Individualized Folic Acid Supplementation based on Polymorphisms of Methylenetetrahydrofolate Reductase (MTHFR) and Methionine Synthase Reductase (MTRR), Compared with Traditional Folic Acid Supplementation, Reduces Gestational Diabetes Mellitus

Individualized Folic Acid Supplementation based on Polymorphisms of Methylenetetrahydrofolate Reductase (MTHFR) and Methionine Synthase Reductase (MTRR), Compared with Traditional Folic Acid Supplementation, Reduces Gestational Diabetes Mellitus | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Individualized Folic Acid Supplementation based on Polymorphisms of Methylenetetrahydrofolate Reductase (MTHFR) and Methionine Synthase Reductase (MTRR), Compared with Traditional Folic Acid Supplementation, Reduces Gestational Diabetes Mellitus Xiaoying Yu, Le Diao, Baoying Du, Ying Wang, Xiaoqin Xv, Anqi Yu, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1168960/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Backgroud : Folic Acid (FA) may contribute to the development of gestational diabetes mellitus (GDM), but existing studies are inconsistent. We examined the genotype distributions and allele frequencies of methylenetetrahydrofolate reductase (MTHFR) C677T, A1298C and methionine synthase reductase (MTRR) A66G polymorphisms of pregnant women in China, and compared the effects of individualized folate supplementation and traditional FA supplementation on GDM. Methods : The genotype distributions and allele frequencies of MTHFR C677T, A1298C and MTRR A66G polymorphisms in 968 pregnant women (case group) were tested. FA metabolism was ranked at four levels, and then pregnant women of different levels are supplemented with different doses of FA at different periods. The case group was followed up for pregnancy complications and compared with 1,940 pregnant women traditionally supplemented with FA in the same hospital (control group). Results : The allele frequencies of MTHFR C677T were 63.3% (C) and 36.7% (T), those of MTHFR A1298C were 79.3% (A) and 20.7% (C), and those of MTRR A66G were 75.0% (A) and 25.0% (G). Compared with control group, the incidence of GDM in the case group were significantly lower, especially in high-risk pregnant women after FA supplementation. Conclusion : Traditional FA supplementation based on personal habits is controversial, but the use of polymorphisms of genes to clarify the FA metabolism of pregnant women, appropriate, timely and accurate supplementation of FA can effectively reduce gestational diabetes, especially for high-risk pregnant women. Maternal & Fetal Medicine Sexual & Reproductive Medicine Folic acid Gestational diabetes mellitus Polymorphisms Pregnancy Introduction Folic acid (FA) is a synthetic form of folate necessary for cell development and biochemical reactions [ 1 ]. It is worth noting that a low intake of FA can also increase the risk of adverse pregnancy outcome [ 2 , 3 ]. Lack of FA in pregnant women will increase the risk of birth defects, especially neural tube malformations [ 4 ]. At the same time, the incidence of other birth defects will increase, such as Down’s syndrome, cleft lip and palate, and congenital heart disease. FA supplementation for pregnant women can reduce the prevalence of fetal neural tube defects which often leading to death or disability [ 5 ]. Some studies demonstrated that FA supplementation continued throughout pregnancy prevents adverse pregnancy outcomes, whereas some study suggest that high-dose FA may lead to an increased risk of gestational hypertension [ 1 , 6 ]. In addition, high doses of FA continued throughout pregnancy are not an effective prevention strategy for preeclampsia [ 7 ]. Excessive FA supplementation can increase the risk of breast cancer in pregnant women, lead to zinc deficiency in the body and cause abnormal fetal development and cover up vitamin B12 deficiency. Research stated that attention should be given to avoid inappropriate FA supplement use in women who are planning or capable of pregnancy [ 1 , 6 ]. FA effects may be more relevant in subjects carrying genetic abnormalities of the enzymes of homocysteine metabolic pathway, in particular, the common homozygous thermolabile 5,10 methylentetrahydrofolate reductase (MTHFR C677T) [ 1 ]. This indicates that, according to polymorphisms of MTHFR and other related genes, it is very important to guide pregnant women to accurately supplement FA. Gestational diabetes mellitus (GDM) is diagnosed when a woman has high blood sugar levels for the first time during pregnancy [ 8 ] and the prevalence of GDM is more than 20% in Asian [ 9 ]. Higher habitual intakes of supplemental folate before pregnancy were significantly associated with lower GDM risk [ 10 ]. But recently research have been conducted that daily intake of FA during early pregnancy was associated with a higher risk of GDM in China [ 11 ]. Addition, higher maternal folate coupled with vitamin B12 insufficiency was associated with higher GDM risk in Singapore [ 12 ]. However, none of these studies provide accurate FA supplementation for pregnant women based on Polymorphisms of genes. A number of studies have investigated variations in genes related to folate metabolism [ 13 , 14 ]. Several key enzymes, including methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) are involved in the folate metabolic pathway [ 15 ]. MTHFR is involved in the one-carbon cycle, and is a crucial enzyme that regulates nucleotide synthesis and DNA methylation [ 14 , 16 ]. The MTHFR C677T gene polymorphism (rs1801133) and A1298C gene polymorphism (rs1801131) are common gene variants of MTHFR and have been shown to alter the enzyme activity [ 14 , 16 ]. Methionine as a precursor for S-adenosylmethionine, is produced via the transfer of a methyl group from 5-methyltetrahydrofolate, which is catalyzed by MTR and MTRR [ 17 , 18 ]. Similar to MTHFR C677T and A1298C, MTRR A66G is also a common polymorphism, which plays an important role in folate metabolism [ 14 ]. Recently research revealed that after supplemented with FA, the complication rates were significantly reduced, especially for GDM, compared with pregnant women without FA supplementation [ 14 ]. However, there are limited studies on the relationship between FA supplementation and the risk of gestational diabetes in the Chinese population. There has been consensus on the necessity and benefits of FA supplementation for pregnant women. However, few studies have used polymorphisms of gene to accurately guide pregnant women to supplement FA during pregnancy. Most studies are based on experience or common sense in life. In particular, it is crucial to identify high-risk pregnant women through genetic testing methods, more accurate FA supplementation and more careful care. Therefore, we compared the difference between pregnant women with empirical FA supplementation and pregnant women with genetic guidance and precise FA supplementation during pregnancy to identify high-risk pregnant women and highlight the necessity and importance of genetic testing to accurately guide pregnant women to supplement FA. Materials And Methods Study population and SNP genotyping The study was approved by the ethics committee of Shaoxing Second Hospital. A total of 2908 pregnant women were enrolled in this study between 2014 and 2019. Clinical information including age, body mass index (BMI), history of abortion, first pregnancy, physical activities, and diseases of reproductive system during pregnancy was completed by all subjects. Informed consent was obtained from all participants. