Concordant fatal congenital anomaly in twin pregnancy: a case report and review of the literature.

BACKGROUND: When a pregnant mother finds out she has a fetus with a congenital defect, the parents feel profound worry, anxiety, and melancholy. Anomalies can happen in singleton or twin pregnancies, though they are more common in twin pregnancies. In twins, several congenital defects are typically discordant. We present a rare case of concordant fatal anomaly in twin pregnancy in a 22-year-old African patient primigravida mother from Western Ethiopia who presented for routine antenatal care. An obstetric ultrasound scan showed anencephaly, meningomyelocele, and severe ventriculomegaly. After receiving the counseling, the patient was admitted to the ward, and the pregnancy was terminated with the medical option. Following a successful in-patient stay, she was given folic acid supplements and instructed to get preconception counseling before getting pregnant again. CONCLUSION: The case demonstrates the importance of early obstetric ultrasound examination and detailed anatomic scanning, in twin pregnancies in particular. This case also calls for routine preconceptional care.

Assessing a Fermented Whey Beverage Biofortified with Folate as a Potential Folate Source for Humans.

Folate, a vital water-soluble vitamin (B9), requires specific attention as its recommended daily intake frequently is not reached in countries without mandatory fortification. In this regard, biofortification with microorganisms like Bifidobacterium and Streptococcus offers a compelling approach for enhancing food with natural folates. A randomized, nonblinded, and monocentric human pilot study is conducted to assess the bioavailability of a folate-biofortified fermented whey beverage, comprising 3 intervention days and a controlled replenishment phase before and during the assay. Folate plasma concentration (5-CH3-H4folate) is determined using a stable isotope dilution assay and LC-MS/MS detection. Biokinetic parameters (cmax and tmax) are determined, and areas under the curve (AUC) normalized to the basal folate plasma concentration are calculated. An average bioavailability of 17.1% in relation to the 5-CH3-H4folate supplement, ranging from 0% to 39.8%, is obtained. These results reiterate the significance of additional research into folate bioavailability in general and dairy products. Further investigations are warranted into folate-binding proteins (FBP) and other potential limiting factors within the food and individual factors. In summary, biofortification via fermentation emerges as a promising avenue for enhancing the natural folate content in dairy and other food products.

Ocoxin Oral Solution Triggers DNA Damage and Cell Death in Ovarian Cancer.

Ovarian cancer is the most fatal of all the reproductive cancers within the female population, mainly due to its late diagnosis that limits surgery and medical treatment. Classically, ovarian cancer therapy has included conventional chemotherapy, and other therapeutic approaches are now being used to treat these patients, but the outcomes of the disease are still poor. Therefore, new strategies are needed to improve life expectancy and life quality of ovarian cancer patients. Considering that, we investigated the effect of the nutritional supplement Ocoxin Oral Solution (OOS) in ovarian cancer models. OOS contains several nutritional supplements, some of them with demonstrated antitumoral action. In vitro studies showed that OOS inhibited the proliferation of several ovarian cancer cell lines, especially of those representative of the endometrioid subtype, in a time- and dose-dependent manner. A fast cell death induction after OOS treatment was observed, and when the molecular mechanisms leading to this effect were investigated, an activation of the DNA damage checkpoint was detected, as shown by activation (phosphorylation) of CHK1 and CHK2 kinases that was followed by the phosphorylation of the target protein histone H2AX. When tested in animal models of ovarian cancer, OOS reduced tumor growth without any observed secondary effects. Moreover, such reduction in tumor proliferation was caused by the induction of DNA damage as corroborated by the in vivo phosphorylation of CHK2 and Histone H2AX. Finally, OOS potentiated the action of carboplatin or olaparib, the standard of care treatments used in ovarian clinics, opening the possibility of including OOS in combination with those standard of care agents in patients with ovarian cancer.

Bibliometric Analysis and a Call for Increased Rigor in Citing Scientific Literature: Folic Acid Fortification and Neural Tube Defect Risk as an Example.

