Abstract: Association Between Maternal Use of Folic Acid Supplements and Risk of Autism Spectrum Disorders in Children

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Importance  Prenatal folic acid supplements reduce the risk of neural tube defects in children, but it has not been determined whether they protect against other neurodevelopmental disorders.
Objective  To examine the association between maternal use of prenatal folic acid supplements and subsequent risk of autism spectrum disorders (ASDs) (autistic disorder, Asperger syndrome, pervasive developmental disorder–not otherwise specified [PDD-NOS]) in children.
Design, Setting, and Patients  The study sample of 85 176 children was derived from the population-based, prospective Norwegian Mother and Child Cohort Study (MoBa). The children were born in 2002-2008; by the end of follow-up on March 31, 2012, the age range was 3.3 through 10.2 years (mean, 6.4 years). The exposure of primary interest was use of folic acid from 4 weeks before to 8 weeks after the start of pregnancy, defined as the first day of the last menstrual period before conception. Relative risks of ASDs were estimated by odds ratios (ORs) with 95% CIs in a logistic regression analysis. Analyses were adjusted for maternal education level, year of birth, and parity.
Main Outcome Measure  Specialist-confirmed diagnosis of ASDs.
Results  At the end of follow-up, 270 children in the study sample had been diagnosed with ASDs: 114 with autistic disorder, 56 with Asperger syndrome, and 100 with PDD-NOS. In children whose mothers took folic acid, 0.10% (64/61 042) had autistic disorder, compared with 0.21% (50/24 134) in those unexposed to folic acid. The adjusted OR for autistic disorder in children of folic acid users was 0.61 (95% CI, 0.41-0.90). No association was found with Asperger syndrome or PDD-NOS, but power was limited. Similar analyses for prenatal fish oil supplements showed no such association with autistic disorder, even though fish oil use was associated with the same maternal characteristics as folic acid use.
Conclusions and Relevance  Use of prenatal folic acid supplements around the time of conception was associated with a lower risk of autistic disorder in the MoBa cohort. Although these findings cannot establish causality, they do support prenatal folic acid supplementation.

Supplementation with folic acid around the time of conception reduces the risk of neural tube defects in children.1– 7 This protective effect has led to mandatory fortification of flour with folic acid in several countries,8and it is generally recommended that women planning to become pregnant take a daily supplement of folic acid starting 1 month before conception.8– 9
There also is evidence that maternal folic acid supplementation during pregnancy may be associated with reduced risk of other neurodevelopmental disorders in children. A recent study of 38 954 children in the Norwegian Mother and Child Cohort Study (MoBa) found that maternal intake of folic acid supplements from 4 weeks before to 8 weeks after the start of pregnancy was associated with a lower risk of severe language delay at age 3 years.10 A case-control study from California of autism spectrum disorders (ASDs) showed that maternal intake of folic acid and prenatal vitamins during the 3 months prior to pregnancy and the first month of pregnancy was associated with a lower risk of ASDs in the offspring, and complementary genetic analyses indicated that the association was modified by gene variants that determine the ability to utilize available folate.11– 12
Although ethical considerations preclude placebo-controlled randomized trials that eliminate folic acid, observational studies of mothers who do and do not use supplements may be informative. We used the MoBa cohort to investigate the association between the use of maternal folic acid supplements before and in early pregnancy and the subsequent risk of ASDs (autistic disorder, Asperger syndrome, pervasive developmental disorder–not otherwise specified [PDD-NOS]) in the offspring.
JAMA. 2013;309(6):570-577. doi:10.1001/jama.2012.155925.
Norwegian Institute of Public Health, Oslo (Drs Surén, Haugen, Lie, Magnus, Reichborn-Kjennerud, Øyen, and Stoltenberg and Mss Roth and Schjølberg); Centre for Paediatric Epidemiology and Biostatistics, UCL Institute of Child Health, London, United Kingdom (Dr Surén); Mailman School of Public Health, Columbia University, New York, New York (Drs Bresnahan, Hornig, Lipkin, and Susser and Ms Roth); New York State Psychiatric Institute, New York (Drs Bresnahan and Susser); National Institute of Neurological Disorders and Stroke, Bethesda, Maryland (Dr Hirtz); Institute of Psychiatry, University of Oslo, Oslo (Dr Reichborn-Kjennerud); MRC Centre for Causal Analysis in Translational Epidemiology, University of Bristol, Bristol, United Kingdom (Dr Davey Smith); Nic Waals Institute, Lovisenberg Hospital, Oslo (Dr Øyen); and Department of Public Health and Primary Health Care, University of Bergen, Bergen, Norway (Dr Stoltenberg).

Abstract: Long term calcium intake and rates of all cause and cardiovascular mortality: community based prospective longitudinal cohort study

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