Vitamin B12, folate, and cognition in 6-to 9-year-olds: a randomized controlled trial

BACKGROUND AND OBJECTIVES: Vitamin B12 and folate are important for normal brain development. Our objective for this study was to measure the effects of 6-month supplementation of vitamin B12 and/or folic acid in early childhood on cognition when the children were 6 to 9 years old. METHODS: The study is a follow-up of a factorial randomized, double-blind, placebo-controlled trial in 1000 North Indian children. Children 6 to 30 months of age were randomly assigned to receive a placebo or 1.8 µg of vitamin B12, 150 mg of folic acid, or both daily for 6 months. After 6 years, we re-enrolled 791 of these children for cognitive assessments. We compared the scores of the main outcomes (the Wechsler Intelligence Scale for Children, Fourth Edition [India], the Crichton Verbal Scale, and subtests of the NEPSY-II) between the study groups. We also measured the associations between markers of the B vitamins (plasma cobalamin, folate, and total homocysteine concentrations) in early childhood and the cognitive outcomes. RESULTS: There were no differences between the intervention groups and the placebo group on the cognitive outcomes. Plasma cobalamin, folate, and total homocysteine concentrations in early childhood were associated with the cognitive outcomes at follow-up in the unadjusted models. These associations disappeared in models adjusted for relevant confounders. CONCLUSIONS: Our findings, from both an observational and a randomized design suggest that vitamin B12 and folate in children 6 to 36 months have limited public health relevance for long-term cognition.Thrasher Research Fund (grant 02827) and the Research Council of Norway (grants 172226 and 234495) provided financial support for the original and the follow-up study.AcceptedVersio

Milk-cereal mix supplementation during infancy and impact on neurodevelopmental outcomes at 12 and 24 months of age: A randomized controlled trial in India

Inadequate protein intake and lack of micronutrients may affect neurodevelopment in infants. This randomised controlled trial was conducted to measure the effect of two milk–cereal mixes with modest and high amounts of protein and enriched with multiple micronutrients, given between 6 and 12 months, on cognitive, language, motor and behavioural scores at 12 and 24 months of age, compared with no-supplementation. The two supplements were also compared with each other. The study was conducted in urban Delhi, India, and the infants were randomised in a 1:1:1 ratio to the three study groups. At 12 and 24 months of age, 1134 and 1214 children were available, respectively. At 12 months of age, compared with no-supplement group, an increase in the motor scores (mean difference, MD 1·52, 95 % CI: 0·28, 2·75) and a decrease in the infant temperament scores (MD − 2·76, 95 % CI: −4·23, −1·29) in the modest-protein group was observed. Those in the high-protein group had lower socio-emotional scores (MD − 1·40, 95 % CI: −2·43, −0·37) and higher scores on Infant Temperament Scale (MD 2·05, 95 % CI: 0·62, 3·48) when compared with modest-protein group. At 24 months, no significant differences in any of the neurodevelopment scores between the three study groups was found. In conclusion, supplementation with modest amount of protein and multiple micronutrients may lead to short-term small improvements in motor function and infant temperament. There appears no advantage of supplementing with high protein, rather negative effects on infant behaviour were observedpublishedVersio

Enteral Calcium or Phosphorus Supplementation in Preterm or Low Birth Weight Infants: a Systematic Review and Meta-analysis