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Medical Ethics Committee of Shaoxing Second Hospital. Informed consent was obtained from all participants. SNP of MTHFR C677T, MTHFR A1298C and MTRR A66G were determined by PCR and Sanger sequencing by ABI 3730XL DNA Analyzer (ABI, USA). Assessment of Potential Risk and Individualized Intervention with FA A total of 968 cases of individualized intervention of FA through genetic testing polymorphisms and 1,940 cases of controls with empirical supplementation of FA were included in this study. According to the genotypes of these three polymorphisms, the FA metabolism ability of pregnant women was evaluated. The risk of abnormal pregnancy outcome was further evaluated and divided into four levels: unidentify, low, middle and high, and then supplemented with different doses of FA according to the risk level of abnormal pregnancy outcome and its gestational age. Assessment of GDM GDM was diagnosed at the same clinic visit, based on plasma glucose concentrations measured at a fasting state and two hours after a 75g oral glucose tolerance test (OGTT) was administered. Plasma glucose concentrations were analyzed using the colorimetry method (Advia 2400 Chemistry system, Siemens Medical Solutions Diagnostics; and Beckman LX20 Pro analyzer, Beckman Coulter). Participants were classified as having GDM, if they met one of the following: (1) ≥ 4.5 mmol/L of fasting plasma glucose concentrations, (2) ≥ 10 mmol/L and 8.5 mmol/L of plasma glucose concentrations 1-hour and 2-hour post-OGTT, respectively. Complications Observation and Statistical Analysis The complications of pregnant women in cases and controls, including GDM, thyroid function, gestational hypertension, abortion, premature birth, macrosomia and underweight were recorded and analyzed. Statistical analysis were performed using SPSS 19.0 (IBM, NY, USA). If continuous variables conformed to a normal distribution, unpaired t-tests were used to analyze differences. Otherwise, the Mann-Whitney U test was used. When comparing datasets containing multiple groups, one-way analysis of variance was used for normally distributed datasets, and the Kruskal-Wallis test was used for datasets not normally distributed. Categorical variables were summarized as the counts and percentages, and analyzed using the c2 test or Fisher’s exact test, as appropriate. A two-sided values of P<0.05 were considered statistically significant. Results Participant characteristics History of abortion, first pregnancy, diseases of reproductive system, Body Mass Index (BMI) and age according to maternal characteristics are presented in Table 1 . Case pregnant women tended to be younger, which is significant lower than control pregnant women (median 28 vs. 30, P< 0.001). The proportion of case pregnant women with reproductive system diseases is higher than that of control pregnant women (percentage, 5.27% vs. 1.49%, P< 0.001). There were no significant differences in BMI, history of abortion, and first pregnancy between the two groups. Table 1 Clinical characteristics of case and control pregnant women. Clinical characteristics Cases Controls P value Age / years Median (range) 28 (16-44) 30 (17-47) <0.001 BMI / Mean±SD 21.75±2.98 21.69±3.11 0.289 History of abortion 458 (47.31%) 867 (44.69%) 0.181 First pregnancy 333 (34.40%) 692 (35.67%) 0.500 Diseases of reproductive system 51 (5.27%) 29 (1.49%) <0.001 Distribution of Genotypes and Allelic Frequencies Relative to Polymorphisms of the MTHFR and MTRR Genes The distribution of genotype and allele frequencies of polymorphisms in the case group are presented in Table 2 . The distribution of genotype of MTHFR C677T were 39.8% (CC), 47.0% (CT) and 13.2% (TT); those of MTHFR A1298C were 63.4% (AA), 31.7% (AC) and 4.9% (CC), and those of MTRR A66G were 55.6% (AA), 38.7% (AG) and 5.7% (GG). The allele frequencies of MTHFR C677T were 63.3% (C) and 36.7% (T); those of MTHFR A1298C were 79.3% (A) and 20.7% (C), and those of MTRR A66G were 75.0% (A) and 25.0% (G). Table 2 Distribution of genotype and allele frequencies of polymorphisms Genotypes Frequency Allele Frequency MTHFR C677T CC 385 (39.8%) C 63.3% CT 455 (47.0%) T 36.7% TT 128 (13.2%) MTHFR A1298C AA 614 (63.4%) A 79.3% AC 307 (31.7%) C 20.7% CC 47 (4.9%) MTRR A66G AA 538 (55.6%) A 75.0% AG 375 (38.7%) G 25.0% GG 55 (5.7%) FA metabolic capacity and supplement FA metabolism is further ranked according to the genotypes of pregnant women, including four levels: unidentify, low, middle and high. According to the genotype and gestational weeks in Table 3 , guide pregnant women to supplement individualized FA dosage. Table 3 Risk rank of folate metabolism and FA supplementation Risk rank Genotypes Folic acid supplementation (MTHFR C677T/ MTHFR A1298C/ MTRR A66G) 3 months before conception Early pregnancy (0-12 weeks) Late pregnancy (13-40 weeks) Unidentify CC AA AA CC AC AA 400 µg/ day 400 µg/ day dietary Low CT AA AA CT AC AA 400 µg/ day 400 µg/ day 400 µg/ day Middle CC CC AA CC AA AG CC AC AG CC AA GG CC AC GG CT CC AA CT AA AG CT AC AG CT AA GG CT AC GG TT AA AA TT AC AA 400 µg/ day 800 µg/ day 400 µg/ day High CC CC AG CC CC GG CT CC AG CT CC GG TT CC AA TT AA AG TT AC AG TT AA GG TT AC GG TT CC AG TT CC GG 800 µg/ day 800 µg/ day 400 µg/ day Frequency complications after supplementation with FA dur ing Pregnancy in the case and control pregnant women The frequency complications after supplementation with FA during Pregnancy in the case and control pregnant women are presented in Table 4 . We found that GDM was significantly reduced in the case group, compared with those in control groups (P< 0.001). The macrosomia was also reduced in the case group, compared with those in control groups (P< 0.031). The complications of thyroid function, gestational hypertension, abortion, premature birth and underweight were not significantly different between these two groups. Table 4 Frequency complications after supplementation with FA during pregnancy in the case and control pregnant women. Clinical characteristics Cases (N=968) Controls (N=1940) P value Gestational diabetes mellitus 55 (5.7%) 220 (11.3%) <0.001 Thyroid function Hypothyroidism 15 (1.6%) 19 (1.3%) 0.545 Hyperthyreosis 122 (13.0%) 182 (12.5%) 0.691 Normal 800 1259 Missing 31 480 Gestational hypertension 12 (1.2%) 28 (1.4%) 0.657 Premature birth 43 91 0.359 Macrosomia (>4kg) 40 (4.4%) 131 (6.5%) 0.031 Underweight (<2.5kg) 8 (0.9%) 16 (0.8%) 0.879 Apgar score (<8) 15 (1.7%) 35 (1.8%) 0.736 Risk rank of folate metabolism, distribution, and corresponding gestational complications frequency The corresponding gestational complications of GDM, hypothyroidism, hyperthyreosis and gestational hypertension under risk rank of folate metabolism were summarized in Table 5 . In case group, the percent of pregant women at four risk including unidentify, low, middle and high, is 18.4%, 27.0%, 46.9% and 7.7%, respectively. Compared with unidentify, low and middle levels in pregnant women, the GDM among the high risk levels in pregnant women were obviously reduce (percent 18.4%, 27.0%, 46.9% vs. 7.7%). There were no significant differences among the four risk levels for hypothyroidism, hyperthyreosis and gestational hypertension in pregnant women. Table 5 Risk rank of folate metabolism, distribution, and