Association between folic acid supplementation and the risk for gestational diabetes mellitus: a meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

XIA Shuangbo ^1,2 , ZHANG Jinjuan ^1,2 , CHEN Xue ^1,2,3 , DU Yushan ^1,2 ,  LIU Jufen ^1,2

1. Institute of Reproductive and Child Health/National Health Commission, Key Laboratory of Reproductive Health, Beijing 100191, P. R. China;
2. Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, P. R. China;
3. School of Public Health, Bengbu Medical College, Bengbu 233000, P. R. China;

Corresponding author：

LIU Jufen, Email: liujufen@bjmu.edu.cn

Keywords：

Folate; Gestational diabetes mellitus; Folic acid supplementation; Meta-analysis; Observational study

DOI：

10.7507/1672-2531.202207061

Video：

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Objective To systematically review the association between folic acid supplementation before and/or during pregnancy and the risk for gestational diabetes mellitus (GDM). Methods The PubMed, EMbase, The Cochrane Library, SinoMed and CNKI databases were searched to collect studies on folic acid supplementation and GDM from inception to November 2021. Two reviewers independently screened the literature, extracted data, and assessed the risk of bias of the included studies. Meta-analysis was then performed using RevMan 5.4 software. Results A total of 19 studies involving 53 128 cases were included. The results of meta-analysis showed that there was no significant association between folic acid supplementation and the risk for GDM (RR=0.98, 95%CI 0.85 to 1.13, P=0.74). Subgroup analysis revealed that folic acid supplementation was associated with a decreased risk for GDM in Europe and the United States (RR=0.81, 95%CI 0.71 to 0.92, P<0.001), in areas that fortified grain cereal products with folic acid (RR=0.81, 95%CI 0.69 to 0.94, P=0.005). Conclusion There is no significant association between folic acid supplementation and the risk for GDM. However, supplementation may decrease the risk for GDM among women in Europe and the United States. Due to the limited quantity and quality of the included studies, more high-quality studies are needed to verify the above conclusion.

Citation： XIA Shuangbo, ZHANG Jinjuan, CHEN Xue, DU Yushan, LIU Jufen. Association between folic acid supplementation and the risk for gestational diabetes mellitus: a meta-analysis. Chinese Journal of Evidence-Based Medicine, 2022, 22(12): 1445-1452. doi: 10.7507/1672-2531.202207061 Copy

