Follow-Up of Children Born to Mothers in Folic Acid Clinical Trial (FACT 4 Child): A Prospective Cohort Study Based on a Double-Blinded Randomised Controlled Trial

Maryam Ghiasi¹, Lonnie Zwaigenbaum², Diane Moddemann³, Ruth Rennicks White^{1

4}, Alysha L J Dingwall-Harvey⁵, Kimberly P Grattan¹, Marisa Murray¹, Natalie Rybak⁶, Heather Walker¹, Thierry Lacaze-Masmonteil^{7

8}, Elizabeth Asztalos^{9

10}, Laura M Gaudet¹¹, Stephen Robson¹², William Hague¹³, Donnette Simms-Stewart¹⁴, Graeme Smith¹⁵, Emmanuel Bujold¹⁶, Daniel J Corsi^{5

17}, Gary Goldfield⁵, Darine El-Chaâr^{4

18}, Shi Wu Wen^{4

11}, Mark C Walker^{1

4}

Affiliations

¹ Acute Care Research Program, Ottawa Hospital Research Institute, Ottawa, Canada.
² Department of Pediatrics, University of Alberta, Edmonton, Canada.
³ Department of Pediatrics and Child Health, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
⁴ Department of Obstetrics, Gynecology & Newborn Care, The Ottawa Hospital, Ottawa, Canada.
⁵ BORN Ontario, Children's Hospital of Eastern Ontario, Ottawa, Canada.
⁶ Eastern Ontario Regional Laboratory Association, Ottawa, Canada.
⁷ Maternal Infant Child and Youth Research Network (MICYRN), Vancouver, British Columbia, Canada.
⁸ Clinical Professor of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
⁹ Department of Newborn and Developmental Paediatrics, Sunnybrook Health Sciences Centre, Toronto, Canada.
¹⁰ Department of Paediatrics, University of Toronto, Toronto, Canada.
¹¹ Methodological and Implementation Research Program, Ottawa Hospital Research Institute, Ottawa, Canada.
¹² Institute of Cellular Medicine, the Medical School, Newcastle University, Newcastle upon Tyne, UK.
¹³ Obstetric Medicine, Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia.
¹⁴ Department of Obstetrics and Gynecology, Faculty of Medical Sciences, The University of the West Indies, Mona, Jamaica.
¹⁵ Queen's Perinatal Research Unit, Kingston General Hospital, Department of Obstetrics and Gynecology, Queens University, Kingston, Ontario, Canada.
¹⁶ Department of Obstetrics and Gynecology, Faculty of Medicine, Université Laval, Quebec City, Canada.
¹⁷ Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada.
¹⁸ Inflammation and Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Canada.

PMID: 40859816
DOI: 10.1111/1471-0528.18341

Follow-Up of Children Born to Mothers in Folic Acid Clinical Trial (FACT 4 Child): A Prospective Cohort Study Based on a Double-Blinded Randomised Controlled Trial

Maryam Ghiasi et al. BJOG. 2025.

. 2025 Aug 27.

doi: 10.1111/1471-0528.18341. Online ahead of print.

Authors

Affiliations

¹ Acute Care Research Program, Ottawa Hospital Research Institute, Ottawa, Canada.
² Department of Pediatrics, University of Alberta, Edmonton, Canada.
³ Department of Pediatrics and Child Health, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
⁴ Department of Obstetrics, Gynecology & Newborn Care, The Ottawa Hospital, Ottawa, Canada.
⁵ BORN Ontario, Children's Hospital of Eastern Ontario, Ottawa, Canada.
⁶ Eastern Ontario Regional Laboratory Association, Ottawa, Canada.
⁷ Maternal Infant Child and Youth Research Network (MICYRN), Vancouver, British Columbia, Canada.
⁸ Clinical Professor of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
⁹ Department of Newborn and Developmental Paediatrics, Sunnybrook Health Sciences Centre, Toronto, Canada.
¹⁰ Department of Paediatrics, University of Toronto, Toronto, Canada.
¹¹ Methodological and Implementation Research Program, Ottawa Hospital Research Institute, Ottawa, Canada.
¹² Institute of Cellular Medicine, the Medical School, Newcastle University, Newcastle upon Tyne, UK.
¹³ Obstetric Medicine, Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia.
¹⁴ Department of Obstetrics and Gynecology, Faculty of Medical Sciences, The University of the West Indies, Mona, Jamaica.
¹⁵ Queen's Perinatal Research Unit, Kingston General Hospital, Department of Obstetrics and Gynecology, Queens University, Kingston, Ontario, Canada.
¹⁶ Department of Obstetrics and Gynecology, Faculty of Medicine, Université Laval, Quebec City, Canada.
¹⁷ Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada.
¹⁸ Inflammation and Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Canada.

