Maternal Folate Levels Research Articles

Maternal Serum Folate During Pregnancy and Congenital Heart Disease in Offspring

The association of folate supplementation with congenital heart disease (CHD) prevention is controversial. To examine the association of maternal serum folate levels at early to midpregnancy with CHD risk in offspring. This case-control study recruited participants from one of China's largest cardiac referral centers between 2015 and 2018. CHD cases and non-CHD controls were matched according to maternal age at a ratio of 1:4. Data were analyzed from May to August 2023. Maternal serum levels of folate, vitamin B12, and homocysteine were measured around the gestational age of 16 weeks. The primary outcome was CHD, which was confirmed using echocardiography. The association between CHD risk in offspring with maternal folate levels was measured using adjusted odds ratios (aORs) with 95% CIs in conditional logistic regression analyses. Interactions between folate, vitamin B12, and homocysteine and CHD were estimated on a multiplicative scale. A total of 129 CHD cases with ventricular septal defect as the most common phenotype and 516 matched controls were included. The mean (SD) maternal age at pregnancy was 31.6 (5.3) years. There was a U-shaped association between maternal serum folate levels at early to midpregnancy and CHD risk in offspring. Compared with the offspring in the second and third quartiles of maternal folate, those in the lowest (aOR, 3.09; 95% CI, 1.88-5.08) and highest quartiles (OR, 1.81; 95% CI, 1.07-3.06) had increased odds of CHD. The ORs were higher when applying the World Health Organization criteria to determine the normal range for serum folate levels. Interaction analyses suggested that the adverse associations between low and high maternal folate and CHD risk might be further magnified by vitamin B12 deficiency or elevated homocysteine. In this case-control study of CHD, low maternal serum folate levels in early to midpregnancy were associated with an increased CHD risk in offspring, and excessively high folate levels were also associated with an elevated CHD risk. Further investigation is needed to make causal inferences for the observed associations and elucidate the underlying mechanisms.

Folate deficiency in pregnancy and the risk of preterm birth: A nested case-control study.

Preterm birth (PTB) and its complications are important public health problems. Its aetiology is multifactorial and involves both modifiable and non-modifiable factors. Among the modifiable risk factors, micronutrient deficiencies, including maternal folate deficiency, are increasingly being studied in PTB. In this study, we estimated the prevalence of folate deficiency during pregnancy and examined its association with PTB among rural Bangladeshi women. We conducted a nested case-control study using data from a population-based cohort of 3000 pregnant women who were enrolled between 8 and 19 weeks of gestation following ultrasound confirmation of gestational age. Sociodemographic, epidemiologic, clinical, and pregnancy outcomes data were collected through home visits, while blood samples were collected at enrolment and 24-28 weeks of gestation during pregnancy. We included all women who delivered preterm (defined as live births <37 weeks of gestation) as cases (n = 235) and a random sample of women having a term birth as controls (n = 658). The main exposure was folate concentrations in maternal serum during 24-28 weeks of pregnancy. We categorised women into folate deficient (<3 ng/mL) and not deficient (≥3 ng/mL). We then performed multivariable logistic regression analysis to examine the association between maternal folate levels and PTB, adjusting for relevant covariates. Thirty-eight per cent of the enrolled pregnant women were folate deficient. Maternal serum folate deficiency was significantly associated with PTB (adjusted OR (aOR) = 1.73; 95% confidence interval (CI) = 1.27-2.36). The risk of PTB was also higher among women who were of short stature (aOR = 1.83; 95% CI = 1.27-2.63), primiparous (aOR = 1.60; 95% CI = 1.15-2.22), and had exposure to passive smoking (aOR = 1.54; 95% CI = 1.02-2.31). The prevalence of folate deficiency was high among pregnant women in rural Bangladesh, and folate deficiency was significantly associated with an increased risk of preterm birth.

