Folate for Pregnancy & Neural Tube Defect Prevention

Table of Contents

1. What Neural Tube Defects Are
2. The Neural Tube Closure Window
3. The MRC Vitamin Study (1991)
4. Czeizel & Dudas Hungarian Primary Prevention Trial
5. The China Folic Acid Campaign Study (Berry 1999)
6. US Mandatory Food Fortification (1998)
7. What CDC, USPSTF, ACOG, WHO and SOGC State
8. MTHFR Variants: What the Evidence Shows
9. Methylfolate (5-MTHF) and Folic Acid: What Studies Compared
10. Other Birth Defects and Outcomes Studied
11. Doses Used in Trials and Named in Guidelines
12. Cautions
13. Key Research Papers
14. Connections
15. Featured Videos

What Neural Tube Defects Are

Neural tube defects (NTDs) are major birth defects of the brain and spine that occur early in pregnancy as a result of improper closure of the embryonic neural tube; the two most common are anencephaly and spina bifida (CDC, Williams 2015). ACOG's 2017 practice bulletin describes NTDs as the second most common major congenital anomaly after cardiac malformations, with prevalence that varies by geographic region, race and environmental factors. The USPSTF estimates that about 3,000 pregnancies are affected each year in the US. Myelomeningocele (open spina bifida) occurs in approximately 1 per 1,000 births worldwide (Copp 2015). In the China campaign study described below, the rate among women who registered before their last menstrual period and took no folic acid was 4.8 per 1,000 pregnancies in the northern region and 1.0 per 1,000 in the southern region.

The three classic phenotypes are:

• Spina bifida — the vertebral column is open, often with spinal cord involvement. In myelomeningocele, the most clinically significant subtype, the lumbosacral neural tube fails to close; the exposed neural tissue degenerates in utero, and the resulting neurological deficit varies with the level of the lesion. Associated problems include the Chiari II brain malformation, hydrocephalus, and urological and orthopaedic sequelae (Copp 2015). ACOG notes that most infants with spina bifida survive after surgical repair.
• Anencephaly — with spina bifida, one of the two most common NTDs (CDC, Williams 2015). ACOG describes it as incompatible with life.
• Encephalocele — the third neural tube defect counted as an outcome in the MRC Vitamin Study, alongside anencephaly and spina bifida.

ACOG notes that NTDs may occur as an isolated malformation, with other malformations, as part of a genetic syndrome, or as a result of teratogenic exposure. For myelomeningocele, Copp and colleagues estimate the genetic component at 60-70%, with few causative genes identified, and list reduced folate intake, anticonvulsant therapy, diabetes mellitus and obesity as non-genetic maternal risk factors. The MTHFR C677T variant is a moderate genetic risk factor (see the MTHFR section).

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The Neural Tube Closure Window

The USPSTF's 2023 statement notes: “The neural plate completes its formation and closure early in pregnancy (usually 26 to 28 days after fertilization).” CDC states that NTDs “happen in the first few weeks of pregnancy, often before you know you are pregnant.”

That timing shapes how the public-health bodies frame folic acid:

• USPSTF: “The critical period for folic acid supplementation starts at least 1 month before conception and continues through the first 2 to 3 months of pregnancy.” The Task Force also notes that nearly half of all US pregnancies are unplanned.
• CDC: for anyone thinking about becoming pregnant, CDC's guidance is to start folic acid at least 1 month before conception.
• SOGC (Canada, 2015): its advice on folic acid applies to all women who may become pregnant, “because so many pregnancies are unplanned.”

Blood folate rises slowly. In a 24-week trial, red blood cell folate had not reached a plateau in any supplemented group, and the authors suggested that the recommended period of supplementation before conception be extended beyond 4 weeks (Lamers 2006). A second 24-week trial also found that steady state had not been reached (Venn 2002).

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The MRC Vitamin Study (1991)

The Medical Research Council Vitamin Study, published in The Lancet on 20 July 1991, is the randomized trial of folic acid for preventing a recurrent neural tube defect.

Design

The trial was randomized, double-blind and factorial, run at 33 centres in seven countries. It enrolled 1,817 women at high risk because of a previous affected pregnancy, who were randomized to one of four groups:

• Folic acid
• A mixture of seven other vitamins (A, D, B1, B2, B6, C and nicotinamide)
• Both
• Neither

The folic acid dose was 4 mg a day (as reported in Czeizel's 2004 review). The outcome was a neural tube defect (anencephaly, spina bifida or encephalocele) in the fetus or infant.

