Table 4 Summary of the studies examining associations of maternal folate status with offspring cognitive function
Author, Year, Sample size, Age, Country, Study design | Nutrient | Cognitive function | Results after adjustment for confounders | QS and RB |
|---|---|---|---|---|
23WU BTF; 2012  N = 154  Age 18 Months  Canada  Prospective | Plasma folate and tHcy concentrations assessed at 16 and 36 weeks gestation No folate deficiency (plasma folate <6.8 nmol/l) High tHcy not reported | Bayley Scales of Infant Development Receptive language, expressive language, cognitive skills, fine motor and gross motor | No association of folate and tHcy with cognitive function Confounders adjusted for: The child’s sex, BF, ethnicity, MA, MIQ, maternal fatty acid level | 13 Medium |
24Tamura T; 2005  N = 355  Age 5 years  USA  Prospective  Mothers participated in zinc supplementation trial during pregnancy | Red cell and plasma folate concentrations – 19, 26 and 37 weeks gestation and tHcy concentrations-26 and 37 weeks Low folate-(plasma folate <11 nmol/L) 19 weeks- 7.4 %; 26 weeks- 8.2 %; 37 weeks- 14.0 % Red cell folate <430 nmol/L) 19 weeks- 7.2 %; 26 weeks- 3.8 %; 37 weeks- 3.3 % High tHcy (tHcy > 7 μmol/L) 26 weeks- 8.4 %; 37 weeks- 22.1 % | Differential Ability Scale (verbal, nonverbal and General IQ), Visual and Auditory Sequential Memory (visual and auditory memory span) Knox Cube (attention span and short-term memory) Gross Motor Scale (Gross motor development and Grooved Pegboard (manipulative dexterity) | No difference in the mental and psychomotor developmental scores between children of mothers with normal and deficient folate and tHcy groups. No difference in test scores even across range of folate status (quartiles) Confounders adjusted for: The child’s sex, GA, BWT, MA, BMI, MS, MIQ, alcohol and drug use, HE | 15 Medium |
25Bhate V; 2008  N = 108  Age 9 years  India  Prospective community based birth cohort | Erythrocyte folate and tHcy concentrations assessed at 28 weeks gestation No details about low folate or high tHcy concentrations | Raven’s Coloured Progressive Matrices-Intelligence; Visual recognition Colour Trial Test-sustained attention and executive function Digit-span test-short-term or working memory | No association of erythrocyte folate, tHcy with any of the cognitive tests Confounders adjusted for: The child’s sex, age, education, weight and head circumference, B12 level, SES, education of the head of the family | 14 Medium |
26Veena SR; 2010  N = 536  Age 9-10 years  India  Prospective birth cohort | Plasma folate and tHcy concentrations assessed at 30 ± 2 weeks gestation Low folate-(folate <11 nmol/L)-4 % High tHcy (tHcy > 7 μmol/L)-3 % | Kauffman Assessment Battery for Children-II Learning, long-term retrieval, short-term memory and reasoning Wechsler Intelligence Scale for Children-III attention and concentration Koh’s block design visuo-spatial ability Verbal fluency | No difference in all the cognitive test scores between folate deficient and normal groups. ↑folate concentrations (SD)-↑learning (0.10 SD), visuo-spatial ability (0.10 SD) and attention and concentration (0.10 SD) No association between tHcy concentrations across the entire range or hyperhomocysteinemia and cognitive function Confounders adjusted for: The child’s sex, GA, age, education, weight and head circumference at birth, parity, MA, maternal BMI, ME, PE, SES, religion, rural/urban residence, the child’s current head circumference, BMI and folate concentrations | 16 Medium |
27Gross RL; 1974  N = 32  Age 6 weeks to 4 years  Africa  Case–control study | Folic acid deficiency (based on bone marrow exam or serum folate level) (Hb 3.2-8.9 g %) | Denver Developmental Screening Test (gross motor, fine motor, language and personal-social) | Folic acid deficiency was associated with abnormal or delayed development on one or more of the 4 areas examined Confounders adjusted for: No information | 6 High |
28Del Rio Garcia; 2009  N = 253  Age Infancy (1- 12 months)  Mexico  Prospective birth cohort | Daily dietary intake of folate (first trimester FFQ) Deficient daily folate intake (<400 μg) -70 % | Bayley Scales of Infant Development -II (Mental Development Index(MDI) and Psychomotor Development Index (PDI)) | Folate intake deficiency-↓ MDI (β = -1.8) in infants of mothers who were carriers of MTHFR677 TT genotype Confounders adjusted for: BWT, BF, current age, energy intake at age 6 months, maternal BMI, pregnancy hypertension, ME, HE and MTHFR 1298A > C genotype | 16 Medium |
29Villamor E; 2012  N = 1210  Age 3 years  USA  Prospective pre-birth cohort | Average daily intake of folate at 1st and 2nd trimester (FFQ + Supplements) Peri-conceptional intake of folate from supplements (LMP-4 weeks gestation) | Peabody Picture Vocabulary Test-Receptive Language Wide Range Assessment of Visual Motor Abilities-visual-motor; visual-spatial and fine motor | First but not 2nd trimester folate intake (food + supplement) positively related to receptive language but not with visuo-motor abilities. Every increment of 600 μg/day folate intake -↑1.6 points receptive language. No association of peri-conceptional folate intake with cognitive function Confounders adjusted for: MA, parity, ethnicity, MS, pre-pregnancy BMI, ME, PE, MIQ, energy, fish and iron intake, income, the child’s sex and English as primary language | 15 Medium |
