Analysis of Maternal Prenatal Weight and Offspring Cognition and Behavior: Results From the Promotion of Breastfeeding Intervention Trial (PROBIT) Cohort.

Importance: Prenatal experiences can influence fetal brain development. Objective: To examine associations of maternal prenatal body mass index (BMI) with cognition and behavior of offspring born full-term. Design, Setting, and Participants: This cohort study examined follow-up data from a breastfeeding promotion intervention at 31 hospitals and affiliated polyclinics in the Republic of Belarus. Participants included 11 276 children who were evaluated from birth (1996-1997) to adolescence (2017-2019), with maternal BMI information available in prenatal medical records. Exposures: Maternal BMI, calculated as weight in kilograms divided by height in meters squared, after 35 weeks gestation; secondary analyses examined maternal BMI at other time points and paternal BMI. Main Outcomes and Measures: Trained pediatricians assessed child cognition with the Wechsler Abbreviated Scales of Intelligence (WASI) at 6.5 years and the computerized self-administered NeuroTrax battery at 16 years, both with an approximate mean (SD) of 100 (15). Parents and teachers rated behaviors at 6.5 years using the Strengths and Difficulties Questionnaire (SDQ, range 0-40). Mixed-effects linear regression analyses corrected for clustering, adjusted for the randomized intervention group and baseline parental sociodemographic characteristics, and were considered mediation by child BMI. Results: Among 11 276 participants, 9355 women (83%) were aged 20 to 34 years, 10 128 (89.8%) were married, and 11 050 (98.0%) did not smoke during pregnancy. Each 5-unit increase in of maternal late-pregnancy BMI (mean [SD], 27.2 [3.8]) was associated with lower offspring WASI performance intelligence quotient (IQ) (-0.52 points; 95% CI, -0.87 to -0.17 points) at 6.5 years and lower scores on 5 of 7 NeuroTrax subscales and the global cognitive score at 16 years (-0.67 points; 95% CI, -1.06 to -0.29 points). Results were similar after adjustment for sociodemographic characteristics, pregnancy complications, and paternal BMI and were not mediated by child weight. Higher late pregnancy maternal BMI was also associated with more behavioral problems reported on the SDQ by teachers but not associated with parent-reported behaviors (externalizing behaviors: 0.13 points; 95% CI, 0.02 to 0.24 points; and total difficulties: 0.14 points, 95% CI, -0.02 to 0.30 points). Results were similar for maternal BMI measured in the first trimester or postpartum. In contrast, higher 6.5-year paternal BMI was associated with slightly better child cognition (WASI verbal IQ: 0.42 points; 95% CI, 0.02 to 0.82 points; NeuroTrax executive function score: 0.68 points; 95% CI, 0.24 to 1.12 points) and fewer teacher-reported behavioral problems (total difficulties: -0.29 points; 95% CI, -0.46 to -0.11 points). Conclusions and Relevance: This cohort study supports findings from animal experiments and human observational studies in settings with higher maternal BMI and obesity rates. Higher maternal prenatal BMI may be associated with poorer offspring brain development, although residual confounding cannot be excluded.

Delivery by caesarean section and offspring adiposity and cardio-metabolic health at ages 6.5, 11.5 and 16 years: results from the PROBIT cohort in Belarus.

BACKGROUND: Caesarean delivery has been associated with later adiposity, perhaps via early programming or perhaps because of residual confounding by maternal or birth characteristics. OBJECTIVES: Examine associations of caesarean delivery with adiposity and cardio-metabolic biomarkers. METHODS: Observational analysis of 15 069 children in the PROBIT cohort in Belarus. We examined measures of child anthropometry and blood pressure at 6.5, 11.5 and 16 years and fasting blood (11.5 years). RESULTS: Caesarean-delivered children were slightly heavier at 6.5 (mean BMI 15.8 vs. 15.6 kg/m2 ), 11.5 (18.4 vs. 18.2) and 16 years (21.5 vs. 21.3). After adjustment for prenatal characteristics including maternal third trimester BMI, however, we observed no association of caesarean versus vaginal delivery with child BMI (ß 0.05 kg/m2 ; 95%CI: -0.03, 0.14), sum of skinfolds (0.14 mm; -0.13, 0.42), waist circumference (-0.07 cm; -0.23, 0.10), obesity (OR 0.99; 0.76, 1.29), or systolic (-0.20 mmHg; -0.70, 0.30) or diastolic (-0.17 mmHg, -0.60, 0.26) blood pressure at 6.5 years; results were similar at 11.5 and 16 years. At 11.5 years, we observed a modest association of caesarean delivery with fasting insulin (0.33 mU/L; 0.00, 0.65). CONCLUSIONS: Caesarean delivery had little or no association with adiposity or related cardio-metabolic biomarkers in childhood. Adjustment for maternal BMI attenuated all outcome effect estimates.

Associations of atopic dermatitis and asthma with child behaviour: Results from the PROBIT cohort.

