Secondary hyperparathyroidism: Predictors and relationship with vitamin D status, bone turnover markers and bone mineral density.

INTRODUCTION: Secondary hyperparathyroidism (SHPT) has adverse implications for bone health but is relatively understudied. In this study we examine the prevalence and determinants of SHPT and describe the relationship of SHPT with bone turnover markers and bone mineral density (BMD) in older Irish adults. METHOD: Eligible participants (n = 4139) were identified from the Trinity-Ulster-Department of Agriculture (TUDA) study, a cohort of Irish adults aged ≥60 years. Exclusion criteria included an estimated glomerular filtration rate (eGFR) <30 ml/min and serum calcium >2.5 mmol/l to remove hyperparathyroidism due to advanced chronic kidney disease (CKD) and primary hyperparathyroidism respectively. The relationship between SHPT and bone turnover markers and BMD (measured by densitometry) was examined in a subsample (n = 1488). Vitamin D deficiency was defined as 25-hydroxyvitamin D [25 (OH)D] <30 nmol/l. RESULTS: Participants had a mean age of 73.6 ± 7.9 years, 65.1 % were female and 19.4 % were found to be vitamin D deficient. The prevalence of SHPT decreased as vitamin D increased, from 30.6 % in those deficient to 9.8 % in those with 25(OH)D ≥ 50 nmol/l and increased with declining kidney function. In non­calcium supplement users, principal determinants of SHPT were vitamin D deficiency (OR 4.18, CI 3.05-5.73, p < 0.001), eGFR 30-44 ml/min (OR 3.69, CI 2.44-5.57, p < 0.001), loop diuretic use (OR 3.52, CI 2.59-4.79, p < 0.001) and to a lesser extent body mass index (p = 0.001), eGFR 45-59 ml/min (p < 0.001) and 25(OH)D level 30-49 nmol/l (p = 0.002). Similar findings were observed in calcium supplement users, though proton pump inhibitors were also associated with SHPT (OR 1.55, CI 1.08-2.22, p = 0.018) while vitamin D 30-49 nmol/l was not. In participants with SHPT versus those without, bone turnover markers were higher: bone alkaline phosphatase (p = 0.017) and tartrate-resistant acid phosphatase (p = 0.033), whilst there was lower BMD at the neck of femur (0.880 vs. 0.903 g/cm2, p = 0.033) and total hip (0.968 vs. 0.995 g/cm2, P = 0.017). DISCUSSION: The results show that up to one in six older Irish adults had SHPT and this was associated with lower BMD and higher concentrations of bone turnover markers. Both vitamin D deficiency and 25(OH)D level 30-49 nmol/l were important predictors of SHPT. Loop diuretics and PPIs may also increase the risk of SHPT, and their use may need to be carefully considered in this population. Further studies examining the potential impact of these factors on bone health in similar populations to our study sample are warranted.

Scientific opinion on the tolerable upper intake level for folate.

Following a request from the European Commission (EC), the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on the revision of the tolerable upper intake level (UL) for folic acid/folate. Systematic reviews of the literature were conducted to assess evidence on priority adverse health effects of excess intake of folate (including folic acid and the other authorised forms, (6S)-5-methyltetrahydrofolic acid glucosamine and l-5-methyltetrahydrofolic acid calcium salts), namely risk of cobalamin-dependent neuropathy, cognitive decline among people with low cobalamin status, and colorectal cancer and prostate cancer. The evidence is insufficient to conclude on a positive and causal relationship between the dietary intake of folate and impaired cognitive function, risk of colorectal and prostate cancer. The risk of progression of neurological symptoms in cobalamin-deficient patients is considered as the critical effect to establish an UL for folic acid. No new evidence has been published that could improve the characterisation of the dose-response between folic acid intake and resolution of megaloblastic anaemia in cobalamin-deficient individuals. The ULs for folic acid previously established by the Scientific Committee on Food are retained for all population groups, i.e. 1000 µg/day for adults, including pregnant and lactating women, 200 µg/day for children aged 1-3 years, 300 µg/day for 4-6 years, 400 µg/day for 7-10 years, 600 µg/day for 11-14 years and 800 µg/day for 15-17 years. A UL of 200 µg/day is established for infants aged 4-11 months. The ULs apply to the combined intake of folic acid, (6S)-5-methyltetrahydrofolic acid glucosamine and l-5-methyltetrahydrofolic acid calcium salts, under their authorised conditions of use. It is unlikely that the ULs for supplemental folate are exceeded in European populations, except for regular users of food supplements containing high doses of folic acid/5-methyl-tetrahydrofolic acid salts.

The association between proton pump inhibitors and hyperparathyroidism: a potential mechanism for increased fracture-results of a large observational cohort study.

