No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Homocysteine and Folate Levels as Risk Factors for Recurrent Early Pregnancy Loss
Abstract
Objective: To estimate the relative risk of recurrent early pregnancy loss for different total plasma homocysteine and serum folate concentrations.
Methods: In a case-control study, we measured homocysteine (fasting and afterload), folate (serum and red cells), pyridoxal 5′-phosphate, and cobalamin concentrations in 123 women who had at least two consecutive spontaneous early pregnancy losses each and compared concentrations with those of 104 healthy controls.
Results: Women with recurrent early pregnancy losses had significantly lower serum folate concentrations than controls, whereas the other measurements were similar to those of controls. Elevated homocysteine, fasting greater than 18.3 μmol/L and afterload greater than 61.5 μmol/L, was a risk factor for recurrent early pregnancy loss, with odds ratios (ORs) and 95% confidence intervals (95% CIs) of 3.6 (1.2, 12.7) and 2.7 (0.9, 8.8) in the group with recurrent miscarriages: 6.4 (1.9, 24.3) and 4.3 (1.2, 17.3) in primary aborters, and 4.2 (1.3, 15.4) and 3.4 (1.0, 12.8) in those with three or more miscarriages. The ORs (95% CIs) in the same study populations for serum folate concentrations less than 8.4 nmol/L were 2.1 (0.9, 4.8), 2.7 (1.0, 7.8), and 3.2 (1.3, 8.1), respectively. A significant dose-response relationship between serum folate concentrations and risk of recurrent early pregnancy loss suggested a protective effect by high serum folate concentrations.
Conclusion: Elevated homocysteine and reduced serum folate concentrations were risk factors for recurrent spontaneous early pregnancy losses. Folic acid supplementation might be beneficial in women with histories of early pregnancy loss.
After observing the induction of fetal death by the folic acid antagonist 4-aminopteroylglutamic acid in 1952, Thiersch1 suggested that spontaneous abortions might be caused by folic acid deficiency. The first studies that investigated the relationship between folate deficiency and early pregnancy loss were published in the following decades.2-6 The consistent conclusion was that disturbed formino glutamic acid excretion tests or low folate concentrations might identify women predisposed to spontaneous abortion. More recent reports did not find lower folate concentrations,7,8 but they investigated folate concentrations in those women after, not during, their pregnancies. In several reports, other sensitive markers of dysfunctional folate metabolism appeared to be related to recurrent early pregnancy loss, one of which was elevated plasma total homocysteine concentration.7,9-11
Homocysteine is a demethylated derivative of methionine, and B vitamins are needed for its efficient metabolism. Folate and cobalamin (vitamin B12) are involved in homocysteine remethylation, and pyridoxal 5′-phosphate (the active form of vitamin B6) in homocysteine transsulfuration. Elevated homocysteine can occur in cases of dietary or genetic vitamin deficiency, or reduced enzyme activities. In a preliminary study in 1992, Steegers-Theunissen et al9 first suggested the relationship between recurrent early pregnancy loss and elevated homocysteine concentrations. Recently, others7,10,11 have confirmed that association.
The definition of hyperhomocysteinemia, whether or not fasting or afterload homocysteine concentrations were incorporated, influenced the percentage of hyperhomocysteinemia in cases and controls. A dose-response effect for homocysteine concentrations was noted in cardiovascular disease,12,13 so it would be more appropriate to estimate the relative risk (RR) for recurrent early pregnancy loss at different cutoff levels, and for fasting and afterload homocysteine, separately. Therefore, we did a case-control study to estimate the RR of recurrent early pregnancy loss for different homocysteine and folate concentrations.
... Higher concentrations of homocysteine result in a clinical condition of hyperhomocysteinemia (#100 μmol/L) or homocystinuria (B500 μmol/L) (Medina et al., 2001). Physiological conditions shown that hyperhomocysteinemia is associated with folate and cobalamine deficiencies and might lead to early pregnancy loss, mental disorders, and tumors (Nelan et al., 2000). Furthermore, increased homocysteine concentration is also associated with an increased risk of coronary artery and cerebrovascular diseases, including atherosclerosis and thrombosis (Nelan et al., 2000). ...
... Physiological conditions shown that hyperhomocysteinemia is associated with folate and cobalamine deficiencies and might lead to early pregnancy loss, mental disorders, and tumors (Nelan et al., 2000). Furthermore, increased homocysteine concentration is also associated with an increased risk of coronary artery and cerebrovascular diseases, including atherosclerosis and thrombosis (Nelan et al., 2000). It is known that ascorbic acid is the coexistent component with homocysteine in biological fluids, but its concentration is relatively very much higher than homocysteine and is one of the main interferents for the determination of homocysteine. ...
... (52) HHcy may cause damage to endothelial cells, and therefore it may also cause the damage the blood vessels of the placenta, leading to pregnancy losses. Nelen et al. (53) has found that an increase in fasting Hcy (≥18.3 mmol/L) and Hcy after exercise (≥61.5 mmol/L) were associated with RPL. Methylenetetrahydrofolate reductase (MTHFR) gene mutation is related to elevated total homocysteine (tHct) expressions, in particular, among women with low folate intake. ...
Objective
26% of all pregnancies end in miscarriage, and up to 10% of clinically diagnosed pregnancies, and recurrent pregnancy loss is 5% among couples of childbearing ages. Although there are several known causes of pregnancy loss in the first half, including recurrent pregnancy loss, including parental chromosomal abnormalities, uterine malformations, endocrinological disorders, and immunological abnormalities, about half of the cases of pregnancy loss in its first half remain unexplained.
Methods
The review includes observational controlled studies (case-control or cohort, longitudinal studies, reviews, meta-analyses), which include the study of biochemical factors for predicting pregnancy losses in the first half, in singlet pregnancy. The Newcastle-Ottawa Scale (NOS) was used to assess the research quality.
Results
Finally, 27 studies were included in the review, which has 134904 examined patients. The results of the review include estimates of β-human chorionic gonadotropin, progesterone, pregnancy-associated protein – A, angiogenic vascular factors, estradiol, α-fetoprotein, homocysteine and CA-125 as a predictors or markers of the first half pregnancy losses.
Conclusion
It may be concluded that to date, research data indicate the unavailability of any reliable biochemical marker for predicting pregnancy losses in its first half and require either a combination of them or comparison with clinical evidence. A fairly new model shall be considered for the assessment of α-fetoprotein in vaginal blood, which may have great prospects in predicting spontaneous miscarriages.
... Uno de los hallazgos más trascendentes de este estudio fue que casi la mitad de las embarazadas enroladas presentara niveles de folato y vitamina B12 por debajo de los valores de referencia. Esto coincide con un estudio anterior (29) que incluyó 52 embarazadas del primer trimestre pero utilizando como punto de corte < 4,0 ng/mL (34% vs. 32 % [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38]). ...
The study of biochemical markers in pregnant women allows for the early diagnosis of pregnancy pathologies and for the prevention or lessening of those affecting their children. The objective was the description of hemoglobin, hematocrit, serum iron, serum ferritin, reticulocytes, total protein, albumin, Ca, P, Mg, alkaline phosphatase, total cholesterol, HDL-cholesterol, serum folate, and B12 vitamin values in 314 pregnant women before the 16 th gestational week (between 2000 and 2002). Exclusion criteria were multiple pregnancies, major congenital anomalies and Rh isoimmunization disease. Biochemical techniques were applied according to international standards with previous informed consent, with internal and external quality controls. 14% of pregnant women were anemic and 39% had no iron stores; only 24% reaching a proper reticulocyte response. Besides 33% had low protein levels, 20.5% low albumin levels and 61.4% low calcium levels, meanwhile near half of them did not reach minimal levels of serum folate or B12 vitamin. These results could have a deleterious influence over fetal growth, higher incidence of preterm delivery and less iron stores in newborn. Preconceptional interventions are proposed, such as intake of food with iron and folate enrichment and iron supplement during pregnancy.
... Furthermore, Hcy and related B-vitamins like vitamin B12 and folate have been shown to play a crucial role in foetal nutrition, growth and development (Hoet and Hanson 1999;Molloy et al. 2009). It has been found that high total Hcy and low B-vitamin concentrations are associated with birth defects and common pregnancy complications, such as preeclampsia and recurrent early pregnancy loss (Aubard et al. 2000;Nelen et al. 2000;Vollset et al. 2000;Refsum 2001). Recently, the imbalance between the two vitamins (vitamin B12 and folate) has been one of the main areas of interest by researchers furthering understanding of the effect of these vitamins on human health. ...
The most extremely unfavourable outcome of pregnancy is the death of the mother and newborn. Negative outcomes for mothers or babies can occur as a result of complications or issues during pregnancy, birth or the post-partum period. Early elevated maternal homocysteine (Hct) levels during pregnancy have been linked to altered placental development. There is evidence that suggests an elevated maternal blood Hct level is the new obstetrical risk factor, and the association between hyperhomocysteinemia (HHct) and numerous obstetrical problems was recently recognised.
Hct is an essential amino acid, which contains sulphur and is formed from the metabolism of methionine. HHct has several known aetiologies, including genetic anomalies; a deficiency in folic acid, vitamin B6 and vitamin B12; hypothyroidism; old age; and renal illnesses. Vascular problems, coronary artery disease, atherosclerosis and embolic illnesses can all occur as a result of high blood levels of Hct. Hct levels are lower in normal pregnancies than it is in women who are not pregnant. Many pregnancy-related problems, including pre-eclampsia (PE), recurrent pregnancy loss (RPL), placental abruption, premature delivery and foetal growth restriction (FGR) have been connected to HHct in recent research.
We looked for pertinent literature using a thorough and systematic search from PubMed, Medline, Embase, Cochrane Library, Google, etc., and articles that were published before August 2022 based on serum Hct levels and various placenta-mediated complications for this review.
In this review, we described the synthesis and metabolism of Hct in humans, Hct levels at various phases of normal pregnancy and the association between Hct and placenta-mediated pregnancy complications.
The outcomes discovered can help obstetricians increase the likelihood of a successful pregnancy in cases where placenta-mediated issues are present. Lowering Hct levels with a high dose of folic acid tablets during the subsequent pregnancy may be useful for women who experienced these difficulties in prior pregnancies as a result of HHct.
