelled using adjusted linear regression models in an imputed dataset for children who attended at least one clinic (n=574).Results:The median prenatal blood lead concentration was 3.60 (IQR 2.61–4.16) µg/dl. There was no evidence for any associations of prenatal lead exposure with z-scores for BMI, height or weight in adjusted models from age 4 to 61 months. There were no associations for other anthropometric measures including mid-upper arm circumference, head circumference and waist circumference. There was some evidence for a weakly positive effect of prenatal lead exposure on head circumference in girls at age 43 and 61 months (at 61 months unstandardised B coefficient 1.59 (95% CI 0.12, 3.16) cm, p=0.048) but not at other ages.Conclusions:There was no consistent evidence of associations between prenatal exposure to lead and measures of growth and anthropometry from age 4 to 61 months in this cohort of children in the UK.

Association of Gluten Intake During the First 5 Years of Life With Incidence of Celiac Disease Autoimmunity and Celiac Disease Among Children at Increased Risk

To investigate if the amount of gluten intake during the first 5 years of life in genetically predisposed children is associated with increased risk of celiac disease autoimmunity and celiac disease.This prospective observational birth cohort study, The Environmental Determinants of Diabetes in the Young (TEDDY), followed children from birth up to 15 years of age at 6 clinical research centers in Finland, Sweden, Germany, and the United States. Between 2004 and 2010, 8676 newborns carrying HLA antigen genotypes associated with type 1 diabetes and celiac disease were enrolled. Data on gluten intake were available in 6605 children (49% female) and this was the group included in the analysis. Median follow-up was 9.0 years (range, 1.0–13.0 years).Serum tissue transglutaminase (tTG) autoantibodies were measured annually in 6757 children from the age of 2 years. Gluten intake was estimated from 3-day food records collected at ages 6, 9, and 12 months and then biannually until 5 years old. Composite foods and recipes were broken down to ingredients. Absolute gluten intake (grams/day) was calculated.The primary outcome was celiac disease autoimmunity, defined as positive tTG autoantibodies found in 2 consecutive serum samples. Radiobinding assays were used to measure autoantibodies. In the US centers, IgA–tTG autoantibodies were measured. In the European centers, both IgA and IgG–tTG autoantibodies were measured. Diagnosis of celiac disease was confirmed by intestinal biopsy (Marsh score ≥2) or if a biopsy was not done, by persistently elevated tTG autoantibody levels (average of 2 yearly samples ≥ 100 U). Decision to perform endoscopy and biopsy was not determined by study protocol.1216 (18%) children developed celiac disease autoimmunity, and 447 (7%) developed celiac disease. The incidence for both outcomes peaked at 2 to 3 years of age. Children homozygous for HLA DR3-DQ2 were at the highest risk of celiac disease autoimmunity and celiac disease. Swedish residence, female sex, and family history of celiac disease were also associated with increased risk for both outcomes. The authors found that higher gluten intake during the first 5 years after birth was associated with an increased risk of celiac disease autoimmunity (hazard ratio, 1.30 [95% CI, 1.22–1.38]; absolute risk of 28.1% by the age of 3 years if a reference amount of gluten was consumed; absolute risk was 34.2% if the gluten amount consumed was 1-g/d higher than the reference amount. Similarly, the authors found that higher gluten intake during the first 5 years after birth was associated with an increased risk of celiac disease (hazard ratio, 1.50 [95% CI, 1.35–1.66]; absolute risk by the age of 3 years if the reference amount of gluten was consumed, 20.7%; absolute risk if the gluten amount consumed was 1-g/d higher than the reference amount, 27.9%. A post hoc analysis that focused on dietary gluten intake at the age of 2 years (just prior to the peak of celiac disease autoimmunity or celiac disease) found that daily gluten consumption of as little as 2 g (equivalent to 1 slice of bread) was associated with an increased risk of developing celiac disease autoimmunity or celiac disease; that risk was further increased for each gram of gluten ingested beyond this threshold.Higher gluten intake during the first 5 years of life was associated with increased risk of celiac disease autoimmunity and celiac disease among genetically predisposed children.In an accompanying editorial, it was pointed out that the amount of gluten ingested during the first 5 years after birth cannot completely explain the increased prevalence of celiac disease. Previous work examining the relationship between HLA genetics, gluten consumption, and celiac disease prevalence found no significant relationship between the amount of gluten ingested and the prevalence of celiac disease. As well, the prevalence of celiac disease in Finland is higher (1%–2.5%) than in Italy (0.7%–1.1%), yet infant wheat consumption in Italy is much higher than in Finland. Further investigation is needed, but pediatricians could consider counseling families of known genetic predisposition for celiac disease or type 1 diabetes to delay or diminish gluten ingestion in infants.

Antimicrobial Prescribing during Infant Hospital Admissions in a Birth Cohort in Dhaka, Bangladesh.