Association of Maternal Vitamin B12 and Folate Levels with Gestational Diabetes Mellitus and Insulin Resistance

Background: The incidence of gestational diabetes mellitus (GDM) has increased in recent decades. Established prevention methods for GDM include diet and exercise. Recent interest has focused on the roles of vitamin B12 and folate in the development of GDM. These micronutrients are essential for one-carbon metabolism, which is involved in many metabolic pathways. However, the study results were conflicting and varied by geographic area. Objectives: The aim of this study was to evaluate the relationship between GDM and vitamin B12 levels in our region. Methods: This case-control study enrolled 180 pregnant women at 24 - 28 weeks of gestation. Half of the participants had GDM, and the other half were healthy individuals. All participants attended outpatient pregnancy care clinics at Shiraz University of Medical Sciences from June 2020 to April 2021. Gestational age, age, and body mass index were matched between the two groups. Vitamin B12, folate, insulin, and homocysteine levels were measured in both groups and insulin resistance was calculated. The results were compared between the two groups, and the relationship between vitamin B12 levels and insulin resistance in each group was investigated. Results: Vitamin B12 deficiency was present in 15.6% of the women with GDM. There were no cases of vitamin B12 deficiency in the control group. The GDM group had lower vitamin B12 levels (365.22 ± 136.82 pg/mL vs. 496.08 ± 156.46 pg/mL, P = 0.001). There was a negative correlation between serum vitamin B12 level and insulin resistance index (P = 0.001, r = -0.62). Folate levels were higher in the GDM group (17.93 ± 3.66 ng/mL vs. 14.60 ± 5.32 ng/mL, P = 0.001), but these levels did not significantly relate to insulin resistance or GDM. Conclusions: In our region, there is a significant relationship between low levels of vitamin B12 and both insulin resistance and GDM, which suggests the need for larger studies and attention to the detection and treatment of vitamin B12 deficiency during pregnancy.

Advances in Folic Acid Biosensors and Their Significance in Maternal, Perinatal, and Paediatric Preventive Medicine.

Auxotrophic primates like human beings rely on exogenous dietary vitamin B9 supplementation to meet their metabolic demands. Folates play a crucial role in nucleotide synthesis and DNA methylation. Maternal folate deficiency causes several pregnancy-related complications, perinatal defects, and early childhood cognitive impairments. New evidence suggests excess FA is a potential risk factor resulting in unfavourable genomic and epigenomic alterations. Thus, it is essential to revisit the need to consistently monitor maternal folate levels during pregnancy. Yet, to date, no point-of-care folate-monitoring biosensor is commercially available. Here, we critically appraise the advances in folate biosensors to understand the translational gaps in biosensor design. Further, our review sheds light on the potential role of folate biosensors in strengthening maternal, perinatal, and child healthcare.

The Association Between Maternal Nutritional Status During Pregnancy and Caries Experience in Their Offspring: A Literature Review

Previous studies have discovered intergenerational linkage between maternal nutritional status and the subsequent health of their offspring. This literature review aimed to explore the connection between the nutritional status of mothers during pregnancy and the occurrence of dental caries in their children. PubMed and Scopus were used for searching articles, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) protocol. The process involved eliminating duplicate articles, and further refinement included articles published within the timeframe of 2013-2023 and those published in the English language. Review articles, studies involving animals, letters to the editor, book sections, and conference proceedings were excluded. Articles that did not provide information on the variables of interest and sample details were also excluded. Data extraction included author names, article titles, publication years, study designs, indicators of maternal nutritional status, type of dentition under consideration, and the reported outcomes. After meticulous removal of duplicate articles and careful application of the inclusion and exclusion criteria, 7 articles met the study's eligibility criteria. The study results collectively indicated that lower levels and intake of maternal plasma vitamin D, reduced maternal plasma folate levels, inadequate gestational weight gain, and overall poor maternal nutritional status were associated with an increased risk of dental caries in their children. It is crucial for mothers to maintain a diet that guarantees the adequate nutrition of the developing fetus.