Triclosan (TCS) is a broad-spectrum antibacterial agent and widely exists in environmental media and organisms. TCS exposure was reported to have adverse effects on reproduction including embryo implantation disorder. During the embryo implantation window, it is vital that the endometrium develops into a receptive state under the influence of ovarian hormones. However, the effect of TCS on embryo implantation and endometrial receptivity remains unclear. In current study, we found decreased embryo implantation rate, serum estrogen (E2) and progesterone (P4) levels in mice exposed to TCS from gestation day (GD) 0.5 to 5.5. Through RNA-seq, we identified nearly 800 differentially expressed genes (DEGs), which were enriched in pathways including uterus development, inflammatory response and immune system process. Among those enriched pathways, the tight junction pathway is essential for the establishment of receptive state of endometrium. Then, genes involved in tight junction pathway including Cldn7, Cldn10 and Crb3 were validated by RT-qPCR and the results were consistent with the RNA-seq. Through immunofluorescence staining and western blotting, we confirmed that the tight junction protein levels of CLDN7 and CRB3 were increased. All these findings suggest that pre-implantation TCS exposure reduces the rate of embryo implantation through up-regulating the expression of tight junction genes and affecting the receptivity of endometrium. Our data could be used to determine the sensitive time frame for TCS exposure and offer new strategy to prevent implantation failure.
Introduction:
Proper nutrition during pregnancy is important to prevent nutritional imbalances that interfere with pregnancy. Micronutrients play critical roles in embryogenesis, fetal growth, and maternal health, as energy, protein, vitamin, and mineral needs can increase during pregnancy. Increased needs can be met by increasing the intake of dietary micronutrients. Severe micronutrient deficiency or excess during pregnancy can have negative effects on fetal growth (intrauterine growth retardation, low birth weight, or congenital malformations) and pregnancy development (pre-eclampsia or gestational diabetes). We investigate whether it is necessary to continue micronutrient supplementation during pregnancy to improve women's health in this stage and whether this supplementation could prevent and control pathologies associated with pregnancy.
Aim:
The present review aims to summarize evidence on the effects of nutritional deficiencies on maternal and newborn morbidity.
Methods:
This aim is addressed by critically reviewing results from published studies on supplementation with different nutrients during pregnancy. For this, major scientific databases, scientific texts, and official webpages have been consulted. PubMed searches using the terms "pregnancy" OR "maternal-fetal health" AND "vitamins" OR "minerals" OR "supplementation" AND "requirement" OR "deficiency nutrients" were performed.
Results:
There are accepted interventions during pregnancy, such as folic acid supplementation to prevent congenital neural tube defects, potassium iodide supplementation to correct neurodevelopment, and oral iron supplementation during the second half of pregnancy to reduce the risk of maternal anemia and iron deficiency. A number of micronutrients have also been associated with pre-eclampsia, gestational diabetes mellitus, and nausea and vomiting in pregnancy. In general, experimental studies are necessary to demonstrate the benefits of supplementation with different micronutrients and to adjust the recommended daily doses and the recommended periconceptional nutrition for mothers.
Conclusions:
Presently, there is evidence of the benefits of micronutrient supplementation in perinatal results, but indiscriminate use is discouraged due to the fact that the side effects of excessive doses are not known. Evidence supports the idea that micronutrient deficiencies negatively affect maternal health and the outcome of pregnancy. No single micronutrient is responsible for the adverse effects; thus, supplementing or correcting one deficiency will not be very effective while other deficiencies exist.
Resumen
Los abortos espontáneos recurrentes (AER) se definen por la existencia de al menos tres pérdidas embriofetales antes de las 24 semanas de amenorrea. Afectan aproximadamente al 1-2% de las parejas fértiles. Existen múltiples etiologías; sin embargo, en el 50% de los casos no se encuentra ninguna causa. La clasificación de las causas de los abortos espontáneos recurrentes es esencial para comprender los mecanismos fisiopatológicos, efectuar las exploraciones y decidir el tratamiento. Las anomalías uterinas, las anomalías cromosómicas y genéticas, las perturbaciones hormonales o metabólicas, las causas infecciosas, las trombofilias hereditarias o adquiridas, las anomalías inmunológicas, las causas masculinas y los factores ambientales son los principales factores responsables de AER.
BACKGROUND: Uric acid (UA) and homocysteine (HCys) are involved in cardiovascular diseases. Patients with obesity (PwO) are characterized by elevated cardiovascular risk. OBJECTIVE: To evaluate the relationship between HCys and UA concentrations in 1141 overweight patients and PwO with and without metabolic syndrome (MS). METHODS: MS was defined according to IDF criteria (2005). Anthropometric data were recorded and blood biochemical parameters were assessed with routine methods on fasting blood samples. Statistics: Spearman correlation and multiple regression analysis. RESULTS: Gender, obesity and MS influenced both UA and HCys levels, which were increased in males, MS patients, PwO with MS and positively correlated (p < 0.001). Patients without MS had normal or slightly high levels. Hypertension, hyperuricemia and hyperhomocysteinemia were found in PwO with MS. UA concentration correlated with systolic blood pressure, triglycerides and HDL (all p < 0.05). Multivariate analysis showed that HCys concentration was an independent determinant factor affecting UA levels (T value 3.5, p < 0.001). CONCLUSIONS: HCys and UA levels positively and significantly correlated in PwO, especially in those with MS. The significant correlation between UA and hypertension, triglycerides, HDL suggests the clinical usefulness of monitoring UA together with HCys concentrations as cardiovascular risk marker in these patients.
Infertility is an increasing problem that affects couples attempting pregnancy. A growing body of evidence points to a link between diet and female fertility. In fact, data show that a diet high in trans fats, refined carbohydrates, and added sugars can negatively affect fertility. Conversely, a diet based on the Mediterranean dietary patterns, i.e., rich in dietary fiber, omega-3 (ɷ-3) fatty acids, plant-based protein, and vitamins and minerals, has a positive impact on female fertility. An unhealthy diet can disrupt microbiota composition, and it is worth investigating whether the composition of the gut microbiota correlates with the frequency of infertility. There is a lack of evidence to exclude gluten from the diet of every woman trying to become pregnant in the absence of celiac disease. Furthermore, there are no data concerning adverse effects of alcohol on female fertility, and caffeine consumption in the recommended amounts also does not seem to affect fertility. On the other hand, phytoestrogens presumably have a positive influence on female fertility. Nevertheless, there are many unanswered questions with regard to supplementation in order to enhance fertility. It has been established that women of childbearing age should supplement folic acid. Moreover, most people experience vitamin D and iodine deficiency; thus, it is vital to control their blood concentrations and consider supplementation if necessary. Therefore, since diet and lifestyle seem to be significant factors influencing fertility, it is valid to expand knowledge in this area.
One-carbon metabolism is crucial for the maintenance of healthy pregnancy and alterations in this pathway have been associated with various pregnancy-related complications. Therefore, the present study was conducted to test the hypothesis that the altered folic acid, vitamin B12 and homocysteine levels are associated with the risk of early pregnancy loss (EPL). Plasma folic acid, vitamin B12 and homocysteine levels were analyzed in 83 females with EPL and 70 healthy pregnant females in their first trimester. Further, meta-analyses of folic acid, vitamin B12 and homocysteine were also performed involving various eligible studies. Results from our case-control study and meta-analyses showed that folic acid deficiency is not associated with the risk of EPL. On the other hand, low vitamin B12 and hyperhomocysteinemia were individually found to be significant risk factors for EPL in the present study (p<0.001, P<0.05, respectively) and meta-analysis as well (p<0.001, P<0.01, respectively). Vitamin B12 deficiency in combination with hyperhomocysteinemia was a more serious risk factor for EPL (Odds Ratio = 4.98, P <0.002). Therefore we conclude that vitamin B12 deficiency and elevated homocysteine levels are independent risk factors for EPL, and even riskier in combination. The assessment of vitamin B12 and homocysteine levels may serve as a good screening marker for EPL risk.
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.
Threatened miscarriage is one of the most common complications causing pregnancy loss, and it affects approximately 20% of confirmed pregnancies. More and more women are seeking treatment with complementary and alternative medicine (CAM) for this common complication, and it has been reported that women have had successful pregnancies after threatened miscarriage when being treated with CAM, which mainly includes Chinese herbal medicines, acupuncture, and nutritional supplements as well as psychological interventions and other approaches. However, many experts are concerned about the safety and adverse events of certain CAM approaches in women with threatened miscarriage. Therefore, this review focuses on the status of CAM for threatened miscarriage and presents the potential therapeutic efficacy and safety of CAM based on some clinical and experimental studies. We thus hope to provide some instructive suggestions for the application of CAM for treating threatened miscarriage in the future.
Research Question
Are there genetic determinants shared by unrelated women with unexplained recurrent early miscarriage (REM)?
Design
We selected 30 REM cases and 30 controls with extreme-phenotype among women from eastern Brittany (France), previously enrolled in an incident case-control study on thrombophilic mutations. Cases and controls were selected based on the number of early miscarriages or live-births, respectively. Peripheral blood was collected for DNA extraction at initial visit. We compared the burden of low frequency variants in the coding part of the genes using Whole Exome Sequencing (WES).
Result(s)
Cases had 3 to 17 early miscarriages (20 cases: ≥5 previous losses). Controls had 1 to 4 live births (20 controls: ≥3 previous live births) and not any miscarriage. WES data were available for 29 cases and 30 controls. A total of 209,387 variants were found (mean variant per patient: 59,073.05) with no difference between groups (P =0.68). The top 5 most significantly associated genes were ABCA4, NFAM1, TCN2, AL078585.1 and EPS15. Previous studies suggest the involvement of vitamin B12 deficiency in REM. TCN2 encodes for vitamin B12 transporter into cells. Therefore, holotranscobalamin (active vitamin B12) was measured for both cases and controls (81.2±32.1 vs. 92.9±34.3 pmole/L, respectively, P=0.186). Five cases but no control were below 50 pmole/L, (P=0.052).
Conclusion(s)
Our study highlights 4 new genes of interest in REM, some of which belong to known networks of genes involved in embryonic development (clathrin-mediated endocytosis and ciliary pathway). Additionally, our study confirms the involvement of TCN2 (vitamin B12 pathway) in the early first trimester of pregnancy.
Study question:
Is there any relationship between vitamin D [25 (OH) vitamin D], total plasma homocysteine and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in women with recurrent pregnancy losses (RPL)?
Summary answer:
Women with MTHFR 677TT (homozygous mutation, TT) genotype have significantly lower vitamin D levels, higher homocysteine and natural killer (NK) cell cytotoxicities than those of women with MTHFR 677CC (wild type, CC) and 677CT (heterozygous mutation, CT) genotypes.
