Folic Acid Clinical Trial: Follow up of Children (FACT 4 Child)

Asthma Clinical Trial

Official title:

Folic Acid Clinical Trial: Follow up of Children (FACT 4 Child)

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT03269110
• Other study ID #: CTO 816
• Status: Enrolling by invitation
• Start date: July 1, 2017
• Est. completion date: July 31, 2024

Study information

• Verified date: March 2024
• Source: Ottawa Hospital Research Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

FACT 4 Child is a follow up study of mothers who participated in the Folic Acid Clinical Trial (NCT01355159) and their children at 4-6 years of age to determine the effect of high dose folic acid supplementation on social impairments associated with Autism Spectrum Disorders (ASDs), and deficiencies in a range of executive function and emotional and behavioural problems in young children, and the risk of death.

Description:

The Folic Acid Clinical Trial (FACT) was developed to conclusively determine the effect of high dose folic acid supplementation in pregnancy on the prevention of preeclampsia in a randomized controlled trial (RCT) design.

The primary objective of the FACT 4 Child study is to examine the effect of maternal folic acid supplementation in pregnancy on the risk of social impairments, as well as executive function, emotional and behavioural problems associated with Autism Spectrum Disorders (ASD) and other developmental disorders, and death in offspring aged 4-6 y of mothers recruited to the CIHR funded FACT.

The effect of folic acid supplementation throughout pregnancy may potentially have an impact on both the mother and her offspring, which highlights the importance and relevance of this study to the management of women with preeclampsia. Results of this study will allow care providers to have the evidence of potential effects of high dose folic acid that can then be discussed; allowing women to make an informed choice about their management and care.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 2578
• Est. completion date: July 31, 2024
• Est. primary completion date: December 31, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 4 Years to 6 Years

Eligibility

Inclusion Criteria:

1. Capability of participant to comprehend and comply with study requirements

2. Mother participated in FACT

Exclusion Criteria:

1. Confirmed spontaneous termination (miscarriage) or elective termination or stillborn

2. Confirmed death of offspring at 6 weeks postpartum and/or at discharge from hospital

Related Conditions & MeSH terms

• Asthma
• Autism Spectrum Disorder
• Behavioural Problem
• Death
• Eclampsia
• Emotional Problem
• Executive Dysfunction
• Pre-Eclampsia
• Problem Behavior

Intervention

Diagnostic Test:
• SRS 2, CBCL, BRIEF-P
This study does not involve an intervention.