Empirical antimicrobial use is common in hospitalized infants and may contribute to antimicrobial resistance in low- and middle-income countries. In this observational birth cohort study nested in a randomized controlled trial in Dhaka, Bangladesh, inpatient antimicrobial prescription data were extracted from serious adverse event forms completed for hospitalizations of infants (0–12 months of age). The primary outcome was the proportion of inpatient admissions where systemic antimicrobials were prescribed. Infant and hospitalization-related factors associated with antimicrobial prescriptions were determined. Among 1254 infants, there were 448 admissions to 32 facilities from 2014 to 2016. Antimicrobials were prescribed in 73% of admissions with a mean antimicrobial exposure rate of 0.25 antimicrobials per day of admission [95% confidence intervals (95% CIs): 0.24–0.27]. The most common antibiotics were aminoglycosides (29%), penicillins (26%) and third-generation cephalosporins (25%). In all, 58% of antibiotics were classified as ‘access’, 38% ‘watch’ and 1% ‘reserve’ using the World Health Organization (WHO) Essential Medicines List classification. WHO-recommended antimicrobial regimens were used in 68% of neonatal sepsis and 9% of lower respiratory tract infection (LRTI) admissions. ‘Watch’ antimicrobials were used in 26% of neonatal sepsis and 76% of LRTI admissions. Compared with private facilities, antimicrobial prescription rates were lower at government [rate ratio (RR) 0.71; 95% CI: 0.61–0.83] and charitable facilities (RR 0.39; 95% CI: 0.28–0.53), after adjustment for household wealth index and parental education. Younger infant age, older maternal age and longer admission were associated with higher prescription rates. These findings highlight the need for paediatric antimicrobial stewardship programs in Bangladesh.

Prenatal lead exposure: associations with growth and anthropometry in early childhood in a UK observational birth cohort study

Background:Lead is a neurotoxic metal that crosses the placenta freely. It has adverse effects on a range of birth outcomes. The few studies reporting on the associations of prenatal exposure to lead and child growth have had conflicting results. This study aimed to examine the effect of low-level prenatal exposure to lead on children’s growth from 4 to 61 months old.Methods:Pregnant women were enrolled in the UK Avon Longitudinal Study of Parents and Children (ALSPAC). Whole blood samples for pregnancies with a live birth were analysed for lead (n=4140). A 10% subsample of the offspring cohort (Children in Focus) were invited to clinics at 10 time points (4–61 months) at which anthropometric measurements were carried out; z-scores for height, weight and BMI were calculated using the 1990 British Growth Reference Standards. Associations between prenatal log10-lead concentrations and z-scores and other anthropometric measures were modelled using adjusted linear regression models in an imputed dataset for children who attended at least one clinic (n=574).Results:The mean prenatal blood lead concentration was 3.59±1.50 (range 1.22–14.70) µg/dl. There was no evidence for any associations of low-level prenatal lead exposure with z-scores for BMI, height or weight in adjusted models from age 4 to 61 months. There were no associations for other anthropometric measures including mid-upper arm circumference, head circumference and waist circumference. There was some evidence for a weakly positive effect of prenatal lead exposure on head circumference in girls at age 43 and 61 months (at 61 months unstandardised B coefficient 1.59 (95% CI 0.12, 3.16) cm, p=0.048) but not at other ages.Conclusions:There was no consistent evidence of associations between prenatal exposure to lead and measures of growth and anthropometry from age 4 to 61 months in this cohort of children in the UK.

Prenatal airshed pollutants and preterm birth in an observational birth cohort study in Detroit, Michigan, USA

Detroit, Michigan, currently has the highest preterm birth (PTB) rate of large cities in the United States. Disproportionate exposure to ambient air pollutants, including particulate matter ≤2.5 μm (PM2.5), PM ≤ 10 μm (PM10), nitrogen dioxide (NO2) and benzene, toluene, ethylbenzene, and xylenes (BTEX) may contribute to PTB. Our objective was to examine the association of airshed pollutants with PTB in Detroit, MI. The Geospatial Determinants of Health Outcomes Consortium (GeoDHOC) study collected air pollution measurements at 68 sites in Detroit in September 2008 and June 2009. GeoDHOC data were coupled with 2008–2010 Michigan Air Sampling Network measurements in Detroit to develop monthly ambient air pollution estimates at a spatial density of 300 m2. Using delivery records from two urban hospitals, we established a retrospective birth cohort of births by Detroit women occurring from June 2008 to May 2010. Estimates of air pollutant exposure throughout pregnancy were assigned to maternal address at delivery. Our analytic sample size included 7961 births; 891 (11.2%) were PTB. After covariate adjustment, PM10 (P = 0.003) and BTEX (P < 0.001), but not PM2.5 (P = 0.376) or NO2 (P = 0.582), were statistically significantly associated with PTB. In adjusted models, for every 5-unit increase in PM10 there was a 1.21 times higher odds of PTB (95% CI 1.07, 1.38) and for every 5-unit increase in BTEX there was a 1.54 times higher odds of PTB (95% CI 1.25, 1.89). Consistent with previous studies, higher PM10 was associated with PTB. We also found novel evidence that higher airshed BTEX is associated with PTB. Future studies confirming these associations and examining direct measures of exposure are needed.

