Folic acid supplementation in pregnancy

INTRODUCTION — Folate is an essential nutrient, important in DNA and RNA synthesis, DNA methylation, hematopoiesis, and possibly normal neuronal function. Physiologic requirements are higher in pregnancy because of increased hematopoiesis and fetal and placental growth. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies", section on 'Overview of intake and metabolism'.)  

Periconceptional folic acid supplementation decreases the occurrence and recurrence of neural tube defects (NTDs). It is recommended for all females capable of becoming pregnant, particularly those planning to conceive. Preconception patient education about the need for supplementation is important during medical wellness visits as many patients are not aware of this recommendation until after they seek prenatal care or they choose not to follow the recommendation because of cost or inconvenience [1,2]. Individuals who do not take supplements still consume some folic acid as folate is a natural component of a variety of foods, and grain products in many countries are fortified with folic acid.

This topic will discuss the role of folic acid supplementation for prevention of NTDs, dosing in females at average versus high risk of NTDs, potential pregnancy benefits unrelated to NTDs, potential risks of supplementation, and NTDs that occur despite supplementation. Prenatal screening and diagnosis of NTDs are reviewed separately. (See "Neural tube defects: Overview of prenatal screening, evaluation, and pregnancy management".)

FOLATE AND FOLIC ACID — Although the terms folate and folic acid are often used interchangeably, folate is a water-soluble B vitamin (B9) that occurs naturally in foods, and folic acid is the synthetic form of folate.

Sources

●Food sources – Folate (B9) occurs naturally in several foods, including beef liver, leafy vegetables, peas and beans, avocados, eggs, and milk (table 1) [3,4]. Folic acid is added to fortify certain foods, including wheat flour, rice, pasta, breads, cereals, and cornmeal (maize flour).

●Pharmacologic sources – Folic acid is available in multivitamins, prenatal vitamins, and as a pure folic acid supplement. It has also been added to some oral estrogen-progestin contraceptive pills to ensure adequate baseline folate levels in the event of unplanned pregnancy from inconsistent/incorrect contraceptive use or conception soon after discontinuation.

Both folate and folic acid are reduced to their metabolically active form, L-5-methyltetrahydrofolate (L-5-methyl-THFL), during absorption across the intestinal mucosa; some hepatic metabolism also occurs [5]. The calcium salt of L-5-methyl-THFL is commercially available and included in some vitamin supplements instead of folic acid.

In healthy volunteers, folic acid supplements, dietary folate, and L-5-methyl-THFL supplements resulted in similar increases in plasma folate and red cell folate concentrations [5].

Food fortification — Fortification provides approximately 163 micrograms of folic acid per day to the target population in the United States, which may or may not be adequate to prevent neural tube defects (NTDs) without a folic acid supplement [6,7]. Models using blood folate concentrations to estimate the optimal folic acid dose suggest that 163 micrograms may be inadequate and that 400 micrograms per day may be needed; however, epidemiologic data have demonstrated significant reductions in NTD rates in countries where food fortification is at the same level as that in the United States and folic acid supplementation is not widespread [8-12].

The adequacy of current levels of food fortification is supported by a 2017 systematic review by the US Preventive Services Task Force (USPSTF) that noted studies of folic acid supplementation performed after 1998, when food fortification with folic acid became routine in the United States, have not demonstrated a protective association [13], suggesting that current levels of food fortification alone may be sufficient to prevent most folate-sensitive NTDs. It is also possible that misclassification and recall bias in post-food fortification studies reduced the magnitude of the effect associated with supplementation.

Given the limitations of the post-food fortification studies, in 2017 the USPSTF reaffirmed its 2009 recommendation that all females of reproductive age planning or capable of pregnancy take a supplement containing 0.4 to 0.8 mg of folic acid once per day to reduce their risk of having a child with an NTD [14]. (See 'Candidates' below and 'Universal prophylaxis for the general obstetric population' below.)

Causes of suboptimal levels — Varying degrees of folate deficiency may result from:

●Decreased intake due to:

•Low-carbohydrate diets, since bread and pasta are made of fortified grains [15].

•High consumption of foods designated as "organic," as they are exempt from folic acid fortification regulations.