The health benefits of vitamin B9 (folate) are well documented, particularly in regard to neural tube defects during pregnancy; however, much remains to be learned regarding the health effects and risks of consuming folic acid supplements and foods fortified with folic acid. In 2020, our laboratory conducted a population-based analysis of the Food Fortification Initiative (FFI) dataset to determine the strength of the evidence regarding the prevalence of neural tube defects (NTD) at the national level in response to mandatory fortification of cereal grains with folic acid. We found a very weak correlation between the prevalence of NTDs and the level of folic acid fortification irrespective of the cereal grain fortified (wheat, maize, or rice). We found a strong linear relationship between reduced NTDs and higher socioeconomic status (SES). Our paper incited a debate on the proper statistics to employ for population-level data. Subsequently, there has been a large number of erroneous citations to our original work. The objective here was to conduct a bibliometric analysis to quantitate the accuracy of citations to Murphy and Westmark's publication entitled, "Folic Acid Fortification and Neural Tube Defect Risk: Analysis of the Food Fortification Initiative Dataset". We found a 70% inaccuracy rate. These findings highlight the dire need for increased rigor in citing scientific literature, particularly in regard to biomedical research that directly impacts public health policy.

Daily oral iron supplementation during pregnancy.

BACKGROUND: Iron and folic acid supplementation have been recommended in pregnancy for anaemia prevention, and may improve other maternal, pregnancy, and infant outcomes. OBJECTIVES: To examine the effects of daily oral iron supplementation during pregnancy, either alone or in combination with folic acid or with other vitamins and minerals, as an intervention in antenatal care. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Trials Registry on 18 January 2024 (including CENTRAL, MEDLINE, Embase, CINAHL, ClinicalTrials.gov, WHO's International Clinical Trials Registry Platform, conference proceedings), and searched reference lists of retrieved studies. SELECTION CRITERIA: Randomised or quasi-randomised trials that evaluated the effects of oral supplementation with daily iron, iron + folic acid, or iron + other vitamins and minerals during pregnancy were included. DATA COLLECTION AND ANALYSIS: Review authors independently assessed trial eligibility, ascertained trustworthiness based on pre-defined criteria, assessed risk of bias, extracted data, and conducted checks for accuracy. We used the GRADE approach to assess the certainty of the evidence for primary outcomes. We anticipated high heterogeneity amongst trials; we pooled trial results using a random-effects model (average treatment effect). MAIN RESULTS: We included 57 trials involving 48,971 women. A total of 40 trials compared the effects of daily oral supplements with iron to placebo or no iron; eight trials evaluated the effects of iron + folic acid compared to placebo or no iron + folic acid. Iron supplementation compared to placebo or no iron Maternal outcomes: Iron supplementation during pregnancy may reduce maternal anaemia (4.0% versus 7.4%; risk ratio (RR) 0.30, 95% confidence interval (CI) 0.20 to 0.47; 14 trials, 13,543 women; low-certainty evidence) and iron deficiency at term (44.0% versus 66.0%; RR 0.51, 95% CI 0.38 to 0.68; 8 trials, 2873 women; low-certainty evidence), and probably reduces maternal iron-deficiency anaemia at term (5.0% versus 18.4%; RR 0.41, 95% CI 0.26 to 0.63; 7 trials, 2704 women; moderate-certainty evidence), compared to placebo or no iron supplementation. There is probably little to no difference in maternal death (2 versus 4 events, RR 0.57, 95% CI 0.12 to 2.69; 3 trials, 14,060 women; moderate-certainty evidence). The evidence is very uncertain for adverse effects (21.6% versus 18.0%; RR 1.29, 95% CI 0.83 to 2.02; 12 trials, 2423 women; very low-certainty evidence) and severe anaemia (Hb < 70 g/L) in the second/third trimester (< 1% versus 3.6%; RR 0.22, 95% CI 0.01 to 3.20; 8 trials, 1398 women; very low-certainty evidence). No trials reported clinical malaria or infection during pregnancy. Infant outcomes: Women taking iron supplements are probably less likely to have infants with low birthweight (5.2% versus 6.1%; RR 0.84, 95% CI 0.72 to 0.99; 12 trials, 18,290 infants; moderate-certainty evidence), compared to placebo or no iron supplementation. However, the evidence is very uncertain for infant birthweight (MD 24.9 g, 95% CI -125.81 to 175.60; 16 trials, 18,554 infants; very low-certainty evidence). There is probably little to no difference in preterm birth (7.6% versus 8.2%; RR 0.93, 95% CI 0.84 to 1.02; 11 trials, 18,827 infants; moderate-certainty evidence) and there may be little to no difference in neonatal death (1.4% versus 1.5%, RR 0.98, 95% CI 0.77 to 1.24; 4 trials, 17,243 infants; low-certainty evidence) or congenital anomalies, including neural tube defects (41 versus 48 events; RR 0.88, 95% CI 0.58 to 1.33; 4 trials, 14,377 infants; low-certainty evidence). Iron + folic supplementation compared to placebo or no iron + folic acid Maternal outcomes: Daily oral supplementation with iron + folic acid probably reduces maternal anaemia at term (12.1% versus 25.5%; RR 0.44, 95% CI 0.30 to 0.64; 4 trials, 1962 women; moderate-certainty evidence), and may reduce maternal iron deficiency at term (3.6% versus 15%; RR 0.24, 95% CI 0.06 to 0.99; 1 trial, 131 women; low-certainty evidence), compared to placebo or no iron + folic acid. The evidence is very uncertain about the effects of iron + folic acid on maternal iron-deficiency anaemia (10.8% versus 25%; RR 0.43, 95% CI 0.17 to 1.09; 1 trial, 131 women; very low-certainty evidence), or maternal deaths (no events; 1 trial; very low-certainty evidence). The evidence is uncertain for adverse effects (21.0% versus 0.0%; RR 44.32, 95% CI 2.77 to 709.09; 1 trial, 456 women; low-certainty evidence), and the evidence is very uncertain for severe anaemia in the second or third trimester (< 1% versus 5.6%; RR 0.12, 95% CI 0.02 to 0.63; 4 trials, 506 women; very low-certainty evidence), compared to placebo or no iron + folic acid. Infant outcomes: There may be little to no difference in infant low birthweight (33.4% versus 40.2%; RR 1.07, 95% CI 0.31 to 3.74; 2 trials, 1311 infants; low-certainty evidence), comparing iron + folic acid supplementation to placebo or no iron + folic acid. Infants born to women who received iron + folic acid during pregnancy probably had higher birthweight (MD 57.73 g, 95% CI 7.66 to 107.79; 2 trials, 1365 infants; moderate-certainty evidence), compared to placebo or no iron + folic acid. There may be little to no difference in other infant outcomes, including preterm birth (19.4% versus 19.2%; RR 1.55, 95% CI 0.40 to 6.00; 3 trials, 1497 infants; low-certainty evidence), neonatal death (3.4% versus 4.2%; RR 0.81, 95% CI 0.51 to 1.30; 1 trial, 1793 infants; low-certainty evidence), or congenital anomalies (1.7% versus 2.4; RR 0.70, 95% CI 0.35 to 1.40; 1 trial, 1652 infants; low-certainty evidence), comparing iron + folic acid supplementation to placebo or no iron + folic acid. A total of 19 trials were conducted in malaria-endemic countries, or in settings with some malaria risk. No studies reported maternal clinical malaria; one study reported data on placental malaria. AUTHORS' CONCLUSIONS: Daily oral iron supplementation during pregnancy may reduce maternal anaemia and iron deficiency at term. For other maternal and infant outcomes, there was little to no difference between groups or the evidence was uncertain. Future research is needed to examine the effects of iron supplementation on other maternal and infant health outcomes, including infant iron status, growth, and development.

