Low Vitamin B12 Concentrations Research Articles

A new perspective on vitamin B12 deficiency in rheumatology: a case-based review.

Vitamin B12 (cobalamin) deficiency is common in patients with rheumatic diseases. Pernicious anemia is a well-known cause, but recent reports suggest that autoimmune-derived deficiency may not be limited to this cause alone. Symptoms of low vitamin B12 concentration are often deceptive, mimicking and overlapping with symptoms of other conditions. Neuropsychiatric manifestations, anemia, and fatigue are frequently attributed to a rheumatic disease without further evaluation. In this study, we present three cases of patients with neuropathic pain, depression, fatigue, and muscle weakness, initially attributed to a rheumatic disease, which almost completely resolved after implementing vitamin B12 supplementation. Furthermore, we provide an overview of current scientific reports regarding the potential use of cobalamin in rheumatology. Treatment of pain and neuropathy, often very challenging in long-lasting rheumatic diseases, can be more effective after a course of vitamin B12, even when no apparent deficiency is detected in laboratory tests. Considering recent research demonstrating vitamin B12's nerve-protecting properties, we recommend that physicians should assess vitamin B12 levels early in the diagnostic process of rheumatic diseases. In specific cases, physicians should consider cobalamin supplementation regardless of vitamin B12 serum concentration.

Parasitic, bacterial, viral, immune-mediated, metabolic and nutritional factors associated with nodding syndrome.

Nodding syndrome is a neglected, disabling and potentially fatal epileptic disorder of unknown aetiology affecting thousands of individuals mostly confined to Eastern sub-Saharan Africa. Previous studies have identified multiple associations-including Onchocerca volvulus, antileiomodin-1 antibodies, vitamin B6 deficiency and measles virus infection-yet, none is proven causal. We conducted a case-control study of children with early-stage nodding syndrome (symptom onset <1 year). Cases and controls were identified through a household survey in the Greater Mundri area in South Sudan. A wide range of parasitic, bacterial, viral, immune-mediated, metabolic and nutritional risk factors was investigated using conventional and state-of-the-art untargeted assays. Associations were examined by multiple logistic regression analysis, and a hypothetical causal model was constructed using structural equation modelling. Of 607 children with nodding syndrome, 72 with early-stage disease were included as cases and matched to 65 household- and 44 community controls. Mansonella perstans infection (odds ratio 7.04, 95% confidence interval 2.28-21.7), Necator americanus infection (odds ratio 2.33, 95% confidence interval 1.02-5.3), higher antimalarial seroreactivity (odds ratio 1.75, 95% confidence interval 1.20-2.57), higher vitamin E concentration (odds ratio 1.53 per standard deviation increase, 95% confidence interval 1.07-2.19) and lower vitamin B12 concentration (odds ratio 0.56 per standard deviation increase, 95% confidence interval 0.36-0.87) were associated with higher odds of nodding syndrome. In a structural equation model, we hypothesized that Mansonella perstans infection, higher vitamin E concentration and fewer viral exposures increased the risk of nodding syndrome while lower vitamin B12 concentration, Necator americanus and malaria infections resulted from having nodding syndrome. We found no evidence that Onchocerca volvulus, antileiomodin-1 antibodies, vitamin B6 and other factors were associated with nodding syndrome. Our results argue against several previous causal hypotheses including Onchocerca volvulus. Instead, nodding syndrome may be caused by a complex interplay between multiple pathogens and nutrient levels. Further studies need to confirm these associations and determine the direction of effect.

Serum Concentrations and Dietary Intake of Vitamin B12 in Children and Adolescents on Metformin: A Case–Control Study

