Association between folic acid supplementation during pregnancy and the risk of autism spectrum disorder in the offspring: a meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

 JIA Rongjie ¹ , JIN Shihao ²

1. The 305 Hospital of People’s Liberation Army, Beijing 100017, P.R.China;
2. School of Public Health, Tianjin Medical University, Tianjin 300070, P.R.China;

Corresponding author：

JIA Rongjie, Email: jiarongjie13@yeah.net

Keywords：

Maternal folate; Autism spectrum disorder; Pregnancy; Offspring; Meta-analysis; Systematic review; Case-control study; Cohort study

DOI：

10.7507/1672-2531.202105058

Video：

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Objective To systematically review the association between maternal folate supplementation during pregnancy and the risk of autism spectrum disorder (ASD) in the offspring.Methods PubMed, EMbase, Web of Science, The Cochrane Library, Scopus, CNKI, WanFang Data, VIP and CBM databases were electronically searched to collect case-control and cohort studies on the association between maternal folate supplementation during pregnancy and the risk of ASD in the offspring from inception to December 2020. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies. Meta-analysis was then performed using RevMan 5.3 and Stata 14.0 software.Results A total of 17 studies involving 10 812 cases and 876 241 controls were included. The results of meta-analysis showed that there was no significant association between maternal folate supplementation during pregnancy and the risk of ASD in the offspring in the total population. The subgroup analysis revealed that maternal folate supplementation during pregnancy was statistically associated with a reduced risk of ASD in the offspring in the Asian population (OR=0.71, 95%CI 0.53 to 0.96, P=0.03). However, there were no statistical correlations in European and American populations.Conclusions Current evidence shows that maternal folate supplementation during pregnancy may reduce the risk of ASD in the offspring in the Asian population. Due to limited quality and quantity of the included studies, more high-quality studies are required to verify the above conclusions.

Citation： JIA Rongjie, JIN Shihao. Association between folic acid supplementation during pregnancy and the risk of autism spectrum disorder in the offspring: a meta-analysis. Chinese Journal of Evidence-Based Medicine, 2021, 21(10): 1141-1147. doi: 10.7507/1672-2531.202105058 Copy

