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

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Association Between Maternal Use of Folic Acid Supplements and Risk of Autism Spectrum Disorders in Children ORIGINAL CONTRIBUTION Association Between Maternal Use of Folic Acid Supplements and Risk of Autism Spectrum Disorders in Children ˚ ´ Pal Suren, MD, MPH Importance Prenatal folic acid supplements reduce the risk of neural tube defects Christine Roth, MSc in children, but it has not been determined whether they protect against other neu- Michaeline Bresnahan, PhD rodevelopmental disorders. Margaretha Haugen, PhD Objective To examine the association between maternal use of prenatal folic acid supplements and subsequent risk of autism spectrum disorders (ASDs) (autistic disor- Mady Hornig, MD der, Asperger syndrome, pervasive developmental disorder–not otherwise specified Deborah Hirtz, MD [PDD-NOS]) in children. Kari Kveim Lie, MD Design, Setting, and Patients The study sample of 85 176 children was derived from the population-based, prospective Norwegian Mother and Child Cohort Study W. Ian Lipkin, MD (MoBa). The children were born in 2002-2008; by the end of follow-up on March 31, Per Magnus, MD, PhD 2012, the age range was 3.3 through 10.2 years (mean, 6.4 years). The exposure of Ted Reichborn-Kjennerud, MD, PhD 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. Synnve Schjølberg, MSc Relative risks of ASDs were estimated by odds ratios (ORs) with 95% CIs in a logistic George Davey Smith, MD, DSc regression analysis. Analyses were adjusted for maternal education level, year of birth, and parity. Anne-Siri Øyen, PhD Main Outcome Measure Specialist-confirmed diagnosis of ASDs. Ezra Susser, MD, DrPH Results At the end of follow-up, 270 children in the study sample had been diag- Camilla Stoltenberg, MD, PhD nosed 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 UPPLEMENTATION WITH FOLIC autistic disorder, compared with 0.21% (50/24 134) in those unexposed to folic acid. acid around the time of concep- The adjusted OR for autistic disorder in children of folic acid users was 0.61 (95% CI, tion reduces the risk of neural 0.41-0.90). No association was found with Asperger syndrome or PDD-NOS, but power 1-7 tube defects in children. This was limited. Similar analyses for prenatal fish oil supplements showed no such asso- Sprotective effect has led to mandatory ciation with autistic disorder, even though fish oil use was associated with the same fortification of flour with folic acid in maternal characteristics as folic acid use. 8 several countries, and it is generally Conclusions and Relevance Use of prenatal folic acid supplements around the recommended that women planning to time of conception was associated with a lower risk of autistic disorder in the MoBa become pregnant take a daily supple- cohort. Although these findings cannot establish causality, they do support prenatal ment of folic acid starting 1 month be- folic acid supplementation. fore conception.8,9 JAMA. 2013;309(6):570-577 www.jama.com There also is evidence that mater- nal folic acid supplementation during Author Affiliations: Norwegian Institute of Public Maryland (Dr Hirtz); Institute of Psychiatry, Univer- Health, Oslo (Drs Sure´n, Haugen, Lie, Magnus, Rei- sity of Oslo, Oslo (Dr Reichborn-Kjennerud); MRC Cen- pregnancy may be associated with re- chborn-Kjennerud, Øyen, and Stoltenberg and Mss tre for Causal Analysis in Translational Epidemiology, duced risk of other neurodevelopmen- Roth and Schjølberg); Centre for Paediatric Epidemi- University of Bristol, Bristol, United Kingdom (Dr Davey ology and Biostatistics, UCL Institute of Child Health, Smith); Nic Waals Institute, Lovisenberg Hospital, Oslo London, United Kingdom (Dr Sure´n); Mailman School (Dr Øyen); and Department of Public Health and Pri- For editorial comment see p 611. of Public Health, Columbia University, New York, New mary Health Care, University of Bergen, Bergen, Nor- York (Drs Bresnahan, Hornig, Lipkin, and Susser and way (Dr Stoltenberg). Author Video Interview available at Ms Roth); New York State Psychiatric Institute, New Corresponding Author: Pa˚ l Sure´ n, MD, MPH, York (Drs Bresnahan and Susser); National Institute Norwegian Institute of Public Health, PO Box 4404, www.jama.com. of Neurological Disorders and Stroke, Bethesda, Nydalen, N-0403 Oslo, Norway ([email protected]). 