The International Society of Pediatric and Adolescent Diabetes (ISPAD) recommends metformin (MET) use for metabolic disturbances and hyperglycemia, either in combination with insulin therapy or alone. A caveat of MET therapy has been suggested to be biochemical vitamin B12 deficiency, as seen mainly in studies conducted in adults. In the present case-control study, children and adolescents of different weight status tiers on MET therapy for a median of 17 months formed the cases group (n = 23) and were compared with their peers not taking MET (n = 46). Anthropometry, dietary intake, and blood assays were recorded for both groups. MET group members were older, heavier, and taller compared with the controls, although BMI z-scores did not differ. In parallel, blood phosphorus and alkaline phosphatase (ALP) concentrations were lower in the MET group, whereas MCV, Δ4-androstenedione, and DHEA-S were higher. No differences were observed in the HOMA-IR, SHBG, hemoglobin, HbA1c, vitamin B12, or serum 25(OH)D3 concentrations between groups. Among those on MET, 17.4% exhibited vitamin B12 deficiency, whereas none of the controls had low vitamin B12 concentrations. Participants on MET therapy consumed less energy concerning their requirements, less vitamin B12, more carbohydrates (as a percentage of the energy intake), and fewer fats (including saturated and trans fats) compared with their peers not on MET. None of the children received oral nutrient supplements with vitamin B12. The results suggest that, in children and adolescents on MET therapy, the dietary intake of vitamin B12 is suboptimal, with the median coverage reaching 54% of the age- and sex-specific recommended daily allowance. This low dietary intake, paired with MET, may act synergistically in reducing the circulating vitamin B12 concentrations. Thus, caution is required when prescribing MET in children and adolescents, and replacement is warranted.

The Effects of Serum Folic Acid and Vitamin B12 on the Risk of Gestational Diabetes Mellitus.

In order to gain more knowledge on the risk of gestational diabetes mellitus (GDM), and to provide evidence for clinical guidance on the optimum level of serum folic acid and vitamin B12, this study aimed to clarify the relationship between serum folic acid and vitamin B12 and the risk of GDM. This retrospective case-control study was conducted based on the clinical information system of the Maternal and Child Health Hospital of Hubei Province. Clinical data including maternal socio-demographical characteristics, serum folic acid, and vitamin B12 were collected. Logistic regression analyses and restricted cubic splines were performed to examine the impact of serum folic acid and vitamin B12 on the risk of GDM. Significantly elevated risks of GDM were observed in groups with high serum folic acid concentration (OR = 1.84, 95% CI: 1.07-3.16), and in low vitamin B12 concentration (OR = 2.14, 95% CI: 1.26-3.65). After stratified by age, the increased risk of GDM was still noticed in a low level of vitamin B12 among mothers aged <30 years (OR = 4.76, 95% CI: 1.45-15.61). In mothers with pre-pregnancy BMI <24, elevated risk of GDM was significantly associated with a high folic acid (OR = 2.09, 95% CI: 1.11-3.93) or a low vitamin B12 concentration (OR = 2.24, 95% CI: 1.22-4.14). Moreover, the risk of GDM was on the decline with the increased level of folic acid in the beginning, and it started to manifest an upward trend when the serum folic acid reached 19.02 ng/mL. This study demonstrated that serum folic acid excess or vitamin B12 deficiency could contribute to the increased risk of GDM, and revealed the potential side effect of serum folic acid overdose. As serum folic acid and vitamin B12 tests are widely applied in clinical practice, this finding could help clinicians to evaluate maternal risk from a new perspective.

High Plasma Vitamin B12 and Cancer in Human Studies: A Scoping Review to Judge Causality and Alternative Explanations.

Patients with cancer have been reported to show elevated plasma concentrations of vitamin B12, thus causing uncertainties regarding safety of vitamin B12. We conducted a systematic literature search and a scoping review of human studies published in PubMed between January 2005 and March 2022, to investigate the association between vitamin B12 (concentrations of B12 biomarkers, intake, and genetic determinants) and cancer. Except for liver cancer, the association between plasma vitamin B12 concentrations and cancer was not consistent across the studies. Vitamin B12 intake from food, or food and supplements, showed even less consistent associations with cancer. There was no evidence for temporality, coherence, or a biologically meaningful dose-response relationship between plasma vitamin B12 concentrations and cancer. Genetically determined high plasma vitamin B12 was likely to be associated with cancer. Available randomized controlled trials have used a high dose of multivitamin supplements and cancer was the unplanned outcome, thus the causality of B12 in cancer cannot be judged based on these trials. Additionally, low plasma vitamin B12 concentrations were common in patients with cancer. Therefore, there is not sufficient evidence to assume that high plasma vitamin B12, high B12 intake, or treatment with pharmacological doses of vitamin B12, is causally related to cancer. Low vitamin B12 status in patients with cancer needs to be diagnosed and treated in order to prevent the hematological and neurological sequela of the deficiency.