Folate deficiency increases the incidence of dolutegravir-associated foetal defects in a mouse pregnancy model

Dolutegravir (DTG) is a recommended first-line regimen for all people with Human Immunodeficiency Virus (HIV) infection. Initial findings from Botswana, a country with no folate fortification program, showed an elevated prevalence of neural tube defects (NTDs) with peri-conceptional exposure to DTG. Here we explore whether a low folate diet influences the risk of DTG-associated foetal anomalies in a mouse model. C57BL/6 mice fed a folate-deficient diet for 2 weeks, were mated and then randomly allocated to control (water), or 1xDTG (2.5mg/kg), or 5xDTG (12.5mg/kg) both administered orally with 50mg/kg tenofovir disoproxil fumarate 33.3mg/kg emtricitabine. Treatment was administered once daily from gestational day (GD) 0.5 to sacrifice (GD15.5). Foetuses were assessed for gross anomalies. Maternal and foetal folate levels were quantified. 313 litters (103 control, 106 1xDTG, 104 5xDTG) were assessed. Viability, placental weight, and foetal weight did not differ between groups. NTDs were only observed in the DTG groups (litter rate: 0% control; 1.0% 1xDTG; 1.3% 5xDTG). Tail, abdominal wall, limb, craniofacial, and bleeding defects all occurred at higher rates in the DTG groups versus control. Compared with our previous findings on DTG usage in folate-replete mouse pregnancies, folate deficiency was associated with higher rates of several defects, including NTDs, but in the DTG groups only. We observed a severe left-right asymmetry phenotype that was more frequent in DTG groups than controls. Maternal folate deficiency may increase the risk for DTG-associated foetal defects. Periconceptional folic acid supplementation could be considered for women with HIV taking DTG during pregnancy, particularly in countries lacking folate fortification programs. This project has been funded by Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN275201800001I and award #R01HD104553. LS is supported by a Tier 1 Canada Research Chair in Maternal-Child Health and HIV. HM is supported by a Junior Investigator award from the Ontario HIV Treatment Network.

Associations between maternal folate status and choline intake during pregnancy and neurodevelopment at 3-4 years of age in the Alberta Pregnancy Outcomes and Nutrition (APrON) study.

Folate and choline are methyl donor nutrients that may play a role in fetal brain development. Animal studies have reported that prenatal folate and choline supplementation are associated with better cognitive outcomes in offspring and that these nutrients may interact and affect brain development. Human studies that have investigated associations between maternal prenatal folate or choline levels and neurodevelopmental outcomes have reported contradictory findings and no human studies have examined the potential interactive effect of folate and choline on children's neurodevelopment. During the second trimester of pregnancy, maternal red blood cell folate was measured from blood samples and choline intake was estimated using a 24-h dietary recall in 309 women in the APrON cohort. At 3-5 years of age, their children's neurodevelopment was assessed using the Wechsler Preschool and Primary Scales of Intelligence - Fourth EditionCND, NEPSY-II language and memory subtests, four behavioral executive function tasks, and the Movement Assessment Battery for Children - Second Edition. Adjusted regressions revealed no associations between maternal folate and choline levels during pregnancy and most of the child outcomes. On the Dimensional Change Card Sort, an executive function task, there was an interaction effect; at high levels of choline intake (i.e., 1 SD above the mean; 223.03 mg/day), higher maternal folate status was associated with decreased odds of receiving a passing score (β = -0.44; 95%CI -0.81, -0.06). In conclusion, maternal folate status and choline intake during the second trimester of pregnancy were not associated with children's intelligence, language, memory, or motor outcomes at 3-4 years of age; however, their interaction may have aninfluence children's executive functions.

Abnormal transcriptome-wide DNA demethylation induced by folate deficiency causes neural tube defects.

Neural tube defect (NTDs) is one of the most common and serious fetal and neonatal birth defects. Neural tube closure (NTC) is an exquisitely coordinated process and this procedure is influenced by both genetic and environmental factor. Folic acid (FA) supplementation is an effective for prevention of a proportion of NTDs, however, the mechanism remains unclear. In this study, our data demonstrated genome-wide enrichment of 5-hydroxymethylcytosine (5hmC) modification on active transcriptional start sites (TSS) and decreased 5-methylcytosine (5mC) binding to TSS under folate deficiency in mESCs (mouse embryonic stem cells). Furthermore, folate deficiency promoted 5hmC enrichment enhancer histone 3 lysine 27 acetylation (H3K27ac) binding to Shh pathway genes in mESCs. Upregulation of Shh target genes was observed in mouse brain tissue under low levels of maternal serum folate, along with increased expression of 5-methylcytosine dioxygenase Tet1 levels. Taken together, we found that folate deficiency promoted DNA demethylation and enriched 5hmC through recruitment of H3K27ac to activate the Shh signaling pathway. These results suggest that the 5hmC modification increases concomitantly with a positive correlation to Shh gene expression in folate deficiency-induced mouse NTDs.

