The term folic acid (Folate) is often used as a generic name for a group of compounds based on the structure of folate, which cannot be resynthesized by the body and must be obtained through diet or supplementation.
What are the benefits and side effects of folic acid in empirical medicine? See discussed in the text for details
What is folic acid?
Folic acid is a kind of vitamin B group, the same as water-soluble vitamins, the origin of the word folic acid is Latin folium, meaning leaves, is a one-carbon metabolism essential nutritional molecules, and amino acid metabolism, methylation process, DNA and RNA synthesis, neurotransmitter synthesis and gene expression are closely related.
Folic acid plays an important role in protein synthesis, metabolism, and other processes involved in cell proliferation and tissue growth.
Folate deficiency is often associated with inadequate dietary intake, alcohol abuse and liver disease, malabsorption, increased need during pregnancy and lactation, and drug interference.
How is Folate different from Folic acid?
Dietary folate is a natural nutrient found in foods such as leafy greens, legumes, egg yolks, liver, and citrus fruits.
Folic acid refers to synthetic dietary supplements found in artificially added foods (such as flour and breakfast cereals) and medicinal vitamins.
Neither folate nor Folic acid is metabolically active and must be converted to 5-methyltetrahydrofolate (5-MTHF) in cells to be used by the body, and 5-MTHF is also known as active folate.
What are the concerns about supplementing Folic acid?
Folic acid is a form of general supplements, commonly found in multivitamins, which undergo multi-step conversion after ingestion into the human body to become active folic acid (5-MTHF) with valuable value, and studies have found that some people have poor MTHFR enzyme activity due to genetic mutations, so the conversion process is less efficient
When supplemented in large quantities in the form of folic acid, it leads to the accumulation of unmetabolized folic acid in the blood
The literature also suggests that unmetabolized folate may be associated with certain adverse health conditions, including low immunity, decreased brain function, and cancer. Note 8
Although the above thesis still needs more research to verify, but before that the best way to take folic acid is still from natural food, if there is really additional demand, you can choose to choose an active folic acid supplement containing 5-MTHF (5-methyltetrahydrofolate) form, in addition to high human rate of use, but also to avoid possible metabolic problems. Note 9
What are the proven benefits of folic acid?
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Folic acid is good for blood sugar regulation
Diabetes is the most prevalent metabolic disease, with an estimated 4 million people living with diabetes worldwide, including 6.3420 million in the United States alone, or 10.5% of the population.
High blood sugar relates with the symptoms like frequent urination, thirst, blurred vision, fatigue and recurrent infections etc. (Patients are 3 times more likely to be hospitalized than people without diabetes.)
In addition to relieving symptoms, glycemic management aims to reduce long-term complications of diabetes, and good glycemic management can reduce the occurrence and progression of microvascular complications.
A systematic literature review and meta-analysis (24 randomized controlled trials, 34,646 participants) noted that folic acid supplementation reduced fasting blood glucose, fasting insulin, and insulin resistance (HOMA-IR) measures compared with controls, but did not have any significant changes in glycosylated hemoglobin (HbA1c). Note 1
In addition, subgroup analyses showed that blood glucose improvement was more pronounced with high doses (≥5 mg).
*Conclusion: Folic acid supplementation may be a positive effect on glycaemic regulation, but may not be clinically important due to relatively small improvement
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Folic acid assists blood lipid regulation
Dyslipidemia refers to a disorder of one or more lipoproteins in the blood, such as elevated total cholesterol, LDL cholesterol, or triglycerides, or low levels of HDL cholesterol alone.
In many countries, the incidence of dyslipidemia is high and continues to increase due to Westernization of diet, obesity, population ageing, reduced physical activity, and other adverse lifestyle effects, and is one of the most important and modifiable risk factors for cardiovascular disease.
A systematic literature review and meta-analysis (38 randomized controlled trials, 21,787 participants) noted that folic acid supplementation helped reduce serum triglyceride and total cholesterol concentrations compared with placebo. Note 1
However, folic acid supplementation did not affect serum concentrations of low-density lipoprotein cholesterol or high-density lipoprotein cholesterol, whereas a significant dose-response relationship was observed between folic acid supplementation and serum HDL cholesterol concentrations.