OBJECTIVES To assess effects of calcium or phosphorous supplementation compared with no supplementation in human milk-fed preterm or low birth weight infants. METHODS Data sources include Cochrane Central Register of Controlled Trials, Medline and Embase. We included Randomized controlled trials (RCTs) and non-randomized trials (quasi-randomized). RESULTS Three studies (4 reports; 162 infants) were included. At latest follow-up (38 weeks), there was reduction in osteopenia (3 studies, 159 participants, relative risk 0.68, 95% confidence interval [CI] 0.46–0.99). At latest follow-up (6 weeks), there was no effect on weight (1 study, 40 participants, mean difference [MD] 138.50 g, 95% CI −82.16 to 359.16); length (1 study, 40 participants, MD 0.77 cm, 95% CI −0.93 to 2.47); and head circumference (1 study, 40 participants, MD 0.33 cm, 95% CI −0.30 to 0.96). At latest follow-up, there was no effect on alkaline phosphatase (55 weeks) (2 studies, 122 participants, MD −126.11 IU/L, 95% CI −298.5 to 46.27, I2 = 73.4%); serum calcium (6 weeks) (1 study, 40 participants, MD 0.54 mg/dL, 95% CI −0.19 to 1.27); and serum phosphorus (6 weeks) (1 study, 40 participants, MD 0.07 mg/dL, 95% CI −0.22 to 0.36). The certainty of evidence ranged from very low to low. No studies reported on mortality and neurodevelopment outcomes. CONCLUSIONS The evidence is insufficient to determine whether enteral supplementation with calcium or phosphorus for preterm or low birth weight infants who are fed mother's own milk or donor human milk is associated with benefit or harm.publishedVersio

Enteral Zinc Supplementation in Preterm or Low Birth Weight Infants: A Systematic Review and Meta-analysis

BACKGROUND AND OBJECTIVES Evidence on the effect of zinc supplementation on health outcomes in preterm or low birth weight (LBW) infants is unclear. We estimated the effect of enteral zinc versus no zinc supplementation in human milk fed preterm or LBW infants on mortality, growth, morbidities, and neurodevelopment. METHODS Data sources include PubMed, Cochrane Central and Embase databases through March 24, 2021. Study selection was randomized or quazi-experimental trials. Two reviewers independently screened, extracted data, and assessed quality. We reported pooled relative risks (RR) for categorical outcomes, and mean differences (MD) for continuous outcomes. RESULTS Fourteen trials with 9940 preterm or LBW infants were included. Moderate to low certainty evidence showed that enteral zinc supplementation had little or no effect on mortality (risk ratio 0.73, 95% confidence interval [CI] 0.46 to 1.16), but increased weight (MD 378.57, 95% CI 275.26 to 481.88), length (MD 2.92, 95% CI 1.53 to 4.31), head growth (MD 0.56, 95% CI 0.23 to 0.90), and decreased diarrhea (RR 0.81; 95% CI 0.68 to 0.97). There was no effect on acute respiratory infections, bacterial sepsis, and psychomotor development scores. The effect of zinc supplementation on mental development scores is inconclusive. There was no evidence of serious adverse events. Eight trials had some concerns or high risk of bias, small-sized studies, and high heterogeneity between trials led to moderate to very low certainty of evidence. CONCLUSIONS Zinc supplementation in preterm or LBW infants have benefits on growth and diarrhea prevention. Further research is needed to generate better quality evidence.publishedVersio

Cameron-Liebler sets of k-spaces in PG(n,q)

Cameron-Liebler sets of k-spaces were introduced recently by Y. Filmus and F. Ihringer. We list several equivalent definitions for these Cameron-Liebler sets, by making a generalization of known results about Cameron-Liebler line sets in PG(n, q) and Cameron-Liebler sets of k-spaces in PG(2k + 1, q). We also present a classification result

Enteral Vitamin D Supplementation in Preterm or Low Birth Weight Infants: A Systematic Review and Meta-analysis