1.	Lord C, Elsabbagh M, Baird G, et al. Autism spectrum disorder. Lancet, 2018, 392(10146): 508-520.
2.	Hyman SL, Levy SE, Myers SM, et al. Identification, evaluation, and management of children with autism spectrum disorder. Pediatrics, 2020, 145(1): e20193447.
3.	Mandy WP, Charman T, Skuse DH. Testing the construct validity of proposed criteria for DSM-5 autism spectrum disorder. J Am Acad Child Adolesc Psychiatry, 2012, 51(1): 41-50.
4.	Maenner MJ, Shaw KA, Baio J, et al. Prevalence of autism spectrum disorder among children aged 8 years-autism and developmental disabilities monitoring network, 11 sites, United States, 2016. MMWR Surveill Summ, 2020, 69(4): 1-12.
5.	Sun X, Allison C, Matthews FE, et al. Prevalence of autism in mainland China, Hong Kong and Taiwan province: a systematic review and meta-analysis. Mol Autism, 2013, 4(1): 7.
6.	武丽杰. 孤独症谱系障碍儿童家庭疾病负担的现状与思考. 中国学校卫生, 2018, 39(3): 321-324.
7.	Rossignol DA, Genuis SJ, Frye RE. Environmental toxicants and autism spectrum disorders: a systematic review. Transl Psychiatry, 2014, 4(2): e360.
8.	Bottiglieri T. Folate, vitamin B12, and neuropsychiatric disorders. Nutr Rev, 1996, 54(12): 382-390.
9.	Kinde B, Gabel HW, Gilbert CS, et al. Reading the unique DNA methylation landscape of the brain: Non-CpG methylation, hydroxymethylation, and MeCP2. Proc Natl Acad Sci USA, 2015, 112(22): 6800-6806.
10.	Tan M, Yang T, Zhu J, et al. Maternal folic acid and micronutrient supplementation is associated with vitamin levels and symptoms in children with autism spectrum disorders. Reprod Toxicol, 2020, 91: 109-115.
11.	Sharman Moser S, Davidovitch M, Rotem RS, et al. High dose folic acid during pregnancy and the risk of autism. The birth order bias: a nested case-control study. Reprod Toxicol, 2019, 89: 173-177.
12.	Wells G, Shea B, O'Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa: Ottawa Health Research Institute, 2014.
13.	康德英, 许能锋. 循证医学(第3版). 北京: 人民卫生出版社, 2015: 80.
14.	Nilsen RM, Surén P, Gunnes N, et al. Analysis of self-selection bias in a population-based cohort study of autism spectrum disorders. Paediatr Perinat Epidemiol, 2013, 27(6): 553-563.
15.	DeVilbiss EA, Magnusson C, Gardner RM, et al. Antenatal nutritional supplementation and autism spectrum disorders in the Stockholm youth cohort: population based cohort study. BMJ, 2017, 359: j4273.
16.	Surén P, Roth C, Bresnahan M, et al. Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA, 2013, 309(6): 570-577.
17.	Levine SZ, Kodesh A, Viktorin A, et al. Association of maternal use of folic acid and multivitamin supplements in the periods before and during pregnancy with the risk of autism spectrum disorder in offspring. JAMA Psychiatry, 2018, 75(2): 176-184.
18.	Steenweg-de Graaff J, Ghassabian A, Jaddoe VW, et al. Folate concentrations during pregnancy and autistic traits in the offspring. The Generation R Study. Eur J Public Health, 2015, 25(3): 431-433.
19.	Al-Farsi YM, Waly MI, Deth RC, et al. Low folate and vitamin B12 nourishment is common in Omani children with newly diagnosed autism. Nutrition, 2013, 29(3): 537-541.
20.	Schmidt RJ, Tancredi DJ, Ozonoff S, et al. 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, 96(1): 80-89.
21.	Virk J, Liew Z, Olsen J, et al. Preconceptional and prenatal supplementary folic acid and multivitamin intake and autism spectrum disorders. Autism, 2016, 20(6): 710-718.