Results

• 1,195 women had a completed pregnancy with a known outcome. Of these, 27 had a neural tube defect: 6 in the two folic acid groups and 21 in the two groups without folic acid.
• Folic acid: a 72% protective effect (relative risk 0.28, 95% CI 0.12-0.71).
• The other vitamins: no significant protective effect (relative risk 0.80, 95% CI 0.32-1.72).
• No harm from folic acid could be shown, though the authors noted that the study had limited ability to detect rare or slight adverse effects.

The authors concluded that folic acid supplementation starting before pregnancy “can now be firmly recommended for all women who have had an affected pregnancy.” CDC's current figure for women with a prior NTD-affected pregnancy is 4,000 mcg of folic acid a day.

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Czeizel & Dudas Hungarian Primary Prevention Trial

The 1992 Czeizel & Dudas trial, published in the New England Journal of Medicine, asked whether periconceptional vitamins reduce a first occurrence of a neural tube defect, rather than a recurrence in women already affected.

Women in Hungary who were planning a pregnancy (in most cases their first) were randomized to one of two daily tablets:

• A multivitamin containing 12 vitamins, including 0.8 mg of folic acid, plus 4 minerals and 3 trace elements
• A trace-element supplement (copper, manganese, zinc and a very low dose of vitamin C)

The tablets were taken for at least one month before conception and until the date of the second missed menstrual period or later. Pregnancy was confirmed in 4,753 women.

Results:

• Neural tube defects in the vitamin group: 0 of 2,104 women with a known outcome
• Neural tube defects in the trace-element group: 6 of 2,052 women with a known outcome (P=0.029)
• All congenital malformations: 13.3 per 1,000 in the vitamin group vs 22.9 per 1,000 in the trace-element group (P=0.02)
• Cleft lip with or without cleft palate was not reduced.

The authors concluded that periconceptional vitamin use decreases the first occurrence of neural tube defects. Because the active tablet was a multivitamin, the trial alone cannot separate the effect of folic acid from that of the other vitamins (a limitation Bailey and Berry note for most of the studies). The 2015 Cochrane review rated the first-occurrence evidence as inconclusive. Only one trial measured first occurrence, and it showed “no evidence of an effect” (RR 0.07, 95% CI 0.00-1.32), even though there were no cases in the folic acid group.

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The China Folic Acid Campaign Study (Berry 1999)

Berry and colleagues (NEJM 1999) evaluated a public-health campaign run from 1993 to 1995 in two regions of China: a northern region with high NTD rates and a southern region with low rates. This was not a randomized trial. Women were asked to take a pill containing 400 mcg of folic acid alone every day, from their premarital examination until the end of the first trimester of pregnancy.

Results:

• Women studied: 130,142 women who took folic acid at some point before or during pregnancy, and 117,689 who did not. There were 102 and 173 neural tube defects in their fetuses or infants, respectively.
• Northern region: 4.8 per 1,000 among non-users who registered before their last menstrual period, vs 1.0 per 1,000 with periconceptional use.
• Southern region: 1.0 per 1,000 vs 0.6 per 1,000, a 41% reduction in risk (95% CI 3-64%).
• Greatest reduction: 85% (95% CI 62-94%), in northern-region women with periconceptional use who took the pills more than 80% of the time.

The authors concluded that 400 mcg of folic acid a day around conception can reduce NTD risk in areas with both high and low rates. The US Public Health Service had already recommended 400 mcg a day for all women capable of becoming pregnant in 1992.

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US Mandatory Food Fortification (1998)

Before fortification, only an estimated 29% of US women of reproductive age took a supplement containing 400 mcg of folic acid daily (Honein 2001). The FDA authorized adding folic acid to enriched grain products in March 1996, and compliance became mandatory in January 1998. Since 1998, enriched cereal grain products have been fortified with 140 mcg of folic acid per 100 g (Williams 2015). Folic acid fortification programmes followed in many countries (Copp 2015).

