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Cited by 92Folate and B Vitamins ResearchChild Nutrition and Water AccessPorphyrin Metabolism and Disorders

Vitamin B-12 status in infancy is positively associated with development and cognitive functioning 5 y later in Nepalese children

Open access
Kvestad, Ingrid, Hysing, Mari, Shrestha, Merina, Ulak, Manjeswori, Thorne-Lyman, Andrew L, Henjum, Sigrun, Ueland, Per M, Midttun, Øyvind +4 more·2017·The American Journal of Clinical Nutrition
DOI 10.3945/ajcn.116.144931
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Abstract

Background: Poor vitamin B-12 (cobalamin) status is widespread in South Asia. Insufficient vitamin B-12 status has been linked to poor neurodevelopment in young children.Objective: We measured the associations between vitamin B-12 status in infancy (2-12 mo) and the development and cognitive functioning in Nepalese children 5 y later.Design: Vitamin B-12 status was assessed in infancy with the use of plasma cobalamin, total homocysteine (tHcy), and methylmalonic acid (MMA). At 5 y of age, we measured development with the use of the Ages and Stages Questionnaire, 3rd edition (ASQ-3), and cognitive functioning by using the Developmental Neuropsychological Assessment, 2nd edition (NEPSY II), in 320 children. In regression models, we estimated the associations between vitamin B-12 status, including a combined indicator of vitamin B-12 status (3cB12) and scores on the ASQ-3 and NEPSY II subtests.Results: All markers of vitamin B-12 status with the exception of plasma cobalamin were significantly associated with the total ASQ-3 scores in the multiple regression models. A 1-unit increase in the 3cB12 score was associated with an increase in the total ASQ-3 score of 4.88 (95% CI: 2.09, 7.68; P = 0.001). Increases in both plasma tHcy and MMA (indicating poorer status) were associated with a decrease in scores on the NEPSY II affect recognition and geometric puzzle subtests. Each unit increment in 3cB12 scores was associated with increases of 0.82 (95% CI: 0.49, 1.14; P < 0.0005), 0.59 (95% CI: 0.10, 1.09; P = 0.020), and 0.24 (95% CI: 0.02, 0.47; P = 0.035) in the affect recognition, geometric puzzle, and block construction scores, respectively.Conclusions: Vitamin B-12 status in infancy is associated with development and performance on social perception tasks and visuospatial abilities at 5 y of age. The long-term effects of poor vitamin B-12 status in infancy need further investigation in randomized controlled trials.

AI snapshot

Written from the paper’s full text.

TL;DR

In a Nepalese cohort, vitamin B-12 status measured in infancy was associated with development and cognitive functioning 5 y later. Higher combined B-12 status (3cB12) predicted higher ASQ-3 total and NEPSY II affect recognition, geometric puzzle, and block construction scores, while elevated tHcy/MMA predicted lower scores.

Key findings

  • Among 306 children with baseline blood samples, 45 (14.7%) had plasma vitamin B-12 <148 pmol/L, 174 (56.5%) had elevated tHcy (>10 μmol/L), 242 (77.1%) had elevated MMA (>0.28 μmol/L), and 198 (64.7%) had 3cB12 scores below the cutoff (reported as 20.5 in the text), indicating low vitamin B-12 status; none had poor folate status (<10 nmol/L).
  • All vitamin B-12 markers except plasma cobalamin were significantly associated with total ASQ-3 scores. A 1-unit increase in 3cB12 was associated with a 4.88-point increase in total ASQ-3 score (95% CI: 2.09, 7.68; P = 0.001); each 2-fold increase in MMA was associated with a −3.12-point change (95% CI: −5.35, −0.90), and tHcy was also inversely associated (coefficient −6.78; P = 0.007).
  • In NEPSY II, each 1-unit increase in 3cB12 was associated with increases of 0.82 (95% CI: 0.49, 1.14; P < 0.0005) in affect recognition, 0.59 (95% CI: 0.10, 1.09; P = 0.020) in geometric puzzle, and 0.24 (95% CI: 0.02, 0.47; P = 0.035) in block construction raw scores. Higher tHcy and MMA were associated with lower affect recognition and geometric puzzle scores.
  • No significant associations were found for ASQ-3 communication, gross motor, fine motor, or personal-social subscales; lower 3cB12 and higher MMA/tHcy were associated with increased odds of being in the lowest quartile for problem solving (3cB12 OR: 0.64; 95% CI: 0.47, 0.88). No consistent associations were found for NEPSY II attention/executive or sensorimotor domains.