Targeted co-delivery of rapamycin and oxaliplatin by liposomes suppresses tumor growth and metastasis of colorectal cancer.

The activation of tumor cell immunogenicity through oxaliplatin (OXP)-induced immunogenic cell death (ICD) has significant implications in cancer treatment. However, the anti-tumor effect of OXP monotherapy still has many shortcomings, and the systemic administration of OXP leads to low drug concentration at the tumor site, which is susceptible to systemic toxic side effects. In this study, a combined therapeutic strategy using folate-modified nanoliposomes co-delivered with rapamycin (Rapa) and OXP (abbreviated as FA@R/O Lps) is proposed for the treatment of colorectal cancer (CRC). Rapa and OXP can directly inhibit tumor cell proliferation and induce apoptosis. OXP induces ICD by triggering the release of danger signals, such as HMGB1, ATP, and calreticulin. FA@R/O Lps with a particle size of about 134.1±1.8 nm and a small dispersion were successfully prepared. This novel liposomal system can be used to target and increase drug accumulation in tumors. In-vivo experiments showed that FA@R/O Lps successfully inhibit CRC growth and liver metastasis, and simultaneously reduce off-target toxicity. In particular, FA@R/O Lps showed greater therapeutic effects than free Rapa/OXP and R/O Lps. Taken together, this study provides a novel combination of Rapa and OXP, and a nano-delivery system for enhanced anti-CRC efficacy. The results suggest that FA@R/O Lps could be a promising strategy for the treatment of CRC.