1.	中华医学会糖尿病学分会. 中国2型糖尿病防治指南(2020年版). 中华糖尿病杂志, 2021, 13(4): 315-409.
2.	Vounzoulaki E, Khunti K, Abner SC, et al. Progression to type 2 diabetes in women with a known history of gestational diabetes: systematic review and meta-analysis. BMJ, 2020, 369: m1361.
3.	Behboudi-Gandevani S, Bidhendi-Yarandi R, Panahi MH, et al. The effect of mild gestational diabetes mellitus treatment on adverse pregnancy outcomes: a systemic review and meta-analysis. Front Endocrinol (Lausanne), 2021, 12: 640004.
4.	Chen L, Yang T, Chen L, et al. Risk of congenital heart defects in offspring exposed to maternal diabetes mellitus: an updated systematic review and meta-analysis. Arch Gynecol Obstet, 2019, 300(6): 1491-1506.
5.	Ornoy A, Reece EA, Pavlinkova G, et al. Effect of maternal diabetes on the embryo, fetus, and children: congenital anomalies, genetic and epigenetic changes and developmental outcomes. Birth Defects Res C Embryo Today, 2015, 105(1): 53-72.
6.	Wang H, Li N, Chivese T, et al. IDF diabetes atlas: estimation of global and regional gestational diabetes mellitus prevalence for 2021 by International Association of Diabetes in Pregnancy Study Group's criteria. Diabetes Res Clin Pract, 2022, 183: 109050.
7.	Gao C, Sun X, Lu L, et al. Prevalence of gestational diabetes mellitus in mainland China: a systematic review and meta-analysis. J Diabetes Investig, 2019, 10(1): 154-162.
8.	Rogers LM, Cordero AM, Pfeiffer CM, et al. Global folate status in women of reproductive age: a systematic review with emphasis on methodological issues. Ann N Y Acad Sci, 2018, 1431(1): 35-57.
9.	Liu J, Jin L, Meng Q, et al. Changes in folic acid supplementation behaviour among women of reproductive age after the implementation of a massive supplementation programme in China. Public Health Nutr, 2015, 18(4): 582-588.
10.	Liu HY, Liu SM, Zhang YZ. Maternal folic acid supplementation mediates offspring health via DNA methylation. Reprod Sci, 2020, 27(4): 963-976.
11.	Cheng Z, Gu R, Lian Z, et al. Evaluation of the association between maternal folic acid supplementation and the risk of congenital heart disease: a systematic review and meta-analysis. Nutr J, 2022, 21(1): 20.
12.	Chen Z, Xing Y, Yu X, et al. Effect of folic acid intake on infant and child allergic diseases: systematic review and meta-analysis. Front Pediatr, 2021, 8: 615406.
13.	Bayer AL, Fraker CA. The folate cycle as a cause of natural killer cell dysfunction and viral etiology in type 1 diabetes. Front Endocrinol (Lausanne), 2017, 8: 315.
14.	Cheng G, Sha T, Gao X, et al. The associations between the duration of folic acid supplementation, gestational diabetes mellitus, and adverse birth outcomes based on a birth cohort. Int J Environ Res Public Health, 2019, 16(22): 4511.
15.	Zhu B, Ge X, Huang K, et al. Folic acid supplement intake in early pregnancy increases risk of gestational diabetes mellitus: evidence from a prospective cohort study. Diabetes Care, 2016, 39(3): e36-e37.
16.	Huang L, Yu X, Li L, et al. Duration of periconceptional folic acid supplementation and risk of gestational diabetes mellitus. Asia Pac J Clin Nutr, 2019, 28(2): 321-329.
17.	Liu PJ, Liu Y, Ma L, et al. Associations between gestational diabetes mellitus risk and folate status in early pregnancy and MTHFR C677T polymorphisms in Chinese women. Diabetes Metab Syndr Obes, 2020, 13: 1499-1507.
18.	Wells G, Shea B, O'Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.
19.	He J, Jiang D, Cui X, et al. Vitamin B12 status and folic acid/vitamin B12 related to the risk of gestational diabetes mellitus in pregnancy: a systematic review and meta-analysis of observational studies. BMC Pregnancy Childbirth, 2022, 22(1): 587.
20.	Yang Y, Cai Z, Zhang J. Association between maternal folate status and gestational diabetes mellitus. Food Sci Nutr, 2021, 9(4): 2042-2052.
21.	Hamling J, Lee P, Weitkunat R, et al. Facilitating meta-analyses by deriving relative effect and precision estimates for alternative comparisons from a set of estimates presented by exposure level or disease category. Stat Med, 2008, 27(7): 954-970.
22.	Berglund SK, García-Valdés L, Torres-Espinola FJ, et al. Maternal, fetal and perinatal alterations associated with obesity, overweight and gestational diabetes: an observational cohort study (PREOBE). BMC Public Health, 2016, 16: 207.