Proton pump inhibitors (PPIs) are associated with increased risk of osteoporotic fracture; however, the mechanism is unclear. PPI users taking calcium supplements were more likely to have hyperparathyroidism compared to non-users (OR 1.56, CI 1.08-2.23, p = 0.018). This highlights the importance of monitoring PPI use, especially in older adults. PURPOSE: Proton pump inhibitors (PPIs) are associated with increased risk of osteoporotic fracture. Hyperparathyroidism may be implicated, but few studies have considered this relationship. This study evaluated the relationship between PPI use and hyperparathyroidism in older adults. METHODS: Participants were from the TUDA study, a large cross-sectional cohort of older Irish adults. Participants with an estimated glomerular filtration rate (eGFR) < 30 ml/min and serum calcium > 2.5 mmol/l were excluded to avoid hyperparathyroidism due to chronic renal disease and primary hyperparathyroidism. Hyperparathyroidism was defined as a parathyroid hormone (PTH) > 65 pg/ml. Multivariate regression models were used to analyse the relationship between PPI use and hyperparathyroidism. RESULTS: A total of 4139 participants met the inclusion criteria, of whom 37.8% (n = 1563) were taking PPI medication. PPI use was identified in 41.4% of calcium supplement users and 35.4% of non-calcium supplement users. Overall, compared to non-users of PPIs, those taking PPIs were older (74.8 vs 72.9 years, p < 0.001) and had a higher prevalence of hyperparathyroidism (17.8 vs 11.0%, p < 0.001). In those taking calcium supplements (but not in non-users), PPI use was significantly associated with hyperparathyroidism (OR 1.56, CI 1.08-2.23, p = 0.018) after adjusting for age, sex, body mass index, serum vitamin D, eGFR, timed-up-and-go, dairy intake, medications, and comorbidities. DISCUSSION: The results are consistent with the hypothesis of PPIs reducing calcium absorption, leading to a rise in PTH which could mediate increased fracture risk. No relationship of PPI use with hyperparathyroidism was observed in non-users of calcium supplements, possibly owing to lower dietary calcium intake. These results highlight the importance of monitoring PPI use, especially in older adults at risk of fracture.

Vitamin B-6 and riboflavin, their metabolic interaction, and relationship with MTHFR genotype in adults aged 18-102 years.

BACKGROUND: The generation of the active form of vitamin B-6, pyridoxal 5'-phosphate (PLP), in tissues is dependent upon riboflavin as flavin mononucleotide, but whether this interaction is important for maintaining vitamin B-6 status is unclear. OBJECTIVE: To investigate vitamin B-6 and riboflavin status, their metabolic interaction, and relationship with methylenetetrahydrofolate reductase (MTHFR) genotype in adulthood. METHODS: Data from 5612 adults aged 18-102 y were drawn from the Irish National Adult Nutrition Survey (NANS; population-based sample) and the Trinity-Ulster Department of Agriculture (TUDA) and Genovit cohorts (volunteer samples). Plasma PLP and erythrocyte glutathione reductase activation coefficient (EGRac), as a functional indicator of riboflavin, were determined. RESULTS: Older (≥65 y) compared with younger (<65 y) adults had significantly lower PLP concentrations (P < 0.001). A stepwise decrease in plasma PLP was observed across riboflavin categories, from optimal (EGRac ≤1.26), to suboptimal (EGRac: 1.27-1.39), to deficient (EGRac ≥1.40) status, an effect most pronounced in older adults (mean ± SEM: 76.4 ± 0.9 vs 65.0 ± 1.1 vs 55.4 ± 1.2 nmol/L; P < 0.001). In individuals with the variant MTHFR 677TT genotype combined with riboflavin deficiency, compared with non-TT (CC/CT) genotype participants with sufficient riboflavin, we observed PLP concentrations of 52.1 ± 2.9 compared with 76.8 ±0.7 nmol/L (P < 0.001). In participants with available dietary data (i.e., NANS cohort, n = 936), PLP was associated with vitamin B-6 intake (nonstandardized regression coefficient ß: 2.49; 95% CI 1.75, 3.24; P < 0.001), supplement use (ß: 81.72; 95% CI: 66.01, 97.43; P < 0.001), fortified food (ß: 12.49; 95% CI: 2.08, 22.91; P = 0.019), and EGRac (ß: -65.81; 95% CI: -99.08, -32.54; P < 0.001), along with BMI (ß: -1.81; 95% CI: -3.31, -0.30; P = 0.019). CONCLUSIONS: These results are consistent with the known metabolic dependency of PLP on flavin mononucleotide (FMN) and suggest that riboflavin may be the limiting nutrient for maintaining vitamin B-6 status, particularly in individuals with the MTHFR 677TT genotype. Randomized trials are necessary to investigate the PLP response to riboflavin intervention within the dietary range. The TUDA study and the NANS are registered at www.ClinicalTrials.gov as NCT02664584 (27 January 2016) and NCT03374748 (15 December 2017), respectively.Clinical Trial Registry details: Trinity-Ulster-Department of Agriculture (TUDA) study, ClinicalTrials.gov no. NCT02664584 (January 27th 2016); National Adult Nutrition Survey (NANS), ClinicalTrials.gov no. NCT03374748 (December 15th 2017).

