scholarly journals A Novel Review of Homocysteine and Pregnancy Complications

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Chuce Dai ◽  
Yiming Fei ◽  
Jianming Li ◽  
Yang Shi ◽  
Xiuhua Yang
Keyword(s):  
Folic Acid ◽  
Pregnancy Complications ◽  
Methylenetetrahydrofolate Reductase ◽  
Normal Pregnancy ◽  
Positive Outcome ◽  
Mthfr Gene ◽  
Folate Intake ◽  
Daily Diet ◽  
B12 Deficiency ◽  
Work Done

Homocysteine (Hct) is a substance produced in the metabolism of methionine. It is an essential type of amino acid gained from the daily diet. Methylenetetrahydrofolate reductase (MTHFR) gene mutation is related to elevated total homocysteine (tHct) expressions, in particular, among women with low folate intake. Hyperhomocysteinemia (HHct) is caused by numerous factors, such as genetic defects, lack of folic acid, vitamin B6 and B12 deficiency, hypothyroidism, drugs, aging, and renal dysfunction. Increased Hct in peripheral blood may lead to vascular illnesses, coronary artery dysfunction, atherosclerotic changes, and embolic diseases. Compared to nonpregnant women, the Hct level is lower in normal pregnancies. Recent studies have reported that HHct was associated with numerous pregnancy complications, including recurrent pregnancy loss (RPL), preeclampsia (PE), preterm delivery, placental abruption, fetal growth restriction (FGR), and gestational diabetes mellitus (GDM). Besides, it was discovered that neonatal birth weight and maternal Hct levels were negatively correlated. However, a number of these findings lack consistency. In this review, we summarized the metabolic process of Hct in the human body, the levels of Hct in different stages of normal pregnancy reported in previous studies, and the relationship between Hct and pregnancy complications. The work done is helpful for obstetricians to improve the likelihood of a positive outcome during pregnancy complications. Reducing the Hct level with a high dosage of folic acid supplements during the next pregnancy could be helpful for females who have suffered pregnancy complications due to HHct.

scholarly journals Folic Acid Exerts Dose-Dependent Biphasic Effects on Cardiac Development of Zebrafish Embryos

2021 ◽  
Author(s):  
Xuhui Han ◽  
Bingqi Wang ◽  
Hongjie Wang ◽  
Yao Zu
Keyword(s):  
Folic Acid ◽  
Methylenetetrahydrofolate Reductase ◽  
Cardiac Development ◽  
Mthfr Gene ◽  
Folate Metabolism ◽  
Marker Genes ◽  
Zebrafish Embryos ◽  
Cardiovascular Development ◽  
Knock Out ◽  
Dose Dependent

Folic acid, one of the 13 essential vitamins, plays an important role in cardiovascular development. Mutations in folic acid synthesis gene 5,10-methylenetetrahydrofolate reductase (MTHFR) is significantly associated with the occurrence of congenital heart disease. However, the mechanisms underlying the regulation of cardiac development by mthfr gene are poorly understood. Here, we exposed zebrafish embryos to excessive folate or folate metabolism inhibitors. And we established a knock-out mutant of mthfr gene in zebrafish by using CRISPR/Cas9. The zebrafish embryos of insufficient or excessive folic acid, and mthfr-/- mutant all gave rise to early pericardial edema and cardiac defect at 3 days after fertilization(dpf). Furthermore, the folic acid treated embryos showed abnormal movement at 5dpf. The expression levels of cardiac marker genes hand2, gata4 and nppa changed in the abnormality of folate metabolism embryos and mthfr-/- mutant, and there is evidence that they are related to the change of methylation level caused by the change of folate metabolism. In conclusion, our study provides a novel model for the in-depth study of MTHFR gene and folate metabolism. And our results reveal that folic acid has a dose-dependent biphasic effect on early cardiac development.

scholarly journals Maternal Homocysteine before Conception and throughout Pregnancy Predicts Fetal Homocysteine and Birth Weight

2004 ◽  
Vol 50 (8) ◽  
pp. 1406-1412 ◽  
Author(s):  
Michelle M Murphy ◽  
John M Scott ◽  
Victoria Arija ◽  
Anne M Molloy ◽  
Joan D Fernandez-Ballart
Keyword(s):  
Folic Acid ◽  
Birth Weight ◽  
Confidence Interval ◽  
Pregnancy Outcome ◽  
Pregnancy Complications ◽  
Odds Ratio ◽  
Geometric Mean ◽  
Normal Pregnancy ◽  
Time Points ◽  
Total Homocysteine

