Targeted Folic Acid Supplements Outperform Mandatory Bread Fortification in Portugal

Targeted folic acid supplementation for women of childbearing age provides substantially greater population health benefits than mandatory bread fortification in Portugal, according to a risk-benefit assessment published in Food Safety and Risk. Portuguese researchers evaluated fifteen dietary scenarios using national survey data and Monte Carlo simulations to quantify population health impacts in disability-adjusted life years. Providing daily supplements of 400 micrograms of folic acid to women of reproductive age without fortifying bread achieved an estimated net reduction of 1,285 disability-adjusted life years compared to baseline habitual intake. Conversely, mandatory bread fortification produced net population health losses across all evaluated fortification concentrations, reaching 2,888 lost healthy life years under the highest fortification scenario. These divergent outcomes reflect an underlying demographic conflict between preventing congenital malformations in newborns and exacerbating irreversible neurological harm among older adults.

The investigation addressed widespread dietary folate inadequacy identified across Portugal in the National Food and Physical Activity Survey (IAN-AF 2015–2016). Folate is an essential B vitamin required for metabolic processes and normal cellular division during rapid growth phases. Because humans cannot synthesize folate, adequate dietary intake is critical, particularly as poor diets were associated with 10.6 percent of global deaths in 2021. Survey findings revealed that folate had the highest prevalence of intakes below the average requirement among all micronutrients in Portugal, with 66 percent of women and 54 percent of men having inadequate intakes. Folate deficiency causes megaloblastic anaemia, wherein reduced cellular division rates produce abnormally large red blood cells with poorly differentiated nuclei. While natural dietary folate is safe in high amounts, synthetic folic acid carries physiological risks, leading the European Food Safety Authority to set an adult tolerable upper intake level of 1,000 micrograms daily.

A major public health concern associated with elevated synthetic folic acid consumption involves individuals experiencing vitamin B12 deficiency, a condition prevalent among Portuguese older adults. Increased folic acid exposure can produce a transient correction of megaloblastic anaemia without addressing underlying B12 depletion. This hematological remission can obscure clinical diagnosis by eliminating recognizable blood anomalies, making deficiency detection substantially more challenging. Consequently, diagnosis is delayed and accompanying neurological symptoms progress, potentially causing irreversible damage to the nervous system. Although mandatory food fortification is widely considered a sustainable public health approach capable of delivering nutrients to broad populations without altering dietary patterns, it inevitably exposes demographic groups that derive no health benefits from additional folic acid. In Portugal, this indiscriminate exposure introduces serious neurological risks to older individuals who already consume inadequate dietary vitamin B12.

To evaluate these competing physiological outcomes, the study modeled fifteen scenarios combining baseline foods, fortified bread, and dietary supplements. The reference scenario represented the current habitual dietary folate intake of the Portuguese population without mandatory fortification. Bread and toast was selected as the optimal vehicle because of its dietary ubiquity and baking stability. The researchers evaluated four mandatory fortification levels: 70 micrograms per 100 grams of bread in scenario A, 140 micrograms in scenario B, 280 micrograms in scenario C, and 420 micrograms in scenario D. Additional scenario configurations simulated populations consuming unfortified diets without supplements in scenario REF1, fortified bread alone in scenarios A1 through D1, and targeted supplementation of 400 micrograms daily among women of childbearing age aged 15 to 49 years with complete adherence in scenario E.

Exposure assessment utilized food consumption data from the two-day dietary recall of the IAN-AF 2015–2016 survey. Folic acid quantities in bread were converted into dietary folate equivalents using a factor of 1.7. Habitual daily folate intake distributions across demographic groups were generated using the SPADE software package. For scenario E, where intake distributions for women of childbearing age could not be derived using SPADE, researchers calculated kernel density estimates based on two-day recall averages. To quantify variability and uncertainty, the team performed Monte Carlo simulations with 10,000 iterations in R Studio, applying PERT distributions based on habitual intake matrices and bootstrap confidence bounds. Colorectal cancer and cardiovascular disease were excluded from the quantitative assessment due to substantial dose-response uncertainties and inconclusive empirical evidence.

Health effects were modeled using mathematical dose-response functions adapted from previous Dutch assessments. Irreversible neurological damage due to masked vitamin B12 deficiency was calculated using equations integrating baseline B12 deficiency rates, anaemia probabilities, neurological damage likelihood, symptom masking across folate levels, and a false diagnosis probability assuming clinicians miss deficiency without anaemia. For megaloblastic anaemia, researchers applied an exponential regression function based on the World Health Organization threshold of 13.4 nanomoles per liter of serum folate, equivalent to 220 micrograms per day of dietary folate equivalents, above which anaemia probability reached zero. For neural tube defects, a non-linear dose-response equation linked maternal dietary folate equivalent intake to the probability of an infant being born with neural tube defects, applying an international conversion factor of 1 nanogram per milliliter equal to 2.265 nanomoles per liter.