Outcomes in the US:

• Birth certificates (Honein 2001): spina bifida and anencephaly fell from 37.8 to 30.5 per 100,000 live births, a 19% decline (prevalence ratio 0.81). The authors noted that factors other than fortification may have contributed.
• Surveillance programs (CDC, Williams 2015): in programs that included prenatal diagnoses, prevalence fell from 10.7 per 10,000 live births in 1995-1996 to 7.0 per 10,000 in 1999-2011, a 35% reduction. Across all 19 programs the reduction was 28%.
• Births averted: about 1,326 NTD-affected births a year (95% CI 1,122-1,531), reported as approximately 1,300.
• Cost: CDC estimated about $508 million a year in lifetime direct costs avoided for the births prevented.
• Blood folate: serum folate deficiency fell from 30% to under 1%. Even so, 21.6% of US women of childbearing age still did not have red blood cell folate concentrations associated with a lower NTD risk.
• Hispanic women: NTD prevalence fell in every racial/ethnic group examined but remained consistently higher among Hispanics. CDC noted that fewer Hispanic women (17%) than non-Hispanic white women (30%) report consuming at least 400 mcg of folic acid a day. It also reported that fortifying corn masa flour at the same level was under consideration and would likely prevent about 40 more cases a year.

The trial and population figures come from different designs (a randomized trial in high-risk women, birth certificates, surveillance registries), so they are not directly comparable. CDC's 2015 report concludes that “mandatory folic acid fortification remains an effective public health intervention.” How methylfolate compares with folic acid is covered in the methylfolate section below.

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What CDC, USPSTF, ACOG, WHO and SOGC State

The guideline bodies state the following:

• US Public Health Service (1992, MMWR): recommended that all women of childbearing age in the US who are capable of becoming pregnant consume 0.4 mg of folic acid per day. Because the effects of higher intakes were not well known but include complicating the diagnosis of vitamin B12 deficiency, it advised keeping total folate consumption below 1 mg per day except under a physician's supervision.
• CDC (current): “All women capable of becoming pregnant should get 400 micrograms (mcg) of folic acid daily.” For a past NTD-affected pregnancy: “The current recommendation is to get 4,000 mcg of folic acid every day.” (CDC: About Folic Acid)
• USPSTF (2023 reaffirmation, grade A): “all persons planning to or who could become pregnant take a daily supplement containing 0.4 to 0.8 mg (400 to 800 μg) of folic acid.” The Task Force concluded with high certainty that the net benefit is substantial. The recommendation does not apply to persons with a previous NTD-affected pregnancy or at very high risk for other reasons. (USPSTF recommendation)
• ACOG, AAFP and AAP: as summarized by the USPSTF, all three recommend 400 mcg (0.4 mg) per day for persons of reproductive age who are planning a pregnancy and are at average risk.
• WHO: “All women, from the moment they begin trying to conceive until 12 weeks of gestation, should take a folic acid supplement (400 μg folic acid daily).” WHO recommends that women who have had a fetus or baby with a neural tube defect be offered high-dose supplementation (5 mg folic acid daily). (WHO eLENA)
• SOGC (Canada): the 2015 guideline listed 0.4 mg for low-risk women, starting at least 2 to 3 months before conception. It listed 1.0 mg for moderate risk and 4.0 mg for higher risk, including a previous NTD-affected pregnancy in either partner, each starting at least 3 months before conception and continuing to 12 weeks' gestation. The 2022 update (Guideline No. 427) recommends a low daily dose for all women who could become pregnant. It reserves high-dose folic acid for women who have had a previous pregnancy affected by a neural tube defect or another folate-sensitive anomaly, and says “directed personalized approaches could be considered” for women with complex risks.

The recommendations quoted above are all stated in terms of folic acid.

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MTHFR Variants: What the Evidence Shows

The MTHFR gene encodes methylenetetrahydrofolate reductase, which converts 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate (5-MTHF), the main circulating form of folate (Frosst 1995). Frosst and colleagues identified the common C677T substitution on about 38% of unselected chromosomes. The variant reduces enzyme activity and makes the enzyme heat-sensitive (thermolabile), and people with two copies had significantly higher plasma homocysteine.