*Conclusion: Folic acid supplementation may have a positive effect on blood lipid regulation, but more studies are needed to observe the effect on different populations
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Folic acid reduces the incidence of autism
Autism spectrum disorder is a multifactorial neurodevelopmental disorder caused by a combination of genetic and environmental factors, including folate deficiency, neonatal hypoxia, maternal obesity, and gestational diabetes (8 in 1 children at age 54 years old, 4.3:1 male-to-female ratio).
People with autism exhibit problem behaviors such as aggression, self-harm, resistance to order, and inability to talk normally, often accompanied by social anxiety, attention deficits, hyperactivity, sleep disturbances, and obsessive-compulsive disorder. As a result, it is difficult for patients to obtain the same level of education as their peers and maintain independent living.
A meta-analysis (10 observational studies) suggested that folic acid supplementation in early pregnancy was associated with a reduced risk of autism. Note 1
In addition, subgroup analysis found that the minimum dose of folic acid is estimated to be at least 400 μg per day for protective effect.
*Conclusion: Prenatal folic acid supplementation in pregnant women (especially in the first trimester) is associated with a lower risk of autism spectrum disorder in offspring.
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Folic acid reduces the risk of preterm birth
Preterm birth, defined as birth between weeks 20 and 37 of gestation, is a major obstetric health care problem and an important factor in perinatal morbidity, mortality and long-term disability.
It is estimated that about 1500 million babies are born prematurely worldwide each year, resulting in 100 million of them deaths.
Preterm birth is considered a multifactorial syndrome, with nearly 70% of preterm births caused by spontaneous delivery or rupture of membranes, and the remainder by iatrogenic causes. As such, it can be broadly divided into spontaneous preterm birth and preterm birth.
A meta-analysis (27 observational studies) found that blood folate levels, folate supplementation, and dietary folate intake were inversely associated with the risk of preterm birth (although there was no clear link between dietary folic acid and the risk of natural preterm birth). Note 1
*Conclusion: Folic acid supplementation during pregnancy is significantly associated with a lower risk of preterm birth and higher maternal folate levels
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Folic acid reduces the incidence of stroke
Stroke can be classified as haemorrhagic or occlusive/ischemic stroke, the majority (80%) of which falls into the latter category, and stroke is the fourth leading cause of death after heart disease, cancer and chronic lower respiratory tract disease in terms of mortality, and the largest cause of disability, with about 50% of survivors being permanently disabled.
Risk factors associated with stroke, including history of hypertension, smoking, diabetes, waist-hip ratio, dietary risk score, physical inactivity, alcohol consumption, psychosocial stress and depression, cardiac causes, and apolipoprotein B to A1 ratio.
A systematic literature review and meta-analysis (12 randomized controlled trials, 47,523 patients with cardiovascular disease) showed that folic acid treatment significantly reduced the risk of stroke compared with those treated with control (particularly at a daily dose of < 2 mg, with a follow-up of ≥ 40 months). Note 1
In addition, there was no significant difference in the risk of all-cause mortality, cardiovascular mortality, and coronary heart disease between the two groups.
*Conclusion: Oral folic acid can help reduce stroke risk in patients with cardiovascular disease, but more large, precisely designed trials are needed to support this
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Folic acid prevents neural tube defects
Neural tube defects (NTDs), congenital malformations of the brain and spinal cord caused by the failure of the neural tube to close within 21–28 days of pregnancy, are the second most common serious birth defect, affecting about 1000.0 to 5 out of every 2,<> pregnancies worldwide.
The most common forms of neural tube defects are spina bifida, which is due to failure of posterior (tail) neural tube fusion, and anencephaly, and anencephaly, which is due to failure of anterior (cranial) neural tube fusion.
Anencephaly is fatal, and many anencephaly children are stillborn or die shortly after birth. Spina bifida has a high likelihood of living with physical and intellectual disability for life, and only a few of these children will be able to live independently as adults.