corresponding gestational complications frequency, according to genotypes. Risk rank MTHFR C677T MTHFR A1298C MTRR A66G N (percent) N=968 Gestational diabetes mellitus Gestational hypertension Hypothyroidism Hyperthyreosis Unidentify CC AA AA 178 (18.4%) 12 (6.7%) 2 (2.1%) 5/175 (2.9%) 19/175 (10.9%) CC AC AA Low CT AA AA 261 (27.0%) 14 (5.4%) 3 (1.6%) 1 /252(0.4%) 28/252 (11.1%) CT AC AA Middle TT AA AA 454 (46.9%) 28 (6.2%) 6 (1.3%) 7/439 (1.6%) 62/439 (13.7%) CC AA AG CC AC AG CC AA GG CC AC GG CC CC AA CT CC AA CT AA AG CT AC AG CT AA GG CT AC GG High TT AA AG 75 (7.7%) 1 (1.3%) 1 (1.9%) 2/72 (2.8%) 13/72 (17.3%) TT AC AG CC CC AG TT AA GG CC CC GG Note: Thyroid function is missing in 29 cases. Discussion The folate metabolism pathway plays an important role in cell division [ 3 , 19 ] and DNA methylation, repair and synthesis [ 20 – 22 ], and it is critically important for the health of pregnant women and the development of fetuses [ 14 ]. Research showed that FA supplementation continued throughout pregnancy prevents adverse pregnancy outcomes [ 1 ]. MTHFR is a key enzyme in folate metabolism [ 23 ]. Some genetic polymorphisms code for a less efficient enzyme, increasing serum concentrations of homocysteine [ 23 ]. This has been associated with inadequate feto-maternal circulation and increased risk of adverse pregnancy outcome [ 14 , 23 ]. Two polymorphic variants in this gene (C677T and A1298C) have been implicated in a mild form of MTHFR deficiency associated with hyperhomocysteinemia [ 24 ]. Recently studies have showed that the C677T and A1298C Single-nucleotide polymorphisms (SNPs) of the MTHFR gene could elevate blood homocysteine [ 25 – 27 ], which may cause fetal nervous system malformation and spina bifida cystica [ 28 ]. The MTRR mutation prevents the conversion of homocysteine to methionine and is the main cause of FA and methyl vitamin deficiency. Among them, A66G is the most important and most studied mutation and has the risk of elevating blood homocysteine [ 29 ]. Through the polymorphisms of MTHFR C677T, A1298C and MTRR A66G, it is possible to detect the level of FA absorption and utilization by different individuals as soon as possible, thereby screening high-risk groups prone to FA deficiency, and realizing personalized FA supplements to reduce the risk of pregnancy syndrome and birth defects in newborns. The rate of GDM in the case group is significantly lower than the control group. Especially in high-risk pregnant women, there are fewer pregnant women with GDM. In the case group, there are 75 of pregnant women at high risk, but only a pregnant women have GDM, which is the lower among pregnant women with other three risk levels. FA has a significant effect on GDM [ 14 ]. A higher intake of habitual FA supplementation before pregnancy is significantly associated with a lower risk of GDM [ 10 ]. FA can increase the nitric oxide (NO) level and restore Type II diabetes associated-endothelial dysfunction [ 30 ]. In addition, we also noticed that pregnant women in the control group were older than those in the case group, but there were significantly more pregnant women in the case group with reproductive system diseases than the control group. Age may be a possible risk factor for pregnancy complications [ 14 ]. This indicates that for older pregnant women with reproductive system diseases, accurate FA supplementation through gene polymorphism testing may be more important. In this research, the pregnant women at high risk, that is pregnant women with poor FA metabolism, the precise FA supplement dose significantly reduces the risk of gestational diabetes. Therefore, compared with pregnant women who have not supplemented with FA [ 14 ] or supplemented with FA according to common sense, it is clinically beneficial to identify high-risk pregnant women and individualized supplementation of FA according to polymorphisms of genes. As a consequence, the results show that, compared with traditional FA supplementation, individualized FA supplementation based on the polymorphisms of MTHFR and MTRR may be a powerful measure to reduce GDM. Conclusions According to Polymorphisms of genes, pregnant women who accurately supplemented FA had a lower risk of diabetes during pregnancy than non-tested pregnant women, and this event was more pronounced in high-risk pregnant women. Too much or too little FA supplement according to personal habits is controversial, and the use of genetic testing to clarify the FA metabolism of pregnant women, appropriate and timely and accurate supplementation of FA can effectively reduce gestational diabetes, especially for high-risk pregnant women. Declarations AUTHOR CONTRIBUTIONS: JMZ, XYY and LD conceived and designed the study. XYY, BYD, YW, XQX and AQY acquired the data. JMZ and XYY analyzed and interpreted the data. LD and XYY drafted the article. ACKNOWLEDGEMENTS: None. CONFLICTS OF INTEREST: All authors report no conflict of interest related to the submitted work. FUNDING: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Ethics approval and consent to participate This study was approved by the Ethics Committee of Shaoxing Second Hospital, Shaoxing, China. All participants signed an informed consent. All methods were carried out in accordance with relevant guidelines and regulations. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. References Orabona R, Zanardini C, Zatti S, Sartori E, Prefumo F. Folic Acid Supplementation in Pregnancy: A Matter of Doses? Hypertension. 2020;76:30–1. Kontic-Vucinic O, Sulovic N, Radunovic N. Micronutrients in women's reproductive health: I. Vitamins. Int J Fertil Womens Med. 2006;51:106–15. Scholl TO, Johnson WG. Folic acid: influence on the outcome of pregnancy. 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Polymorphisms of the methylenetetrahydrofolate reductase gene (C677T and A1298C) in nulliparous women complicated with preeclampsia. Gynecol Endocrinol. 2014;30:392–6. Mills JL, Scott JM, Kirke PN, McPartlin JM, Conley MR, Weir DG, et al. Homocysteine and neural tube defects. J Nutr. 1996;126:756S-60S. Ranganathan P, McLeod HL. Methotrexate pharmacogenetics: the first step toward individualized therapy in rheumatoid arthritis. Arthritis Rheum. 2006;54:1366–77. van Etten RW, de Koning EJ, Verhaar MC, Gaillard CA, Rabelink TJ. Impaired NO-dependent vasodilation in patients with Type II (non-insulin-dependent) diabetes mellitus is restored by acute administration of folate. Diabetologia. 2002;45:1004–10. