Folate is a vitamin important in growth and development. Everyone needs folate, but it is especially important for women to get enough of it during the early stages of pregnancy to help reduce the risk of foetal brain and spinal cord abnormalities such as spina bifida. In this podcast, I look at the key roles of folate in the body, explain how it helps prevent birth defects and the key dietary and supplement sources of it.
Folate, also known as folacin or folic acid, is a water-soluble B-group vitamin essential to human health. Its primary form in the body is as a coenzyme called tetrahydrofolate and serves as part of an enzyme complex that transfers carbon compounds. Folate metabolism is tightly linked to the metabolism of vitamin B12 and the two vitamins act in concert to help synthesise the DNA required for rapidly growing cells. Cellular growth, repair and red blood cell formation are all tightly linked to having a good supply of folate.
Folic acid is the term used for the synthetic form of folate and is used extensively in dietary supplements and food fortification. The bioavailability of dietary folate ranges from 50 per cent for foods to 100 per cent for supplements of folic acid.
The need for folate in rises considerably during pregnancy and whenever cells are rapidly multiplying, so the recommendations for pregnant women are much higher than for other adults.
Folic acid has been proven to be effective in reducing the risks of neural tube defects in the developing foetus. The brain and spinal cord develop from the neural tube, and defects in its orderly formation during the early weeks of pregnancy may result in various central nervous system disorders such as spina bifida. Folic acid supplements taken one month before conception and continued throughout the first trimester of pregnancy (which is termed the periconception period) can help reduce the risk of neural tube defects and is one of the key pieces of advice given to women planning a pregnancy.
Because many pregnancies are unplanned and because neural tube defects occur early in development before many women realise they are pregnant, Australia like many countries around the world has mandated folic acid fortification into the food supply which is added to flour used in bread making except for flour that is used in breads marketed as ‘organic’.
Since mandatory folic acid fortification in Australia, there has been a fall in the incidence of NTDs, but the group that has seen the greatest impact is the Indigenous population. Pre-fortification, there were 2.4 cases of spina bifida per 1000 births in the Indigenous population. Post-fortification, rates had dropped to 0.8 cases of spina bifida per 1000 births. And I’ll link to this research report in the show notes. This is a clear example of the nutritional and health disparity that exists between indigenous and non-indigenous Australians and where folic acid fortification has a much greater impact because of the lower quality diet on average in this group https://researchimpact.uwa.edu.au/research-impact-stories/folate-fortification-reduces-neural-tube-defects
Some research suggests that folate taken before and during pregnancy may also help reduce the risk of congenital birth defects, such as cleft lip and cleft palate, and some other neurodevelopmental disorders. And while the research is not as strong as that for reducing the risk of neural tube defects, such findings strengthen recommendations for women to pay attention to their folate needs.
Outside of folate’s role in foetal development, another key role is to break down the amino acid homocysteine which has been implicated as a risk factor in the development of cardiovascular disease. Without adequate folate, homocysteine accumulates in the blood, which seems to enhance blood clot formation and arterial wall deterioration. Fortified foods and folic acid supplements raise blood folate and reduce blood homocysteine levels to an extent that may help to reduce the risk heart disease. Clinical trials using folic acid supplements, however, have not consistently shown a reduction in the risk of death from cardiovascular causes.
Deficiency
Folate deficiency impairs cell division and protein synthesis – processes critical to growing tissues. In a folate deficiency, the replacement of red blood cells and GI tract cells falters. Not surprisingly, then, two of the first symptoms of a folate deficiency are anaemia and deterioration of cells lining the gastrointestinal tract.
The anaemia of folate deficiency is characterised by large, immature red blood cells. Without folate, DNA damage destroys many of the red blood cells as they attempt to divide and mature. The result is fewer, but larger, red blood cells that cannot carry oxygen or travel through the capillaries as efficiently as normal red blood cells. This form of large-cell anaemia is known as macrocytic or megaloblastic anaemia. It is also the same type of anaemia caused by B12 deficiency.
