Preconception and prenatal folic acid supplementation

INTRODUCTION — Folate (vitamin B9) is an essential nutrient, important in DNA and RNA synthesis, DNA methylation, hematopoiesis, and possibly normal neuronal function. Folic acid supplementation is recommended for all females capable of becoming pregnant, particularly those planning to conceive, because, in addition to its other physiologic functions, periconceptional use decreases the occurrence and recurrence of fetal neural tube defects (NTDs). 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 folate since it 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 low versus increased risk of NTDs, potential pregnancy benefits unrelated to NTDs, potential risks of supplementation, and why NTDs 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, whereas folic acid is the synthetic form of folate.

Sources

●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 from conception soon after contraceptive discontinuation.

Calcium and glucosamine methylfolate salts are metabolically active forms of folic acid that are included in some supplements instead of folic acid.

●Natural food sources – Folate occurs naturally in several foods, including beef liver, leafy vegetables, peas and beans, avocados, eggs, and milk (table 1).

●Food fortification – Folic acid is added to fortify certain foods, including wheat flour, rice, pasta, breads, cereals, and cornmeal (maize flour). 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 [3,4]. 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 [5-9].

Pharmacokinetics — Both folate and folic acid are absorbed in the proximal small intestine and reduced to their metabolically active form, L-5-methyltetrahydrofolate (L-5-MTHF) during passage across the mucosa; some hepatic metabolism also occurs [10]. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies", section on 'Overview of intake and metabolism'.)

In healthy volunteers, dietary folate, folic acid supplements, and L-5-MTHF supplements resulted in similar increases in plasma folate and red blood cell (RBC) folate concentrations [10].

Dietary requirement — Dietary guidelines for Americans recommend 0.6 mg dietary folate equivalents daily for pregnant and lactating people [11]. Physiologic requirements are 0.2 mg higher during pregnancy and lactation because of fetal and placental growth and increased hematopoiesis.

Causes of folate deficiency — Varying degrees of folate deficiency may result from (see "Causes and pathophysiology of vitamin B12 and folate deficiencies", section on 'Causes of folate deficiency'):

●Inadequate intake due to:

•Low-carbohydrate diets, since bread and pasta are made of fortified grains

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

•Food insecurity

•Anorexia nervosa and other medical/behavioral conditions affecting food intake

●Interference with folate metabolism by some medications (eg, phenytoin, sulfasalazine, trimethoprim, methotrexate, triamterene).

●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 [12].

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

●Folate receptor autoantibodies that impair folate-related physiological processes.

●Increased requirements from conditions such as chronic hemolytic anemia and exfoliative dermatitis.

Diagnosis of suboptimal levels — Normal RBC and serum/plasma folate levels by trimester are shown in the table (table 2). The most accurate test for evaluation of folate status is the RBC folate concentration, which reflects body stores of folate, whereas the serum/plasma folate level reflects the current concentration in the circulation. It is not known whether one of these levels is more predictive of NTD risk than the other. A disadvantage of measuring RBC folate levels is that it is prone to laboratory reproducibility issues [13,14].

True folate deficiency is rare in the United States, while suboptimal levels (the level below that for optimal prevention of NTDs) are common: 23 percent of females of childbearing age in the United States have suboptimal folate levels [15].

●Suboptimal RBC level – The World Health Organization (WHO) considers a suboptimal RBC folate level to be <400 ng/mL (906 nmol/L by Molloy method, 748 nmol/L by the National Health and Nutrition Examination Survey [NHANES] assay) [16], which aligns with findings from a study on RBC folate levels and congenital cardiac anomalies [17].

●Suboptimal serum/plasma level – WHO was unable to identify a threshold for suboptimal serum/plasma folate levels [18]. The Society of Obstetricians and Gynaecologists of Canada (SOGC) considers serum folate levels of 12.3 to 13.2 ng/mL (28 to 30 nmol/L) protective of NTDs [19,20]. 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 [21]. In another study, a serum/plasma level >7.0 ng/mL (15.9 nmol/L) was suggested for pregnant people [3]. 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.

FOLIC ACID SUPPLEMENTATION FOR PREVENTING NTDS

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 reducing the occurrence and recurrence of neural tube defects (NTDs) [22-27]. For example, in a meta-analysis of randomized trials [23]:

●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 the occurrence of NTDs by 93 percent compared with no interventions/placebo or vitamins and minerals without folic acid (0 in 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, daily folic acid supplementation reduced NTDs by 69 percent (12 in 3433 versus 42 in 3275; RR 0.31, 95% CI 0.17-0.58; five trials, 6708 births).