Reduced circulating folate among older adults caused by continuous work: nested cross-sectional study conducted in a country with folic acid fortification program

Population aging is 1 of the biggest challenges facing public health today, and cognitive dysfunction is an important concern. Cognitive impairment may be associated with high folate concentrations and low vitamin B12 concentrations; the latter is a common problem among elderly people. Therefore, we hypothesized there was a high circulating folate concentration among older people living in a country with a mandatory folic acid fortification program. We conducted a cross-sectional study to investigate nutritional status of folate and vitamin B12 among aged people. Three dietary recalls, serum folate (sfolate), erythrocyte (red blood cell) folate (RBC folate), and serum vitamin B12 and homocysteine were collected. Linear regression models were used to investigate factors associated with circulating vitamins. We interviewed 169 participants. Half reported inadequate consumption of folate. However, RBC folate deficiency was observed in 27%, 13% in the serum, and a 10% excess of sfolate. One-quarter reported inadequate consumption of B12, but only 5% had deficiency. Factors negatively associated with circulating folate were continuous work and smoking, and positively associated with polyunsaturated fatty acid. Factor negatively associated with the circulating B12 were use of a dental prosthesis and intake of saturated fatty acid. Permanent investigation of excess of sfolate and B12 deficiency, especially among older adults living in countries exposed to a mandatory folic acid fortification program, is important because of the possible relation to the cognitive function.

Vitamin B12 and gestational diabetes mellitus: a systematic review and meta-analysis.

The relationship between vitamin B12 and gestational diabetes mellitus (GDM) remains controversial. To comprehensively evaluate the relationship between vitamin B12 and GDM, and to provide more information on GDM prevention, this study provides a systematic review and meta-analysis of vitamin B12 and GDM. As of September 22, 2021, 304 articles were searched in PubMed, Web of Science, EMBASE, and Cochrane databases, of which 15 studies met the inclusion criteria. Results presented there was no association between maternal vitamin B12 concentration during the first trimester with GDM, however, low vitamin B12 concentration in the second or third trimester of pregnancy was related to an increased risk of GDM. Compared with the non-GDM group, the vitamin B12 concentration in the GDM group was remarkably decreased (MD: -10·79; 95%CI: -21·37, -0·21), and vitamin B12 deficiency increased the risk for GDM (OR: 1·59; 95%CI: 1·10, 2·29). These effects were more significant among Asians. In addition, an increased ratio of high folate to low vitamin B12 in serum also increased the risk of GDM (OR: 1·87; 95% CI: 1·46, 2·41). These results suggest that more vitamin B12 may need to be provided during pregnancy.

Dietary Intake and Status of Vitamin B12 in Slovenian Population.

Vitamin B12 deficiency poses a health concern, especially in vulnerable populations. Dietary vitamin B12 intake was obtained by two 24 h dietary recalls and food propensity questionnaires in a representative Slovenian cross-sectional food consumption survey, SI.Menu (n = 1248 subjects; 10–74 years). For a subgroup of 280 participants, data on serum vitamin B12 were available through the Nutrihealth study. The estimated usual population-weighted mean daily vitamin B12 intakes were 6.2 µg (adults), 5.4 µg (adolescents), and 5.0 µg (elderly). Lower intakes were observed in females. Inadequate daily vitamin B12 intake (<4 µg) was detected in 37.3% of adolescents, 31.7% of adults, and 58.3% elderlies. The significant predictors for inadequate daily vitamin B12 intake were physical activity score in all age groups, sex in adolescents and adults, financial status and smoking in elderly, and employment in adults. Meat (products), followed by milk (products), made the highest vitamin B12 contribution in all age groups. In adolescents, another important vitamin B12 contributor was cereals. The mean population-weighted serum vitamin B12 levels were 322.1 pmol/L (adults) and 287.3 pmol/L (elderly). Low serum vitamin B12 concentration (<148 nmol/L) and high serum homocysteine (>15 µmol/L) were used as criteria for vitamin B12 deficiency. The highest deficiency prevalence was found in elderlies (7.0%), particularly in males (7.9%). Factors associated with high serum homocysteine were also investigated. In conclusion, although vitamin B12 status was generally not critical, additional attention should be focused particularly to the elderly.