Abstract Background: Increased homocysteine has been associated with pregnancy complications. Methods: We investigated prospectively the effect of maternal homocysteine on normal pregnancy outcome. The study included 93 women and their offspring; 39 of the women took folic acid during the second and/or third trimesters of pregnancy. We measured homocysteine at preconception; at weeks 8, 20, and 32 of pregnancy; during labor; and in the fetal cord; we also recorded birth weight. Results: Geometric mean (SE) maternal total homocysteine (tHcy) increased between 32 weeks of pregnancy and labor [7.98 (1.05) μmol/L in unsupplemented women and 6.26 (1.07) μmol/L in supplemented women; P <0.0001 for both]. Fetal tHcy was lower than maternal tHcy [6.39 (1.06) μmol/L in unsupplemented pregnancies (P <0.0001), and 5.18 (1.06) μmol/L in supplemented pregnancies (P <0.05)]. Maternal tHcy was correlated from preconception throughout pregnancy (8 weeks, r = 0.708; 20 weeks, r = 0.637; 32 weeks, r = 0.537; labor, r = 0.502; P <0.0001 for all time points) and with fetal tHcy [preconception, r = 0.255 (P <0.05); 8 weeks, r = 0.321 (P <0.01); 20 weeks, r = 0.469; 32 weeks, r = 0.550; labor, r = 0.624 (P <0.0001)]. Mothers in the highest tHcy tertile at 8 weeks of pregnancy were three times [odds ratio, 3.26 (95% confidence interval, 1.05–10.13); P <0.05] and at labor were four times [3.65 (1.15–11.56); P <0.05] more likely to give birth to a neonate in the lowest birth weight tertile. Neonates of mothers in the highest tHcy tertile at labor weighed, on average, 227.98 g less than those of mothers in the low and medium tertiles (P = 0.014). Conclusions: Supplemented mothers had lower tHcy at labor than unsupplemented mothers, as did their neonates. Maternal and fetal tHcy was significantly correlated throughout the study. Neonates of mothers in the highest tertile of homocysteine weighed less.

Folate, Homocysteine and Neural Tube Defects: An Overview

2001 ◽  
Vol 226 (4) ◽  
pp. 243-270 ◽  
Author(s):  
Nathalie M.J. Van Der Put ◽  
Henny W.M. Van Straaten ◽  
Frans J.M. Trijbels ◽  
Henk J. Blom
Keyword(s):  
Neural Tube ◽  
Neural Tube Defects ◽  
Genetic Risk ◽  
Methylenetetrahydrofolate Reductase ◽  
Mthfr Gene ◽  
Folate Intake ◽  
Elevated Blood ◽  
Moderate Risk ◽  
Mthfr Polymorphisms ◽  
Increased Risk

Folate administration substantially reduces the risk on neural tube defects (NTD). The interest for studying a disturbed homocysteine (Hcy) metabolism in relation to NTD was raised by the observation of elevated blood Hcy levels in mothers of a NTD child. This observation resulted in the examination of enzymes involved in the folate-dependent Hcy metabolism. Thus far, this has led to the identification of the first and likely a second genetic risk factor for NTD. The C677T and A1298C mutations in the methylenetetrahydrofolate reductase (MTHFR) gene are associated with an increased risk of NTD and cause elevated Hcy concentrations. These levels can be normalized by additional folate intake. Thus, a dysfunctional MTHFR partly explains the observed elevated Hcy levels in women with NTD pregnancies and also, in part, the protective effect of folate on NTD. Although the MTHFR polymorphisms are only moderate risk factors, population-wide they may account for an important part of the observed NTD prevalence.

scholarly journals Effect of MTHFR A1298C and MTRR A66G genetic mutations on homocysteine levels in the Chinese population: a systematic review and meta-analysis

2017 ◽  
Vol 5 (4) ◽  
pp. 220-229 ◽  
Author(s):  
Jiancheng Wang ◽  
Nengtai Ouyang ◽  
Long Qu ◽  
Tengfei Lin ◽  
Xianglin Zhang ◽  
...  
Keyword(s):  
Chinese Population ◽  
Methylenetetrahydrofolate Reductase ◽  
Meta Analysis ◽  
Random Effect ◽  
Mthfr Gene ◽  
Folate Intake ◽  
Folic Acid Fortification ◽  
Mthfr A1298c ◽  
Methionine Synthase Reductase ◽  
Mtrr A66g