23.	Chen X, Zhang Y, Chen H, et al. Association of maternal folate and vitamin B 12 in early pregnancy with gestational diabetes mellitus: a prospective cohort study. Diabetes Care, 2021, 44(1): 217-223.
24.	Kim MW, Ahn KH, Ryu KJ, et al. Preventive effects of folic acid supplementation on adverse maternal and fetal outcomes. PLoS One, 2014, 9(5): e97273.
25.	Li M, Li S, Chavarro JE, et al. Prepregnancy habitual intakes of total, supplemental, and food folate and risk of gestational diabetes mellitus: a prospective cohort study. Diabetes Care, 2019, 42(6): 1034-1041.
26.	Li Q, Zhang Y, Huang L, et al. High-dose folic acid supplement use from prepregnancy through midpregnancy is associated with increased risk of gestational diabetes mellitus: a prospective cohort study. Diabetes Care, 2019, 42(7): e113-e115.
27.	Maas VYF, Poels M, Lamain-de Ruiter M, et al. Associations between periconceptional lifestyle behaviours and adverse pregnancy outcomes. BMC Pregnancy Childbirth, 2021, 21(1): 492.
28.	Salmenhaara M, Uusitalo L, Uusitalo U, et al. Diet and weight gain characteristics of pregnant women with gestational diabetes. Eur J Clin Nutr, 2010, 64(12): 1433-1440.
29.	Jankovic-Karasoulos T, Furness DL, Leemaqz SY, et al. Maternal folate, one-carbon metabolism and pregnancy outcomes. Matern Child Nutr, 2021, 17(1): e13064.
30.	Zhang H, Zhao Y. Ambient air pollution exposure during pregnancy and gestational diabetes mellitus in Shenyang, China: a prospective cohort study. Environ Sci Pollut Res Int, 2021, 28(7): 7806-7814.
31.	Zhao M, Yang S, Hung TC, et al. Association of pre- and early-pregnancy factors with the risk for gestational diabetes mellitus in a large Chinese population. Sci Rep, 2021, 11(1): 7335.
32.	刘小晖, 何晓春, 毛宝宏, 等. 围孕期叶酸摄入与妊娠期高血压疾病的相关性研究. 中国妇幼健康研究, 2020, 31(9): 1209-1217.
33.	孟建芳. 妊娠不同时期补充微量元素及叶酸对妊娠结局的影响. 中国妇幼保健, 2016, 31(23): 4954-4956.
34.	杨晓清, 罗丽, 高玉华, 等. 广元地区妊娠期糖尿病发病情况及影响因素分析. 中国计划生育和妇产科, 2016, 8(6): 21-24.
35.	王香华, 王灿辉, 鲁翠萍, 等. 血清Vb12和叶酸水平对暴露于二甲双胍的新生儿体重的影响. 现代诊断与治疗, 2019, 30(12): 2031-2034.
36.	祝凯, 代敏慧, 王芳, 等. 湘西地区妊娠期糖尿病影响因素分析. 社区医学杂志, 2021, 19(13): 783-787.
37.	Chen Y, Lu M, Nie J, et al. Increasing prevalence of gestational diabetes mellitus when carrying the T variant allele of the MTHFR gene C677T polymorphism: a systematic review and meta-analysis. Arch Gynecol Obstet, 2022, 305(5): 1193-1202.
38.	Wu L, Cui L, Tam WH, et al. Genetic variants associated with gestational diabetes mellitus: a meta-analysis and subgroup analysis. Sci Rep, 2016, 6: 30539.
39.	Song Q, Wei J, Wang J, et al. Rate of correct use of folic acid supplementation among pregnant women - Beijing municipality, China, 2017-2019. China CDC Wkly, 2021, 3(37): 783-787.
40.	Sid V, Wu N, Sarna LK, et al. Folic acid supplementation during high-fat diet feeding restores AMPK activation via an AMP-LKB1-dependent mechanism. Am J Physiol Regul Integr Comp Physiol, 2015, 309(10): R1215-1225.
41.	Kaye AD, Jeha GM, Pham AD, et al. Folic acid supplementation in patients with elevated homocysteine levels. Adv Ther, 2020, 37(10): 4149-4164.
42.	Gong T, Wang J, Yang M, et al. Serum homocysteine level and gestational diabetes mellitus: a meta-analysis. J Diabetes Investig, 2016, 7(4): 622-628.
43.	Adaikalakoteswari A, Vatish M, Alam MT, et al. Low vitamin B12 in pregnancy is associated with adipose-derived circulating miRs targeting PPARγ and insulin resistance. J Clin Endocrinol Metab, 2017, 102(11): 4200-4209.
44.	Sawaengsri H, Wang J, Reginaldo C, et al. High folic acid intake reduces natural killer cell cytotoxicity in aged mice. J Nutr Biochem, 2016, 30: 102-107.
45.	Crider KS, Yang TP, Berry RJ, et al. Folate and DNA methylation: a review of molecular mechanisms and the evidence for folate's role. Adv Nutr, 2012, 3(1): 21-38.
46.	Zhu W, Shen Y, Liu J, et al. Epigenetic alternations of microRNAs and DNA methylation contribute to gestational diabetes mellitus. J Cell Mol Med, 2020, 24(23): 13899-13912.
47.	刘晓清, 宋雯霞, 王慧, 等. 妊娠期糖尿病的表观遗传学研究进展. 中国妇幼保健, 2022, 37(6): 1159-1162.
48.	田丹, 王欣, 魏文文, 等. 表观遗传学在妊娠期糖尿病中的研究进展. 医学研究生学报, 2021, 34(6): 640-645.

