Vitamin B9 (Folate)

Introduction

One of the B vitamins is folate, which is sometimes referred to as folacin and vitamin B9. Because it is more stable during processing and storage, manufactured folic acid, which the body converts into folate, is used as a dietary supplement and in food fortification.

The body needs folate to metabolize amino acids needed for cell division as well as to produce DNA and RNA.

Folate is a necessary nutrient because the human body cannot produce it; therefore, it must be consumed through diet.

It’s found in many foods naturally. In the United States, 400 mcg of folate per day from food or dietary supplements is the recommended intake for adults.

Folate deficiency anemia is treated with folic acid, a type of folate. Pregnant mothers who want to lower their baby’s risk of neural tube abnormalities (NTDs) can also take folic acid supplements.

More than half of kids born with NTDs are thought to have low levels during the early stages of pregnancy.

Fortification of specific foods is used in more than 80 nations, either voluntarily or mandated. foods high in folic acid as a way to slow down the occurrence of NTDs.

Prolonged use of relatively high doses of folic acid supplements is linked to a little decrease in the risk of stroke and an increase in the risk of prostate cancer.

There are worries that folic acid supplements in high doses may conceal a vitamin B12 deficiency. Folate deficiency can result from inadequate folate intake.

This could lead to anemia of a kind where the red blood cells grow unnaturally large. Feeling exhausted, experiencing palpitations in the heart, breathing difficulties, open sores on the tongue, and skin or hair color changes are some of the symptoms.

Within a month of eating poorly, children may acquire a folate shortage. Adults should consume 10 to 30 mg of folate total day, with blood levels above 7 nmol/L (3 ng/mL).

Folate was identified in the years 1931–1943. It is included in the List of Essential Medicines by the World Health Organization. With more than 10 million prescriptions written for it in 2020, it was the 67th most often prescribed drug in the US.

Because it was present in dark-green leafy vegetables, the word “folic” comes from the Latin word folium, which means leaf.

Definition

The term “foliate” (vitamin B9) describes a variety of folic acid forms and related substances, such as methyltetrahydrofolate (the main form present in the blood), methyltetrahydrofolate, folinic acid, folacin, and pteroylglutamic acid.

Tetrahydrofolic acid is the active form of folic acid. Vitamin M, vitamin Bc, and L. casei factor were among the historical names.

Although they are occasionally used synonymously, the terms folate and folic acid have slightly distinct meanings depending on the situation.

The conjugate base of folic acid is referred to as folate in the realm of organic chemistry. In the realm of biochemistry, the term “folates” designates a group of physiologically active substances that are connected to and comprise folic acid.

In the context of nutrition, the phrase “folic acid” refers to the synthetic form of the vitamin that is taken as a dietary supplement; folates, on the other hand, are a family of vital nutrients related to folic acid that are derived from natural sources.

Chemically speaking, folates are made up of three different chemical moieties that are connected. A pterin (2-amino-4-hydroxy-pteridine) heterocyclic ring is connected to a p-aminobenzoyl group via a methylene bridge.

The p-aminobenzoyl group is then joined to either glutamic acid or poly-glutamate by an amide linkage.

The N10 nitrogen atom of the p-aminobenzoyl group and/or the N5 nitrogen atom of the pteridine ring can both accept one-carbon units in a range of oxidation states.

Health Effects

During times of frequent cell division and growth, including infancy and pregnancy, folate is particularly crucial.

Because hematopoietic cells and neoplasms divide more often than other cells, they are particularly affected by folate deficiency, which inhibits DNA synthesis and cell division.

Because mRNA may be recycled and used again, folate deprivation has less of an impact on RNA transcription and subsequent protein synthesis than on DNA synthesis, which requires the creation of a new genomic copy.

Birth Defects

Pregnant women who are deficient in folate may be at risk for neural tube abnormalities (NTDs), of which there were 300,000 cases globally before dietary fortification became law in several countries.

It is advised that any woman hoping to become pregnant take a folate-containing dietary supplement both before and during her pregnancy because NTDs happen early in pregnancy (first month), necessitating high levels of folate at conception.