Investigating Genetic Determinants of Plasma Inositol Status in Adult Humans.

BACKGROUND: Myo-inositol (MI) is incorporated into numerous biomolecules, including phosphoinositides and inositol phosphates. Disturbance of inositol availability or metabolism is associated with various disorders, including neurological conditions and cancers, whereas supplemental MI has therapeutic potential in conditions such as depression, polycystic ovary syndrome, and congenital anomalies. Inositol status can be influenced by diet, synthesis, transport, utilization, and catabolism. OBJECTIVES: We aimed to investigate potential genetic regulation of circulating MI status and to evaluate correlation of MI concentration with other metabolites. METHODS: GC-MS was used to determine plasma MI concentration of >2000 healthy, young adults (aged 18-28 y) from the Trinity Student Study. Genotyping data were used to test association of plasma MI with single nucleotide polymorphisms (SNPs) in candidate genes, encoding inositol transporters and synthesizing enzymes, and test for genome-wide association. We evaluated potential correlation of plasma MI with d-chiro-inositol (DCI), glucose, and other metabolites by Spearman rank correlation. RESULTS: Mean plasma MI showed a small but significant difference between males and females (28.5 and 26.9 µM, respectively). Candidate gene analysis revealed several nominally significant associations with plasma MI, most notably for SLC5A11 (solute carrier family 5 member 11), encoding a sodium-coupled inositol transporter, also known as SMIT2 (sodium-dependent myo-inositol transporter 2). However, these did not survive correction for multiple testing. Subsequent testing for genome-wide association with plasma MI did not identify associations of genome-wide significance (P < 5 × 10-8). However, 8 SNPs exceeded the threshold for suggestive significant association with plasma MI concentration (P < 1 × 10-5), 3 of which were located within or close to genes: MTDH (metadherin), LAPTM4B (lysosomal protein transmembrane 4 ß), and ZP2 (zona pellucida 2). We found significant positive correlation of plasma MI concentration with concentration of dci and several other biochemicals including glucose, methionine, betaine, sarcosine, and tryptophan. CONCLUSIONS: Our findings suggest potential for modulation of plasma MI in young adults by variation in SLC5A11, which is worthy of further investigation.

Associations of atrophic gastritis and proton-pump inhibitor drug use with vitamin B-12 status, and the impact of fortified foods, in older adults.

BACKGROUND: Atrophic gastritis (AG) and use of proton pump inhibitors (PPIs) result in gastric acid suppression that can impair the absorption of vitamin B-12 from foods. The crystalline vitamin B-12 form, found in fortified foods, does not require gastric acid for its absorption and could thus be beneficial for older adults with hypochlorhydria, but evidence is lacking. OBJECTIVES: To investigate associations of AG and PPI use with vitamin B-12 status, and the potential protective role of fortified foods, in older adults. METHODS: Eligible participants (n = 3299) not using vitamin B-12 supplements were drawn from the Trinity-Ulster and Department of Agriculture cohort, a study of noninstitutionalized adults aged ≥60 y and recruited in 2008-2012. Vitamin B-12 status was measured using 4 biomarkers, and vitamin B-12 deficiency was defined as a combined indicator value < -0.5. A pepsinogen I:II ratio <3 was considered indicative of AG. RESULTS: AG was identified in 15% of participants and associated with significantly lower serum total vitamin B-12 (P < 0.001) and plasma holotranscobalamin (holoTC; P < 0.001), and higher prevalence of vitamin B-12 deficiency (38%), compared with PPI users (21%) and controls (without AG and nonusers of PPIs; 15%; P < 0.001). PPI drugs were used (≥6 mo) by 37% of participants and were associated with lower holoTC concentrations, but only in participants taking higher doses (≥30 mg/d). Regular, compared with nonregular, consumption of fortified foods (i.e., ≥5 and 0-4 portions/wk, respectively) was associated with higher vitamin B-12 biomarkers in all participants, but inadequate to restore normal vitamin B-12 status in those with AG. CONCLUSIONS: Older adults who have AG and/or use higher doses of PPIs are more likely to have indicators of vitamin B-12 deficiency. Fortified foods, if consumed regularly, were associated with enhanced vitamin B-12 status, but higher levels of added vitamin B-12 than currently provided could be warranted to optimize status in people with AG.