BACKGROUND AND OBJECTIVES Many preterm and low birth weight (LBW) infants have low vitamin D stores. The objective of this study was to assess effects of enteral vitamin D supplementation compared with no vitamin D supplementation in human milk fed preterm or LBW infants. METHODS Data sources include Cochrane Central Register of Controlled Trials, Medline, and Embase from inception to March 16, 2021. The study selection included randomized trials. Data were extracted and pooled with fixed and random-effects models. RESULTS We found 3 trials (2479 participants) that compared vitamin D to no vitamin D. At 6 months, there was increase in weight-for-age z-scores (mean difference 0.12, 95% confidence interval [CI] 0.01 to 0.22, 1 trial, 1273 participants), height-for-age z-scores (mean difference 0.12, 95% CI 0.02 to 0.21, 1 trial, 1258 participants); at 3 months there was decrease in vitamin D deficiency (risk ratio 0.58, 95% CI 0.49 to 0.68, I2=58%, 2 trials, 504 participants) in vitamin D supplementation groups. However, there was little or no effect on mortality, any serious morbidity, hospitalization, head circumference, growth to 6 years and neurodevelopment. The certainty of evidence ranged from very low to moderate. Fourteen trials (1969 participants) assessed dose and reported no effect on mortality, morbidity, growth, or neurodevelopment, except on parathyroid hormone and vitamin D status. No studies assessed timing. Limitations include heterogeneity and small sample size in included studies. CONCLUSIONS Enteral vitamin D supplementation improves growth and vitamin D status in preterm and LBW infants.publishedVersio

Utilisation, equity and determinants of full antenatal care in India: analysis from the National Family Health Survey 4

Objectives: We examined the utilisation, equity and determinants of full antenatal care (ANC), defined as 4 or more antenatal visits, at least one tetanus toxoid (TT) injection and consumption of iron folic acid (IFA) for a minimum of 100 days, in India. Methods: We analysed a sample of 190,898 women from India’s National Family Health Survey 4. Concentration curves and concentration index were used to assess equity in full ANC utilisation. Multivariable logistic regression model was used to examine the factors associated with full ANC utilisation. Results: In India, 21% of pregnant women utilised full ANC, ranging from 2.3–65.9% across states. Overall, 51.6% had 4 or more ANC visits, 30.8% consumed IFA for atleast 100 days, and 91.1% had one or more doses of tetanus toxoid. Full ANC utilisation was inequitable across place of residence, caste and maternal education. Registration of pregnancy, utilisation of government’s Integrated Child Development Services (ICDS) and health insurance coverage were associated with higher odds of full ANC utilisation. Lower maternal education, lower wealth quintile(s), lack of father’s participation during antenatal visits, higher birth order, teenage and unintended pregnancy were associated with lower odds of full ANC utilisation. Conclusions: Full ANC utilisation in India was inadequate and inequitable. Although half of the women did not receive the minimum recommended ANC visits, the utilisation of TT immunisation was almost universal. The positive association of full ANC with ICDS utilisation and child’s father involvement may be leveraged for increasing the uptake of full ANC. Strategies to address the socio-demographic factors associated with low and inequitable utilisation of full ANC are imperative for strengthening India’s maternal health program.publishedVersio

Enteral Iron Supplementation in Preterm or Low Birth Weight Infants: A Systematic Review and Meta-analysis

BACKGROUND AND OBJECTIVES Iron is needed for growth and development of infants globally, but preterm and low birth weight (LBW) infants are at risk for severe iron deficiencies. To assess the effect of enteral iron supplementation on mortality, morbidity, growth, and neurodevelopment outcomes in preterm or LBW infants fed human milk. Secondary objectives were to assess the effect on biomarkers and dose and timing. METHODS Data sources include PubMed, Embase and Cochrane Library databases to March 16, 2021. Study Selection includes controlled or quasi experimental study designs. Two reviewers independently extracted data. RESULTS Eight trials (eleven reports; 1093 participants, 7 countries) were included. No trials reported mortality. At latest follow-up, there was little effect on infection (very low certainty evidence, 4 studies, 401 participants, relative risk [RR] 0.98, 95% confidence interval [95% CI] 0.56 to 1.73, I2 = 0.00%) and necrotising enterocolitis (3 studies, 375 participants, RR 1.47, 95% CI 0.68 to 3.20, I2 = 0.00%). There was an increase in linear growth (length) (moderate certainty evidence, 3 studies, 384 participants, mean difference 0.69 cm, 95% CI 0.01 to 1.37, I2 = 0%) but little effect on weight, head circumference, or cognitive development. There was an improvement in anemia (moderate certainty evidence, 2 studies, 381 participants, RR 0.25, 95% CI 0.10 to 0.62, I2 = 0.00%) but no effect on serum ferritin. Limitations include heterogeneity in the included studies. CONCLUSIONS There are important benefits for human milk-fed preterm and LBW infants from enteral iron supplementation. However, more randomized control trials are required to improve the certainty of evidence.publishedVersio

