Assessment of the effects of ethnicity, home language, and socioeconomic status on neurodevelopmental performance in a multiethnic population

For many very low-birth-weight (VLBW) infants, there is insufficient mother's milk, and a supplement of pasteurized donor human milk or preterm formula is required. Awareness of the benefits of mother's milk has led to an increase in use of donor milk, despite limited data evaluating its efficacy. To determine if nutrient-enriched donor milk compared with formula, as a supplement to mother's milk, reduces neonatal morbidity, supports growth, and improves neurodevelopment in VLBW infants. In this pragmatic, double-blind, randomized trial, VLBW infants were recruited from 4 neonatal units in Ontario, Canada, within 96 hours of birth between October 2010 and December 2012. Follow-up was completed in July 2015. Infants were fed either donor milk or formula for 90 days or to discharge when mother's milk was unavailable. The primary outcome was the cognitive composite score on the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) at 18 months' corrected age (standardized mean, 100 [SD, 15]; minimal clinically important difference, 5 points). Secondary outcomes included Bayley-III language and motor composite scores, growth, and a dichotomous mortality and morbidity index. Of 840 eligible infants, 363 (43.2%) were randomized (181 to donor milk and 182 to preterm formula); of survivors, 299 (92%) had neurodevelopment assessed. Mean birth weight and gestational age of infants was 996 (SD, 272) g and 27.7 (2.6) weeks, respectively, and 195 (53.7%) were male. No statistically significant differences in mean Bayley-III cognitive composite score (adjusted scores, 92.9 in donor milk group vs 94.5 in formula group; fully adjusted mean difference, -2.0 [95% CI, -5.8 to 1.8]), language composite score (adjusted scores, 87.3 in donor milk group vs 90.3 in formula group; fully adjusted mean difference, -3.1 [95% CI, -7.5 to 1.3]), or motor composite score (adjusted scores, 91.8 in donor milk group vs 94.0 in formula group; fully adjusted mean difference, -3.7 [95% CI, -7.4 to 0.09]) were observed between groups. There was no statistically significant difference in infants positive for the mortality and morbidity index (43% in donor milk group, 40% in formula group) or changes in growth z scores. Among VLBW infants, use of supplemental donor milk compared with formula did not improve neurodevelopment at 18 months' corrected age. If donor milk is used in settings with high provision of mother's milk, this outcome should not be considered a treatment goal. isrctn.org Identifier: ISRCTN35317141.

Neighborhood adversity's impact on 18-month neurodevelopmental impairment (NDI) is not well-described. The aim of our study was to determine whether area deprivation index (ADI), a measure of neighborhood socioeconomic disadvantage, at birth is associated with 18-month NDI of preterm infants born in dense urban setting. A retrospective case-cohort study was performed in infants born at 23-32weeks gestational age (GA) with birth weight (BW) ≤1250g between 2013 and 2017 and evaluated for NDI at 18-month corrected age (CA). Socioeconomic deprivation was computed geospatially using subject addresses that were mapped to national ADI rankings. Subjects were categorized as low (<26th percentile) or high (26-100th percentile) ADI neighborhoods and with/without NDI if any of Bayley-III cognition, language, or motor composite scores were <70. The relationship between ADI and NDI was analyzed using logistic regression adjusted for GA and BW and group comparisons were made. Data were available in 119 patients (GA = 27.2 ± 2.2weeks, BW = 870 ± 246g). Children with NDI at 18-month CA were born at an earlier GA (p < .001) with lower BW (p < .03) and to mothers living in high ADI neighborhoods (p < .02). Patients from lower ADI neighborhoods at birth had higher Bayley-III cognition (p < .0001), language (p < .005), and motor (p = .03) composite scores at 18-month CA. Cognition (p < .01), language (p < .003) and motor (p < .03) composite scores decreased with increasing ADI percentiles. Among infants born 23-32weeks GA in a dense urban setting, ADI at birth is associated with NDI at 18months with lower cognitive, language, and motor scores in preterm infants from higher ADI neighborhoods.