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1168960","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":73410509,"identity":"bc17aac7-2574-4b8a-a46d-dfac4707a774","order_by":0,"name":"Xiaoying Yu","email":"","orcid":"","institution":"Shaoxing Second Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiaoying","middleName":"","lastName":"Yu","suffix":""},{"id":73410510,"identity":"89f0299a-70d9-41b1-9042-1c176baeb2ab","order_by":1,"name":"Le Diao","email":"","orcid":"","institution":"Shanghai Zhangjiang Institute of Medical Innovation, Shanghai Biotecan Pharmaceuticals Co., Ltd","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Le","middleName":"","lastName":"Diao","suffix":""},{"id":73410511,"identity":"dc8a28c6-b892-442f-99d6-f3c0b0d261ce","order_by":2,"name":"Baoying Du","email":"","orcid":"","institution":"Shaoxing Second Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Baoying","middleName":"","lastName":"Du","suffix":""},{"id":73410512,"identity":"2d87c5a0-0c34-4ba9-afd7-82ce6e8bb009","order_by":3,"name":"Ying Wang","email":"","orcid":"","institution":"Shaoxing Second Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ying","middleName":"","lastName":"Wang","suffix":""},{"id":73410513,"identity":"92f355f0-a726-49a4-a6ad-7cddf721a786","order_by":4,"name":"Xiaoqin Xv","email":"","orcid":"","institution":"Shaoxing Second Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiaoqin","middleName":"","lastName":"Xv","suffix":""},{"id":73410514,"identity":"a1ca960d-fd36-49c8-9337-a977a609c7dc","order_by":5,"name":"Anqi Yu","email":"","orcid":"","institution":"Shanghai Zhangjiang Institute of Medical Innovation, Shanghai Biotecan Pharmaceuticals Co., Ltd","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Anqi","middleName":"","lastName":"Yu","suffix":""},{"id":73410515,"identity":"3a63f620-00d7-4137-9e7a-84cffc3187e1","order_by":6,"name":"Jiangman Zhao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAElEQVRIiWNgGAWjYDACCRA2gHI+VNjw8PM3kKCFccaZNBnJGQeI0AIDzLwth20MGhLw65Cf3fzwgUWBXZ582OFnD2c2nOcxYDjA+OFjDm4tjHOOGRtIGCQXG95OMzf4uOM2jzlzA7PkzG24tTBLJJhJSBgwJ26cnWAmOfPMbR7LhgNszLx4tLBJpH8DaqkHakn/Js3bdo7H4EACfi08EjkgWw4nzpfOMQNqOUBYi4RETjHQL8cTN0jnlEnOOJPMIznjYDNev8jPSN/4WOJPdeL82enbJD5U2Nnz8zcf/PARjxZIEAAJgwNwPmMDfvUgJR9A1hFWNwpGwSgYBSMVAAAPv1EMa4e30QAAAABJRU5ErkJggg==","orcid":"","institution":"Shanghai Zhangjiang Institute of Medical Innovation, Shanghai Biotecan Pharmaceuticals Co., Ltd","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Jiangman","middleName":"","lastName":"Zhao","suffix":""}],"badges":[],"createdAt":"2021-12-14 07:14:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1168960/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1168960/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":19669921,"identity":"6758b668-49b8-4c03-92b3-32d127f6e998","added_by":"auto","created_at":"2022-03-28 06:14:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":525303,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1168960/v1/278c7178-15fa-4c29-9ee7-20ed09796749.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Individualized Folic Acid Supplementation based on Polymorphisms of Methylenetetrahydrofolate Reductase (MTHFR) and Methionine Synthase Reductase (MTRR), Compared with Traditional Folic Acid Supplementation, Reduces Gestational Diabetes Mellitus","fulltext":[{"header":"Introduction","content":"\u003cp\u003eFolic acid (FA) is a synthetic form of folate necessary for cell development and biochemical reactions [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. It is worth noting that a low intake of FA can also increase the risk of adverse pregnancy outcome [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Lack of FA in pregnant women will increase the risk of birth defects, especially neural tube malformations [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. At the same time, the incidence of other birth defects will increase, such as Down\u0026rsquo;s syndrome, cleft lip and palate, and congenital heart disease. FA supplementation for pregnant women can reduce the prevalence of fetal neural tube defects which often leading to death or disability [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Some studies demonstrated that FA supplementation continued throughout pregnancy prevents adverse pregnancy outcomes, whereas some study suggest that high-dose FA may lead to an increased risk of gestational hypertension [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In addition, high doses of FA continued throughout pregnancy are not an effective prevention strategy for preeclampsia [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Excessive FA supplementation can increase the risk of breast cancer in pregnant women, lead to zinc deficiency in the body and cause abnormal fetal development and cover up vitamin B12 deficiency. Research stated that attention should be given to avoid inappropriate FA supplement use in women who are planning or capable of pregnancy [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. FA effects may be more relevant in subjects carrying genetic abnormalities of the enzymes of homocysteine metabolic pathway, in particular, the common homozygous thermolabile 5,10 methylentetrahydrofolate reductase (MTHFR C677T) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. This indicates that, according to polymorphisms of MTHFR and other related genes, it is very important to guide pregnant women to accurately supplement FA.\u003c/p\u003e \u003cp\u003eGestational diabetes mellitus (GDM) is diagnosed when a woman has high blood sugar levels for the first time during pregnancy [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] and the prevalence of GDM is more than 20% in Asian [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Higher habitual intakes of supplemental folate before pregnancy were significantly associated with lower GDM risk [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. But recently research have been conducted that daily intake of FA during early pregnancy was associated with a higher risk of GDM in China [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Addition, higher maternal folate coupled with vitamin B12 insufficiency was associated with higher GDM risk in Singapore [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, none of these studies provide accurate FA supplementation for pregnant women based on Polymorphisms of genes.\u003c/p\u003e \u003cp\u003eA number of studies have investigated variations in genes related to folate metabolism [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Several key enzymes, including methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) are involved in the folate metabolic pathway [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. MTHFR is involved in the one-carbon cycle, and is a crucial enzyme that regulates nucleotide synthesis and DNA methylation [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The MTHFR C677T gene polymorphism (rs1801133) and A1298C gene polymorphism (rs1801131) are common gene variants of MTHFR and have been shown to alter the enzyme activity [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Methionine as a precursor for S-adenosylmethionine, is produced via the transfer of a methyl group from 5-methyltetrahydrofolate, which is catalyzed by MTR and MTRR [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Similar to MTHFR C677T and A1298C, MTRR A66G is also a common polymorphism, which plays an important role in folate metabolism [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRecently research revealed that after supplemented with FA, the complication rates were significantly reduced, especially for GDM, compared with pregnant women without FA supplementation [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. However, there are limited studies on the relationship between FA supplementation and the risk of gestational diabetes in the Chinese population. There has been consensus on the necessity and benefits of FA supplementation for pregnant women. However, few studies have used polymorphisms of gene to accurately guide pregnant women to supplement FA during pregnancy. Most studies are based on experience or common sense in life. In particular, it is crucial to identify high-risk pregnant women through genetic testing methods, more accurate FA supplementation and more careful care. Therefore, we compared the difference between pregnant women with empirical FA supplementation and pregnant women with genetic guidance and precise FA supplementation during pregnancy to identify high-risk pregnant women and highlight the necessity and importance of genetic testing to accurately guide pregnant women to supplement FA.