A Cochrane Review (4 studies, 6425 women) noted that folic acid supplementation from preconception to early pregnancy reduced the incidence of neural tube defects by 72%. Note 1
*Conclusion: Folic acid supplementation before to early pregnancy is a positive help in preventing neural tube defects
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Folic acid reduces the incidence of hypertension in pregnancy
Hypertensive disorders of pregnancy, including preeclampsia and gestational hypertension, are the most common complications of pregnancy and are associated with adverse health outcomes for mothers and their children.
Preeclampsia is diagnosed with new elevated blood pressure and proteinuria after 20 weeks’ gestation and is an important cause of fetal death, preterm birth, and intrauterine growth restriction.
Hypertension during pregnancy, on the other hand, refers to a new increase in blood pressure that does not occur in proteinuria after 20 weeks of pregnancy. It is found in 6% to 17% of pregnancies and is associated with preterm and small-for-gestational-age infants.
A meta-analysis (13 cohort studies and 1 randomized controlled trial involving more than 300,000 women) noted that the risk of gestational hypertension was not associated with folic acid supplementation during pregnancy. However, folic acid supplementation during pregnancy can significantly reduce the risk of preeclampsia. Note 2
In addition, results from subgroup analysis showed that a reduction in the risk of preeclampsia was associated with folic acid multivitamin supplementation (not folic acid supplementation alone).
*Conclusion: Multivitamin supplementation containing folic acid during pregnancy may help reduce the risk of preeclampsia, but more randomized controlled trials are needed due to high heterogeneity between studies.
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Folic acid reduces the risk of congenital heart disease
Congenital heart disease is the most common type of congenital malformation, defined primarily as a large number of structural and functional defects that occur during cardiac embryogenesis, accounting for one-third of all major congenital malformations.
Worldwide, 1.35 million babies are born with congenital heart disease each year and are considered a substantial cause of early fetal death.
Causes are generally divided into two categories: genetic and non-genetic. Non-genetic causes include environmental teratogens (dioxins, PCBs, pesticides), maternal exposure (alcohol, isotretinoin, thalidomide, antiepileptic drugs), and infectious pathogens
A meta-analysis (20 case-control studies) noted that folic acid supplementation during pregnancy was a protective factor against congenital heart defects in Chinese and European patients, reducing the risk of congenital heart defects by approximately 40%, while no association was found in the United States. Note 3
*Conclusion: Folic acid supplementation during pregnancy significantly reduces the risk of congenital heart defects in newborns in Chinese and European observations.
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Folic acid reduces cleft lip and palate events
Oral clefts are a variant of congenital cleft lip deformities caused by abnormal facial development during pregnancy, including: cleft lip only, cleft lip with palate, and cleft palate only, the most common orofacial congenital malformations in babies, accounting for 65% of all head and neck malformations, usually non-fatal.
It is estimated that cleft lip occurs in about 1 in 700 to 1 in 1000 live births in different populations around the world, with great variability depending on geographical origin, ethnicity and socio-economic conditions.
About 70% of cleft lip cases are nonsyndromic, meaning that the patient has no other physiological or developmental abnormalities
When cleft lip and palate occur, it has a great impact on the baby’s functions such as feeding, speech, language and speech formation, breathing, oral function, occlusion, and tooth formation.
A meta-analysis (6 cohort studies and 31 case-control studies) suggests that maternal folic acid supplementation reduces the risk of cleft lip and palate in all types. Note 4
Further Subgroup Analysis found that:
Folic acid supplementation alone reduced the risk of nonsyndromic cleft palate by 27% and single cleft palate by 25%
Multivitamin supplementation with folic acid reduced the risk of cleft palate by 35% and cleft palate alone by 31%
The timing of use is the most protective effect from before pregnancy to the first 3 months of pregnancy (compared to those who have not taken it)
*Conclusion: Continuous folic acid supplementation (or folic acid-containing multivitamins) before pregnancy to 3 months after pregnancy can help reduce the event of cleft lip and palate in newborns
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Folic acid is beneficial for gastric precancerous lesions
Gastric cancer is the second most common cause of cancer-related death and the fourth highest incidence of cancer in the world, with prognosis varying by stage. The 5-year survival rate for advanced gastric cancer is less than 20%.
