Folic Acid Supplements During Pregnancy and Child Psychomotor Development After the First Year of Life

Valera-Gran, Desireé; Hera, Manuela García de la; Navarrete-Muñoz, Eva María; Fernández-Somoano, Ana; Tardón, Adonina; Júlvez, Jordi; Forns, Joan; Lertxundi, Nerea; Ibarluzea, Jesús; Murcia, Mario; Rebagliato, Marisa; Vioque, Jesús

doi:10.1001/jamapediatrics.2014.2611

Cited by 101 publications

(94 citation statements)

References 45 publications

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“…Elevated folic acid intakes (greater than the UL of 1 mg/d), particularly in periconceptional women, have raised concerns about the impact on maternal and embryonic health (9)(10)(11). In previous murine studies, we observed more developmental delays and heart defects in embryos (17) and more liver damage in adults (16) fed a diet containing 10 times the recommended diet content for folic acid, which is equivalent to current recommendations for high-risk women (3).…”

Section: Discussionmentioning

confidence: 58%

“…Fortification has reduced NTD incidence (4) and may benefit individuals with genetic variants in folate metabolism (5,6). As folic acidsupplement use has increased (7), so have concerns that elevated consumption may have negative effects (8) such as smallfor-gestational-age infants (9,10) and developmental delays (11). Pregnant women are advised to take $400 mg folic acid/d (1, 2); 4-5 mg folic acid/d is recommended for women in high-risk groups (3).…”

Section: Introductionmentioning

confidence: 99%

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Moderate folic acid supplementation and MTHFD1-synthetase deficiency in mice, a model for the R653Q variant, result in embryonic defects and abnormal placental development

Christensen

Hou

Bahous

et al. 2016

The American Journal of Clinical Nutrition

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Background: Moderately high folic acid intake in pregnant women has led to concerns about deleterious effects on the mother and fetus. Common polymorphisms in folate genes, such as methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolaseformyltetrahydrofolate synthetase (MTHFD1) R653Q, may modulate the effects of elevated folic acid intake. Objectives: We investigated the effects of moderate folic acid supplementation on reproductive outcomes and assessed the potential interaction of the supplemented diet with MTHFD1-synthetase (Mthfd1S) deficiency in mice, which is a model for the R653Q variant. Design: Female Mthfd1S +/+ and Mthfd1S +/2 mice were fed a folic acid-supplemented diet (FASD) (5-fold higher than recommended) or control diets before mating and during pregnancy. Embryos and placentas were assessed for developmental defects at embryonic day 10.5 (E10.5). Maternal folate and choline metabolites and gene expression in folate-related pathways were examined. Results: The combination of FASD and maternal MTHFD1-synthetase deficiency led to a greater incidence of defects in E10.5 embryos (diet 3 maternal genotype, P = 0.0016; diet 3 embryonic genotype, P = 0.054). The methylenetetrahydrofolate reductase (MTHFR) protein and methylation potential [ratio of S-adenosylmethionine (major methyl donor):S-adenosylhomocysteine) were reduced in maternal liver. Although 5-methyltetrahydrofolate (methylTHF) was higher in maternal circulation, the methylation potential was lower in embryos. The presence of developmental delays and defects in Mthfd1S +/2 embryos was associated with placental defects (P = 0.003). The labyrinth layer failed to form properly in the majority of abnormal placentas, which compromised the integration of the maternal and fetal circulation and presumably the transfer of methylTHF and other nutrients. Conclusions: Moderately higher folate intake and MTHFD1-synthetase deficiency in pregnant mice result in a lower methylation potential in maternal liver and embryos and a greater incidence of defects in embryos. Although maternal circulating methylTHF was higher, it may not have reached the embryos because of abnormal placental development; abnormal placentas were observed predominantly in abnormally developed embryos. These findings have implications for women with high folate intakes, particularly if they are polymorphic for MTHFD1 R653Q.

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Section: Discussionmentioning

confidence: 58%

Section: Introductionmentioning

confidence: 99%

Moderate folic acid supplementation and MTHFD1-synthetase deficiency in mice, a model for the R653Q variant, result in embryonic defects and abnormal placental development

Christensen

Hou

Bahous

et al. 2016

The American Journal of Clinical Nutrition

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“…A total of 22 original papers that looked at the association between folic acid supplementation in pregnancy and neurodevelopment/autism were identified after the screening, with 15 studies showing a beneficial effect of folic acid supplementation on neurodevelopment/autism, 6 studies found no statistically significant effect, while one study found a harmful effect at high dose of folic acid supplementation [18]. Two papers that suggested an adverse effect of folic acid on ASDs were not included in our review because no data on individual subjects were available in these two studies [19, 20].…”