Correlations between serum vitamin B12 and folate levels among mother-infant dyads in Punjab state, North-West India.

Adequate vitamin B12 levels in infancy are crucial for normal psychomotor and cognitive development of infants. Our aim was to examine serum vitamin B12, folate and ferritin levels in exclusively breastfed healthy full-term infants (age group: 1-6months), and also investigate their correlation with maternal markers. A cross-sectional study was conducted on 100 exclusively breastfed healthy full-term infants (age group: 1-6months) along with their lactating mothers. Serum vitamin B12, folate and ferritin levels were determined for each mother-infant dyad using enzyme-linked immunosorbent assay. The mean serum vitamin B12, folate and ferritin levels were 512 vs. 535 pg/mL, 15 vs. 12 ng/mL and 313 vs. 114 ng/mL in infants and mothers, respectively. Among 100 infants, 26 (26%) had lower vitamin B12 levels and 5 (5%) had inadequate folate levels. In addition, 22 (22%) of 100 lactating mothers were deficient in vitamin B12 levels and 14 (14%) had inadequate folate levels. We found a statistically significant positive correlation between infant and maternal vitamin B12 (r=0.659, P < 0.001) and folate levels (r=0.51, P < 0.001). Vitamin B12 deficiency was observed in 26% of infants and 22% of lactating mothers. Vitamin B12 and folate levels of infants were positively correlated with maternal levels in the state of Punjab, North-West India. Our findings support that maternal vitamin B12 status can be used as a valuable predictor of infant vitamin B12 status.

Summary for Patients: Maternal Folate Level and Congenital Heart Disease.

Summary for Patients: Maternal Folate Level and Congenital Heart Disease.

Folate, Vitamin B12, and Homocysteine Levels in Women With Neural Tube Defect-Affected Pregnancy in Addis Ababa, Ethiopia.

BackgroundNeural tube defects (NTDs) are prevalent congenital defects associated with pre-pregnancy diet with low levels of maternal folate. They are linked to severe morbidity, disability, and mortality, as well as psychological and economic burdens.ObjectiveThe goal of this study was to determine the levels of folate, vitamin B12, and homocysteine in the blood of women who had a pregnancy impacted by NTDs.Subjects and MethodsA hospital-based case–control study was undertaken between September 2019 and August 2020. The study comprised a total of 100 cases and 167 controls. Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of folate, vitamin B12, and homocysteine in the serum.ResultsOnly 39% of the cases and 54.5% of control mothers reported periconceptional use of folic acid/multivitamin, which indicated a statistically significant difference (p = 0.014). Logistic regression indicated that periconceptional use of folic acid/multivitamin was associated with NTDs (p = 0.015, OR = 1.873, 95% CI: 1.131–3.101). We found that 57% of the cases and 33.5% of controls, as well as 43% of cases and 20.4% of controls had serum folate and vitamin B12 levels below the cut-off value, respectively. Twenty-seven percent of the cases and 6.6% of controls had hyperhomocysteinemia (HHcy). The median concentrations of folate, vitamin B12, and homocysteine in cases and controls were 4.78 and 8.86 ng/ml; 266.23 and 455 pg/ml; 13.43 and 9.7 μmol/l, respectively. The median concentration of folate (p < 0.001) and vitamin B12 (p < 0.001) were significantly lower in the cases than controls, while the homocysteine concentration (p < 0.001) was significantly lower in the controls than cases. Folate [OR (95% CI) = 1.652 (1.226–2.225; p = 0.001)], vitamin B12 [OR (95% CI) = 1.890 (1.393–2.565; p < 0.001], and homocysteine [OR (95% CI) = 0.191 (0.09–0.405; p < 0.001)] levels were associated with NTDs.ConclusionFolate and vitamin B12 are deficient in both cases and control mothers. The lower levels of folate and vitamin B12 with an elevated homocysteine level in NTD-affected pregnancy may be an indication that these biochemical variables were risk factors for NTDs. Folate/multivitamin supplementation and/or food fortification should be promoted.

