Mary Rose Sweeney

Folic acid fortification and public health: Report on threshold doses above which unmetabolised folic acid appear in serum

BackgroundAll flour in the USA is fortified with folic acid at a level of 140 μg/100 g which is estimated to supply an extra 100 μg daily to the average diet. Some researchers have advocated that this be increased to double and even four times this amount. Based on previous research these higher levels are likely to lead to the appearance of unmetabolised vitamin in the circulation, which may have safety implications for sub-groups of the population. The UK and the Republic of Ireland will likely introduce mandatory fortification also in the next year or so.The aim of this study was to capture the short-term effect of folic acid fortification on unmetabolised folic acid in serum after chronic consumption of folic acid.MethodsAfter pre-saturation with 400 μg folic acid supplements daily for 14-weeks, healthy folate replete adults (n = 20) consumed folic acid fortified bread, at three different levels (400 μg, 200 μg, 100 μg) over a period of one week each. The dose was administered in two-equal sized slices consumed at 09.00 hrs and 13.00 hrs. Serum samples for total folate and folic acid were collected at baseline, after 14-weeks of supplementation, and pre and post (at 1, 2, 3 and 4 hours) each dose tested.ResultsUnmetabolised folic acid was detected after the 14-week supplementation period. Folic acid was not detected in either the 200 μg or 100 μg (current US regime) doses tested but was present at the highest level (400 μg) tested.ConclusionOur findings suggest that persons exposed to the current US fortification programme supplying an average of 100 μg per day or less are unlikely to have unmetabolised folic acid in serum. It also seems that daily consumption of the higher level of 200 μg or less is unlikely to be problematic. Increasing the level however to 400 μg on the other hand is likely to lead to unmetabolised folic acid appearance.

Folic acid levels in some food staples in Ireland are on the decline: implications for passive folic acid intakes?

BACKGROUND Neural tube defects are largely preventable by the maternal periconceptual consumption of folic acid. The aim of this study was to examine the levels of synthetic folic acid in foods and the range of food stuffs with added folic acid available to consumers in Ireland at the current time. METHODS Three audits of fortified foods available in supermarkets in the Republic of Ireland were conducted. Researchers visited supermarkets and obtained folic acid levels from nutrition labels in 2004, 2008 and 2013/4. Levels were compared using MS Excel. RESULTS The profile of foods fortified with folic acid in 2013/4 has changed since 2004. The percentage of foods fortified with folic acid has decreased as has the level of added folic acid in some food staples, such as fat/dairy spreads. CONCLUSION Bread, milk and spreads no longer contain as much folic acid as previously (2004 and 2008). This may contribute to a decrease in folate intake and therefore may contribute to an increase in NTD rates. Research on current blood concentrations of folate status markers is now warranted.

Persistent circulating unmetabolised folic acid in a setting of liberal voluntary folic acid fortification. Implications for further mandatory fortification

BackgroundIreland is an example of a country that has extensive voluntary fortification with folic acid. After a public consultation process, in 2006, the Food Safety Authority in Ireland FSAI [1] recommended mandatory fortification. However due to safety considerations this decision is now on hold. Before mandatory fortification goes ahead, existing levels of unmetabolised folic acid and their anticipated increase after fortification needs investigation because of the potential of folic acid to mask pernicious anaemia and possibly accelerate the growth of existing cancers. The aim of this study was to examine the levels of circulatory unmetabolised folic acid in Irish adults (both fasted and un-fasted) and new-born infants (fasted) before the proposed implementation of mandatory folic acid fortification. A secondary aim was to predict the increase in circulatory unmetabolised folic acid levels after fortification.MethodsStudy 1. Setting: Irish Blood Transfusion Service (IBTS). Whole blood samples were collected from blood donors (n = 50) attending for routine blood donation sessions (representing the general population). Subjects were not fasted prior to sampling. Study 2. Setting: Coombe Womens and Infants University Hospital, Dublin. Whole blood samples were collected by venipuncture from mothers (n = 20), and from their infants umbilical-cords (n = 20) immediately after caesarean section. All women had been fasted for at least 8 hours prior to the surgery. A questionnaire on habitual and recent dietary intakes of folic acid was administered by an interviewer to all subjects. The data collection period was February to April 2006. Serum samples were analysed for plasma folate, plasma folic acid and red cell folate.ResultsBlood Donor Group: Circulatory unmetabolised folic acid was present in 18 out of 20 mothers (fasted) (CI: 68.3%–99.8%) comprising 1.31% of total plasma folate, 17 out of 20 babies (fasted) (CI: 62.1%–96.8%), and 49 out of 50 blood donors (unfasted) (CI: 88.0%–99.9%), comprising 2.25% of total plasma folate,ConclusionWhile the levels of circulatory unmetabolised folic acid reported are low, it is persistently present in women immediately after caesarean section who were fasting indicating that there would be a constant/habitual exposure of existing tumours to folic acid, with the potential for accelerated growth. Mandatory fortification might exacerbate this. This has implications for those with responsibility for drafting legislating in this area.