•Food insecurity

•Anorexia nervosa and other medical conditions affecting food intake

●Interference by some medications (eg, phenytoin, sulfasalazine, trimethoprim, methotrexate).

●Medical or surgical conditions associated with malabsorption (most commonly: inflammatory bowel disease and major intestinal resection or bypass; less commonly: documented celiac disease, significant liver disease, renal failure requiring dialysis, and ethanol abuse). In addition, obesity may be associated with derangements in one-carbon metabolism and/or gut dysbiosis, resulting in suboptimal folate levels despite supplementation [16].

●Methylenetetrahydrofolate reductase (MTHFR) polymorphisms (eg, MTHFR 677C->T or 677TT).

Diagnosis of suboptimal levels — Normal serum/plasma and red cell folate levels by trimester are shown in the table (table 2). The most accurate test for evaluation of folate status is the red cell folate concentration, which reflects body stores of folate whereas serum/plasma folate reflects current concentrations in the circulation. It is not known whether one of these levels is more predictive of risk of NTDs than the other. The disadvantage of measurement of red cell folate concentration is that it is more prone to laboratory issues with reproducibility [17,18].

True folate deficiency is rare in the United States, while suboptimal levels (ie, level below that for optimal prevention of NTDs) are common (23 percent of females of childbearing age in the United States [19]). The World Health Organization defined a suboptimal red cell folate level as <400 ng/mL (906 nmol/L), which aligns with findings from a subsequent study on red cell folate levels and congenital cardiac anomalies [20], but WHO was unable to identify a threshold for suboptimal serum/plasma level [21]. The Society of Obstetricians and Gynaecologists of Canada concluded that serum folate levels of 28 to 30 nmol/L are protective of NTDs [22,23]. In one study, a serum/plasma level >11.3 ng/mL (25.5 nmol/L) was suggested for optimal NTD prevention in nonanemic, non-vitamin B-12-deficient, nonpregnant females [24]. In another study, a serum/plasma level >7.0 ng/mL (15.9 nmol/L) was suggested for pregnant people [6]. The discordancy may be related to hemodilution in pregnancy or to population differences in race/ethnicity and environmental factors in the two studies, or to chance.

Routine measurement of the red cell folate level is not practical since it is common. Furthermore, it has not been proven to be an effective approach for reduction of NTDs. Instead, empiric folic acid supplementation is recommended for all females. (See 'Folic acid supplementation for prevention of neural tube defects' below.)

FOLIC ACID SUPPLEMENTATION FOR PREVENTION OF NEURAL TUBE DEFECTS

Evidence of efficacy — The body of evidence from randomized trials and large prospective and retrospective studies supports the efficacy of folic acid supplementation and dietary fortification for decreasing the occurrence and recurrence of neural tube defects (NTDs) [3,13,25-28]. For example, in a meta-analysis of randomized trials [25]:

●For females with no previously affected pregnancy, daily folic acid supplementation (at least 0.4 mg alone or in combination with other vitamins and minerals) reduced NTDs by 93 percent compared with no interventions/placebo or vitamins and minerals without folic acid (0/2471 versus 6/2391; relative risk [RR] 0.07, 95% CI 0.00-1.32; one trial, 4862 births).

●When females with and without a previously affected pregnancy were included in the analysis, NTDs were reduced by 70 percent (12/3433 versus 42/3275; RR 0.31, 95% CI 0.17-0.58; five trials, 6708 births).

●When only females with a previously affected pregnancy were analyzed, NTDs were reduced by a similar amount (12/3433 versus 42/3275; RR 0.34, 95% CI 0.18-0.64; four trials, 1846 births).

Candidates — Most major national medical organizations and public health authorities recommend that all females of childbearing potential, not just those who are attempting to conceive, receive a once per day folic acid supplement [14,29,30]. This broad recommendation is based on the large number of unplanned pregnancies (as many as 50 percent of pregnancies in the United States are unplanned [31]) and closure of the neural tube very early in gestation (at 26 to 28 days after conception [ie, by six weeks of gestation]), before many individuals know that they are pregnant.