Locations

Country	Name	City	State
Australia	Women's and Children's Hospital	Adelaide	South Australia
Australia	Townsville	Douglas	Queensland
Australia	Ipswich	Ipswich	Queensland
Australia	Royal Women's	Parkville	Victoria
Australia	Nepean	Penrith	New South Wales
Australia	Sunshine	St Albans	Victoria
Canada	Calgary Foothills Medical Center	Calgary	Alberta
Canada	Edmonton Lois Hole Hospital for Women	Edmonton	Alberta
Canada	Fredericton Dr. Everett Chalmers Regional Hospital	Fredericton	New Brunswick
Canada	Hamilton McMaster University	Hamilton	Ontario
Canada	Kingston	Kingston	Ontario
Canada	London	London	Ontario
Canada	Moncton Hospital	Moncton	New Brunswick
Canada	Quebec City (CHUL) Centre Hospitalier Universitaire	Montreal	Quebec
Canada	Sainte-Justine	Montreal	Quebec
Canada	St-Luc	Montreal	Quebec
Canada	St-Mary's Hospital	Montreal	Quebec
Canada	The Ottawa Hospital, Civic Campus	Ottawa	Ontario
Canada	The Ottawa Hospital, General Campus	Ottawa	Ontario
Canada	Regina Qu'Appelle Health Region	Regina	Saskatchewan
Canada	St-John's Women's Health Centre	St John's	Newfoundland and Labrador
Canada	Sunnybrook Health Sciences	Toronto	Ontario
Canada	St-Paul's Hospital	Vancouver	British Columbia
Canada	Winnipeg University of Manitoba	Winnipeg	Manitoba
Jamaica	Jubilee	Kingston
Jamaica	Spanishtown	Kingston
Jamaica	University of West Indies	Kingston 7
United Kingdom	Wansbeck General Hospital	Ashington	Northumberland
United Kingdom	Blackburn	Blackburn
United Kingdom	Burnley	Burnley
United Kingdom	Fairfield	Bury	Lancashire
United Kingdom	Cumberland Infirmary Carlisle	Carlisle
United Kingdom	Leighton	Crewe	Cheshire
United Kingdom	North Manchester	Crumpsall
United Kingdom	Darlington Memorial Hospital	Darlington	County Durham
United Kingdom	North Durham	Durham
United Kingdom	Gateshead Queen Elizabeth Hospital	Gateshead	Tyne And Wear
United Kingdom	Hinchingbrooke	Huntingdon	Cambridgeshire
United Kingdom	West Middlesex University Hospital	Isleworth	Middlesex
United Kingdom	Lincolnshire	Lincoln	Lincolnshire
United Kingdom	Guy's and St. Thomas	London
United Kingdom	St George's Hospital	London	Tooting
United Kingdom	South Tees Hospital	Middlesbrough
United Kingdom	Newcastle upon Tyne Hospitals	Newcastle upon Tyne
United Kingdom	North Tyneside General Hospital	North Shields
United Kingdom	Norfolk & Norwich	Norwich
United Kingdom	Nottingham City Hospital	Nottingham
United Kingdom	Nottingham Queens Medical Centre	Nottingham
United Kingdom	Oldham	Oldham
United Kingdom	Rochdale	Rochdale	Lancashire
United Kingdom	South Tyneside Distrcit Hospital	South Shields	Tyne And Wear
United Kingdom	North Tees Hospital	Stockton
United Kingdom	Sunderland Royal Hospital	Sunderland
United Kingdom	Hillingdon Hospital	Uxbridge
United Kingdom	Warrington Hospital	Warrington
United Kingdom	West Cumberland Hospital	Whitehaven
United Kingdom	49 Marine Avenue	Whitley Bay
United Kingdom	Royal Wolverhampton - New Cross Hospital	Wolverhampton

Sponsors (1)

Lead Sponsor	Collaborator
Ottawa Hospital Research Institute

Countries where clinical trial is conducted

Australia,  Canada,  Jamaica,  United Kingdom, 

References & Publications (75)

Achenbach T. Manual for the Child Behavior Checklist/2-1 and 1992 Profile. Burlington (VT): University of Vermont Department of Psychiatry, 1992.

Achenbach TM, & Rescorla, L. A. Manual for the ASEBA School-Age Forms & Profiles. Burlington, VT: University of Vermont, Research Center for Children, Youth, & Families, 2001.

Achenbach TM, & Rescorla, L.A. Manual for the ASEBA Preschool forms and Profiles. Burlington, VT: University of Vermont Department of Psychiatry, 2000.

Achenbach TM, Dumenci, L., & Rescorla, L. A. Ten-Year Comparisons of Problems and Competencies for National Samples of Youth: Self, Parent, and Teacher Reports. Journal of Emotional and Behavioral Disorders 2002;10:194-203.

ACOG Committee on Practice Bulletins--Obstetrics. ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002. Obstet Gynecol. 2002 Jan;99(1):159-67. doi: 10.1016/s0029-7844(01)01747-1. — View Citation

Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999 Oct;23(2):185-8. doi: 10.1038/13810. — View Citation

Anderson P. Assessment and development of executive function (EF) during childhood. Child Neuropsychol. 2002 Jun;8(2):71-82. doi: 10.1076/chin.8.2.71.8724. — View Citation

Andrews, D. Children With School Problems: A Physician's Manual: The Canadian Paediatric Society, 2012.

AP Association. Diagnostic and statistical manual of mental disorders (5th Ed.). Washington, DC.: American Psychiatric Publishing, 2013.