What is known already:
Vitamin D insufficiency, MTHFR C677T polymorphism and hyperhomocysteinemia have been reported as risk factors for RPL. However, the relationship between these risk factors is not known in this population.
Study design, size, duration:
This is a retrospective cross-sectional study, including 837 women with RPL, who were enrolled in Reproductive Medicine and Immunology, Chicago Medical School, between 2012 and 2017.
Participants/materials, setting, methods:
Women with two or more RPL prior to 20 weeks of gestation were included. To investigate whether the MTHFR C677T polymorphism affects the levels of homocysteine and vitamin D as well as immune parameters in women with RPL, biochemical data, such as plasma total homocysteine and serum vitamin D levels, and immune parameters, including NK cell cytotoxicity, were analyzed by MTHFR C677T genotype (CC, CT and TT).
Main results and the role of chance:
The serum level of vitamin D in TT was significantly lower when compared with those of CT (P = 0.001) and CC (P = 0.003), while the level of homocysteine in TT was significantly higher than those in CT (P = 0.01) and CC (P = 0.01). NK cytotoxicity in TT was significantly higher than that of CC (P = 0.04) but not CT (P = 0.09). There was a significant negative correlation between the levels of vitamin D and homocysteine in TT (r = -0.357, P < 0.01). In multivariate analysis, vitamin D insufficiency (<30 ng/ml) was an independent risk factor for hyperhomocysteinemia (adjusted odds ratio 1.89, 95% CI 1.41-2.52).
Limitations, reasons for caution:
The study was retrospective and included only women with RPL but not healthy fertile controls. In addition, folic acid, vitamin B6 and B12 intake, which could modify the level of homocysteine and vitamin D, were not investigated. Thus, a considerable part of women might have folic acid and vitamin D supplementation and prenatal vitamin pills, and there are probable confounders in this study associated with unrestricted vitamin supplementation. Therefore, the findings should be carefully interpreted and applied to RPL women with MTHFR gene polymorphism.
Wider implications of the findings:
The findings attained in this analysis regarding the MTHFR polymorphism and its relationship with vitamin D, homocysteine and NK cytotoxicity may aid in uncovering the underlying etiology and mechanism for RPL. The study highlights an interplay between nutrition and immune responses in RPL.
Study funding/competing interest(s):
No external funding was received for this study. None of the authors have any conflict of interest to declare.
Trial registration number:
N/A.
Background: Methylenetetrahydrofolate reductase (MTHFR) has a key role in converting homocysteine to methionine so its deficiency might cause homocysteine accumulation and arterial destruction. The aim of this study was to evaluate the activity of methylenetetrahydrofolate reductase (MTHFR), homocysteine, and MDA levels in preeclampsia patients.
Material and Methods: In this case–control study, 30 preeclampsia patients and 30 healthy pregnant women as control group were selected and matched for maternal age, gestational age, and BMI. Preeclampsia was confirmed by examining hypertension and urinary proteinuria. Serum homocysteine and MDA level as well as MTHFR activity were measured manually.
Results: Homocysteine and MDA levels were significantly different between women with preeclampsia and normal pregnancies (p-value <0.001). Also, the results indicate that MTHFR activity in the two groups was statistically different (p-value <0.001).
Conclusion: It can be concluded that the regulation of homocysteine and its metabolic enzymes plays a significant role in controlling blood pressure and consequently in the pathophysiology of Preeclampsia and it can be a goal for prevention and treatments.
Poor ovarian response (POR1) limits the success of infertility treatment modality. In this study, we aim to investigate if POR is associated with serum 25(OH) vitamin D (VD2) levels and pro-inflammatory immune responses in infertile women with a history of in-vitro fertilization and embryo transfer failures. A retrospective cross-sectional study included 157 women with IVF failures. Study patients were divided into four groups based on serum 25(OH)VD level and ovarian responses during the most recent IVF cycle; low VD (LVD3) with POR, LVD with normal ovarian response (NOR4), normal VD (NVD5) with POR, and NVD with NOR. Serum 25(OH)VD level, cellular- and auto-immunity, and metabolic parameters, including homocysteine and plasminogen activator inhibitor-1 were investigated. Peripheral blood CD56+ NK cell levels (%) and NK cytotoxicity were significantly higher in POR-LVD when compared to the other groups (P < 0.05, respectively). CD19 + B and CD19+/5+ B-1 cell levels were significantly higher in women with POR-LVD as compared with those of NOR-LVD and POR-NVD (P < 0.05, respectively). TNF-α/IL-10 producing Th1/Th2 cell ratio of POR-LVD was significantly higher than those of POR-NVD and NOR-NVD (P < 0.05 respectively). Peripheral blood homocysteine level of POR-LVD was significantly higher than those of NOR-LVD and POR-NVD (P < 0.05 respectively). We conclude that assessment of cellular and autoimmune abnormalities and metabolic factors, such as homocysteine should be considered in women with POR and LVD. VD and folic acid supplementation may be explored further as a possible therapeutic option for POR with immune and metabolic etiologies.
Study question:
Does maternal periconceptional no folic acid supplementation have an increased risk of neural tube defects (NTDs) associated with previous spontaneous abortion or first-trimester fever?
Summary answer:
Maternal periconceptional no folic acid supplementation can increase the risk of NTDs associated with previous spontaneous abortion or first-trimester fever, independent of known confounding factors.
What is known already:
Maternal periconceptional folic acid deficiency can increase the risk of NTDs. However, whether an interaction between periconceptional no folic acid supplementation and history of spontaneous abortion or first-trimester fever may have an increased risk of NTDs remains unknown.
Study design, size, duration:
A population-based case-control study was performed including 104 nuclear families with offspring with NTDs and 100 control families with normal offspring between 1993 and 2002.
Participants/materials, setting, methods:
We investigated the potential interaction between periconceptional no folic acid use and a maternal history of spontaneous abortion or first-trimester fever in the risk for NTDs. Information on exposure factors was obtained at the onset of pregnancy, and pregnancy outcomes were collected during the first week after delivery or at the time of termination of the pregnancy. A multivariate logistic regression analysis was performed.
Main results and the role of chance:
The interaction between periconceptional no folic acid use and a maternal history of spontaneous abortion markedly increased the risk of NTDs (adjusted odds ratio (aOR) 18.68, 95% CI, 4.43-78.76) after adjusting for potential confounding factors. The interaction coefficient was found to be 2.08, higher than 1, indicating that there is a significant interaction between two factors. Mothers who did not take periconceptional folic acid and had first-trimester fever had an increased risk of NTDs (aOR 21.81, 95% CI, 8.81-80.73). However, the interaction coefficient was found to be 0.62, less than 1, indicating that there is no significant interaction between two factors.
Limitations, reasons for caution:
A potential limitation was that the interval between the previous spontaneous abortion and the beginning of the subsequent pregnancy could not be estimated accurately, but was at least 1 year or more.
Wider implications of the findings:
We emphasize that a previous spontaneous abortion may represent a first occurrence of NTDs rather than be the cause of NTDs. Our findings indicate that mothers with a history of spontaneous abortion are ideal candidates for periconceptional folic acid supplementation.
Study funding/competing interest(s):
This work was supported by National Natural Science Foundation of China (41871360) and Danone Nutrition Center for Dietary Nutrition Research and Education Foundation (DIC2015-05). There are no competing interests to declare.
Background:
Most studies of folate metabolism and reproduction have been conducted after pregnancy and in folate-deficient populations. However, measurement of maternal folate status preconceptionally may be most relevant to certain folate-linked early processes preceding a successful pregnancy, and there has been a major increase in folate concentrations in women of childbearing age in high resource settings.
Objective:
To examine associations between preconceptional biomarkers of maternal folate status (folate and homocysteine) and reproductive outcomes in folate-replete women.
Study design:
Cohort nested within the Effects of Aspirin in Gestation and Reproduction trial, a block-randomized, double-blind, placebo-controlled trial whereby women were randomized to daily low-dose aspirin (81 mg/day) or placebo and all women received folic acid (400 μg/day). In total, 1228 women with 1-2 previous pregnancy losses and no documented infertility were recruited from 4 clinical sites in the United States (2006-2012) and were attempting pregnancy for up to 6 menstrual cycles. Log-binomial regression models were used to estimate relative risks and 95% confidence intervals between preconception serum folate and plasma homocysteine for anovulation, pregnancy, and pregnancy loss.
Results:
Greater plasma homocysteine was nonlinearly associated with greater risks of pregnancy loss only among women with 2 previous losses: a relative risk of 1.43 (95% confidence interval, 1.08-1.89) was found for plasma homocysteine concentrations at the study median of 8.0 μmol/L compared with a US population median of 6.0 μmol/L. No meaningful relationships were found between serum folate and any reproductive outcome or between plasma homocysteine and anovulation or becoming pregnant.
Conclusion:
These data justify further study of the role of folate and homocysteine metabolism in normal and abnormal early pregnancy.
Cooking with kerosene emits toxic pollutants that may impact pregnancy outcomes. Sixty-eight women in their first trimester of pregnancy, kerosene users (n = 42) and liquefied natural gas (LNG) users (n = 26), were followed until birth. Maternal and cord blood were collected immediately after birth. Levels of micronutrients and heavy metals were quantified. Pregnancy outcomes (gestation age (GA), birth weight (BW), and chest and head circumference) were also measured. Mean (± standard deviation (SD)) age of mothers in kerosene and LNG groups were similar (p = 0.734). Mean (±SD) BW of newborns of LNG users was significantly higher compared to newborns of kerosene users (3.43 ± 0.32 vs. 3.02 ± 0.43, p < 0.001). Mean GA (in weeks) was similar between the two groups (p = 0.532). Women in the kerosene group had significantly higher cord blood levels of zinc, lead, mercury, iodine and vitamin B6 and lower levels of folic acid compared to LNG users (p < 0.05). Newborns of kerosene users had reduced levels of zinc, lead, mercury, iodine, vitamins B6 and B12, folic acid, and homocysteine compared with LNG users (p < 0.05). Also, cooking with kerosene was significantly associated with reduced birth weight after adjusting for potential confounders (β ± standard error (SE) = −0.326 ± 0.155; p = 0.040). Smoke from kerosene stove was associated with reduced birth weight and micronutrients imbalance in mothers and newborns.