One-carbon metabolite supplementation increases vitamin B12, folate, and methionine cycle metabolites in beef heifers and fetuses in an energy dependent manner at day 63 of gestation.

One-carbon metabolites (OCM) are metabolites and cofactors which include folate, vitamin B12, methionine, and choline that support methylation reactions. The objectives of this study were to investigate the effects of moderate changes in maternal body weight gain in combination with OCM supplementation during the first 63 d of gestation in beef cattle on (1) B12 and folate concentrations in maternal serum (2) folate cycle intermediates in maternal and fetal liver, allantoic fluid (ALF), and amniotic fluid (AMF) and (3) metabolites involved in one-carbon metabolism and related metabolic pathways in maternal and fetal liver. Heifers were either intake restricted (RES) and fed to lose 0.23 kg/d, or fed to gain 0.60 kg/d (CON). Supplemented (+ OCM) heifers were given B12 and folate injections weekly and fed rumen-protected methionine and choline daily, while non-supplemented (-OCM) heifers were given weekly saline injections. These two treatments were combined in a 2 × 2 factorial arrangement resulting in 4 treatments: CON-OCM, CON + OCM, RES-OCM, and RES + OCM. Samples of maternal serum, maternal and fetal liver, ALF, and AMF were collected at slaughter on day 63 of gestation. Restricted maternal nutrition most notably increased (./ ≤ 0.05) the concentration of vitamin B12 in maternal serum, 5,10-methylenetetrahydrofolate and 5,10-methenyltetrahydrofolate in maternal liver, and cystathionine in the fetal liver; conversely, maternal restriction decreased (P = 0.05) 5,10-methylenetetrahydrofolate concentration in fetal liver. Supplementing OCM increased (P ≤ 0.05) the concentrations of maternal serum B12, folate, and folate intermediates, ALF and AMF 5-methyltetrahydrofolate concentration, and altered (P ≤ 0.02) other maternal liver intermediates including S-adenosylmethionine, dimethylglycine, cystathionine Glutathione reduced, glutathione oxidized, taurine, serine, sarcosine, and pyridoxine. These data demonstrate that OCM supplementation was effective at increasing maternal OCM status. Furthermore, these data are similar to previously published literature where restricted maternal nutrition also affected maternal OCM status. Altering OCM status in both the dam and fetus could impact fetal developmental outcomes and production efficiencies. Lastly, these data demonstrate that fetal metabolite abundance is highly regulated, although the changes required to maintain homeostasis may program altered metabolism postnatally.

Maternal stresses that occur during pregnancy, such as restricted nutrition, can impact the developmental outcomes of the offspring in a process known as developmental programming. This programming can occur through epigenetics, which involves changes in fetal gene expression and can occur through the addition of methyl groups to DNA. These changes regulate gene transcription in the offspring and can alter offspring health, efficiency, and life-long outcomes. One-carbon metabolites (OCM), which are nutrients like the amino acid methionine and the vitamins B12, folate, and choline, act as intermediates or cofactors for the donation of methyl groups to DNA. This study investigated the effects of differing maternal rates of gain along with OCM supplementation during early gestation on OCM and related metabolite concentrations in the dam and fetus. We found that supplementing OCM to beef heifers increased maternal OCM and related metabolite concentrations and fetal fluid OCM concentrations. We also found that low maternal gain increased maternal serum and liver OCM concentrations. We can conclude from these findings that both maternal rate of gain and OCM supplementation can impact maternal OCM concentrations at day 63 of gestation and further research is needed to see if those maternal impacts will affect the developing fetus or calf later in its life.

Separation of reproductive decline from lifespan extension during methionine restriction.

Lifespan-extending interventions are generally thought to result in reduced fecundity. The generality of this principle and how it may extend to nutrition and metabolism is not understood. We considered dietary methionine restriction (MR), a lifespan-extending intervention linked to Mediterranean and plant-based diets. Using a chemically defined diet that we developed for Drosophila melanogaster, we surveyed the nutritional landscape in the background of MR and found that folic acid, a vitamin linked to one-carbon metabolism, notably was the lone nutrient that restored reproductive capacity while maintaining lifespan extension. In vivo isotope tracing, metabolomics and flux analysis identified the tricarboxylic cycle and redox coupling as major determinants of the MR-folic acid benefits, in part, as they related to sperm function. Together these findings suggest that dietary interventions optimized for longevity may be separable from adverse effects such as reproductive decline.