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003ch2\u003eStudy population and SNP genotyping\u003c/h2\u003e\n\u003cp\u003eThe study was approved by the ethics committee of Shaoxing Second Hospital. A total of 2908 pregnant women were enrolled in this study between 2014 and 2019. Clinical information including age, body mass index (BMI), history of abortion, first pregnancy, physical activities, and diseases of reproductive system during pregnancy was completed by all subjects. Informed consent was obtained from all participants. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Medical Ethics Committee of Shaoxing Second Hospital. Informed consent was obtained from all participants. SNP of MTHFR C677T, MTHFR A1298C and MTRR A66G were determined by PCR and Sanger sequencing by ABI 3730XL DNA Analyzer (ABI, USA). \u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eAssessment of Potential Risk and Individualized Intervention with FA\u003c/h2\u003e\n\u003cp\u003eA total of 968 cases of individualized intervention of FA through genetic testing polymorphisms and 1,940 cases of controls with empirical supplementation of FA were included in this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAccording to the genotypes of these three polymorphisms, the FA metabolism ability of pregnant women was evaluated. The risk of abnormal pregnancy outcome was further evaluated and divided into four levels: unidentify, low, middle and high, and then supplemented with different doses of FA according to the risk level of abnormal pregnancy outcome and its gestational age.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eAssessment of GDM\u003c/h2\u003e\n\u003cp\u003eGDM was diagnosed at the same clinic visit, based on plasma glucose concentrations measured at a fasting state and two hours after a 75g oral glucose tolerance test (OGTT) was administered. Plasma glucose concentrations were analyzed using the colorimetry method (Advia 2400 Chemistry system, Siemens Medical Solutions Diagnostics; and Beckman LX20 Pro analyzer, Beckman Coulter). Participants were classified as having GDM, if they met one of the following: (1) \u0026ge; 4.5 mmol/L of fasting plasma glucose concentrations, (2) \u0026ge; 10 mmol/L and 8.5 mmol/L of plasma glucose concentrations 1-hour and 2-hour post-OGTT, respectively. \u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eComplications Observation and Statistical Analysis\u003c/h2\u003e\n\u003cp\u003eThe complications of pregnant women in cases and controls, including GDM, thyroid function, gestational hypertension, abortion, premature birth, macrosomia and underweight were recorded and analyzed. Statistical analysis were performed using SPSS 19.0 (IBM, NY, USA). If continuous variables conformed to a normal distribution, unpaired t-tests were used to analyze differences. Otherwise, the Mann-Whitney U test was used. When comparing datasets containing multiple groups, one-way analysis of variance was used for normally distributed datasets, and the Kruskal-Wallis test was used for datasets not normally distributed. Categorical variables were summarized as the counts and percentages, and analyzed using the c2 test or Fisher\u0026rsquo;s exact test, as appropriate. A two-sided values of P\u0026lt;0.05 were considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv class=\"Section2\" id=\"Sec8\"\u003e\n \u003ch2\u003eParticipant characteristics\u003c/h2\u003e\n \u003cp\u003eHistory of abortion, first pregnancy, diseases of reproductive system, Body Mass Index (BMI) and age according to maternal characteristics are presented in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Case pregnant women tended to be younger, which is significant lower than control pregnant women (median 28 vs. 30, P\u0026lt; 0.001). The proportion of case pregnant women with reproductive system diseases is higher than that of control pregnant women (percentage, 5.27% vs. 1.49%, P\u0026lt; 0.001). There were no significant differences in BMI, history of abortion, and first pregnancy between the two groups.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable border=\"1\" id=\"Tab1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eClinical characteristics of case and control pregnant women.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eClinical characteristics\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCases\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eControls\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge / years\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28 (16-44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30 (17-47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eBMI / Mean\u0026plusmn;SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21.75\u0026plusmn;2.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21.69\u0026plusmn;3.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.289\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eHistory of abortion\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e458 (47.31%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e867 (44.69%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.181\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eFirst pregnancy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e333 (34.40%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e692 (35.67%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.500\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiseases of reproductive system\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e51 (5.27%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29 (1.49%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003ch2\u003e\u003cstrong\u003eDistribution of Genotypes and Allelic Frequencies Relative to Polymorphisms of the MTHFR and MTRR Genes\u003c/strong\u003e\u003c/h2\u003e\n \u003cp\u003eThe distribution of genotype and allele frequencies of polymorphisms in the case group are presented in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. The distribution of genotype of MTHFR C677T were 39.8% (CC), 47.0% (CT) and 13.2% (TT); those of MTHFR A1298C were 63.4% (AA), 31.7% (AC) and 4.9% (CC), and those of MTRR A66G were 55.6% (AA), 38.7% (AG) and 5.7% (GG). The allele frequencies of MTHFR C677T were 63.3% (C) and 36.7% (T); those of MTHFR A1298C were 79.3% (A) and 20.7% (C), and those of MTRR A66G were 75.0% (A) and 25.0% (G).\u0026nbsp;\u003c/p\u003e\n \u003ctable border=\"1\" id=\"Tab2\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eDistribution of genotype and allele frequencies of polymorphisms\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGenotypes\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFrequency\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAllele\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFrequency\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMTHFR C677T\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e385 (39.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e63.