1. 中华医学会糖尿病学分会. 中国2型糖尿病防治指南(2020年版). 中华糖尿病杂志, 2021, 13(4): 315-409.
2. Vounzoulaki E, Khunti K, Abner SC, et al. Progression to type 2 diabetes in women with a known history of gestational diabetes: systematic review and meta-analysis. BMJ, 2020, 369: m1361.
3. Behboudi-Gandevani S, Bidhendi-Yarandi R, Panahi MH, et al. The effect of mild gestational diabetes mellitus treatment on adverse pregnancy outcomes: a systemic review and meta-analysis. Front Endocrinol (Lausanne), 2021, 12: 640004.
4. Chen L, Yang T, Chen L, et al. Risk of congenital heart defects in offspring exposed to maternal diabetes mellitus: an updated systematic review and meta-analysis. Arch Gynecol Obstet, 2019, 300(6): 1491-1506.
5. Ornoy A, Reece EA, Pavlinkova G, et al. Effect of maternal diabetes on the embryo, fetus, and children: congenital anomalies, genetic and epigenetic changes and developmental outcomes. Birth Defects Res C Embryo Today, 2015, 105(1): 53-72.
6. Wang H, Li N, Chivese T, et al. IDF diabetes atlas: estimation of global and regional gestational diabetes mellitus prevalence for 2021 by International Association of Diabetes in Pregnancy Study Group's criteria. Diabetes Res Clin Pract, 2022, 183: 109050.
7. Gao C, Sun X, Lu L, et al. Prevalence of gestational diabetes mellitus in mainland China: a systematic review and meta-analysis. J Diabetes Investig, 2019, 10(1): 154-162.
8. Rogers LM, Cordero AM, Pfeiffer CM, et al. Global folate status in women of reproductive age: a systematic review with emphasis on methodological issues. Ann N Y Acad Sci, 2018, 1431(1): 35-57.
9. Liu J, Jin L, Meng Q, et al. Changes in folic acid supplementation behaviour among women of reproductive age after the implementation of a massive supplementation programme in China. Public Health Nutr, 2015, 18(4): 582-588.
10. Liu HY, Liu SM, Zhang YZ. Maternal folic acid supplementation mediates offspring health via DNA methylation. Reprod Sci, 2020, 27(4): 963-976.
11. Cheng Z, Gu R, Lian Z, et al. Evaluation of the association between maternal folic acid supplementation and the risk of congenital heart disease: a systematic review and meta-analysis. Nutr J, 2022, 21(1): 20.
12. Chen Z, Xing Y, Yu X, et al. Effect of folic acid intake on infant and child allergic diseases: systematic review and meta-analysis. Front Pediatr, 2021, 8: 615406.
13. Bayer AL, Fraker CA. The folate cycle as a cause of natural killer cell dysfunction and viral etiology in type 1 diabetes. Front Endocrinol (Lausanne), 2017, 8: 315.
14. Cheng G, Sha T, Gao X, et al. The associations between the duration of folic acid supplementation, gestational diabetes mellitus, and adverse birth outcomes based on a birth cohort. Int J Environ Res Public Health, 2019, 16(22): 4511.
15. Zhu B, Ge X, Huang K, et al. Folic acid supplement intake in early pregnancy increases risk of gestational diabetes mellitus: evidence from a prospective cohort study. Diabetes Care, 2016, 39(3): e36-e37.