22.	Strøm M, Granström C, Lyall K, et al. Research letter: folic acid supplementation and intake of folate in pregnancy in relation to offspring risk of autism spectrum disorder. Psychol Med, 2018, 48(6): 1048-1054.
23.	DeSoto M, Hitlan R. Synthetic folic acid supplementation during pregnancy may increase the risk of developing autism. J Ped Biochem, 2016, 4(2): 251-261.
24.	李侠, 凌子羽, 王建敏, 等. 儿童孤独症围孕期危险因素的1∶1配对病例对照研究. 华中科技大学学报(医学版), 2015, 44(3): 357-361.
25.	苏媛媛. 孤独症, 智力低下儿童环境危险因素的研究. 天津: 天津医科大学, 2012.
26.	孙艳丽, 邵婷, 姚余有, 等. 母亲妊娠特有焦虑与学龄前儿童孤独症样行为关系的出生队列研究. 中华预防医学杂志, 2016, (2): 118-122.
27.	蒋辉, 刘俐, 陈维清. 母亲孕期被动吸烟和补充叶酸与其子女孤独症行为的交互作用. 中华流行病学杂志, 2016, 37(7): 940-944.
28.	陈强, 黄丽霞, 徐文娟, 等. 珠海市1.5-3岁孤独症谱系障碍患病率及危险因素研究. 中国儿童保健杂志, 2014, (6): 649-651.
29.	Baxter AJ, Brugha TS, Erskine HE, et al. The epidemiology and global burden of autism spectrum disorders. Psychol Med, 2015, 45(3): 601-613.
30.	Berry RJ, Crider KS, Yeargin-Allsopp M. Periconceptional folic acid and risk of autism spectrum disorders. JAMA, 2013, 309(6): 611-613.
31.	王虹, 王芳, 范利军, 等. 叶酸通过调节p53/p21(waf1/cip1)信号途径促进小鼠神经干细胞增殖和分化. 神经解剖学杂志, 2012, 28(3): 247-252.
32.	Mooijaart SP, Gussekloo J, Frölich M, et al. Homocysteine, vitamin B-12, and folic acid and the risk of cognitive decline in old age: the Leiden 85-Plus study. Am J Clin Nutr, 2005, 82(4): 866-871.
33.	Smith AD, Kim YI, Refsum H. Is folic acid good for everyone? Am J Clin Nutr, 2008, 87(3): 517-533.
34.	Degroote S, Hunting D, Takser L. Periconceptional folate deficiency leads to autism-like traits in Wistar rat offspring. Neurotoxicol Teratol, 2018, 66: 132-138.
35.	Zhang Q, Wu H, Zou M, et al. Folic acid improves abnormal behavior via mitigation of oxidative stress, inflammation, and ferroptosis in the BTBR T+ tf/J mouse model of autism. J Nutr Biochem, 2019, 71: 98-109.
36.	DeVilbiss EA, Gardner RM, Newschaffer CJ, et al. Maternal folate status as a risk factor for autism spectrum disorders: a review of existing evidence. Br J Nutr, 2015, 114(5): 663-672.
37.	Roth C, Magnus P, Schjølberg S, et al. Folic acid supplements in pregnancy and severe language delay in children. JAMA, 2011, 306(14): 1566-1573.
38.	Naninck EFG, Stijger PC, Brouwer-Brolsma EM. The importance of maternal folate status for brain development and function of offspring. Adv Nutr, 2019, 10(3): 502-519.
39.	Frye RE, Sequeira JM, Quadros EV, et al. Cerebral folate receptor autoantibodies in autism spectrum disorder. Mol Psychiatry, 2013, 18(3): 369-381.
40.	Frye RE, Slattery J, Delhey L, et al. Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial. Mol Psychiatry, 2018, 23(2): 247-256.
41.	李楠楠, 夏薇, 孙彩虹, 等. 叶酸对孤独症儿童的辅助治疗效果研究. 中国儿童保健杂志, 2013, 21(1): 13-15, 19.
42.	Crider KS, Bailey LB, Berry RJ. Folic acid food fortification-its history, effect, concerns, and future directions. Nutrients, 2011, 3(3): 370-384.
43.	De Wals P, Tairou F, Van Allen MI, et al. Reduction in neural-tube defects after folic acid fortification in Canada. N Engl J Med, 2007, 357(2): 135-142.
44.	Honein MA, Paulozzi LJ, Mathews TJ, et al. Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects. JAMA, 2001, 285(23): 2981-2986.
45.	孙长颢, 凌文华, 黄国伟. 营养与食品卫生学(8版). 北京: 人民卫生出版社, 2017: 108.
46.	Hao L, Ma J, Stampfer MJ, et al. Geographical, seasonal and gender differences in folate status among Chinese adults. J Nutr, 2003, 133(11): 3630-3635.
47.	Pu D, Shen Y, Wu J. Association between MTHFR gene polymorphisms and the risk of autism spectrum disorders: a meta-analysis. Autism Res, 2013, 6(5): 384-392.