• How common: two copies of C677T (the TT genotype) range from 1% or less among Black populations in Africa and the US to 20% or more among Italians and US Hispanics (Botto & Yang 2000). CDC states: “More people in the United States have one or two copies of the MTHFR C677T variant than don't have it.”
• A1298C: a second common variant. Botto and Yang report that A1298C together with C677T could also be associated with a higher spina bifida risk.
• NTD risk: in Botto and Yang's pooled analysis, the TT genotype in the infant was associated with a moderately higher risk of spina bifida (odds ratio 1.8, 95% CI 1.4-2.2), and maternal TT also appears to be a moderate risk factor (pooled odds ratio 2.0, 95% CI 1.5-2.8).
• Blood folate: in a meta-analysis of 40 studies (Tsang 2015), red blood cell folate measured by microbiologic assay was 16% higher in CC than in TT women (95% credible interval 12-20%).
• Response to folic acid: Crider and colleagues gave 932 genotyped women in northern China 100, 400 or 4,000 mcg of folic acid a day, or 4,000 mcg a week, for 6 months (Crider 2011). Folate was lower in TT women at every dose, but genotype did not significantly interact with folic acid dose. The 100 mcg/day and 4,000 mcg/week doses did not lower high homocysteine in TT women.
• CDC on Hispanic women (2015): the T allele, common among Hispanics, has been associated with lower plasma and red blood cell folate, and “persons with this polymorphism have more genetic susceptibility to a folate insufficiency.”

What public-health bodies state about MTHFR

• CDC (CDC: MTHFR Gene Variant and Folic Acid Facts): “People with an MTHFR gene variant can process all types of folate, including folic acid. Folic acid is the only type of folate shown to help prevent neural tube defects.” Also: “Your folic acid intake is more important than your MTHFR genotype for determining the amount of folate in your blood.” And: “If you could become pregnant, you should get 400 mcg of folic acid daily, even if you have an MTHFR variant.”
• USPSTF (2023): the recommendation covers all persons who could become pregnant. MTHFR comes up only as a research gap: “More research is needed to better understand how genetic variants such as MTHFR slow folate metabolism.” The statement makes no genotype-specific recommendation and names no alternative form of folate.
• SOGC (2022): lists “metabolic and genetic factors” among the things that make optimizing folic acid supplementation complex, and says personalized approaches could be considered for women with complex risks.

The NTD-prevention trials described above (MRC 1991, Czeizel 1992) and the China campaign all used folic acid. Studies comparing 5-MTHF with folic acid, including in TT women, measured blood folate and homocysteine rather than birth defects; they are summarized in the next section.

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Methylfolate (5-MTHF) and Folic Acid: What Studies Compared

Folic acid is a synthetic form of the vitamin, found only in fortified foods, supplements and drugs. It has no coenzyme activity until it is reduced inside the cell. L-5-methyltetrahydrofolate (L-5-MTHF) is the main form of folate in food and the only form normally found in the circulation. It is also available commercially as a crystalline calcium salt stable enough for supplements (Pietrzik 2010). Pietrzik, Bailey and Shane's 2010 review reports that studies comparing the two found comparable physiological activity, bioavailability and absorption at equimolar doses, and that 5-MTHF was at least as effective as folic acid at improving folate status. The review describes two possible advantages of 5-MTHF: a reduced potential for masking the blood signs of vitamin B12 deficiency, and less interaction with drugs that inhibit dihydrofolate reductase.

The comparative trials:

• Lamers 2006: 144 women aged 19-33 took 400 mcg folic acid, an equimolar 416 mcg of [6S]-5-MTHF, 208 mcg of [6S]-5-MTHF, or placebo for 24 weeks. Red blood cell folate rose significantly more with 416 mcg 5-MTHF than with 400 mcg folic acid (P<0.001). Genotype was not a factor in this design.
• Venn 2002: 104 women aged 18-49 took 113 mcg of [6S]-5-MTHF, 100 mcg of folic acid, or placebo for 24 weeks. Increases in plasma and red cell folate did not differ between the two forms (red cell folate rose 251 vs 275 nmol/L over placebo).
• Prinz-Langenohl 2009 (by MTHFR genotype): 16 TT and 8 CC women each took a single dose of 400 mcg folic acid and 416 mcg [6S]-5-MTHF in a crossover design, with plasma folate measured for 8 hours. The plasma folate peak and area under the curve were higher after 5-MTHF in both genotypes. Unmetabolized folic acid appeared regularly in plasma after folic acid but rarely after 5-MTHF. This was a single-dose plasma study, not a measure of red cell folate or of birth outcomes.
• Fohr 2002 (homocysteine, by genotype): 160 women took 400 mcg folic acid, an equimolar 480 mcg of racemic 5-MTHF, or placebo for 8 weeks. Folic acid lowered homocysteine by at least 13% in all three genotypes, with the largest fall (20%) in TT women at 4 weeks. 5-MTHF significantly lowered homocysteine only in CT women. The authors concluded that TT women seemed to benefit most from either form, and that in CT and CC women folic acid lowered homocysteine more than 5-MTHF.