Methods

  • Two-stage cluster sampling in Bhaktapur, Nepal; 500 lactating women and their infants aged 2–12 mo were enrolled in 2008–2009. At follow-up in 2012–2013, 330 children were located, 321 assessed, and 320 had valid assessments; 306 were included in ASQ-3 analyses and 305 in NEPSY II analyses with baseline blood samples.
  • Exposures in infancy were plasma cobalamin, total homocysteine (tHcy), methylmalonic acid (MMA), and a combined indicator of vitamin B-12 status (3cB12). Outcomes at 5 y were the Ages and Stages Questionnaire, 3rd edition (ASQ-3) total and subscale scores and six NEPSY II subtests (inhibition, statue, visuomotor precision, affect recognition, geometric puzzles, block construction).
  • Multiple linear and logistic regression models estimated associations, adjusted for confounders and clustering; ASQ-3 subscales were categorized at the 25th percentile for logistic models.

Limitations

  • Stated by the authors: follow-up included only 320 of 500 children; the original study was cross-sectional and lacked long-term tracking measures; ASQ-3 and NEPSY II were not formally validated in a Nepalese population; 160 children were over the maximum recommended age range for ASQ-3; multiple comparisons (28 ASQ-3 and 32 NEPSY II analyses) increased risk of type I errors; residual confounding could not be ruled out; 3cB12 lacked holotranscobalamin and has been validated only in adults aged ≥18 y; MMA is challenging to use as a marker in infancy.
  • Evident from the text: the observational design cannot establish causality, and the authors state that randomized controlled trials are needed to confirm long-term effects.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3945/ajcn.116.144931

Cites

46 of 46 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 39 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Among the 306 children, 174 (56.5%) had elevated tHcy (>10 umol/L).

    “Furthermore, 174 children (56.5%) had elevated tHcy (.10 mmol/L), 242 children (77.1%) had elevated MMA (.0.28 mmol/L), and 198 children (64.7%) had 3cB12 scores below the cutoff of 20.5, indicating low vitamin B-12 status (32).”
    Quote in the paperNot a substantial claim
  • Findingown data

    An increase in cobalamin concentration was associated with increased scores in the affect recognition and geometric puzzle subtests.

    “An increase in cobalamin concentration was associated with increased scores in the affect recognition and geometric puzzle subtests.”
    Quote in the paperSubstantial claim
  • Findingown data

    Increases in both plasma tHcy and MMA (indicating poorer status) were associated with a decrease in scores on NEPSY II affect recognition and geometric puzzle subtests.

    “Increases in both plasma tHcy and MMA (indicating poorer status) were associated with a decrease in scores on the NEPSY II affect recognition and geometric puzzle subtests.”
    Quote in the paperSubstantial claim
  • Findingnone given

    There were no significant associations between cobalamin concentration and ASQ-3 total and subscale scores.

    “There were no significant associations between the cobalamin concentration and ASQ-3 total and subscale scores.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Among the 306 children, 198 (64.7%) had 3cB12 scores below the cutoff of 20.5, indicating low vitamin B-12 status.

    “Furthermore, 174 children (56.5%) had elevated tHcy (.10 mmol/L), 242 children (77.1%) had elevated MMA (.0.28 mmol/L), and 198 children (64.7%) had 3cB12 scores below the cutoff of 20.5, indicating low vitamin B-12 status (32).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 14
  • Classified as probably not a substantial claim. 41

  • May combine two claims.

    Findingown data

    In ASQ-3 subscale analyses, associations were found in the problem-solving subscale but not in the communication, gross and fine motor, and personal-social subscales.

    “In the ASQ-3 subscale analyses, we found associations in the problem-solving subscale but not in the communication, gross and fine motor, and personal-social subscales (Table 6).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Each unit increment in 3cB12 scores was associated with increases of 0.82 (95% CI: 0.49, 1.14), 0.59 (95% CI: 0.10, 1.09), and 0.24 (95% CI: 0.02, 0.47) in affect recognition, geometric puzzle, and block construction scores, respectively.