AbstractBackground and ObjectivesThe Chinese population typically has inadequate folate intake and no mandatory folic acid fortification. Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) are the two key regulatory enzymes in the folate/homocysteine (Hcy) metabolism. Hcy has been implicated in the pathogenesis of cardiovascular disease. We conducted a meta-analysis to assess whether the MTHFR gene A1298C and the MTRR gene A66G polymorphisms affect Hcy levels in the Chinese population.MethodsThis analysis included 13 studies with Hcy levels reported as one of the study measurements. Summary estimates of weighted mean differences and 95% confidence intervals (CIs) were obtained using random-effect models.ResultsOverall, there were no significant differences in Hcy concentrations between participants with the MTHFR 1298 CC (12 trials,n= 129), AA (n= 2166; β, −0.51 μmol/L; 95%CI: −2.14, 1.11;P= 0.53), or AC genotype (n= 958; β, 0.55 μmol/L; 95%CI: −0.72, 1.82;P= 0.40). Consistently, compared to those with the MTRR 66 GG genotype (6 trials,n= 156), similar Hcy concentrations were found in participants with the AA (n= 832; β, −0.43 μmol/L; 95%CI: −1.04, 0.17;P= 0.16) or AG (n=743; β, −0.57 μmol/L; 95%CI: −1.46, 0.31;P= 0.21) genotype. Similar results were observed for the dominant and recessive models.ConclusionsNeither the MTHFR A1298C polymorphism nor the MTRR A66G polymorphism affects Hcy levels in the Chinese population.

scholarly journals Food Intervention with Folate Reduces TNF-α and Interleukin Levels in Overweight and Obese Women with the MTHFR C677T Polymorphism: A Randomized Trial

Nutrients ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 361 ◽  
Author(s):  
Jéssica Vanessa de Carvalho Lisboa ◽  
Marina Ramalho Ribeiro ◽  
Rafaella Cristhine Pordeus Luna ◽  
Raquel Patrícia Ataíde Lima ◽  
Rayner Anderson Ferreira do Nascimento ◽  
...  
Keyword(s):  
Folic Acid ◽  
Methylenetetrahydrofolate Reductase ◽  
Mthfr C677t ◽  
Folate Intake ◽  
C677t Polymorphism ◽  
Obese Women ◽  
Mthfr C677t Polymorphism ◽  
Tnf Α ◽  
Group 2 ◽  
Group 1

Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism associated with body fat accumulation could possibly trigger an inflammatory process by elevating homocysteine levels and increasing cytokine production, causing several diseases. This study aimed to evaluate the effects of food intervention, and not folate supplements, on the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) in overweight and obese women with the MTHFR C677T polymorphism. A randomized, double-blind eight-week clinical trial of 48 overweight and obese women was conducted. Participants were randomly assigned into two groups. They received 300 g of vegetables daily for eight weeks containing different doses of folate: 95 µg/day for Group 1 and 191 µg/day for Group 2. MTHFR C677T polymorphism genotyping was assessed by digestion with HinfI enzyme and on 12% polyacrylamide gels. Anthropometric measurements, 24-h dietary recall, and biochemical analysis (blood folic acid, vitamin B12, homocysteine (Hcy), TNF-α, IL-1β, and IL-6) were determined at the beginning and end of the study. Group 2 had a significant increase in folate intake (p < 0.001) and plasma folic acid (p < 0.05) for individuals with the cytosine–cytosine (CC), cytosine–thymine (CT), and thymine–thymine (TT) genotypes. However, only individuals with the TT genotype presented reduced levels of Hcy, TNF-α, IL-6, and IL-1β (p < 0.001). Group 1 showed significant differences in folate consumption (p < 0.001) and folic acid levels (p < 0.05) for individuals with the CT and TT genotypes. Food intervention with folate from vegetables increased folic acid levels and reduced interleukins, TNF-α, and Hcy levels, mainly for individuals with the TT genotype.

C677T Methylenetetrahydrofolate Reductase and Plasma Homocysteine Levels among Thai Vegans and Omnivores

2013 ◽  
Vol 83 (2) ◽  
pp. 86-91 ◽  
Author(s):  
Saowanee Kajanachumpol ◽  
Kalayanee Atamasirikul ◽  
Phieuvit Tantibhedhyangkul
Keyword(s):  
Vitamin B12 ◽  
Methylenetetrahydrofolate Reductase ◽  
Vitamin B12 Deficiency ◽  
Mthfr C677t ◽  
Mthfr Gene ◽  
Serum Folate ◽  
Geometric Means ◽  
C677t Mutation ◽  
B12 Deficiency ◽  
Mthfr Mutation