In vivo determination of the bioavailability of folic acid through the utilization of the PBPK model in conjunction with UPLC.

This paper employed a physiologically based pharmacokinetic model (PBPK) to investigate the transformations of folic acid and its metabolites in vivo. Additionally, an ultra-performance liquid chromatography (UPLC) method was developed to accurately measure the body's retention rate and conversion rate of folic acid, tetrahydrofolate, and 5-methyltetrahydrofolate. Furthermore, the bioavailability of folic acid in the body was assessed by combining this method with an evaluation technique for animal models. The study found that the gastric metabolism time was 2 h, while the small intestinal metabolism duration was 4 h. The maximum conversion rate was observed in plasma and liver after 6 h, and in the brain after 8 h. This serves as a framework for creating a model to assess the bioavailability of folic acid in living organisms, to enhance the safety and efficacy of folic acid intake.

Magnetic particles with polymeric shells bearing lithocholic and folic acid moieties: Nano-warriors to fight colon cancer.

In the study, we aimed to investigate the activity of nanoformulations containing 5-fluorouracil and polymer-magnetic hybrids bearing membrane-penetrating and ligand-receptor-recognizing agents against colorectal cancer cells. The formation and characterization of iron oxide particles covered with polymeric shells comprising lithocholic acid and folic acid moieties are presented. The efficiency of nanoformulations combined by the simple mixing of low doses of 5-fluorouracil with the obtained hybrids was demonstrated against DLD-1 and HT-29 colon cancer cells. The most pronounced cytotoxic potential against HT-29 cells was observed in the cases of particles based on block and randomly arranged copolymers functionalized by FA motifs with depletion of viable cells by approximately 50 % compared to control cells and cells treated by 5-FU applied in free form. In the case of the DLD-1 cell line, the percentage of viable DLD-1 cells decreased by about 30 to 40% after treatment with the block and randomly arranged copolymer decorated by FA-moiety, when compared to 5-FU at the free form and the untreated control. The induction of apoptosis associated with PS-translocation was determined to be the main mechanism of their cytotoxic effects. Moreover, the safety profiles of the nanoformulations were established through hemolysis assay and the analysis of the viability of human colorectal fibroblasts. It was indicated that all tested nanoparticles met the compatibility requirements at the in vitro level. It should be emphasized that in many cases, there was a significant improvement in the compatibility of hybrids with the FA motif compared to non-functionalized hybrids with the addition of 5-FU. These findings suggest that the presence of FA might modulate the toxicity of chemotherapeutic agents.

Late-life dietary folate restriction reduces biosynthesis without compromising healthspan in mice.

Folate is a vitamin required for cell growth and is present in fortified foods in the form of folic acid to prevent congenital abnormalities. The impact of low-folate status on life-long health is poorly understood. We found that limiting folate levels with the folate antagonist methotrexate increased the lifespan of yeast and worms. We then restricted folate intake in aged mice and measured various health metrics, metabolites, and gene expression signatures. Limiting folate intake decreased anabolic biosynthetic processes in mice and enhanced metabolic plasticity. Despite reduced serum folate levels in mice with limited folic acid intake, these animals maintained their weight and adiposity late in life, and we did not observe adverse health outcomes. These results argue that the effectiveness of folate dietary interventions may vary depending on an individual's age and sex. A higher folate intake is advantageous during the early stages of life to support cell divisions needed for proper development. However, a lower folate intake later in life may result in healthier aging.