It is recommended by the Centers for Disease Control and Prevention (CDC) that an individual consume 400 micrograms of Folic acid to avoid non-transferable diseases.

The advice is not fully followed, since many women become pregnant unintentionally or may not become aware of their pregnancy until much later in the first trimester—a crucial time for lowering the risk of non-traumatic diseases (NTDs).

Some nations have imposed compulsory or optional programs for fortifying wheat flour and other cereals, while others do not have such initiatives and instead rely on public health and medical professionals to advise women who are fertile.

A meta-analysis of spina bifida birth prevalence worldwide revealed that There was a 30% decrease in live births with spina bifida when obligatory fortification was compared to nations with voluntary fortification or no fortification program.

A drop of more than 50% was observed in certain countries. Since other forms of folate have not been researched, the US Preventive Services Task Force advises using folic acid as a supplement or fortification element.

Pregnancy-related folate supplementation was associated with a 28% decreased relative risk of congenital heart abnormalities in the fetus.

Folic acid supplementation during pregnancy did not seem to lower the risk of preterm births.

According to one systematic review, folic acid had no influence on a child’s growth, mortality, body composition, respiratory health, or cognitive development between the ages of.

One and nine. Maternal folic acid supplementation did not appear to be associated with a higher risk of childhood asthma.

Fertility

Folate aids in the process of spermatogenesis. Folate is essential for the quality and maturation of oocytes in women, as well as for implantation, placentation, fetal growth, and organ development.

Heart Disease

A meta-analysis revealed that multi-year folic acid supplementation, at levels beyond the upper limit of 1,000 μg/day in the majority of the clinical trials included, decreased the relative risk of cardiovascular disease by a negligible 4%.

There were no changes in the risk of cardiovascular disease according to two earlier meta-analyses, which would not have taken into account the findings of more recent clinical studies.

Stroke

With supplementation, the absolute risk of stroke drops from 4.4% to 3.8% (representing a 10% drop in relative risk).

The relative risk decreased similarly, according to two other meta-analyses. Only those with a history of coronary heart disease or cardiovascular disease were eligible for two of these three.

The stratified analysis revealed that risk was lowered more when there was a greater decrease in homocysteine, suggesting that the favorable outcome may be linked to lowering the circulating homocysteine content.

Additionally, the effect was greater for research done in nations where folic acid fortification of grains was not required.

In comparison to trials using higher doses of folic acid, the subset of trials using a lower supplement showed a greater favorable effect.

Cancer

The risk of colon, breast, ovarian, pancreatic, brain, lung, cervical, and prostate cancers may rise with chronically low folate consumption.

High intakes were thought to speed up the development of preneoplastic lesions that could eventually lead to cancer, particularly colon cancer, shortly after fortification programs were put into place.

There have been inconsistent findings from later meta-analyses comparing the effects of high versus low dietary folate, higher serum folate, and supplementary folate in the form of folic acid.

A small but statistically significant reduction in the risk of colon cancer was observed when dietary folate levels were compared between low and high.

Comparing low to high dietary folate levels had no effect on the risk of prostate cancer. An examination of Studies including dietary supplements containing folic acid revealed a statistically significant 24% increase in the incidence of prostate cancer.

It was demonstrated that higher quantities of serum folate may be obtained via supplementing with folic acid at 1,000–2,500 μg/day, which is the dosage utilized in the majority of the supplement trials mentioned.

This is in comparison to diets rich in food-derived folate. According to the second supplementation review, there was no discernible change in the incidence of any cancer, including hematological malignancies.

Colorectal cancer, other gastrointestinal cancers, genitourinary cancers, lung cancer, or total cancer incidence in those who took folic acid supplements.

Folic acid treatment was not linked to an increased risk of colorectal cancer, according to a third supplementing meta-analysis that was restricted to reporting solely on the incidence of colorectal cancer.

Anti-Folate Chemotherapy

For tissues and cells that divide quickly, folate is essential. Cancer is treated with medications that disrupt the metabolism of folate, as cancer cells proliferate quickly.