Hyperhomocysteinemia among vegetarians and vegans is caused mostly by vitamin B12 deficiency. A C-to-T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene results in a thermolabile MTHFR, which may affect homocysteine (Hcy) levels. The importance of this gene mutation among populations depends on the T allele frequency. Blood Hcy, vitamin B12, folate, vitamin B6, and MTHFR C677T mutation status were determined in 109 vegans and 86 omnivores aged 30 - 50 years. The vegans had significantly higher Hcy levels than the omnivores, geometric means (95 % CI) 19.2 (17.0 - 21.7) µmol/L vs. 8.53 (8.12 - 8.95) µmol/L, p < 0.001. A C-to-T mutation in the vegans increased plasma Hcy, albeit insignificantly; geometric means 18.2 µmol/L, 20.4 µmol/L, and 30.0 µmol/L respectively in CC, CT, and TT MTHFR genotypes. There was also a significant decrease in serum folate; geometric means 12.1 ng/mL, 9.33 ng/mL, and 7.20 ng/mL respectively, in the CC, CT, and TT mutants, p = 0.006, and particularly, in the TT mutant compared with the CC wild type, 7.20 ng/mL vs. 12.1 ng/mL, p = 0.023. These findings were not seen in the omnivores. It was concluded that hyperhomocysteinemia is prevalent among Thai vegans due to vitamin B12 deficiency. C-to-T MTHFR mutation contributes only modestly to the hyperhomocysteinemia.

Homocysteine and Cardiovascular Disease: Interactions Between Nutrition, Genetics and Lifestyle

2004 ◽  
Vol 29 (6) ◽  
pp. 773-780 ◽  
Author(s):  
John T. Brosnan
Keyword(s):  
Cardiovascular Disease ◽  
Folic Acid ◽  
Renal Disease ◽  
Methylenetetrahydrofolate Reductase ◽  
Coffee Consumption ◽  
Plasma Homocysteine ◽  
Folate Intake ◽  
Vitamin B ◽  
Methionine Metabolism ◽  
Vitamin Deficiencies

Homocysteine is a sulfur-containing amino acid that arises during methionine metabolism. Although its concentration in plasma is only about 10 micromolar, even moderate hyperhomocysteinemia is associated with increased incidence of cardiovascular disease and Alzheimer's disease. Elevations in plasma homocysteine are commonly found as a result of vitamin deficiencies, polymorphisms of enzymes of methionine metabolism, and renal disease. Pyridoxal, folic acid, riboflavin, and Vitamin B12 are all required for methionine metabolism, and deficiences of each of these vitamins result in elevated plasma homocysteine. A polymorphism of methylenetetrahydrofolate reductase (C677T), which is quite common in most populations with a homozygosity rate of 10-15%, is associated with moderate hyperhomocysteinemia, especially in the context of marginal folate intake. Plasma homocysteine is inversely related to plasma creatinine in patients with renal disease. This is due to an impairment in homocysteine removal in renal disease. The role of these factors, and of modifiable life style factors, in affecting methionone metabolism and in determining plasma homocysteine levels is discussed. Key words: methionine, liver metabolism, folic acid, vitamin B12, polymorphisms, neural tube defects, end-stage renal disease, coffee consumption

Drug and Environmental Factors Associated with Adverse Pregnancy Outcomes Part III: Folic Acid: Pharmacology, Therapeutic Recommendations, and Economics

1998 ◽  
Vol 32 (10) ◽  
pp. 1087-1095 ◽  
Author(s):  
Dale P Lewis ◽  
Don C Van Dyke ◽  
Phyllis J Stumbo ◽  
Mary J Berg
Keyword(s):  
Folic Acid ◽  
Mechanism Of Action ◽  
Neural Tube ◽  
Neural Tube Defects ◽  
Neural Tube Defect ◽  
Methylenetetrahydrofolate Reductase ◽  
Folate Intake ◽  
Cardiovascular Morbidity And Mortality ◽  
Cereal Grain ◽  
Therapeutic Recommendations