●When only females with a previously affected pregnancy were analyzed, daily folic acid supplementation reduced NTDs by 66 percent (12 in 962 versus 36 in 884; RR 0.34, 95% CI 0.18-0.64; four trials, 1846 births).

Rationale for universal prophylaxis in females of childbearing potential — 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 daily folic acid supplement [28-30]. This broad recommendation is based on the need for adequate folate/folic acid intake very early in pregnancy when the neural tube is developing (closure of the neural tube occurs 26 to 28 days after conception [ie, by 6 weeks of gestation]) and the potential for inadequate intake at this time because a large number of pregnancies are unplanned (as many as 50 percent of pregnancies in the United States [31]). Even if the pregnancy is planned, many individuals do not know that they are pregnant this early in gestation and thus may not start taking a supplement before closure of the neural tube. Furthermore, many individuals are initially seen for prenatal care later in the first trimester and thus may not receive information about or a prescription for folic acid supplementation during the critical period of neural tube development.

Administration

Pregnancies at low NTD risk — For females at low risk of NTD in offspring (table 3), the standard folic acid supplement (multivitamin, prenatal vitamin) is 0.4 mg daily, 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. The supplement is in addition to the amount of food folate contained in a healthy eating pattern.

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 begin 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 blood cell (RBC) folate levels will take three months to normalize because of RBC turnover.

Pregnancies at increased NTD risk — Females who are at higher risk of having a child with an NTD than the general obstetric population are candidates for higher dose folic acid supplementation. Examples of candidates for higher dose supplementation and dosing recommendations are shown in the table (table 3). The higher dose (1 to 4 mg daily) 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 higher risk and is discussed below. The supplement is in addition to the amount of food folate contained in a healthy eating pattern. (See 'Which pregnancies are at increased NTD risk?' below.)

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 [36].

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 definitively excluded [37].

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 times per day is a practical means of ingesting a total dose of 4 mg daily. Alternatively, three 1 mg folic acid tablets/capsules can be taken at one time for patient convenience. The dose is reduced to 0.4 mg after 12 weeks of gestation, as described previously.

Although expert consensus groups consistently recommend 4 mg daily 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 [38,39]. 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 (0.4 mg versus >0.4 mg) or whether folic acid is given alone or with other vitamins and minerals [23].

Which pregnancies are at increased NTD risk? — The most robust data for the efficacy of higher dose folic acid supplementation are for females with a previously affected offspring [23,40]. 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 NTDs in offspring is increased at least 10-fold among females with a previously affected offspring, a personal history of an NTD, a partner with an NTD, or a partner with an affected child with a previous partner (table 4).

These females should be offered preconception/first-trimester supplementation with high-dose (4 mg) daily folic acid supplementation (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 in 593 [1 percent] versus 21 in 602 [3.5 percent]; RR 0.28, 95% CI 0.12-0.71) [40]. (See 'Pregnancies at increased NTD risk' above.)

Family history of an NTD in a second or third degree relative — The risk of an NTD in offspring is mildly increased if there is a family history of an 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 daily periconception/first-trimester folic acid for this population. (See 'Pregnancies at increased NTD risk' above.)

Maternal use of antiseizure medications — Maternal use of antiseizure medications increases the risk of major congenital malformations, particularly NTDs. The risk varies among medications and is highest with valproate. All guidelines recommend at least 0.4 mg daily folic acid supplementation for females taking antiseizure medications. Some experts recommend at least 1 mg daily for all females of childbearing potential who are taking these medications and higher doses (2 to 4 mg daily) for those taking carbamazepine or valproate. Evidence of the efficacy of folic acid supplementation in these individuals and preconception and pregnancy dosing are discussed separately. (See "Management of epilepsy during preconception, pregnancy, and the postpartum period", section on 'Folic acid supplementation'.)

Maternal use of medications that reduce folic acid availability or activity — Medications that may inhibit folic acid absorption, reduce its activity, or have other interactive effects may increase the risk of NTDs [42]. Examples of such medications that are not antiseizure medications and which are uncommonly used in pregnant patients include triamterene, trimethoprim, and sulfasalazine.

It is reasonable to offer higher dose folic acid supplementation preconception/first trimester to females taking medications that interfere with folate absorption or metabolism. We suggest 1 mg daily. (See 'Pregnancies at increased NTD risk' above.)