Prenatal Folate and Choline Levels and Brain and Cognitive Development in Children: A Critical Narrative Review.

Women’s nutritional status during pregnancy can have long-term effects on children’s brains and cognitive development. Folate and choline are methyl-donor nutrients and are important for closure of the neural tube during fetal development. They have also been associated with brain and cognitive development in children. Animal studies have observed that prenatal folate and choline supplementation is associated with better cognitive outcomes in offspring and that these nutrients may have interactive effects on brain development. Although some human studies have reported associations between maternal folate and choline levels and child cognitive outcomes, results are not consistent, and no human studies have investigated the potential interactive effects of folate and choline. This lack of consistency could be due to differences in the methods used to assess folate and choline levels, the gestational trimester at which they were measured, and lack of consideration of potential confounding variables. This narrative review discusses and critically reviews current research examining the associations between maternal levels of folate and choline during pregnancy and brain and cognitive development in children. Directions for future research that will increase our understanding of the effects of these nutrients on children’s neurodevelopment are discussed.

DNA methylation signatures in cord blood associated with birthweight are enriched for dmCpGs previously associated with maternal hypertension or pre-eclampsia, smoking and folic acid intake

ABSTRACT Many epidemiological studies have linked low birthweight to an increased risk of non-communicable diseases (NCDs) in later life, with epigenetic proceseses suggested as an underlying mechanism. Here, we sought to identify neonatal methylation changes associated with birthweight, at the individual CpG and genomic regional level, and whether the birthweight-associated methylation signatures were associated with specific maternal factors. Using the Illumina Human Methylation EPIC array, we assessed DNA methylation in the cord blood of 557 and 483 infants from the UK Pregnancies Better Eating and Activity Trial and Southampton Women’s Survey, respectively. Adjusting for gestational age and other covariates, an epigenome-wide association study identified 2911 (FDR≤0.05) and 236 (Bonferroni corrected p ≤ 6.45×10−8) differentially methylated CpGs (dmCpGs), and 1230 differentially methylated regions (DMRs) (Stouffer ≤0.05) associated with birthweight. The top birthweight-associated dmCpG was located within the Homeobox Telomere-Binding Protein 1 (HMBOX1) gene with a 195 g (95%CI: −241, −149 g) decrease in birthweight per 10% increase in methylation, while the top DMR was located within the promoter of corticotropin-releasing hormone-binding protein (CRHBP). Furthermore, the birthweight-related dmCpGs were enriched for dmCpGs previously associated with gestational hypertension/pre-eclampsia (14.51%, p = 1.37×10−255), maternal smoking (7.71%, p = 1.50 x 10−57) and maternal plasma folate levels during pregnancy (0.33%, p = 0.029). The identification of birthweight-associated methylation markers, particularly those connected to specific pregnancy complications and exposures, may provide insights into the developmental pathways that affect birthweight and suggest surrogate markers to identify adverse prenatal exposures for stratifying for individuals at risk of later NCDs.