Vitamin D and Hospital Admission in Older Adults: A Prospective Association.

The health effects of vitamin D are well documented, with increasing evidence of its roles beyond bone. There is, however, little evidence of the effects of vitamin D on hospitalisation among older adults. This study aimed to prospectively determine the relationship of vitamin D status in older adults with hospital admission and emergency department (ED) attendance. Trinity University of Ulster Department of Agriculture (TUDA) is a large cross-sectional study of older adults with a community population from three disease-defined cohorts (cognitive dysfunction, hypertension, and osteoporosis). Participants included in this analysis were recruited between 2008 and 2012. ED and hospital admission data were gathered from the date of TUDA participation until June 2013, with a mean follow up of 3.6 years. Of the 3093 participants, 1577 (50.9%) attended the ED during the period of follow-up. Attendees had lower mean serum 25(OH)D concentrations than non-attendees (59.1 vs. 70.6 nmol/L). Fully adjusted models showed an inverse association between vitamin D and ED attendance (Hazard Ratio (HR) 0.996; 95% Confidence Interval (CI) 0.995-0.998; p < 0.001). A total of 1269 participants (41%) were admitted to hospital during the follow-up. Those admitted had lower mean vitamin D concentrations (58.4 vs. 69.3 nmol/L, p < 0.001). In fully adjusted models, higher vitamin D was inversely associated with hospital admission (HR 0.996; 95% CI 0.994-0.998; p < 0.001) and length of stay (LOS) (ß = -0.95, p = 0.006). This study showed independent prospective associations between vitamin D deficiency and increased hospitalisation by older adults. The need for further evaluation of current recommendations in relation to vitamin D supplementation, with consideration beyond bone health, is warranted and should focus on randomised controlled trials.

Effects of maternal folic acid supplementation during the second and third trimesters of pregnancy on neurocognitive development in the child: an 11-year follow-up from a randomised controlled trial.

BACKGROUND: Maternal folic acid (FA) supplementation before and in early pregnancy prevents neural tube defects (NTD), but it is uncertain whether continuing FA after the first trimester has benefits on offspring health. We aimed to evaluate the effect of FA supplementation throughout pregnancy on cognitive performance and brain function in the child. METHODS: Follow-up investigation of 11-year-old children, residing in Northern Ireland, whose mothers had participated in a randomised trial of Folic Acid Supplementation in the Second and Third Trimesters (FASSTT) in pregnancy and received 400 µg/day FA or placebo from the 14th gestational week. Cognitive performance (Full Scale Intelligence Quotient, Verbal Comprehension, Working Memory, Perceptual Reasoning, and Processing Speed) was assessed using the Wechsler Intelligence Scale for Children. Neuronal function was assessed using magnetoencephalographic (MEG) brain imaging. RESULTS: Of 119 mother-child pairs in the FASSTT trial, 68 children were assessed for neurocognitive performance at 11-year follow-up (Dec 2017 to Nov 2018). Children of mothers randomised to FA compared with placebo scored significantly higher in two Processing Speed tests, i.e. symbol search (mean difference 2.9 points, 95% CI 0.3 to 5.5, p = 0.03) and cancellation (11.3 points, 2.5 to 20.1, p = 0.04), whereas the positive effect on Verbal Comprehension was significant in girls only (6.5 points, 1.2 to 11.8, p = 0.03). MEG assessment of neuronal responses to a language task showed increased power at the Beta (13-30 Hz, p = 0.01) and High Gamma (49-70 Hz, p = 0.04) bands in children from FA-supplemented mothers, suggesting more efficient semantic processing of language. CONCLUSIONS: Continued FA supplementation in pregnancy beyond the early period currently recommended to prevent NTD can benefit neurocognitive development of the child. MEG provides a non-invasive tool in paediatric research to objectively assess functional brain activity in response to nutrition and other interventions. TRIAL REGISTRATION: ISRCTN ISRCTN19917787 . Registered on 15 May 2013.

Knowledge gaps in understanding the metabolic and clinical effects of excess folates/folic acid: a summary, and perspectives, from an NIH workshop.