On the contrary, early gastric cancer has a good prognosis, with a 5-year survival rate of more than 90%. Therefore, it is important to individualize the management of high-risk groups of gastric cancer.
Risk factors for gastric cancer are Helicobacter pylori infection, salt intake, smoking, alcohol consumption, family history of gastric cancer, atrophic gastritis, and intestinal metaplasia. In particular, atrophic gastritis and intestinal metaplasia are considered to be Gastric precancerous conditions. Therefore, effective diagnosis and management is a very important research topic for the prevention of gastric cancer.
A systematic literature review and meta-analysis (11 randomized controlled trials, 1252 participants in chronic atrophic gastritis) pointed out that folic acid has a beneficial effect on the treatment of gastric precancerous lesions when the daily dose is maintained at 20 to 30 mg and the course of treatment is maintained for 3 to 6 months, as measured by chronic atrophic gastritis and intestinal metaplasia. Note 1
*Conclusion: Folic acid supplementation may help prevent or even reverse the progression of gastric precancerous lesions
Pregnancy/Pregnancy Preparation Folic Acid Dosage?
According to the Centers for Disease Control and Prevention, all women planning to become pregnant or of childbearing age should consume 400 micrograms (mcg) of folic acid per day to get enough folic acid to help prevent certain birth defects
This is because about half of all pregnancies are unplanned, and major birth defects in the baby’s brain or spine appear early in pregnancy (after 3-4 weeks of pregnancy), which is usually before you realize you are pregnant.
Doses higher than 400 micrograms (mcg) are generally recommended during pregnancy or pregnancy preparation and consultation with a physician for the exact dosage to ensure safety
The mother or child’s biological father has a neural tube defect
History of pregnancy with neural tube defects
You or your child’s biological father has a family history of neural tube defects
Have diabetes
Take medications to treat epilepsy, type 2 diabetes, lupus, psoriasis, rheumatoid arthritis, asthma, or inflammatory bowel disease
Have kidney disease and need hemodialysis (dialysis)
Have sickle cell disease (a genetic disorder also known as sickle anemia)
Diseases of abnormal liver function
Drink more than one alcoholic beverage per day
What are the side effects of folic acid?
Excessive intake of folic acid from food has no adverse effects, but additional supplements should be noted that most adults have few side effects when they take a daily dose of less than 1000 micrograms (mcg).
However, long-term high-dose folic acid may cause abdominal cramps, bitter mouth, diarrhea, skin rash, sleep disturbance, irritability, confusion, nausea, stomach upset, loss of appetite, difficulty concentrating, skin reactions, seizures, exhaust, and excitement Wait
What are the safety precautions for folic acid?
- If you have ever had any abnormal allergic reaction to food or medicine, please be careful. Allergic reactions may occur. Symptoms include rash, itching, redness, and difficulty breathing.
- It is safe to take oral folic acid in proper amount during pregnancy and lactation, the dosage is about 300 to 400 mcg per day
- Excessive serum folic acid levels are associated with an increased risk of prostate cancer. Note 6
- Taking folic acid supplements may worsen seizures, especially at high doses.
- Those who have undergone coronary angioplasty should use caution. Early studies have found that the use of folic acid, vitamin B6 and vitamin B12 in related patients after surgery may increase the risk of in-stent restenosis and increase the target vessel reconstruction ( target vessel revascularization). Note 7
- Do not use in combination with anticonvulsant (used to treat epilepsy). Folic acid can increase the speed at which the body breaks down the drug, thereby reducing the effectiveness of the drug. Related drug names are: Fosphenytoin, phenytoin, and primidone
- Do not use in combination with the anti-cancer drug Methotrexate, because the drug is a folic acid antagonist, so the combined use may reduce the efficacy of the drug
- Do not use with central nervous system depressants: Barbiturates drugs may reduce the effectiveness of drugs
- Do not use in combination with the antimalarial agent Pyrimethamine, which may reduce the effectiveness of the drug