Effects Of Different Doses Of Folic Acid On Serum Folic Acid And Homocysteine Levels In Pregnant Women With Different Genetic Signs

Background and ObjectiveFolic acid is a B-group vitamin.Folic acid can be transformed into a variety of active coenzyme forms,involving the transfer of a carbon unit in the machine,which plays an important role in the biosynthesis of purine,pyrimidine,nucleic acids and proteins,and in the cell division,and is a kind of substance necessary to maintain the normal life process of the organism^[1].People who get folic acid can only absorb exogenous folic acid through the gut and cannot synthesize folic acid by oneself.Folic acid is the most abundant in liver,green leafy vegetables,legumes and fruits.But folic acid meets light,heat is extremely easy to destroy,in the food storage processing process loses up to 80%,the average absorption rate of folic acid in food is about 70%,the bioavailability is only the 1/2²/3 of oral folic acid preparation^[2].Studies show that^[3]pregnant women are 10 times times more likely to have folic acid than non-pregnant women,which increases the risk of folic acid deficiency in pregnant women.Folic acid（FA,sphenoid glutamate）is a synthetic form of folic acid,highly stable and active,and widely used for supplementation and food fortification.Current studies have confirmed that folic acid supplementation in gestational weeks can significantly reduce the risk of neural tube defects（NTDs）in offspring^[4].Many countries have made it clear that pregnant women who plan to conceive take 400μg folic acid daily from the early stages of pregnancy until the early end of pregnancy^[5].At present,the study is to observe the effect of folic acid supplementation in early pregnancy,the effect of folic acid supplementation in the middle and late pregnancy is less,there is no agreement on whether to maintain folic acid intake throughout pregnancy.The mutation frequency of the key enzymes 5,10-MTHFR C677T,A1298C and MTRR A66G three sites was different in the metabolism of folic acid in vivo,and the individual’s ability to use folic acid differed^[6-7].MTHFR C677T mutation will change the activity of one alanine into valine in the active region of MTHFR,which can induce the changes of enzyme activity,in which the enzyme activity of the heterozygosity is reduced to 65%and the homozygous is reduced to 30%.A1298C is another polymorphic locus of the MTHFR gene,which converts glutamic acid to alanine,and the enzyme activity of the heterozygosity drops to 83%,and the homozygous is reduced to 61%^[8].MTRR is a flavonoid-related enzyme that sustains the activity of methionine synthase,the a66g polymorphism of the enzyme-encoded gene will lead to the substitution of methionine with isoleucine,so that the activity of the enzyme is reduced significantly,and the activity of methionine synthase is reduced,The accumulation of homocysteine in vivo^[9],hcy can lead to a series of vascular endothelial damage,early pregnancy can lead to fetal deformities^[10]and miscarriage^[11],which may lead to some pregnancy complications such as preterm birth^[12],gestational hypertensive disorder^[13-14],gestational diabetes mellitus^[15],Colditz etc.^[16]and China CDC Maternal and child genetic examination Project according to the conclusion of three loci gene polymorphism of MTHFR C677T,A1298C and MTRR A66G on folic acid utilization capacity,the utilization of folic acid was divided into four grades:no-risk,low-risk,moderate-risk,and high-risk,puting forward to the pregnant women for folic acid utilization ability of gene detection,screening folic acid utilization ability of poor people,according to each person’s genetic characteristics to supplement different doses of folic acid.The polymorphism of folic acid metabolism-related genes resulted in a large difference in serum concentration level.It is easy to cause the expected effect to be reduced or ineffective,this study through the detection of folic acid metabolism-related gene polymorphism,assessment of folic acid metabolism capacity,observation of different pregnancy serum folic acid and homocysteine levels change,for patients to develop individualized folic acid supplementation program.Materials and MethodsThe research objectAccording to the inclusion criteria to choose a total of 1371 pregnant women who received regular perinatal care at our hospital between July 2015 and August2017 were selected for the present study.A questionnaire survey was adopted to collect the general information of the study subjects,including age,height,and weight.There were no statistically significant differences in age,height,and weight between the groups.Early pregnancy,mid-pregnancy,and late pregnancy were defined according to the eighth edition of"Obstetrics and Gynecology"（edited by Xie et al.）^[2]as 0-13⁺⁶ weeks,14-27⁺⁶ weeks,and beyond 28 weeks,respectively.The inclusion criteria were as follows:suffers from thyroid disease,diabetes mellitus,malignant tumor or immune system disease;suffers from poor absorption or metabolic disorders such as gastro-intestinal disease,liver disease,kidney disease;taking drugs that antagonize folic acid absorption,such as antiepileptic drugs,sulfa drugs and methotrexate;smoking,obese pregnant women;defects in previous pregnancies,or in the case of first-degree relatives who had undergone neural tube defects in pregnancy.GroupingThe Taqman-MGB probe was used to examine the C677T and A1298C loci in the 5,10-methylenetetrahydrofolate reductase（MTHFR）gene and the A66G locus in the methionine synthase reductase（MTRR）gene.Based on their folic acid utilization ability,the included women were divided into no-risk,low-risk,moderate-risk,and