These studies measured blood markers of folate status, not neural tube defects. CDC's 2015 report cites a dose-response model in which red blood cell folate concentrations above 1,000 nmol/L were sufficient to substantially reduce NTD risk at the population level. CDC states that folic acid is the only type of folate shown to help prevent neural tube defects.

Unmetabolized folic acid

• Unmetabolized folic acid in plasma occurs regularly after folic acid supplementation but rarely after 5-MTHF (Prinz-Langenohl 2009).
• At delivery, folic acid above 0.20 nmol/L was found in 44% of 87 pregnant women and in 55% of cord blood samples, and this was not explained by maternal supplement use. The authors concluded that 400 mcg/day of folic acid in pregnancy is not likely to accumulate in the fetus, in contrast to 5-MTHF and THF, which do accumulate there (Obeid 2010).
• In 105 postmenopausal women (not a pregnancy study), detectable unmetabolized folic acid was associated with about 23% lower natural killer cell cytotoxicity. The authors called for further studies of long-term high folic acid intake (Troen 2006).

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Other Birth Defects and Outcomes Studied

Whether periconceptional folate affects birth defects other than NTDs is less settled:

• Cochrane review (De-Regil 2015, 5 trials, 7,391 women): folic acid, alone or with other vitamins and minerals, prevents NTDs (RR 0.31, 95% CI 0.17-0.58; high-quality evidence) but “does not have a clear effect on other birth defects.” No effect was shown on cleft palate, cleft lip, congenital cardiovascular defects (low-quality evidence for each) or miscarriage.
• Congenital heart defects and orofacial clefts (Bailey & Berry 2005): observational studies generally support an association between multivitamins containing folic acid and fewer heart defects and clefts. One randomized trial gives the strongest evidence that multivitamins prevent heart defects but no evidence that they prevent clefts, and most studies cannot separate an effect of folic acid from that of the other vitamins.
• All congenital malformations (Czeizel 1992): 13.3 vs 22.9 per 1,000 with a multivitamin vs a trace-element supplement. Cleft lip with or without cleft palate was not reduced.
• Autism (Surén 2013, Norway, 85,176 children): autistic disorder was diagnosed in 0.10% of children whose mothers used folic acid from 4 weeks before to 8 weeks after the start of pregnancy, vs 0.21% in unexposed children (adjusted OR 0.61, 95% CI 0.41-0.90). No association was found for Asperger syndrome or PDD-NOS, though power was limited. The authors state that the findings cannot establish causality.
• Very high maternal folate and autism (Raghavan 2018, Boston, 1,257 mother-child pairs): the frequency of multivitamin use showed a U-shaped relationship with autism risk. Very high maternal plasma folate at birth (60.3 nmol/L or more) was associated with 2.5 times the risk (95% CI 1.3-4.6), compared with the middle 80th percentile. The authors call the study hypothesis-generating and say it does not question the importance of adequate folic acid in pregnancy.

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Doses Used in Trials and Named in Guidelines

In the trials

• MRC Vitamin Study (1991), women with a prior affected pregnancy: 4 mg folic acid a day
• Czeizel & Dudas (1992), first occurrence: a multivitamin with 0.8 mg folic acid, from at least one month before conception until the second missed period or later
• China campaign (Berry 1999): 400 mcg folic acid alone, from the premarital examination to the end of the first trimester
• Cochrane 2015: in subgroup analyses, the protective effect on both first occurrence and recurrence was not affected by daily dose (400 mcg or higher) or by whether folic acid was given alone or with other vitamins and minerals.

In guidelines, for average risk

• US Public Health Service (1992) and CDC: 400 mcg (0.4 mg) of folic acid daily; CDC adds at least 1 month before conception
• USPSTF (2023): 0.4 to 0.8 mg daily
• WHO: 400 mcg daily from trying to conceive until 12 weeks of gestation
• SOGC (2015): 0.4 mg in a multivitamin for at least 2 to 3 months before conception, through pregnancy and breastfeeding

In guidelines, after a prior NTD-affected pregnancy

• CDC: 4,000 mcg of folic acid daily
• WHO: 5 mg of folic acid daily
• SOGC (2015): 4.0 mg daily for at least 3 months before conception until 12 weeks' gestation, then a multivitamin with 0.4-1.0 mg
• The USPSTF recommendation does not cover this group.

