Personalized folic acid supplementation in pregnant women based on MTHFR and MTRR gene polymorphisms

doi:10.5246/jcps.2025.11.078

Abstract

Abstract:

Folic acid (FA) deficiency during pregnancy is a significant risk factor for neural tube defects in infants. Appropriate supplementation with FA has been shown to effectively mitigate the risk of such congenital anomalies. However, genetic polymorphisms related to FA metabolism influence individual variations in FA utilization among pregnant women, highlighting the need for personalized supplementation strategies. This study aimed to explore the impact of genetic variations in FA metabolism-related genes, specifically methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR), on tailoring FA supplementation during pregnancy. Using fluorescence hybridization sequencing, we analyzed polymorphisms in the MTHFR and MTRR genes among 694 pregnant women, who were divided into an individualized supplementation group and a control group. Pregnancy outcomes were monitored through outpatient visits and telephone follow-ups to evaluate the effect of personalized FA supplementation guided by genetic profiling. Notable differences in genotype frequencies of MTHFR (rs1801133, rs1801131) and MTRR (rs1801394) were observed between pregnant women with and without a heightened risk of FA metabolism disorders (P < 0.05). Similarly, allele frequencies of MTHFR (rs1801133) and MTRR (rs1801394) varied significantly among women with different risk profiles (P < 0.05). The results demonstrated that the individualized group exhibited significantly lower incidences of birth defects, preterm delivery, spontaneous abortion, premature rupture of membranes, abnormal amniotic fluid, and gestational hypertension compared to the control group (P < 0.05). These findings suggested that polymorphisms in MTHFR and MTRR genes were key determinants of FA metabolism and might contribute to adverse pregnancy outcomes in populations with a high prevalence of FA metabolism disorders. Furthermore, integrating genetic screening into FA supplementation protocols enabled more effective prevention of pregnancy complications and improved overall maternal and fetal health outcomes.

Key words: Folic acid, Gene polymorphism, Methylenetetrahydrofolate reductase, Methionine synthase reductase, Pregnancy outcome

Supporting:

Xiaojun Pang, Qianqian Li, Dongwang Li, Yingjun Zhang. Personalized folic acid supplementation in pregnant women based on MTHFR and MTRR gene polymorphisms[J]. Journal of Chinese Pharmaceutical Sciences, 2025, 34(11): 1041-1050.

Figures/Tables 8

Table 1. Risk rank of impaired FA metabolism.

Table 2. Comparison of genotype frequencies of pregnant women with different risks (n, %).

Table 3. Comparison of allele frequencies in pregnant women at different risks (n, %).

Table 4. Comparison of genotype frequency in different groups of pregnant women (n, %).

Table 5. Comparison of allele frequency in different groups of pregnant women (n, %).

Table 6. Comparison of pregnancy between the two groups (n, %).

Table 7. Comparison of comorbidity occurrence during pregnancy in both groups (n, %).

Table 8. Comparison of pregnancy complications occurrence in both groups (n, %).

