<unk>  is especially important during periods of frequent cell division and growth, such as infancy and pregnancy.<unk>  deficiency hinders DNA synthesis and cell division, affecting hematopoietic cells and neoplasms the most because of their greater frequency of cell division. RNA transcription and subsequent protein synthesis are less affected by<unk>  deficiency, as the mRNA can be recycled and used again (as opposed to DNA synthesis, where a new genomic copy must be created). Birth defects Deficiency of<unk>  in pregnant women has been implicated in neural tube defects (NTDs), with an estimate of 300,000 cases worldwide prior to the implementation in many countries of mandatory food fortification. NTDs occur early in pregnancy (first month), therefore women must have abundant<unk>  upon conception and for this reason there is a recommendation that any woman planning to become pregnant consume a<unk> -containing dietary supplement before and during pregnancy. The Center for Disease Control and Prevention (CDC) recommends a daily amount of 400 micrograms of<unk> ic acid for the prevention of NTDs. Compliance with this recommendation is not complete, and many women become pregnant without this being a planned pregnancy, or may not realize that they are pregnant until well into the first trimester, which is the critical period for reducing risk of NTDs. Countries have implemented either mandatory or voluntary food fortification of wheat flour and other grains, or else have no such program and depend on public health and healthcare practitioner advice to women of childbearing age. A meta-analysis of global birth prevalence of spina bifida showed that when mandatory fortification was compared to countries with voluntary fortification or no fortification program, there was a 30% reduction in live births with spina bifida. Some countries reported a greater than 50% reduction. The United States Preventive Services Task Force recommends<unk> ic acid as the supplement or fortification ingredient, as forms of<unk>  other than<unk> ic acid have not been studied. A meta-analysis of<unk>  supplementation during pregnancy reported a 28% lower relative risk of newborn congenital heart defects. Prenatal supplementation with<unk> ic acid did not appear to reduce the risk of preterm births. One systematic review indicated no effect of<unk> ic acid on mortality, growth, body composition, respiratory, or cognitive outcomes of children from birth to 9 years old. There was no relation between maternal<unk> ic acid supplementation and an increased risk for childhood asthma. Fertility<unk>  contributes to spermatogenesis. In women,<unk>  is important for oocyte quality and maturation, implantation, placentation, fetal growth and organ development. Heart disease One meta-analysis reported that multi-year<unk> ic acid supplementation, in amounts in most of the included clinical trials at higher than the UL of 1,000 μg/day, reduced the relative risk of cardiovascular disease by a modest 4%. Two older meta-analyses, which would not have incorporated results from newer clinical trials, reported no changes to the risk of cardiovascular disease. Stroke The absolute risk of stroke with supplementation decreases from 4.4% to 3.8% (a 10% decrease in relative risk). Two other meta-analyses reported a similar decrease in relative risk. Two of these three were limited to people with pre-existing cardiovascular disease or coronary heart disease. The beneficial result may be associated with lowering circulating homocysteine concentration, as stratified analysis showed that risk was reduced more when there was a larger decrease in homocysteine. The effect was also larger for the studies that were conducted in countries that did not have mandatory grain<unk> ic acid fortification. The beneficial effect was larger in the subset of trials that used a lower<unk> ic acid supplement compared to higher. Cancer Chronically insufficient intake of<unk>  may increase the risk of colorectal, breast, ovarian, pancreatic, brain, lung, cervical, and prostate cancers. Early after fortification programs were implemented, high intakes were theorized to accelerate the growth of preneoplastic lesions that could lead to cancer, specifically colon cancer. Subsequent meta-analyses of the effects of low versus high dietary<unk> , elevated serum<unk> , and supplemental<unk>  in the form of<unk> ic acid have reported at times conflicting results. Comparing low to high dietary<unk>  showed a modest but statistically significant