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Table 4 Summary of the studies examining associations of maternal folate status with offspring cognitive function

From: Association between maternal nutritional status in pregnancy and offspring cognitive function during childhood and adolescence; a systematic review

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
  1. QS quality score, RB risk of bias, tHcy total homocysteine, Hb haemoglobin, LMP last menstrual period, FFQ food frequency questionnaire, BMI body mass index, GA gestational age, MA maternal age, BWT birthweight, BF breast-feeding, SES socio-economic status, ME maternal education, PE paternal education, MIQ maternal intelligence, HE home environment, MS maternal smoking, MTHFR methylenetetrahydrofolate reductase