Because it prevents the inactive dihydrofolate (DHF) from being converted into the active tetrahydrofolate (THF), the antifolate medication methotrexate is frequently used to treat cancer.

Methotrexate, however, has the potential to be toxic, causing adverse effects such as gastrointestinal irritation that make eating regularly more challenging.

It has been documented that bone marrow depression can cause acute renal and liver failure as well as leukopenia and thrombocytopenia.

Leucovorin, a medication containing folinic acid and a type of folate (formyl-THF), is used to “rescue” or counteract the harmful effects of methotrexate.

Supplemental folic acid has minimal proven benefit in cancer treatment. When using methotrexate, folinic acid supplements are given to patients to ensure that less rapidly dividing cells have enough folate to continue functioning normally.

Methotrexate’s effects are still there even in the case of rapidly dividing cancer cells, which quickly exhaust folate supplies.

Neurological Disorders

Folate and vitamin B12 are needed for homocysteine to be converted to methionine. Dementia, Alzheimer’s disease, and cognitive impairment are linked to elevated plasma homocysteine and inadequate folate.

Folic acid and vitamin B12 supplements reduce plasma homocysteine. Nevertheless, folic acid supplementation.

Either by itself or in conjunction with other B vitamins, did not appear to stop the onset of cognitive impairment or slow down the rate of cognitive decline, according to many reviews.

According to a 2017 meta-analysis, pregnant women who supplemented their diet with folic acid had a 23% lower relative chance of developing autistic spectrum disorders.

This was verified by subset analysis among American, European, and Asian populations. There is evidence that clinical depression and folate deficiency are related.

Utilizing folic acid in combination with selective serotonin reuptake inhibitors (SSRIs) may be beneficial, according to limited data from randomized controlled trials.

Low levels of folate have been linked to depression, according to research. However, the precise processes leading to the onset of depression and schizophrenia are not fully understood.

The bioactive folate, Tetrahydrobiopterin (BH4), an essential cofactor in several stages of monoamine synthesis, including the synthesis of dopamine and serotonin, is produced by recycling the inactive.

Dihydrobiopterin (BH2) through methyltetrahydrofolate (5-MTHF), a direct target of methyl donors like S-adenosyl methionine (SAMe).

In addition to mediating the effects of most antidepressants, BH4 regulates monoamine neurotransmission.

Folic Acid, B12 and Iron

Iron, vitamin B12, and folic acid interact in a complicated way. Iron deficiency can be concealed by folic acid or vitamin B12 deficiencies, thus it’s important to take all three in balance when taking dietary supplements.

Malaria

The World Health Organization has changed its iron-folic acid supplementation guidelines for children in malaria-prone regions, like.

India, after some research, revealed that giving iron supplements to children under five may increase their death from the disease.

Metabolism

The liver’s dihydrofolate reductase enzyme, which transforms folate into tetrahydrofolate (THF), is responsible for the biological activity of folate in the body.

In humans, this activity is rate-limiting, resulting in increased blood concentrations of unmetabolized folic acid as intake from dietary supplements and fortified foods approaches or surpasses the 1,000 μg daily U.S. Tolerable Upper Intake Level.

Biosynthesis

Since humans and other animals cannot synthesize folate, they must get it through their diet. By variants on the same biosynthetic pathway, folate can be synthesized de novo by all plants, fungi, some bacteria, protozoa, and archaea.

Dihydropteroate synthase and dihydrofolate synthase combine to synthesize the folate molecule from pterin pyrophosphate, glutamate, and para-aminobenzoic acid.

Para-aminobenzoic acid is a byproduct of the shikimate pathway, whereas pterin is itself generated from guanosine triphosphate (GTP) by a sequence of enzymatically catalyzed processes.

Bioactivation

THF and its methylated derivatives carry out all of the biological activities of folic acid. Folic acid must therefore first be converted to THF.

Dihydrofolate reductase, the same enzyme, catalyzes both of the chemical processes involved in this four-electron reduction.