A nutrigenetic approach to examine the relationship between vitamin B12 status and cardio‐metabolic traits in multiple ethnic groups – findings from the GeNuIne Collaboration

AbstractLow vitamin B12 concentration has been shown to be a risk factor for cardio‐metabolic traits in numerous observational studies; however, the relationship has remained inconsistent. It is possible that certain genotypes jointly contribute to cardio‐metabolic diseases and vitamin B12 deficiency, and these may be modulated by dietary factors. The main objective of this article is to summarise the findings from the GeNuIne (Gene‐Nutrient Interactions) Collaboration on the effect of gene–nutrient interactions on vitamin B12 concentrations and cardio‐metabolic disease risk factors in population‐based studies from different ethnic groups. Interactions between vitamin B12‐related single‐nucleotide polymorphisms (SNPs) and protein energy intake (%) on waist circumference (Pinteration =0.002) and body fat percentage (Pinteraction =0.034) were observed in Sri Lankan and Indonesian populations, respectively. In the study in Brazilian adolescents, the metabolic and vitamin B12‐related SNPs showed a significant interaction with dietary carbohydrate and protein intakes on oxidised low‐density lipoprotein cholesterol and homocysteine concentrations, respectively. In the Asian Indian population, an association between obesity‐related SNPs and vitamin B12 concentrations (p = 0.018) was observed. In summary, these studies in multiple ethnic groups show that the association between genetically low vitamin B12 concentrations and cardio‐metabolic traits may be modified by dietary intake. Further studies utilising larger sample sizes are needed to confirm or refute our findings.

Association between abnormal maternal serum levels of vitamin B12 and preeclampsia: a systematic review and meta-analysis.

Some evidence has shown an association between maternal vitamin B12 levels and the development of preeclampsia in pregnant women, but the relationship between preeclampsia and vitamin B12 is not clear. The aim of this systematic review was to compare serum vitamin B12 levels in women with preeclampsia with those in normotensive pregnant women. The PubMed/MEDLINE, Scopus, and Web of Science databases were searched up to August 2019, along with the reference lists of included articles. The literature was searched for observational studies that investigated vitamin B12 levels in women with preeclampsia. Data were extracted independently by 2 authors. Data were pooled using a random-effects model. Vitamin B12 levels in women with preeclampsia were significantly lower than those in healthy women (mean, -15.24 pg/mL; 95%CI, -27.52 to -2.954; P < 0.015), but heterogeneity between studies was high (I2 = 97.8%; P = 0.0103). Subgroup analyses based on folic acid supplementation, homocysteine concentrations, and gestational age at the time of sampling for vitamin B12 assessment did not identify the sources of heterogeneity. Women with preeclampsia had significantly lower vitamin B12 concentrations than normotensive pregnant women.

Vitamin B12 Status and Optimal Range for Hemoglobin Formation in Elite Athletes.

Background: Athletes and coaches believe in the ergogenic effect of vitamin B12 (which results from enhanced erythropoiesis) and they often insist on its unjustified supplementation. Therefore, our study aimed to assess the vitamin B12 status in Polish elite athletes and its influence on red blood cell parameters. Methods: In total, 1131 blood samples were collected during six years from 243 track and field athletes divided into strength and endurance groups, as well as according to the declared use of vitamin B12 injections. Results: An average vitamin B12 concentration in all subjects was 739 ± 13 pg/mL, with no cases of deficiency. A weak but significant relationship was found between vitamin B12 and hemoglobin concentrations. A significant increase in hemoglobin appeared from very low vitamin B12 concentration and up to approx. 400 pg/mL, while hemoglobin did not significantly change from 700 pg/mL and onwards. Vitamin B12 injections were used by 34% of athletes, significantly more often by endurance than by strength athletes. In athletes who declared no use of injections, a higher concentration of vitamin B12 was observed in the endurance group. Conclusion: The main finding of the present study is the determination of the range of vitamin B12 concentration which may favor better hemoglobin synthesis in athletes. They should regularly monitor vitamin B12 concentration and maintain the range of 400–700 pg/mL as it may improve red blood cell parameters. We might suggest application of a supplementation if necessary. Special attention is required in athletes with a vitamin B12 concentration below 400 pg/mL.