Maternal medical conditions that reduce folic acid availability or activity — Several maternal medical conditions have been associated with reduced RBC 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 daily folic acid supplementation for females with these conditions, beginning ideally three months prior to conception and continuing until birth (table 3). (See 'Pregnancies at increased NTD risk' above.)

Individuals with sickle cell disease have chronic hemolytic anemia, which further increases folate requirements. We suggest 4 mg daily throughout pregnancy to account for ongoing turnover of RBCs, in agreement with American College of Obstetricians and Gynecologists (ACOG) recommendations [43].

Preexisting diabetes — Females with preexisting (pregestational) diabetes are at increased risk of NTD in offspring. For this reason, we suggest 1 mg daily folic acid supplementation preconception/first trimester for these individuals; this dose is readily available, may be more effective than a lower dose, and has no known harms or side effects. However, it is important to note that good periconceptional glucose management is the key factor for preventing NTDs and other anomalies in these pregnancies and NTDs in females with preexisting diabetes may not be folate-sensitive. (See "Pregestational (preexisting) diabetes: Preconception counseling, evaluation, and management", section on 'Congenital malformations'.)

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

●ACOG recommends at least 0.4 mg daily folic acid for females with diabetes who are 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 [44].

●The American Diabetes Association also suggests a minimum dose of at least 0.4 mg daily [45], which was effective in at least two case-control studies [46,47] and in at least one study in animals [48].

Populations in which higher folic acid dose is unlikely to reduce NTD risk — We suggest not prescribing higher doses of folic acid supplementation for females with obesity and females with methylenetetrahydrofolate reductase (MTHFR) polymorphisms; we use routine low-NTD risk population dosing (0.4 mg daily throughout pregnancy) for these individuals, even though these conditions have been associated with an increased risk of NTDs. (See 'Pregnancies at low NTD risk' above.)

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 daily 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 can be considered [49].

Testing for MTHFR polymorphisms is not recommended as routine folic acid supplementation at 0.4 mg daily will adequately increase RBC and serum folate concentrations whether or not the individual has a polymorphism [50,51]. 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 [52].

When should folate levels be monitored? — We do not monitor folate levels in patients on folic acid supplementation. One study reported that over 99 percent of pregnant people who provided a first-trimester blood sample (80 percent were receiving folic acid supplementation) had a plasma total folate level indicative of maximal NTD risk reduction (25.5 nmol/L) regardless of folic acid dose [53].

Some authors suggest that females with 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 [19]); however, there is insufficient evidence to recommend for or against this practice. No prospective studies have evaluated whether routinely monitoring levels during pregnancy improves outcome (eg, reduction of NTDs).

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 [19]. This approach 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.

Occurrence of NTDs despite folic acid supplementation — Adequate intake of folate will not prevent all primary or recurrent cases of neural tube defects (NTDs). The percentage of NTDs that is preventable with folic acid supplementation is unclear; estimates range from less than 50 to over 70 percent [54].

The frequency of recurrent NTDs despite high-dose folic acid supplementation (4 mg) remains as high as 1 percent [54-56]. This is likely due to autoantibodies to folate receptors and to folate-independent pathways, such as aneuploidy, poor glucose control in diabetes, first-trimester hyperthermia, and specific genetic syndromes that include NTDs.

There are no consensus recommendations regarding additional evaluation or intervention following an NTD 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 [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) and anemia, but available data are insufficient to support a clear benefit for most other outcomes.

Maternal anemia — Administration of both folic acid (0.4 mg daily) and iron (30 to 60 mg daily) supplementation is important for prevention of maternal anemia. In a meta-analysis of studies from low- and middle-income countries, this combination was associated with a 48 percent reduction in the risk of maternal anemia in the third trimester compared with folic acid supplementation alone (average RR 0.52, 95% CI 0.41-0.66) [58]. (See "Anemia in pregnancy", section on 'Prevention of iron deficiency'.)

Congenital anomalies other than NTDs (possibly effective) — 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 [23]. 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 [59-64]. In addition, an observational study reported an inverse association between red blood cell (RBC) folate levels and congenital cardiac anomalies, with the risk increasing proportionately to the deficiency of RBC folate [17]. 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 [65].

We suggest high-dose folic acid supplementation (1 mg daily) beginning one to three months preconception and continuing through the first trimester for females with a history of one of the following potentially folate-sensitive anomalies in themselves or their partner, a prior offspring, or a first- or second-degree relative. The benefit of this approach for reducing the risk of potentially folate-sensitive anomalies is based on low-quality evidence [26,61,66-70], 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.