Tetrahydrofolate is the last product in the reduction of folic acid to dihydrofolate. One molecule of NADPH is consumed in each stage (biosynthetically generated from vitamin B3) and generates a single NADP molecule.

Mechanistically, hydride is moved from NADPH to the pteridine ring’s C6 position. By using serine hydroxymethyltransferase (SHMT), tetrahydrofolate is modified by adding a one-carbon (1C) methyl group, resulting in 5,10- methylenetetrahydrofolate (5,10-CH2-THF).

Along with producing glycine and pyridoxal, this process also consumes serine and pyridoxal phosphate (PLP; vitamin B6).

Methylenetetrahydrofolate dehydrogenase II, an additional enzyme, oxidizes 5,10-Methylenetetrahydrofolate is hydrolyzed to yield 5-formyl-THF and 10-formyl-THF, an iminium cation.

The majority of the one-carbon units accessible to the cell are produced by this sequence of reactions that use the serine’s β-carbon atom as the carbon source.

Other carbon sources include formate, which adds a 1C unit to THF by the catalytic action of formate–tetrahydrofolate ligase, resulting in 10-formyl-THF.

Sarcosine, histidine, and glycine can also directly add to the 1C pool that is linked to THF.

Drug Interference

Many medications prevent THF from being biosynthesized from folic acid. These include the antifolate dihydrofolate reductase inhibitors, which include trimethoprim.

An antibiotic; pyrimethamine, an antiprotozoal; methotrexate, a chemotherapy medicine; and sulfonamides, which are competitive inhibitors of 4-aminobenzoic acid in dihydropteroate synthetase processes.

One of the most often prescribed medications for treating epilepsy is valproic acid. It is also used to treat bipolar disorder and other psychological disorders.

Because valproic acid is a known folic acid inhibitor, it has been linked to birth defects, including neural tube defects, as well as an increased risk of autism and cognitive impairment in children. There is proof that consuming folate offers protection.

Function

The transportation of single-carbon groups—such as methyl, methylene, or formyl groups—is the primary metabolic role of tetrahydrofolate.

Many biological molecules can be modified or synthesized using these carbon groups as a transfer to other molecules.

Folates are necessary for many chemical events related to cellular metabolism, including the production of DNA, alteration of DNA and RNA, and the creation of methionine from homocysteine.

The combined term for these processes is “folate-mediated one-carbon metabolism.”

DNA Synthesis

Derivatives of folate contribute to the production of pyrimidines and purines.
Two stages in the production of inosine monophosphate—the building block of GMP and AMP—require the presence of formyl folate.

The C1 center needed for the production of dTMP (2′-deoxythymidine-5′-phosphate) from dUMP (2′-deoxyuridine-5′-phosphate) is donated by methylenetetrahydrofolate. Thymidylate synthase is the one that catalyzes the conversion.

Vitamin B12 Activation

Vitamin B12 is changed into methyl-B12 (methylcobalamin) via methyl-THF. Homocysteine methyltransferase catalyzes the reaction between methyl-B12 and homocysteine which results in methionine.

A homocysteine methyltransferase deficiency or a B12 deficiency might result in a “methyl-trap” of THF, where THF transforms into methyl-THF and depletes folate.

Therefore, buildup of methyl-THF might result from a B12 shortage, simulating a folate insufficiency.

Dietary Recommendations

The dietary folate equivalent (DFE) approach was developed because the various forms of folate present in food varied in their bioavailability from added folic acid.

One μg of dietary folate is equivalent to one DFE. A folic acid dosage of 1 μg is equivalent to 1.7 μg DFE.

The explanation for this discrepancy is that only approximately 50% of the folate that is naturally contained in food is absorbed, compared to at least 85% when folic acid is added to food or taken as a dietary supplement along with food.

Dietary Reference Intakes (DRIs) are defined by the U.S. Institute of Medicine as Estimated Average Requirements (EARs), Recommended Dietary Allowances (RDAs), Adequate Intakes (AIs), and Tolerable Upper Intake Levels (ULs).

