Effect of once weekly folic acid supplementation on erythrocyte folate concentrations in women to determine potential to prevent neural tube defects: a randomised controlled dose-finding trial in Malaysia

IntroductionFolic acid (0.4 mg) taken prior to and during early pregnancy reduces the risk of neural tube defects (NTDs). Because these birth defects occur early in pregnancy, before women may know they are pregnant, many countries have mandated the addition of folic acid to food staples. In countries where fortification is not possible, and weekly iron folic acid programmes exist to reduce anaemia, the WHO recommends that 2.8 mg (7×0.4 mg) folic acid be given instead of the current weekly practice of 0.4 mg. Currently, there is a lack of evidence to support if the 2.8 mg folic acid per week dose is sufficient to raise erythrocyte folate concentrations to a level associated with a reduced risk of a NTD-affected pregnancy. We aim to conduct a three-arm randomised controlled trial to determine the effect of weekly folic acid with iron on erythrocyte folate, a biomarker of NTD risk.Methods and analysisWe will recruit non-pregnant women (n=300; 18–45 years) from Selangor, Malaysia. Women will be randomised to receive either 2.8, 0.4 or 0.0 (placebo) mg folic acid with 60 mg iron weekly for 16 weeks, followed by a 4-week washout period. The primary outcome will be erythrocyte folate concentration at 16 weeks and the mean concentration will be compared between randomised treatment groups (intention-to-treat) using a linear regression model adjusting for the baseline measure.Ethics and disseminationEthical approval was obtained from the University of British Columbia (H18-00768) and Universiti Putra Malaysia (JKEUPM-2018-255). The results of this trial will be presented at scientific conferences and published in peer-reviewed journals.Trial registration numbersACTRN12619000818134 and NMRR-19-119-45736.

Legume consumption in Sweden: a descriptive cross-sectional study

Despite the growing evidence supporting legume consumption as part of healthy and sustainable diet, little information is known on legume intake in the Swedish population. The aim of the present study was to describe legume consumers in Sweden, their nutrient intake and study the association with biomarkers of nutritional status using food consumption and biomonitoring data from Swedish adults in the 2010–11 National Riksmaten survey. Total legume intake - including pulses, fresh legumes, soy products, peanuts, sprouts and mixed meals with legumes - was estimated using a web-based 4-d food records in adults 18–80 years (n = 1772). A range of biomarkers including non-fasted plasma ferritin and folate, as well as erythrocyte folate, were measured for a subsample of the population (n = 282). Legumes were consumed by 44% of the population, median intake was 36 g/d (Q1 = 16; Q3 = 71; n = 777). Legumes provided on average 3.3% of individual's total energy intake (%E) with no significant difference between sexes. Pulses were consumed by 33% of consumers contributing to 3.2 ± 2.8 %E intake whereas soy products were consumed by 8.6% of legume consumers but contributing to 6 ± 7.5 %E. Legume intake among self-reported vegetarians (n = 55) was significantly higher (p < 0.000) than for non-vegetarians, with mean daily intakes of 92 ± 99 g/d and 21 ± 42 g/d, respectively. Age (p 0.0066) was significantly higher in Q4 of legume intake and alcohol consumption was significantly lower (p 0.0008); BMI, gender, smoking habits, education and total energy intake did not differ. 23% of legume consumers have a fiber intake of 25–35 g/d whereas only 11% of non-consumers reach recommended intake (p 0.0001). Iron, folate and dietary fiber intakes were significantly higher (p < 0.000) in Q4 of legume intake. 32% of legume consumers meet recommended intakes of folate (RI 300 μg/d) versus 18% for non-consumers (p 0.000). Notably, 5.76% of women of reproductive age (18–44 y.o.) eating legumes reach 400 μg/d versus 0.79% for non-consumers (p 0.002). Plasma ferritin and erythrocyte folate levels did not differ between legume consumers and non-consumers. However, for women in reproductive age (n = 31), plasma folate levels were significantly higher in consumers than non-consumers (p 0.0102). Legume consumers have higher fiber intake and more frequently meet recommended folate intakes while maintaining adequate iron intake. In conclusion, legume consumers in Sweden are characterized by a defined diet pattern that generally is associated with better health.

Folic acid deficiency declined substantially after introduction of the mandatory fortification programme in Queensland, Australia: a secondary health data analysis

Objective:To investigate the prevalence of folic acid deficiency in Queensland-wide data of routine laboratory measurements, especially in high-risk sub-populations.Design:Secondary health data analysis.Setting:Analysis of routine folic acid tests conducted by Pathology Queensland (AUSLAB).Participants:Female and male persons aged 0–117 years with routine folic acid testing between 1 January 2004 and 31 December 2015. If repeat tests on the same person were conducted, only the initial test was analysed (n 291 908).Results:Overall the prevalence of folic acid deficiency declined from 7·5 % before (2004–2008) to 1·1 % after mandatory folic acid fortification (2010–2015; P < 0·001) reflecting a relative reduction of 85 %. Levels of erythrocyte folate increased significantly from a median (interquartile range) of 820 (580–1180) nmol/l in 2008 before fortification to 1020 (780–1350) nmol/l in 2010 (P < 0·001) after fortification. The prevalence of folic acid deficiency in the Indigenous population (14 792 samples) declined by 93 % (17·4 v. 1·3 %; P < 0·001); and by 84 % in non-Indigenous residents (7·0 v. 1·1 %; P < 0·001). In a logistic regression model the observed decrease of folic acid deficiency between 2008 and 2010 was found independent of gender, age and ethnicity (ORcrude = 0·20; 95 % CI 0·18, 0·23; P < 0·001; ORadjusted = 0·21; 95 % CI 0·18, 0·23; P < 0·001).Conclusions:While voluntary folic acid fortification, introduced in 1995, failed especially in high-risk subgroups, the 2009 mandatory folic acid fortification programme coincided with a substantial decrease of folic acid deficiency in the entire population.