1. Lord C, Elsabbagh M, Baird G, et al. Autism spectrum disorder. Lancet, 2018, 392(10146): 508-520.
2. Hyman SL, Levy SE, Myers SM, et al. Identification, evaluation, and management of children with autism spectrum disorder. Pediatrics, 2020, 145(1): e20193447.
3. Mandy WP, Charman T, Skuse DH. Testing the construct validity of proposed criteria for DSM-5 autism spectrum disorder. J Am Acad Child Adolesc Psychiatry, 2012, 51(1): 41-50.
4. Maenner MJ, Shaw KA, Baio J, et al. Prevalence of autism spectrum disorder among children aged 8 years-autism and developmental disabilities monitoring network, 11 sites, United States, 2016. MMWR Surveill Summ, 2020, 69(4): 1-12.
5. Sun X, Allison C, Matthews FE, et al. Prevalence of autism in mainland China, Hong Kong and Taiwan province: a systematic review and meta-analysis. Mol Autism, 2013, 4(1): 7.
6. 武丽杰. 孤独症谱系障碍儿童家庭疾病负担的现状与思考. 中国学校卫生, 2018, 39(3): 321-324.
7. Rossignol DA, Genuis SJ, Frye RE. Environmental toxicants and autism spectrum disorders: a systematic review. Transl Psychiatry, 2014, 4(2): e360.
8. Bottiglieri T. Folate, vitamin B12, and neuropsychiatric disorders. Nutr Rev, 1996, 54(12): 382-390.
9. Kinde B, Gabel HW, Gilbert CS, et al. Reading the unique DNA methylation landscape of the brain: Non-CpG methylation, hydroxymethylation, and MeCP2. Proc Natl Acad Sci USA, 2015, 112(22): 6800-6806.
10. Tan M, Yang T, Zhu J, et al. Maternal folic acid and micronutrient supplementation is associated with vitamin levels and symptoms in children with autism spectrum disorders. Reprod Toxicol, 2020, 91: 109-115.
11. Sharman Moser S, Davidovitch M, Rotem RS, et al. High dose folic acid during pregnancy and the risk of autism. The birth order bias: a nested case-control study. Reprod Toxicol, 2019, 89: 173-177.
12. Wells G, Shea B, O'Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa: Ottawa Health Research Institute, 2014.
13. 康德英, 许能锋. 循证医学(第3版). 北京: 人民卫生出版社, 2015: 80.
14. Nilsen RM, Surén P, Gunnes N, et al. Analysis of self-selection bias in a population-based cohort study of autism spectrum disorders. Paediatr Perinat Epidemiol, 2013, 27(6): 553-563.
15. DeVilbiss EA, Magnusson C, Gardner RM, et al. Antenatal nutritional supplementation and autism spectrum disorders in the Stockholm youth cohort: population based cohort study. BMJ, 2017, 359: j4273.
16. Surén P, Roth C, Bresnahan M, et al. Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA, 2013, 309(6): 570-577.
17. Levine SZ, Kodesh A, Viktorin A, et al. Association of maternal use of folic acid and multivitamin supplements in the periods before and during pregnancy with the risk of autism spectrum disorder in offspring. JAMA Psychiatry, 2018, 75(2): 176-184.
18. Steenweg-de Graaff J, Ghassabian A, Jaddoe VW, et al. Folate concentrations during pregnancy and autistic traits in the offspring. The Generation R Study. Eur J Public Health, 2015, 25(3): 431-433.
19. Al-Farsi YM, Waly MI, Deth RC, et al. Low folate and vitamin B12 nourishment is common in Omani children with newly diagnosed autism. Nutrition, 2013, 29(3): 537-541.
20. Schmidt RJ, Tancredi DJ, Ozonoff S, et al. 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, 96(1): 80-89.
21. Virk J, Liew Z, Olsen J, et al. Preconceptional and prenatal supplementary folic acid and multivitamin intake and autism spectrum disorders. Autism, 2016, 20(6): 710-718.