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e455 (47.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e36.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e128 (13.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMTHFR A1298C\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e614 (63.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e79.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e307 (31.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e47 (4.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMTRR A66G\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e538 (55.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e75.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e375 (38.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e25.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e55 (5.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003ch2\u003e\u003cstrong\u003eFA metabolic capacity and supplement\u003c/strong\u003e\u003c/h2\u003e\n \u003cp\u003eFA metabolism is further ranked according to the genotypes of pregnant women, including four levels: unidentify, low, middle and high. According to the genotype and gestational weeks in Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e, guide pregnant women to supplement individualized FA dosage. \u0026nbsp;\u003c/p\u003e\n \u003ctable border=\"1\" id=\"Tab3\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eRisk rank of folate metabolism and FA supplementation\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRisk rank\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGenotypes\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eFolic acid supplementation\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e(MTHFR C677T/ MTHFR A1298C/ MTRR A66G)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 months before conception\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEarly pregnancy (0-12 weeks)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLate pregnancy (13-40 weeks)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUnidentify\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCC AA AA\u003c/p\u003e\n \u003cp\u003eCC AC AA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e400 \u0026micro;g/ day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e400 \u0026micro;g/ day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003edietary\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCT AA AA\u003c/p\u003e\n \u003cp\u003eCT AC AA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e400 \u0026micro;g/ day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e400 \u0026micro;g/ day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e400 \u0026micro;g/ day\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMiddle\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCC CC AA\u003c/p\u003e\n \u003cp\u003eCC AA AG\u003c/p\u003e\n \u003cp\u003eCC AC AG\u003c/p\u003e\n \u003cp\u003eCC AA GG\u003c/p\u003e\n \u003cp\u003eCC AC GG\u003c/p\u003e\n \u003cp\u003eCT CC AA\u003c/p\u003e\n \u003cp\u003eCT AA AG\u003c/p\u003e\n \u003cp\u003eCT AC AG\u003c/p\u003e\n \u003cp\u003eCT AA GG\u003c/p\u003e\n \u003cp\u003eCT AC GG\u003c/p\u003e\n \u003cp\u003eTT AA AA\u003c/p\u003e\n \u003cp\u003eTT AC AA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e400 \u0026micro;g/ day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e800 \u0026micro;g/ day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e400 \u0026micro;g/ day\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCC CC AG\u003c/p\u003e\n \u003cp\u003eCC CC GG\u003c/p\u003e\n \u003cp\u003eCT CC AG\u003c/p\u003e\n \u003cp\u003eCT CC GG\u003c/p\u003e\n \u003cp\u003eTT CC AA\u003c/p\u003e\n \u003cp\u003eTT AA AG\u003c/p\u003e\n \u003cp\u003eTT AC AG\u003c/p\u003e\n \u003cp\u003eTT AA GG\u003c/p\u003e\n \u003cp\u003eTT AC GG\u003c/p\u003e\n \u003cp\u003eTT CC AG\u003c/p\u003e\n \u003cp\u003eTT CC GG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e800 \u0026micro;g/ day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e800 \u0026micro;g/ day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e400 \u0026micro;g/ day\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eFrequency complications after supplementation\u003c/strong\u003e with FA dur\u003cstrong\u003eing Pregnancy in the case and control pregnant women\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eThe frequency complications after supplementation with FA during Pregnancy in the case and control pregnant women are presented in Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e. We found that GDM was significantly reduced in the case group, compared with those in control groups (P\u0026lt; 0.001). The macrosomia was also reduced in the case group, compared with those in control groups (P\u0026lt; 0.031). The complications of thyroid function, gestational hypertension, abortion, premature birth and underweight were not significantly different between these two groups. \u0026nbsp;\u003c/p\u003e\n \u003ctable border=\"1\" id=\"Tab4\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eFrequency complications after supplementation with FA during pregnancy in the case and control pregnant women.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eClinical characteristics\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCases\u003c/p\u003e\n \u003cp\u003e(N=968)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eControls\u003c/p\u003e\n \u003cp\u003e(N=1940)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eGestational diabetes mellitus\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e55 (5.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e220 (11.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eThyroid function\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHypothyroidism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (1.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 (1.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.545\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHyperthyreosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e122 (13.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e182 (12.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.691\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNormal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e800\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1259\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMissing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e480\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eGestational hypertension\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (1.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28 (1.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.657\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ePremature birth\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.359\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMacrosomia (\u0026gt;4kg)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40 (4.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e131 (6.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.031\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnderweight (\u0026lt;2.5kg)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (0.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (0.