Asztalos EV, Murphy KE, Willan AR, Matthews SG, Ohlsson A, Saigal S, Armson BA, Kelly EN, Delisle MF, Gafni A, Lee SK, Sananes R, Rovet J, Guselle P, Amankwah K, Saleem M, Sanchez J; MACS-5 Collaborative Group. Multiple courses of antenatal corticosteroids for preterm birth study: outcomes in children at 5 years of age (MACS-5). JAMA Pediatr. 2013 Dec;167(12):1102-10. doi: 10.1001/jamapediatrics.2013.2764. — View Citation

Austin PC, Lee DS, Fine JP. Introduction to the Analysis of Survival Data in the Presence of Competing Risks. Circulation. 2016 Feb 9;133(6):601-9. doi: 10.1161/CIRCULATIONAHA.115.017719. — View Citation

Beard CM, Panser LA, Katusic SK. Is excess folic acid supplementation a risk factor for autism? Med Hypotheses. 2011 Jul;77(1):15-7. doi: 10.1016/j.mehy.2011.03.013. Epub 2011 Mar 31. — View Citation

Blaise SA, Alberto JM, Audonnet-Blaise S, Gueant JL, Daval JL. Influence of preconditioning-like hypoxia on the liver of developing methyl-deficient rats. Am J Physiol Endocrinol Metab. 2007 Dec;293(6):E1492-502. doi: 10.1152/ajpendo.00255.2007. Epub 2007 Aug 28. — View Citation

Bolte S, Dickhut H, Poustka F. Patterns of parent-reported problems indicative in autism. Psychopathology. 1999 Mar-Apr;32(2):93-7. doi: 10.1159/000029072. — View Citation

Bolte S, Poustka F, Constantino JN. Assessing autistic traits: cross-cultural validation of the social responsiveness scale (SRS). Autism Res. 2008 Dec;1(6):354-63. doi: 10.1002/aur.49. — View Citation

Braun JM, Kalkbrenner AE, Calafat AM, Yolton K, Ye X, Dietrich KN, Lanphear BP. Impact of early-life bisphenol A exposure on behavior and executive function in children. Pediatrics. 2011 Nov;128(5):873-82. doi: 10.1542/peds.2011-1335. Epub 2011 Oct 24. — View Citation

Buescher AV, Cidav Z, Knapp M, Mandell DS. Costs of autism spectrum disorders in the United Kingdom and the United States. JAMA Pediatr. 2014 Aug;168(8):721-8. doi: 10.1001/jamapediatrics.2014.210. — View Citation

Cai X, Kaiser AP, Hancock TB. Parent and teacher agreement on child behavior checklist items in a sample of preschoolers from low-income and predominantly African American families. J Clin Child Adolesc Psychol. 2004 Jun;33(2):303-12. doi: 10.1207/s15374424jccp3302_12. — View Citation

Chang CM, Yu CC, Lu HT, Chou YF, Huang RF. Folate deprivation promotes mitochondrial oxidative decay: DNA large deletions, cytochrome c oxidase dysfunction, membrane depolarization and superoxide overproduction in rat liver. Br J Nutr. 2007 May;97(5):855-63. doi: 10.1017/S0007114507666410. — View Citation

Charman T, Baird G, Simonoff E, Loucas T, Chandler S, Meldrum D, Pickles A. Efficacy of three screening instruments in the identification of autistic-spectrum disorders. Br J Psychiatry. 2007 Dec;191:554-9. doi: 10.1192/bjp.bp.107.040196. — View Citation

Chatzi L, Papadopoulou E, Koutra K, Roumeliotaki T, Georgiou V, Stratakis N, Lebentakou V, Karachaliou M, Vassilaki M, Kogevinas M. Effect of high doses of folic acid supplementation in early pregnancy on child neurodevelopment at 18 months of age: the mother-child cohort 'Rhea' study in Crete, Greece. Public Health Nutr. 2012 Sep;15(9):1728-36. doi: 10.1017/S1368980012000067. Epub 2012 Feb 8. — View Citation

Christensen DL, Baio J, Van Naarden Braun K, Bilder D, Charles J, Constantino JN, Daniels J, Durkin MS, Fitzgerald RT, Kurzius-Spencer M, Lee LC, Pettygrove S, Robinson C, Schulz E, Wells C, Wingate MS, Zahorodny W, Yeargin-Allsopp M; Centers for Disease Control and Prevention (CDC). Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years--Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2012. MMWR Surveill Summ. 2016 Apr 1;65(3):1-23. doi: 10.15585/mmwr.ss6503a1. Erratum In: MMWR Morb Mortal Wkly Rep. 2016;65(15):404. MMWR Morb Mortal Wkly Rep. 2018 Nov 16;67(45):1279. — View Citation

Constantino JN, & Gruber, C. P. Social Responsiveness Scale (SRS): Manual. Los Angeles: Western Psychological Services, 2005.