Dose and administration

Universal prophylaxis for the general obstetric population — For most females, the standard folic acid supplement (multivitamin, prenatal vitamin) is 0.4 mg taken once per day, beginning at least one month prior to attempting conception and continuing throughout pregnancy and for four to six weeks postpartum or until completion of breastfeeding. This dose should ensure adequate folate levels during organogenesis, which occurs primarily in the first trimester, and also later in pregnancy when folate is required to meet both maternal needs and the growth and (probably) the developmental needs of the fetus [32-34]. All prenatal and many multivitamins contain at least 0.4 mg of folic acid.

Some guidelines recommend beginning folic acid supplementation at least one month before conception while others recommend beginning two to three months before conception, particularly if a previous offspring had an NTD (table 3). We recommend beginning supplementation at least one month before conception because we are not treating severe folate deficiency, folate is well absorbed, and it is not stored in fat so excess intake is excreted. Serum levels will become normal almost as soon as supplements are started, but red cell folate levels will take three months to normalize because of red blood cell (RBC) turnover.

High-dose prophylaxis for females at high risk of offspring with NTD — Females who are at higher risk of having a child with a NTD than the baseline population (such as those with a previous fetus with an NTD (table 4))are candidates for higher (1 to 4 mg) dose folic acid supplementation (table 3). This dose should be initiated one to three months prior to conception and maintained through the first 12 weeks of gestation, after which the dose is reduced to 0.4 mg and continued until four to six weeks postpartum or until completion of breastfeeding [32,35]. The choice of dose between 1 and 4 mg depends on the reason that the patient is high risk and is discussed below. (See 'Females who may benefit from higher dose folic acid supplementation' below.)

In the United States, the tolerable upper limit for folic acid intake in the general adult population is 1 mg. Folic acid supplementation at the 4 mg dose used for prophylaxis in females at high risk of having a child with an NTD is generally believed to be nontoxic in the short term, but the dose should be decreased after the first trimester since the reason for therapy (prevention of NTDs) is no longer relevant and the possibility of adverse fetal effects with long-term high-dose exposure cannot be excluded [36]. (See 'Epigenetic alterations' below.)

Females should be advised not to attempt to achieve high-dose supplementation by taking multiple multivitamins because this may result in ingestion of harmful levels of other vitamins, such as vitamin A, which can be teratogenic. One prenatal vitamin per day and a 1 mg tablet of folic acid three to four times per day is a practical means of ingesting a total dose of 4 to 5 mg per day. Alternatively, three or four 1 mg folic acid tablets/capsules can be taken at one time for patient convenience. One mg tablets/capsules of folic acid are widely available by prescription; 5 mg tablets/capsules are also available in some countries. The dose is reduced to at least 0.4 mg after 12 weeks of gestation, as described previously.

Although expert consensus groups consistently recommend 4 mg per day as the maximum dose, one expert (Wald) has suggested a higher dose (5 mg) for this population since his mathematical model predicted this dose may reduce the risk of NTDs by approximately 85 percent [37,38]. By contrast, a 2015 Cochrane review suggested that the positive effect of folic acid on NTD incidence and recurrence is not affected by the specific folic acid dose (400 micrograms versus higher) or whether folic acid is given alone or with other vitamins and minerals [25].

Monitoring folate levels — We do not monitor folate levels. Although serum/plasma and red cell folate levels can be monitored, the utility of this practice is not known, and serum/plasma levels do not reflect total body saturation levels. No prospective studies have evaluated whether routinely monitoring levels during pregnancy improves outcomes.

Some authors suggest that females with an identified folate deficiency due to a known comorbidity (such as inflammatory bowel disease or bariatric surgery), rather than low dietary intake, should be monitored with monthly serum assessments to ensure adequate supplementation (serum folate level 28 to 30 nmol/L [22]); there is insufficient evidence to recommend for or against this practice. (See "Fertility and pregnancy after bariatric surgery", section on 'Micronutrient supplementation'.)

In a 2022 guideline, the Society of Obstetricians and Gynaecologists of Canada (SOGC) concluded that a personalized approach to folic acid dosing was reasonable for patients who would otherwise be prescribed high-dose folic acid supplementation [22]. This approach required requires such patients to take an oral daily multivitamin containing folic acid 0.4֪ to 1.0 mg and vitamin B12 within the first four to six weeks of a three-month preconception period, then have a blood test to determine their fasting serum folate level. The daily dosage of folic acid supplementation would be continued if results were in the optimal range (serum folate level 28 to 30 nmol/L), and increased to 4 mg if the results were suboptimal.