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.879\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eApgar score (\u0026lt;8)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (1.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35 (1.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.736\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003ch2\u003e\u003cstrong\u003eRisk rank of folate metabolism, distribution, and corresponding gestational complications frequency\u003c/strong\u003e\u003c/h2\u003e\n \u003cp\u003eThe \u003cstrong\u003ecorresponding gestational complications\u003c/strong\u003e of GDM, hypothyroidism, hyperthyreosis and gestational hypertension under risk rank of folate metabolism were summarized in Table \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e. In case group, the percent of pregant women at four risk including unidentify, low, middle and high, is 18.4%, 27.0%, 46.9% and 7.7%, respectively. Compared with unidentify, low and middle levels in pregnant women, the GDM among the high risk levels in pregnant women were obviously reduce (percent 18.4%, 27.0%, 46.9% vs. 7.7%). There were no significant differences among the four risk levels for hypothyroidism, hyperthyreosis and gestational hypertension in pregnant women.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u0026nbsp;\u003ctable border=\"1\" id=\"Tab5\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eRisk rank of folate metabolism, distribution, and corresponding gestational complications frequency, according to genotypes.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRisk rank\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMTHFR C677T\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMTHFR A1298C\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMTRR A66G\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eN (percent)\u003c/p\u003e\n \u003cp\u003eN=968\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGestational diabetes mellitus\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGestational hypertension\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHypothyroidism\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHyperthyreosis\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnidentify\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e178 (18.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12 (6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2 (2.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5/175 (2.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e19/175 (10.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eLow\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e261 (27.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14 (5.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3 (1.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1 /252(0.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e28/252 (11.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMiddle\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e454 (46.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e28 (6.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6 (1.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7/439 (1.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e62/439 (13.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eHigh\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e75 (7.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1 (1.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1 (1.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2/72 (2.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13/72 (17.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"9\"\u003eNote: Thyroid function is missing in 29 cases.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe folate metabolism pathway plays an important role in cell division [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] and DNA methylation, repair and synthesis [\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], and it is critically important for the health of pregnant women and the development of fetuses [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Research showed that FA supplementation continued throughout pregnancy prevents adverse pregnancy outcomes [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. MTHFR is a key enzyme in folate metabolism [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Some genetic polymorphisms code for a less efficient enzyme, increasing serum concentrations of homocysteine [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. This has been associated with inadequate feto-maternal circulation and increased risk of adverse pregnancy outcome [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Two polymorphic variants in this gene (C677T and A1298C) have been implicated in a mild form of MTHFR deficiency associated with hyperhomocysteinemia [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Recently studies have showed that the C677T and A1298C Single-nucleotide polymorphisms (SNPs) of the MTHFR gene could elevate blood homocysteine [\u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], which may cause fetal nervous system malformation and spina bifida cystica [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. The MTRR mutation prevents the conversion of homocysteine to methionine and is the main cause of FA and methyl vitamin deficiency. Among them, A66G is the most important and most studied mutation and has the risk of elevating blood homocysteine [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Through the polymorphisms of MTHFR C677T, A1298C and MTRR A66G, it is possible to detect the level of FA absorption and utilization by different individuals as soon as possible, thereby screening high-risk groups prone to FA deficiency, and realizing personalized FA supplements to reduce the risk of pregnancy syndrome and birth defects in newborns.\u003c/p\u003e \u003cp\u003eThe rate of GDM in the case group is significantly lower than the control group. Especially in high-risk pregnant women, there are fewer pregnant women with GDM. In the case group, there are 75 of pregnant women at high risk, but only a pregnant women have GDM, which is the lower among pregnant women with other three risk levels. FA has a significant effect on GDM [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. A higher intake of habitual FA supplementation before pregnancy is significantly associated with a lower risk of GDM [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. FA can increase the nitric oxide (NO) level and restore Type II diabetes associated-endothelial dysfunction [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. In addition, we also noticed that pregnant women in the control group were older than those in the case group, but there were significantly more pregnant women in the case group with reproductive system diseases than the control group. Age may be a possible risk factor for pregnancy complications [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. This indicates that for older pregnant women with reproductive system diseases, accurate FA supplementation through gene polymorphism testing may be more important.