Each recommendation above is stated in terms of folic acid. Decisions about supplements and doses before and during pregnancy belong with a clinician.

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Cautions

• Vitamin B12 deficiency: the 1992 US Public Health Service recommendation advised keeping total folate below 1 mg a day except under a physician's supervision, because higher intakes can complicate the diagnosis of B12 deficiency. SOGC's 2015 guideline states that folic acid supplementation is unlikely to mask B12 deficiency (pernicious anemia), and that testing is not required before starting it in women considering a pregnancy. To address even theoretical concerns, SOGC recommends taking folic acid in a multivitamin that includes 2.6 mcg/day of B12. Pietrzik's 2010 review suggests that the potential for masking may be lower with 5-MTHF.
• Unmetabolized folic acid: see the methylfolate section. What it means for fetal development has not been established.
• Twin pregnancy and epigenetics: SOGC's 2015 guideline notes reported associations of folic acid supplementation with fetal epigenetic changes and with a higher likelihood of twin pregnancy. The USPSTF found adequate evidence that folic acid at usual doses is not associated with serious harms, and cites a high-quality trial that found no difference in twin deliveries between 4 mg and 0.4 mg a day.
• Colorectal adenomas: in a randomized trial of 1,021 people with a recent history of colorectal adenomas (Cole 2007), 1 mg/day of folic acid did not reduce adenoma risk. At the second follow-up, advanced lesions occurred in 11.6% vs 6.9% (RR 1.67, 95% CI 1.00-2.80, P=0.05). Folic acid was also associated with higher risks of three or more adenomas and of non-colorectal cancers. The authors called for further research into whether folic acid might increase colorectal neoplasia risk.
• Very high maternal folate and autism: an observational association, described in the other outcomes section.
• Cerebral folate deficiency: in this infantile-onset disorder, folate in the cerebrospinal fluid is low while serum and red cell folate are normal. Blocking autoantibodies against folate receptors were found in 25 of 28 affected children and in none of 28 controls. Oral folinic acid normalized cerebrospinal-fluid 5-MTHF and was followed by clinical improvement (Ramaekers 2005).
• Methotrexate: methotrexate is classified as an antimetabolite because it antagonizes folic acid metabolism. A Cochrane review of 6 trials (624 people with rheumatoid arthritis) found that folic or folinic acid reduced gastrointestinal side effects (RR 0.74), abnormal liver-enzyme rises (RR 0.23) and withdrawal from methotrexate. It had no significant effect on how well methotrexate worked (Shea 2013).