BackgroundChildren in low and middle income countries may have many risk factors for poor cognitive development, and are accordingly at a high risk of not reaching their developmental potential. Determinants for cognitive development in early life can be found among biological and socioeconomic factors, as well as in stimulation and learning opportunities.ObjectiveThe present study aimed to identify determinants of cognitive, language and motor development in 6–11 months old Nepalese infants.MethodsSix hundred infants with a length-for-age z-score <-1 were assessed with the Bayley Scales of Infant and Toddler development, 3rd edition (Bayley-III). Information on socioeconomic factors, child and maternal demographics, clinical and biological factors, and the home environment were collected. In a manual stepwise variable selection procedure, we examined the association between selected biological, socioeconomic and stimulation and learning opportunity variables and the Bayley-III cognitive, language and motor development subscale scores in multiple linear regression models.ResultsThe length-for-age z-scores was positively associated with the cognitive composite score [standardized beta (ß): 0.22, p < 0.001] and the motor composite score [(ß): 0.14, p = 0.001]. Children born with low birth weight (<2500 g) scored significantly lower on all subscale scores. Diarrheal history was associated with poor language composite scores, and females had higher language composite scores than boys [(ß): 0.11, p = 0.015]. Children who had been hospitalized during the first month of life had also lower cognitive and motor composite scores than those who had not been hospitalized. Parental reports of physical punishment and lack of spontaneous vocalization were associated with poor cognitive and language composite scores, respectively. The statistical models with the various subscale scores as dependent variables explained between 8 to 16 percent of the variability in the cognitive developmental outcomes.ConclusionOur findings reveal important determinants for developmental scores in infancy, and underline the role of biological risk factors faced by marginalized children in low and middle income countries such as in Nepal.

To determine the concurrent validity of the Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS), a criterion-specified questionnaire that assesses a child's adaptive skills in everyday contexts, and the Bayley Infant and Toddler Scales of Development, Third Edition (Bayley-III). In a prospective cohort study, 431 WIDEA-FS and Bayley-III assessments were completed among 341 children, aged 10 to 36months corrected age (158 females, 183 males; median [interquartile range] gestational age at birth 32wks [29-38]), monitored in a high-risk neonatal intensive care unit follow-up clinic. WIDEA-FS scores were significantly associated with Bayley-III scores in all domains. Lower scores on the WIDEA-FS were significantly associated with an increased risk of adverse developmental performance on all Bayley-III scales. The association was strongest for motor and language Bayley-III scores when tested at <30months of age, and for cognitive Bayley-III scores when tested at ≥30months of age. The WIDEA-FS has concurrent validity with the Bayley-III and may be a useful tool in high-risk follow-up settings. WIDEA-FS mobility, communication, and social cognition domains are concurrently valid in infants at high-risk for neurodevelopmental disability. Bayley-III motor, language, and cognitive composite scores are concurrently valid in the same group. The WIDEA-FS mobility and communication domains may be most clinically useful in children <30months.

BackgroundTrace elements, including zinc (Zn) and copper (Cu), although toxic at higher concentrations are known to play important roles in the maintenance of human health and neurodevelopment. Few epidemiological studies have investigated the association between prenatal or early postnatal Cu and Zn levels and child neurodevelopment. The aim of this research is to assess the association between child neurodevelopment at 18 months of age and cord blood and breast milk concentrations of Cu and Zn in Italian mother-child pairs enrolled in the Italian Northern Adriatic Cohort II (NAC-II), a part of the “Public health impact of long-term, low-level, mixed element exposure in susceptible population strata” project PHIME. MethodsThe study population consisted of 632 children, and their mothers, born within the NAC-II, who were tested with the Bayley Scales of Infant and Toddler Development third edition (BSID-III) at age 18 months. Cu and Zn concentrations were measured in cord blood and breast milk samples. Only children born at term (≥37 gestational week), who completed the BSID-III test and had at least 1 measure of Cu and Zn concentrations were included in the analysis. Information about socio-demographics and lifestyles were collected through questionnaires at different phases of follow-up. Cu and Zn concentrations were log2 transformed because of their skewed distribution. Multiple linear regression models were performed to study the association between each BSID-III composite score (cognitive, motor and language) and each metal concentration. Separate models were applied for each biological sample. The β coefficient (β) and its 95% confidence interval (95% CI) were estimated. Stratified analyses by child's sex were also conducted. ResultsThe mean ± standard deviation (SD) of cognitive, motor and language composite scores were respectively: 106 ± 8, 101 ± 5 and 97 ± 8. The mean ± SD of Cu and Zn concentrations (ng/g) were respectively 699.2 ± 129.0 and 2538 ± 589 in cord blood and 607 ± 498 and 3226 ± 1428 in breast milk. No association between metal concentration and cognitive composite score was found. A higher motor composite score was associated with higher Cu concentrations in cord blood (β = 4.31 95% CI 2.03; 6.59). No associations were found between language composite score and metal concentrations. The effect of Cu cord blood concentration on motor composite score was confirmed when stratified by sex: males (β = 5.49 95% CI 2.15; 8.36) and females (β = 3.11; 95% CI 0.00; 6.22). A direct association, in females only, was found between language composite score and Cu concentration in cord blood (β = 5.60 95% CI 0.63; 10.57) and in breast milk (β = 3.04 95% CI 1.06; 5.03), respectively. ConclusionThe results from this cohort study showed a strong direct association between prenatal Cu levels and child motor neurodevelopment at 18 months. However, for generalizability, future research on the effects of Zn and Cu on neurodevelopment should include a larger range of early-life concentration of trace elements.