Impact of an Integrated Health, Nutrition, and Early Child Stimulation and Responsive Care Intervention Package Delivered to Preterm or Term Small for Gestational Age Babies During Infancy on Growth and Neurodevelopment: Study Protocol of an Individually Randomized Controlled Trial in India (Small Babies Trial)

BACKGROUND: Preterm and term small for gestational age (SGA) babies are at high risk of experiencing malnutrition and impaired neurodevelopment. Standalone interventions have modest and sometimes inconsistent effects on growth and neurodevelopment in these babies. For greater impact, intervention may be needed in multiple domains-health, nutrition, and psychosocial care and support. Therefore, the combined effects of an integrated intervention package for preterm and term SGA on growth and neurodevelopment are worth investigating. METHODS: An individually randomized controlled trial is being conducted in urban and peri-urban low to middle-socioeconomic neighborhoods in South Delhi, India. Infants are randomized (1:1) into two strata of 1300 preterm and 1300 term SGA infants each to receive the intervention package or routine care. Infants will be followed until 12 months of age. Outcome data will be collected by an independent outcome ascertainment team at infant ages 1, 3, 6, 9, and 12 months and at 2, 6, and 12 months after delivery for mothers. DISCUSSION: The findings of this study will indicate whether providing an intervention that addresses factors known to limit growth and neurodevelopment can offer substantial benefits to preterm or term SGA infants. The results from this study will increase our understanding of growth and development and guide the design of public health programs in low- and middle-income settings for vulnerable infants. TRIAL REGISTRATION: The trial has been registered prospectively in Clinical Trial Registry - India # CTRI/2021/11/037881, Registered on 08 November 2021

Impact of an integrated health, nutrition, and early child stimulation and responsive care intervention package delivered to preterm or term small for gestational age babies during infancy on growth and neurodevelopment: study protocol of an individually randomized controlled trial in India (Small Babies Trial)

Background: Preterm and term small for gestational age (SGA) babies are at high risk of experiencing malnutrition and impaired neurodevelopment. Standalone interventions have modest and sometimes inconsistent effects on growth and neurodevelopment in these babies. For greater impact, intervention may be needed in multiple domains-health, nutrition, and psychosocial care and support. Therefore, the combined effects of an integrated intervention package for preterm and term SGA on growth and neurodevelopment are worth investigating. Methods: An individually randomized controlled trial is being conducted in urban and peri-urban low to middle-socioeconomic neighborhoods in South Delhi, India. Infants are randomized (1:1) into two strata of 1300 preterm and 1300 term SGA infants each to receive the intervention package or routine care. Infants will be followed until 12 months of age. Outcome data will be collected by an independent outcome ascertainment team at infant ages 1, 3, 6, 9, and 12 months and at 2, 6, and 12 months after delivery for mothers. Discussion: The findings of this study will indicate whether providing an intervention that addresses factors known to limit growth and neurodevelopment can offer substantial benefits to preterm or term SGA infants. The results from this study will increase our understanding of growth and development and guide the design of public health programs in low- and middle-income settings for vulnerable infants. Trial registration: The trial has been registered prospectively in Clinical Trial Registry - India # CTRI/2021/11/037881, Registered on 08 November 2021. Keywords: Child health; Early child stimulation; Growth failure; Intrauterine growth restriction; Responsive stimulation; Small for gestational age; Small vulnerable newborns; preterm. © 2024. The Author(s).The study was funded by Centre for Intervention Science in Maternal and Child Health at the University of Bergen (Bergen, Norway). The funding agency did not play any role in the design of the study and is neither involved in nor has any influence over the collection of analysis or interpretation of data.publishedVersio