Folate, an essential nutrient found naturally in foods in a reduced form, is present in dietary supplements and fortified foods in an oxidized synthetic form (folic acid). There is widespread agreement that maintaining adequate folate status is critical to prevent diseases due to folate inadequacy (e.g., anemia, birth defects, and cancer). However, there are concerns of potential adverse effects of excess folic acid intake and/or elevated folate status, with the original concern focused on exacerbation of clinical effects of vitamin B-12 deficiency and its role in neurocognitive health. More recently, animal and observational studies have suggested potential adverse effects on cancer risk, birth outcomes, and other diseases. Observations indicating adverse effects from excess folic acid intake, elevated folate status, and unmetabolized folic acid (UMFA) remain inconclusive; the data do not provide the evidence needed to affect public health recommendations. Moreover, strong biological and mechanistic premises connecting elevated folic acid intake, UMFA, and/or high folate status to adverse health outcomes are lacking. However, the body of evidence on potential adverse health outcomes indicates the need for comprehensive research to clarify these issues and bridge knowledge gaps. Three key research questions encompass the additional research needed to establish whether high folic acid or total folate intake contributes to disease risk. 1) Does UMFA affect biological pathways leading to adverse health effects? 2) Does elevated folate status resulting from any form of folate intake affect vitamin B-12 function and its roles in sustaining health? 3) Does elevated folate intake, regardless of form, affect biological pathways leading to adverse health effects other than those linked to vitamin B-12 function? This article summarizes the proceedings of an August 2019 NIH expert workshop focused on addressing these research areas.

Long-Chain Polyunsaturated Fatty Acids, Homocysteine at Birth and Fatty Acid Desaturase Gene Cluster Polymorphisms are Associated with Children's Processing Speed up to Age 9 Years.

Both pre- and early postnatal supplementation with docosahexaenoic acid (DHA), arachidonic acid (AA) and folate have been related to neural development, but their long-term effects on later neural function remain unclear. We evaluated the long-term effects of maternal prenatal supplementation with fish-oil (FO), 5-methyltetrahydrofolate (5-MTHF), placebo or FO + 5-MTHF, as well as the role of fatty acid desaturase (FADS) gene cluster polymorphisms, on their offspring's processing speed at later school age. This study was conducted in NUHEAL children at 7.5 (n = 143) and 9 years of age (n = 127). Processing speed tasks were assessed using Symbol Digit Modalities Test (SDMT), Children Color Trails Test (CCTT) and Stroop Color and Word Test (SCWT). Long-chain polyunsaturated fatty acids, folate and total homocysteine (tHcy) levels were determined at delivery from maternal and cord blood samples. FADS and methylenetetrahydrofolate reductase (MTHFR) 677 C > T genetic polymorphisms were analyzed. Mixed models (linear and logistic) were performed. There were significant differences in processing speed performance among children at different ages (p < 0.001). The type of prenatal supplementation had no effect on processing speed in children up to 9 years. Secondary exploratory analyses indicated that children born to mothers with higher AA/DHA ratio at delivery (p < 0.001) and heterozygotes for FADS1 rs174556 (p < 0.05) showed better performance in processing speed at 9 years. Negative associations between processing speed scores and maternal tHcy levels at delivery were found. Our findings suggest speed processing development in children up to 9 years could be related to maternal factors, including AA/DHA and tHcy levels, and their genetic background, mainly FADS polymorphism. These considerations support that maternal prenatal supplementation should be quantitatively adequate and individualized to obtain better brain development and mental performance in the offspring.

The relationship between maternal plasma homocysteine in early pregnancy and birth weight.

Background: There is limited evidence that plasma homocysteine (Hcy) is increased in women with adverse pregnancy outcomes, such as low birth weight (LBW).Objective: We examined the relationship between maternal Hcy at the first prenatal visit and birth weight.Study design: In a prospective observational study, women were recruited during their first prenatal visit after sonographic confirmation of gestational age. Along with the standard tests, blood was also taken for the measurement of maternal serum and red blood cell (RBC) folate, vitamin B12, and Hcy. In addition to collecting standard clinical and sociodemographic details, a detailed questionnaire on vitamin supplementation was completed under supervision. Birth outcomes were collected immediately after delivery.Results: Of 498 women recruited, 213 (42.8%) were nulliparous, 97 (19.4%) were obese, 64 (12.9%) selfreported as current smokers, and 489 (98.2%) were taking folic acid (FA) supplements at presentation. The mean (SD) birth weight was 3426.3 g (600.7), 14.0% of infants were small for gestational age, and 7.4% were large for gestational age. Mean (SD) plasma Hcy was 7.1 (2.1) µmol/l. On multiple linear regression, higher plasma Hcy was associated with selfreported smoking (p = .009), relative income poverty (p = .037) and Irish nativity (p = .009). There was no relationship between maternal plasma Hcy and birth weight centile, either overall or when analyzed separately for either smokers (r = 0.0001, p = .98) and nonsmokers (r = -0.007, p = .097). Plasma Hcy was correlated negatively with serum folate, RBC folate, and serum vitamin B12. There was no association between maternal Hcy and the duration of FA supplementation in weeks (r = -0.08, p = .083) or between maternal Hcy and gestational age at phlebotomy (r = -0.54, p = .35).Conclusions: In this well-characterized cohort of women in early pregnancy, there was no correlation between maternal plasma Hcy and birth weight. However, higher Hcy was associated with maternal smoking and social deprivation which may explain the association reported previously between an increased Hcy and LBW.RationaleThis study was conducted to investigate the relationship between maternal homocysteine in early pregnancy and infant birth weight. Increased plasma homocysteine in early pregnancy was not associated with a lower birth weight. However, there was a positive correlation between increasing plasma homocysteine and maternal smoking and social disadvantage which are risk factors for lower birth weight. This study highlights the importance of correcting for confounding variables, such as smoking and social disadvantage, when evaluating the relationship maternal nutritional biomarkers and intrauterine fetal development.RationaleThis study was conducted to investigate the relationship between maternal homocysteine in early pregnancy and infant birth weight. Increased plasma homocysteine in early pregnancy was not associated with a lower birth weight. However, there was a positive correlation between increasing plasma homocysteine and maternal smoking and social disadvantage which are risk factors for lower birth weight. This study highlights the importance of correcting for confounding variables, such as smoking and social disadvantage, when evaluating the relationship maternal nutritional biomarkers and intrauterine fetal development.