A Comparative Study Evaluating the Effectiveness of Folate-Based B Vitamin Intervention on Cognitive Function of Older Adults under Mandatory Folic Acid Fortification Policy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

The policies regarding the mandatory fortification of food with folic acid (FA) may impact the effectiveness of folate-based B vitamin treatment on cognitive function in older adults. We critically and systematically review the literature to assess whether food fortification policies affect folate-based B vitamin treatment efficacy on cognition function in older adults. Electronic databases, including PubMed, Web of Science, and CNKI, were searched for "Cognitive Function", "Folate", and "Older Adults". The study had specific criteria for inclusion, which were as follows: (1) the studies should initially have randomized controlled trials that were conducted on older adults aged 60 or above; (2) the studies must assess the relationship between folate status and cognitive performance; and (3) the studies should clarify the policies regarding food fortification with FA. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines. Two reviewers independently extracted all the data, and any discrepancies were resolved by consensus. All the data collected were compiled, compared, and analyzed critically. Random effects models were used to assess the effects of interventions. The systematic review included fifty-one articles involving 42,768 participants. Of these, the 23 articles were included in the meta-analysis. The meta-analysis on the effects of folate-based B vitamin supplementation on cognitive function showed a significant overall impact (Z = 3.84; p = 0.0001; SMD, 0.18; 95% CI, 0.09, 0.28). Further analysis revealed that FA food fortification policies were not implemented in countries where folate-based B vitamin supplementation improved cognitive impairment in older adults (Z = 3.75; p = 0.0002; SMD, 0.27; 95% CI, 0.13, 0.40). However, the FA intervention did not have significant outcomes in areas where FA food fortification policies were mandatory (Z = 0.75; p = 0.45; SMD, 0.03; 95% CI, -0.06, 0.13). Supplementing with oral folic acid, alone or in combination, has been linked to improved cognitive performance in older adults. While mandatory FA fortification has the improved folic acid status, additional folate-based B vitamin supplements do not appear to influence cognitive function.

Excess Folic Acid and Vitamin B12 Deficiency: Clinical Implications?

BACKGROUND: In the 1940s to 1950s, high-dose folic acid supplements (>5 mg/d) were used clinically to reverse the megaloblastic anemia of vitamin B12 deficiency caused by pernicious anemia. However, this treatment strategy masked the underlying B12 deficiency and possibly exacerbated its neuropathological progression. The issue of masking and exacerbating B12 deficiency has recently been rekindled with the institution of folic acid fortification and the wide-spread use of folic acid supplements. OBJECTIVES: The objectives of this review are to describe clinical and epidemiological evidence that excess folic acid exacerbates B12 deficiency, to summarize a hypothesis to explain this phenomenon, and to provide guidance for clinicians. RESULTS: Cognitive function test scores are lower and blood homocysteine and methylmalonic acid concentrations are higher in people with low B12 and elevated folate than in those with low B12 and nonelevated folate. High-dose folic acid supplementation in patients with pernicious anemia or epilepsy cause significant reductions in serum B12. It is hypothesized that high-dose folic acid supplements cause depletion of serum holotranscobalamin and thus exacerbate B12 deficiency. CONCLUSION: The evidence for excess folic acid exacerbating B12 deficiency is primarily correlative or from uncontrolled clinical observations, and the hypothesis to explain the phenomenon has not yet been tested. Nonetheless, the evidence is sufficiently compelling to warrant increased vigilance for identifying B12 deficiency in at risk individuals, including older adults and others with low B12 intake or conditions that are associated with B12 malabsorption, who also ingest excessive folic acid or are prescribed folic acid in high doses.

Plain language titleExcess Folic Acid and Vitamin B12 Deficiency: Clinical Implications?Plain language summaryIt has been known for many decades that high doses of the B vitamin supplement, folic acid, can alleviate the anemia of vitamin B12 deficiency, at least temporarily. However, by alleviating the anemia, such folic acid supplements were said to "mask" the underlying vitamin B12 deficiency, thus allowing neurological damage to continue or possibly be exacerbated. Consequently, treating vitamin B12 deficiency with high dose folic acid was discontinued in the 1970s. The issue of whether folic acid supplements can exacerbate vitamin B12 deficiency reemerged in the 1990s with folic acid fortification of cereals and grains in the United States and Canada (and now in over 80 countries around the world) to prevent spina bifida and other birth defects. This narrative review summarizes the results of studies that have assessed the relationships between folic acid and folate and vitamin B12 status in patients and in populations. A recent hypothesis on how folic acid might exacerbate vitamin B12 deficiency is summarized, and recommendations to clinicians are made for increased vigilance in assessing vitamin B12 status in certain groups at risk of vitamin B12 deficiency, including older adults, people with gastrointestinal issues and other factors that cause vitamin B12 malabsorption, people with unexplained neurological problems, and people who follow vegan or vegetarian diets which are naturally low in vitamin B12.