Constantino JN, Davis SA, Todd RD, Schindler MK, Gross MM, Brophy SL, Metzger LM, Shoushtari CS, Splinter R, Reich W. Validation of a brief quantitative measure of autistic traits: comparison of the social responsiveness scale with the autism diagnostic interview-revised. J Autism Dev Disord. 2003 Aug;33(4):427-33. doi: 10.1023/a:1025014929212. — View Citation

Constantino JNGC. Social Responsiveness Scale, Second Edition. Los Angeles: Western Psychological Services, 2012.

Cooney CA, Dave AA, Wolff GL. Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring. J Nutr. 2002 Aug;132(8 Suppl):2393S-2400S. doi: 10.1093/jn/132.8.2393S. — View Citation

Crider KS, Cordero AM, Qi YP, Mulinare J, Dowling NF, Berry RJ. Prenatal folic acid and risk of asthma in children: a systematic review and meta-analysis. Am J Clin Nutr. 2013 Nov;98(5):1272-81. doi: 10.3945/ajcn.113.065623. Epub 2013 Sep 4. — View Citation

Duarte CS, Bordin IA, de Oliveira A, Bird H. The CBCL and the identification of children with autism and related conditions in Brazil: pilot findings. J Autism Dev Disord. 2003 Dec;33(6):703-7. doi: 10.1023/b:jadd.0000006005.31818.1c. — View Citation

Duku E, Vaillancourt T. Validation of the BRIEF-P in a sample of Canadian preschool children. Child Neuropsychol. 2014;20(3):358-71. doi: 10.1080/09297049.2013.796919. Epub 2013 May 31. — View Citation

Egeland J, Fallmyr O. Confirmatory Factor Analysis of the Behavior Rating Inventory of Executive Function (BRIEF): support for a distinction between emotional and behavioral regulation. Child Neuropsychol. 2010;16(4):326-37. doi: 10.1080/09297041003601462. Epub 2010 Mar 5. — View Citation

Fenech M. Folate (vitamin B9) and vitamin B12 and their function in the maintenance of nuclear and mitochondrial genome integrity. Mutat Res. 2012 May 1;733(1-2):21-33. doi: 10.1016/j.mrfmmm.2011.11.003. Epub 2011 Nov 7. — View Citation

Ferguson SA, Berry KJ, Hansen DK, Wall KS, White G, Antony AC. Behavioral effects of prenatal folate deficiency in mice. Birth Defects Res A Clin Mol Teratol. 2005 Apr;73(4):249-52. doi: 10.1002/bdra.20111. — View Citation

Fombonne E, Marcin C, Bruno R, Tinoco CM, Marquez CD. Screening for autism in Mexico. Autism Res. 2012 Jun;5(3):180-9. doi: 10.1002/aur.1235. Epub 2012 May 11. — View Citation

Forns J, Torrent M, Garcia-Esteban R, Caceres A, Pilar Gomila M, Martinez D, Morales E, Julvez J, Grimalt JO, Sunyer J. Longitudinal association between early life socio-environmental factors and attention function at the age 11 years. Environ Res. 2012 Aug;117:54-9. doi: 10.1016/j.envres.2012.04.007. Epub 2012 May 18. — View Citation

Gioia GA EK, & Isquith, PK. . Behavior Rating Inventory of Executive Function, Preschool Version. Lutz, Fl: Psychological Assessment Resources, Inc., 2003.

Gioia GA, Isquith PK, Retzlaff PD, Espy KA. Confirmatory factor analysis of the Behavior Rating Inventory of Executive Function (BRIEF) in a clinical sample. Child Neuropsychol. 2002 Dec;8(4):249-57. doi: 10.1076/chin.8.4.249.13513. — View Citation

Gioia GA. Isquith PK GP, Kenworthy L. Behavior Rating Inventory of Executive Function (BRIEF). Odessa, Fl: Psychological Assessment Resources, 2000.