BACKGROUND: Conflicting findings from studies evaluating associations of allergic disease with child behaviour require longitudinal studies to resolve. OBJECTIVE: To estimate the magnitude of associations of atopic dermatitis (AD) in infancy, and symptoms of asthma and AD at 6.5 years, with child behaviour at 6.5 years. METHODS: Secondary cohort analysis of the Promotion of Breastfeeding Intervention Trial (PROBIT). PROBIT enrolled 17 046 infants at birth and followed them up at 6.5 years (n = 13 889). Study paediatricians collected data on infantile AD at repeated follow-up examinations during the first year of life. At 6.5 years, paediatricians performed skin prick tests and parents reported asthma and AD symptoms during the prior year. In addition, parents and teachers completed the Strength and Difficulties Questionnaire, which includes scales on hyperactivity/inattention, emotional problems, conduct problems, peer problems and prosocial behaviours. RESULTS: Physician-diagnosed AD in the first year of life was not associated with increased risk for behavioural problems at 6.5 years. Emotional problems at 6.5 years were more common among children with AD symptoms (OR: 2.24, 95% CI: 1.62-3.12) and asthma symptoms (OR: 1.45; 95% CI: 1.07-1.96) during the past year at 6.5 years and ORs for children with symptoms of more severe AD and asthma were also higher. AD in the past year was also associated with probable hyperactivity/inattention disorder at 6.5 years (OR: 2.05; 95% CI: 1.09-3.84). Other subscales of the SDQ were not related to asthma or AD symptoms during the past year. CONCLUSIONS AND CLINICAL RELEVANCE: Children with AD symptoms were at higher risk for concomitant hyperactivity/inattention and emotional disorder, and children with asthma symptoms were at higher risk of having concomitant emotional problems. However, AD during infancy did not predict childhood behaviours.

The Effect of Longer-Term and Exclusive Breastfeeding Promotion on Visual Outcome in Adolescence.

Purpose: Breastfeeding may influence early visual development. We examined whether an intervention to promote increased duration and exclusivity of breastfeeding improves visual outcomes at 16 years of age. Methods: Follow-up of a cluster-randomized trial in 31 Belarusian maternity hospitals/polyclinics randomized to receive a breastfeeding promotion intervention, or usual care, where 46% vs. 3% were exclusively breastfed at 3 months respectively. Low vision in either eye was defined as unaided logMAR vision of ≥0.3 or worse (equivalent to Snellen 20/40) and was used as the primary outcome. Open-field autorefraction in a subset (n = 963) suggested that 84% of those with low vision were myopic. Primary analysis was based on modified intention-to-treat, accounting for clustering within hospitals/clinics. Observational analyses also examined the effect of breastfeeding duration and exclusivity, as well as other sociodemographic and environmental determinants of low vision. Results: A total of 13,392 of 17,046 (79%) participants were followed up at 16 years. Low vision prevalence was 19.6% (95% confidence interval [CI]: 17.5, 22.0%) in the experimental group versus 21.6% (19.5, 23.8%) in the control group. Cluster-adjusted odds ratio (OR) of low vision associated with the intervention was 0.92 (95% CI: 0.73, 1.16); 0.88 (95% CI: 0.74, 1.05) after adjustment for parental and early life factors. In observational analyses, breastfeeding duration and exclusivity had no significant effect on low vision. However, maternal age at birth (OR: 1.13, 95% CI: 1.07, 1.14/5-year increase) and urban versus rural residence were associated with increased risk of low vision. Lower parental education, number of older siblings was associated with a lower risk of low vision; boys had lower risk compared with girls (0.64, 95% CI: 0.59,0.70). Conclusions: Exclusive breastfeeding promotion had no significant effect on visual outcomes in this study, but other environmental factors showed strong associations. (ClinicalTrials.gov number, NCT01561612.).

Breastfeeding during infancy and neurocognitive function in adolescence: 16-year follow-up of the PROBIT cluster-randomized trial.

BACKGROUND: Evidence on the long-term effect of breastfeeding on neurocognitive development is based almost exclusively on observational studies. In the 16-year follow-up study of a large, cluster-randomized trial of a breastfeeding promotion intervention, we evaluated the long-term persistence of the neurocognitive benefits of the breastfeeding promotion intervention previously observed at early school age. METHODS AND FINDINGS: A total of 13,557 participants (79.5% of the 17,046 randomized) of the Promotion of Breastfeeding Intervention Trial (PROBIT) were followed up at age 16 from September 2012 to July 2015. At the follow-up, neurocognitive function was assessed in 7 verbal and nonverbal cognitive domains using a computerized, self-administered test battery among 13,427 participants. Using an intention-to-treat (ITT) analysis as our prespecified primary analysis, we estimated cluster- and baseline characteristic-adjusted mean differences between the intervention (prolonged and exclusive breastfeeding promotion modelled on the Baby-Friendly Hospital Initiative) and control (usual care) groups in 7 cognitive domains and a global cognitive score. In our prespecified secondary analysis, we estimated mean differences by instrumental variable (IV) analysis to account for noncompliance with the randomly assigned intervention and estimate causal effects of breastfeeding. The 16-year follow-up rates were similar in the intervention (79.7%) and control groups (79.3%), and baseline characteristics were comparable between the two. In the cluster-adjusted ITT analyses, children in the intervention group did not show statistically significant differences in the scores from children in the control group. Prespecified additional adjustment for baseline characteristics improved statistical precision and resulted in slightly higher scores among children in the intervention for verbal function (1.4 [95% CI 0.3-2.5]) and memory (1.2 [95% CI 0.01-2.4]). IV analysis showed that children who were exclusively breastfed for ≥3 (versus <3) months had a 3.5-point (95% CI 0.9-6.1) higher verbal function, but no differences were observed in other domains. While our computerized, self-administered cognitive testing reduced the cluster-level variability in the scores, it may have increased individual-level measurement errors in adolescents. CONCLUSIONS: We observed no benefit of a breastfeeding promotion intervention on overall neurocognitive function. The only beneficial effect was on verbal function at age 16. The higher verbal ability is consistent with results observed at early school age; however, the effect size was substantially smaller in adolescence. PROBIT TRIAL REGISTRATION: ClinicalTrials.gov NCT01561612.