high-risk groups.According to folic acid supplementation dosage,the non-risk group was subdivided into non-intervention and 0.4 mg groups,while the low-risk,moderate-risk and high-risk groups were subdivided into 0.4 mg and 0.8 mg groups.Indicators of observationFolic acid and homocysteine levels in subjects’peripheral blood during early,mid-and late pregnancy were examined using direct chemiluminescence and enzymatic methods.Statistical methodsUsing SPSS 21 statistical software for statistics,the measurement data obeys normal distribution by means of the mean±standard deviation,the comparison between groups using the repeated measurement data analysis of variance,more than22 of the comparison using Bonferroni method and the Test level of correction,α,=α/m（α<0.05,m was the number of comparisons between groups）;Inspection levelα=0.05.Results1 Folic acid utilization ability risk Level results.The genetic test results of folic acid utilization ability no-risk appeared at 24.8%,the frequency of low-risk was9.12%,the frequency of moderate-risk was 26.11%,and the frequency of high-risk appeared 39.97%.2 Serum levels and homocysteine of folic acid were examined in pregnant women with distinct genetic characteristics after oral administration of various doses of folic acid.No-risk group Serum levels:The 0.4 mg group had a higher serum level of folic acid during early,mid-,and late pregnancy than the non-intervention group（P<0.05）.Serum folic acid level in the non-intervention group was lower in middle and late pregnancy than in early pregnancy（P<0.05）,and the difference in serum folic acid level in the 0.4mg folic acid group in early,middle and late pregnancy was not statistically significant（P>0.05）.Serum Hcy level:in the0.4mg folic acid group,serum Hcy was lower than in the non-intervention group in early,middle and late pregnancy,and the level tends to decreasing in pregnancy（P<0.05）.The level of early pregnancy was highest in the non-intervention group,decreased in the middle pregnancy,and increased again in the late pregnancy.Low-risk 0.4 mg folic acid group compared with 0.8 mg folic acid group There was no significant difference in serum folic acid levels between the 0.4 mg group and the 0.8 mg group in early pregnancy（P>0.05）.However,the serum folic acid level was significantly lower in the 0.4 mg group than in the 0.8 mg group during mid-and late pregnancy（P<0.05）;Serum folic of 0.4mg folic acid group was lower than that of early pregnancy（P<0.05）,while serum folic of 0.8mg folic acid group had no statistically significant difference in early,mid-,and late pregnancy（P>0.05）.Serum Hcy:0.4mg folic acid group and 0.8mg folic acid group showed no statistical significance in early,mid-,and late pregnancy（P>0.05）.The serum Hcy levels of0.4mg folic acid group and 0.8mg folic acid group of mid-,and late pregnancy were lower than those of early pregnancy（P<0.05）.Moderate-risk group and High-risk 0.4 mg folic acid group compared with 0.8mg folic acid group Serum folic acid:the folic acid supplementation group of0.4mg was lower than that of 0.8mg folic acid group in early,mid-,and late pregnancy（P<0.05）.Serum folic of 0.4mg folic acid supplementation group was lower in mid-,and late pregnancy than in early pregnancy（P<0.05）,while serum folic of 0.8mg folic acid supplementation group was not statistically different in early,mid-,and late pregnancy（P>0.05）.Serum Hcy:the serum Hcy of 0.4mg folic acid group was higher than that of 0.8mg folic acid group in early,mid-and late pregnancy（P<0.05）.The changes of serum Hcy in the two groups were observed during pregnancy.The folic acid supplementation group with 0.4mg was decreased in the middle and increased in the late pregnancy,and the folic acid supplementation group with 0.8mg was decreased in the middle and late stages of pregnancy.3 The serum level of folic and Hcy was compared between pregnant women with different genetic characteristics after oral administration of the same dosage of folic acid.The results were as follows:When the women received 0.4 mg folic acid supplementation,the serum folic acid level was significantly higher in the no-risk group than in the moderate-risk group and the high-risk group（P<0.008）.A higher serum level of folic acids was also found in the low-risk group than in the high-risk group（P<0.008）.In contrast,the serum folic acid levels did not differ significantly among the other groups during early pregnancy.At mid-pregnancy,the high-risk group was lower than the other three groups,the moderate-risk group was lower than the no-risk group（p<0.008）,there was no statistical significance between the rest groups;At late pregnancy,the high-risk group was lower than the other three groups,moderate-risk group and low-risk were lower than those no-risk group（p<0.008）.Serum Hcy:In early pregnancy and late pregnancy,the high-risk group was higher than the no-risk group and the low-risk group（P<0.008）,and there was no statistically significant difference between the other groups;In the middle pregnancy,the high-risk group was higher than the no-risk group（P<0.008）,and there was no statistical difference between the remaining groups.When the women received 0.8 mg folic acid supplementation,the serum folic acid levels did not differ significantly between the low-risk,moderate-risk,and high-risk groups at the early,middle,and late stages of pregnancy（P>0.05）.Conclusions1.There are individual differences in the ability to use folic acid,and the demand for folic acid varies in different pregnancy cycles;2.Individualized folic acid supplementation can maintain the concentration of serum folic acid and prevent the increase of homocysteine concentration in the late pregnancy.