Hsiao MN, Tseng WL, Huang HY, Gau SS. Effects of autistic traits on social and school adjustment in children and adolescents: the moderating roles of age and gender. Res Dev Disabil. 2013 Jan;34(1):254-65. doi: 10.1016/j.ridd.2012.08.001. Epub 2012 Sep 7. — View Citation

James SJ, Melnyk S, Jernigan S, Pavliv O, Trusty T, Lehman S, Seidel L, Gaylor DW, Cleves MA. A functional polymorphism in the reduced folate carrier gene and DNA hypomethylation in mothers of children with autism. Am J Med Genet B Neuropsychiatr Genet. 2010 Sep;153B(6):1209-20. doi: 10.1002/ajmg.b.31094. — View Citation

Johnson S, Wolke D. Behavioural outcomes and psychopathology during adolescence. Early Hum Dev. 2013 Apr;89(4):199-207. doi: 10.1016/j.earlhumdev.2013.01.014. Epub 2013 Feb 27. — View Citation

Julvez J, Fortuny J, Mendez M, Torrent M, Ribas-Fito N, Sunyer J. Maternal use of folic acid supplements during pregnancy and four-year-old neurodevelopment in a population-based birth cohort. Paediatr Perinat Epidemiol. 2009 May;23(3):199-206. doi: 10.1111/j.1365-3016.2009.01032.x. Epub 2009 Mar 11. — View Citation

Kamio Y, Moriwaki A, Inada N. Utility of teacher-report assessments of autistic severity in Japanese school children. Autism Res Treat. 2013;2013:373240. doi: 10.1155/2013/373240. Epub 2013 Dec 11. — View Citation

Keating E, Goncalves P, Campos I, Costa F, Martel F. Folic acid uptake by the human syncytiotrophoblast: interference by pharmacotherapy, drugs of abuse and pathological conditions. Reprod Toxicol. 2009 Dec;28(4):511-20. doi: 10.1016/j.reprotox.2009.07.001. Epub 2009 Jul 16. — View Citation

Kerek R, Geoffroy A, Bison A, Martin N, Akchiche N, Pourie G, Helle D, Gueant JL, Bossenmeyer-Pourie C, Daval JL. Early methyl donor deficiency may induce persistent brain defects by reducing Stat3 signaling targeted by miR-124. Cell Death Dis. 2013 Aug 8;4(8):e755. doi: 10.1038/cddis.2013.278. — View Citation

King CR. A novel embryological theory of autism causation involving endogenous biochemicals capable of initiating cellular gene transcription: a possible link between twelve autism risk factors and the autism 'epidemic'. Med Hypotheses. 2011 May;76(5):653-60. doi: 10.1016/j.mehy.2011.01.024. Epub 2011 Mar 8. — View Citation

Knapp M, Romeo R, Beecham J. Economic cost of autism in the UK. Autism. 2009 May;13(3):317-36. doi: 10.1177/1362361309104246. — View Citation

LaSalle JM. A genomic point-of-view on environmental factors influencing the human brain methylome. Epigenetics. 2011 Jul;6(7):862-9. doi: 10.4161/epi.6.7.16353. Epub 2011 Jul 1. — View Citation

Mann JR, McDermott S, Bao H, Hardin J, Gregg A. Pre-eclampsia, birth weight, and autism spectrum disorders. J Autism Dev Disord. 2010 May;40(5):548-54. doi: 10.1007/s10803-009-0903-4. — View Citation

Martinussen MP, Risnes KR, Jacobsen GW, Bracken MB. Folic acid supplementation in early pregnancy and asthma in children aged 6 years. Am J Obstet Gynecol. 2012 Jan;206(1):72.e1-7. doi: 10.1016/j.ajog.2011.07.033. Epub 2011 Jul 29. — View Citation

McQuiston S, Kloczko N. Speech and language development: monitoring process and problems. Pediatr Rev. 2011 Jun;32(6):230-8; quiz 239. doi: 10.1542/pir.32-6-230. No abstract available. — View Citation

Moretti P, Sahoo T, Hyland K, Bottiglieri T, Peters S, del Gaudio D, Roa B, Curry S, Zhu H, Finnell RH, Neul JL, Ramaekers VT, Blau N, Bacino CA, Miller G, Scaglia F. Cerebral folate deficiency with developmental delay, autism, and response to folinic acid. Neurology. 2005 Mar 22;64(6):1088-90. doi: 10.1212/01.WNL.0000154641.08211.B7. — View Citation