16. Huang L, Yu X, Li L, et al. Duration of periconceptional folic acid supplementation and risk of gestational diabetes mellitus. Asia Pac J Clin Nutr, 2019, 28(2): 321-329.
17. Liu PJ, Liu Y, Ma L, et al. Associations between gestational diabetes mellitus risk and folate status in early pregnancy and MTHFR C677T polymorphisms in Chinese women. Diabetes Metab Syndr Obes, 2020, 13: 1499-1507.
18. Wells G, Shea B, O'Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.
19. He J, Jiang D, Cui X, et al. Vitamin B12 status and folic acid/vitamin B12 related to the risk of gestational diabetes mellitus in pregnancy: a systematic review and meta-analysis of observational studies. BMC Pregnancy Childbirth, 2022, 22(1): 587.
20. Yang Y, Cai Z, Zhang J. Association between maternal folate status and gestational diabetes mellitus. Food Sci Nutr, 2021, 9(4): 2042-2052.
21. Hamling J, Lee P, Weitkunat R, et al. Facilitating meta-analyses by deriving relative effect and precision estimates for alternative comparisons from a set of estimates presented by exposure level or disease category. Stat Med, 2008, 27(7): 954-970.
22. Berglund SK, García-Valdés L, Torres-Espinola FJ, et al. Maternal, fetal and perinatal alterations associated with obesity, overweight and gestational diabetes: an observational cohort study (PREOBE). BMC Public Health, 2016, 16: 207.
23. Chen X, Zhang Y, Chen H, et al. Association of maternal folate and vitamin B 12 in early pregnancy with gestational diabetes mellitus: a prospective cohort study. Diabetes Care, 2021, 44(1): 217-223.
24. Kim MW, Ahn KH, Ryu KJ, et al. Preventive effects of folic acid supplementation on adverse maternal and fetal outcomes. PLoS One, 2014, 9(5): e97273.
25. Li M, Li S, Chavarro JE, et al. Prepregnancy habitual intakes of total, supplemental, and food folate and risk of gestational diabetes mellitus: a prospective cohort study. Diabetes Care, 2019, 42(6): 1034-1041.
26. Li Q, Zhang Y, Huang L, et al. High-dose folic acid supplement use from prepregnancy through midpregnancy is associated with increased risk of gestational diabetes mellitus: a prospective cohort study. Diabetes Care, 2019, 42(7): e113-e115.
27. Maas VYF, Poels M, Lamain-de Ruiter M, et al. Associations between periconceptional lifestyle behaviours and adverse pregnancy outcomes. BMC Pregnancy Childbirth, 2021, 21(1): 492.
28. Salmenhaara M, Uusitalo L, Uusitalo U, et al. Diet and weight gain characteristics of pregnant women with gestational diabetes. Eur J Clin Nutr, 2010, 64(12): 1433-1440.
29. Jankovic-Karasoulos T, Furness DL, Leemaqz SY, et al. Maternal folate, one-carbon metabolism and pregnancy outcomes. Matern Child Nutr, 2021, 17(1): e13064.