Females who may benefit from higher dose folic acid supplementation — Preconception patient education about the need for high-dose prophylaxis is critical as many females who have had a prior pregnancy with an NTD or who are otherwise high-risk may not be aware of the recommendation for high-dose folic acid until after they seek prenatal care [39].

The most robust data for the efficacy of higher dose folic acid supplementation are for females with a previously affected offspring [25,40]. More limited data support recommendations for higher dose folic acid supplementation in the specific other high-risk groups discussed below [41].

Either parent with a personal history of NTD or a previously affected offspring — Compared with pedigrees with no affected parents or siblings, the risk of NTD in offspring is increased at least 10-fold among females with a previously affected offspring, a personal history of a NTD, a partner with a NTD, or a partner with an affected child with a previous partner (table 4).

These females should be offered periconceptional/first-trimester supplementation with high-dose (4 mg) folic acid (table 3). In females with a previously affected pregnancy, this dose reduced the risk of recurrent NTDs by approximately 70 percent in a seminal trial (6/593 versus 21/602; RR 0.28, 95% CI 0.12-0.71) [40]. Of note, in females who were not pregnant at randomization and complied with therapy, NTDs were reduced by 83 percent. (See 'High-dose prophylaxis for females at high risk of offspring with NTD' above.)

Family history of a NTD in a second or third degree relative — The risk of a NTD in offspring is mildly increased if there is a family history of a NTD in one second- or third-degree relative. The risk is estimated to increase from 0.1 to 0.5 percent with no affected relative to 1 to 2 percent with an affected second-degree relative versus 0.5 to 1 percent with an affected third-degree relative.

We suggest 1 mg per day periconceptional/first-trimester folic acid dosing for this population. (See 'High-dose prophylaxis for females at high risk of offspring with NTD' above.)

Use of antiseizure medications

●Valproic acid and carbamazepine – Females taking antiseizure medications associated with a high risk for NTDs in offspring, such as valproic acid and carbamazepine, should be transitioned to a treatment regimen associated with lower NTD risk prior to conception, if medically possible. If not possible, the optimal management of folic acid supplementation in this setting is unknown.

We suggest that females with epilepsy on valproate or carbamazepine who are planning to become pregnant take 4 mg per day periconceptional/first-trimester folic acid supplementation to reduce the risk of NTDs based on indirect data from studies in other high-risk females (ie, those with previously affected offspring, personal or partner history of NTD) [40]. Ideally, supplementation should be initiated three months prior to conception. Although a large study of congenital anomalies in live born children of mothers taking antiseizure medications showed no reduction in overall congenital anomalies with folic acid supplementation, even when stratified by folic acid dose (high-dose: odds ratio [OR] 1.82, 95% CI 1.30-2.56; low-dose or no folic acid: OR 1.94, 95% CI 1.21-3.13), pregnancy terminations were not analyzed, only six children had nervous system defects, and the majority of mothers initiated high-dose folic acid from the second month of pregnancy [42]. (See 'High-dose prophylaxis for females at high risk of offspring with NTD' above.)

●Other antiseizure medications – For females who are taking other antiseizure medications (eg, levetiracetam, lamotrigine) which have not been associated with as high a risk of NTD, and sexually active females of reproductive age who are not actively planning pregnancy, we suggest 0.4 mg per day folic acid. (See "Management of epilepsy during preconception, pregnancy, and the postpartum period", section on 'Folic acid supplementation'.)

In all cases, the patient's neurologist should be consulted as folic acid supplementation may reduce serum antiseizure medication levels below therapeutic levels [43].

Clinical guidelines regarding the dose of folic acid supplementation in females with epilepsy vary and are not definitive. For example:

●A 2010 American Academy of Neurology and American Epilepsy Society guideline states that data are insufficient to determine whether doses higher than 0.4 mg offer greater protective benefits [44].

●The American College of Obstetricians and Gynecologists (ACOG) recommends 4 mg of folic acid once per day for females at high risk of having offspring with NTDs [35], and includes females taking antiseizure medications in this category [45].