Socioeconomic differences in childhood BMI trajectories in Belarus.

OBJECTIVE: To examine associations of parental socioeconomic position with early-life offspring body mass index (BMI) trajectories in a middle-income country. SUBJECTS: Overall, 12,385 Belarusian children born 1996-97 and enrolled in a randomised breastfeeding promotion trial at birth, with 3-14 measurements of BMI from birth to 7 years. METHODS: Cohort analysis in which exposures were parental education (common secondary or less; advanced secondary or partial university; completed university) and occupation (manual; non-manual) at birth, and the outcome was BMI z-score trajectories estimated using multilevel linear spline models, controlling for trial arm, location, parental BMI, maternal smoking status and number of older siblings. RESULTS: Infants born to university-educated mothers were heavier at birth than those born to secondary school-educated mothers [by 0.13 BMI z-score units (95% confidence interval, CI: 0.07, 0.19) for girls and 0.11 (95% CI: 0.05, 0.17) for boys; equivalent for an infant of average birth length to 43 and 38 g, respectively]. Between the ages of 3-7 years children of the most educated mothers had larger BMI increases than children of the least educated mothers. At age 7 years, after controlling for trial arm and location,  children of university-educated mothers had higher BMIs than those born to secondary school-educated mothers by 0.11 z-score (95% CI: 0.03, 0.19) among girls and 0.18 (95% CI: 0.1, 0.27) among boys, equivalent to differences in BMI for a child of average height of 0.19 and 0.26 kg/m2, respectively. After further controlling for parental BMI, these differences attenuated to 0.08 z-score (95% CI: 0, 0.16) and 0.16 z-score (95% CI: 0.07, 0.24), respectively, but changed very little after additional adjustment for number of older siblings and mother's smoking status. Associations were similar when based on paternal educational attainment and highest household occupation. CONCLUSIONS: In Belarus, consistent with some middle-income countries, higher socioeconomic position was associated with greater BMI trajectories from age 3 onwards.

Effect of an Intervention to Promote Breastfeeding on Asthma, Lung Function, and Atopic Eczema at Age 16 Years: Follow-up of the PROBIT Randomized Trial.

Importance: Atopic diseases, including asthma and atopic eczema, are the most common chronic conditions of childhood. Objective: To investigate whether an intervention to promote prolonged and exclusive breastfeeding protects against asthma, atopic eczema, and low lung function in adolescence. Design, Setting, and Participants: Follow-up of the Promotion of Breastfeeding Intervention Trial (PROBIT), a cluster randomized trial in 30 Belarusian maternity hospitals and affiliated polyclinics; recruitment of 17 046 healthy term infants took place from June 15, 1996, to December 31, 1997. Data analysis was conducted from May 9, 2016, to April 21, 2017. The primary analytic approach was by modified intention-to-treat analysis. Interventions: Randomization to receive a breastfeeding promotion intervention vs usual care. Main Outcomes and Measures: Spirometry and flexural eczema on standardized skin examination by study pediatricians were the primary outcomes; secondary outcomes were self-reported asthma diagnosis ever, and wheezing and flexural eczema symptoms in the previous year. Results: A total of 13 557 (79.5%) participants were followed up from September 15, 2012 to July 15, 2015. The intervention (7064 [79.7%]) and control (6493 [79.4%]) groups were similar at follow-up (3590 [50.8%] and 3391 [52.2%] male; mean [SD] age, 16.2 [0.6] and 16.1 [0.5] years, respectively). In the intervention group, 0.3% (21 of 7064) had flexural eczema on skin examination and mean (SD) forced expiratory volume in the first second of expiration/forced vital capacity (FEV1/FVC) ratio z score was -0.10 (1.82), compared with 0.7% (43 of 6493) and 0.35 (1.34), respectively, in the control group. In modified intention-to-treat analysis, accounting for clustering by polyclinic, a 54% lower risk of flexural eczema on skin examination was observed in the intervention compared with the control group (odds ratio [OR], 0.46; 95% CI, 0.25 to 0.86). Self-reported flexural eczema symptoms in the past year (OR, 0.57; 95% CI, 0.27 to 1.18), asthma (OR, 0.76; 95% CI, 0.47 to 1.23), and wheezing in the past year (OR, 0.66; 95% CI, 0.37 to 1.18) were less frequently reported in the intervention compared with the control group, but 95% CIs were wide and included the null. There was no significant difference in the FEV1/FVC ratio z score (ß -0.15; 95% CI, -0.76 to 0.45). All results were similar with additional adjustment for baseline characteristics, on instrumental variable analysis, and with multiple imputation among all 17 046 randomized participants. Conclusions and Relevance: A breastfeeding promotion intervention reduced flexural dermatitis risk but had no detectable effect on lung function or questionnaire-derived measures of atopic eczema or asthma in adolescence in a setting where atopic eczema and allergies are rare. Trial Registration: clinicaltrials.gov Identifier: NCT01561612.