Movsas TZ, Paneth N. The effect of gestational age on symptom severity in children with autism spectrum disorder. J Autism Dev Disord. 2012 Nov;42(11):2431-9. doi: 10.1007/s10803-012-1501-4. — View Citation

Neul JL. The relationship of Rett syndrome and MECP2 disorders to autism. Dialogues Clin Neurosci. 2012 Sep;14(3):253-62. doi: 10.31887/DCNS.2012.14.3/jneul. — View Citation

Oakley GP Jr. Elimination of folic acid-preventable neural tube defects. Am J Prev Med. 2008 Dec;35(6):606-7. doi: 10.1016/j.amepre.2008.09.017. No abstract available. — View Citation

Padmanabhan N, Jia D, Geary-Joo C, Wu X, Ferguson-Smith AC, Fung E, Bieda MC, Snyder FF, Gravel RA, Cross JC, Watson ED. Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development. Cell. 2013 Sep 26;155(1):81-93. doi: 10.1016/j.cell.2013.09.002. — View Citation

Pandolfi V, Magyar CI, Dill CA. Confirmatory factor analysis of the child behavior checklist 1.5-5 in a sample of children with autism spectrum disorders. J Autism Dev Disord. 2009 Jul;39(7):986-95. doi: 10.1007/s10803-009-0716-5. Epub 2009 Mar 5. — View Citation

Repchinsky C. CPS 2008: Compendium of Pharmaceuticals and Specialties : The Canadian Drug Reference for Health Professionals. United States: Canadian Pharmacists Association, 2008.

Roth C, Magnus P, Schjolberg S, Stoltenberg C, Suren P, McKeague IW, Davey Smith G, Reichborn-Kjennerud T, Susser E. Folic acid supplements in pregnancy and severe language delay in children. JAMA. 2011 Oct 12;306(14):1566-73. doi: 10.1001/jama.2011.1433. — View Citation

Roza SJ, van Batenburg-Eddes T, Steegers EA, Jaddoe VW, Mackenbach JP, Hofman A, Verhulst FC, Tiemeier H. Maternal folic acid supplement use in early pregnancy and child behavioural problems: The Generation R Study. Br J Nutr. 2010 Feb;103(3):445-52. doi: 10.1017/S0007114509991954. Epub 2009 Sep 22. — View Citation

Salbaum JM, Kappen C. Genetic and epigenomic footprints of folate. Prog Mol Biol Transl Sci. 2012;108:129-58. doi: 10.1016/B978-0-12-398397-8.00006-X. — View Citation

Schmidt RJ, Hansen RL, Hartiala J, Allayee H, Schmidt LC, Tancredi DJ, Tassone F, Hertz-Picciotto I. Prenatal vitamins, one-carbon metabolism gene variants, and risk for autism. Epidemiology. 2011 Jul;22(4):476-85. doi: 10.1097/EDE.0b013e31821d0e30. — View Citation

Schmidt RJ, Tancredi DJ, Ozonoff S, Hansen RL, Hartiala J, Allayee H, Schmidt LC, Tassone F, Hertz-Picciotto I. Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study. Am J Clin Nutr. 2012 Jul;96(1):80-9. doi: 10.3945/ajcn.110.004416. Epub 2012 May 30. — View Citation

Steenweg-de Graaff J, Roza SJ, Steegers EA, Hofman A, Verhulst FC, Jaddoe VW, Tiemeier H. Maternal folate status in early pregnancy and child emotional and behavioral problems: the Generation R Study. Am J Clin Nutr. 2012 Jun;95(6):1413-21. doi: 10.3945/ajcn.111.030791. Epub 2012 May 9. — View Citation

Suglia SF, Duarte CS, Chambers EC, Boynton-Jarrett R. Social and behavioral risk factors for obesity in early childhood. J Dev Behav Pediatr. 2013 Oct;34(8):549-56. doi: 10.1097/DBP.0b013e3182a509c0. — View Citation

Suren P, Roth C, Bresnahan M, Haugen M, Hornig M, Hirtz D, Lie KK, Lipkin WI, Magnus P, Reichborn-Kjennerud T, Schjolberg S, Davey Smith G, Oyen AS, Susser E, Stoltenberg C. Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA. 2013 Feb 13;309(6):570-7. doi: 10.1001/jama.2012.155925. — View Citation