Background
Enhancer RNAs (eRNAs) are a group of lncRNAs transcribed from enhancers, whose regulatory effects on gene expression are an emerging area of interest. However, the role of eRNAs in regulating trophoblast cells and unexplained recurrent pregnancy loss (URPL) remains elusive.
Methods
We profiled eRNAs in villi from URPL patients and matched controls by RNA-seq. Functions of URPL-related eRNAs were further investigated in vitro.
Results
We identified lnc-SLC4A1-1, which was transcribed from an active enhancer marked with H3K27ac and H3K4me1 and so-called eRNA, highly expressed in URPL patients. Gain-of-function experiments indicated that lnc-SLC4A1-1 facilitated trophoblast cell migration and apoptosis. Mechanistically, as an eRNA, lnc-SLC4A1-1 was retained in the nuclei and recruited transcription factor NF-κB to bind to CXCL8, resulting in increased H3K27ac in the CXCL8 promoter and subsequent elevation of CXCL8 expression. Activation of CXCL8 exacerbated inflammatory reactions in trophoblast cells by inducing TNF-α and IL-1β, which could be blocked by an antagonist of lnc-SLC4A1-1.
Interpretation
These findings indicate that an eRNA, lnc-SLC4A1-1, alters trophoblast function via activation of immune responses and by regulating the NF-κB/CXCL8 axis. Our study provides new insights in understanding lncRNA/eRNA function in pathological pregnancy, potentially informing on therapeutic strategies for URPL.
Fund
National Natural Science Foundation of China, Natural Science Foundation of Jiangsu Province, National Key Research and Development Program, the Priority Academic Program for the Development of Jiangsu Higher Education Institutions.
Over‐nutrition and its late consequences are a dominant theme in medicine today. In addition to the health hazards brought on by over‐nutrition, the medical community has recently accumulated a roster of health benefits with obesity, grouped under “obesity paradox”.
Throughout the world and throughout history until the 20th century, under‐nutrition was a dominant evolutionary force. Under‐nutrition brings with it a mix of benefits and detriments that are opposite to and continuous with those of over‐nutrition. This continuum yields J‐shaped or U‐shaped curves relating body mass index to mortality. The overweight have an elevated risk of dying in middle age of degenerative diseases while the underweight are at increased risk of premature death from infectious conditions.
Micronutrient deficiencies, major concerns of nutritional science in the 20th century, are being neglected. This “hidden hunger” is now surprisingly prevalent in all weight groups, even among the overweight. Because micronutrient replacement is safe, inexpensive, and predictably effective, it is now an exceptionally attractive target for therapy across the spectrum of weight and age. Nutrition‐related conditions worthy of special attention from caregivers include excess vitamin A, excess vitamin D and deficiency of magnesium.
Methods:
A total of 209 PTD cases {extremely preterm (n=22), very preterm (n=43) and moderately preterm (n=144)} and 194 term delivery cases were evaluated for TYMS 14946bp deletion and its association with preterm delivery, pregnancy outcome, baby birth weight and homocysteine estimation.
Results:
The results showed that the distribution of TYMS 14946bp del/del genotype significantly increased the risk of PTD [OR=2.801, p=0.002] and is associated with fetal death. The TYMS 6bp ins/del and 6bp del/del genotype was associated with low birth weight (LBW) compared to 6bp ins/ins genotype in both term and PTD groups, and in case of very (p=0.024) and moderately (p=0.045) sub-cohorts of PTD significantly. Elevated serum homocysteine levels were significantly associated with PTD (p<0.001) and fetal death (p=0.013); and was also found to significantly correlate with TYMS 14946bp del/del genotype in all the pregnancy cases (p=0.008). TYMS 6bp del/del genotype was associated with higher homocysteine levels compared to ins/ins (p=0.005) and ins/del (p=0.062) genotypes within the PTD group.
Conclusion:
The study provides crucial information regarding the importance of TYMS6bpdel/del genotype and associated hyperhomocysteinemia in susceptibility to PTD, fetal death and LBW; and thus indicating their prognostic significance of TYMS 6bp del/del genotype in PTD which is of clinical importance.
Dietary B vitamins play a key role in the regulation of plasma homocysteine, a potentially detrimental amino acid produced endogenously from methionine, when it becomes ≥10 μmol/L. Most lactovegetarian, ovolactovegetarian, and vegan diets are rich in the related B vitamins, with the exception of vitamin B12, which is low because it is only found in dietary animal products: this can result in homocysteine concentrations becoming elevated, which has been associated to a range of increased risk of chronic medical conditions, in particular with cardiovascular disease. This chapter takes a journey through the relationship between dietary B vitamin status of vegetarians, methionine intake, and concentrations of plasma total homocysteine (tHcy).
Pregnancies obtained by Assisted Reproductive Technologies are at higher risk of miscarriage than those obtained naturally. Previously, we reported impaired placental vascular development of in vitro produced (IVP) sheep embryos and defective DNA methylation in the placentae of those embryos. One reason behind these observed defects may be an impaired One Carbon Metabolism (OCM) The present study was performed to test the hypothesis that Cobalamin (Vitamin B12, an important OCM co-factor) supplementation during IVM corrects DNA methylation of IVP embryos and, consequently, ameliorates placental vasculogenesis. To this aim, embryos derived from oocytes matured with Cobalamin (B12 group) or without (negative control group, −CTR) were transferred to synchronized recipient sheep. At day 20 of pregnancy, collected embryos were morphologically evaluated while placentae were subjected to qPCR and histological analysis. The positive control group (+CTR) consisted of conceptuses obtained from naturally mated sheep. Results showed an increased fertilization rate in the B12 group vs –CTR (69.56% vs 57.91% respectively, P = 0.006) not associated with quantitative improvement in blastocyst and/or implantation rate (44.32% vs 36.67% respectively, P > 0.05). Moreover, Cobalamin supplementation during oocyte IVM ameliorated resulting conceptuses quality, in terms of placental vascularization (vessels' maturity and vasculogenetic factors' expression). The expression of DNA methyltransferases (DNMT1, DNMT3A and DNMT3B) was also improved in placentae from the B12 group. In conclusion, Cobalamin supplementation during oocyte IVM improves IVP embryo quality. These results suggest that Cobalamin should be included in standard IVM media.
Folic acid (FA) and iron are essential supplements during pregnancy. Similarly effects of vitamin B12 (B12) inadequacy and high folate and low B12 status, on pregnancy outcome are available. However there are no mandatory recommendations for B12. There are many forms of B12 viz. Cyanocobalamin (Cbl), Methylcobalamin (MeCbl), Adenosylcobalamin (AdCbl), and Hydroxycobalamin (HCbl) though there is limited consensus on which form has better efficacy. In the present study we have determined effect of various forms of B12 in the presence of two FA concentrations namely normal physiological (20 ng/mL; NPFA) and supra-physiological (2000 ng/mL; SPFA) concentration to mimic real time situation where FA is in excess due to supplementation. We assessed trophoblastic proliferation, viability, TNFα and EGFr mRNA expression, homocysteine, β-hCG and MDA levels. Trophoblastic viability was significantly suppressed at SPFA concentration and was restored by B12 treatment with Cbl, AdCbl and combination of MeCbl + AdCbl. The mRNA expressions of TNFα were up-regulated, while EGFr were down-regulated at SPFA concentrations, as validated by RT-PCR. Treatment with MeCbl + AdCbl significantly decreased homocysteine and MDA levels at SPFA concentrations. High levels of FA alone had a detrimental effect on placental health and functions as reflected by decreased viability, EGFr expression and increased TNFα expression, homocysteine and MDA levels. Combination of B12 active forms i.e. MeCbl + AdCbl was found to be most effective in neutralising excess folate effect in-vitro.
Cobalamin and folate are especially important for women of childbearing age due to their ubiquitous role in fetal growth and development. Population-based data on cobalamin and folate status are lacking from Nepal, where diets are mostly vegetarian. The objectives of the study were to investigate cobalamin and folate intake and status, and to explore associations with socio-demographics, anthropometrics, anemia, and dietary habits. Following a random selection of geographical clusters, we collected blood samples from 500 non-pregnant women and 24-h dietary recalls and food frequency questionnaires from a subsample of 379 women. Twenty percent of the women did not consume any food containing cobalamin during the days recalled, and in 72% nutritional cobalamin intake was <1 μg/day. Eighty-four percent of the women had cobalamin intake lower than the estimated average requirement (EAR) (<2 μg/day). In contrast, only 12% of the women had a folate intake less than 100 μg per day, whereas 62% had intake between 100 and 320 μg. Low plasma cobalamin (<150 pmol/L) was found in 42% of the women, most of whom (88%) also had elevated levels of methylmalonic acid. Our results indicated a high prevalence of nutritional cobalamin deficiency, while folate deficiency was uncommon.
Background:
Miscarriage is a common complication of pregnancy that can be caused by a wide range of factors. Poor dietary intake of vitamins has been associated with an increased risk of miscarriage, therefore supplementing women with vitamins either prior to or in early pregnancy may help prevent miscarriage.
Objectives:
The objectives of this review were to determine the effectiveness and safety of any vitamin supplementation, on the risk of spontaneous miscarriage.
Search methods:
We searched the Cochrane Pregnancy and Childbirth Group Trials Register (6 November 2015) and reference lists of retrieved studies.
Selection criteria:
All randomised and quasi-randomised trials comparing supplementation during pregnancy with one or more vitamins with either placebo, other vitamins, no vitamins or other interventions. We have included supplementation that started prior to conception, periconceptionally or in early pregnancy (less than 20 weeks' gestation).
Data collection and analysis:
Three review authors independently assessed trials for inclusion, extracted data and assessed trial quality. We assessed the quality of the evidence using the GRADE approach. The quality of evidence is included for numerical results of outcomes included in the 'Summary of findings' tables.