OBJECTIVE: To review folic acid's mechanism of action, adverse effects, therapeutic recommendations, compliance, and cost. DATA SOURCES: A MEDLINE search was conducted through December 1997. Additional sources were obtained from Current Contents and citations from the references obtained. Search terms included folate, folic acid, neural tube defect, homocysteine, and methylenetetrahydrofolate reductase. STUDY SELECTION: Animal and human studies examining the effects of folate were reviewed. DATA EXTRACTION: Data collected included mechanism of action, safety issues, dosing recommendations, compliance with recommendations, and economics. DATA SYNTHESIS: Folic acid decreases neural tube defect risk through an effect on methionine–homocysteine metabolism. In addition, increased folate intake may reduce cardiovascular morbidity and mortality. Since toxicity is minimal, everyone can potentially benefit from increased folate consumption. To help achieve this, the Food and Drug Administration has mandated that cereal grain be fortified with 140 μg of folic acid per 100 g of grain, which will add approximately 0.1 mg of folate to the average diet. Studies recommend supplementing with 0.2 mg to promote optimal homocysteine concentrations and for preventing neural tube defects. CONCLUSIONS: Despite fortification, most women will still receive less folate than the 0.4 mg/d recommended by the Public Health Service. All population groups would benefit from increased folate intake. Current studies indicate 200 μg/d may be the minimum effective amount of fortification needed for normalizing homocysteine concentrations and preventing a significant number of neural tube defects; thus, a higher level of food fortification may be warranted.

Folate Assays Are No Longer Useful as Screening Tests for Malabsorption Syndrome. Now, Iron and B12 Deficiency Are More Common Than Folate Deficiency in Adults with Untreated Celiac Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3738-3738
Author(s):  
A. Majid Shojania
Keyword(s):  
Celiac Disease ◽  
Folic Acid ◽  
Folate Deficiency ◽  
Tropical Sprue ◽  
Malabsorption Syndrome ◽  
Folate Intake ◽  
Serum Folate ◽  
Red Cell ◽  
B12 Deficiency ◽  
Grain Products

Abstract In the past, before immunological tests for celiac disease became available, many authors advocated the use of red cell folate (RFA) as a screening test for celiac disease. That is, if the red cell folate were normal, then celiac disease was considered very unlikely. Low red cell folate was found in all 24 cases of celiac disease reported by Hoffbrand et al (J Clin Pathol1966;19:17–28). Since Patients with celiac disease and tropical sprue absorb the folic acid used in the fortification of grain products much better than folate polyglutamates present in food, I decided to investigate whether serum or red cell folate is still useful for screening malabsorption syndrome. Methods: Serum folate (SFA) and red cell folate at St. Boniface General Hospital (SBGH) were determined by L. Casei microbilogical assay. During the 30-month period of July 1,1999 – Dec 31, 2001, the search of Laboratory Information System (LIS) at SBGH, revealed 29 patients with strong laboratory evidence of celiac disease (strongly positive gliadin antibody with positive endomysial and or t-transglutaminase antibodies) who also had SFA or RFA results. LIS was searched for the results of complete blood count (CBC), SFA, RFA, serum ferritin (SFer) and serum B12 (SB12). Results: Five out of 29 patients (17.2%) with laboratory evidence of celiac disease had low SFA. Of these 5 patients with low SFA, 4 also had RFA. Only one of these 4 with low SFA had a low RFA. Eleven of the 29 patients also had RFA and only 2 of these 11 (18%) had low RFA. One of the two with low RFA had a normal SFA; and the other had a low SFA, a low SB12 and a low SFer. Twelve of 29 (41.3%) with celiac disease had low SFer and 6 of 29 (20.6%) had low SB12. Four out of 29 (13.8%) had high mean corpuscular volume (MCV)(&gt; 98 fL). All of the four with high MCV had normal RFA, but had low SB12, indicating that macrocytosis in these 4 cases was due to B12 deficiency. Ten out of 12 with low serum ferritin had low MCV (&lt;80 fL). Discussion: The mandated fortification of grain products in USA and Canada (0.14 mg of folic acid per 100 g of grain) was estimated to add about 0.1 mg of folic acid to the daily folate intake of the average adult. However, some studies have shown that the actual increase in daily folate intake, through folic acid fortification, is about 0.2 mg (J Nutr2002;132:2792–8 and Am J Clin Nutr2003;77:221–5). Patients with celiac disease or tropical sprue can absorb this folic acid much better than the folate polyglutamates present in food. Sheehy et al (Blood1961;18:623–36) have demonstrated that many patients with tropical sprue who had developed folate deficiency megaloblastic anemia, despite consuming more than 1 mg of food folates daily, responded to as little as 0.025 mg of folic acid daily. It is for this reason than most of our celiac patients had normal serum folate but were either iron deficient or B12 deficient. In the past, B12 deficiency was considered to be uncommon in untreated adults with celiac disease. Conclusion: As the result of fortification of grain products with folic acid, red cell folate is no longer a useful test as a screening test for malabsorption syndrome. Now, as our data demonstrate, B12 deficiency is more common than folate deficiency in adults with untreated celiac disease. A patient with celiac disease and macrocytic anemia is more likely to be B12 deficient than folate deficient.

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