Age	Infants (AI)	Infants (UL)	Children and adults (RDA)	Children and adults (UL)	Pregnant women(RDA)	Pregnant women(UL)	Lactating women(RDA)	Lactating women(UL)
0–6 months	65	None set	–	–	–	–	–	–
7–12 months	80	None set	–	–	–	–	–	–
1–3 years	–	–	150	300	–	–	–	–
4–8 years	–	–	200	400	–		–	–
9–13 years	–	–	300	600	–	–	–	–
14–18	–	–	400	800	600	800	500	800
19+	–	–	400	1000	600	1000	500	1000

The European Food Safety Authority (EFSA) refers to this combined set of data as Dietary Reference Values; it uses Population Reference Intake (PRI) instead of RDA and Average Requirement (EAR) instead of EAR.

The definitions of AI and UL are the same as in the US. The PRI for both men and women over the age of 18 is 330 μg/day.

Pregnancy-related PRI is 600 μg daily; and 500 μg daily during breastfeeding. The PRIs for children aged 1-17 years grow from 120 to 270 μg/day as they get older.

The U.S. RDAs and these values are not exactly the same. The Committee on Medical Aspects of Food and Nutrition Policy established the UK’s Dietary Reference Value for folate in 1991, and it is 200 μg/day for adults.

Safety

Since folate is a water-soluble vitamin and is frequently eliminated from the body through urine, there is little chance of folic acid poisoning.

High folic acid dosages may have unintended consequences, such as concealing the diagnosis of pernicious anemia caused by vitamin B12 deficiency and perhaps aggravating or starting neuropathy in those who already lack the vitamin.

This data supported the creation of a folate upper limit. When there is enough data, ULs are typically determined for vitamins and minerals.

The 1,000 μg adult upper limit of folate (and lower for children) pertains exclusively to folic acid used as a supplement since consuming large amounts of folate through food has not been linked to any health hazards.

After reviewing the safety concern, the EFSA and the US agreed that the UL should be set at 1,000 μg.

Depending on age, the adult UL was established by the Japan National Institute of Health and Nutrition at 1,300 or 1,400 μg.

Concerns have been raised by reviews of clinical trials that recommended long-term folic acid usage in quantities higher than the UL.

Overdosing on supplements is more concerning than getting it from whole foods, and the ratio of vitamin B12 to other nutrients may play a big role in side effects.

According to one explanation, high folic acid consumption causes detectable levels of unmetabolized folic acid to circulate in the blood because the enzyme dihydrofolate reductase is rate-limiting in its conversion of folic acid to biologically active forms.

Proof of a The detrimental effects of blood folic acid on health are not always present, and there is no cofactor function for folic acid that would suggest that free folic acid plays a causative role in the onset of disease.

However, in addition to the risk of neuropathy described above, low vitamin B12 status along with high folic acid intake also seems to raise the risk of cognitive impairment in the elderly.

Extended usage of dietary supplements containing more than 1,000 μg of folic acid per day has been associated with a higher risk of prostate cancer.

Food Labeling

To comply with U.S. regulations for food and dietary supplement labeling, the quantity in a serving is stated as a percentage of Daily Value (%DV).

For the purpose of labeling folate, 400 μg represented 100% of the Daily Value. The value of 400 μg remained constant as of the update.

On May 27, firms with annual food sales of at least US$10 million were required to comply with the new labeling laws by January 1, 2020, and firms with lower volume food sales had to comply by January 1, 2021.

Reference Daily Intake provides a table with the current and old adult daily values. Labels must list energy, protein, fat, saturated fat, carbs, sugars, and salt in accordance with EU rules.

If nutrients are present in substantial quantities, they may be shown voluntarily. Amounts are expressed as a percentage of Reference Intakes (RIs) rather than Daily Values. In 2011, 200 μg was designated as the 100% RI for folate.

Deficiency

Unhealthy diets deficient in vegetables and other foods high in folate can lead to folate deficiency, as can illnesses like Crohn’s disease or celiac disease that affect the body’s ability to absorb folate.