reduced risk of colon cancer. For prostate cancer risk, comparing low to high dietary<unk>  showed no effect, but the same two studies reported a significant increased risk for prostate cancer correlating to elevated serum<unk> . Two reviews of trials that involved<unk> ic acid dietary supplements reported, respectively, a statistically significant 24% increase in prostate cancer risk and a not significant 17% increase in prostate cancer risk. Supplementation with<unk> ic acid at 1,000 to 2,500 μg/day – the amounts used in many of the supplement trials – would result in higher concentrations of serum<unk>  than what is achieved from diets high in food-derived<unk> . The second study reported no significant increase or decrease in total cancer incidence, colorectal cancer, other gastrointestinal cancer, genitourinary cancer, lung cancer or hematological malignancies in people who were consuming<unk> ic acid supplements. A third supplementation meta-analysis limited to reporting only on colorectal cancer incidence showed that<unk> ic acid treatment was not associated with colorectal cancer risk. Anti-folate chemotherapy<unk>  is important for cells and tissues that divide rapidly. Cancer cells divide rapidly, and drugs that interfere with<unk>  metabolism are used to treat cancer. The antifolate drug methotrexate is often used to treat cancer because it inhibits the production of the active tetrahydrofolate (THF) from the inactive dihydrofolate (DHF). However, methotrexate can be toxic, producing side effects such as inflammation in the digestive tract that make eating normally more difficult. Bone marrow depression (inducing leukopenia and thrombocytopenia) and acute kidney and liver failure have been reported.<unk> inic acid, under the drug name leucovorin, a form of<unk>  (formyl-THF), can help "rescue" or reverse the toxic effects of methotrexate.<unk> ic acid supplements have little established role in cancer chemotherapy. The supplement of<unk> inic acid in people undergoing methotrexate treatment is to give less rapidly dividing cells enough<unk>  to maintain normal cell functions. The amount of<unk>  given is quickly depleted by rapidly dividing (cancer) cells, so this does not negate the effects of methotrexate. Neurological disorders Conversion of homocysteine to methionine requires<unk>  and vitamin B12. Elevated plasma homocysteine and low<unk>  are associated with cognitive impairment, dementia and Alzheimer's disease. Supplementing the diet with<unk> ic acid and vitamin B12 lowers plasma homocysteine. However, several reviews reported that supplementation with<unk> ic acid alone or in combination with other B vitamins did not prevent development of cognitive impairment nor slow cognitive decline. A 2017 meta-analysis found that the relative risk of autism spectrum disorders was reduced by 23% when the maternal diet was supplemented with<unk> ic acid during pregnancy. Subset analysis confirmed this among Asian, European and American populations. Some evidence links a shortage of<unk>  with clinical depression. Limited evidence from randomized controlled trials showed using<unk> ic acid in addition to selective serotonin reuptake inhibitors (SSRIs) may have benefits. Research found a link between depression and low levels of<unk> . The exact mechanisms involved in the development of schizophrenia and depression are not entirely clear, but the bioactive<unk> , methyltetrahydrofolate (5-MTHF), a direct target of methyl donors such as S-adenosyl methionine (SAMe), recycles the inactive dihydrobiopterin (BH2) into tetrahydrobiopterin (BH4), the necessary cofactor in various steps of monoamine synthesis, including that of dopamine. BH4 serves a regulatory role in monoamine neurotransmission and is required to mediate the actions of most antidepressants. 5-MTHF also plays both direct and indirect roles in DNA methylation, NO2 synthesis, and one-carbon metabolism.<unk> ic acid, B12 and iron A complex interaction occurs between<unk> ic acid, vitamin B12, and iron. A deficiency of<unk> ic acid or vitamin B12 may mask the deficiency of iron; so when taken as dietary supplements, the three need to be in balance. Malaria Some studies show iron–folic acid supplementation in children under five may result in increased mortality due to malaria; this has prompted the World Health Organization to alter their iron–folic acid supplementation policies for children in malaria-prone areas, such as India.
Folate
Iron
Calamine
Zinc
Tocopherol
Pantothenic acid
Biotin
Riboflavin