Comparison of Vitamin B12, Vitamin D, and Folic Acid Blood Levels in Plumbism Patients and Controls in Eastern Iran.

The aim of this study was to evaluate the blood levels of folic acid, vitamin B12, and 25-hydroxyvitamin D (25-OHD) in patients with lead poisoning compared with control subjects in Eastern Iran. This analytical case-control study was conducted on 40 lead-poisoned patients who were referred to Imam Reza Hospital in Birjand from 2018 to 2019. Blood samples were collected from an additional 40 individuals without lead poisoning as a control group. The results indicated that the mean vitamin B12, vitamin D, and folic acid levels for the case group were 356.5 ± 200.1pg/ml, 24.38 ± 9.5ng/ml, and 7.4 ± 3.7ng/ml, respectively. Mean folic acid level in the case group was significantly lower than control group (7.4ng/ml vs. 12.70pg/ml, P = 0.001), whereas the mean of the vitamin D levels at the case group was significantly higher than that of the control group (24.3ng/ml vs. 20.1ng/ml, P = 0.03). Moreover, mean vitamin B12 levels were significantly lower in the case group in comparison with the control group (356.5pg/ml vs. 500.8pg/ml) (P < 0.001). In the control group, 3 patients had folic acid below normal level (< 6ng/mL) while 12 cases had folic acid below normal (P < 0.05). Also, none of the control group had low vitamin B12 concentrations (< 180pg/ml), while 7 cases had vitamin b12 below normal (P < 0.05). Our results suggest that lead may induce folate and vitamin B12 dysregulation. Although we found that vitamin D levels were insufficient in both case and control groups, they were significantly higher in the case group. The interpretation of this result is unclear given inconsistent literature reports on this relationship.

Evidence for the association between FTO gene variants and vitamin B12 concentrations in an Asian Indian population

BackgroundLow vitamin B12 concentrations have been associated with major clinical outcomes, including adiposity, in Indian populations. The Fat mass and obesity-associated gene (FTO) is an established obesity-susceptibility locus; however, it remains unknown whether it influences vitamin B12 status. Hence, we investigated the association of two previously studied FTO polymorphisms with vitamin B12 concentrations and metabolic disease-related outcomes and examined whether these associations were modified by dietary factors and physical activity.MethodsA total of 176 individuals with type 2 diabetes, 152 with pre-diabetes, and 220 normal glucose-tolerant individuals were randomly selected from the Chennai Urban Rural Epidemiology Study. Anthropometric, clinical, and biochemical investigations, which included body mass index (BMI), waist circumference, vitamin B12, homocysteine, and folic acid were measured. A validated food frequency questionnaire was used for dietary assessment and self-reported physical activity measures were collected. An unweighted genetic risk score (GRS) was calculated for two FTO single-nucleotide polymorphisms (rs8050136 and rs2388405) by summation of the number of risk alleles for obesity. Interaction analyses were performed by including the interaction terms in the regression model.ResultsThe GRS was significantly associated with increased BMI (P = 0.009) and risk of obesity (P = 0.023). Individuals carrying more than one risk allele for the GRS had 13.13% lower vitamin B12 concentrations, compared to individuals carrying zero risk alleles (P = 0.018). No associations between the GRS and folic acid and homocysteine concentrations were observed. Furthermore, no statistically significant GRS-diet or GRS-physical activity interactions with vitamin B12, folic acid, homocysteine or metabolic-disease outcomes were observed.ConclusionThe study shows for the first time that a genetic risk score using two FTO SNPs is associated with lower vitamin B12 concentrations; however, we did not identify any evidence for the influence of lifestyle factors on this association. Further replication studies in larger cohorts are warranted to investigate the association between the GRS and vitamin B12 concentrations.