Certain genetic disorders affect folate levels, and certain medications (like phenytoin, sulfasalazine, or impropriety-sulfamethoxazole).

Drinking alcohol can hasten folate insufficiency by potentially interfering with folate transport. Glossitis, diarrhea, melancholy, disorientation, anemia, and brain and neural tube abnormalities in fetuses can all result from a folate shortage.

Fatigue, gray hair, mouth ulcers, slow growth, and swollen tongue are some other symptoms. By measuring plasma vitamin B12 and folate levels, as well as a full blood count (CBC), folate deficiency is identified.

Serum folate insufficiency is indicated by levels of 3 μg/L or below. Erythrocyte folate level is a better indicator of tissue reserves after ingestion than serum folate level, which just represents folate status.

Inadequate folate status is indicated by an erythrocyte folate level of 140 μg/L or below. Compared to erythrocyte folate, serum folate responds to folate consumption more quickly.

A folate shortage inhibits cell division, which impedes erythropoiesis, the process of making red blood cells.

Megaloblastic anemia, which is typified by big, immature red blood cells, results from this. This condition.

This results in excessively large red blood cells called megaloblasts (and hypersegmented neutrophils) with copious cytoplasm capable of RNA replication, which is caused by consistently unsuccessful attempts at normal DNA replication, DNA repair, and cell division.

And protein synthesis, albeit with nuclear chromatin breakage and clumping. In an effort to make up for the anemia, some of these big, immature cells—reticulocytes—are discharged from the bone marrow early.

To produce healthy red and white blood cells and avoid anemia, which results in weakness, exhaustion, and difficulty concentrating, both adults and children need folate.

Elevated levels of homocysteine indicate a possible shortage in tissue folate; however, homocysteine is also influenced by vitamin B12, vitamin B6, renal function, and heredity.

A test for methylmalonic acid (MMA) insufficiency can help distinguish between folate and vitamin B12 deficiencies.

Elevated MMA levels signify a vitamin B12 deficit, while normal MMA levels imply folate insufficiency.

The uncommon metabolic condition known as combined masonic and methodological acidulous (CMAMMA) may also be the cause of elevated MMA levels.

Treatment for folate insufficiency is 400–1000 μg of additional oral folic acid daily. Even in cases where malabsorption was the cause of the deficiency, this treatment is incredibly effective at replenishing tissues.

Before starting folic acid treatment for megalomaniac anemia, patients should be evaluated for vitamin B12 insufficiency.

If this is the case, folic acid supplements may help correct the anemia but may also exacerbate neurological issues.

A lack of cobalamin (vitamin B12) can result in a lack of folate, which raises homocysteine levels and can cause birth abnormalities or cardiovascular disease.

Sources

The folate content of hundreds of foods can be searched using a food composition database maintained by.

The Agricultural Research Service of the United States Department of Agriculture, as indicated in the table.

The Food Fortification Initiative provides a list of all the nations that have fortification programs in place, together with information about which foods in each nation receive what nutrients and whether or not fortification is required.

Beginning in January 1998, fortification of enhanced bread, cereals, flour, rice, pasta, corn meal, and other grain products became required in the United States.

By 2023, food fortification with one or more vitamins will be necessary in 140 nations, with 69 of those requiring folate. Wheat flour is the most widely fortified food.

Rice and corn flour come next. Additions of folic acid vary from nation to nation between 0.4 to 5.1 mg/kg; however, the vast majority fall within a narrower range of 1.0 to 2.5 mg/kg, or 100-250 μg/100g.

High-heat cooking can destroy naturally occurring folate in food, especially when acidic foods and sauces are present.

Foods heated in water may lose it since it is soluble in water. The values for naturally occurring folate in cooked foods in the table correspond to foods that are typically consumed cooked.