ImportanceIntake of dietary docosahexaenoic acid (DHA) among toddlers is low. Supplementation may benefit developmental outcomes of toddlers who were born preterm.ObjectiveTo determine whether 6 months of daily DHA supplementation improves developmental outcomes of toddlers who were born preterm.Design, Setting, and ParticipantsA randomized, fully masked, placebo-controlled trial was conducted from April 26, 2012, to March 24, 2017, at a large US pediatric academic center with 9 neonatal intensive care units. Children born at less than 35 weeks’ gestation who were 10 to 16 months corrected age underwent 6 months of intervention. Of 2363 children assessed, 982 were eligible, 605 declined, and 377 enrolled and were randomized. Analyses were according to intent to treat.InterventionsOne-to-one allocation to receive daily microencapsulated DHA, 200 mg, and arachidonic acid (AA), 200 mg (DHA+AA), or microencapsulated corn oil (placebo).Main Outcomes and MeasuresThe primary outcome specified a priori was Bayley Scales of Infant and Toddler Development, third edition (Bayley-III), cognitive composite score at 16 to 22 months corrected age. Secondary outcomes were Bayley-III language and motor composite scores and Infant Behavior Questionnaire–Revised and Early Childhood Behavior Questionnaire effortful control and activity level scores. Subgroup analyses defined a priori were by income, sex, and birth weight.ResultsAmong 377 children randomized and included in the analysis (182 girls and 195 boys; median corrected age, 15.7 months), 338 children (89.7%) had complete data on the primary outcome. Bayley-III cognitive scores did not differ between the DHA+AA and placebo groups (difference in change, 0.5 [95% CI, –1.8 to 2.8]; effect size, 0.05; P = .66). Assignment to the DHA+AA group had a small to medium negative effect on Bayley-III language scores among children with lower birth weights (eg, a child with a birth weight of 1000 g assigned to receive DHA+AA experienced a 4.1-point relative decrease, while a child assigned to placebo did not; P = .03 for interaction). Supplementation had a similar negative effect on effortful control scores among children with annual household incomes greater than $35 000 (difference in change, –0.3 [95% CI, –0.4 to –0.1]; effect size, –0.37; P = .01). Bayley-III motor scores and activity level scores were unaffected.Conclusions and RelevanceDaily supplementation with 200 mg of DHA and 200 mg of AA for 6 months resulted in no improvement in cognitive development and early measures of executive function vs placebo, and may have resulted in negative effects on language development and effortful control in certain subgroups of children. These findings do not support DHA supplementation in the second year of life for children who are born preterm.Trial RegistrationClinicalTrials.gov Identifier: NCT01576783

Background/aim Latest version of Bayley Scales (Bayley-III) and its predecessor (BSID-II) are the most widely used standardized developmental tools in infancy and early childhood. Recent studies showed that Bayley-III scores were higher than BSID-II in 18–24 month-old and mostly premature infants. We aimed to evaluate the generalization of inflated scores of Bayley-III to children aged 6–42 months with different disease groups, and to find out which cut-off points should be used in Bayley-III to detect mild, moderate, and severe developmental delay according to BSID-II standard cut-off points.Materials and methods Two hundred and fifty-five children aged 6–42 months with different diseases and developmental levels were administered both the Bayley-III and BSID-II in the same session between 15 November 2017 and 15 April 2018. ResultsThe mean Bayley-III Cognitive Composite (CC) and Cognitive Language Composite (CLC) scores were respectively 13.1 ± 9.1 and 8.6 ± 8 points higher than BSID-II Mental Development Index (MDI) scores (P < 0.001). The mean Bayley-III Motor Composite (MC) scores were 14.4 ± 10.5 points higher than BSID-II Psychomotor Developmental Index (PDI) scores (P < 0.001). Cognitive delay was found in 126 (49.4%) and 59 (23.1%) children according to BSID-II MDI and Bayley-III CC scores, respectively. Motor delay was found in 174 (69.3%) and 86 (34.3%) children according to the BSID-II PDI and Bayley-III MC scores, respectively. Children had less cognitive (48.6%) and motor delay (54.5%) according to Bayley-III scores. Bayley-III scores were significantly higher than BSID-II scores for all ages (P < 0.001). According to ROC analysis the cut-off scores for mild, moderate, and severe delay were 92.5, 83.2, and 71.2 for Bayley-III CLC; and 98.5, 86.5, and 74.5 for Bayley-III MC, respectively.ConclusionBayley-III scores should be interpreted carefully for all age ranges and different diagnosis. The risk for underestimation of developmental delays by Bayley-III should be kept in mind. Different Bayley-III cut-off scores should be used to define developmental delay levels.