●Cleft lip/palate

●Congenital cardiac anomaly

●Limb reduction defect

●Urinary tract anomaly

●Congenital hydrocephalus

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. We suggest routine low-NTD risk folic acid dosing (0.4 mg daily) for females with a personal or family history of these conditions.

Other pregnancy and newborn outcomes — Folic acid supplementation does not appear to reduce the risk of most adverse pregnancy and newborn outcomes other than congenital anomalies. However, available data are low quality and insufficient to exclude the possibility of a small benefit, which may be dose-related [71].

●Miscarriage, spontaneous preterm birth, prelabor rupture of membranes (probably ineffective) – Meta-analyses of randomized trials have not established a benefit of folic acid supplementation in reducing the risk of miscarriage [72], spontaneous preterm birth, or prelabor rupture of membranes [73,74].

●Hypertensive disorders of pregnancy (probably ineffective) – Randomized trials evaluating folic acid supplementation for prevention of pregnancy-induced hypertension did not show a benefit with supplementation [75,76], even at high doses (4 mg daily) [77], but one trial comparing low-dose (0.4 mg) versus high-dose (4 mg) daily supplementation reported a reduction in severe gestational hypertension, early-onset preeclampsia, and severe preeclampsia in the high-dose group [78]. Meta-analyses of mostly observational studied showed no consistent decrease or increase in risk for hypertensive disorders of pregnancy (preeclampsia, gestational hypertension) with folic acid supplementation [79-82].

●Autism spectrum disorder (possibly effective) – Four of five recent meta-analyses of observational studies have linked folic acid supplementation to a decreased risk of autism spectrum disorder [83-87]; however, the included studies were low quality and the data insufficient to warrant a change in counseling or recommendations for folic acid supplementation. No data from randomized trials are available.

●Depression (possibly effective) – A meta-analysis of observational studies found an association between folic acid supplementation during pregnancy and reduced risk of perinatal depression [88]. Although neurocognitive and other changes have been reported with folate deficiency, there were many limitations to the data, such as a lack of accounting for the effects of genetic and other factors.

POTENTIAL RISKS

Maternal

●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 folic acid supplementation 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). Measurement of vitamin B12 levels is unnecessary in patients at low risk of deficiency. Furthermore, receiving 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".)

●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 daily during pregnancy [89]. This result may well have been due to chance as the body of evidence is inconclusive [90-92]. (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.

●Other — A 2023 evidence review for the US Preventive Services Task Force (USPSTF) found no consistent evidence of a higher risk of twin pregnancies or twin births (combination of live births and stillbirths) among females receiving a folic acid-containing multivitamin [27].

There was also no consistent evidence of a higher risk of childhood asthma or other allergen-related illness (eg, atopy, eczema, atopic dermatitis) and no consistent variation in these outcomes by timing or dose of exposure.

Offspring

●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 [93]. 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 [94-99].

●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 [37]. Studies on the effect of periconceptional/early pregnancy use of high-dose folic acid (≥1 mg daily) and neurocognitive development in offspring are conflicting [100,101]. Given the uncertainties, only females at highest risk of NTDs (table 3) should receive >1 mg daily folic acid. On the other hand, a follow-up study of patients in a randomized trial of 0.4 mg daily folic acid supplementation or placebo during the second and third trimesters until the end of pregnancy reported continued supplementation had beneficial effects on child cognitive development [102,103]. In a USPSTF evidence review, no study reported statistically significant associations between folic acid supplementation and increased risk of autism spectrum disorder, and two studies reported statistically significant reductions of autism associated with folic acid supplementation [27].

●Cancer – A retrospective study reported that children of mothers with epilepsy exposed to high-dose folic acid (mean dose 4.3 mg) in utero had an increased risk of cancer compared with those were not exposed to high-dose folic acid (absolute risk if exposed 1.4 percent [95% CI 0.5-3.6], absolute risk if unexposed 0.6 percent [95% CI 0.3-1.1]) [104]. This association was not seen in children of mothers without epilepsy exposed to high-dose folic acid. More study is needed to confirm the association, and if confirmed, explain why high-dose folic acid would increase the risk of cancer only in offspring of mothers with epilepsy.

INVESTIGATIONAL INTERVENTIONS TO REDUCE NTD RISK — Increased intake of micronutrients that act as methyl donors or cofactors in one-carbon metabolism (eg, vitamin B6, vitamin B12, choline, betaine, methionine) may further protect against NTDs in people who meet clinical recommendations for folic acid intake [105,106].