Evidence of unmetabolised folic acid in cord blood of newborn and serum of 4-day-old infants

Oral folic acid above certain threshold doses results in unmetabolised folic acid in serum. This raises a number of public health safety issues, principally the potential to mask pernicious anaemia; more recently the theoretical potential for high-dose folic acid to promote cancer has been highlighted. In this paper we set out to examine the appearance of unmetabolised folic acid both in cord blood from newborn full-term and premature infants and serum from 4-d-old infants post-formula feeding. Blood was collected from the umbilical cord of eleven infants in the delivery room immediately after birth. A follow-up serum sample (n 9) was collected 4 d later from infants post-formula feeding. We detected unmetabolised folic acid in cord blood from all infants at birth. In addition, unmetabolised folic acid was present in serum of seven infants post-formula feeding, six of which had increased from birth. Our results imply that infants in Ireland, which does not yet have mandatory fortification, could potentially have circulatory unmetabolised folic acid at the time of birth. We do not know if the presence of folic acid in cord blood will have any adverse consequences. However, if theoretical safety concerns are borne out by future research, the likelihood is that the longer the exposure the more likely the potential for harm. This would also be the case in infants exposed to unmetabolised folic acid as a result of formula feeding.

Postprandial serum folic acid response to multiple doses of folic acid in fortified bread.

The benefit of the introduction of mandatory folic acid fortification of all flour products in the USA in 1998 has been amply demonstrated in a reduction of neural tube defect births. Doubt has been cast on the actual level of fortification and recent calculations have shown that the level of folic acid fortification is likely to have been over twice the amount mandated. The implication of this is that a greater proportion of the population are likely to have consumed folic acid at >1 mg/d, the Food and Drug Administration safe upper level of intake. Using the criteria of appearance of synthetic folic acid in serum, the objective of this pilot study was to investigate the consequences of consumption of baked bread preparations containing 1 mg folic acid. Four healthy adult volunteers undertook each dosing schedule 2 weeks apart. This consisted of a single dose of 1000 microg, two doses of 500 microg, three doses of 333 microg, five doses of 200 microg and, finally, ten doses of 100 microg. Serum was collected pre- and postprandially and analysed for synthetic folic acid by a combined HPLC-microbiological assay for folic acid. Folic acid appeared in all subjects at all test doses, with the effect more pronounced as the standard dose was administered in smaller amounts over the test period. Approaches to optimise folic acid intake in target populations as part of a universal fortification strategy should take into consideration the potential hazard of over-exposure in groups consuming high amounts of flour-based products.

Measurements of sub-nanomolar concentrations of unmetabolised folic acid in serum

We describe a combined HPLC/microbiological assay procedure for the sub-nanomolar analysis of unmetabolised folic acid (pteroylglutamate) in human serum. This metabolically unaltered form of the vitamin arises following the consumption of folic acid either in supplemental form or in fortified foods. Following HPLC separation of folic acid from other folate derivatives the folic acid fraction was concentrated by C(18) Sep-Pak cartridges and assayed by Lactobacillus casei microbiological assay. The present assay allows the quantitation and kinetic analysis of the effects of consumption of folic acid.

Unmetabolized folic acid prevalence is widespread in the older Irish population despite the lack of a mandatory fortification program

BACKGROUND In 2006 the Food Safety Authority of Ireland recommended mandatory folic acid fortification of flour for the prevention of neural tube defects in addition to the existing extensive voluntary folic acid fortification culture in place there. This recommendation is now suspended until further scientific evidence surrounding safety becomes available. The safety issues include concerns about the masking of vitamin B-12 deficiency and potential cancer acceleration, both of which may be of concern for the elderly population. OBJECTIVE The aim of this study was to measure the basal (fasted) concentrations of unmetabolized folic acid in the plasma of an elderly population group exposed to this liberal voluntary fortification of foodstuffs in Ireland. DESIGN We invited participants aged 60-86 y from the Lifeways Cross-Generation Cohort Study to participate in this project. After providing informed consent, the participants were invited to provide fasting blood samples and to complete a standard food-frequency questionnaire and a questionnaire on recent and habitual intakes of folic acid. Samples were assayed for total plasma folate, red blood cell folate, homocysteine, and unmetabolized folic acid. RESULTS A total of 137 subjects with a mean age of 67.4 y were studied. Unmetabolized folic acid was detected in 94.1% of the cohort with a mean concentration of 0.39 nmol/L (range: 0.07-1.59 nmol/L), accounting for 1.3% of total plasma folate. CONCLUSION These results indicate unmetabolized folic acid in plasma in most of this elderly Irish cohort, even after an overnight fast. These results should be considered carefully by those legislating in this area.

Familial intergenerational and maternal aggregation patterns in nutrient intakes in the Lifeways Cross-Generation Cohort Study.