ObjectiveTo assess the well-being of preterm newborns using the Bayley-III scales in a Korean-based population, and to evaluate the perinatal risk factors influencing developmental outcome.MethodsUsing the Bayley-III scales, we assessed 120 preterm infants who were referred for evaluation of neurodevelopmental performance. We subdivided them into an extremely preterm group (n=18) and a very/moderate to late preterm group (n=102). Bayley-III mean scores and the rate of infants showing a delay were compared for both groups. The relationship between perinatal risk factors and Bayley-III scores was analyzed. The risk factors were considered as very low birth weight, history of neonatal medical problems, and abnormal radiologic findings in brain magnetic resonance images (MRIs).ResultsAlthough no significant differences in mean scores were observed between the extremely preterm group and the very/moderate to late preterm group, the rate of babies showing developmental delay in motor composite scores was significantly higher in the extremely preterm group. The proportions of preterm infants with cognitive, language, and motor delays were 38.3%, 26.7%, and 35.0%, respectively. Very low birth weight was a significant risk factor for low cognitive, language, and motor composite scores. Also, abnormal radiologic findings on brain MRI were significant indicators of lower motor composite scores.ConclusionCognitive development was the most frequently delayed domain in preterm infants and motor development was more frequently delayed in the extremely preterm group. The very low birth weight and abnormal radiologic findings in brain MRI were predictive factors for neurodevelopmental outcome.

To compare neurodevelopmental outcomes and parent behaviour ratings of children born term with CHD to children born very preterm. A clinical research sample of 181 children (CHD [n = 81]; very preterm [≤32 weeks; n = 100]) was assessed at 18 months. Children with CHD and born very preterm did not differ on Bayley-III cognitive, language, or motor composite scores, or on expressive or receptive language, or on fine motor scaled scores. Children with CHD had lower ross motor scaled scores compared to children born very preterm (p = 0.047). More children with CHD had impaired scores (<70 SS) on language composite (17%), expressive language (16%), and gross motor (14%) indices compared to children born very preterm (6%; 7%; 3%; ps < 0.05). No group differences were found on behaviours rated by parents on the Child Behaviour Checklist (1.5-5 years) or the proportion of children with scores above the clinical cutoff. English as a first language was associated with higher cognitive (p = 0.004) and language composite scores (p < 0.001). Lower median household income and English as a second language were associated with higher total behaviour problems (ps < 0.05). Children with CHD were more likely to display language and motor impairment compared to children born very preterm at 18 months. Outcomes were associated with language spoken in the home and household income.

BackgroundCranial ultrasound cerebral biometric measurements have been used in preterm neonates, particularly in cases of ventriculomegaly. While cerebral biometric measures using MRI have been found to correlate with long-term outcome,...

Asthma during pregnancy is associated with a range of adverse perinatal outcomes. It is also linked to increased rates of neurodevelopmental conditions in the offspring. We aimed to assess whether fractional exhaled nitric oxide (FENO)-based asthma management during pregnancy improves child developmental and behavioural outcomes compared to usual care. The Breathing for Life Trial was a randomised controlled trial that compared FENO-based asthma management during pregnancy to usual care. Participants were invited to the developmental follow-up, the Breathing for Life Trial – Infant Development study, which followed up infants at 6 weeks, 6 months and 12 months. The primary outcomes were measured in infants at 12 months using the Bayley-III: Cognitive, Language and Motor composite scores. Secondary outcomes included Bayley-III social-emotional and adaptive behaviour scores, autism likelihood and sensory and temperament outcomes. The exposure of interest was the randomised intervention group. Two hundred and twenty-two infants and their 217 participating mothers were recruited to the follow-up; 107 mothers were in the intervention group and 113 were in the control group. There was no evidence of an intervention effect for the primary outcomes: Bayley-III cognitive (mean = 108.9 control, 108.5 intervention, p = 0.93), language (mean = 95.9 control, 95.6 intervention, p = 0.87) and motor composite scores (mean = 97.2 control, 97.9 intervention, p = 0.25). Mean scores for secondary outcomes were also similar among infants born to control and FENO group mothers, with few results reaching p < 0.05.Conclusion: In this sample, FENO-guided asthma treatment during pregnancy did not improve infant developmental outcomes in the first year of life.Trial registration: ClinicalTrials.gov Identifier: ACTRN12613000202763.What is Known:• Maternal asthma during pregnancy has been associated with increased rates of neurodevelopmental conditions in offspring, including intellectual disability and autism.What is New:• This is the first study to examine how managing asthma during pregnancy via a FENO-guided algorithm or usual care affects infant developmental and behavioural outcomes. While the results of the study showed no impact of the intervention, and therefore do not support the integration of FENO-based management of asthma in antenatal settings for optimal infant development, they do send a positive message about the implications of active asthma management during pregnancy on infant developmental outcomes.

