Folic Acid

Mechanism of Action

Folate is mainly concentrated in the liver.[16][17] The synthetic form, folic acid, is given as dihydrofolate and is converted to tetrahydrofolate (THF) by the action of the dihydrofolate reductase enzyme, which depends on reduced nicotinamide adenine dinucleotide phosphate. THF is then converted to 5,10-methylenetetrahydrofolate, which can be used in DNA synthesis via deoxythymidine monophosphate or in methionine synthesis.[18]

For DNA synthesis, deoxyuridine monophosphate accepts 1 methyl group from 5,10-methylenetetrahydrofolate via thymidylate synthase, which then accepts the other methyl group to form deoxythymidine monophosphate, allowing the cell cycle to continue while simultaneously regenerating dihydrofolate. Drugs used in cancer chemotherapy disrupt this process by inhibiting vital enzymes necessary for cell cycle progression. Methotrexate, for example, inhibits dihydrofolate reductase. By reducing the availability of THF and its downstream components, methotrexate indirectly deprives thymidylate synthase of its substrates.[19] Humans cannot synthesize deoxythymidine monophosphate in the presence of methotrexate, leading to an imbalanced DNA pool and cell death.

Methionine is a byproduct synthesized as folate reduces homocysteine levels in the blood; 5-10-methylenetetrahydrofolate (MTHF) donates a methyl group to an enzyme, methyl-tetrahydrofolate reductase (MTHFR), and then becomes 5-methyl THF.[19] The 5-methyltetrahydrofolate donates its remaining methyl group to homocysteine via methionine synthase, converting homocysteine to methionine. Transfer of both methyl groups from the original 5,10-methylenetetrahydrofolate regenerates THF and allows reentry into the cycle. Vitamin B₁₂ is a crucial cofactor for methionine synthase, and vitamin B₁₂  deficiency can lead to macrocytic megaloblastic anemia, similar to folate deficiency, but with additional clinical symptoms beyond the scope of this article.[20]

Administration

Adult Dosing

• Folic acid is often administered as an oral supplement. Dosing is usually dependent on the disorder. The recommended daily folic acid intake for adults is 400 mcg.[10]
• The World Health Organization recommends a daily dose of 400 to 800 mcg to prevent neural tube defects in pregnancy. Clinicians generally prescribe iron-folic acid supplements as part of prenatal vitamin supplements during and before pregnancy.[21][22] Most prenatal vitamins include 1 mg of folate, which is more than enough to meet this criterion.[23] For maximum effect, supplementation must begin in the earliest stages of pregnancy, if not months before conception. 
• Folic acid may be given orally, intravenously, or subcutaneously for macrocytic anemia. Oral recommendations are 1 mg to 5 mg once daily, but doses up to 15 mg once daily have also been recommended. 
• The estimated recommended dose to avoid folic acid deficiency in patients receiving hemodialysis ranges from 1 to 5 mg daily. For intravenous administration, 5 mg or less of undiluted folic acid may be infused over at least 1 minute or combined with 50 mL of either normal saline or 5% dextrose in water and infused over 30 minutes. Folic acid may also be given as an infusion when added to other intravenous maintenance solutions. The estimated recommended dose to avoid folic acid deficiency in patients receiving hemodialysis ranges from 1 to 5 mg daily.[24]
• Patients treated with methotrexate should be prescribed folic acid supplements to reduce the adverse effects associated with methotrexate therapy.

Specific Patient Populations

Renal and hepatic dosing: Folic acid dose adjustments are undefined in patients with impaired renal or hepatic function.

Pediatric patients: Pediatric dosing is for megaloblastic anemia.

• 1 to 11 months: 30 to 45 mcg orally, subcutaneously, intramuscularly, or intravenously daily. Start at 15 mcg/kg/dose daily until hematological correction is achieved.
• 1 to 10 years: 0.1 to 4 mg orally daily. Start at 15 mcg/kg/dose daily. Start at 1 mg daily for anemia until hematologic correction is achieved. The maximum dosage is 5 mg daily. Doses greater than 1 mg are rarely more effective. Clinicians may use intramuscular, subcutaneous, or intravenous routes when oral dose malabsorption occurs.
• 11 years and older:  Dosing is the same as for patients aged 1 to 10 years. The maintenance dose for pregnant or breastfeeding patients is 0.8 mg orally daily.

Pregnancy and breastfeeding considerations: Folic acid may be used as a supplement during pregnancy and breastfeeding.

• The recommended daily allowance for supplementation during pregnancy is 600 mcg orally. Fetal harm has not been reported at these doses.
• The recommended daily oral supplementation during pregnancy is 500 mcg. Fetal harm has not been reported at these doses.

Adverse Effects

For the general population, a daily folic acid intake below the established upper intake level of 1000 mcg has not been shown to result in adverse health outcomes. The US National Toxicology Program examined areas of previous concern, including cognition related to vitamin B₁₂ deficiency, cancer, diabetes, thyroid-related disorders, and hypersensitivity-related outcomes. Researchers identified these areas from previous reports of patients receiving more than 400 mcg daily.