30Boeke C; 2013  N = 895  Age 7 years  USA  Prospective pre-birth cohort | Average daily intake of folate at 1st and 2nd trimester (FFQ + Supplements) | Peabody Picture Vocabulary Test-Receptive Language Wide Range Assessment of Memory and Learning-II edition, Design and Picture Memory subtests: visuo-spatial memory Kaufman Brief Intelligence Test-II edition Verbal and non-verbal intelligence | No association of folate intake with cognitive function Confounders adjusted for: MA, parity, ethnicity, MS, pre-pregnancy BMI, ME, PE, MIQ, energy, fish and iron intake, income, the child’s sex and English as primary language | 16 Medium |
31Wehby GL; 2008  N = 6774  Age 3 years  USA  Population based longitudinal | Folic acid supplements (3 months prior to pregnancy and/or during the following 3 months) 3 % used supplement | Denver developmental screening-language, personal-social, gross motor and fine motor | Folic acid use was associated with improved gross motor development (OR = 0.5) Confounders adjusted for: The child’s sex, age, ethnicity, MA, ME, MS, alcohol, drug abuse, income, maternal health status | 11 High |
32Roth C; 2011  N = 38954  Age 3 years  Prospective observational Norway | Folic acid supplements with or without other supplements (4 wks before to 8 wks after conception) 18.9 % used only folic acid 50 % used folic acid + other supplements | Language Grammar Rating scale - Language delay (severe and moderate) Severe-children with minimal expressive language i.e. only 1 word or unintelligible utterances; Moderate-children can produce 2-3 word phrases Gross motor skills-Ages and Stages questionnaire | Use of folic acid resulted in reduced risk of severe (OR = 0.55) and moderate language delay (OR = 0.80) No association between folic acid intake and delay in gross motor skills Confounders adjusted for: Maternal marital status, BMI, parity and education | 17 Low |
33Forns J; 2012  N = 393  Age 11 years  Population based prospective birth cohort; Spain | Folic acid supplements with or without other vitamins Dose and duration: No information. 66.8 % used folic acid + other supplements | Continuous Performance Test (Attention function) Omission error; Commission error HRT-mean response time (for correct hits) | Supplementation with folic acid reduced the incidence rate ratio (IRR = 0.80) of omission errors No association with commission and HRT Confounders adjusted for: Parity, PE, social class, MIQ, maternal mental health, MS, BWT, BF | 14 Medium |
34Julvez J; 2009  N = 420  Age 4 years  Population based prospective birth cohort  Spain | Folic acid supplements with or without other vitamins Dose and duration: No information 34 % used only folic acid 24 % used folic acid + other supplements | McCarthy Scales of Children’s Abilities General cognitive scale and subscales (Verbal, perceptive-performance, memory, quantitative and motor) and executive function (Verbal and perceptive-performance) | Use of maternal folic acid supplement was positively associated with verbal (general cognitive) score (β = 3.98) and verbal (executive function (β = 3.97)), motor skills (β = 4.55) Confounders adjusted for: The child’s sex, age, school season, area of residence, GA, BF, parity, maternal marital status, MS, use of calcium and iron supplements, ME, PE and social class | 14 Medium |
35Holmes-Siedle; 1992  N = 96 Age 2-5 years  UK  Prospective observational | Peri-conceptional multivitamin containing folic acid (0.36 mg) supplements daily with other vitamins and minerals (Minimum 28 days before conception until the second missed menstrual period) | Denver developmental screening test (DDST) (language, motor and social skills) | No significant difference in development score among supplemented group compared to general population Confounders adjusted for: No information | 12 Medium |
36Campoy C; 2011  N = 154  Age 6.5 years  Double blind randomized controlled trial  European centres (Germany, Spain and Hungary) | 4 supplement (milk based) groups Fish oil (N = 37) 5-methyl tetrahydrofolate-400 μg (N = 37) Fish oil + 5-methyl tetrahydrofolate (N = 35) Placebo (N = 45) Daily supplementation from 20th week of gestation until delivery Plasma/erythrocyte folate concentrations during 2nd and 3rd trimester and at the time of delivery; No information about compliance | Kaufman Assessment Battery for Children (KABC): Sequential processing scale Simultaneous processing scale Mental Processing Composite (MPC) | No significant difference in cognitive scores between supplement groups No association of maternal plasma or erythrocyte folate concentrations during pregnancy and at the time of delivery with cognitive function Confounders adjusted for: Unadjusted | 19 Low |