Folate Deficiency

What is folate?

Folate is also known as Vitamin B9. It is one of a group of important vitamins involved in cell metabolism. Folate plays a critical role in the synthesis of DNA, RNA and proteins. Deficiency can therefore cause impairment of cell division and an accumulation of possibly toxic metabolites (eg. homocysteine). Along with Vitamin B12, Folate is important for regulating the manufacture of red blood cells.[1]

The synthetic form of folate is folic acid, which converts to folate in the body. Because folic acid is more easily absorbed by the body, it is the form most commonly used in supplements and fortified foods.

Many plants, particularly green leafy vegetables, and animal products contain folate. Thus, most healthy people absorb sufficient folate from their diets to avoid deficiency, but in some cases the body may increase demand. If supplementation doesn’t occur, this may lead to deficiency. Folate deficiency is most commonly found in pregnant and lactating women, people with chronic conditions of the gastrointestinal tract, people following restricted diets due to weight-loss regimes or medical conditions, people with alcohol dependence and people more than 65 years of age.[2]

Folate deficiency will not go away on its own. Treatment is required and may involve dietary changes and/or oral supplements and treatment of underlying causes, if any are present. If left untreated, folate deficiency may result in folate deficiency anemia, which can cause severe complications.[3]

Symptoms and diagnosis of folate deficiency

Common symptoms of folate deficiency can include:[2][4]

  • Tiredness, fatigue and lethargy
  • Muscle weakness
  • Neurological signs, such as a feeling of pins and needles, tingling, or burning (paresthesia)
  • Psychological problems, such as depression, confusion, memory problems, problems of judgement and understanding
  • Gastrointestinal signs, such as nausea, vomiting, abdominal pain, weight loss and diarrhea
  • Headache and dizziness
  • Pallor
  • Shortness of breath

Headache, dizziness, pallor and shortness of breath are also symptoms of anemia. Anemia, particularly megaloblastic anemia, is often the first sign that there is an underlying folate deficiency, and doctors will usually test for folate and Vitamin B12 deficiencies when they encounter anemia.

Less common symptoms of folate deficiency are:[2]

  • Fast heartbeat (tachycardia)
  • Fast breathing (tachypnoea)
  • Exfoliative dermatitis
  • Heart murmur
  • Painful swallowing
  • A sore tongue (glossitis) and mouth ulcers
  • Petechiae
  • Angular stomatitis (fissures in the corners of the mouth)

In children with congenital malabsorption disorders, which are rare, neurological problems might also be present.

Diagnosis is based on evaluation of symptoms and blood tests. Although there is no official medical consensus of what level of folate in blood serum indicates a deficiency, most practitioners agree that a level of less than seven nanomols per liter (7nmol/L) is problematic. Below that level, the risk of megaloblastic anemia is much higher.[3] If a blood test reveals anemia, this will lead to further evaluation of the possible causes, including analyzing serum folate levels. Elevated homocysteine levels can also indicate a folate deficiency and can therefore be part of the laboratory testing.

The process of diagnosing a folate deficiency involves the exclusion of other possible causes of the symptoms. In cases where anemia is suspected, other possible causes of anemia (eg. iron deficiency, vitamin B12 deficiency, chronic disease and others) must be excluded.

Physicians will evaluate the patient’s diet for signs of insufficient intake, such as might accompany vegan diets, poor diets, or “fad” diets. Often patients present with a history of alcohol intake which contributes to a poor diet. Other patients may be pregnant or lactating. Certain drugs, such as anticonvulsants, can also cause this type of deficiency.

Causes of folate deficiency

Folate deficiency has a number of potential causes. Most healthy people absorb sufficient folate from their diets to avoid deficiency, but in some cases the body may increase demand, which, if supplementation doesn’t occur, may lead to deficiency. In other cases, the body may be unable to absorb enough folate, due to low intake or excessive excretion.

Causes of folate deficiency include:[1][2][3][5]