    “Each unit increment in 3cB12 scores was associated with increases of 0.82 (95% CI: 0.49, 1.14; P , 0.0005), 0.59 (95% CI: 0.10, 1.09; P = 0.020), and 0.24 (95% CI: 0.02, 0.47; P = 0.035) in the affect recognition, geometric puzzle, and block construction scores, respectively.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The median ASQ-3 total score was 270 (IQR: 255-285) of a possible 300.

    “The median ASQ-3 total score was 270 (IQR: 255-285) of a possible 300 (Table 4), whereas the median scores for the subtests ranged from 50 to 60, with 60 being the highest possible score.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    None of the children in the study had poor folate status (<10 nmol/L).

    “None of the children in the study had poor folate status (,10 nmol/L).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    The mean cobalamin concentration at enrollment was 264 pmol/L.

    “The mean cobalamin concentration at enrollment was 264 pmol/L”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Only 45 children (14.7%) had cobalamin concentrations below the cutoff for vitamin B-12 deficiency.

    “only 45 children (14.7%) had concentrations below the cutoff for vitamin B-12 deficiency.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All models were adjusted for clustering.

    “All models were adjusted for clustering.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    We translated, back-translated, and culturally adapted the ASQ-3 questionnaire for the Nepalese setting according to standardized procedures.

    “We translated, back-translated, and culturally adapted the questionnaire particularly for the Nepalese setting according to standardized procedures.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Early in life, vitamin B-12 deficiency is usually secondary to maternal deficiency.

    “Early in life, vitamin B-12 deficiency is usually secondary to maternal deficiency (8).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Ueland, 2003, Hyperhomocysteinemia and B-vitamin deficiencies in infants and children, Clin Chem Lab Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The functional markers tHcy and MMA have been established as useful indicators of vitamin B-12 status and may be more sensitive indicators of mild vitamin B-12 deficiency.

    “However, the functional markers total homocysteine (tHcy) 13 and methylmalonic acid (MMA) have been established as useful indicators of vitamin B-12 status (13) and may be more sensitive indicators of mild vitamin B-12 deficiency (14,15).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [13] Refsum, 2004, Facts and recommendations about total homocysteine determinations: an expert opinion, Clin Chem source

      Not checked in the free run.

    • cites [14] Stabler, 2013, Vitamin B12 deficiency, N Engl J Med source

      Not checked in the free run.

    • cites [15] Bjørke Monsen, 2003, Homocysteine and methylmalonic acid in diagnosis and risk assessment from infancy to adolescence, Am J Clin Nutr source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisereasoning

    These studies do not provide information on possible long-term effects of vitamin B-12 deficiency.

    “These studies do not, however, provide information of possible long-term effects of vitamin B-12 deficiency.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based).

    Study design and conductnone given

    Only variables that changed the estimates by >15% were included in the final multiple regression models.

    “Only variables that changed the estimates by .15%were included in the final models.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Deficits of key micronutrients early in life can lead to impairments in the central nervous system, and vitamin B-12 may be one such critical micronutrient.

    “Deficits of key micronutrients early in life can lead to impairments in the central nervous system (2,3), and vitamin B-12 (cobalamin) may be one such critical micronutrient (4,5).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [2] Prado, 2014, Nutrition and brain development in early life, Nutr Rev source

      Not checked in the free run.

    • cites [3] Fuglestad, 2008, The role of nutrition in cognitive development

      Not checked in the free run.

    • cites [4] Black, 2008, Effects of B-12 and folate deficiency on brain development in children, Food Nutr Bull source

      Not checked in the free run.

    • cites [5] van de Rest, 2012, B vitamins and n-3 fatty acids for brain development and function: review of human studies, Ann Nutr Metab source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Local norms for NEPSY II were not available.

    “Local norms were not available.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    In the translated ASQ-3 questionnaire, there was a strong correlation between the total ASQ-3 scores and the separate ASQ-3 subscale scores (range: 0.62-0.81).

    “In the translated questionnaire, there was a strong correlation between the total ASQ-3 scores and the separate ASQ-3 subscale scores (range: 0.62-0.81).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    None of the associations were altered, and all remained significant when adjusting for breastfeeding, socioeconomic variables, growth, iron status, and maternal energy intake and folate supplementation.

    “None of the associations were altered, and all remained significant when adjusting for breastfeeding, socioeconomic variables, growth, iron status, and maternal energy intake and folate supplementation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Vitamin B-12 is important for intracellular energy production and the generation of methionine, which is needed to produce neurotransmitters and myelin.