Effects of Promoting Long-term, Exclusive Breastfeeding on Adolescent Adiposity, Blood Pressure, and Growth Trajectories: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Evidence that breastfeeding reduces child obesity risk and lowers blood pressure (BP) is based on potentially confounded observational studies. Objective: To investigate the effects of a breastfeeding promotion intervention on adiposity and BP at age 16 years and on longitudinal growth trajectories from birth. Design, Setting, and Participants: Cluster-randomized Promotion of Breastfeeding Intervention Trial. Belarusian maternity hospitals and affiliated polyclinics (the clusters) were allocated into intervention (n = 16) or control arms (n = 15) in 1996 and 1997. The trial participants were 17 046 breastfeeding mother-infant pairs; of these, 13 557 children (79.5%) were followed up at 16 years of age between September 2012 and July 2015. Interventions: Breastfeeding promotion, modeled on the Baby-Friendly Hospital Initiative. Main Outcomes and Measures: Body mass index (BMI, calculated as weight in kilograms divided by height in meters squared); fat and fat-free mass indices and percentage of body fat from bioimpedance; waist circumference; overweight and obesity; height; BP; and longitudinal growth trajectories. The primary analysis was modified intention-to-treat (without imputation for losses to follow-up) accounting for within-clinic clustering. Results: We examined 13 557 children at a median age of 16.2 years (48.5% were girls). The intervention substantially increased breastfeeding duration and exclusivity compared with the control arm (exclusively breastfed: 45% vs 6% at 3 months, respectively). Mean differences at 16 years between intervention and control groups were 0.21 (95% CI, 0.06-0.36) for BMI; 0.21 kg/m2 (95% CI, -0.03 to 0.44) for fat mass index; 0.00 kg/m2 (95% CI, -0.21 to 0.22) for fat-free mass index; 0.71% (95% CI, -0.32 to 1.74) for percentage body fat; -0.73 cm (-2.48 to 1.02) for waist circumference; 0.05 cm (95% CI, -0.85 to 0.94) for height; -0.54 mm Hg (95% CI, -2.40 to 1.31) for systolic BP; and 0.71 mm Hg (95% CI, -0.68 to 2.10) for diastolic BP. The odds ratio for overweight/obesity (BMI ≥85th percentile vs <85th percentile) was 1.14 (95% CI, 1.02-1.28) and the odds ratio for obesity (BMI ≥95th percentile vs <95th percentile) was 1.09 (95% CI, 0.92-1.29). The intervention resulted in a more rapid rate of gain in postinfancy height (1 to 2.8 years), weight (2.8 to 14.5 years), and BMI (2.8 to 8.5 years) compared with the control arm. The intervention had little effect on BMI z score changes after 8.5 years. Conclusions and Relevance: A randomized intervention that increased the duration and exclusivity of breastfeeding was not associated with lowered adolescent obesity risk or BP. On the contrary, the prevalence of overweight/obesity was higher in the intervention arm. All mothers initiated breastfeeding, so findings may not apply to comparisons of the effects of breastfeeding vs formula feeding. Trial Registration: isrctn.org: ISRCTN37687716; and clinicaltrials.gov: NCT01561612.

Prospective associations between problematic eating attitudes in midchildhood and the future onset of adolescent obesity and high blood pressure.

BACKGROUND: Clinically diagnosed eating disorders may have adverse cardiometabolic consequences, including overweight or obesity and high blood pressure. However, the link between problematic eating attitudes in early adolescence, which can lead to disordered eating behaviors, and future cardiometabolic health is, to our knowledge, unknown. OBJECTIVE: We assessed whether variations in midchildhood eating attitudes influence the future development of overweight or obesity and high blood pressure. DESIGN: Of 17,046 children who participated in the Promotion of Breastfeeding Intervention Trial (PROBIT), we included 13,557 participants (79.5% response rate) who completed the Children's Eating Attitudes Test (ChEAT) at age 11.5 y and in whom we measured adiposity and blood pressure at ages 6.5, 11.5, and 16 y. We assessed whether ChEAT scores ≥85th percentile (indicative of problematic eating attitudes) compared with scores <85th percentile at age 11.5 y were associated with new-onset overweight, obesity, high systolic blood pressure, or high diastolic blood pressure between midchildhood and early adolescence. RESULTS: After controlling for baseline sociodemographic confounders, we observed positive associations of problematic eating attitudes at age 11.5 y with new-onset obesity (OR: 2.18; 95% CI: 1.58, 3.02), new-onset high systolic blood pressure (OR: 1.34; 95% CI: 1.05, 1.70), and new-onset high diastolic blood pressure (OR: 1.25; 95% CI: 0.99, 1.58) at age 16 y. After further controlling for body mass index at age 6.5 y, problematic eating attitudes remained positively associated with new-onset obesity (OR: 1.80; 95% CI: 1.28, 2.53); however, associations with new-onset high blood pressure were attenuated (OR: 1.14; 95% CI: 0.89, 1.45 and OR: 1.09; 95% CI: 0.86, 1.39 for new-onset systolic and diastolic blood pressure, respectively). CONCLUSIONS: Problematic eating attitudes in midchildhood seem to be related to the development of obesity in adolescence, a relatively novel observation with potentially important public health implications for obesity control. PROBIT was registered at clinicaltrials.gov as NCT01561612 and isrctn.com as ISRCTN37687716.

Linear spline multilevel models for summarising childhood growth trajectories: A guide to their application using examples from five birth cohorts.

Childhood growth is of interest in medical research concerned with determinants and consequences of variation from healthy growth and development. Linear spline multilevel modelling is a useful approach for deriving individual summary measures of growth, which overcomes several data issues (co-linearity of repeat measures, the requirement for all individuals to be measured at the same ages and bias due to missing data). Here, we outline the application of this methodology to model individual trajectories of length/height and weight, drawing on examples from five cohorts from different generations and different geographical regions with varying levels of economic development. We describe the unique features of the data within each cohort that have implications for the application of linear spline multilevel models, for example, differences in the density and inter-individual variation in measurement occasions, and multiple sources of measurement with varying measurement error. After providing example Stata syntax and a suggested workflow for the implementation of linear spline multilevel models, we conclude with a discussion of the advantages and disadvantages of the linear spline approach compared with other growth modelling methods such as fractional polynomials, more complex spline functions and other non-linear models.