Circulating Micronutrient Biomarkers Are Associated With 3 Measures of Frailty: Evidence From the Irish Longitudinal Study on Ageing.

OBJECTIVES: To examine the associations between 3 frailty instruments and circulating micronutrients in a large representative sample of older adults. DESIGN: Cross-sectional data from a nationally representative cohort study conducted between October 2009 and July 2011. PARTICIPANTS AND SETTING: Adults age ≥50 years (n = 4068) living in the community in Ireland. MEASUREMENTS: Circulating micronutrients (lutein, zeaxanthin, folate, vitamin B-12, and vitamin D) were measured, transformed, and standardized. Frailty was assessed using the Frailty Phenotype, the Frailty Index, and the FRAIL Scale (fatigue, resistance, ambulation, illnesses, and loss of weight), instruments. Multinomial logistic regression determined associations between micronutrients and prefrailty or frailty. Models were adjusted for sociodemographic, lifestyle, health, and seasonal factors. RESULTS: Adjusting for age, sex, and educational attainment, all 3 measures of frailty were associated with lower levels of lutein [relative risk ratios (RRRs): 0.43‒0.63], zeaxanthin (RRRs: 0.49‒0.63), and vitamin D (RRRs: 0.51‒0.75), and with the accumulation of micronutrient insufficiencies (RRRs: 1.42‒1.90). Attenuated but significant associations were also observed with all measures of prefrailty for lutein, vitamin D, and number of micronutrient insufficiencies. The associations with frailty persisted following additional adjustment for social, lifestyle, and health and seasonal factors, and following multiple test correction. CONCLUSIONS AND IMPLICATIONS: We have presented the most consistent evidence in the largest study to date that micronutrient concentrations are associated with prefrailty and frailty in older adults. Our data suggest that low micronutrient status has potential as an easily modifiable marker and intervention target for frailty and supports further investigation into micronutrient supplementation and fortification to prevent frailty and disability among older adults.

Effect of continued folic acid supplementation beyond the first trimester of pregnancy on cognitive performance in the child: a follow-up study from a randomized controlled trial (FASSTT Offspring Trial).

BACKGROUND: Periconceptional folic acid prevents neural tube defects (NTDs), but it is uncertain whether there are benefits for offspring neurodevelopment arising from continued maternal folic acid supplementation beyond the first trimester. We investigated the effect of folic acid supplementation during trimesters 2 and 3 of pregnancy on cognitive performance in the child. METHODS: We followed up the children of mothers who had participated in a randomized controlled trial in 2006/2007 of Folic Acid Supplementation during the Second and Third Trimesters (FASSTT) and received 400 µg/d folic acid or placebo from the 14th gestational week until the end of pregnancy. Cognitive performance of children at 7 years was evaluated using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III) and at 3 years using the Bayley's Scale of Infant and Toddler Development (BSITD-III). RESULTS: From a total of 119 potential mother-child pairs, 70 children completed the assessment at age 7 years, and 39 at age 3 years. At 7 years, the children of folic acid treated mothers scored significantly higher than the placebo group in word reasoning: mean 13.3 (95% CI 12.4-14.2) versus 11.9 (95% CI 11.0-12.8); p = 0.027; at 3 years, they scored significantly higher in cognition: 10.3 (95% CI 9.3-11.3) versus 9.5 (95% CI 8.8-10.2); p = 0.040. At both time points, greater proportions of children from folic acid treated mothers compared with placebo had cognitive scores above the median values of 10 (girls and boys) for the BSITD-III, and 24.5 (girls) and 21.5 (boys) for the WPPSI-III tests. When compared with a nationally representative sample of British children at 7 years, WPPSI-III test scores were higher in children from folic acid treated mothers for verbal IQ (p < 0.001), performance IQ (p = 0.035), general language (p = 0.002), and full scale IQ (p = 0.001), whereas comparison of the placebo group with British children showed smaller differences in scores for verbal IQ (p = 0.034) and full scale IQ (p = 0.017) and no differences for performance IQ or general language. CONCLUSIONS: Continued folic acid supplementation in pregnancy beyond the early period recommended to prevent NTD may have beneficial effects on child cognitive development. Further randomized trials in pregnancy with follow-up in childhood are warranted. TRIAL REGISTRATION: ISRCTN ISRCTN19917787 . Registered 15 May 2013.