    “Vitamin B-12 is also important for intracellular energy production and the generation of methionine, which is needed to produce neurotransmitters and myelin (7).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Shane, 1985, Vitamin B12-folate interrelationships, Annu Rev Nutr source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    One child was tested with ASQ-3 only, and the total number of NEPSY II measurements was 319.

    “One child was tested with ASQ-3 only, and the total number of NEPSY II measurements was 319.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    The original study did not include measures to ensure long-term follow-up, such as alternative addresses, phone numbers, and contact information of relatives, because the study was originally a cross-sectional design.

    “In addition, we did not include measures in the original study to ensure long-term follow-up, such as alternative addresses, phone numbers, and contact information of relatives because the study was originally a cross-sectional design.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    There were no major differences in the demographic characteristics between the initial sample and the children in the follow-up substudy.

    “There were no major differences in the demographic characteristics between the initial sample and the children in the follow-up substudy.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    We were not able to obtain sufficient blood samples at baseline for 14 children; thus, the number of children in the ASQ-3 and NEPSY II analyses were 306 and 305, respectively.

    “We were not able to obtain sufficient blood samples at baseline for 14 children; thus, the number of children in the ASQ-3 and NESPY II analyses were 306 and 305, respectively (Figure 1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    All forms were manually checked for inconsistencies, and the data were entered twice.

    “All forms were manually checked for inconsistencies, and the data were entered twice.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Results from a previous Dutch study in adolescents raised on a vegan diet showed associations between early vitamin B-12 status and later cognitive performance.

    “Results from a previous Dutch study in adolescents raised on a vegan diet showed associations between early vitamin B-12 status and later cognitive performance (19,21).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [19] Torsvik, 2013, Cobalamin supplementation improves motor development and regurgitations in infants: results from a randomized intervention study, Am J Clin Nutr source

      Not checked in the free run.

    • cites [21] Louwman, 2000, Signs of impaired cognitive function in adolescents with marginal cobalamin status, Am J Clin Nutr source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The standardized alpha values for the 5 ASQ-3 subscales ranged from 0.34 to 0.69.

    “The standardized a values for the 5 subscales ranged from 0.34 to 0.69.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Vitamin B-12 is required for cell division together with folate.

    “Together with folate, vitamin B-12 is required for cell division (6).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Dror, 2008, Effect of vitamin B-12 deficiency on neurodevelopment in infants: current knowledge and possible mechanisms, Nutr Rev source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Studies in Nepal and India have revealed that poor cobalamin status is prevalent in both women and children in the general population.

    “Studies in Nepal and India have revealed that poor cobalamin status is prevalent in both women and children in the general population (10)(11)(12).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites (10)(11)(12)

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Several studies have linked vitamin B-12 status and neurodevelopment in children, including in North India and in special groups such as young infants in Norway.

    “There are several studies that have linked vitamin B-12 status and neurodevelopment in children (17)(18)(19)(20)(21), including among young children in the general population in North India (17,18) and in special groups such as young infants, with evidence of poor vitamin B-12 status referred to an outpatient clinic in Norway (19,20).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites (17)(18)(19)(20)(21)

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In South Asia, the risk for cobalamin deficiency is high as a result of widespread poverty, low consumption of animal products because of cultural and religious reasons, and intestinal malfunction as a consequence of frequent gastrointestinal infections.

    “In South Asia, the risk for cobalamin deficiency is high as a result of widespread poverty, low consumption of animal products because of cultural and religious reasons, and intestinal malfunction as a consequence of frequent gastrointestinal infections (8,9).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] Ueland, 2003, Hyperhomocysteinemia and B-vitamin deficiencies in infants and children, Clin Chem Lab Med source

      Not checked in the free run.

    • cites [9] Allen, 2008, Causes of vitamin B12 and folate deficiency, Food Nutr Bull source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The use of MMA as a marker in infancy is particularly challenging because of the physiologic changes in this biomarker at this age.

    “the use of MMA as a marker in infancy is particularly challenging because of the physiologic changes in this biomarker at this age.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    NEPSY II has also been used in low- and middle-income countries.

    “NEPSY II has also been used in low-and middle-income countries (43,44).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [43] Kashala, 2005, Cognition in African children with attention-deficit hyperactivity disorder, Pediatr Neurol source

      Not checked in the free run.