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

●Folic acid supplementation for all females of reproductive potential – We recommend universal preconception/first-trimester folic acid supplementation (Grade 1A). Folic acid supplementation and dietary fortification decrease the occurrence and recurrence of neural tube defects (NTDs) by at least 60 percent. (See 'Folic acid supplementation for preventing NTDs' 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 daily 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 'Rationale for universal prophylaxis in females of childbearing potential' above.)

However, folic acid supplementation will not prevent all NTDs, such as those related to chromosomal abnormalities and other nonfolate-related mechanisms. (See 'Occurrence of NTDs despite folic acid supplementation' above.)

Measurement of maternal folate levels before or after supplementation is unnecessary. (See 'Diagnosis of suboptimal levels' above and 'When should folate levels be monitored?' above.)

●Dosing and administration – Our dosing varies depending on NTD risk:

•For females of reproductive potential at low NTD risk, we prescribe one multivitamin containing 0.4 mg of folic acid once daily beginning at least one month prior to conception and continuing throughout pregnancy, in agreement with most guidelines. (See 'Pregnancies at low NTD risk' above.)

•For females with a previous pregnancy affected by an NTD or with an NTD in either themselves or the biologic father, we prescribe 4 mg of folic acid once daily beginning at least one month (and ideally three months) prior to conception and continuing through the first trimester, in agreement with most guidelines. The dose is decreased to 0.4 mg daily after the first trimester. (See 'Either parent with a personal history of NTD or a previously affected offspring' above and 'Pregnancies at increased NTD risk' above.)

•For females in other risk groups, the optimal folic acid dose is unclear and guidelines and expert opinions vary:

-Family history of NTD in a second- or third-degree relative – We prescribe 1 mg daily at least one month before conception and through the first trimester. The dose is decreased to 0.4 mg daily after the first trimester. (See 'Family history of an NTD in a second or third degree relative' above.)

-Antiseizure medication use – All guidelines recommend at least 0.4 mg daily (but some experts recommend at least 1 mg daily), beginning at least one month before and continuing throughout pregnancy. Higher doses (2 to 4 mg daily) are recommended periconceptionally for those taking carbamazepine or valproate. (See "Management of epilepsy during preconception, pregnancy, and the postpartum period", section on 'Folic acid supplementation'.)

-Use of medications other than antiseizure medications that have been associated with reductions in available folic acid (eg, triamterene, trimethoprim, sulfasalazine) – We prescribe 1 mg daily at least one month before conception and through the first trimester. The dose is decreased to 0.4 mg daily after the first trimester. (See 'Maternal use of medications that reduce folic acid availability or activity' above.)

-History of other congenital malformations (cleft lip/palate, congenital heart anomalies, limb reduction defects, urinary tract anomalies, congenital hydrocephalus) in themselves, their partner, a prior offspring, or a first- or second-degree relative – We prescribe 1 mg daily at least one month before conception and through the first trimester. However, 0.4 mg daily throughout pregnancy is also a commonly prescribed dose. (See 'Congenital anomalies other than NTDs (possibly effective)' above.)

-Pregestational diabetes – We prescribe 1 mg daily at least one month before conception and through the first trimester. However, 0.4 mg daily throughout pregnancy is also a commonly prescribed dose. (See 'Preexisting diabetes' above.)

-Medical condition associated with reduced red blood cell (RBC) folate levels – We prescribe 1 mg daily at least one month before conception and throughout pregnancy. (See 'Maternal medical conditions that reduce folic acid availability or activity' above.)

-Sickle cell disease – We prescribe 4 mg daily at least one month before conception and throughout pregnancy (to account for ongoing turnover of RBCs). (See 'Maternal medical conditions that reduce folic acid availability or activity' above.)

-Obesity or methylenetetrahydrofolate reductase (MTHFR) polymorphisms – We prescribe 0.4 mg daily beginning at least one month before conception and continuing throughout pregnancy. (See 'Populations in which higher folic acid dose is unlikely to reduce NTD risk' above.)

●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 prescribing folic acid as it 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 'Maternal' above.)

●Benefits unrelated to NTDs – Some cleft lip/palate, congenital heart anomalies, limb reduction defects, urinary tract anomalies, and congenital hydrocephalus may be folate-sensitive congenital malformations, but evidence is of low quality. (See 'Congenital anomalies other than NTDs (possibly effective)' above.)

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

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