\u003c/p\u003e \u003cp\u003eIn this research, the pregnant women at high risk, that is pregnant women with poor FA metabolism, the precise FA supplement dose significantly reduces the risk of gestational diabetes. Therefore, compared with pregnant women who have not supplemented with FA [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] or supplemented with FA according to common sense, it is clinically beneficial to identify high-risk pregnant women and individualized supplementation of FA according to polymorphisms of genes. As a consequence, the results show that, compared with traditional FA supplementation, individualized FA supplementation based on the polymorphisms of MTHFR and MTRR may be a powerful measure to reduce GDM.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eAccording to Polymorphisms of genes, pregnant women who accurately supplemented FA had a lower risk of diabetes during pregnancy than non-tested pregnant women, and this event was more pronounced in high-risk pregnant women. Too much or too little FA supplement according to personal habits is controversial, and the use of genetic testing to clarify the FA metabolism of pregnant women, appropriate and timely and accurate supplementation of FA can effectively reduce gestational diabetes, especially for high-risk pregnant women.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAUTHOR CONTRIBUTIONS:\u003c/h2\u003e\n\u003cp\u003eJMZ, XYY and LD conceived and designed the study. XYY, BYD, YW, XQX and AQY acquired the data. JMZ and XYY analyzed and interpreted the data. LD and XYY drafted the article.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eACKNOWLEDGEMENTS:\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eNone.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eCONFLICTS OF INTEREST:\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eAll authors report no conflict of interest related to the submitted work.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eFUNDING:\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of Shaoxing Second Hospital, Shaoxing, China. All participants signed an informed consent. All methods were carried out in accordance with relevant guidelines and regulations.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eConsent for publication\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eCompeting interests\u003c/h2\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eOrabona R, Zanardini C, Zatti S, Sartori E, Prefumo F. Folic Acid Supplementation in Pregnancy: A Matter of Doses? Hypertension. 2020;76:30\u0026ndash;1.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKontic-Vucinic O, Sulovic N, Radunovic N. Micronutrients in women's reproductive health: I. Vitamins. Int J Fertil Womens Med. 2006;51:106\u0026ndash;15.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eScholl TO, Johnson WG. Folic acid: influence on the outcome of pregnancy. 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Contribution of MTR A2756G polymorphism and MTRR A66G polymorphism to the risk of idiopathic male infertility. Medicine (Baltimore). 2019;98:e18273.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXu L, Qin Z, Wang F, Si S, Li L, Lin P, et al. Methylenetetrahydrofolate reductase C677T polymorphism and colorectal cancer susceptibility: a meta-analysis. Biosci Rep. 2017;37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eScott JM, Weir DG, Molloy A, McPartlin J, Daly L, Kirke P. Folic acid metabolism and mechanisms of neural tube defects. Ciba Found Symp. 1994;181:180-7; discussion 7-91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKarimian M, Hosseinzadeh Colagar A. Methionine synthase A2756G transition might be a risk factor for male infertility: Evidences from seven case-control studies. 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Gene. 2019;689:69\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLevin BL, Varga E. MTHFR: Addressing Genetic Counseling Dilemmas Using Evidence-Based Literature. J Genet Couns. 2016;25:901\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJacques PF, Bostom AG, Williams RR, Ellison RC, Eckfeldt JH, Rosenberg IH, et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation. 1996;93:7\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMotulsky AG. Nutritional ecogenetics: homocysteine-related arteriosclerotic vascular disease, neural tube defects, and folic acid. Am J Hum Genet. 1996;58:17\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChedraui P, Salazar-Pousada D, Villao A, Escobar GS, Ramirez C, Hidalgo L, et al. 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Diabetologia. 2002;45:1004\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Folic acid, Gestational diabetes mellitus, Polymorphisms, Pregnancy","lastPublishedDoi":"10.21203/rs.3.rs-1168960/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1168960/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackgroud\u003c/strong\u003e: Folic Acid (FA) may contribute to the development of gestational diabetes mellitus (GDM), but existing studies are inconsistent. We examined the genotype distributions and allele frequencies of methylenetetrahydrofolate reductase (MTHFR) C677T, A1298C and methionine synthase reductase (MTRR) A66G polymorphisms of pregnant women in China, and compared the effects of individualized folate supplementation and traditional FA supplementation on GDM.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: The genotype distributions and allele frequencies of MTHFR C677T, A1298C and MTRR A66G polymorphisms in 968 pregnant women (case group) were tested. FA metabolism was ranked at four levels, and then pregnant women of different levels are supplemented with different doses of FA at different periods. The case group was followed up for pregnancy complications and compared with 1,940 pregnant women traditionally supplemented with FA in the same hospital (control group).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: The allele frequencies of MTHFR C677T were 63.3% (C) and 36.7% (T), those of MTHFR A1298C were 79.3% (A) and 20.7% (C), and those of MTRR A66G were 75.0% (A) and 25.0% (G). Compared with control group, the incidence of GDM in the case group were significantly lower, especially in high-risk pregnant women after FA supplementation.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: Traditional FA supplementation based on personal habits is controversial, but the use of polymorphisms of genes to clarify the FA metabolism of pregnant women, appropriate, timely and accurate supplementation of FA can effectively reduce gestational diabetes, especially for high-risk pregnant women.\u003c/p\u003e","manuscriptTitle":"Individualized Folic Acid Supplementation based on Polymorphisms of Methylenetetrahydrofolate Reductase (MTHFR) and Methionine Synthase Reductase (MTRR), Compared with Traditional Folic Acid Supplementation, Reduces Gestational Diabetes Mellitus","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-01-03 19:45:00","doi":"10.21203/rs.3.rs-1168960/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4633886d-1d9b-445d-b2e1-1e149e4d928b","owner":[],"postedDate":"January 3rd, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":9476086,"name":"Maternal \u0026 Fetal Medicine"},{"id":9476087,"name":"Sexual \u0026 Reproductive Medicine"}],"tags":[],"updatedAt":"2022-03-28T06:14:10+00:00","versionOfRecord":[],"versionCreatedAt":"2022-01-03 19:45:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1168960","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1168960","identity":"rs-1168960","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}