Folate and vitamin B12 levels in early pregnancy and maternal obesity.

OBJECTIVE: There is good evidence that periconceptual Folic Acid (FA) supplementation can prevent two thirds of Neural Tube Defects (NTDs). A two-fold increase in NTD rates have been associated with maternal obesity and, based on limited evidence, national guidelines have recommended prescribing high dose FA for women with a Body Mass Index (BMI) >29.9 kg/m2. This observational study examined the relationship between maternal BMI and serum folate, red blood cell (RBC) folate and plasma vitamin B12 measurements in early pregnancy. STUDY DESIGN: Women were recruited at their convenience during their first antenatal visit to the hospital following sonographic confirmation of an ongoing pregnancy. Clinical, sociodemographic, dietary and supplementation details were collected and computerised. At the time of routine phlebotomy, samples were collected for serum folate, red blood cell (RBC) folate and plasma B12. RESULTS: Of the 496 women, 19.6%. (n = 97) were obese based on a BMI > 29.9 kg/m2. After excluding energy under-reporters, there was no difference between obese women and women with a normal BMI in their dietary or supplementation intakes of folate. Compared with women with a normal BMI (n = 263), obese women had a lower median serum folate (32.0 nmol/L IQR 20.2 vs 36.2 nmol/L IQR 16.3, P = 0.02) and a lower median serum B12 (203.0 pmol/L IQR 102.5 vs 208.0 pmol/L IQR 125.3, P = 0.03), but there was no difference in the mean red blood cell (RBC) folate measurement. There was a negative correlation between increasing BMI and both serum folate (P = 0.03) and plasma B12 (P = 0.03), but no correlation between BMI and RBC folate (P = 0.13). CONCLUSION: Our findings support existing recommendations that obese women should be prescribed higher doses of FA periconceptually. However, to prevent NTDs successfully they may also require B12 supplementation.

Comparison at the first prenatal visit of the maternal dietary intakes of smokers with non-smokers in a large maternity hospital: a cross-sectional study.

OBJECTIVES: Using detailed dietary and supplement questionnaires in early pregnancy, we compared the dietary intakes of micronutrients and macronutrients at the first prenatal visit of women who reported continuing to smoke during pregnancy with the intakes of women who were non-smokers. DESIGN: Cross-sectional study conducted between June 2014 and March 2016. SETTING: Stand-alone tertiary maternity hospital in an urban setting with approximately 8000 deliveries per year. PARTICIPANTS: Women were recruited at their convenience after sonographic confirmation of an ongoing singleton pregnancy (n=502). Detailed dietary and supplement information was available for 398 women. Women <18 years and those who did not speak English fluently were excluded. PRIMARY AND SECONDARY OUTCOME MEASURES: The differences in dietary micronutrients and macronutrients and maternal folate levels between women who continued to smoke in pregnancy compared with non-smokers. RESULTS: Of the 502 women, the mean age was 30.5 (SD 5.6) years, 42.5% were nulliparas, 19.2% were obese and 398 (79.3%) completed the questionnaire satisfactorily. In the 50 (12.6%) current smokers, the micronutrients magnesium, iron, carotene and copper were lower (all p<0.005) whereas sodium and chloride were higher compared with the 348 (87.4%) non-smokers. Smokers reported lower intakes of dietary total folate (p=0.006) compared with non-smokers (i.e., dietary folate equivalents; intake from natural and fortified dietary sources) (p=0.005). Smokers also reported lower intakes of fibre than non-smokers (13.1 g (IQR 7.7) vs 16.3 g (IQR 8.5), p<0.001). The dietary intakes of former smokers compared favourably with non-smokers. CONCLUSIONS: We found that women who continue to smoke during pregnancy have serious dietary inadequacies which could potentially aggravate fetal growth restriction associated with direct toxicity from cigarettes. This provides a further reason to promote smoking cessation interventions in pregnancy, and highlights the need for dietary and supplementation interventions in women who continue to smoke.