Socioeconomic differences in childhood length/height trajectories in a middle-income country: a cohort study.

BACKGROUND: Socioeconomic disadvantage is associated with shorter adult stature. Few studies have examined socioeconomic differences in stature from birth to childhood and the mechanisms involved, particularly in middle-income former Soviet settings. METHODS: The sample included 12,463 Belarusian children (73% of the original cohort) born in 1996-1997, with up to 14 stature measurements from birth to 7 years. Linear spline multi-level models with 3 knots at 3, 12 and 34 months were used to analyse birth length and growth velocity during four age-periods by parental educational achievement (up to secondary school, advanced secondary/partial university, completed university) and occupation (manual, non-manual). RESULTS: Girls born to the most (versus least) educated mothers were 0.43 cm (95% confidence interval (CI): 0.28, 0.58) longer at birth; for boys, the corresponding difference was 0.30 cm (95% CI: 0.15, 0.46). Similarly, children of the most educated mothers grew faster from birth-3 months and 12-34 months (p-values for trend ≤ 0.08), such that, by age 7 years, girls with the most (versus least) educated mothers were 1.92 cm (95% CI: 1.47, 2.36) taller; after controlling for urban/rural and East/West area of residence, this difference remained at 1.86 cm (95% CI: 1.42, 2.31), but after additionally controlling for mid-parental height, attenuated to 1.10 cm (95% CI: 0.69, 1.52). Among boys, these differences were 1.95 cm (95% CI: 1.53, 2.37), 1.89 cm (95% CI: 1.47, 2.31) and 1.16 cm (95% CI: 0.77, 1.55), respectively. Additionally controlling for breastfeeding, maternal smoking and older siblings did not substantively alter these findings. There was no evidence that the association of maternal educational attainment with growth differed in girls compared to boys (p for interaction = 0.45). Results were similar for those born to the most (versus least) educated fathers, or who had a parent with a non-manual (versus manual) occupation. CONCLUSIONS: In Belarus, a middle-income former Soviet country, socioeconomic differences in offspring growth commence in the pre-natal period and generate up to approximately 2 cm difference in height at age 7 years. These associations are partly explained by genetic or other factors influencing parental stature. TRIAL REGISTRATION: Current Controlled Trials: NCT01352247 assigned 9 Sept 2005; ClinicalTrials.gov. Identifier: NCT01561612 received 20 Mar 2012.

The association of early childhood cognitive development and behavioural difficulties with pre-adolescent problematic eating attitudes.

OBJECTIVES: Few studies have prospectively investigated associations of child cognitive ability and behavioural difficulties with later eating attitudes. We investigated associations of intelligence quotient (IQ), academic performance and behavioural difficulties at 6.5 years with eating attitudes five years later. METHODS: We conducted an observational cohort study nested within the Promotion of Breastfeeding Intervention Trial, Belarus. Of 17,046 infants enrolled at birth, 13,751 (80.7%) completed the Children's Eating Attitude Test (ChEAT) at 11.5 years, most with information on IQ (n = 12,667), academic performance (n = 9,954) and behavioural difficulties (n = 11,098) at 6.5 years. The main outcome was a ChEAT score ≥ 85th percentile, indicative of problematic eating attitudes. RESULTS: Boys with higher IQ at 6.5 years reported fewer problematic eating attitudes, as assessed by ChEAT scores ≥ 85th percentile, at 11.5 years (OR per SD increase in full-scale IQ = 0.87; 0.79, 0.94). No such association was observed in girls (1.01; 0.93, 1.10) (p for sex-interaction = 0.016). In both boys and girls, teacher-assessed academic performance in non-verbal subjects was inversely associated with high ChEAT scores five years later (OR per unit increase in mathematics ability = 0.88; 0.82, 0.94; and OR per unit increase in ability for other non-verbal subjects = 0.86; 0.79, 0.94). Behavioural difficulties were positively associated with high ChEAT scores five years later (OR per SD increase in teacher-assessed rating = 1.13; 1.07, 1.19). CONCLUSION: Lower IQ, worse non-verbal academic performance and behavioural problems at early school age are positively associated with risk of problematic eating attitudes in early adolescence.

Is restricted fetal growth associated with later adiposity? Observational analysis of a randomized trial.