570 JAMA, February 13, 2013—Vol 309, No. 6 ©2013 American Medical Association. All rights reserved. Downloaded From: http://jama.jamanetwork.com/ by a University of British Columbia Library User on 02/23/2014 MATERNAL FOLIC ACID SUPPLEMENTS AND AUTISM tal disorders in children. A recent study offspring ages 36 months, 5 years, and Measures of Folic Acid Use of 38 954 children in the Norwegian 7 years, (2) professional and parental and Dietary Folate Intake Mother and Child Cohort Study (MoBa) referrals of children suspected of hav- Since 1998, the Norwegian Director- found that maternal intake of folic acid ing ASD, and (3) linkages to the Nor- ate of Health has recommended that all supplements from 4 weeks before to 8 wegian Patient Registry. Referrals are women attempting to become preg- weeks after the start of pregnancy was elicited through annual newsletters to nant should take one 400-␮g folic acid associated with a lower risk of severe MoBa participants and information on supplement per day from 1 month be- language delay at age 3 years.10 A case- the Norwegian Institute of Public fore conception through the first tri- control study from California of au- Health website. The Norwegian Pa- mester. Folic acid supplements are tism spectrum disorders (ASDs) showed tient Registry collects data on diagno- available over the counter in Norway. that maternal intake of folic acid and ses from all hospitals and outpatient Multivitamin supplements containing prenatal vitamins during the 3 months clinics in Norway beginning in the year folic acid are also available, but at the prior to pregnancy and the first month 2008, thereby capturing data for all chil- time participants were recruited to of pregnancy was associated with a dren diagnosed with ASD by Norwe- MoBa, all such supplements con- lower risk of ASDs in the offspring, and gian health services. tained less than 400 ␮g of folic acid. complementary genetic analyses indi- When a child with ASD or potential In MoBa, detailed information about cated that the association was modi- ASD is detected through any of the the mothers’ supplement intake be- fied by gene variants that determine the mechanisms described above, he or she fore conception and in early preg- ability to utilize available folate.11,12 is invited to participate in a clinical as- nancy was obtained through question- Although ethical considerations pre- sessment that includes the research- naire report at week 18 of gestation. No clude placebo-controlled randomized standard instruments for diagnosis of foods were fortified with folic acid at trials that eliminate folic acid, observa- ASD, the Autism Diagnostic Interview– the time when participants were re- tional studies of mothers who do and do Revised15 and the Autism Diagnostic cruited; synthetic supplements thus not use supplements may be informa- Observation Schedule,16 which have represented the only source of folate tive. We used the MoBa cohort to inves- proven high reliability and validity in apart from the ordinary diet for the tigate the association between the use of making diagnoses of ASD in children. pregnant women. The women were maternal folic acid supplements before Assessments are conducted without asked to record their intake of vita- and in early pregnancy and the subse- knowledge of previous questionnaire mins, minerals, and other supple- quent risk of ASDs (autistic disorder, responses. Diagnostic conclusions are ments according to the ingredient lists Asperger syndrome, pervasive develop- best-estimate clinical diagnoses de- on the supplement containers, within mental disorder–not otherwise speci- rived from test and interview results and 4-week intervals from before the start fied [PDD-NOS]) in the offspring. from information collected from par- of pregnancy. They were not asked to ents and teachers. Diagnoses are based specify the exact amounts, so if folic METHODS on Diagnostic and Statistical Manual of acid was only taken as part of a multi- Study Population Mental Disorders (Fourth Edition) vitamin supplement, the daily dose The MoBa cohort13 is nationwide and (DSM-IV) criteria, and the case defini- would be lower than 400 ␮g. includes 109 000 children born from tion includes codes 299.00 (Autistic Additional information about supple- 1999 to 2009. Mothers were recruited Disorder), 299.80 (Asperger Syn- ment use and dietary intake in mid preg- at ultrasound examinations around drome), and 299.80 (Pervasive Devel- nancy was obtained through a food fre- week 18 of gestation. Cases of ASD in opmental Disorder–Not Otherwise quency questionnaire completed in week the cohort are identified by a sub- Specified). 22. In this questionnaire, women were study of autism, the Autism Birth Co- The registry contains International asked to write the name of supplements hort (ABC) study.14 The analyses in this Statistical Classification of Diseases, 10th they were currently taking (in week 22), study reflect data collected and pro- Revision codes determined by Norwe- and exact amounts of vitamins and min- cessed by March 31, 2012. Participa- gian specialist health services, and the erals were calculated on the basis of this tion in MoBa and the ABC study is ASD case definition of the ABC study information. The food frequency ques- based on written informed consent from includes codes F84.0 (Childhood Au- tionnaire has been described in a previ- the mother. Both studies were ap- tism), F84.1 (Atypical Autism), F84.5 ous article17 and validated through blood proved by the regional committee of (Asperger Syndrome), F84.8 (Other samples and 4-day food records from a medical research ethics for Southeast- Pervasive Developmental Disorder), subsample of the cohort.18 ern Norway.
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