Voluntary fortification is ineffective to maintain the vitamin B12 and folate status of older Irish adults: evidence from the Irish Longitudinal Study on Ageing (TILDA).

Mandatory fortification of staple grains with folic acid and/or vitamin B12 (B12) is under debate in many countries including Ireland, which has a liberal, but voluntary, fortification policy. Older adults can be at risk of both deficiency and high folate status, although little is known on the actual prevalence and the major predictors. Population prevalence estimates from older adults (n 5290 ≥50 years) from the Irish Longitudinal Study on Ageing (TILDA) (Wave 1) are presented here. Measures included plasma total vitamin B12 and folate, whereas predictors included detailed demographic, socio-economic, geographic, seasonal and health/lifestyle data. The prevalence of deficient or low B12 status (45 nmol/l) was observed in 8·9 %, whereas high B12 status was observed in 3·1 % (>601 pmol/l). The largest positive predictor of B12 concentration was self-reported B12 injection and/or supplement use (coefficient 51·5 pmol/; 95 % CI 9·4, 93·6; P=0·016) followed by sex and geographic location. The largest negative predictor was metformin use (-33·6; 95 % CI -51·9, -15·4; P<0·0001). The largest positive predictor of folate concentration was folic acid supplement use (6·0; 95 % CI 3·0, 9·0 nmol/l; P<0·001) followed by being female and statin medications. The largest negative predictor was geographic location (-5·7; 95 % CI -6·7, -4·6; P<0·0001) followed by seasonality and smoking. B-vitamin status in older adults is affected by health and lifestyle, medication, sampling period and geographic location. We observed a high prevalence of low B12 and folate status, indicating that the current policy of voluntary fortification is ineffective for older adults.

Lifestyle, metabolite, and genetic determinants of formate concentrations in a cross-sectional study in young, healthy adults.

Background: Formate is an important metabolite that serves as a donor of one-carbon groups to the intracellular tetrahydrofolate pool. However, little is known of its circulating concentrations or of their determinants. Objective: This study aimed to define formate concentrations and their determinants in a healthy young population. Design: Serum formate was measured in 1701 participants from the Trinity Student Study. The participants were men and women, aged 18 to 28 y, enrolled at Trinity College, Dublin. Formate concentrations were compared with other one-carbon metabolites, vitamin status, potential formate precursors, genetic polymorphisms, and lifestyle factors. Results: Serum formate concentrations ranged from 8.7 to 96.5 µM, with a mean of 25.9 µM. Formate concentrations were significantly higher in women than in men; oral contraceptive use did not further affect them. There was no effect of smoking or of alcohol ingestion, but the TT genotype of the methylenetetrahydrofolate reductase (MTHFR) 677C→T (rs1801133) polymorphism was associated with a significantly decreased formate concentration. Formate was positively associated with potential metabolic precursors (serine, methionine, tryptophan, choline) but not with glycine. Formate concentrations were positively related to serum folate and negatively related to serum vitamin B-12. Conclusions: Formate concentrations were sensitive to the concentrations of metabolic precursors. In view of the increased susceptibility of women with the TT genotype of MTHFR to give birth to infants with neural tube defects as well as the effectiveness of formate supplementation in decreasing the incidence of folate-resistant neural tube defects in susceptible mice, it will be important to understand how this genotype decreases the serum formate concentration. This trial was registered at www.clinicaltrials.gov as NCT03305900.

Should vitamin B12 status be considered in assessing risk of neural tube defects?

There is a strong biological premise for including vitamin B12 with folic acid in strategies to prevent neural tube defects (NTDs), due to the closely interlinked metabolism of these two vitamins. For example, reduction of B12 deficiency among women of reproductive age could enhance the capacity of folic acid to prevent NTDs by optimizing the cellular uptake and utilization of natural folate cofactors. Vitamin B12 might also have an independent role in NTD prevention, such that adding it in fortification programs might be more effective than fortifying with folic acid alone. Globally, there is ample evidence of widespread vitamin B12 deficiency in low- and middle-income countries, but there is also considerable divergence of vitamin B12 status across regions, likely due to genetic as well as nutritional factors. Here, I consider the evidence that low vitamin B12 status may be an independent factor associated with risk of NTDs, and whether a fortification strategy to improve B12 status would help reduce the prevalence of NTDs. I seek to identify knowledge gaps in this respect and specify research goals that would address these gaps.