Table 1.

Characteristics of the animal and human studies that examined associations between maternal prenatal folate and offspring cognitive outcomes.

Identification	Location	Sample	Method Used to Determine Prenatal Folate Level	Maternal Folate Assessment	Dose of Folic Acid Intake or Mean Levels in Blood	Offspring’s/Children’s Age at the Time of Assessment	Offspring’s/Children’s Assessment	Main Results
Animal Studies
[48] Craciunescu et al., 2010	United States	Fetal mice	Diet supplementation	Embryonic days 11–17	Control diet: 2 mg folic acid/kg diet; 1.1 g choline chloride/kg diet	Embryonic day 17	Histological and immune-histochemical assays of fetal brain regions of interest	Folate-deficient mice had fewer neural progenitor cells undergoing mitosis in the septum and greater apoptosis rates in the septum and hippocampus compared to the control mice
					Folate-deficient diet: 10.0 mg folic acid/kg diet, 1 g choline chloride/kg diet
					Folate-deficient choline-supplemented diet: 0.0 mg folic acid/kg diet, 4.95 g choline chloride/kg diet
[68] Jadavji et al., 2015	Canada	Methylenetetrahydrofolate reductase (MTHFR)-deficient male mice	Diet supplementation	6 weeks prior to breeding until the end of lactation	Folate-deficient diet: 0.3 mg folic acid/kg diet	3-week-old male mice	Novel object recognition task, Y-maze task	Maternal folate deficiency in mice was associated with short-term memory impairment in offspring
					Folate sufficient diet: 2 mg folic acid/kg diet
[69] Ferguson et al., 2005	United States	20 female mice per group. 4 males and 4 females/litter were retained for initial behavioral testing. 1 male and 1 female pup/litter were used in postweaning behavioral testing	Diet supplementation	8 weeks prior to breeding until the end of gestation	Folate-deficient diets: (1) 400 nmol folic acid/kg diet and (2) 600 nmol folic acid/kg diet	Postnatal days 4–83	Righting reflex, negative geotaxis, forelimb hanging, motor coordination using Rotarod apparatus, open field activity, elevated plus maze	Maternal folate deficiency in mice produced offspring who exhibited more anxiety-related behavior in the elevated plus maze
					Folate sufficient diet: 1200 nmol folic acid/kg diet
Human Studies
[70] Julvez et al., 2009	Spain	420 mother-child pairs	Maternal self-report questionnaire used to determine whether supplements containing folic acid were taken	First trimester	No or yes	4 years of age	McCarthy Scales of Children’s Abilities, California Preschool Social Competence Scale	Verbal, motor-executive function, verbal-executive function, social competence and inattention symptom scores were positively associated with maternal use of folic acid supplements
[71] Wehby and Murray 2008	United States	6774 mother-child pairs	National survey that included data as to whether supplements containing folic acid had been taken	First trimester	No or yes	3 years of age	16 items from the Denver Developmental Screening Test	Prenatal folic acid supplementation had a positive effect on children’s overall cognitive and gross motor development
[72] McNulty et al., 2019	United Kingdom	37 mother-child pairs in the treatment group and 33 mother-child pairs in the placebo group	Supplements or placebos distributed to the women in 7-day pillboxes	14 weeks gestation until the birth of the child	400 ug/day supplement containing folic acid	7 years of age	Wechsler Preschool and Primary Scale of Intelligence, Third Edition, UK Edition (WPPSI-III)	Children of mothers who were in the treatment group had higher scores on the WPPSI-III compared to the children of mothers who were given a placebo
					Placebo containing no folic acid
[74] Chatzi et al., 2012	Greece	553 mother-child pairs	A questionnaire was administered by a trained research nurse that asked whether the women had taken a folic acid supplement since they became pregnant. Supplement users reported the brand name, the dose, and the frequency of intake, which was converted into a measure of daily intake.	14–18 weeks gestation	No folic acid intake from supplements	18 months of age	Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III)	Children of mothers who reported taking a daily supplement of 5 mg of folic acid or more had a 5 unit increase on receptive communication and a 3.5 unit increase in expressive communication
					Daily intake of 5 mg of folic acid from supplements
					Daily intake of folic acid from supplements higher than 5 mg
[75] Chen et al., 2021	China	32 cohort studies and 7 case–control studies	Systematic review and meta-analysis of research articles that examined the association between prenatal folic acid supplementation and postnatal neurodevelopmental outcomes. All studies discussed folic acid supplementation only	During pregnancy	Varied by study; some reported whether or not women were supplemented; others reported specific supplementation levels.	18 months to 17 years	Varied by study; different measures used to assess intelligence, risk of autistic traits, ADHD, behavior, language, and psychomotor problems	Appropriate maternal folic acid supplementation may have positive effects on children’s intelligence and development, and reduce the risk of autism traits, ADHD, and behavioral and language problems
[76] Villamor et al., 2012	United States	1210 mother-child pairs	Food frequency questionnaires	First and second trimester	Mean estimated folate intake of 949 ± 390 ug/day	3 years of age	Peabody Picture Vocabulary Test, Third Edition (PPVT-III), Wide Range Assessment of Visual Motor Abilities	For each 600 μg per day increase in total folate intake during the first trimester of pregnancy there was a 1.6-point increase in scores on the PPVT-III in the children
[77] Boeke et al., 2013	United States	895 mother-child pairs	Food frequency questionnaires	First and second trimesters	Mean daily estimated folate intake of 972 ug/day in the first trimester and 1268 ug/day in the second trimesters	7 years of age	Wide Range Assessment of Memory and Learning, Second Edition (WRAML2), Kaufman Brief Intelligence Test, Second Edition (KBIT-2)	No associations were found between maternal folate intake and child cognitive outcomes
[85] Veena et al., 2010	India	536 mother-child pairs	Maternal plasma/serum folate concentrations from blood samples	28–32 weeks gestation	Mean plasma/serum folate concentrations of 34.7 nmol/L	9 or 10 years of age	Kaufman Assessment Battery for Children	Positive association between maternal plasma/serum folate concentrations and children’s performance on the Kaufman Assessment Battery for Children
[88] Ars et al., 2019	Netherlands	256 mother-child pairs (62 in the low folate group and 194 in the normal folate group)	Maternal plasma/serum folate concentrations from venous blood samples	First trimester	Low folate group: plasma/serum folate levels below 8 nmol/L	6 years of age	Neuroimaging and NEPSY-II-NL	Low maternal plasma/serum folate concentrations below 8 nmol/L were associated with smaller total brain volume and poorer language and visuospatial skills in children
					Normal folate group: plasma/serum folate levels above 8 nmol/L
[89] Wu et al., 2012	United States	154 mother-child pairs	Food frequency questionnaires and maternal plasma/serum folate concentrations from blood samples	16 weeks gestation	Mean plasma/serum folate concentrations of 36.4 nmol/L	18 months of age	Bayley Scales of Infant Development, Third Edition (Bayley-III)	No association found between maternal plasma/serum folate concentrations and child cognitive function
[90] Tamura et al., 2005	United States	355 mother-child pairs	Maternal red blood cell folate concentrations from blood samples	Second and third trimesters	Mean red blood cell folate concentrations were 873 nmol/L, 1070 nmol/L, and 1096 nmol/L at 19, 26, and 37 weeks gestation, respectively	5 years of age	Differential Ability Scales, Visual and Auditory Sequential Memory Tests, Knox Cube Test, Gross Motor Scale, and Grooved Pegboard Test	No association found between maternal red blood cell folate concentrations and child cognitive function