Neurodevelopment of HIV-exposed uninfected children in South Africa: outcomes from an observational birth cohort study

SummaryBackgroundHIV infection is known to cause developmental delay, but the effects of HIV exposure without infection during pregnancy on child development are unclear. We compared the neurodevelopmental outcomes of HIV-exposed uninfected and HIV-unexposed children during their first 2 years of life.MethodsPregnant women (>18 years of age) at 20–28 weeks' gestation were enrolled into the Drakenstein Child Health cohort study while attending routine antenatal appointments at one of two peri-urban community-based clinics in Paarl, South Africa. Livebirths born to enrolled women during follow-up were included in the birth cohort. Mothers and infants received antenatal and postnatal HIV testing and antiretroviral therapy per local guidelines. Developmental assessments on the Bayley Scales of Infant and Toddler Development, third edition (BSID-III), were done in a subgroup of infants at 6 months of age, and in the full cohort at 24 months of age, with assessors masked to HIV exposure status. Mean raw scores and the proportions of children categorised as having a delay (scores <–2 SDs from the reference mean) on BSID-III were compared between HIV-exposed uninfected and HIV-unexposed children.Findings1225 women were enrolled between March 5, 2012, and March 31, 2015. Of 1143 livebirths, 1065 (93%) children were in follow-up at 6 months and 1000 (87%) at 24 months. Two children were diagnosed with HIV infection between birth and 24-month follow-up and were excluded from the analysis. BSID-III assessments were done in 260 (24%) randomly selected children (61 HIV-exposed uninfected, 199 HIV-unexposed) at 6 months and in 732 (73%) children (168 HIV-exposed uninfected, 564 HIV-unexposed) at 24 months. All HIV-exposed uninfected children were exposed to antiretrovirals (88% to maternal triple antiretroviral therapy). BSID-III outcomes did not significantly differ between HIV-exposed uninfected and HIV-unexposed children at 6 months. At 24 months, HIV-exposed uninfected children scored lower than HIV-unexposed for receptive language (adjusted mean difference −1·03 [95% CI −1·69 to −0·37]) and expressive language (−1·17 [–2·09 to −0·24]), whereas adjusted differences in cognitive (−0·45 [–1·32 to 0·43]), fine motor (0·09 [–0·49 to 0·66]), and gross motor (−0·41 [–1·09 to 0·27]) domain scores between groups were not significant. Correspondingly, the proportions of HIV-exposed uninfected children with developmental delay were higher than those of HIV-unexposed children for receptive language (adjusted odds ratio 1·96 [95% CI 1·09 to 3·52]) and expressive language (2·14 [1·11 to 4·15]).InterpretationUninfected children exposed to maternal HIV infection and antiretroviral therapy have increased odds of receptive and expressive language delays at 2 years of age. Further long-term work is needed to understand developmental outcomes of HIV-exposed uninfected children, especially in regions such as sub-Saharan Africa that have a high prevalence of HIV exposure among children.FundingBill & Melinda Gates Foundation, SA Medical Research Council, Wellcome Trust.

Association of Gluten Intake During the First 5 Years of Life With Incidence of Celiac Disease Autoimmunity and Celiac Disease Among Children at Increased Risk