Plant sources	Folate (μg / 100 g)
Peanuts	246
Sunflower seed kernels	238
Lentils	181
Chickpeas	172
Asparagus	149
Spinach	146
Lettuce	136
Peanuts (oil-roasted)	125
Soybeans	111
Broccoli	108
Walnuts	98

Plant sources	Amount as Folate (μg / 100 g)
Peanut butter	92
Hazelnuts	88
Avocados	81
Beets	80
Kale	65
Bread (not fortified)	65
Cabbage	46
Red bell peppers	46
Cauliflower	44
Tofu	29
Potatoes	28

Animal sources	Amount as Folate (μg / 100 g)
Chicken liver	578
Calf liver	331
Cheese	20–60
Chicken eggs	44
Salmon	35
Chicken	12
Beef	12
Pork	8
Yogurt	8–11
Milk, whole	5
Butter, salted	3

Food Fortification

The technique of adding synthetic folic acid to wheat flour or other foods with the goal of improving blood folate levels in the general public is known as folic acid fortification.

Because it is more stable during processing and storage, it is utilized. Following the identification of the connection between low folic acid and neural tube abnormalities.

Folic acid supplementation was advised for expectant mothers by governments and health organizations across the globe.

Since many women commonly give birth before the neural tube shuts during the first four weeks of pregnancy Several nations have eventually chosen to impose laws requiring dietary fortification, even if they are not informed of their pregnancy.

According to a meta-analysis of the global birth prevalence of spina bifida, there was a 30% decrease in live births with the condition.

When mandatory fortification was compared to nations with voluntary fortification or no fortification program, some nations reported a reduction of more than\ 50%.

More than 80 nations fortify grain products with folic acid, either by law or voluntarily, and these fortified goods account for a sizable portion of the population’s folate intake.

The topic of fortification is contentious since it raises questions about both individual liberty and the potential health risks mentioned in the Safety section.

Concerns exist in the United States that fortification is required by federal law, but that monitoring of any unfavorable impacts of fortification is lacking.

The Food Fortification Initiative is a list of all the nations that have fortification programs in place, along with information on which foods in each nation receive additional nutrients.

In 62 nations, folate is the vitamin that is most frequently required to be supplemented; wheat flour is the item that is most frequently fortified.

Australia and New Zealand

In 2007, Australia and New Zealand came to an agreement to fortify wheat flour under Food Standards Australia New Zealand.

A need of 135 μg of folate per 100 g of bread was established. 2009 saw the program’s implementation in Australia. In 2009.

New Zealand similarly intended to fortify bread (although not organic or unleavened versions), but decided to postpone the move until further study was completed.

The Bakers’ Association and the Green Party had called mandated fortification “mass medication” and opposed it. In July 2009, Food Safety Minister Kate Wilkinson examined the decision to fortify,

noting arguments against assertions that an excessive folate intake is associated with a higher risk of cancer.

In an effort to meet the 50% bread fortification target, the postponed forced fortification program was terminated in 2012 and replaced with a voluntary one.

Canada

Canadian public health initiatives concentrated on raising knowledge of the value of folic acid supplementation for all women of reproductive age and reducing socioeconomic disparities by offering vulnerable women’s groups useful folic acid support.

In 1998, folic acid fortification of food became required, requiring 150 μg of folic acid per 100 grams of enhanced flour and raw cereal grains.

The effects of vitamin B12 The effects of fortification on the rate of neural tube defects in Canada have been positive, demonstrating a 46% decrease in the prevalence of NTDs.

The size of the reduction was proportionate to the rate of NTDs prior to fortification, thereby eliminating regional differences in the rates of NTDs observed in Canada prior to fortification.

United Kingdom

Although iron fortification and folic acid fortification were recommended by the Food Standards Agency, folic acid fortification of wheat flour is optional rather than mandated.

In order to lower the risk of neural tube abnormalities, mandated fortification should be reexamined, according to a 2018 assessment by UK-based academics.

United States

Regulations regulating the addition of folic acid to enriched bread, cereals, flours, maize meals, pasta, rice, and other grain products were released by the US Food and Drug Administration (FDA) in 1996.