References 23

[1]	Gao, L.Y.; Ma, X.; Liu X. Research progress on the functions of vitamins in body. J. Chin. Pharm. Scis. 2016, 25, 329–341.
[2]	Tamura, T.; Picciano, M.F. Folate and human reproduction 2. Am. J. Clin. Nutr. 2006, 83, 993–1016.
[3]	Xue, J.; Li, L.; Zhang, M.L.; Yang, L.J.; Chen, W.J.; Song, L.; Chen, M. Study on the relationship between individualized supplementation of folic acid and health of assisted reproductive couples and fetal development. Mod. Diagn. Treat. 2022, 33, 3161–3164.
[4]	Antony, A.C. In utero physiology: role of folic acid in nutrient delivery and fetal development. Am. J. Clin. Nutr. 2007, 85, 598S–603S.
[5]	Zhang, T.R.; Yu, H.J.; Chen, Q.T.; Liu, M.W.; He, Q.Q. Effects of individualized folic acid supplementation on serum folic acid, homocysteine levels and neonatal outcome in pre-pregnancy women. Guangxi Med. J. 2020, 42, 1512–1516.
[6]	De-Regil, L.M.; Peña-Rosas, J.P.; Fernández-Gaxiola, A.C.; Rayco-Solon, P. Effects and safety of periconceptional oral folate supplementation for preventing birth defects. Cochrane Database Syst. Rev. 2015, 12, CD007950.
[7]	Zheng, J.S.; Guan, Y.H.; Zhao, Y.M.; Zhao, W.; Tang, X.J.; Chen, H.; Xu, M.L.; Wu, L.P.; Zhu, S.L.; Liu, H.J.; Huang, T.; Li, D. Pre-conceptional intake of folic acid supplements is inversely associated with risk of preterm birth and small-for-gestational-age birth: a prospective cohort study. Br. J. Nutr. 2016, 115, 509–516.
[8]	Gaskins, A.J.; Rich-Edwards, J.W.; Hauser, R.; Williams, P.L.; Gillman, M.W.; Ginsburg, E.S.; Missmer, S.A.; Chavarro, J.E. Maternal prepregnancy folate intake and risk of spontaneous abortion and stillbirth. Obstet. Gynecol. 2014, 124, 23–31.
[9]	Wu, H.C. Exploration on the significance of supplementing low-dose folic acid before and during pregnancy on pregnant women and fetuses. China Health Standard Manage. 2021, 12, 21–23.
[10]	Li, W.X.; Dai, S.X.; Zheng, J.J.; Liu, J.Q.; Huang, J.F. Homocysteine metabolism gene polymorphisms (MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) jointly elevate the risk of folate deficiency. Nutrients. 2015, 7, 6670–6687.
[11]	Raigani, M.; Lakpour, N.; Soleimani, M.; Johari, B.; Sadeghi, M.R. A association of MTHFR C677T and MTRR A66G gene polymorphisms with Iranian male infertility and its effect on seminal folate and vitamin B12. Int. J. Fertil. Steril. 2021, 15, 20–25.
[12]	Chen, W.J.; Cu, D.D.; Chen Y.; Gu, J.H. Research progress on the effect of folic acid overdose during pregnancy on progeny. J. Med. Res. Combat Trauma Care. 2021, 34, 663–667.
[13]	Peng, R.; Zhang, H.; Zhang, Y. Recent advance in SNP identifying methods and individualized medication. J. Chin. Pharm. Sci. 2014, 23, 731–738.
[14]	Li, X.J.; Jiang, J.; Xu, M.; Xu, M.; Yang, Y.; Lu, W.; Yu, X.M.; Ma, J.L.; Pan, J.K. Individualized supplementation of folic acid according to polymorphisms of methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR) reduced pregnant complications. Gynecol. Obstet. Invest. 2015, 79, 107–112.
[15]	Yu, X.Y.; Diao, L.; Du, B.Y.; Wang, Y.; Xu, X.Q.; Yu, A.Q.; Zhao, J.M. Individualized folic acid supplementation based on MTHFR and MTRR gene polymorphisms reduces the risk of gestational diabetes mellitus in a Chinese population. Int. J. Clin. Exp. Pathol. 2023, 16, 150–157.
[16]	McNulty, H.; Rollins, M.; Cassidy, T.; Caffrey, A.; Marshall, B.; Dornan, J.; McLaughlin, M.; McNulty, B.A.; Ward, M.; Strain, J.J.; Molloy, A.M.; Lees-Murdock, D.J.; Walsh, C.P.; Pentieva, K. Effect of continued folic acid supplementation beyond the first trimester of pregnancy on cognitive performance in the child: a follow-up study from a randomized controlled trial (FASSTT Offspring Trial). BMC Med. 2019, 17, 196.
[17]	Menezo, Y.; Elder, K.; Clement, A.; Clement, P. Folic acid, folinic acid, 5 methyl TetraHydroFolate supplementation for mutations that affect epigenesis through the folate and one-carbon cycles. Biomolecules. 2022, 12, 197.
[18]	Caffrey, A.; Irwin, R.E.; McNulty, H.; Strain, J.J.; Lees-Murdock, D.J.; McNulty, B.A.; Ward, M.; Walsh, C.P.; Pentieva, K. Gene-specific DNA methylation in newborns in response to folic acid supplementation during the second and third trimesters of pregnancy: epigenetic analysis from a randomized controlled trial. Am. J. Clin. Nutr. 2018, 107, 566–575.
[19]	Caffrey, A.; McNulty, H.; Rollins, M.; Prasad, G.; Gaur, P.; Talcott, J.B.; Witton, C.; Cassidy, T.; Marshall, B.; Dornan, J.; Moore, A.J.; Ward, M.; Strain, J.J.; Molloy, A.M.; McLaughlin, M.; Lees-Murdock, D.J.; Walsh, C.P.; Pentieva, K. Effects of maternal folic acid supplementation during the second and third trimesters of pregnancy on neurocognitive development in the child: an 11-year follow-up from a randomised controlled trial. BMC Med. 2021, 19, 73.
[20]	Ondičová, M.; Irwin, R.E.; Thursby, S.J.; Hilman, L.; Caffrey, A.; Cassidy, T.; McLaughlin, M.; Lees-Murdock, D.J.; Ward, M.; Murphy, M.; Lamers, Y.; Pentieva, K.; McNulty, H.; Walsh, C.P. Folic acid intervention during pregnancy alters DNA methylation, affecting neural target genes through two distinct mechanisms. Clin. Epigenetics. 2022, 14, 63.
[21]	Murray, L.K.; Smith, M.J.; Jadavji, N.M. Maternal oversupplementation with folic acid and its impact on neurodevelopment of offspring. Nutr. Rev. 2018, 76, 708–721.
[22]	Patti, M.A.; Braun, J.M.; Arbuckle, T.E.; MacFarlane, A.J. Associations between folic acid supplement use and folate status biomarkers in the first and third trimesters of pregnancy in the Maternal–Infant Research on Environmental Chemicals (MIREC) Pregnancy Cohort Study. Am. J. Clin. Nutr. 2022, 116, 1852–1863.
[23]	Zhang, X.J.; Liu, J.F.; Jin, Y.S.; Yang, S.; Song, Z.J.; Jin, L.; Wang, L.L.; Ren, A.G. Folate of pregnant women after a nationwide folic acid supplementation in China. Matern. Child Nutr. 2019, 15, e12828.