MATERNAL GENE POLYMORPHISMS OF VITAMIN B12 METABOLIC PATHWAY AND THEIR ASSOCIATION WITH CONGENITAL HEART DISEASES

Congenital heart disease (CHD) describes a huge set of structural and functional abnormalities that arises during cardio embryogenesis. Low levels of maternal vitamin B12 can disturb the homeostasis of the fetal folate metabolism pathway. The gene CUBN encodes for the intrinsic factor– cobalamin receptor (cubilin), which acts as a receptor for intrinsic factor to many compounds such as vitamin B12.Main aim of our study was to analyze association of CUBN G253A (rs1801222) variant with maternal serum folate, vitamin B12 and homocysteine (Hcy) levels and thereby its link with congenital heart defects. 110 pregnant women with vitamin B12 deficiency and carrying fetuses with CHD and equal number of age matched healthy women were selected as cases and control subjects respectively. Maternal serum folate, vitamin B12 and homocysteine levels as well as genetic polymorphism CUBN G253 → A were assessed. In the present study, it was observed that cases with GA genotype, A allele under the dominant (p=&lt;0.001) and allelic models (p&lt;0.001) respectively and cases with AA genotype under the co-dominant (p&lt;0.01) and recessive models (p&lt;0.001) demonstrated an increased risk of an offspring with CHD. Furthermore, while cases with GA and AA genotypes of CUBN G253A variant showed significantly elevated Homocysteine, it was observed that all the CHD case mothers were vitamin B12 deficient irrespective of the CUBN genotype.

Interaction of maternal asthma history and plasma folate levels on child asthma risk in the Boston Birth Cohort.

Previous studies on maternal folate status during pregnancy and child asthma risk yielded mixed results, and few considered maternal asthma history, a known risk factor of childhood asthma. This study examined whether the role of maternal folate in childhood asthma differs by maternal asthma history and whether there is an interaction between the two factors. This study included 1948 mother-child dyads from the Boston Birth Cohort. Childhood asthma was defined based on physician diagnosis documented in electronic medical records, and maternal asthma was based on standard questionnaire interview. Maternal plasma folate level within a few days of delivery was measured by chemiluminescent immunoassay. Logistic regression models were applied to examine individual and joint associations of maternal asthma history and plasma folate level with childhood asthma, adjusting for other covariables. When stratified by maternal asthma history, an L-shaped relationship between maternal folate level and child asthma was observed in children born to mothers with asthma history (pinteraction = 0.03). The highest risk was found in children having maternal asthma history and low maternal folate level (odds ratio = 5.93; 95% confidence interval: 2.86-12.3) compared with children without maternal asthma history and with sufficient maternal folate levels. Sensitivity analyses using different definitions of asthma and stratified by major covariables yielded similar findings. In this US prospective high-risk birth cohort, maternal asthma history and low folate level interactively increased the risk of child asthma. If further confirmed, optimizing maternal folate levels during pregnancy may mitigate child asthma risk in the setting of maternal asthma history.

Association of maternal vitamin B12 and folate levels in early pregnancy with gestational diabetes: a prospective UK cohort study (PRiDE study)

Aims/hypothesisThe prevalence of gestational diabetes mellitus (GDM) is increasing worldwide in all ethnic groups. Low vitamin B12 and low/high folate levels may contribute to GDM risk, but there is conflicting evidence. Our aim is to assess the relationships of early pregnancy vitamin B12 and folate levels with the risk of GDM status at 26–28 weeks of gestation.MethodsThis was a prospective, multi-centre, multi-ethnic cohort study (n = 4746) in the UK. Participants who were eligible to be selectively screened as per the National Institute for Health and Care Excellence (NICE) criteria were included in the study.ResultsGDM prevalence was 12.5% by NICE and 14.7% by International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. Folate deficiency (1.3%) was rare but B12 insufficiency (42.3% at <220 pmol/l) and folate excess (36.5%) were common in early pregnancy. Early pregnancy median B12 levels were lower, and folate levels higher, in women who were diagnosed with GDM at 26–28 weeks. B12 was negatively associated with fasting plasma glucose (1 SD: −0.06 mmol/l; 95% CI −0.04, −0.08; p < 0.0001) and 2 h plasma glucose levels (−0.07 mmol/l; 95% CI −0.02, −0.12; p = 0.004). Higher B12 was associated with 14.4% lower RR of IADPSG-GDM (0.856; 95% CI 0.786, 0.933; p = 0.0004) after adjusting for key confounders (age, parity, smoking status, ethnicity, family history, household income and folate status). Approximately half of this association was mediated through BMI. Folate was positively associated with 2 h plasma glucose levels (0.08 mmol/l; 95% CI 0.04, 0.13; p = 0.0005) but its relationship with fasting plasma glucose was U-shaped (quadratic β: 0.011; p = 0.05). Higher folate was associated with 11% higher RR of IADPSG-GDM (adjusted RR 1.11; 95% CI 1.036, 1.182; p = 0.002) (age, parity, smoking status, ethnicity, family history, household income and B12 status). Although no interactions were observed for B12 and folate (as continuous variables) with glucose levels and GDM risk, a low B12–high folate combination was associated with higher blood glucose level and risk of IADPSG-GDM (adjusted RR 1.742; 95% CI 1.226, 2.437; p = 0.003).Conclusions/interpretationB12 insufficiency and folate excess were common in early pregnancy. Low B12 and high folate levels in early pregnancy were associated with small but statistically significant changes in maternal blood glucose level and higher RR of GDM. Our findings warrant additional studies on the role of unmetabolised folic acid in glucose metabolism and investigating the effect of optimising early pregnancy or pre-conception B12 and folate levels on subsequent hyperglycaemia.Trial registration:ClinicalTrials.gov NCT03008824.Graphical abstract