Alcohol interferes with the absorption of folate and speeds the rate that folate breaks down and is excreted from the body. Because people with alcoholism also tend to eat poor-quality diets low in folate-containing foods, this only makes the problem of folate deficiency worse.
Intestinal surgeries or digestive disorders such as coeliac disease and inflammatory bowel disease can decrease the absorption of folate which puts a person at risk of deficiency.
Folate toxicity
Does folate present any toxicity concerns? Naturally occurring folate from foods alone appears to cause no harm. Excess folate from fortified foods or supplements, however, can reach levels that are high enough to mask a vitamin B12 deficiency and delay the diagnosis of neurological damage. That is because folic acid supplements can correct the anaemia that is caused by vitamin B12 deficiency, but not the nerve damage that the vitamin B12 deficiency also causes.
If you choose to use a folic acid supplement, stick with the lower range available of 400 mcg a day or less, as you will likely obtain additional folic acid from fortified foods like cereals and breads, as well as natural folate in food.
Because the synthesis of DNA and the transfer of methyl groups depend on folate, its relationships with cancer are complex, depending on the type of cancer and the timing of folate supplementation. Some research suggests that sufficient folate may protect against the initiation of cancer, whereas other studies report that high intakes may enhance progression once cancer has begun. Cancer cells divide rapidly, and drugs that interfere with folate metabolism are used to treat cancer. One such drug is methotrexate which limits the activity of enzymes that need folate, thereby slowing cancer growth. For this reason, it is advised that the use of supplemental folate during chemotherapy should be discouraged because of the possibility of tumour protection and reduced survival.
But could there be an issue with population-wide folic acid fortification for potentially changing cancer risk? Because almost everyone in the population is now consuming more folic acid, there have been concerns raised for some time that this could lead to a theoretical greater risk of cancer in some individuals.
This is a thorny issue to untangle as adequate folate helps ensure normal cell development and DNA replication and thus help prevent mutations that could start of the cancer process. Conversely, too much folate may speed up cancer growth.
Looking at the opposing actions of folate together led to the hypothesis that inadequate dietary folate can increase the risk of some forms of cancer (particularly colorectal cancer), but excessive amounts may exacerbate the progression of existing colorectal cancer in some individuals.
Previous clinical research looking at cancer-promoting effects of supplemental folic acid on colorectal cancer progression has indicated that the risk may be more than a theoretical one. Understanding how folic acid fortification may be affecting colorectal risk in the wider population though gives the best guide to seeing if the risk is real.
Using data from the United States NIH-AARP Diet and Health Study which commenced in 1995 and involves well over 500,000 people, researchers were able to study how folate intake affected colorectal cancer risk. The researchers had available to them diet and health information on the participants both before and after mandatory fortification of folic acid into the US food supply began in 1997. And I’ll link to the study in the show notes https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3173023
As the amount of folate consumed increased, there was a clear drop in the incidence of colorectal cancer and this benefit was seen both for folate consumed from food and that derived as folic acid from supplementation. The association between levels of folate intake and cancer risk was similar both before and after food fortification became mandatory.
The results from this study were taken over a timeframe of 8.5 years which is a substantial period of time to see changes in colorectal cancer rates though further follow-up in the years ahead will help validate the findings.
Concerns that folic acid fortification of the food supply could have unintended negative health outcomes appear to be lessened, at least when viewed at the level of the whole population. This does not discount that it could pose some risk in a subset of individuals, and scientists will continue to research this area.
Food sources
So finally, where do you naturally find folate in foods? It is abundant in legumes, fruits and vegetables. The vitamin’s name suggests the word foliage, and indeed, dark leafy green vegetables such as spinach and broccoli are excellent sources. As too are avocados. Beef liver is also a good source. With fortification, grain products like bread also contribute to folate intake.
So that’s it for today’s show. You can find the show notes either in the app you’re listening to this podcast on if it supports it, or else head over to my webpage www.thinkingnutrition.com.au and click on the podcast section to find this episode to read the show notes.
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I’m Tim Crowe and you’ve been listening to Thinking Nutrition.