Main results:
We included a total of 40 trials (involving 276,820 women and 278,413 pregnancies) assessing supplementation with any vitamin(s) starting prior to 20 weeks' gestation and reporting at least one primary outcome that was eligible for the review. Eight trials were cluster-randomised and contributed data for 217,726 women and 219,267 pregnancies in total.Approximately half of the included trials were assessed to have a low risk of bias for both random sequence generation and adequate concealment of participants to treatment and control groups. Vitamin C supplementationThere was no difference in the risk of total fetal loss (risk ratio (RR) 1.14, 95% confidence interval (CI) 0.92 to 1.40, seven trials, 18,949 women; high-quality evidence); early or late miscarriage (RR 0.90, 95% CI 0.65 to 1.26, four trials, 13,346 women; moderate-quality evidence); stillbirth (RR 1.31, 95% CI 0.97 to 1.76, seven trials, 21,442 women; moderate-quality evidence) or adverse effects of vitamin supplementation (RR 1.16, 95% CI 0.39 to 3.41, one trial, 739 women; moderate-quality evidence) between women receiving vitamin C with vitamin E compared with placebo or no vitamin C groups. No clear differences were seen in the risk of total fetal loss or miscarriage between women receiving any other combination of vitamin C compared with placebo or no vitamin C groups. Vitamin A supplementationNo difference was found in the risk of total fetal loss (RR 1.01, 95% CI 0.61 to 1.66, three trials, 1640 women; low-quality evidence); early or late miscarriage (RR 0.86, 95% CI 0.46 to 1.62, two trials, 1397 women; low-quality evidence) or stillbirth (RR 1.29, 95% CI 0.57 to 2.91, three trials, 1640 women; low-quality evidence) between women receiving vitamin A plus iron and folate compared with placebo or no vitamin A groups. There was no evidence of differences in the risk of total fetal loss or miscarriage between women receiving any other combination of vitamin A compared with placebo or no vitamin A groups. Multivitamin supplementationThere was evidence of a decrease in the risk for stillbirth among women receiving multivitamins plus iron and folic acid compared iron and folate only groups (RR 0.92, 95% CI 0.85 to 0.99, 10 trials, 79,851 women; high-quality evidence). Although total fetal loss was lower in women who were given multivitamins without folic acid (RR 0.49, 95% CI 0.34 to 0.70, one trial, 907 women); and multivitamins with or without vitamin A (RR 0.60, 95% CI 0.39 to 0.92, one trial, 1074 women), these findings included one trial each with small numbers of women involved. Also, they include studies where the comparison groups included women receiving either vitamin A or placebo, and thus require caution in interpretation.We found no difference in the risk of total fetal loss (RR 0.96, 95% CI 0.93 to 1.00, 10 trials, 94,948 women; high-quality evidence) or early or late miscarriage (RR 0.98, 95% CI 0.94 to 1.03, 10 trials, 94,948 women; moderate-quality evidence) between women receiving multivitamins plus iron and folic acid compared with iron and folate only groups.There was no evidence of differences in the risk of total fetal loss or miscarriage between women receiving any other combination of multivitamins compared with placebo, folic acid or vitamin A groups. Folic acid supplementationThere was no evidence of any difference in the risk of total fetal loss, early or late miscarriage, stillbirth or congenital malformations between women supplemented with folic acid with or without multivitamins and/or iron compared with no folic acid groups. Antioxidant vitamins supplementationThere was no evidence of differences in early or late miscarriage between women given antioxidant compared with the low antioxidant group (RR 1.12, 95% CI 0.24 to 5.29, one trial, 110 women).
Authors' conclusions:
Taking any vitamin supplements prior to pregnancy or in early pregnancy does not prevent women experiencing miscarriage. However, evidence showed that women receiving multivitamins plus iron and folic acid had reduced risk for stillbirth. There is insufficient evidence to examine the effects of different combinations of vitamins on miscarriage and miscarriage-related outcomes.
Background:
To better understand the complex mechanisms of bone formation it is fundamental that genes central to signalling/regulatory pathways and matrix formation are identified. Cell systems were used to analyse genes differentially expressed during extracellular matrix mineralization and bhmt3, coding for a betaine-homocysteine S-methyltransferase, was shown to be down-regulated in mineralizing gilthead seabream cells.
Methods:
Levels and sites of bhmt3 expression were determined by qPCR and in situ hybridization throughout seabream development and in adult tissues. Transcriptional regulation of bhmt3 was assessed from the activity of promoter constructs controlling luciferase gene expression. Molecular phylogeny of vertebrate BHMT was determined from maximum likelihood analysis of available sequences.
Results:
bhmt3 transcript is abundant in calcified tissues and localized in cartilaginous structures undergoing endo/perichondral ossification. Promoter activity is regulated by transcription factors involved in bone and cartilage development, further demonstrating the central role of Bhmt3 in chondrogenesis and/or osteogenesis. Molecular phylogeny revealed the explosive diversity of bhmt genes in neoteleost fish, while tissue distribution of bhmt genes in seabream suggested that neoteleostean Bhmt may have undergone several steps of subfunctionalization.
Conclusions:
Data on bhmt3 gene expression and promoter activity evidences a novel function for betaine-homocysteine S-methyltransferase in bone and cartilage development, while phylogenetic analysis provides new insights into the evolution of vertebrate BHMTs and suggests that multiple gene duplication events occurred in neoteleost fish lineage.
General significance:
High and specific expression of Bhmt3 in gilthead seabream calcified tissues suggests that bone-specific betaine homocysteine methyltransferases could represent a suitable marker of chondral ossification.
Acquired and inherited thrombophilia are associated with recurrent pregnancy loss (RPL). Antithrombotic therapy could restore hemostatic balance and improve early placentation and gestational outcome. We evaluated the efficacy of enoxaparin adapted to the fertility program for prevention of pregnancy loss in 35 women (W) with early RPL and thrombophilia. Previous to the diagnosis of thrombophilla, they had had a total of 105 gestations of which 89 (85%) ended in early pregnancy loss. After diagnosis of thrombophilia, 35 subsequent pregnancies were treated with enoxaparin. In 5 cases assisted reproductive techniques were necessary to achieve pregnancy due to couple infertility. In 17 W who had had at least one preclinical pregnancy loss, enoxaparin (20 mg/d/sc) was started previous to conception and adapted to the fertility program. All the women continued with the gestational regime. Eighteen W with only clinical pregnancy loss started enoxaparin (20 mg twice per day sc) after biochemical pregnancy diagnosis. During gestations heparin dose was adjusted with anti Xa test, maintaining a range between 0.3 at 0.6 u/ml. With antithrombotic therapy, 30/35 (85%) of the pregnancies ended in live birth versus 16/105 (15%) of the pregnancies without treatment (p < 0.001). These results suggest that enoxaparin adapted to the fertility program can be effective in the prevention of preclinical and clinical abortion in women with thrombophilia.
Aims:
The genetics of folate metabolism is one of the most significant mechanisms influencing fetal growth and may underlie some cases of unexplained recurrent miscarriage. Reduced folate carrier 1 encoded by SLC19A1 gene is a transporter of folate. Folate deficiency and elevated levels of homocysteine could be disadvantageous for the female reproductive system health. Thus, the balance between homocysteine and folate status can be used to measure the risk of recurrent pregnancy loss.
Methods:
The purpose of this study was to determine the association between -43T>C, 80G>A, and 696C>T polymorphisms of the SLC19A1 gene in 147 women who had unexplained recurrent miscarriage in comparison with 150 healthy women. Amplification refractory mutation system-polymerase chain reaction was used to genotype the molecular polymorphisms of this gene.
Results:
The results indicated that the -43T>C single nucleotide of the SLC19A1 gene was significantly associated with a risk of recurrent miscarriage in Iranian women (p < 0.05). No significant association was observed for the other two polymorphisms. The haplotype frequency distribution of -43C/80G/696C, -;43C/80G/696T, -43C/80G, and 80G/696T was significantly different in patients than controls, which may represent a novel risk factor for idiopathic recurrent pregnancy loss.
Conclusions:
Polymorphisms and haplotypes of the SLC19A1 gene can be considered a risk factor for idiopathic recurrent pregnancy loss.
Based on animal studies, epidemiologic studies and intervention trials, maternal folic acid is known to be protective for neural tube defects (NTD), primarily spina bifida and anencephalus. To reduce the risk of NTD, the U.S. Food and Drug Administration mandated that all enriched cereal grain products be fortified with folic acid as of January 1998. Recent data demonstrate that this public health action is associated with increased folate blood levels among U.S. women of childbearing age and that the national rate of spina bifida has decreased by 20%. Rates of anencephaly appear not to have declined. Epidemiologic data on use of folate and folate antagonists have also implicated folic acid in prevention of other birth defects such as facial clefts and cardiac and limb defects. Dietary folic acid is likely to be inadequate for maximal protection against NTD. Because about half of pregnancies in the U.S. are unplanned, according to the March of Dimes, birth defect prevention includes a recommended daily dose of 400 A,g synthetic folic acid for women of childbearing age. Uniform compliance is estimated to decrease the incidence of NTD by up to 70%. This could reduce the overall incidence from 2 to 0.6 per 1000 pregnancies and prevent disease in similar to2000 babies per year in the U.S. Four thousand micrograms of folic acid per day is recommended for women with previous pregnancies affected by NTD.
Background:
Periconceptional supplementation with folic acid results in a significant reduction in the incidence of neural tube defects (NTDs). Nonetheless, NTDs remain a leading cause of perinatal morbidity and mortality worldwide, and the mechanism(s) by which folate exerts its protective effects are unknown. Homocysteine is an amino acid that accumulates under conditions of folate-deficiency, and is suggested as a risk factor for NTDs. One proposed mechanism of homocysteine toxicity is its accumulation into proteins in a process termed homocysteinylation.
Methods & results:
Herein, we used a folate-deficient diet in pregnant mice to demonstrate that there is: (i) a significant inverse correlation between maternal serum folate levels and serum homocysteine; (ii) a significant positive correlation between serum homocysteine levels and titers of autoantibodies against homocysteinylated protein; and (iii) a significant increase in congenital malformations and NTDs in mice deficient in serum folate. Furthermore, in mice administered the folate-deplete diet before conception, supplementation with folic acid during the gestational period completely rescued the embryos from congenital defects, and resulted in homocysteinylated protein titers at term that are comparable to that of mice administered a folate-replete diet throughout both the pre- and postconception period. These results demonstrate that a low-folate diet that induces NTDs also increases protein homocysteinylation and the subsequent generation of autoantibodies against homocysteinylated proteins.
Conclusion:
These data support the hypotheses that homocysteinylation results in neo-self antigen formation under conditions of maternal folate deficiency, and that this process is reversible with folic acid supplementation. Birth Defects Research (Part A), 2016. © 2016 Wiley Periodicals, Inc.
