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PLoS One. 2016 Nov 22;11(11):e0165626. doi: 10.1371/journal.pone.0165626. eCollection 2016.

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

Gao Y1,2,3, Sheng C1, Xie RH2,4,5, Sun W6, Asztalos E7,8, Moddemann D9, Zwaigenbaum L10,11, Walker M2,3,12, Wen SW2,3,12.

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Department of Obstetrics and Gynecology, Nanfang Hospital of Southern Medical University, Guangzhou, Guangdong, China.
OMNI Research Group, Department of Obstetrics and Gynecology, University of Ottawa Faculty of Medicine, Ottawa, Canada.
Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada.
Hunan University of Medicine Department of Nursing, Huaihua, Hunan, China.
McLaughlin Center for Population Risk Assessment, University of Ottawa Faculty of Medicine, Ottawa, Canada.
Department of Obstetrics and Gynecology, Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
Centre for Mother, Infant and Child Research, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
Departments of Pediatrics and Obstetrics and Gynecology Faculty of Medicine, University of Toronto, Toronto, Canada.
Department of Pediatrics and Child Health and Neonatal Follow-up Program, University of Manitoba, Winnipeg, Canada.
Departments of Pediatrics and of Psychiatry, University of Alberta, Edmonton, Canada.
Autism Research Centre, Glenrose Rehabilitation Hospital, Edmonton, Canada.
School of Epidemiology, Public Health, and Preventive Medicine, University of Ottawa, Ottawa, Canada.


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: and 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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