The Effects of Maternal Iron and Folate Supplementation on Pregnancy and Infant Outcomes in Africa: A Systematic Review.

BACKGROUND: Iron and folate deficiency are prevalent in pregnant women in Africa. However, limited research exists on the differential effect of oral iron-only, folate-only, or Iron Folic Acid (IFA) supplementation on adverse pregnancy and infant outcomes. This systematic review addresses this gap, focusing on studies conducted in Africa with limited healthcare access. Understanding these differential effects could lead to more targeted and potentially cost-effective interventions to improve maternal and child health in these settings. METHODS: A systematic review was conducted following PRISMA guidelines. The primary exposures were oral iron-only, folate-only, or IFA oral supplementation during pregnancy, while the outcomes were adverse pregnancy and infant outcomes. A qualitative synthesis guided by methods without meta-analysis was performed. RESULTS: Our qualitative synthesis analysed 10 articles reporting adverse pregnancy (adverse birth outcomes, stillbirths, and perinatal mortality) and infant outcomes (neonatal mortality). Consistently, iron-only supplementation demonstrated a reduction in perinatal death. However, evidence is insufficient to assess the relationship between iron-only and IFA supplementation with adverse birth outcomes, stillbirths, and neonatal mortality. CONCLUSION: Findings suggested that iron-only supplementation during pregnancy may reduce perinatal mortality in African women. However, evidence remains limited regarding the effectiveness of both iron-only and IFA supplementation in reducing stillbirths, and neonatal mortality. Moreover, additional primary studies are necessary to comprehend the effects of iron-only, folate-only, and IFA supplementation on pregnancy outcomes and infant health in the African region, considering rurality and income level as effect modifiers.

Associations of Nutrients and Dietary Preferences with Recurrent Pregnancy Loss and Infertility.

This review examines associations of nutrients and dietary preferences with recurrent pregnancy loss (RPL), miscarriage, and infertility. Research articles, reviews, and meta-analyses of RPL and infertility that focused on nutrition, meals, and lifestyle were reviewed, and associations of nutrients and dietary preferences with pregnancy are discussed in relation to recent research findings. Studies related to RPL were given the highest priority, followed by those dealing with miscarriage and infertility. Multivitamin supplements-even when lacking folic acid or vitamin A-reduced total fetal loss. High-dose folic acid supplementation before conception reduced the risk of miscarriage and stillbirth. A meta-analysis revealed a strong association of vitamin D deficiency/insufficiency with miscarriage. Another meta-analysis revealed that seafood and dairy products reduced the risk of miscarriage, whereas a caffeine intake of 300 mg/day or more was associated with miscarriage. A balanced diet that included nutrients with antioxidant properties helped prevent miscarriage, whereas a diet that included processed foods and nutrients with proinflammatory effects increased the risk of miscarriage. Associations of nutrients with RPL warrant further research.

Folate-mediated transgenerational inheritance of sperm DNA methylation patterns correlate with spinal axon regeneration.

In mammals, the molecular mechanisms underlying transgenerational inheritance of phenotypic traits in serial generations of progeny after ancestral environmental exposures, without variation in DNA sequence, remain elusive. We've recently described transmission of a beneficial trait in rats and mice, in which F0 supplementation of methyl donors, including folic acid, generates enhanced axon regeneration after sharp spinal cord injury in untreated F1 to F3 progeny linked to differential DNA methylation levels in spinal cord tissue. To test whether the transgenerational effect of folic acid is transmitted via the germline, we performed whole-genome methylation sequencing on sperm DNA from F0 mice treated with either folic acid or vehicle control, and their F1, F2, and F3 untreated progeny. Transgenerational differentially methylated regions (DMRs) are observed in each consecutive generation and distinguish folic acid from untreated lineages, predominate outside of CpG islands and in regions of the genome that regulate gene expression, including promoters, and overlap at both the differentially methylated position (DMP) and gene levels. These findings indicate that molecular changes between generations are caused by ancestral folate supplementation. In addition, 29,719 DMPs exhibit serial increases or decreases in DNA methylation levels in successive generations of untreated offspring, correlating with a serial increase in the phenotype across generations, consistent with a 'wash-in' effect. Sibship-specific DMPs annotate to genes that participate in axon- and synapse-related pathways.

The potential contributions of bouillon fortification to meeting micronutrient requirements among women and preschool children in Senegal: A modeling study using household consumption and expenditure survey data.