PMID: 40859816
DOI: 10.1111/1471-0528.18341

Abstract

Objective: To assess the impact of high-dose folic acid supplementation (4.0-5.1 mg), started between 8⁺⁰ and 16⁺⁶ weeks of gestation and continued until delivery, on social impairments associated with Autism Spectrum Disorders, deficiencies in executive function, and emotional and behavioural problems in children.

Design: FACT 4 Child is a follow-up of mothers and their children born during the Folic Acid Clinical Trial (FACT), an international multi-centre double-blinded randomised trial to assess the effect of high-dose folic acid supplementation on preventing preeclampsia in women with increased risk.

Setting: Multi-centre international follow-up study.

Population: Mothers and their children enrolled in FACT, among them 664 completed the follow-up.

Methods: Mothers reported on social and executive function and emotional and behavioural problems in their children aged 4-9 years using standardised, validated questionnaires.

Main outcome: The proportion of children with at least one score > 1.5 SD above expected mean.

Results: Among 319 children in the intervention group, 43 (13.5%) had a score in the elevated range, compared with 51/345 (14.8%) in the placebo group (RR = 0.91; 95% CI: 0.63 to 1.33; p = 0.63).

Conclusion: In children born to women at risk for preeclampsia, rates of neurodevelopmental outcomes were not different between high-dose folic acid and control groups in this study. Our finding suggests that a high dose of folic acid supplementation may not be needed in pregnant women with increased risk. A larger-scale study is needed to determine neurodevelopmental outcomes associated with different dosages and timing of folic acid supplementation during pregnancy.

Keywords: autism spectrum disorders; folic acid; neurodevelopment; pregnancy; social impairments.

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References

1. S. W. Wen, X. K. Chen, M. Rodger, et al., “Folic Acid Supplementation in Early Second Trimester and the Risk of Preeclampsia,” American Journal of Obstetrics and Gynecology 198, no. 1 (2008): 45, https://doi.org/10.1016/j.ajog.2007.06.067.
1. S. W. Wen, Y. Guo, M. Rodger, et al., “Folic Acid Supplementation in Pregnancy and the Risk of Pre‐Eclampsia‐A Cohort Study,” PLoS One 11, no. 2 (2016): e0149818, https://doi.org/10.1371/journal.pone.0149818.
1. S. W. Wen, R. R. White, N. Rybak, et al., “Effect of High Dose Folic Acid Supplementation in Pregnancy on Pre‐Eclampsia (FACT): Double Blind, Phase III, Randomised Controlled, International, Multicentre Trial,” British Medical Journal 362 (2018): k3478, https://doi.org/10.1136/bmj.k3478.
1. M. J. Maenner, Z. Warren, A. R. Williams, et al., “Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years—Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2020,” MMWR Surveillance Summaries 72, no. 2 (2023): 1–14, https://doi.org/10.15585/mmwr.ss7202a1.
1. A. V. S. Buescher, Z. Cidav, M. Knapp, and D. S. Mandell, “Costs of Autism Spectrum Disorders in the United Kingdom and the United States,” JAMA Pediatrics 168, no. 8 (2014): 721–728, https://doi.org/10.1001/jamapediatrics.2014.210.

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Follow-Up of Children Born to Mothers in Folic Acid Clinical Trial (FACT 4 Child): A Prospective Cohort Study Based on a Double-Blinded Randomised Controlled Trial

Affiliations

Follow-Up of Children Born to Mothers in Folic Acid Clinical Trial (FACT 4 Child): A Prospective Cohort Study Based on a Double-Blinded Randomised Controlled Trial

Authors

Affiliations

Abstract

References

Grants and funding

LinkOut - more resources

Full Text Sources