Interaction between Metformin, Folate and Vitamin B12 and the Potential Impact on Fetal Growth and Long-Term Metabolic Health in Diabetic Pregnancies.

Metformin is the first-line treatment for many people with type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus (GDM) to maintain glycaemic control. Recent evidence suggests metformin can cross the placenta during pregnancy, thereby exposing the fetus to high concentrations of metformin and potentially restricting placental and fetal growth. Offspring exposed to metformin during gestation are at increased risk of being born small for gestational age (SGA) and show signs of ‘catch up’ growth and obesity during childhood which increases their risk of future cardiometabolic diseases. The mechanisms by which metformin impacts on the fetal growth and long-term health of the offspring remain to be established. Metformin is associated with maternal vitamin B12 deficiency and antifolate like activity. Vitamin B12 and folate balance is vital for one carbon metabolism, which is essential for DNA methylation and purine/pyrimidine synthesis of nucleic acids. Folate:vitamin B12 imbalance induced by metformin may lead to genomic instability and aberrant gene expression, thus promoting fetal programming. Mitochondrial aerobic respiration may also be affected, thereby inhibiting placental and fetal growth, and suppressing mammalian target of rapamycin (mTOR) activity for cellular nutrient transport. Vitamin supplementation, before or during metformin treatment in pregnancy, could be a promising strategy to improve maternal vitamin B12 and folate levels and reduce the incidence of SGA births and childhood obesity. Heterogeneous diagnostic and screening criteria for GDM and the transient nature of nutrient biomarkers have led to inconsistencies in clinical study designs to investigate the effects of metformin on folate:vitamin B12 balance and child development. As rates of diabetes in pregnancy continue to escalate, more women are likely to be prescribed metformin; thus, it is of paramount importance to improve our understanding of metformin’s transgenerational effects to develop prophylactic strategies for the prevention of adverse fetal outcomes.

Maternal Vitamin B12 Status and Risk of Cleft Lip and Cleft Palate Birth Defects in Tamil Nadu State, India.

The causal role of maternal nutrition in orofacial clefts is uncertain. We tested hypotheses that low maternal vitamin B12 and low folate status are each associated with an increased risk of isolated cleft lip with or without cleft palate (CL±P) in a case-control study in Tamil Nadu state, India. Case-mothers of CL±P children (n = 47) and control-mothers of unaffected children (n = 50) were recruited an average of 1.4 years after birth of the index child and plasma vitamin B12, methylmalonic acid (MMA), total homocysteine (tHcy), and folate were measured at that time. Logistic regression analyses estimated associations between nutrient biomarkers and case-control status. Odds ratios (ORs) contrasting biomarker levels showed associations between case-mothers and low versus high plasma vitamin B12 (OR = 2.48, 95% CI, 1.02-6.01) and high versus low plasma MMA, an indicator of poor B12 status (OR = 3.65 95% CI, 1.21-11.05). Case-control status was not consistently associated with folate or tHcy levels. Low vitamin B12 status, when defined by a combination of both plasma vitamin B12 and MMA levels, had an even stronger association with case-mothers (OR = 6.54, 95% CI, 1.33-32.09). Mothers of CL±P children in southern India were 6.5 times more likely to have poor vitamin B12 status, defined by multiple biomarkers, compared to control-mothers. Further studies in populations with diverse nutritional backgrounds are required to determine whether poor maternal vitamin B12 or folate levels or their interactions are causally related to CL±P.