Although the rationale for administering high-dose supplementation is that the relatively high risk of NTDs associated with some antiseizure medications is thought to be mediated by a decrease in serum folate levels, the effectiveness and appropriate dose of perinatal folic acid supplementation in females taking antiseizure medications have not been investigated in randomized trials, and observational studies have not shown a benefit [42,46]. (See "Risks associated with epilepsy during pregnancy and postpartum period", section on 'Valproate'.)

Folic acid supplementation may have additional benefits beyond reduction in NTDs, as discussed below. (See 'Effect of folic acid supplementation on other pregnancy outcomes' below.)

Therapy with medications other than antiseizure medications that reduce folic acid activity — Medications other than antiseizure medications (eg, triamterene, trimethoprim, sulfasalazine) have been associated with reductions in available folic acid and thus may increase the risk of NTDs. These medications, which are uncommonly used in pregnant patients, may inhibit folic acid absorption, reduce its activity, or have other interactive effects [47].

It is reasonable to offer increased periconceptional/first-trimester folic acid supplementation to females taking these medications. We suggest 1 mg per day folic acid,. (See 'High-dose prophylaxis for females at high risk of offspring with NTD' above.)

Maternal medical conditions associated with decreased folic acid — Several maternal medical conditions have been associated with reduced red cell folate levels, likely through reduced folic acid absorption or increased folic acid clearance. These include medical or surgical conditions associated with malabsorption, such as celiac disease, inflammatory bowel disease, and major intestinal resection or bypass (including some types of bariatric surgery). Less common conditions include advanced liver disease, renal failure requiring dialysis, and unhealthy alcohol use. We suggest 1 mg per day folic acid supplementation for females with these conditions, beginning ideally three months prior to conception and continuing until birth (table 3). (See 'High-dose prophylaxis for females at high risk of offspring with NTD' above.)

Individuals with sickle cell disease (SCD) have chronic hemolytic anemia, which further increases folate requirements. ACOG recommends 4 mg daily to account for ongoing turnover of red cells [48].

Preexisting diabetes — Females with preexisting (pregestational inclusive of T2DM) diabetes are at increased risk of a pregnancy complicated by an NTD. For this reason, we suggest 1 mg per day periconceptional/first-trimester folic acid supplementation for these individuals; this dose is readily available, may be more effective than a lower dose, and has no known harms or side effects. (See 'High-dose prophylaxis for females at high risk of offspring with NTD' above.)

Studies evaluating outcome with different folic acid doses have not been performed, and guidelines vary:

●ACOG recommends at least 0.4 mg per day folic acid for females with diabetes contemplating pregnancy, and opines that higher doses (0.8 to 1 mg) may be beneficial in high risk females, such as those with other risk factors for NTDs [49].

●The American Diabetes Association also suggests a minimum dose of at least 0.4 mg per day [50], which was effective in at least two case-control studies [51,52] and in at least one study in animals [53].

It is important to note that good periconceptional glucose control is the key factor for prevention of NTDs and other anomalies in these pregnancies. (See "Pregestational (preexisting) diabetes: Preconception counseling, evaluation, and management", section on 'Congenital malformations'.)

Other populations (obesity, MTHFR polymorphism) — We suggest not prescribing higher doses of folic acid supplementation for females with obesity and females with methylenetetrahydrofolate reductase (MTHFR) polymorphisms; we use routine universal prophylaxis dosing (0.4 mg per day) for these individuals, even though these conditions have been associated with an increased risk of NTDs. (See 'Universal prophylaxis for the general obstetric population' above.)

Testing for MTHFR polymorphisms is not recommended as routine folic acid supplementation at 0.4 mg per day will adequately increase red cell and serum folate concentrations whether or not the individual has a polymorphism [54,55]. Supplementation with an equimolar dose of 5-methyl tetrahydrofolate (5-MTHF), an alternative form of folic acid, has the advantage that it is not influenced by possible MTHFR gene mutations [56].