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Key Research Papers

1. MRC Vitamin Study Research Group (1991). Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet — PubMed PMID: 1677062
2. Czeizel AE, Dudas I (1992). Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med — PubMed PMID: 1307234
3. Berry RJ et al. (1999). Prevention of neural-tube defects with folic acid in China. N Engl J Med. — PubMed PMID: 10559448
4. Honein MA et al. (2001). Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects. JAMA. — PubMed PMID: 11410096
5. Williams J et al. CDC (2015). Updated estimates of neural tube defects prevented by mandatory folic acid fortification - United States, 1995-2011. MMWR. — PubMed PMID: 25590678
6. De-Regil LM et al. (2015). Effects and safety of periconceptional oral folate supplementation for preventing birth defects. Cochrane Database. — PubMed PMID: 26662928
7. Suren P et al. (2013). Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA. — PubMed PMID: 23403681
8. Lamers Y et al. (2006). Red blood cell folate concentrations increase more after supplementation with [6S]-5-methyltetrahydrofolate than with folic acid in women of childbearing age. Am J Clin Nutr. — PubMed PMID: 16825690
9. Pietrzik K et al. (2010). Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. — PubMed PMID: 20608755
10. Wilson RD et al. SOGC (2015). Pre-conception folic acid and multivitamin supplementation for the primary and secondary prevention of neural tube defects and other folic acid-sensitive congenital anomalies. J Obstet Gynaecol Can. — PubMed PMID: 26334606
11. Crider KS et al. (2011). MTHFR 677C→T genotype is associated with folate and homocysteine concentrations in a large, population-based, double-blind trial of folic acid supplementation. Am J Clin Nutr 93:1365-72. — PubMed PMID: 21508090
12. Bailey LB, Berry RJ (2005). Folic acid supplementation and the occurrence of congenital heart defects, orofacial clefts, multiple births, and miscarriage. Am J Clin Nutr. — PubMed PMID: 15883454
13. US Preventive Services Task Force; Barry MJ et al. (2023). Folic Acid Supplementation to Prevent Neural Tube Defects: US Preventive Services Task Force Reaffirmation Recommendation Statement. JAMA 330:454-459. — PubMed PMID: 37526713
14. American College of Obstetricians and Gynecologists (2017). Practice Bulletin No. 187 Summary: Neural Tube Defects. Obstet Gynecol 130:1394-1396. — PubMed PMID: 29189691
15. US Public Health Service / CDC (1992). Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR Recomm Rep 41(RR-14):1-7. — PubMed PMID: 1522835
16. Wilson RD, O'Connor DL (2022). Guideline No. 427: Folic Acid and Multivitamin Supplementation for Prevention of Folic Acid-Sensitive Congenital Anomalies. J Obstet Gynaecol Can 44:707-719.e1 (corrigendum: 44:1114). — PubMed PMID: 35691683
17. Czeizel AE (2004). The primary prevention of birth defects: Multivitamins or folic acid? Int J Med Sci 1:50-61. — PubMed PMID: 15912190
18. Copp AJ et al. (2015). Spina bifida. Nat Rev Dis Primers 1:15007. — PubMed PMID: 27189655
19. Frosst P et al. (1995). A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10:111-3. — PubMed PMID: 7647779
20. Botto LD, Yang Q (2000). 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol 151:862-77. — PubMed PMID: 10791559
21. Tsang BL et al. (2015). Assessing the association between the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: a systematic review and meta-analysis of trials and observational studies. Am J Clin Nutr 101:1286-94. — PubMed PMID: 25788000
22. Prinz-Langenohl R et al. (2009). [6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C→T polymorphism of methylenetetrahydrofolate reductase. Br J Pharmacol 158:2014-21. — PubMed PMID: 19917061
23. Fohr IP et al. (2002). 5,10-Methylenetetrahydrofolate reductase genotype determines the plasma homocysteine-lowering effect of supplementation with 5-methyltetrahydrofolate or folic acid in healthy young women. Am J Clin Nutr 75:275-82. — PubMed PMID: 11815318
24. Venn BJ et al. (2002). Increases in blood folate indices are similar in women of childbearing age supplemented with [6S]-5-methyltetrahydrofolate and folic acid. J Nutr 132:3353-5. — PubMed PMID: 12421850
25. Obeid R et al. (2010). Concentrations of unmetabolized folic acid and primary folate forms in pregnant women at delivery and in umbilical cord blood. Am J Clin Nutr 92:1416-22. — PubMed PMID: 20844072
26. Troen AM et al. (2006). Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J Nutr 136:189-94. — PubMed PMID: 16365081
27. Raghavan R et al. (2018). Maternal Multivitamin Intake, Plasma Folate and Vitamin B12 Levels and Autism Spectrum Disorder Risk in Offspring. Paediatr Perinat Epidemiol 32:100-111. — PubMed PMID: 28984369
28. Cole BF et al. (2007). Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 297:2351-9. — PubMed PMID: 17551129
29. Ramaekers VT et al. (2005). Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. N Engl J Med 352:1985-91. — PubMed PMID: 15888699
30. Shea B et al. (2013). Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev CD000951. — PubMed PMID: 23728635

PubMed Topic Searches

1. PubMed: folate neural tube defect prevention
2. PubMed: folic acid fortification outcomes
3. PubMed: MTHFR pregnancy NTD
4. PubMed: 5-MTHF methylfolate pregnancy
5. PubMed: folate autism periconceptional
6. PubMed: folate congenital heart defect

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Connections

• All Vitamins
• Vitamin B9 Overview
• B9 Benefits Hub
• B9 Methylation & Homocysteine
• B9 Cardiovascular & Stroke
• B9 Depression & Mental Health
• Folate and Pregnancy
• Vitamin B12
• Vitamin B6
• Vitamin B2 (Riboflavin)
• Choline
• Vitamin D
• Iodine
• Iron
• Methionine
• Homocysteine
• Anemia
• Lentils
• Broccoli
• Deficiency
• Toxicity
• History
• Sources

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