High gluten intake during childhood may confer risk of celiac disease. To investigate if the amount of gluten intake is associated with celiac disease autoimmunity and celiac disease in genetically at-risk children. The participants in The Environmental Determinants of Diabetes in the Young (TEDDY), a prospective observational birth cohort study designed to identify environmental triggers of type 1 diabetes and celiac disease, were followed up at 6 clinical centers in Finland, Germany, Sweden, and the United States. Between 2004 and 2010, 8676 newborns carrying HLA antigen genotypes associated with type 1 diabetes and celiac disease were enrolled. Screening for celiac disease with tissue transglutaminase autoantibodies was performed annually in 6757 children from the age of 2 years. Data on gluten intake were available in 6605 children (98%) by September 30, 2017. Gluten intake was estimated from 3-day food records collected at ages 6, 9, and 12 months and biannually thereafter until the age of 5 years. The primary outcome was celiac disease autoimmunity, defined as positive tissue transglutaminase autoantibodies found in 2 consecutive serum samples. The secondary outcome was celiac disease confirmed by intestinal biopsy or persistently high tissue transglutaminase autoantibody levels. Of the 6605 children (49% females; median follow-up: 9.0 years [interquartile range, 8.0-10.0 years]), 1216 (18%) developed celiac disease autoimmunity and 447 (7%) developed celiac disease. The incidence for both outcomes peaked at the age of 2 to 3 years. Daily gluten intake was associated with higher risk of celiac disease autoimmunity for every 1-g/d increase in gluten consumption (hazard ratio [HR], 1.30 [95% CI, 1.22-1.38]; absolute risk by the age of 3 years if the reference amount of gluten was consumed, 28.1%; absolute risk if gluten intake was 1-g/d higher than the reference amount, 34.2%; absolute risk difference, 6.1% [95% CI, 4.5%-7.7%]). Daily gluten intake was associated with higher risk of celiac disease for every 1-g/d increase in gluten consumption (HR, 1.50 [95% CI, 1.35-1.66]; absolute risk by age of 3 years if the reference amount of gluten was consumed, 20.7%; absolute risk if gluten intake was 1-g/d higher than the reference amount, 27.9%; absolute risk difference, 7.2% [95% CI, 6.1%-8.3%]). Higher gluten intake during the first 5 years of life was associated with increased risk of celiac disease autoimmunity and celiac disease among genetically predisposed children.

Profiles of gene expression in maternal blood predict offspring birth weight in normal pregnancy.

The association between lower birth weight and increased disease risk in adulthood has drawn attention to the physiological processes that shape the gestational environment. We implement genome-wide transcriptional profiling of maternal blood samples to identify subsets of genes and associated transcription control pathways that predict offspring birth weight. Female participants (N = 178, mean = 27.0 years) in a prospective observational birth cohort study were contacted between 2009 and 2014 to identify new pregnancies. An in-home interview was scheduled for early in the third trimester (mean = 30.3 weeks) to collect pregnancy-related information and a blood sample, and birth weight was measured shortly after delivery. Transcriptional activity in white blood cells was determined with a whole-genome gene expression direct hybridization assay. Fifty transcripts were differentially expressed in association with offspring birth weight, with 18 up-regulated in relation to lower birth weight, and 32 down-regulated. Examination of transcription control pathways identified increased activity of NF-κB, AP-1, EGR1, EGR4, and Gfi families, and reduced the activity of CEBP, in association with lower birth weight. Transcript origin analyses identified non-classical CD16+ monocytes, CD1c+ myeloid dendritic cells, and neutrophils as the primary cellular mediators of differential gene expression. These results point toward a systematic regulatory shift in maternal white blood cell activity in association with lower offspring birth weight, and they suggest that analyses of gene expression during gestation may provide insight into regulatory and cellular mechanisms that influence birth outcomes.

Nutrition-specific and nutrition-sensitive factors associated with mid-upper arm circumference as a measure of nutritional status in pregnant Ethiopian women: Implications for programming in the first 1000 days.

Poor nutritional status in pregnancy expressed as low mid-upper arm circumference (MUAC) is associated with low birth weight. The study aims were to assess the nutritional status of pregnant Ethiopian women using MUAC and examine association with nutrition-specific and nutrition-sensitive factors, using baseline data of a prospective longitudinal observational birth cohort study conducted in three rural districts in the Oromia region of Ethiopia. Recruitment into the cohort was rolling over a period of nine months, and the data used for this analysis were collected while the women were between 12–32 weeks of gestation. Detailed household socio-demographics, agricultural production, women’s health, morbidity and diets, with weights, heights and MUAC, and anemia prevalence (HemoCue) were collected. The prevalence of low MUAC (< 23 cm) was 41%. Controlling for location and clustering, wealth quintile (OR = 0.88, CI = 0.82 to 0.96, p<0.01) was associated with decreased risk of low MUAC, while trimester (OR = 1.31, CI = 1.16 to 1.48, p<0.001) was associated with increased risk of low MUAC. The only significant factor amenable to nutrition-specific interventions was altitude-adjusted anemia, which was associated with increased risk of low MUAC (OR = 1.28, CI = 1.09 to 1.49, p<0.01). Significant factors amenable to nutrition-sensitive factors and associated with higher odds of low MUAC were household food insecurity (OR = 1.04, CI = 1.02 to 1.06, p<0.001), distance to the clinic in minutes (OR = 1.01, CI = 1.0 to 1.01, p<0.0001) and season of recruitment (lean versus non lean) (OR = 1.30, CI = 1.10 to 1.54, p<0.01). Literacy (OR = 0.85, CI = 0.74 to 0.98, p<0.05) and numeracy (OR = 0.75, CI = 0.62 to 0.91, p<0.01) were also significantly associated with lower odds of low MUAC. Poor nutritional status in pregnancy expressed as percent with low MUAC was high in Ethiopian women. It was associated with several nutrition-specific and -sensitive factors indicating the importance of multisectoral actions in improving outcomes within the first 1000 days.