There are no prospective data that higher dose folic acid supplementation for females with obesity is more effective in prevention of occurrence or recurrence of NTDs. At least some of the association between obesity and NTDs is likely due to unrecognized diabetes in these individuals; either 0.4 or 1 mg per day folic acid is a reasonable dose in females with diabetes, as discussed above. Additionally, in individuals with obesity, poor dietary folate intake, increased inflammation, and altered gut biome all likely contribute to a relative folate deficient state. As prepregnancy obesity is a risk factor for NTDs, preconception determination of folate and homocysteine levels with correction of deficiencies as well as assessment of insulin resistance should be considered [57].  

EFFECT OF FOLIC ACID SUPPLEMENTATION ON OTHER PREGNANCY OUTCOMES — Folic acid supplementation may have pregnancy benefits unrelated to prevention of neural tube defects (NTDs), but available data are insufficient to support a clear benefit.

Congenital malformations other than NTDs — A 2015 meta-analysis of randomized trials concluded that folic acid supplementation, alone or in combination with vitamins and minerals, does not have a clear effect on the frequency of congenital anomalies other than NTDs [25]. However, some cleft lip/palate, congenital heart anomalies, limb reduction defects, urinary tract anomalies, and congenital hydrocephalus may be folate-sensitive malformations, based in part on the observation that the incidence of these congenital malformations has fallen following introduction of universal folic acid fortification or supplementation [58-63]. In addition, an observational study reported an inverse association between red cell folate levels and congenital cardiac anomalies, with the risk of coronary heart disease increasing proportionately to the deficiency of RBC folate [20]. Animal studies also provide some experimental support for folic acid supplementation to reduce the risk of cleft lip/palate from concurrent exposure to procarbazine, a folic acid inhibitor [64].

We suggest a higher dose (1 mg per day) of one to three months preconception/first-trimester folic acid supplementation for females with a history of one of the following malformations in themselves or their partner, a prior offspring, or a first- or second-degree relative:

●Cleft lip/palate

●Congenital cardiac anomalies

●Limb reduction defects

●Urinary tract anomalies

●Congenital hydrocephalus

The benefit of this approach is based on low-quality evidence, but the congenital anomalies are serious and the potential for harm from this dose of folic acid is low. The efficacy of this approach is unproven. (See 'High-dose prophylaxis for females at high risk of offspring with NTD' above.)

We suggest routine universal prophylaxis dosing (0.4 mg per day) for females with a personal or family history of abdominal wall abnormalities, pyloric stenosis, trisomy 21, hypospadias, or undescended testes, rather than high-dose supplementation. Conflicting results have been reported for reducing the risk of abdominal wall abnormalities and pyloric stenosis. No reductions have been observed for hypospadias, undescended testes, or trisomy 21. (See 'Universal prophylaxis for the general obstetric population' above.)

Growth restriction, autism, hypertensive disorders of pregnancy — We suggest routine universal prophylaxis dosing (0.4 mg per day) for females at increased risk for these disorders rather than high-dose supplementation. (See 'Universal prophylaxis for the general obstetric population' above.)

Meta-analyses have linked folic acid supplementation to a decreased risk of small for gestational age newborns [65,66] and decreased risk of autism [67-71]. The included studies were low quality and the data insufficient to warrant a change in counseling or recommendations for folic acid supplementation. The body of data does not indicate a consistent decrease or increase in risk for hypertensive disorders of pregnancy (preeclampsia, gestational hypertension) [72,73], even at high doses (4 mg daily) [74].

Spontaneous preterm birth — We suggest routine universal prophylaxis dosing (0.4 mg per day) for these individuals rather than high-dose supplementation. (See 'Universal prophylaxis for the general obstetric population' above.)

In a meta-analysis of randomized trials including over 5000 pregnant people with asymptomatic singleton gestations and no prior preterm birth, folic acid supplementation did not reduce the risk of preterm birth (<37 or <34 weeks) or preterm prelabor rupture of membranes compared with unsupplemented pregnancies [75].

Miscarriage — We suggest routine universal prophylaxis dosing (0.4 mg per day) for these individuals rather than high-dose supplementation. (See 'Universal prophylaxis for the general obstetric population' above.)

In a meta-analysis of randomized trials of vitamin supplementation for preventing miscarriage, folic acid supplementation (with or without multivitamins and/or iron) did not reduce the risk of early or late miscarriage compared with no folic acid supplementation [76]. In addition, a prospective cohort study of healthy folate-replete females attempting pregnancy after one or two previous pregnancy losses found that lower preconception serum folate levels were not associated with higher rates of anovulation, inability to conceive, or pregnancy loss [77].