    • cites [44] Mulenga, 2001, Performance of Zambian children on the NEPSY: a pilot study, Dev Neuropsychol source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    Misclassification due to limited validation is unlikely to be differential with respect to vitamin B-12 status and would add noise and a loss of statistical power rather than create associations that are not real.

    “This is unlikely to be differential with respect to vitamin B-12 status and as such would add noise and a loss of statistical power rather than create associations that are not real.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The NEPSY II scaled scores have a total possible range from 1 to 19.

    “The NEPSY II scaled scores have a total possible range from 1 to 19 (30).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Brooks, 2009, NEPSY-II: a developmental neuropsychological assessment, second edition, Child Neuropsychol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The ASQ-3 is a comprehensive developmental checklist standardized for children aged 1-66 mo.

    “The Ages and Stages Questionnaire, 3rd edition (ASQ-3), is a comprehensive developmental checklist standardized for children aged 1-66 mo with age-appropriate questionnaires (28).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Squires, 2009

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The NEPSY II is a comprehensive neuropsychological test battery that consists of 32 subtests in 6 functional domains for children aged 3-16 y.

    “The Developmental Neuropsychological Assessment, 2nd edition (NEPSY II), is a comprehensive neuropsychological test battery that consists of 32 subtests in 6 functional domains for children aged 3-16 y (30).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Brooks, 2009, NEPSY-II: a developmental neuropsychological assessment, second edition, Child Neuropsychol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Another mechanism may be through functional isolation in which the effect of vitamin B-12 on neurodevelopment may be mediated by factors such as enhanced activity concentrations in children and consequently enhanced stimulation and learning possibilities provided by the caregivers.

    “Another mechanism may be through functional isolation in which the effect of vitamin B-12 on neurodevelopment may be mediated by factors such as enhanced activity concentrations in children and consequently enhanced stimulation and learning possibilities provided by the caregivers (40).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Black, 2003, Micronutrient deficiencies and cognitive functioning, J Nutr source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    ASQ-3 and NEPSY II have not formally been validated in a Nepalese population.

    “ASQ-3 and NEPSY II have not formally been validated in a Nepalese population.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The number of children in Nepal that fail to meet their developmental potential is large.

    “The number of children in Nepal that fail to meet their developmental potential has been shown to be large (1)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Peet, 2015, Early childhood development and schooling attainment: longitudinal evidence from British, Finnish and Philippine birth cohorts, PLoS One source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The study had a prospective design.

    “Strengths include the prospective design”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    The lack of holotranscobalamin variable in the study, both as an individual marker and in calculating c3B12, is a limitation.

    “The lack of this variable in our study, both as an individual marker and in calculating c3B12, is a limitation to our study.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ASQ-3 has been previously used in several studies in low- and middle-income countries.

    “ASQ-3 has been previously used in several studies in low-and middleincome countries (29,41,42)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [29] Kvestad, 2013, The assessment of developmental status using the ages and stages questionnaire-3 in nutritional research in north Indian young children, Nutr J source

      Not checked in the free run.

    • cites [41] Handal, 2007, Sociodemographic and nutritional correlates of neurobehavioral development: a study of young children in a rural region of Ecuador, Rev Panam Salud Publica source

      Not checked in the free run.

    • cites [42] Fernald, 2009

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    We calculated a combined indicator of vitamin B-12 status (3cB12) based on the 3 biomarkers (cobalamin, MMA, and tHcy) according to the method suggested by Fedosov et al. in which age and folate status are taken into account.

    “We calculated a combined indicator of vitamin B-12 status (3cB12) based on the 3 biomarkers (cobalamin, MMA, and tHcy) according to the method suggested by Fedosov et al. (32) in which age and folate status are taken into account.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Fedosov, 2015, Combined indicator of vitamin B12 status: modification for missing biomarkers and folate status and recommendations for revised cut-points, Clin Chem Lab Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The ASQ-3 is designed to be answered by caregivers but can also be assessed directly with the child by a trained professional.

    “The ASQ-3 is designed to be answered by caregivers but can also be assessed directly with the child by a trained professional (29), as we did in this study.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Kvestad, 2013, The assessment of developmental status using the ages and stages questionnaire-3 in nutritional research in north Indian young children, Nutr J source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Although the authors adjusted for potential confounders, they cannot rule out residual confounding.

    “Although we adjusted for potential confounders, we cannot rule out residual confounding.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Limited validation might result in the misclassification of child development status.