Vitamin B12and folate status in Spanish lacto-ovo vegetarians and vegans

Studies on the nutritional status of vegetarians in Spain are lacking. Prevention of vitamin B12deficiency is the main concern, as dietary sources are of animal origin. The present study aimed to evaluate vitamin B12and folate status of Spanish vegetarians using classical markers and functional markers. Participants were adult and healthy lacto-ovo vegetarians (forty-nine subjects) and vegans (fifty-four subjects) who underwent blood analyses and completed a FFQ. Serum vitamin B12, homocysteine (Hcy), methylmalonic acid (MMA), erythrocyte folate and haematological parameters were determined. The effects of the type of plant-based diet, and the intake of supplements and foods were studied by a FFQ. Mean erythrocyte folate was 1704 (sd609) nmol/l. Clinical or subclinical vitamin B12deficiency was detected in 11 % of the subjects (MMA>271 nmol/l) and 33 % of the participants showed hyperhomocysteinaemia (Hcy>15 µmol/l). Regarding plant-based diet type, significantly higher Hcy was observed in lacto-ovo vegetarians compared with vegans (P = 0·019). Moreover, use of vitamin B12supplements involved an improvement of vitamin B12status but further increase in erythrocyte folate (P = 0·024). Consumption of yoghurts was weakly associated with serum vitamin B12adequacy (P = 0·049) and that of eggs with lower Hcy (P = 0·030). In conclusion, Spanish vegetarians present high folate status but vitamin B12subclinical deficiency was demonstrated using functional markers. The lack of influence of dietary sources on functional markers and the strong effect of vitamin B12supplement intake emphasise the need of cobalamin supplementation in both lacto-ovo vegetarians and vegans.

Micronutrient status in middle childhood and age at menarche: results from the Bogotá School Children Cohort

Childhood intake of animal foods is associated with age at first menstrual period (menarche). It is unknown whether the micronutrients present in these foods could explain this association. Our objective was to investigate the associations of micronutrient status biomarkers in middle childhood with age at menarche. We quantified circulating Hb, ferritin, mean corpuscular volume, Zn, vitamin B12, erythrocyte folate and retinol in 1464 pre-menarcheal girls aged 5–12 years in Bogotá, Colombia, and followed them for a median 5·7 years for the occurrence and date of menarche. We estimated median age at menarche and hazard ratios (HR) with 95 % CI by levels of each biomarker with use of Kaplan–Meier survival probabilities and Cox regression, respectively. Median age at menarche was 12·4 years. Middle childhood Hb was inversely related to age at menarche whereas plasma ferritin was positively associated with this outcome in a linear manner. HR of menarche for every 1sdof Hb (11 g/l) and ferritin (23·2 µg/l) were 1·11 (95 % CI 1·04, 1·18;P=0·001) and 0·94 (95 % CI 0·88, 0·99;P=0·02), respectively, after adjustment for baseline age, C-reactive protein concentration, maternal age at menarche and parity and socioeconomic status. The association with ferritin was stronger in girls aged 9–10 years at baseline. Additional adjustment for baseline height- and BMI-for-age did not change the results. We conclude that higher Fe status in middle childhood is related to later age at menarche whereas Hb concentrations are inversely associated with age at onset of menses.

Folate status in women of childbearing age with obesity: a review

Several studies have described a positive association between elevated BMI and birth defects risk. Data on plasma concentration of folate in pregnant women with obesity have shown values far below those recommended, regardless of diet, while folate levels should increase before pregnancy to reduce neural tube defects. We report a descriptive review of the most recent studies (from 2005 to 2015) to evaluate folate status through a population of women of childbearing age affected by obesity. The literature contains few studies, which present conflicting results regarding folate status in non-pregnant women of childbearing age affected by obesity, and it appears that there is a modification in folate metabolism, with a reduction in plasma folate levels and an increase in erythrocyte folate uptake. In conclusion, the folate status in women of childbearing age should be assessed by both plasma and erythrocyte levels to start a personalised and more adequate supplementation before conception. Further studies need to be conducted in a larger population, which take into account variables that can affect folate metabolism, such as dietary intake, lifestyle and genetic factors, oral contraceptives or other drug use, previous weight-loss programmes, or a history of bariatric surgery.

Folate intakes from diet and supplements may place certain Canadians at risk for folic acid toxicity

To examine the prevalence of folate inadequacy and toxicity based on usual intakes from food and supplements, as well as biomarkers of folate, secondary data analyses were performed using cross-sectional, nationally representative data from the Canadian Community Health Survey, Cycle 2.2 (n32 776), as well as biomarker data from the Canadian Health Measures Survey, Cycles 1, 2 and 3 (n15 754). On the basis of unfortified food sources, Canadians would struggle to consume adequate amounts of folate. When folate intakes from all food sources were considered, the overall prevalence of folate inadequacy was low across all age/sex groups, with the exception of females >70 years. However, >10 % of supplement users were above the tolerable upper intake level, increasing to almost 18 % when overage factors were accounted for. In addition, between 20 and 52 % of supplement users had elevated erythrocyte folate concentrations, depending on the cut-off used. Results from this study suggest that insufficient dietary intakes of folate in Canadians have been ameliorated because of the fortification policy, although folate inadequacy still exists across all age groups. However, supplement users appear to be at an increased risk of folic acid (FA) overconsumption as well as elevated erythrocyte folate. As such, the general population should be informed of the potential risks of FA overconsumption resulting from supplement use. This study suggests a need for more careful assessment of the risks and benefits of food fortification, particularly fortification above mandated levels, and FA supplement use in the general population.