22. Strøm M, Granström C, Lyall K, et al. Research letter: folic acid supplementation and intake of folate in pregnancy in relation to offspring risk of autism spectrum disorder. Psychol Med, 2018, 48(6): 1048-1054.
23. DeSoto M, Hitlan R. Synthetic folic acid supplementation during pregnancy may increase the risk of developing autism. J Ped Biochem, 2016, 4(2): 251-261.
24. 李侠, 凌子羽, 王建敏, 等. 儿童孤独症围孕期危险因素的1∶1配对病例对照研究. 华中科技大学学报(医学版), 2015, 44(3): 357-361.
25. 苏媛媛. 孤独症, 智力低下儿童环境危险因素的研究. 天津: 天津医科大学, 2012.
26. 孙艳丽, 邵婷, 姚余有, 等. 母亲妊娠特有焦虑与学龄前儿童孤独症样行为关系的出生队列研究. 中华预防医学杂志, 2016, (2): 118-122.
27. 蒋辉, 刘俐, 陈维清. 母亲孕期被动吸烟和补充叶酸与其子女孤独症行为的交互作用. 中华流行病学杂志, 2016, 37(7): 940-944.
28. 陈强, 黄丽霞, 徐文娟, 等. 珠海市1.5-3岁孤独症谱系障碍患病率及危险因素研究. 中国儿童保健杂志, 2014, (6): 649-651.
29. Baxter AJ, Brugha TS, Erskine HE, et al. The epidemiology and global burden of autism spectrum disorders. Psychol Med, 2015, 45(3): 601-613.
30. Berry RJ, Crider KS, Yeargin-Allsopp M. Periconceptional folic acid and risk of autism spectrum disorders. JAMA, 2013, 309(6): 611-613.
31. 王虹, 王芳, 范利军, 等. 叶酸通过调节p53/p21(waf1/cip1)信号途径促进小鼠神经干细胞增殖和分化. 神经解剖学杂志, 2012, 28(3): 247-252.
32. Mooijaart SP, Gussekloo J, Frölich M, et al. Homocysteine, vitamin B-12, and folic acid and the risk of cognitive decline in old age: the Leiden 85-Plus study. Am J Clin Nutr, 2005, 82(4): 866-871.
33. Smith AD, Kim YI, Refsum H. Is folic acid good for everyone? Am J Clin Nutr, 2008, 87(3): 517-533.
34. Degroote S, Hunting D, Takser L. Periconceptional folate deficiency leads to autism-like traits in Wistar rat offspring. Neurotoxicol Teratol, 2018, 66: 132-138.
35. Zhang Q, Wu H, Zou M, et al. Folic acid improves abnormal behavior via mitigation of oxidative stress, inflammation, and ferroptosis in the BTBR T+ tf/J mouse model of autism. J Nutr Biochem, 2019, 71: 98-109.
36. DeVilbiss EA, Gardner RM, Newschaffer CJ, et al. Maternal folate status as a risk factor for autism spectrum disorders: a review of existing evidence. Br J Nutr, 2015, 114(5): 663-672.
37. Roth C, Magnus P, Schjølberg S, et al. Folic acid supplements in pregnancy and severe language delay in children. JAMA, 2011, 306(14): 1566-1573.
38. Naninck EFG, Stijger PC, Brouwer-Brolsma EM. The importance of maternal folate status for brain development and function of offspring. Adv Nutr, 2019, 10(3): 502-519.
39. Frye RE, Sequeira JM, Quadros EV, et al. Cerebral folate receptor autoantibodies in autism spectrum disorder. Mol Psychiatry, 2013, 18(3): 369-381.
40. Frye RE, Slattery J, Delhey L, et al. Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial. Mol Psychiatry, 2018, 23(2): 247-256.
41. 李楠楠, 夏薇, 孙彩虹, 等. 叶酸对孤独症儿童的辅助治疗效果研究. 中国儿童保健杂志, 2013, 21(1): 13-15, 19.
42. Crider KS, Bailey LB, Berry RJ. Folic acid food fortification-its history, effect, concerns, and future directions. Nutrients, 2011, 3(3): 370-384.
43. De Wals P, Tairou F, Van Allen MI, et al. Reduction in neural-tube defects after folic acid fortification in Canada. N Engl J Med, 2007, 357(2): 135-142.
44. Honein MA, Paulozzi LJ, Mathews TJ, et al. Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects. JAMA, 2001, 285(23): 2981-2986.
45. 孙长颢, 凌文华, 黄国伟. 营养与食品卫生学(8版). 北京: 人民卫生出版社, 2017: 108.
46. Hao L, Ma J, Stampfer MJ, et al. Geographical, seasonal and gender differences in folate status among Chinese adults. J Nutr, 2003, 133(11): 3630-3635.
47. Pu D, Shen Y, Wu J. Association between MTHFR gene polymorphisms and the risk of autism spectrum disorders: a meta-analysis. Autism Res, 2013, 6(5): 384-392.

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