    “limited validation might result in the misclassification of child development status.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    160 of the children assessed were over the maximum recommended age range of 66 mo for ASQ-3.

    “160 of the children assessed were over the maximum recommended age range of 66 mo for ASQ-3.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    This Dutch study has limited generalizability given the small sample size and specific characteristics of the population.

    “This study has limited generalizability, however, given the small sample size and specific characteristics of the population.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [19] Torsvik, 2013, Cobalamin supplementation improves motor development and regurgitations in infants: results from a randomized intervention study, Am J Clin Nutr source

      Not checked in the free run.

    • cites [21] Louwman, 2000, Signs of impaired cognitive function in adolescents with marginal cobalamin status, Am J Clin Nutr source

      Not checked in the free run.

46 of 46

  • The paper relies on this without support.

    Insufficient maternal cobalamin status in pregnancy and during exclusive breastfeeding can put children at risk for deficiency in a critical period for the development of the central nervous system.

    “Insufficient maternal cobalamin status in pregnancy and during exclusive breastfeeding can put children at risk for deficiency in a critical period for the development of the central nervous system.”

  • The paper relies on this without support.

    The geometric puzzles test is a purer visuospatial test in which cognitive abilities as visuospatial analysis and mental rotation are key elements.

    “The geometric puzzles test is a purer visuospatial test in which cognitive abilities as visuospatial analysis and mental rotation are key elements.”

  • The paper relies on this without support.

    This study is the first to investigate the associations between early vitamin B-12 status and later neurodevelopment and cognitive functioning in a general population at risk for poor vitamin B-12 status.

    “To our knowledge, this is the first study to investigate the associations between early vitamin B-12 status and later neurodevelopment and cognitive functioning in a general population at risk for poor vitamin B-12 status.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Discussion denies a significant executive-function association shown in Table 7

    Minor

    The discussion says there were no significant associations in attention and executive functioning, but Table 7 reports an adjusted inhibition completion-time association with P = 0.037.

  • Adjusted tHcy confidence interval excludes its reported coefficient

    Minor

    The adjusted total ASQ-3 tHcy coefficient is printed as 26.78, while its stated confidence interval is 211.90 to 29.95. Under the text's notation for negative values, that interval does not contain the coefficient.

2 of 2

Cites

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Authors
Kvestad, I., Hysing, M., Shrestha, M., Ulak, M., Thorne-Lyman, A. L., Henjum, S., Ueland, P. M., Midttun, Ø., Fawzi, W., Chandyo, R. K., Shrestha, P. S., & Strand, T. A.
Affiliations
  • Uni Research (Norway) (NO)
  • Tribhuvan University Teaching Hospital (NP)
  • OsloMet – Oslo Metropolitan University (NO)
  • Haukeland University Hospital (NO)
  • Bevital (Norway) (NO)
  • Innlandet Hospital Trust (NO)
Corresponding author
Strand, Tor A
ORCID
Venue
The American Journal of Clinical Nutrition
Publisher
Elsevier BV
Published
2017-05
Volume
105
Issue
5
Pages
1122-1131
ISSN
0002-9165 (ISSN-L)
DOI
10.3945/ajcn.116.144931
OpenAlex
W2602539103
Semantic Scholar
8a47420dfd7322a3bb831e41675fb715f4356879
Cited by
92
References
46
Citations by year
2026: 4 · 2025: 7 · 2024: 6 · 2023: 11 · 2022: 8 · 2021: 9 · 2020: 17 · 2019: 15 · 2018: 12 · 2017: 3
FWCI
11.24
Type
journal article
Language
en
Open access
Licence
Locations
  • American Journal of Clinical Nutrition (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
  • Health Sciences › Nursing › Nutrition and Dietetics › Child Nutrition and Water Access
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Porphyrin Metabolism and Disorders
Keywords
vitamin B12, infancy, brain development, cognitive function, total homocysteine, methylmalonic acid, social perception, visuospatial ability, affect recognition, block construction, Nepal, South Asia, micronutrient status, child development, longitudinal follow-up, ASQ-3, NEPSY
MeSH terms
Adult, Asia, Child Development, Cognition, Female, Homocysteine, Humans, Infant, Male, Methylmalonic Acid, Nepal, Neuropsychological Tests, Nutritional Status, Vitamin B 12, Vitamin B 12 Deficiency, Young Adult, Cognitive Dysfunction, Neurodevelopmental Disorders

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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