POTENTIAL RISKS

Unrecognized vitamin B12 deficiency — In patients with megaloblastic anemia (macrocytic anemia associated with multilobed neutrophils on the blood smear), it is important to rule out vitamin B12 deficiency before administering folic acid because treatment with folic acid may delay diagnosis of the deficiency and allow progression of neurologic abnormalities and some hematologic abnormalities. Causes of vitamin B12 deficiency are listed in the table (table 5). Taking folic acid as part of a multivitamin or prenatal vitamin containing vitamin B12 reduces any potential risk. (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency".)

Twinning — An association between rates of dichorionic twinning and distributions of methylenetetrahydrofolate reductase (MTHFR) pathogenic variants has led to speculation about a relationship between folic acid and multiple gestation. Some modeling studies, based on pooled results of randomized trials, suggested that folic acid supplementation to prevent neural tube defects (NTDs) resulted in a 45 percent increase in dizygotic twinning (odds ratio [OR] 1.45, 95% CI 1.06-1.98) [78,79]. However, large prospective studies of folic acid supplementation have reported a slight decrease in twin births (OR 0.91, 95% CI 0.82-1.00) [80]. Studies of twinning using historic controls may be confounded by increased contemporary usage of fertility medications and assisted reproduction.

Epigenetic alterations — As folic acid plays a role in DNA methylation, there is a theoretical concern that maternal folic acid supplementation could lead to fetal epigenetic changes leading to long-term adverse effects [81]. One particular area of concern has centered on immune phenotypes that may alter childhood risk of atopic disease and reactive airway disease. However, epidemiologic studies have reported inconsistent findings on the association of maternal folic acid exposure or folate levels and increased incidence or severity of childhood respiratory outcomes and atopic disease [82-87].

Breast cancer — A 35-year follow-up study of females who participated in a placebo-controlled randomized trial of folic acid supplementation in pregnancy reported a nonsignificant increase in breast cancer mortality in those who received 0.2 or 5 mg folic acid supplementation once per day during pregnancy [88]. This result may well have been due to chance as the body of evidence is inconclusive [89-91]. (See "Overview of cancer prevention", section on 'Folic acid' and "Vitamin intake and disease prevention", section on 'Cancer'.)

At this time, no change in the recommendations for folic acid supplementation in pregnancy is appropriate, but further study is warranted.

Neurocognitive development — One review suggested that excessive maternal folic acid intake may be associated with adverse neurologic effects in offspring unrelated to the neural tube [36]. Studies on the effect of periconceptional/early pregnancy use of high-dose folic acid (≥1 mg per day) and neurocognitive development in offspring are conflicting [92,93]. Given the uncertainties, only females at highest risk of NTDs (table 3) should receive >1 mg per day of folic acid.

TREATMENT FAILURES — Adequate intake of folic acid will not prevent all primary or recurrent cases of neural tube defects (NTDs). The percentage of NTDs that is preventable with folic acid is unclear; estimates range from less than 50 to over 70 percent [94].

The frequency of recurrent NTDs despite high-dose folic acid supplementation (4 mg) remains as high as 1 percent [94-96]. This is likely due to autoantibodies to folate receptors and folate-independent pathways, such as aneuploidy, poorly controlled diabetes, first-trimester hyperthermia, and specific genetic syndromes that include NTDs.

There are no consensus recommendations regarding additional evaluation or intervention following a recurrence despite adequate folic acid supplementation. Because folate-resistant NTDs cannot always be identified with certainty, folic acid supplementation is recommended for all females planning or capable of pregnancy. Glycemic control prior to conception in patients with poorly controlled diabetes, use of anti-pyretics during first-trimester febrile illness, and avoidance of saunas/hot tubs are all reasonable precautions for prevention of first or recurrent NTDs. Other interventions, such as use of inositol, are under investigation [97].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Nutrition and supplements in pregnancy".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Vitamin B12 deficiency and folate deficiency (The Basics)")

Fact sheets for patients can be found on the following websites:

●Centers for Disease Control and Prevention

●United States Department of Health and Human Service

●March of Dimes

SUMMARY AND RECOMMENDATIONS

●Rationale – The body of evidence supports the efficacy of folic acid supplementation and dietary fortification to decrease the occurrence and recurrence of neural tube defects (NTDs) by at least 70 percent. (See 'Evidence of efficacy' above and 'Food fortification' above and 'Either parent with a personal history of NTD or a previously affected offspring' above.)