  • Low dietary intake due to medically restricted diets such as those followed by people with phenylketonuria or due to fad diets concentrating on foods that do not contain enough folate. Infants who are fed unfortified goat’s milk will also experience folate deficiency, as folate is not naturally present in goat’s milk.
  • Malabsorption, which can be due to age, liver problems or gastrointestinal problems causing chronic diarrhoea, such as sprue, celiac disease or inflammatory bowel disease. Other causes of malabsorption are pancreatitis, bariatric surgery and extensive surgery involving the large or small intestine. Malabsorption is also a risk for people who use drugs that interfere with the absorption of folate, such as proton-pump inhibitors, some anticonvulsants such as carbramezapine, phenytoin, valproic acid, and phenobarbitol.[6]
  • Disorders such as leukaemia, carcinomas and lymphomas, which increase the body’s demand for folate and may consequently lead to deficiency if folic acid supplements aren’t taken.
  • Age, which causes changes in the gastrointestinal systems of people more than 65 years of age. These may lead to reduced absorption and reduced dietary intake.
  • Alcohol-related damage to the liver, which affects the way in which folate is stored in the liver and increases the amount of folate excreted in urine. People with alcohol dependence may also have a nutritionally insufficient diet.
  • Pregnancy and lactation, which raise the body’s demand for folate considerably due to the growth of new tissue in both mother and fetus. Sufficient folic acid supplementation is crucial for pregnant women, as a deficiency may cause birth defects. (See below.)
  • Smoking or exposure to secondhand smoke.[7]
  • Renal dialysis, which affects the amounts of homocysteine in the body and therefore increases the amount of folic acid needed.

Risks related to folate deficiency

There are several possible health consequences of having folate deficiency. These include:

Megaloblastic anemia

Megaloblasts are large, poorly-formed red blood cells that form in cases of anemia caused by, among others, folate or B12 deficiencies. Megaloblastic anemia is a result of folate deficiency as well as one of the most easily-identified symptoms: sometimes, a deficiency is only identified when anemia presents. If it results from folate deficiency, this anemia, is treated by taking oral or intravenous folate supplements.[8]

Birth defects

Folic acid is very important in the correct development of cells and is crucial for the correct development of fetuses. Pregnant women and women planning to become pregnant should increase their folic acid intake to 400 micrograms a day.

Women should increase their intake to 5mg a day if they are or wish to become pregnant and are affected by the following factors:[9] If a women is affected by diabetes, celiac disease, a BMI of more than 30 or is treated with drugs that affect folate absorption, additional supplementation must be considered.

Folic acid deficiency in the mother can cause defects in the neural tube, which is the structure that eventually develops into the baby’s spinal cord. Neural tube defects (NTDs) can include spina bifida, caudal regressive (affecting the lowest part of the spine), and cleft palate. Extremely rare, but severe, complications of folic acid deficiency can include anencephaly and encephaloceles, which involve the baby’s skull and brain.[10]

Treatment of folate deficiency

In most cases, folate deficiency is relatively easy to correct. In cases where a deficiency has set in due to poor diet or age, taking a folic acid supplement or modifying the diet is sufficient. However, if there is an underlying problem, like alcoholic changes to the liver or a drug interaction or condition causing malabsorption, specialised treatment will be required. The underlying causes of folate deficiency need to be addressed to prevent the problem recurring.

Folate deficiency is relatively easily treated in cases where the deficiency is not severe. However, where it has caused anemia, folic acid supplementation and/or correcting diet alone will not be enough. In women with megaloblastic anemia, vitamin B12 deficiency must be ruled out before any folic acid treatment can begin. If complications have occurred, or if there is an underlying condition or factor causing the folate deficiency, the patient may have to be referred to one or more of the following kinds of doctor:[2]

  • Gastroenterologist, a doctor specialising in diseases and disorders of the esophagus, stomach, small intestine, colon and rectum, as well as the pancreas, gallbladder, bile ducts and liver
  • Dietitian, a certified expert on diet and nutrition
  • Hematologist, a doctor specialising in diseases and disorders of the blood

Natural sources of folic acid

Folate is readily available in many whole foods, such as:[9]

  • Leafy green vegetables (spinach, kale, broccoli, cabbage, and brussels sprouts)
  • Beetroot
  • Citrus fruits
  • Liver. However, liver should be avoided by pregnant women, due to the high levels of Vitamin A it contains. Vitamin A can cause birth defects.
  • Beans and legumes (peas, pinto, cannellini, garbanzo beans/chickpeas)

Supplementation

In some countries, such as the United States, South Africa, Chile, Canada and Costa Rica, grain cereal products (bread, pasta and cereal) are fortified with folic acid.[11] This is a major factor in reducing the number of neural tube defects that occur, but it is still recommended that anyone who is at risk of a deficiency, such as pregnant women, should make sure to get 400 micrograms of folate a day. This is especially the case if the following risk factors are present:

  • Celiac disease or other intestinal absorption disorders
  • Thalassemia or sickle cell anemia (hereditary red blood cell disorders)
  • Clinical obesity: high BMI: > 30kg/m2
  • Family history of, or partner with a family history of, neural tube defects. In this case, folic acid acts as “insurance.”
  • Rapid cell turnover (hemolysis) occuring as a result of chronic hematological disorders[3]