To reduce micronutrient deficiencies, Senegal mandates the fortification of refined oil with vitamin A and wheat flour with iron and folic acid. Expanding Senegal's large-scale food fortification programs to include fortified bouillon could help fill the remaining gaps in dietary micronutrient requirements. Using 7-day household food consumption data collected between 2018 and 2019, we assessed the potential contributions of bouillon fortified with vitamin A (40-250 µg/g bouillon), folic acid (20-120 µg/g), vitamin B12 (0.2-2 µg/g), iron (0.6-5 mg/g), and zinc (0.6-5 mg/g) for meeting micronutrient requirements of women of reproductive age (WRA; 15-49 years old) and children (6-59 months old). Most households (90%) reported consuming bouillon, including poor and rural households. At modeled fortification levels, bouillon fortification reduced the national prevalence of inadequacy by up to ∼20 percentage points (pp) for vitamin A, 34 pp (WRA) and 20 pp (children) for folate, 20 pp for vitamin B12, 38 pp (WRA) and 30 pp (children) for zinc, and ∼8 pp for iron. Predicted reductions in inadequacy were generally larger among poor and rural populations, especially for vitamins A and B12. Our modeling suggests that bouillon fortification has the potential to substantially reduce dietary inadequacy of multiple micronutrients and could also help address inequities in dietary micronutrient inadequacies in Senegal.

Association between dietary folate intake and HPV infection: NHANES 2005-2016.

BACKGROUND: Recent studies have established a correlation between folate levels and the incidence of cervical cancer. Given that Human Papillomavirus (HPV) infection is a primary etiological factor in the development of cervical cancer, the nature of the relationship between dietary folate intake and HPV infection remains an area of ongoing investigation. METHODS: To investigate the association between dietary folate intake and HPV infection, this study utilized data from the National Health and Nutrition Examination Survey (NHANES) spanning from 2005 to 2016. Multivariate logistic regression analysis was employed to examine the potential associations. Furthermore, the use of restricted cubic splines (RCS) facilitated the exploration of any non-linear correlations. Additionally, subgroup analyses were used to explore this correlation in different populations. RESULTS: The study encompassed a total of 6747 women aged between 18 and 59 years. For every one mcg increase in folate intake, the incidence of HPV infection is reduced by 1% (OR = 0.99, p<0.05). Besides, folate intake was categorized into quartiles as follows: Q1 (<211 mcg/day), Q2 (211-311 mcg/day), Q3 (311-448 mcg/day), and Q4 (>448 mcg/day). The adjusted odds ratios (OR) for the different folate levels were as follows: Q2: 0.94 (95% CI: 0.76-1.16), Q3: 0.84 (95% CI: 0.67-1.04), and Q4: 0.63 (95% CI: 0.49-0.81). The RCS analysis confirmed a nonlinear relationship between dietary folate intake and HPV infection risk. Notably, a significant inverse association was observed when dietary folate intake exceeded 193.847 mcg/day. CONCLUSIONS: In conclusion, the findings of this study indicate a negative association between dietary folate intake and the risk of HPV infection. This association demonstrates a nonlinear pattern, particularly evident at higher levels of folate consumption.

Vitamin B6, B12, and Folate's Influence on Neural Networks in the UK Biobank Cohort.

BACKGROUND: One-carbon metabolism coenzymes may influence brain aging in cognitively unimpaired adults. METHODS: Baseline data were used from the UK Biobank cohort. Estimated intake of vitamin B6, B12, and folate was regressed onto neural network functional connectivity in five resting-state neural networks. Linear mixed models tested coenzyme main effects and interactions with Alzheimer's disease (AD) risk factors. RESULTS: Increased B6 and B12 estimated intake were linked with less functional connectivity in most networks, including the posterior portion of the Default Mode Network. Conversely, higher folate was related to more connectivity in similar networks. AD family history modulated these associations: Increased estimated intake was positively associated with stronger connectivity in the Primary Visual Network and Posterior Default Mode Network in participants with an AD family history. In contrast, increased vitamin B12 estimated intake was associated with less connectivity in the Primary Visual Network and the Cerebello-Thalamo-Cortical Network in those without an AD family history. CONCLUSIONS: The differential patterns of association between B vitamins and resting-state brain activity may be important in understanding AD-related changes in the brain. Notably, AD family history appears to play a key role in modulating these relationships.