The overall health impact of each scenario was quantified in disability-adjusted life years, combining years of life lived with disability and years of life lost due to premature mortality. Years lived with disability were derived from disease case numbers, disability weights, and average clinical durations. Neurological damage was evaluated as irreversible and non-fatal, with disability-adjusted life years calculated solely from years lived with disability using a disability weight of 0.203 and an average duration based on remaining life expectancy at age 65. Megaloblastic anaemia was assigned a one-year duration until clinical remission and a disability weight of 0.052 for moderate anaemia. Neural tube defects integrated distinct epidemiological parameters reflecting severe conditions such as anencephaly and spina bifida. Overall net health impacts were established by summing disability-adjusted life years across all three health outcomes and comparing totals against the reference scenario.

The findings revealed that scenario E produced the lowest overall disease burden across all evaluated options, accumulating approximately 3,419 disability-adjusted life years with a 95 percent credible interval of 3,174 to 3,677 DALYs. Compared to the reference scenario, scenario E achieved the most favorable overall health impact, yielding 1,285 healthy years saved with a credible interval of 1,281 to 1,289 DALYs. In stark contrast, scenario D caused the highest overall disease burden at 7,594 disability-adjusted life years with a credible interval of 7,337 to 7,851 DALYs, resulting in 2,888 lost healthy years relative to baseline. In scenario B, for example, the model estimated 476 lost healthy years with a credible interval of 127 to 824 DALYs.

The results highlighted an inherent epidemiological paradox: increasing fortification concentrations reduced cases of megaloblastic anaemia and neural tube defects, but simultaneously elevated the incidence of neurological damage among older adults. Fortification levels of 280 micrograms or more of folic acid per 100 grams of bread caused net negative overall health impacts across all scenario variations. For example, scenario B1 with 140 micrograms fortification and no baseline supplements saved 459 healthy years, whereas scenario C1 at 280 micrograms caused 328 lost healthy years. Furthermore, in scenario D1, characterized by the maximum fortification level of 420 micrograms per 100 grams of bread without supplements, the estimated incidence of neonates born with neural tube defects remained higher than in scenario E, which combined unfortified food with recommended periconceptional supplementation.

The health benefits of fortification in Portugal were substantially lower than those previously estimated for the Dutch population using identical methodology and fortification levels. The authors explained that these discrepancies stemmed from a higher likelihood of vitamin B12 deficiency among Portuguese older adults and differing dietary habits influencing bread consumption and baseline nutritional status. In addition, the Portuguese study applied an anaemia cut-off of approximately 220 micrograms daily derived from the World Health Organization serum folate threshold of 13.4 nanomoles per liter, whereas the Dutch study used a 300 microgram recommended daily intake. The Portuguese model also selected a disability weight of 0.203 for moderate neurological damage, compared to 0.064 assigned in the Dutch analysis. Internationally, mandatory fortification has been adopted in more than 81 countries, yielding variable neural tube defect reductions of 68 percent in Australia, 46 percent in Canada, and 19 percent in the United States.

In Portugal, the estimated incidence of neural tube defects is approximately one in every 970 live births, close to the European average of one in a thousand pregnancies reported by EUROCAT. Although a 1991 international trial demonstrated that adherence to folic acid supplementation could prevent 72 percent of neural tube defects, following Portuguese recommendations in scenario E resulted in a 51 percent reduction, preventing approximately 45 cases compared to baseline. However, empirical compliance in Portugal remains poor: survey data showed that only 13.8 percent of women commenced supplementation pre-conceptionally, 46.2 percent initiated supplementation in the first trimester, and 6.1 percent did not take folic acid at any point. The authors noted limitations, including assuming universal diagnostic failure for masked B12 deficiency and excluding vegetarian populations due to unavailable data. The researchers concluded that public health policy should prioritize promoting compliance with targeted periconceptional supplementation and healthier diets rather than implementing mandatory bread fortification.

Subject of Research: Risk-benefit assessment of folic acid bread fortification and supplementation scenarios in Portugal

Article Title: Risk–benefit assessment of different scenarios of bread fortification and supplementation with folic acid in Portugal

Article References: Oliveira, B. C., Nunes, T. P., & Pires, S. M. (2026). Risk–benefit assessment of different scenarios of bread fortification and supplementation with folic acid in Portugal. Food Safety and Risk, 13(1), Article 48. https://doi.org/10.1186/s40550-026-00172-y

Image Credits: AI Generated

DOI: 10.1186/s40550-026-00172-y

Keywords: folic acid, bread fortification, dietary supplementation, risk-benefit assessment, neural tube defects, vitamin B12 deficiency, public health, disability-adjusted life years, Risk, benefit, assessment, different