The C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene was implicated to be associated with thrombophilia due to its role in catalyzing the formation of 5-methylenetetrahydrofolate, a co-substrate for the conversion of homocysteine to methionine. Several case–control studies were investigated MTHFR C677T polymorphism as risk for recurrent pregnancy loss (RPL). These studies rendered contradictory results, some indicating that the polymorphism is associated with the risk of RPL whereas others concluded there is no association. To shed light on these inconclusive findings, a meta-analysis of all available studies published from Asian population relating the C677T polymorphism to the risk of RPL was conducted. The following electronic databases were searched without language restrictions: PubMed, Google Scholars, Elsevier and Springer Link up to December, 2015. Meta-analysis was performed using MetaAnalyst and Mix version 1.7. Meta-analysis results suggested that MTHFR C677T polymorphism contributed to the increased RPL risk in Asian population using all five genetic models (for T vs. C: OR 1.35, 95 % CI 1.09–1.68, p = 0.009; for TT + CT vs. CC: OR 1.44, 95 % CI 1.14–1.82, p = 0.006; for CT vs. CC: OR 1.39, 95 % CI 1.07–1.8, p = 0.01; for TT vs. CC: OR 1.79, 95 % CI 1.23.2.6, p = 0.007; for TT vs. CT + CC: OR 1.61, 95 % CI 1.02–2.56, p = 0.04). In conclusion, this meta-analysis demonstrates a strong association between the MTHFR C677T variant and RPL in Asian population and raising the importance of the use of folate in its treatment and prevention.
Hyperhomocysteinemia is a result of disturbed methionine metabolism. Mild and moderate forms are commonly caused by deficiency of folic acid and vitamins B12 and B6. Rare severe forms of hyperhomocysteinemia are due to homozygotic enzyme mutations. Hyperhomocysteinemia is an independent risk factor for the development of atherosclerotic vascular disease. Recent studies also indicate an association with preeclampsia, HELLP syndrome, recurrent early pregnancy loss, and congenital anomalies such as neural tube defects. Several studies of recurrent early pregnancy loss have documented an association with folic acid deficiency and hyperhomocysteinemia. Folic acid supplementation to prevent neural tube defects is recommended for women attempting to conceive (and during early pregnancy). The efficacy of folic acid supplementation and the results of animal studies support a role of homocysteine in the pathogenesis of neural tube defects. The pathogenesis of endothelial dysfunction in preeclampsia involves oxidative stress. Elevated levels of stable oxidation products and decreased levels of antioxidants are found in the preeclamptic placenta and maternal plasma. Homocysteine induces oxidative stress and is toxic to endothelial cells. Plasma homocysteine levels decrease during normal pregnancy. Several studies have reported increased plasma homocysteine levels in pregnancies complicated by preeclampsia, but this has been disputed. The increase of plasma homocysteine in preeclampsia is small and may result from disturbed renal function and alterations of methionine metabolism due to oxidative stress. Thus it is not clear whether hyperhomocysteinemia is involved in the etiology of preeclampsia.
Objective: To assess the relation between first trimester screening markers and maternal folic acid and vitamin B12 levels. Material and Method: A retrospective study was conducted with 49 women of any age with a singleton pregnancy between 11-14 weeks of gestation who were offered routine first trimester prenatal screening and whose folic acid and vitamin B12 levels were measured during their first visit for any reason and who gave birth between September 2004 to May 2007 in the university hospital. Any possible correlation between these elements and screening markers were assessed. Pregnancies with male and female fetuses were compared. Results: There were no patients with folic acid deficiency and in only 2 patients vitamin B12 level was low. Only one patient had an increased biochemical risk and all the patients gave birth to healthy babies. No significant correlation was found between assessed parameters when all patients were analyzed; however, when analysis was based on fetal gender it was found that maternal folic acid level was negatively correlated with PAPP-A levels in only pregnant women that gave birth to male fetuses (r: -0.376, p= 0.04). There was no significant difference in pregnancies with male and female fetuses with respect to assessed parameters. Conclusion: There is a significant negative correlation between folic acid and PAPP-A in pregnancies with a male fetus, but not in pregnancies with a female fetus. The underlying mechanism is not clear and further studies are needed.
Purpose:
To determine whether 5-methylenetetrahydrofolate (MTHF) is more effective than folic acid supplementation in treatment of recurrent abortion in different MTHFR gene C677T and A1298C polymorphisms.
Methods:
A randomized, double blind, placebo-controlled trial conducted April 2011-September 2014 in recurrent abortion clinics in Tehran, Iran. The participants were women with three or more idiopathic recurrent abortion, aged 20 to 45 years. Two hundred and twenty eligible women who consented to participate were randomly assigned to receive either folic acid or 5-MTHF according to the stratified blocked randomization by age and the number of previous abortions. Participants took daily 1 mg 5-methylentetrahydrofolate or 1 mg folic acid from at least 8 weeks before conception to the 20th week of the pregnancy. The primary outcome was ongoing pregnancy rate at 20th week of pregnancy, and the secondary outcomes were serum folate and homocysteine at the baseline, after 8 weeks, and at the gestational age of 4, 8, 12, and 20 weeks, MTHFR gene C677T and A1298C polymorphisms.
Results:
There was no significant difference in abortion rate between two groups. Serum folate increased significantly in both groups over time; these changes were significantly higher in the group receiving 5-MTHF than the group receiving folic acid (value = 2.39, p<00.1) and the result was the same by considering the time (value = 1.24, p<0.01). Plasma tHcys decreased significantly in both groups over time; however these changes were not significantly different between the groups (value = 0.01, p = 0.47).
Conclusion:
The results do not support any beneficial effect of 5-MTHF vs. folate supplementation in women with recurrent abortion with any MTHFR C677T and/or A1298C polymorphism.
Trial registration:
ClinicalTrials.gov NCT01976676.
Neben der Erkennung und Verhütung von Risikofaktoren ist eine frühe Diagnosestellung entscheidend für eine erfolgreiche Behandlung der Osteoporose. So selbstverständlich wie wir heute eine Krebsvorsorge durchführen, so wichtig ist es, zuverlässige Informationen über Stärke oder Schwäche des Knochens zu gewinnen — erst recht, wenn Risikofaktoren vorliegen.
BACKGROUND/OBJECTIVES: The objective of this study was to conduct a method comparison of a modified food frequency questionnaire (FFQ), designed to estimate usual dietary intake of selected micronutrients and antioxidants including folate, choline, betaine, vitamin C and carotenoids (α-carotene, β-carotene, lutein, lycopene and β-cryptoxanthin) with 24-h dietary recalls (24-HR) in women of reproductive age.
SUBJECTS/METHODS: Sixty-four British women of reproductive age (18-40 years) were recruited in Oxford, UK and provided complete dietary data for analysis.
METHODS: We compared micronutrient estimates from the FFQ against estimates derived from three multiple-pass, 24-HR interviews, by evaluating Pearson's correlation coefficients and Bland-Altman plots.
RESULTS: Median intakes of most nutrients were higher when measured by FFQ compared with 24-HR. Strong correlation coefficients were observed for folate (r=0.80) and choline (r=0.68), whereas moderate correlation coefficients were observed for vitamin C (0.50) and lycopene (0.43). Weak correlation coefficients were observed for betaine (0.39) and other carotenoids (r=0.26-0.38). Bland-Altman plots indicated that there was a large amount of variability in the FFQ estimates of nutrient intakes compared to those using 24-HR, particularly for carotenoids.
CONCLUSIONS: The findings indicate that this FFQ estimated higher mean intakes for most nutrients. Pearson's correlation coefficients were comparable with previous research; however, the Bland-Altman plots suggest a high variability in mean nutrient estimates between the FFQ and 24-h. We recommend further investigation of the validity of this FFQ before use.European Journal of Clinical Nutrition advance online publication, 30 September 2015; doi:10.1038/ejcn.2015.159.
Objective: The study aims to state the effectiveness of a new combination treatment composed
of folic acid, doxycycline, low dose aspirin and natural progesterone in cases of recurrent
early pregnancy loss. Study design: A clinical comparative hospital-based study. Setting: Women
Health Hospital – Assiut University – Egypt. Materials and methods: All patients with recurrent
early pregnancy loss at 10 weeks or less attending our antenatal care unit were included. The
patients were recruited over a period of 16 months and allocated into two groups. The study group
received a regimen of folic acid, doxycycline, aspirin, and progesterone. The control group did not
receive the previous regimen in the proposed way. The main outcome measures the live birth rate
and complications of pregnancy in both groups. Results: Three hundred patients were recruited,
with 150 women in each group. A high rate of live births was found in the study group (76.0%)
more than the control group (59.3%). Women in the Control Group reported more complications
(76.0% vs. 51.3%). These were mainly abortion (40.0% vs. 23.3%), pre-eclampsia (16.0% vs.
10.7%) and oligohydramnios (10.0% vs. 6.7%). Conclusion: The implementation of combination
treatment of folic acid, doxycycline, low dose aspirin and natural progesterone resulted in a significant
increase in the live birth rate, a significant reduction in miscarriages, and lower incidence of
complications in patients with recurrent early pregnancy loss.
This study aimed to investigate the association between the methylene tetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms and premature delivery susceptibility.
With matched age and gender, 108 premature delivery pregnant women as cases and 108 healthy pregnant women as controls were recruited in this case-control study. The cases and controls had same gestational weeks. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was adopted to analyze C677T and A1298C polymorphisms of the participants. Linkage disequilibrium (LD) and haplotype analysis were conducted by Haploview software. The differences for frequencies of gene type, allele and haplotypes in cases and controls were tested by chi-square test. The relevant risk of premature delivery was represented by odds ratios (ORs) with 95% confidence intervals (95% CIs).
TT gene type frequency of C677T polymorphsim was higher in cases than the controls (P=0.004, OR=3.077, 95% CI=1.469-6.447), so was allele T (P=0.002, OR=1.853, 95% CI=1.265-2.716). Whereas, CC gene type of A1298C polymorphism had a lower distribution in cases than the controls (P=0.008, OR=0.095, 95% CI=0.012-0.775), so was allele C (P=0.047, OR=0.610, 95% CI=0.384-0.970). Haplotype analysis and linkage disequilibrium test conducted on the alleles of two polymorphisms in MTHFR gene, we discovered that haplotype T-A had a higher distribution in cases, which indicated that susceptible haplotype T-A was the candidate factor for premature delivery.
Gene type TT of MTHFR C677T polymorphism might make premature delivery risk rise while gene type CC of A1298C polymorphism might have protective influence on premature delivery.