Nutritional Status and Cognitive Impairment among the Very Old in a Community Sample from Southern Brazil.

To determine which factors, especially those related to nutrition, are associated with cognitive function in the oldest old, here considered those at least 80 years of age. A cross-sectional, population-based study. Veranópolis, Rio Grande do Sul, Brazil, and surrounding rural areas. Individuals aged 80 years and older. The Mini Nutritional Assessment, anthropometric measurements, and serum levels of albumin and vitamin B12 were associated with cognitive function according to the Mini Mental State Examination (MMSE) and the Clock Drawing Test (CDT). Socio-demographic data were obtained through a structured questionnaire. Multivariate analysis was used to determine the associations. According to the MMSE and the CDT, the prevalence of cognitive impairment was 47.7% [95%CI 39.7-55.7] and 58.2% [95%CI 50.3-66.1], respectively. In the adjusted analysis, the only positive linear association with MMSE scores indicating cognitive impairment was age. However, CDT scores indicating cognitive impairment were five times higher among those with low serum vitamin B12 concentrations. For the other variables, there was a positive association between age, being widowed, a low educational level and central nervous system drugs. Being single, living with children and living alone were protective factors for cognitive impairment. Although cognitive impairment was positively associated with old age, being widowed and low educational level in this population, the only nutritional variable positively associated with cognitive impairment was a low vitamin B12 concentration.

Associations between metformin use and vitamin B12 levels, anemia, and neuropathy in patients with diabetes: a meta-analysis.

Metformin is first-line therapy for patients with diabetes. However, it may lower vitamin B12 concentrations, which could have hematological or neurological implications. This meta-analyses reviewed all available studies on associations between metformin use and vitamin B12 levels, anemia, and neuropathy in diabetic patients. PubMed, Web of Knowledge, Cochrane Library, and Embase were searched to identify all relevant studies published in English prior to March 2018. Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated for dichotomous outcomes and pooled mean differences (MDs) and 95% CIs were calculated for continuous outcomes. Thirty-one studies were included in the meta-analyses. Compared with diabetic patients not taking metformin, patients taking metformin had a significantly higher risk of vitamin B12 deficiency (RR 2.09; 95% CI 1.49, 2.93; P < 0.0001; I2 = 64%) and significantly lower serum vitamin B12 concentrations (MD -63.70; 95% CI -74.35, -53.05] pM; P < 0.00001; I2 = 87%), which depended on dose and duration of treatment. Metformin use was also associated with significantly greater percentage decrease in serum vitamin B12 concentrations from baseline in diabetic patients (MD -14.68%; 95% CI -17.98%, -11.39%; P < 0.00001; I2 = 33%). Analyses revealed no significant association between metformin use and the prevalence of anemia or neuropathy. Metformin use led to significantly lowered vitamin B12 concentrations and significantly higher risk of vitamin B12 deficiency in diabetic patients. More quality studies are needed to explore the associations between metformin use and anemia and neuropathy in these patients. Annual vitamin B12 assessment in diabetic patients taking metformin is recommended.

Folate and vitamin B12 status and their relation to hematological indices in healthy adults of Iranians: Azar cohort study.

Folate and vitamin B12 are essential micronutrients, the deficiency of which can be associated with public health problems worldwide. The aims of this study were to assess the folate and vitamin B12 status of healthy adults and the effect of gender differences on their deficiency using serum folate, vitamin B12 and red blood cell (RBC) folate as biomarkers and their relation to hematological indices. This study was a part of the Azar cohort study, which is designed as a noncommunicable disease survey in the population of Shabestar, East Azerbaijan, Iran. A total of 95 healthy adults (35 men, 60 women) were chosen according to exclusion criteria and assessed using demographic characteristics and blood sampling. Low concentrations of serum folate, vitamin B12 and RBC folate were detected in 16.8%, 61.1% and 40% of all subjects, respectively. Prevalence of low serum folate and vitamin B12 was higher in men than women (25.7% versus 11.7% for serum folate, 77.1% versus 51.7% for serum vitamin B12).A significant positive correlation was found between hemoglobin and serum folate, vitamin B12 and RBC folate concentrations ( r = 0.279, 0.335, 0.228, respectively). No statistically significant correlation between mean corpuscular volume and serum folate, vitamin B12 and RBC folate was seen ( r = -0.049, -0.030, -0.016, respectively). There was a high prevalence of low folate and vitamin B12 concentrations in our community. Regarding the impact of these two vitamins deficiency on overall health, we suggest further investigations with more participants. In addition, monitoring hematological indices could be useful in people with folate and vitamin B12 deficiency.