BACKGROUND: Several recent "developmental origins" studies have reported increased long-term risks of adiposity, especially truncal adiposity, among children born small for gestational age (SGA). OBJECTIVE: We assessed the effects of SGA birth and weight gain in early infancy on adiposity at age 11.5 y. DESIGN: From a cluster-randomized breastfeeding promotion trial in 17,046 Belarusian children, we measured height, weight, waist and hip circumferences, triceps and subscapular skinfold thicknesses, and bioimpedance measures of percentage body fat at age 11.5 y. Children born SGA (birth weight <10th percentile) and those born large for gestational age (LGA; >90th percentile for gestational age) were compared with those born appropriate for gestational age (AGA). Weight gain from birth to 6 mo was categorized as high (>0.67-SD increase in weight-for-age), low (>0.67-SD decrease in weight-for-age), or normal. Multilevel statistical models accounted for clustered measurement and controlled for maternal and paternal height and body mass index (BMI), maternal education, geographic region, urban compared with rural residence, and the child's exact age at follow-up. RESULTS: Children born SGA had a significantly lower BMI, percentage body fat, and fat mass index than did those born AGA, with a dose-response effect across 2 subcategories of SGA (P < 0.001 for all comparisons). No difference was observed in waist-to-hip ratio, although the subscapular-to-triceps skinfold ratio was slightly but significantly (P < 0.001) higher in children born SGA. Differences among the study groups continued to increase since the previous follow-up at 6.5 y. SGA infants with catch-up growth in the first 3-6 mo had growth and adiposity measures intermediate between those born SGA without catch-up and those born AGA. Opposite effects of similar magnitude were observed in children born LGA. CONCLUSION: The 11.5-y-old Belarusian children born SGA were shorter, were thinner, and had less body fat than their non-SGA peers, irrespective of postnatal weight gain. The Promotion of Breastfeeding Intervention Trial was registered at www.isrctn.org as ISRCTN-37687716.

Effects of promoting longer-term and exclusive breastfeeding on childhood eating attitudes: a cluster-randomized trial.

BACKGROUND: Observational studies suggest that breastfeeding benefits later maternal child-feeding practices, which in turn may contribute to positive eating attitudes. We investigated the effect of a randomized intervention to increase duration and exclusivity of breastfeeding on pre-adolescent eating attitudes. METHODS: Long-term follow-up of the Promotion of Breastfeeding Intervention Trial (PROBIT), a cluster-randomized trial in 31 maternity hospitals and affiliated polyclinics in Belarus. Sites were randomly assigned an experimental intervention to promote longer duration and exclusivity of breastfeeding in mothers who initiated breastfeeding (n = 16 sites), or a control intervention of continuing usual care (n = 15 sites); 17 046 healthy infants were enrolled in 1996-7, of whom 13 751 (80.7%) completed the Children's Eating Attitude Test (ChEAT) at 11.5 years of age. A ChEAT score ≥ 22.5 (85th percentile) was used as an indicator of problematic eating attitudes. Analysis was based on intention-to-treat, accounting for clustering within hospitals/clinics. RESULTS: Compared with the control arm, the experimental intervention substantially increased breastfeeding exclusivity (43.3% vs 6.4% exclusively breastfed at 3 months of age) and duration of any breastfeeding throughout infancy. The proportion of children with ChEAT scores ≥ 22.5 was lower in the experimental than control arm (boys 11.4% vs 17.2%; girls 18.5% vs 23.4%) [cluster-adjusted odds ratio (OR), boys: 0.44; 95% confidence interval (CI): 0.21,0.93; girls: 0.51; 95% CI: 0.27,0.99). Results were robust to adjustment for potential confounders and using a ChEAT score ≥ 25.5 (91st percentile) as the outcome (OR: 0.53; 95% CI: 0.28,1.03). CONCLUSIONS: An intervention to improve the duration and exclusivity of breastfeeding among term infants in Belarus was associated with a reduction in problematic eating attitudes at 11.5 years of age.

Cohort profile: The promotion of breastfeeding intervention trial (PROBIT).

The PROmotion of Breastfeeding Intervention Trial (PROBIT) is a multicentre, cluster-randomized controlled trial conducted in the Republic of Belarus, in which the experimental intervention was the promotion of increased breastfeeding duration and exclusivity, modelled on the Baby-friendly hospital initiative. Between June 1996 and December 1997, 17,046 mother-infant pairs were recruited during their postpartum hospital stay from 31 maternity hospitals, of which 16 hospitals and their affiliated polyclinics had been randomly assigned to the arm of PROBIT investigating the promotion of breastfeeding and 15 had been assigned to the control arm, in which breastfeeding practices and policies in effect at the time of randomization was continued. Of the mother-infant pairs originally recruited for the study, 16,492 (96.7%) were followed at regular intervals until the infants were 12 months of age (PROBIT I) for the outcomes of breastfeeding duration and exclusivity; gastrointestinal and respiratory infections; and atopic eczema. Subsequently, 13,889 (81.5%) of the children from these mother-infant pairs were followed-up at age 6.5 years (PROBIT II) for anthropometry, blood pressure (BP), behaviour, dental health, cognitive function, asthma and atopy outcomes, and 13,879 (81.4%) children were followed to the age of 11.5 years (PROBIT III) for anthropometry, body composition, BP, and the measurement of fasted glucose, insulin, adiponectin, insulin-like growth factor-I, and apolipoproteins. The trial registration number for Current Controlled Trials is ISRCTN37687716 and that for ClinicalTrials.gov is NCT01561612. Proposals for collaboration are welcome, and enquires about PROBIT should be made to an executive group of the study steering committee (M.S.K., R.M.M., and E.O.). More information, including information about how to access the trial data, data collection documents, and bibliography, is available at the trial website (http://www.bristol.ac.uk/social-community-medicine/projects/probit/).

Effects of promoting longer-term and exclusive breastfeeding on cardiometabolic risk factors at age 11.5 years: a cluster-randomized, controlled trial.