Thiols are compounds that contain one sulphanyl group (-SH) in their molecule. Due to this fact, many thiols play very specific and indispensable roles on which a given organism is very dependent. Regarding the redox properties of thiol groups practically all mercaptans can be detected very easily by means of electrochemical methods due to the fact that the oxidation of SH group provides great amount of electrons for the electrode reaction. Electrochemical techniques suitable for the detection of these compounds are still in progress. They can be used partly in stationary systems (where above all the methods of differential pulse polarography, voltamperometric techniques or catalytic signals are used) and partly in dynamic, flow-through and/or electromigration systems (where above all the methods of voltammetry, amperometry or coulometry are used). Development of miniaturized methods and their implementation into analytical system is a current aim. This study presents a survey of the most often used techniques and methods (as well of their modifications) used for the assessment of thiol compounds cysteine and homocysteine.
Implantation failure and pregnancy loss are estimated to affect up to 75 % of fertilized ova; however, as of yet, there is limited empirical evidence, particularly at the population level, for understanding the environmental determinants of these losses. The purpose of this review is to summarize the current knowledge on prepregnancy nutrition and early pregnancy outcomes with particular focus on the outcome of spontaneous abortion among pregnancies conceived naturally and early pregnancy end points among pregnancies conceived through in vitro fertilization. To date, there is limited evidence to support associations of prepregnancy vitamin D and caffeine intake with pregnancy loss. There is suggestive data supporting a link between a healthy diet and lower risk of pregnancy loss. High folate and minimal to no alcohol intake prior to conception have the most consistent evidence supporting an association with lower risk of pregnancy loss.
Maternal under-nutrition increases the risk of developing metabolic diseases. We studied the effects of chronic maternal dietary vitamin B12 restriction on lean body mass (LBM), fat free mass (FFM), muscle function, glucose tolerance and metabolism in Wistar rat offspring. Prevention/reversibility of changes by rehabilitating restricted mothers from conception or parturition and their offspring from weaning was assessed. Female weaning Wistar rats (n = 30) were fed ad libitum for 12 weeks, a control diet (n = 6) or the same with 40% restriction of vitamin B12 (B12R) (n = 24); after confirming deficiency, were mated with control males. Six each of pregnant B12R dams were rehabilitated from conception and parturition and their offspring weaned to control diet. While offspring of six B12R dams were weaned to control diet, those of the remaining six B12R dams continued on B12R diet. Biochemical parameters and body composition were determined in dams before mating and in male offspring at 3, 6, 9 and 12 months of their age. Dietary vitamin B12 restriction increased body weight but decreased LBM% and FFM% but not the percent of tissue associated fat (TAF%) in dams. Maternal B12R decreased LBM% and FFM% in the male offspring, but their TAF%, basal and insulin stimulated glucose uptake by diaphragm were unaltered. At 12 months age, B12R offspring had higher (than controls) fasting plasma glucose, insulin, HOMA-IR and impaired glucose tolerance. Their hepatic gluconeogenic enzyme activities were increased. B12R offspring had increased oxidative stress and decreased antioxidant status. Changes in body composition, glucose metabolism and stress were reversed by rehabilitating B12R dams from conception, whereas rehabilitation from parturition and weaning corrected them partially, highlighting the importance of vitamin B12 during pregnancy and lactation on growth, muscle development, glucose tolerance and metabolism in the offspring.
Environmental and genetic factors are thought to be involved in the pathogenesis of recurrent pregnancy loss (RPL)/spontaneous abortions (SA), which include endocrine, anatomical abnormalities within the genital organs, autoimmune diseases and some gene variants. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme of the folate/methionine metabolic pathway and it is well established fact that folate deficiency causes pregnancy complications like recurrent pregnancy loss, preeclempsia and birth defects affected pregnancies. MTHFR A1298C polymorphism reduces the enzymatic activity and mimics as folate deficiency. To date, many studies have investigated the association between MTHFR A1298C polymorphism and RPL risk; however, the result is still controversial and inconclusive. The aim of the present study was to address the association of MTHFR A1298C polymorphism with RPL risk by meta—analysis. By searching electronic databases, total seventeen studies were identified for present meta—analysis. Crude odds ratios (OR) with 95 % confidence intervals (CIs) was used to assess the strength of association between A1298C polymorphism and RPL. The results indicate that the A1298C polymorphism is not associated with RPL (ORCvs A = 1.13 ,95 % CI= 0.87—1.46, P = 0.36 ; ORACvs AA = 1.22 ,95 % CI= 0.94— 1.6, P = 0.13; ORCCvsAA =1.35, 95 % CI= 76—2.36, P = 0.30; ORCC+AC vs AA = 1.15, 95 % CI= 88 —1.49, P = 0.29; ORCCvs AC+AA = 1.29, 95 % CI= 76 —2.12, P = 0.34). Further prospective studies were needed to confirm the precise relationship between the MTHFR A1298C polymorphism and RPL.
Elevated plasma homocysteine is a known risk factor for atherosclerotic vascular disease, but the strength of the relationship and the interaction of plasma homocysteine with other risk factors are unclear.
To establish the magnitude of the vascular disease risk associated with an increased plasma homocysteine level and to examine interaction effects between elevated plasma homocysteine level and conventional risk factors.
Case-control study.
Nineteen centers in 9 European countries.
A total of 750 cases of atherosclerotic vascular disease (cardiac, cerebral, and peripheral) and 800 controls of both sexes younger than 60 years.
Plasma total homocysteine was measured while subjects were fasting and after a standardized methionine-loading test, which involves the administration of 100 mg of methionine per kilogram and stresses the metabolic pathway responsible for the irreversible degradation of homocysteine. Plasma cobalamin, pyridoxal 5'-phosphate, red blood cell folate, serum cholesterol, smoking, and blood pressure were also measured.
The relative risk for vascular disease in the top fifth compared with the bottom four fifths of the control fasting total homocysteine distribution was 2.2 (95% confidence interval, 1.6-2.9). Methionine loading identified an additional 27% of at-risk cases. A dose-response effect was noted between total homocysteine level and risk. The risk was similar to and independent of that of other risk factors, but interaction effects were noted between homocysteine and these risk factors; for both sexes combined, an increased fasting homocysteine level showed a more than multiplicative effect on risk in smokers and in hypertensive subjects. Red blood cell folate, cobalamin, and pyridoxal phosphate, all of which modulate homocysteine metabolism, were inversely related to total homocysteine levels. Compared with nonusers of vitamin supplements, the small number of subjects taking such vitamins appeared to have a substantially lower risk of vascular disease, a proportion of which was attributable to lower plasma homocysteine levels.
An increased plasma total homocysteine level confers an independent risk of vascular disease similar to that of smoking or hyperlipidemia. It powerfully increases the risk associated with smoking and hypertension. It is time to undertake randomized controlled trials of the effect of vitamins that reduce plasma homocysteine levels on vascular disease risk.
To determine the effects of daily supplementation of 0.5 mg folic acid on homocysteine and folate concentrations, we investigated 49 women with a history of unexplained recurrent miscarriages. A methionine loading test (including the vitamin concentrations of concern) was used preceding and after 2 mo of folic acid intake. Subsequently, these effects were studied after stratification for C677T 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism. Folic acid supplementation (for 2 mo) reduced the median fasting and delta (after-load minus fasting) total plasma homocysteine (tHcy) concentrations 27% (P < 0.001) and 14% (P < 0.05), respectively. Median serum and red cell folate concentrations increased 275 and 70%, respectively (P < 0.01). The homocysteine-lowering effect was most marked in women with the highest tHcy concentrations at baseline. All MTHFR-genotypes (homozygous T/T, n = 8; heterozygous T/C, n = 23; wild type C/C, n = 18) had a different response to the supplementation. After 2 mo, homozygous women showed the greatest decline in median fasting (-41%; P < 0.01) tHcy concentrations, but the lowest absolute increase in serum folate concentration (+26 nmol/L; P < 0.05). In conclusion, 2 mo of daily supplementation of 0. 5 mg folic acid in women with a history of unexplained recurrent miscarriages caused, in general, substantially reduced tHcy concentrations. This effect was most distinct in women with the highest tHcy concentrations at baseline and in women homozygous for the 677 C-->T mutation of the MTHFR-gene.
The objective of this study was to establish whether or not patients with unexplained recurrent abortion have an increased
incidence of haemostatic or metabolic abnormalities. Fifty-two patients with a history of unexplained habitual abortion (two
or more spontaneous abortions before 16 weeks' gestation) were tested for protein S, protein C and antithrombin (AT) III deficiency,
activated protein C (aPC) resistance, hyperhomocysteinaemia and anticardiolipin antibodies (ACA). The control group consisted
of 67 healthy women with a history of only uncomplicated pregnancies. Blood samples were taken for measuring protein S, protein
C, AT III, ACA and activated protein C resistance and a methionine loading test was performed. Of the 46 patients tested for
protein S deficiency, 8 (17.4%) were positive. Of the 43 patients tested, two (4.7%) were protein C deficient and none was
AT III deficient. Of the 42 patients tested for ACA, eight (19.1%) had detectable antibodies. Of the 44 patients tested for
aPC resistance, two (4.6%) were positive. Finally, 35 patients were tested for hyperhomocysteinaemia and six (17.1%) were
positive. It was concluded that parous women with a history of unexplained recurrent abortion have an increased incidence
of hyperhomocysteinaemia and a trend of increased incidence of ACA can be found.
The relationship between excretion of forminoglutamic acid (figlu) in the urine and spontaneous abortion in the first and second trimesters of pregnancy was investigated in 135 nonanemic women after spontaneous abortion and curettage. The 135 were subdivided into Group A, 95 cases with no known reason for spontaneous abortion, and Group B, 40 women in whom probable abortion cause was known; Group C was control. In Group A, figlu was detected in urine of 40 (42.1%). In Group B, where abortion causes ranged from diabetes, to toxoplasmosis, to cervical incompetence, figlu was positive in only 2 (5%) cases. 3/35 controls (8.6%) were positive for figlu. The percentage of positive figlu findings in Group A was significantly higher when compared with Group B (P .001) and with Group C (P .001). In Group A, the positive figlu excretion was statistically unrelated to previous abortions (P .05), previous pregnancies (P .05), or age groups (P .05). Further, when the 40 Group B cases and the 35 Group C cases were compared with the above, there was no change in the results. If increased figlu excretion can be considered an index of folic acid deficiency, then it is possible that this deficiency may be an etiological factor in cases of spontaneous abortion.