Section: Discussionmentioning

confidence: 99%

“…Data from recent ASDs surveillance in the United States revealed a major increase in ASDs prevalence during a period with no change in policies regarding prenatal folic acid supplementation or folic acid food fortification (2002 to 2008), suggesting that ecological analyses are seriously flawed [21]. On the other hand, in a small sample of children (77) born to mothers used folic acid supplementation >5 mg/day during pregnancy had a statistically significantly lower mean psychomotor scale score (difference, -4.35 points; 95% CI, -8.34 to -0.36) than children whose mothers used a recommended dosage of folic acid supplements (0.4–1.0 mg/day) [18]. The finding from a single study with small sample needs to be replicated.…”

Section: Discussionmentioning

confidence: 99%

New Perspective on Impact of Folic Acid Supplementation during Pregnancy on Neurodevelopment/Autism in the Offspring Children – A Systematic Review

et al. 2016

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It has been conclusively established that folic acid supplementation prior to and during early pregnancy (up to 12 weeks of gestation) can prevent neural tube defects (NTDs). We hypothesized that folate effects may extend from neuro-structural defects to alterations in neuro-behavioural and emotional skills including autism spectrum disorders (ASDs) and other developmental disorders. The objective of this review was to comprehensively evaluate evidence on the impact of folic acid on neurodevelopment other than NTDs. We conducted an online search of relevant literature compiled by the National Library of Medicine from Medline and EMBASE (searched on Dec 31, 2014: http://www.ncbi.nlm.nih.gov/entrez/query/fcgi and http://www.elsevier.com/online-tools/embase). We first created 3 files (search restricted to English literature) using the following key words: 1) folate or folic acid (171322 papers identified by this search); 2) maternal or pregnancy or pregnant or gestation or gestational or prenatal or antenatal or periconception or periconceptional (1349219 papers identified by this search); and 3) autism or autism spectrum disorders or developmental delay or development or neurodevelopment or mental or cognitive or language or personal-social or gross motor or fine motor or behaviour or intellectual or intelligence or Bayley Scale (8268145 papers identified by this search). We then merged the 3 files and reviewed the papers that addressed these three issues simultaneously. A total of 22 original papers that examined the association between folic acid supplementation in human pregnancy and neurodevelopment/autism were identified after the screening, with 15 studies showing a beneficial effect of folic acid supplementation on neurodevelopment/autism, 6 studies showed no statistically significant difference, while one study showed a harmful effect in > 5 mg folic acid supplementation/day during pregnancy. Folic acid supplementation in pregnancy may have beneficial effects on the neurodevelopment of children beyond its proven effect on NTDs.

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“…Additionally, high periconceptional folate exposure has been associated with improved neurodevelopment (12)(13)(14)(15) and a reduction in the risk of various pediatric cancers (16)(17)(18) in offspring. In contrast, high periconceptional folic acid exposure has been shown in some studies, but not all, to increase the risk of asthma (19), atopic dermatitis (20), obesity, and metabolic syndrome (21) and in one study to increase the risk of a detrimental effect on psychomotor development (22). Higher choline intakes during pregnancy have been associated with improved cognitive development (23,24), whereas low intakes of vitamin B-12 or an imbalance between folic acid and vitamin B-12 intakes have been associated with intrauterine growth restriction, reduced cognitive function, and increased risk of adiposity and diabetes (21,25,26).…”

Section: Introductionmentioning

confidence: 93%

Pregnant Canadian Women Achieve Recommended Intakes of One-Carbon Nutrients through Prenatal Supplementation but the Supplement Composition, Including Choline, Requires Reconsideration

Masih

Plumptre

et al. 2015

The Journal of Nutrition

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Vitamin supplements were an important source of one-carbon nutrients during pregnancy in our sample. Without supplements, many women would not have consumed quantities of folate and vitamin B-6 consistent with recommendations. Given the importance of choline in pregnancy, further research to consider inclusion in prenatal supplements is warranted. This trial was registered at clinicaltrials.gov as NCT02244684.

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Folic Acid Supplements During Pregnancy and Child Psychomotor Development After the First Year of Life

Abstract: To our knowledge, this is the first time a detrimental effect of high dosages of FA supplements during pregnancy on psychomotor development after the first year of life has been shown. Further research from longitudinal studies is warranted to confirm these results.

Cited by 101 publications

References 45 publications

Moderate folic acid supplementation and MTHFD1-synthetase deficiency in mice, a model for the R653Q variant, result in embryonic defects and abnormal placental development

Moderate folic acid supplementation and MTHFD1-synthetase deficiency in mice, a model for the R653Q variant, result in embryonic defects and abnormal placental development

New Perspective on Impact of Folic Acid Supplementation during Pregnancy on Neurodevelopment/Autism in the Offspring Children – A Systematic Review

Pregnant Canadian Women Achieve Recommended Intakes of One-Carbon Nutrients through Prenatal Supplementation but the Supplement Composition, Including Choline, Requires Reconsideration

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