This ruling, which went into effect on January 1st, 1998, was primarily intended to lower the risk of neural tube birth abnormalities in infants.

Concerns were raised over the inadequate quantity of folate that was added. It was anticipated that the fortification program would boost a person’s daily consumption of folic acid by 70–130 μg; in reality, an almost twofold increase was seen.

This may result from the fact that many foods have 160–175% more fortification than is necessary. A large portion of the elderly population takes supplements that increase their daily consumption of folic acid by 400 μg.

This is concerning as between 70 and 80 percent of people have discernible levels of metabolized folic acid in their blood, a result of fortification and supplementation with folic acid.

Nevertheless, at the blood level obtained by food fortification, folic acid does not appear to have any co-factor activity that would raise the possibility that free folic acid plays a causative role in the development of disease.

The U.S. National Center for Health Statistics conducts the biennial National Health and Nutrition Examination Survey (NHANES) to assess the nation’s adult and pediatric population’s health and nutritional status. A handful of the results are reported in What We Eat in America.

What We Eat in America reports on a few of the findings. According to the 2013–2014 survey, men aged 20 and above took in an average of 249 μg of folate from food.

And 207 μg of folic acid from food items that have been fortified, for a total of 601 μg of dietary folate equivalents (DFEs) a day; each microgram of folic acid is equivalent to 1.7 μg of food folate.

The levels for women are 199, 153, and 459 μg/day, in that order. This indicates that more than half of the people are consuming more folic acid than the recommended daily allowance (as DFEs), and that fortification contributed to a larger increase in folic acid intake than initially anticipated.

Still, less than half of expectant mothers are going above the 600 μg daily recommended daily allowance.

In the US, neural tube defects impacted roughly 4,100 pregnancies annually prior to folic acid fortification.

The risk of neural tube abnormalities has decreased by 35%, according to a 2015 data from the Centers for Disease Control and Prevention, following the FDA’s order to add folic acid to diets based on grains.

This corresponds to a yearly savings of almost $508 million in total direct costs for the newborns affected by NTD that were avoided.

History

Scientists thought anemia and folate insufficiency were the same illness in the 1920s. An important discovery made by researcher Lucy Wills in 1931 helped to establish folate as the nutrient needed to avoid anemia during pregnancy.

Wills proved that brewer’s yeast may be used to reverse anemia. It was discovered that folate was the remedial ingredient in brewer’s yeast in the late 1930s.

In 1941, Roger J. Williams, Esmond E. Snell, and Herschel K. Mitchell isolated it for the first time by extracting it from spinach leaves.

Because it was present in dark-green leafy vegetables, the word “folic” comes from the Latin word folium, which means leaf.

Past names included vitamin M following a study on monkeys, vitamin BC following research on chicks, and L. casei factor following research on chicks.

In 1943, Bob Stokstad, who was employed by the American Cyanamid Company at Lederle Laboratories, succeeded in isolating the pure crystalline form and determining its chemical structure.

Under the supervision and guidance of Director of Research Dr. Yellapragada Subbarow, the team known as the “folic acid boys” conducted this historical research effort in 1945 at the Lederle Lab in Pearl River, NY, with the goal of acquiring folic acid in a pure crystalline form.

Sidney Farber employed the antifolate aminopterin, which was created as a result of this research, to treat juvenile leukemia in 1948.

Scientists started to understand the molecular mechanisms of action of folate in the 1950s and 1960s.

Researchers first connected the risk of neural tube abnormalities to a folate shortage in The governments of the United States and Canada decided in the late 1990s that even with folic acid supplements and public education campaigns.

It was still difficult for women who were pregnant or nursing to meet the recommended daily intake of folate.

As a result, those two nations began to implement folate fortification programs. As of December 2018, folic acid fortification of food was required in 62 nations.

Animals

When there is a possibility of a folate shortage, veterinarians may test dogs and cats. More so than dogs, cats with exocrine pancreatic insufficiency may have low serum folate levels.

The prevalence of cleft lip and cleft palate in dog breeds at risk was considerably reduced by dietary folic acid supplementation.

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