Prevalence and Predictors of Subclinical Micronutrient Deficiency in German Older Adults: Results from the Population-Based KORA-Age Study.

Subclinical micronutrient deficiency in older adults is associated with chronic age-related diseases and adverse functional outcomes. In Germany, the older population is at risk of insufficient micronutrient intake, but representative studies on micronutrient status in old and very old adults are scarce. This study’s objectives were to estimate the prevalence of subclinical vitamin D, folate, vitamin B12 and iron deficiencies among older adults, aged 65 to 93, from the KORA-Age study in Augsburg, Germany (n = 1079), and to examine associated predictors, using multiple logistic regression. Serum concentrations of 25-hydroxyvitamin D (25OHD), folate, vitamin B12, and iron were analyzed. The prevalence of subclinical vitamin D and vitamin B12 deficiencies were high, with 52.0% and 27.3% of individuals having low 25OHD (<50 nmol/L) and low vitamin B12 concentrations (<221 pmol/L), respectively. Furthermore, 11.0% had low iron (men <11.6 µmol/L, women <9.0 µmol/L) and 8.7% had low folate levels (<13.6 nmol/L). Common predictors associated with subclinical micronutrient deficiency included very old age, physical inactivity, frailty and no/irregular use of supplements. Subclinical micronutrient deficiency is a public health concern among KORA-Age participants, especially for vitamins D and B12. The predictors identified provide further rationale for screening high-risk subgroups and developing targeted public health interventions to tackle prevailing micronutrient inadequacies among older adults.

Is it necessary to be afraid of vitamin B12 deficiency during metformin treatment?

Metformin, a biguanide derivative, is the most frequently used antihyperglycaemic agent in the world. Various adverse effects can occur during the drug therapy. One of them is vitamin B12 deficiency, which may be either asymptomatic (biochemical) or may lead to neurological and/or haematological disorders. Causal diagnosis of these disorders is hampered due to the fact that nervous system symptoms are similar to neurological complications developing over the course of diabetes mellitus. It is estimated that 5.8 to 33% of metformin treated patients have a low (below the reference level) serum vitamin B12 concentration. The interrelation between vitamin B12 deficiency and metformin usage has been known for decades and over that time many studies have been carried out to assess the issue. Unfortunately, these studies were mainly observational, retrospective and performed on nonhomogeneous groups of patients. Recently a meta-analysis of studies concerning only diabetic patients was performed and it demonstrated the existence of a relationship between metformin treatment and vitamin B12 deficiency. Nevertheless, further well-designed, large-scale, randomized studies performed on a homogenous group of patients and employing homogenous criteria for diagnosing vitamin B12 deficiency are necessary in order to decide whether serum vitamin B12 concentration should be routinely checked among metformin treated patients.

Folate Transporters in Placentas from Preterm Newborns and Their Relation to Cord Blood Folate and Vitamin B12 Levels