FAQs

Q:How much folic acid should I take every day?
A: The daily need of folic acid differs between adults (200mcg) and people younger than 14 years of age (150-200mcg). It must be emphasized that men, children and women who are not likely to become pregnant obtain a sufficient amount of folate in a healthy diet, containing a wide variety of foods. Pregnant and lactating women need at least 400 micrograms a day and possibly as much as 800mcg. Pregnant and lactating women with diabetes, or a family history of neural tube defects, should consult a specialist for optimum supplementation during pregnancy.[12]

Q:How much folic acid is too much?
A: The safe upper limit for daily folate/folic acid intake is 1000 micrograms a day. Beyond this, there might be adverse effects.[13] Not much is known about the long-term adverse effects of exceeding the upper limit, if any.[14]

Q:How does taking extra folate affect a Vitamin B12 deficiency?
A: Vitamin B12 deficiency can cause severe neurological damage. It can also cause megaloblastic anemia. Large doses of folate can cure the anemia but will not prevent the neurological damage. It is possible that taking extra folate in cases of B12 deficiency can worsen the severity of the B12 deficiency, but this is not known for certain. It is best to consult a physician if there is a possibility of a B12 deficiency.[13]

Q: Is folate supplementation safe for people with cancer?
A: It is not known for certain whether folate supplementation is safe for people with cancer. Some studies suggest that folic acid reduces the chance of developing cancer and accelerates the progression of certain types of cancer; other studies suggest the opposite.[12] It is best to consult specialist physicians and/or oncological caregivers before beginning supplementation.

Q: How does megaloblastic anemia differ from other anemias?
A: Anemia occurs when an individual has too few or deformed red blood cells (erythrocytes). For example, anemia can occur when an individual’s iron levels are too low, e.g.when they are undergoing chemotherapy, or when they have kidney disease.

Megaloblastic anemia is also known as Vitamin B12-related anemia, folate-related anemia, or macrocytic anemia. It occurs when the body produces short-lived, large, poorly-developed red blood cells.[14]

Other types of anemia are sickle-cell anemia, aplastic anemia and hemolytic anemia. Sickle-cell anemia is hereditary and causes rigid red blood cells that do not readily flow through the blood vessels.

Aplastic anemia occurs when the bone marrow stops making enough red blood cells, often when the body’s immune system attacks it.

Hemolytic anemia can be inherited, as in the case of thalassemia or glucose-6 phosphate dehydrogenase deficiency. It can also be caused by autoimmune disorders, infections or leaky heart valves. It occurs when red blood cells break up in the blood vessels or the spleen.[15]


  1. University of Maryland Medical Centre. “Vitamin B9 (Folic acid)” 5 August 2015. Accessed 8 February 2018.

  2. British Medical Journal Best Practice. “Folate deficiency.”. Updated November 2017. Accessed February 2018.

  3. Louise Newson. “Folate deficiency.” 10 June 2016. Accessed 8 February 2018.

  4. NHS Choices. “Vitamin B12 or folate deficiency anemia.”. 16 May 2016. Accessed 8 February 2018.

  5. Vinod Devalia, Malcolm S. Hamilton, Anne M. Molloy, on behalf of the British Committee for Standards in Haematology. “Guidelines for the diagnosis and treatment of cobalamin and folate disorders”. 18 June 2014. Accessed 8 February 2018.

  6. Steven C Schacter, MD and Joseph I Sirven, MD.. “Folic acid”. October 2013, reviewed 5 January 2018. Accessed 8 February 2018.

  7. EO Erdemir and J Bergstrom. “Relationship between smoking and folic acid, vitamin B12 and some haematological variables in patients with chronic periodontal disease.”. December 2006. Accessed 8 February 2018.

  8. Laurence Knott. “Macrocytosis and Macrocytic Anaemia”. 9 July 2017. Accessed 8 February 2018.

  9. NHS Choices. [“Why do I need folic acid in pregnancy?]”(https://www.nhs.uk/chq/pages/913.aspx?categoryid=54). Last reviewed 18 March 2015. Accessed 8 February 2018.

  10. Anjum Gandhi. “Neural tube defects.”. 21 July 2014. Accessed 8 February 2018.

  11. Krista S Crider, Lynn B Bailey, Robert J Berry. “Folic Acid Food Fortification—Its History, Effect, Concerns, and Future Directions.”. March 2011. Accessed 8 February 2018.

  12. Gail Rees. “Food Fact Sheet: Folic Acid.” August 2016. Accessed 13 February 2018.

  13. Frequently Asked Questions. “Folic acid: frequently asked questions.”. 16 December 2016. Accessed 13 February 2018.

  14. Children’s National Health System. “Pediatric Anemia (pernicious or megaloblastic)”. Accessed 13 February 2018.

  15. American Society of Hematology. “For patients: anemia”. Accessed 13 February 2018.