OBJECTIVE The current study prospectively examines the intra-uterine hypothesis by comparing maternal, paternal and grandparental lineage influences on children’s diet and also maternal–child aggregation patterns during pregnancy and early childhood. DESIGN Prenatal dietary information was available for expectant mothers, fathers and up to four grandparents through a detailed validated semi-quantitative FFQ. At 6-year follow-up, when children averaged 5 years of age, dietary information was re-collected for mothers and a subset of maternal grandmothers using the same FFQ. Child’s FFQ version was used for children. Anthropometric and sociodemographic variables were also collected. SETTINGS Three-generation familial cohort representative of the contemporary Irish national population. SUBJECTS Children aged 5 years (n 567) and their parents and grandparents. RESULTS Associations for energy, macronutrient and fibre intakes were compared using Pearson’s correlations, intra-class correlations (ICC) and linear regression models, adjusted for energy and potential confounders. Significant, moderatestrength positive correlations were observed for nutrient intakes in children’s nuclear families (ICC (range)50?22–0?28). The father–child associations (r (range)5 0?13–0?20) were weaker than the mother–child associations (r (range)50?14–0?33). In general, associations were stronger for maternal postnatal intake–child intake than for maternal prenatal intake–child intake, except for percentage of energy from fat (adjusted b50?16, 95% CI 0?05, 0?26; P50?004), which was stronger for maternal prenatal intake, specifically in non-breast-fed children (adjusted b50?28, 95% CI 0?12, 0?44; P50?001). Among all grandparents, correlations were significant only for maternal grandmother–mother pairs (r (range)50?10–0?36). Significant positive ICC were observed for nutrient intakes of maternal grandmother–mother–child triads (ICC (range)50?12–0?27), not found in paternal lines. CONCLUSIONS These findings suggest that maternal-environment programming influences dietary intake.

Overweight and obesity on the island of Ireland: an estimation of costs

Objectives The increasing prevalence of overweight and obesity worldwide continues to compromise population health and creates a wider societal cost in terms of productivity loss and premature mortality. Despite extensive international literature on the cost of overweight and obesity, findings are inconsistent between Europe and the USA, and particularly within Europe. Studies vary on issues of focus, specific costs and methods. This study aims to estimate the healthcare and productivity costs of overweight and obesity for the island of Ireland in 2009, using both top-down and bottom-up approaches. Methods Costs were estimated across four categories: healthcare utilisation, drug costs, work absenteeism and premature mortality. Healthcare costs were estimated using Population Attributable Fractions (PAFs). PAFs were applied to national cost data for hospital care and drug prescribing. PAFs were also applied to social welfare and national mortality data to estimate productivity costs due to absenteeism and premature mortality. Results The healthcare costs of overweight and obesity in 2009 were estimated at €437 million for the Republic of Ireland (ROI) and €127.41 million for NI. Productivity loss due to overweight and obesity was up to €865 million for ROI and €362 million for NI. The main drivers of healthcare costs are cardiovascular disease, type II diabetes, colon cancer, stroke and gallbladder disease. In terms of absenteeism, low back pain is the main driver in both jurisdictions, and for productivity loss due to premature mortality the primary driver of cost is coronary heart disease. Conclusions The costs are substantial, and urgent public health action is required in Ireland to address the problem of increasing prevalence of overweight and obesity, which if left unchecked will lead to unsustainable cost escalation within the health service and unacceptable societal costs.

Synthetic folic acid intakes and status in children living in Ireland exposed to voluntary fortification

BACKGROUND In the context of mandatory and voluntary folic acid fortification, the exposure of children to folic acid has been a focus of concern, particularly regarding the possibility of whether any potentially adverse effects will emerge in the future. OBJECTIVE We explored concentrations of fasting unmetabolized folic acid (UFA) in the circulation of children living in Ireland who were exposed to the voluntary folic acid-fortification regimen in place in Ireland. DESIGN Healthy children who were attending Our Ladys Childrens Hospital, Crumlin, for routine minor surgery were recruited to provide a fasting 3-mL blood sample that was taken while a general anesthetic was administered. The samples were analyzed for plasma folate, red blood cell folate, and UFA concentrations. A short dietary questionnaire that captured recent and habitual intakes of folic acid, both as supplements and as fortified foods, was completed face to face with parents. RESULTS We collected fasting samples (n = 68) and completed questionnaires that captured recent and habitual daily folic acid intakes of children grouped as follows: 0-5 y of age: 6 girls and 21 boys (27 children total); 6-10 y of age: 10 girls and 10 boys (20 children total); and 11-16 y of age: 10 girls and 11 boys (21 children total). UFA was detected in 10.3% of the samples tested (range: 0.5-1.3 nmol/L). Mean plasma folate and red blood cell folate concentrations were 35.1 nmol/L (range: 21-47 nmol/L) and 956 nmol/L (range: 305-2319 nmol/L), respectively. Mean daily intake of folic acid from fortified foods and supplements was 109 μg (range: 0-767 μg). CONCLUSIONS We showed that there was UFA in the plasma of just >10% of the children sampled after an overnight fast. These findings should be considered by policy makers who are responsible for folic acid fortification. This trial was registered at www.isrctn.com as ISRCTN90038765.