Tan TX, Dedrick RF, Marfo K. Factor structure and clinical implications of child behavior checklist/1.5-5 ratings in a sample of girls adopted from China. J Pediatr Psychol. 2007 Aug;32(7):807-18. doi: 10.1093/jpepsy/jsm025. Epub 2007 Apr 19. — View Citation

Toriello HV; Policy and Practice Guideline Committee of the American College of Medical Genetics. Policy statement on folic acid and neural tube defects. Genet Med. 2011 Jun;13(6):593-6. doi: 10.1097/GIM.0b013e31821d4188. — View Citation

Villamor E, Rifas-Shiman SL, Gillman MW, Oken E. Maternal intake of methyl-donor nutrients and child cognition at 3 years of age. Paediatr Perinat Epidemiol. 2012 Jul;26(4):328-35. doi: 10.1111/j.1365-3016.2012.01264.x. Epub 2012 Mar 14. — View Citation

Waddell C, McEwan K, Shepherd CA, Offord DR, Hua JM. A public health strategy to improve the mental health of Canadian children. Can J Psychiatry. 2005 Mar;50(4):226-33. doi: 10.1177/070674370505000406. — View Citation

Waterland RA, Travisano M, Tahiliani KG, Rached MT, Mirza S. Methyl donor supplementation prevents transgenerational amplification of obesity. Int J Obes (Lond). 2008 Sep;32(9):1373-9. doi: 10.1038/ijo.2008.100. Epub 2008 Jul 15. — View Citation

Whitrow MJ, Moore VM, Rumbold AR, Davies MJ. Effect of supplemental folic acid in pregnancy on childhood asthma: a prospective birth cohort study. Am J Epidemiol. 2009 Dec 15;170(12):1486-93. doi: 10.1093/aje/kwp315. Epub 2009 Oct 30. — View Citation

Wigham S, McConachie H, Tandos J, Le Couteur AS; Gateshead Millennium Study core team. The reliability and validity of the Social Responsiveness Scale in a UK general child population. Res Dev Disabil. 2012 May-Jun;33(3):944-50. doi: 10.1016/j.ridd.2011.12.017. Epub 2012 Jan 25. — View Citation

Wilkinson LA. A best practice guide to assessment and intervention for autism and Asperger syndrome in schools. London: Jessica Kingsley Publishers, 2010.

Wilson RD; GENETICS COMMITTEE; MOTHERISK. RETIRED: Pre-conceptional vitamin/folic acid supplementation 2007: the use of folic acid in combination with a multivitamin supplement for the prevention of neural tube defects and other congenital anomalies. J Obstet Gynaecol Can. 2007 Dec;29(12):1003-1013. doi: 10.1016/S1701-2163(16)32685-8. Erratum In: J Obstet Gynaecol Can. 2008 Mar;30(3):193. Goh, Ingrid [corrected to Goh, Y Ingrid]. English, French. — View Citation

Wolff GL, Kodell RL, Moore SR, Cooney CA. Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. FASEB J. 1998 Aug;12(11):949-57. — View Citation

* Note: There are 75 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Neurocognitive disability	The primary outcome is a competing composite endpoint of neurocognitive disability and death. Neurocognitive disability is a composite outcome related to social impairments, executive function, emotional and behavioural problems which have been associated with Autism Spectrum Disorder (ASD). It will be defined by an abnormal score on any of three standardized and validated assessment tools: SRS-2 BRIEF-P, or CBCL which will be administered to the parents of children aged 4-6 years. Deaths reported between 6 weeks to 4-6 years of age will be recorded as a competing event and treated as part of the primary endpoint.	From six weeks of age to date of data collection taken at one time point between the ages of 4 to 6 years.
Secondary	Severe Morbidity	Secondary outcomes to be assessed in FACT 4 Child include severe morbidity of FACT offspring, captured by the Mother-Child Health Survey at the age of 4 - 6 years, including incidence of: Severe morbidity defined by any illnesses during the previous years that has necessitated hospitalization or medication/treatment for >2 months	From six weeks of age to date of data collection taken at one time point between the ages of 4 to 6 years.