30. Zhang H, Zhao Y. Ambient air pollution exposure during pregnancy and gestational diabetes mellitus in Shenyang, China: a prospective cohort study. Environ Sci Pollut Res Int, 2021, 28(7): 7806-7814.
31. Zhao M, Yang S, Hung TC, et al. Association of pre- and early-pregnancy factors with the risk for gestational diabetes mellitus in a large Chinese population. Sci Rep, 2021, 11(1): 7335.
32. 刘小晖, 何晓春, 毛宝宏, 等. 围孕期叶酸摄入与妊娠期高血压疾病的相关性研究. 中国妇幼健康研究, 2020, 31(9): 1209-1217.
33. 孟建芳. 妊娠不同时期补充微量元素及叶酸对妊娠结局的影响. 中国妇幼保健, 2016, 31(23): 4954-4956.
34. 杨晓清, 罗丽, 高玉华, 等. 广元地区妊娠期糖尿病发病情况及影响因素分析. 中国计划生育和妇产科, 2016, 8(6): 21-24.
35. 王香华, 王灿辉, 鲁翠萍, 等. 血清Vb12和叶酸水平对暴露于二甲双胍的新生儿体重的影响. 现代诊断与治疗, 2019, 30(12): 2031-2034.
36. 祝凯, 代敏慧, 王芳, 等. 湘西地区妊娠期糖尿病影响因素分析. 社区医学杂志, 2021, 19(13): 783-787.
37. Chen Y, Lu M, Nie J, et al. Increasing prevalence of gestational diabetes mellitus when carrying the T variant allele of the MTHFR gene C677T polymorphism: a systematic review and meta-analysis. Arch Gynecol Obstet, 2022, 305(5): 1193-1202.
38. Wu L, Cui L, Tam WH, et al. Genetic variants associated with gestational diabetes mellitus: a meta-analysis and subgroup analysis. Sci Rep, 2016, 6: 30539.
39. Song Q, Wei J, Wang J, et al. Rate of correct use of folic acid supplementation among pregnant women - Beijing municipality, China, 2017-2019. China CDC Wkly, 2021, 3(37): 783-787.
40. Sid V, Wu N, Sarna LK, et al. Folic acid supplementation during high-fat diet feeding restores AMPK activation via an AMP-LKB1-dependent mechanism. Am J Physiol Regul Integr Comp Physiol, 2015, 309(10): R1215-1225.
41. Kaye AD, Jeha GM, Pham AD, et al. Folic acid supplementation in patients with elevated homocysteine levels. Adv Ther, 2020, 37(10): 4149-4164.
42. Gong T, Wang J, Yang M, et al. Serum homocysteine level and gestational diabetes mellitus: a meta-analysis. J Diabetes Investig, 2016, 7(4): 622-628.
43. Adaikalakoteswari A, Vatish M, Alam MT, et al. Low vitamin B12 in pregnancy is associated with adipose-derived circulating miRs targeting PPARγ and insulin resistance. J Clin Endocrinol Metab, 2017, 102(11): 4200-4209.
44. Sawaengsri H, Wang J, Reginaldo C, et al. High folic acid intake reduces natural killer cell cytotoxicity in aged mice. J Nutr Biochem, 2016, 30: 102-107.
45. Crider KS, Yang TP, Berry RJ, et al. Folate and DNA methylation: a review of molecular mechanisms and the evidence for folate's role. Adv Nutr, 2012, 3(1): 21-38.
46. Zhu W, Shen Y, Liu J, et al. Epigenetic alternations of microRNAs and DNA methylation contribute to gestational diabetes mellitus. J Cell Mol Med, 2020, 24(23): 13899-13912.
47. 刘晓清, 宋雯霞, 王慧, 等. 妊娠期糖尿病的表观遗传学研究进展. 中国妇幼保健, 2022, 37(6): 1159-1162.
48. 田丹, 王欣, 魏文文, 等. 表观遗传学在妊娠期糖尿病中的研究进展. 医学研究生学报, 2021, 34(6): 640-645.

Chinese Journal of Evidence-Based Medicine

Association between folic acid supplementation and the risk for gestational diabetes mellitus: a meta-analysis

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