BACKGROUND: The duration and exclusivity of breastfeeding in infancy have been inversely associated with future cardiometabolic risk. We investigated the effects of an experimental intervention to promote increased duration of exclusive breastfeeding on cardiometabolic risk factors in childhood. METHODS AND RESULTS: We followed-up children in the Promotion of Breastfeeding Intervention Trial, a cluster-randomized trial of a breastfeeding promotion intervention based on the World Health Organization/United Nations Children's Fund Baby-Friendly Hospital Initiative. In 1996 to 1997, 17 046 breastfeeding mother-infant pairs were enrolled from 31 Belarusian maternity hospitals and affiliated polyclinics (16 intervention versus 15 control sites); 13 879 (81.4%) children were followed up at 11.5 years, with 13 616 (79.9%) who had fasted and did not have diabetes mellitus. The outcomes were blood pressure; fasting insulin, adiponectin, glucose, and apolipoprotein A1; and the presence of metabolic syndrome. Analysis was by intention to treat, accounting for clustering within hospitals/clinics. The intervention substantially increased breastfeeding duration and exclusivity in comparison with the control arm (43% versus 6% and 7.9% versus 0.6% exclusively breastfed at 3 and 6 months, respectively). Cluster-adjusted mean differences at 11.5 years between experimental versus control groups were as follows: 1.0 mm Hg (95% confidence interval, -1.1 to 3.1) for systolic and 0.8 mm Hg (-0.6 to 2.3) for diastolic blood pressure; -0.1 mmol/L (-0.2 to 0.1) for glucose; 8% (-3% to 34%) for insulin; -0.3 µg/mL (-1.5 to 0.9) for adiponectin; and 0.0 g/L (-0.1 to 0.1) for apolipoprotein A1. The cluster-adjusted odds ratio for metabolic syndrome, comparing experimental versus control groups, was 1.21 (0.85 to 1.72). CONCLUSIONS: An intervention to improve breastfeeding duration and exclusivity among healthy term infants did not influence cardiometabolic risk factors in childhood. CLINICAL TRIAL REGISTRATION: Current Controlled Trials: ISRCTN37687716 (http://www.controlled-trials.com/ISRCTN37687716). URL: http://clinicaltrials.gov. Unique identifier: NCT01561612.

Filter paper blood spot enzyme linked immunoassay for adiponectin and application in the evaluation of determinants of child insulin sensitivity.

BACKGROUND: Adiponectin is an adipocyte-derived hormone that acts as a marker of insulin sensitivity. Bloodspot sampling by fingerstick onto filter paper may increase the feasibility of large-scale studies of the determinants of insulin sensitivity. We first describe the validation of an enzyme-linked immunoassay (ELISA) for quantifying adiponectin from dried blood spots and then demonstrate its application in a large trial (PROBIT). METHODS: We quantified adiponectin from 3-mm diameter discs (≈3 µL of blood) punched from dried blood spots obtained from: i) whole blood standards (validation); and ii) PROBIT trial samples (application) in which paediatricians collected blood spots from 13,879 children aged 11.5 years from 31 sites across Belarus. We examined the distribution of bloodspot adiponectin by demographic and anthropometric factors, fasting insulin and glucose. RESULTS: In the validation study, mean intra-assay coefficients of variation (n=162) were 15%, 13% and 10% for 'low' (6.78 µg/ml), 'medium' (18.18 µg/ml) and 'high' (33.13 µg/ml) internal quality control (IQC) samples, respectively; the respective inter-assay values (n=40) were 23%, 21% and 14%. The correlation coefficient between 50 paired whole bloodspot versus plasma samples, collected simultaneously, was 0.87 (95% CI: 0.78 to 0.93). Recovery of known quantities of adiponectin (between 4.5 to 36 µg/ml) was 100.3-133%. Bloodspot adiponectin was stable for at least 30 months at -80°C. In PROBIT, we successfully quantified fasting adiponectin from dried blood spots in 13,329 of 13,879 (96%) children. Mean adiponectin (standard deviation) concentrations were 17.34 µg/ml (7.54) in boys and 18.41 µg/ml (7.92) in girls and were inversely associated with body mass index, fat mass, triceps and subscapular skin-fold thickness, waist circumference, height and fasting glucose. CONCLUSIONS: Bloodspot ELISA is suitable for measuring adiponectin in very small volumes of blood collected on filter paper and can be applied to large-scale studies.

Effects of an intervention to promote breastfeeding on maternal adiposity and blood pressure at 11.5 y postpartum: results from the Promotion of Breastfeeding Intervention Trial, a cluster-randomized controlled trial.

BACKGROUND: Differences between mothers who do and do not succeed in breastfeeding are likely to confound associations of lactation with later maternal adiposity. OBJECTIVE: We compared adiposity and blood pressure (BP) in women randomly assigned to an intervention to promote prolonged and exclusive breastfeeding or usual care. DESIGN: We performed a cluster-randomized trial at 31 hospitals in Belarus in 1996-1997. RESULTS: Of 17,046 women enrolled at delivery, we assessed 11,867 women (69.6%) at 11.5 y postpartum. The prevalence of exclusive breastfeeding ≥3 mo was 44.5% in 6321 women in the intervention group and 7.1% in 5546 women in the control group. At 11.5 y postpartum, mean (±SD) body mass index (BMI; in kg/m(2)) was 26.5 ± 5.5, the percentage of body fat was 33.6% ± 8.3%, and systolic BP was 124.6 ± 14.6 mm Hg. On intention-to-treat analysis (without imputation) with adjustment for clustering by hospital, mean outcomes were lower in intervention compared with control mothers for BMI (mean difference: -0.27; 95% CI: -0.91, 0.37), body fat (-0.49%; 95% CI: -1.25%, 0.27%), and systolic BP (-0.81 mm Hg; 95% CI: -3.33, 1.71 mm Hg), but effect sizes were small, CIs were wide, and results were attenuated further toward the null after adjustment for baseline characteristics. Results were similar in sensitivity analyses [ie, by using conventional observational analyses disregarding treatment assignment, instrumental variable analyses to estimate the causal effect of breastfeeding, and multiple imputation to account for missing outcome measures (n = 17,046)]. CONCLUSION: In women who initiated breastfeeding, an intervention to promote longer breastfeeding duration did not result in an important lowering of adiposity or BP. This trial was registered at clinicaltrials.gov as NCT01561612 and at Current Controlled Trials as ISRCTN37687716.