Folic acid supplementation will not prevent all NTDs, such as those related to chromosomal abnormalities and other non-folate-related mechanisms. (See 'Treatment failures' above.)

●Dosing – We recommend periconceptional/first-trimester folic acid supplementation to reduce the occurrence and recurrence of NTDs (Grade 1A), in agreement with most guidelines (see 'Folic acid supplementation for prevention of neural tube defects' above). Measurement of maternal folate levels before or after supplementation is unnecessary. (See 'Diagnosis of suboptimal levels' above.)

•For most females of reproductive potential, we suggest one multivitamin containing 0.4 mg of folic acid once per day beginning at least one month prior to conception and continuing through the first trimester (Grade 2B). (See 'Universal prophylaxis for the general obstetric population' above.)

Most major national medical organizations and public health authorities recommend that all females of childbearing potential, not just those who are attempting to conceive, receive a folic acid supplement once per day because a large number of unplanned pregnancies occur and the neural tube closes very early in gestation, before many individuals know they are pregnant. (See 'Candidates' above.)

•For females with a previous pregnancy affected by an NTD or with an NTD in either themselves or the biologic father, we suggest 4 mg of folic acid once per day beginning at least one month (and ideally three months) prior to conception and continuing through the first trimester (Grade 2B). The dose is decreased to 0.4 mg per day after the first trimester. (See 'Either parent with a personal history of NTD or a previously affected offspring' above and 'High-dose prophylaxis for females at high risk of offspring with NTD' above.)

•For females in other risk groups, the optimal periconceptional/first-trimester folic acid dose is unclear. We suggest the following (Grade 2C) (see 'Females who may benefit from higher dose folic acid supplementation' above):

-Family history of NTD in a first- or second-degree relative – 1 mg

-Females on valproic acid or carbamazepine – 4 mg-

-Females taking other antiseizure medications – 0.4 mg

-Females taking medications other than antiseizure medications that have been associated with reductions in available folic acid (eg, triamterene, trimethoprim, sulfasalazine) – 1 mg

-Females with medical conditions associated with reduced red cell folate levels – 1 mg

-Females with pregestational diabetes – 1 mg

-Females with sickle cell disease - 4 mg

●Females with megaloblastic anemia – In females with megaloblastic anemia (macrocytic anemia associated with multilobed neutrophils on the blood smear), it is important to rule out vitamin B12 deficiency before administering folic acid as treatment with folic acid may delay diagnosis of vitamin B12 deficiency and allow progression of neurologic abnormalities and some hematologic abnormalities. Causes of vitamin B12 deficiency are listed in the table (table 5). Taking folic acid as part of a multivitamin or prenatal vitamin with vitamin B12 reduces any potential risk. (See 'Unrecognized vitamin B12 deficiency' above.)

●Reduction of non-NTD anomalies – Some cleft lip/palate, congenital heart defects, limb reduction defects, urinary tract defects, and congenital hydrocephalus may be folate-sensitive congenital malformations, but evidence is of low quality.

We suggest 1 mg per day periconceptional/first-trimester folic acid supplementation for females with a history of one of these malformations in themselves or their partner, a prior offspring, or a first- or second-degree relative (Grade 2C). (See 'Congenital malformations other than NTDs' above.)

●Harms – In the absence of vitamin B12 deficiency, there are no clear harms from folic acid supplementation. (See 'Potential risks' above.)

●Optimum folate level – We do not monitor folate levels. If monitored, red blood cell folate levels ≥907 nmol/L and serum folate levels of 28 to 30 nmol/L are desirable for protection against folate sensitive NTDs. (See 'Diagnosis of suboptimal levels' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Lauri Hochberg, MD, and Joanne Stone, MD, who contributed to an earlier version of this topic review.