The association of low serum folic acid (SFA) with various pregnancy complications, especially abortion, was studied. 3 groups participated in the study: 1) 9 nonpregnant, 27 nonanemic, and 25 anemic pregnant women (uncomplicated cases) comprised the control group; 2) 66 nonanemic cases complaining of either incomplete or inevitable abortion (23 cases) and threatened abortion (43 cases) were grouped; and 3) 35 abortion cases were followed. Group 1 SFA levels ranged from 9.6-14.14; in none of the uncomplicated cases was the level below 4.9 ng/ml. In Group 2, the mean SFA level in the incomplete/inevitable abortion cases was 2.7 ng/ml. In the threatened abortion cases within Group 2, mean SFA was 7 ng/ml. 15 first trimester patients suffering from threatened abortion had SFA levels less than 4 ng/ml, and in all 15 abortion occurred. 7 second trimester cases had mean SFA less than 4 ng/ml, and 5 of them aborted. Group 3 was further divided into 2 groups according to anemia therapy: 1 received a total dose of intramuscular iron and the other a total dose of intramuscular iron with intramuscular folic acid. Anemia improved markedly in both groups, but was better in the combined therapy group. Administration of massive doses of iron caused folic acid depletion and increased abortion incidence. This effect was prevented when folic acid was given along with iron therapy.
At weaning, 162 sows were assigned randomly to six treatments (27 in each treatment) according to a 2 X 3 factorial arrangement: two levels of supplementary folic acid (0 and 5 mg/kg of diet) and three treatments to stimulate ovulation (none, flushing and pregnant mare serum gonadotropin [PMSG] injection). All sows were mated twice within 7 d after weaning. Of the 162 animals originally selected, 123 sows were pregnant and used in this trial. The flushing treatment consisted of allowing sows ad libitum access to feed from the day after weaning through the 1st day of behavioral estrus, whereas control animals received 2.4 kg of feed daily. The hormonal treatment consisted of one i.m. injection of 1,250 IU of PMSG the day after weaning. The commercial-type diet used as the control was computed to contain .6 mg folates per kilogram. Folic acid supplementation elevated (P less than .001) serum folates between weaning and 30 d of gestation. Fetuses of sows fed the diet supplemented with folic acid had a higher (P less than .05) total protein concentration than fetuses of control sows, whereas RNA and DNA concentrations and protein:DNA ratio were not affected. The PMSG treatment elevated (P less than .05) ovulation rate, whereas the flushing or folic acid treatments had no effect on this trait. The addition of 5 mg/kg folic acid to the commercial-type diet improved (P less than .05) the survival rate of fetuses during early gestation and tended (P = .096) to increase the number of fetuses presumably living at 30 d of gestation when this treatment was associated with high ovulation rate.(ABSTRACT TRUNCATED AT 250 WORDS)
1. The effect of different intakes of folic acid (FA) and vitamin C on pregnancy in the Dunkin-Hartley guinea-pig was examined. Female guinea-pigs were subjected to three graded intakes of FA and vitamin C ('deficient', 'intermediate' similar to recommended daily intakes (RDI), and 'supplemented') during early gestation and up to the time of neural tube closure (17th day of gestation), and then returned to the RDI of these vitamins. 2. Plasma and blood cell concentrations of these vitamins were measured once before and at the end of the dietary treatments. Reproductive performance was assessed in terms of the number of resorbed and aborted embryos and weight and size of the live fetuses on the 36th day of gestation. 3. The short-term deficiency of either of these two vitamins, insufficient to affect maternal health, had a dramatic effect on the reproductive performance. 4. The RDI of FA was significantly less effective than the supplemented intake in preventing embryonic deaths. The RDI of vitamin C produced lighter and smaller live fetuses than the supplemented intake. 5. The implications of these findings with regard to vitamin status in early pregnancy in man are discussed.
To determine the risk of elevated total homocysteine (tHcy) levels for arteriosclerotic vascular disease, estimate the reduction of tHcy by folic acid, and calculate the potential reduction of coronary artery disease (CAD) mortality by increasing folic acid intake.
MEDLINE search for meta-analysis of 27 studies relating homocysteine to arteriosclerotic vascular disease and 11 studies of folic acid effects on tHcy levels.
Studies dealing with CAD, cerebrovascular disease, and peripheral arterial vascular disease were selected. Three prospective and six population-based case-control studies were considered of high quality. Five cross-sectional and 13 other case-control studies were also included. Causality of tHcy's role in the pathogenesis of vascular disease was inferred because of consistency across studies by different investigators using different methods in different populations.
Elevations in tHcy were considered an independent graded risk factor for arteriosclerotic vascular diseases. The odds ratio (OR) for CAD of a 5-mumol/L tHcy increment is 1.6 (95% confidence interval [CI], 1.4 to 1.7) for men and 1.8 (95% CI, 1.3 to 1.9) for women. A total of 10% of the population's CAD risk appears attributable to tHcy. The OR for cerebrovascular disease (5-mumol/L tHcy increment) is 1.5 (95% CI, 1.3 to 1.9). Peripheral arterial disease also showed a strong association. Increased folic acid intake (approximately 200 micrograms/d) reduces tHcy levels by approximately 4 mumol/L. Assuming that lower tHcy levels decrease CAD mortality, we calculated the effect of (1) increased dietary folate, (2) supplementation by tablets, and (3) grain fortification. Under different assumptions, 13,500 to 50,000 CAD deaths annually could be avoided; fortification of food had the largest impact.
A 5-mumol/L tHcy increment elevates CAD risk by as much as cholesterol increases of 0.5 mmol/L (20 mg/dL). Higher folic acid intake by reducing tHcy levels promises to prevent arteriosclerotic vascular disease. Clinical trials are urgently needed. Concerns about masking cobalamin deficiency by folic acid could be lessened by adding 1 mg of cobalamin to folic acid supplements.
To establish the prevalence of hyperhomocysteinemia in women with unexplained recurrent early pregnancy loss.
In a patient-control study, the methionine-homocysteine metabolism was investigated by a standardized oral methionine-loading test.
Gynecologic outpatient department of university hospital.
One-hundred and two women who had been referred to the hospital because they suffered from at least two consecutive unexplained spontaneous abortions (study group) as well as 41 controls who were recruited by public advertisement were selected.
Blood samples were collected just before and 6 hours after oral methionine administration to determine plasma total homocysteine concentrations.
Plasma total homocysteine concentrations 6 hours after methionine loading. Hyperhomocysteinemia was defined as total homocysteine concentration at 6 hours exceeding the 97.5 percentile level of the controls.
Hyperhomocysteinemia was diagnosed in 21 women of the study group (21%). In the parous women of the study group, the prevalence of hyperhomocysteinemia was more than two times greater compared with the nulliparous subjects (33% and 14%, respectively).
Hyperhomocysteinemia is a risk factor in women with unexplained recurrent early pregnancy loss.
We evaluated the folate and cobalamin status in 29 non-pregnant women with a history of recurrent spontaneous abortion (three
or more consecutive) of unknown aetiology in comparison to 29 healthy nulligravidae of similar reproductive age (controls).
Serum concentrations of folate and cobalamin showed no significant differences between the two groups. No correlation between
age and vitamin concentrations was found. In the study group there was a significant negative correlation of the number of
previous abortions and the concentration of serum folate. Patients with at least four previous miscarriages had significantly
lower serum values of folic acid than women with three abortions, but not than controls. The underlying cause of this finding
remains unclear. In conclusion, the serum concentrations of folic acid and vitamin B12 are not significantly altered in women
with unexplained recurrent spontaneous abortions, and an association between a deficiency of these vitamins and an increased
risk of pregnancy loss appears to be questionable in the majority of gestations.
To evaluate the medical relevance of hyperhomocysteinemia in women with primary recurrent miscarriages.
Case report and retrospective cross-sectional study.
Hematology outpatient department of a university hospital.
Case report concerning a woman with five consecutive fetal losses. One hundred consecutive women with primary recurrent unexplained miscarriages (study group) and matched healthy controls (control group) with no antecedent fetal loss.
Venous blood sample collection in resting individuals.
Plasma total homocysteine concentrations, plasma folate concentrations, and DNA analysis for the C677T mutation of the 5,10 methylene tetrahydrofolate reductase gene. Normal threshold homocysteine concentration was obtained from values found in the control group (95th percentile).
The case patient was hyperhomocysteinemic, was homozygous for the C677T mutation in the methylene tetrahydrofolate reductase gene, and had plasma folate deficiency. Folic acid and pyridoxine administration normalized the homocysteine concentration and favored a successful pregnancy. In the retrospective study, 12 of 100 patients were hyperhomocysteinemic. Twenty percent had the C677T methylene tetrahydrofolate reductase genotype and 15% had low plasma folate concentrations. The highest values of homocysteine concentration were found in patients with both the C677T genotype and folate deficiency.
Hyperhomocysteinemia should be identified in women with recurrent miscarriages because therapeutic normalization might permit a normal birth.
p 292) 1 report the strong increase of periconceptional use of folic acid to reduce risk of fetal neural-tube defects in the Netherlands. Part of this increase is related to a mass media campaign in 1995. Several private initiatives were also taken during a longer period (information on oral contraceptive packs, advertisements by producers, media activities). We investigated periconceptional use of folic acid tablets in the Northern Netherlands in October and November 1998, and in three previous awareness studies. 2–5
1.
Oral doses of 6 to 12 mg. 4-amino P. G. A. induced fetal death in the first trimester of pregnancy followed by spontaneous delivery of the products of conception in 10 out of 12 cases treated.
2.
The doses lethal to the embryos had only a slight and transitory depressing effect on the hemoglobin and white blood counts of the mothers.
3.
In three instances, a second course of the drug was given needlessly because of persistent positive “pregnancy tests.”
4.
The lesions found in the younger fetuses were depression of hematopoiesis, necrosis of the liver, adrenals, and intestinal epithelia.
5.
In three older fetuses the drug failed to produce immediate death, but apparently induced malformations of the cranium. One of these fetuses died later and was delivered spontaneously. The other two were alive when surgically removed.
6.
The study shows that usage of the drug to induce abortions should in the absence of reliable pregnancy tests be limited to patients in whom surgical intervention is possible to avoid malformations.
7.
The action of the drug is regarded as entirely “antifolic,” indicating the importance of folic acid in the early embryonic life.
8.
The probable role of a folic acid deficiency in certain spontaneous abortions, in the development of malformations, and the importance of folic acid in seasonal breeding in some species is suggested by this study.