Researchers identified these areas from previous reports of patients receiving more than 400 mcg daily. Overall, the National Toxicology Program report concluded that no definitive evidence exists for adverse effects associated with folic acid.[25][26] However, rare instances of gastrointestinal tract upset have been reported.[27] The National Toxicology Program report and subsequent literature reviews have drawn similar conclusions while emphasizing the need for further investigation. Overall, the benefits of folic acid intake outweigh any potential risks. Furthermore, mandatory folic acid fortification programs worldwide have yielded no established risks of adverse effects.

Contraindications

Hypersensitivity to folic acid or its formulation is a potential contraindication to its administration. Clinicians should recognize that research has not yet established hypersensitivity reactions to folic acid; however, a history of anaphylactic reaction to any substance should deter administration of the offending agent.

Monitoring

Folate deficiency can manifest in numerous ways. Measurement of blood folate levels provides a definitive diagnosis, but other signs also exist. Low levels of folate lead to macrocytic megaloblastic anemia. A simple blood smear of an individual with folate deficiency will reveal erythrocyte macrocytosis and hypersegmented polymorphonuclear cells.[28] The abnormal morphology results from impaired DNA synthesis, which causes precursor cells in the bone marrow to have immature nuclei relative to their cytoplasm.

Additionally, oral ulcers may appear without neurologic symptoms, in contrast to vitamin B₁₂ deficiency, which causes subacute combined degeneration.[29] Folate deficiency in pregnancy contributes heavily to fetal neural tube defects. Moreover, interruption of DNA synthesis due to folate deficiency elevates homocysteine levels. Hyperhomocysteinemia is also present in vitamin B₁₂ deficiency, but vitamin B₁₂ deficiency is also associated with elevated methylmalonic acid levels, and the neurologic signs of subacute combined degeneration are absent in folate deficiency. Therefore, clinicians must rule out a concurrent vitamin B₁₂ deficiency before administering folic acid in apparent folate deficiency anemia. The rationale is that folic acid administration will address the anemia associated with vitamin B₁₂ deficiency, but methylmalonic acid levels will remain elevated, leading to toxic neurologic effects. Therefore, measurement of vitamin B₁₂ levels before folic acid administration is advisable to avoid the potential development of subacute combined degeneration.

Deficient folate levels have been detected in up to 16% of patients on antiepileptic drugs, including gabapentin, phenytoin, carbamazepine, valproate, and primidone.[30] Women using antiepileptic drugs may develop folic acid deficiency during pregnancy and require a higher dose to maintain adequate treatment levels. However, the recommendation is to reduce the antiepileptic drug to the minimum effective dose and increase folic acid supplementation to achieve the maximum protective effect against neural tube defect formation in the fetus. Results from research found that many women use antiepileptic drugs for nonepileptic disorders, such as migraines. Sexually active women of reproductive age who are not using contraception are encouraged to use antiepileptic drugs only to treat epilepsy.[31][32] Together, these consequences of folate deficiency can help the examiner initiate a workup to evaluate folate deficiency.

Toxicity

Like other water-soluble vitamins, folic acid is not stored in the body; therefore, toxicity is not a common concern. However, infrequent neurologic adverse effects have been noted in the context of folate supplementation in individuals with pernicious anemia.[33] Folate contributes minimally to direct toxicity. Instead, the neurologic adverse effects are more directly caused by the masking of subacute combined degeneration, resulting from ongoing vitamin B₁₂ deficiency that continues to destroy neuronal cells despite folate supplementation, resolving the anemic aspect seen in pernicious anemia. One published case report described fatal poisoning, but the authors acknowledge that the findings may be a unique manifestation of folic acid toxicity in humans.[27]

Enhancing Healthcare Team Outcomes

The relative safety of folic acid allows clinicians to administer it to patients with little concern for adverse effects. However, specific best practices should be considered to ensure positive outcomes. To increase folate levels, the primary care clinician should counsel patients to consume a healthy diet that includes vegetables, eggs, and milk. Dietitians can be consulted to ensure inpatients receive appropriate food selections to enhance folate delivery. Pregnant women should be informed of folate deficiency risks and advised to take supplements. Clinicians should refer to the American College of Obstetricians and Gynecologists recommendations for prepregnancy counseling for women of childbearing age and recommend folic acid supplements based on the patient's health condition.

In contrast, pregnant women should be prescribed antiepileptic drugs only for epilepsy and at the lowest effective dose possible to prevent complications from low folic acid levels. Nurses and pharmacists can alert clinicians that antiepileptic medications are included in the pregnant patient's medication list. The source of macrocytic megaloblastic anemia must be determined before supplement administration begins, because folate and vitamin B₁₂ deficiency can present similarly in patients. Therefore, clinicians should consider verifying the vitamin B₁₂ levels in patients to optimize treatment plans and improve patient outcomes when prescribing folic acid. As described previously, clinicians, advanced practice clinicians, nurses, pharmacists, and dietitians should work collaboratively as an interprofessional team and communicate when treating patients who may benefit from folic acid supplementation. Lastly, care coordination is pivotal in ensuring seamless and efficient patient care. Clinicians, advanced practice clinicians, nurses, pharmacists, and other healthcare professionals must work together to streamline the patient's journey, from diagnosis through treatment and follow-up. Interprofessional coordination minimizes errors, reduces delays, and enhances patient safety, ultimately leading to improved outcomes and patient-centered care that prioritizes the well-being and satisfaction of patients requiring folic acid supplementation.