Unexpected interactions between dolutegravir and folate: randomized trial evidence from South Africa.

Objective:Dolutegravir exposure at conception was associated with a preliminary signal of increased infant neural tube defect risk. As low maternal folate levels are linked with neural tube defects, we aimed to assess serum folate concentrations in women starting dolutegravir.Design:We analysed serum folate concentrations from stored plasma among women enrolled in the South African ADVANCE trial.Methods:We compared changes in mean serum folate and occurrence of low serum folate (<14.0 nmol/l) at weeks 0, 12 and 24 across study arms. In ADVANCE, 1053 treatment-naïve participants were randomized to initiate tenofovir–alafenamide/emtricitabine + dolutegravir (TAF/FTC + DTG), tenofovir–disoproxil–fumarate (TDF)/FTC + DTG or TDF/FTC/efavirenz (EFV).Results:Analysis includes 406 females, mean age 31.5 years and baseline CD4+ cell count 356 cells/μl. At baseline, folate concentrations were similar across treatment arms. However, serum folate increased over 12 weeks in the TAF/FTC + DTG arm (+4.0 ± 8.1 nmol/l), while folate concentrations decreased slightly in the TDF/FTC + DTG arm (−1.8 ± 8.9 nmol/l) and decreased in the TDF/FTC/EFV arm (−5.9 ± 8.1 nmol/l). Women taking TDF/FTC/EFV had low folate concentrations at both 12 and 24 weeks compared with the other arms (P < 0.001). Of 26 women who became pregnant on study before week 24, folate concentrations increased between baseline and 12 weeks by a mean 2.4 ± 7.1 nmol/l in the TAF/FTC + DTG arm and 2.3 ± 8.4 nmol/l in the TDF/FTC + DTG arm, but decreased by −3.3 ± 8.1 with TDF/FTC/EFV arm.Conclusion:Unexpectedly, no declines were noted in the dolutegravir-containing arms, and concentrations were considerably higher than in the EFV arm. The possibility that dolutegravir may block cellular uptake of folate warrants investigation.

ANNE VİTAMİN DÜZEYLERİNİN BEBEK DOĞUM AĞIRLIĞI ÜZERİNE ETKİSİ

Aim: Malnutrition and vitamin deficiency during pregnancy result in low birth weight, neural tube defects, placenta and fetus anomalies and preterm delivery. The aim of this study is to investigate the effects of maternal vitamin D, B12, folate and homocysteine levels on infant birth weight. Materials and Method: The retrospective study population comprised 76 pregnancies delivered at Goztepe Training and Research Hospital affiliated to Istanbul Medeniyet University between January 2017 and December 219. Womens were grouped as normal and low according to the vitamin D, B12, folate and homocysteine levels recorded at 37-42 weeks of gestation. Maternal serum vitamin D, B12, folate and homocysteine levels were defined as low &amp;lt;20 ng/mL, &amp;lt;200 pg/mL&amp;lt;2.5 ng/mL, and &amp;lt;5 µM/L, respectively. It was investigated whether there was a significant difference between infant birth weight in both groups and the effects of mother serum vitamin levels on the infant birth weight. Results: The mean maternal age and gestational age were 24.7±4.5 and 39.6±1 week, respectively. The mean infant birth weight was 3320±345 gram. There was no relationship between maternal vitamin D, B12 and homocysteine levels during pregnancy and neonatal birth weight (p &amp;gt;0.05). When confounding variables were adjusted, a positive correlation was found between maternal folate level and infant birth weight (p &amp;lt;0.05). Conclusion: According to the results of this study, it can be considered that the level of maternal folate plays an important role in determining the birth weight of the infants.