Folate deficiency during pregnancy has been related to low birth weight, preterm (PT) birth and other health risks in the offspring; however, it is unknown whether prematurity is related to low folate transport through the placenta due to altered expression of specific folate transporters. We determined placental expression (mRNA and protein concentrations by RT-qPCR and WB respectively) of specific folate transporters: RFC, PCFT/HCP1 and FOLR1 in chorionic (fetal) and basal (maternal) plates of placentas of PT pregnancies (PT, 32–36 weeks, n = 51). Term placentas were used as controls (T, 37–41 weeks, n = 47). Folates and vitamin B12 levels were measured by electrochemiluminescence in umbilical cord blood of newborns. FOLR1 mRNA expression was lower and protein concentration higher in PT placentas (both plates) relative to the control group (p <0.05). In addition, gestational age was positively correlated with mRNA expression (Rho = 0.7), and negatively with protein concentration (Rho = -0.7 for chorionic and -0.43 for basal plate). PCFT/HCP1 mRNA was lower in PT placentas, without changes in protein levels. RFC did not differ in PT placentas compared to controls. PT newborns presented higher cord blood folate level (p = 0.049) along with lower vitamin B12 concentration compared to controls (p = 0.037).In conclusion, placental FOLR1 mRNA was positively associated with gestational age. Conversely, FOLR1 protein concentrations along with folate/vitamin B12 ratio in cord blood were negatively associated with gestational age. Placental FOLR1 is likely the main placental folate transporter to the fetus in newborns.

Periconceptional maternal one-carbon biomarkers are associated with embryonic development according to the Carnegie stages

Is periconceptional maternal one-carbon (I-C) metabolism associated with embryonic morphological development in non-malformed ongoing pregnancies? Serum vitamin B12, red blood cell (RBC) folate and plasma total homocysteine (tHcy) are associated with embryonic development according to the Carnegie stages. Derangements in maternal I-C metabolism affect reproductive and pregnancy outcomes, as well as future health of the offspring. Between 2010 and 2014, women with singleton ongoing pregnancies were enrolled in a prospective periconceptional cohort study. A total of 234 pregnancies, including 138 spontaneous or IUI pregnancies with strict pregnancy dating and 96 pregnancies derived from IVF, ICSI or cryopreserved embryo transfer (IVF/ICSI pregnancies), underwent longitudinal transvaginal three-dimensional ultrasound (3D US) scans from 6+0 up to 10+2 weeks of gestation. Carnegie stages were defined using internal and external morphologic criteria in a virtual reality system. Maternal venous blood samples were collected at enrollment for serum vitamin B12, RBC folate and plasma tHcy assessment. Associations between biomarker concentrations and longitudinal Carnegie stages were investigated using linear mixed models. We performed a median of three 3D US scans per pregnancy (range 1-5) resulting in 600 good quality data sets for the Carnegie stage annotation (80.5%). Vitamin B12 was positively associated with embryonic development in the total study population (β = 0.001 (95% CI: 0.000; 0.002), P < 0.05) and in the subgroup of strictly dated spontaneous pregnancies (β = 0.002 (95% CI: 0.001; 0.003), P < 0.05). Low vitamin B12 concentrations (-2SD, 73.4 pmol/l) were associated with delayed embryonic development by 1.4 days (95% CI: 1.3-1.4) compared with high concentrations (+2SD, 563.1 pmol/l). RBC folate was positively associated with Carnegie stages only in IVF/ICSI pregnancies (β = 0.001 (95% CI: 0.0005; 0.0015), P < 0.05). In this group, low RBC folate concentrations (-2SD, 875.4 nmol/l) were associated with a 1.8-day delay (95% CI: 1.7-1.8) in development compared with high concentrations (+2SD, 2119.9 nmol/l). tHcy was negatively associated with embryonic development in the total study population (β = -0.08 (95% CI: -0.14; -0.02), P < 0.01), as well as in the IVF/ICSI subgroup (β = -0.08 (95% CI: -0.15; -0.01), P < 0.05). High tHcy concentrations (+2SD, 10.4 µmol/l) were associated with a delay of 1.6 days (95% CI: 1.5-1.7) in embryonic development compared with low concentrations (-2SD, 3.0 µmol/l). The study was performed in a tertiary care center, resulting in high rates of folic acid supplement use and comorbidity that may reduce the external validity of our findings. In periconceptional care, maternal I-C biomarkers should be taken into account as predictors of embryonic morphological development. Combining embryonic size measurements with morphological assessment could better define normal embryonic development. The work was funded by the Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. RPMST is CSO of the startup company Slimmere Zorg and CEO of eHealth Care Solutions. The authors declare no conflicts of interest. Not applicable.