Effects of promoting longer-term and exclusive breastfeeding on adiposity and insulin-like growth factor-I at age 11.5 years: a randomized trial.

IMPORTANCE: Evidence that longer-term and exclusive breastfeeding reduces child obesity risk is based on observational studies that are prone to confounding. OBJECTIVE: To investigate effects of an intervention to promote increased duration and exclusivity of breastfeeding on child adiposity and circulating insulin-like growth factor (IGF)-I, which regulates growth. DESIGN, SETTING, AND PARTICIPANTS: Cluster-randomized controlled trial in 31 Belarusian maternity hospitals and their affiliated clinics, randomized into 1 of 2 groups: breastfeeding promotion intervention (n = 16) or usual practices (n = 15). Participants were 17,046 breastfeeding mother-infant pairs enrolled in 1996 and 1997, of whom 13,879 (81.4%) were followed up between January 2008 and December 2010 at a median age of 11.5 years. INTERVENTION: Breastfeeding promotion intervention modeled on the WHO/UNICEF Baby-Friendly Hospital Initiative (World Health Organization/United Nations Children's Fund). MAIN OUTCOME MEASURES: Body mass index (BMI), fat and fat-free mass indices (FMI and FFMI), percent body fat, waist circumference, triceps and subscapular skinfold thicknesses, overweight and obesity, and whole-blood IGF-I. Primary analysis was based on modified intention-to-treat (without imputation), accounting for clustering within hospitals and clinics. RESULTS: The experimental intervention substantially increased breastfeeding duration and exclusivity when compared with the control (43% vs 6% exclusively breastfed at 3 months and 7.9% vs 0.6% at 6 months). Cluster-adjusted mean differences in outcomes at 11.5 years of age between experimental vs control groups were: 0.19 (95% CI, -0.09 to 0.46) for BMI; 0.12 (-0.03 to 0.28) for FMI; 0.04 (-0.11 to 0.18) for FFMI; 0.47% (-0.11% to 1.05%) for percent body fat; 0.30 cm (-1.41 to 2.01) for waist circumference; -0.07 mm (-1.71 to 1.57) for triceps and -0.02 mm (-0.79 to 0.75) for subscapular skinfold thicknesses; and -0.02 standard deviations (-0.12 to 0.08) for IGF-I. The cluster-adjusted odds ratio for overweight/obesity (BMI ≥ 85th vs <85th percentile) was 1.18 (95% CI, 1.01 to 1.39) and for obesity (BMI ≥ 95th vs <85th percentile) was 1.17 (95% CI, 0.97 to 1.41). CONCLUSIONS: AND RELEVANCE Among healthy term infants in Belarus, an intervention that succeeded in improving the duration and exclusivity of breastfeeding did not prevent overweight or obesity, nor did it affect IGF-I levels at age 11.5 years. Breastfeeding has many advantages but population strategies to increase the duration and exclusivity of breastfeeding are unlikely to curb the obesity epidemic. TRIAL REGISTRATION: isrctn.org: ISRCTN37687716; and clinicaltrials.gov: NCT01561612.

Filter paper blood spot enzyme linked immunoassay for insulin and application in the evaluation of determinants of child insulin resistance.

BACKGROUND: In large-scale epidemiology, bloodspot sampling by fingerstick onto filter paper has many advantages, including ease and low costs of collection, processing and transport. We describe the development of an enzyme-linked immunoassay (ELISA) for quantifying insulin from dried blood spots and demonstrate its application in a large trial. METHODS: We adapted an existing commercial kit (Mercodia Human Insulin ELISA, 10-1113-01) to quantify insulin from two 3-mm diameter discs (≈6 µL of blood) punched from whole blood standards and from trial samples. Paediatricians collected dried blood spots in a follow-up of 13,879 fasted children aged 11.5 years (interquartile range 11.3-11.8 years) from 31 trial sites across Belarus. We quantified bloodspot insulin levels and examined their distribution by demography and anthropometry. RESULTS: Mean intra-assay (n = 157) coefficients of variation were 15% and 6% for 'low' (6.7 mU/L) and 'high' (23.1 mU/L) values, respectively; the respective inter-assay values (n = 33) were 23% and 11%. The intraclass correlation coefficient between 50 paired whole bloodspot versus serum samples, collected simultaneously, was 0.90 (95% confidence interval 0.85 to 0.95). Bloodspot insulin was stable for at least 31 months at -80°C, for one week at +30°C and following four freeze-thaw cycles. Paediatricians collected a median of 8 blood spots from 13,487 (97%) children. The geometric mean insulin (log standard deviation) concentrations amongst 12,812 children were 3.0 mU/L (1.1) in boys and 4.0 mU/L (1.0) in girls and were positively associated with pubertal stage, measures of central and peripheral adiposity, height and fasting glucose. CONCLUSIONS: Our simple and convenient bloodspot assay is suitable for the measurement of insulin in very small volumes of blood collected on filter paper cards and can be applied to large-scale epidemiology studies of the early-life determinants of circulating insulin.