BackgroundDocosahexaenoic acid (DHA), choline and uridine-5-monophosphate (UMP) are important brain nutrients which form phosphatidylcholine, the most abundant brain membrane phospholipid. DHA, choline and UMP supplementation increases rodent brain phospholipids, synaptic...

Neurodevelopmental Outcome and Health-related Quality of Life in Children With Single-ventricle Heart Disease Before Fontan Procedure

To evaluate the association between 2 g of intrapartum azithromycin given to laboring mothers and neurodevelopmental outcomes after birth asphyxia. This was a neurodevelopmental follow-up study of children born at 34 weeks of gestation or later who had concern for asphyxia and whose mothers were enrolled in A-PLUS (the Azithromycin Prevention in Labor Use Study). Mothers in A-PLUS were randomized to receive a single oral dose of azithromycin (2 g) or placebo during labor. This follow-up to A-PLUS spanned six sites across five countries (India [two sites], Pakistan, Zambia, Democratic Republic of Congo, and Guatemala). Asphyxia was defined as 5-minute Apgar score less than 7 or the need for bag-and-mask ventilation at birth. The primary outcome was the CCS (Cognitive Composite Score) of the BSID-III (Bayley Scales of Infant and Toddler Development, 3rd Edition) at a corrected age of 24±1 months. Secondary outcomes included the LCS (Language Composite Score) and MCS (Motor Composite Score) of the BSID-III at a corrected age of 24±1 months. Masked examiners administered the BSID-III and the ASQ-3 (Ages & Stages Questionnaires, 3rd Edition). Outcomes were analyzed using a generalized linear model and were adjusted for site, gestational age at delivery, and maternal and child baseline characteristics that differed between treatment groups. Of 529 eligible mother-child dyads screened, 403 (197 in the azithromycin arm and 206 in the placebo arm) were enrolled and completed the neurodevelopmental follow-up at a corrected age of 24±1 months. The primary outcome, the CCS of the BSID-III, did not differ significantly between groups (azithromycin: 90.9±11.2 vs placebo: 90.9±11.7; mean difference: 0.29; 95% CI, -1.77 to 2.34). No significant differences were observed between treatment arms in the BSID-III's LCS and MCS or in the total scores of the ASQ-3's five domains. Subgroup analysis by region (sub-Saharan Africa vs South Asia) also showed no differences in BSID-III or ASQ-3 scores between the azithromycin and placebo groups. In this follow-up study, a single oral dose of azithromycin given to laboring mothers who delivered neonates with birth asphyxia did not improve neurodevelopmental outcomes at 2 years of age. ClinicalTrials.gov, NCT03871491.

ObjectiveThis study aims to assess the role of continuous EEG (cEEG) background patterns and duration of cross-clamp time and cardiopulmonary bypass (CPB) in children with congenital heart disease (CHD) undergoing cardiac surgery and its correlation with abnormal neurodevelopmental outcomes at 12–24 months on Bayley Scales of Infant and Toddler Development (BSID-III).MethodsThis retrospective cohort study included infants with CHD and cEEG monitoring, who underwent surgery by 44 weeks gestational age.Results34 patients were included, who were operated at median age − 7 days. Longer duration of cross- camp time was associated with poor language composite scores (LCS) (p value = 0.036). A significant association existed between severity of encephalopathy in 24-hour post-operative period and poor LCS (p value = 0.026).ConclusionMajority of neonates with CHD have below average cognitive, language and motor composite scores on BSID-III. Longer duration of cross-clamp time and severity of encephalopathy during 24-hour post-operative EEG monitoring are associated with poor LCS.