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A geneticist's perspective.

STRONG EVIDENCE EXISTS THAT VITAMIN [B.sub.9], known as folate in its natural form and folic acid in its synthetic form--in adequate quantities and at appropriate timing--can reduce the risk for neural tube defects (NTDs). (1-3) The potential risk reduction is estimated to be as high as 70%, and these definitive findings are the basis for the decision to institute folic acid food fortification in the United States and other countries. The US government mandates a fortified level of 140 mcg folic acid/100 g flour. In May 2009, the US Preventive Services Task Force (USPSTF) revised its earlier recommendations and stated that women capable of childbearing should maintain a folic acid intake of 400 to 800 mcg/d. (4)

Public awareness campaigns have been built around these findings and recommendations. The current estimated incidence of NTDs--3000 births per year in the US--represents a substantial decrease from the years before food fortification was initiated. In 2004, the Centers for Disease Control and Prevention (CDC) estimated that decrease at 26%, (5) but it has been suggested that those figures underreport the decrease in incidence because they were drawn from vital statistics that may not include early diagnosis and elective termination. (6) Canadian studies based on more complete ascertainment show post-fortification decreases in NTD incidence of up to 54%. (6)

Unresolved NTD issues

Despite this success, many issues surrounding NTDs remain unresolved. The cause of NTDs has not been satisfactorily explained. The mechanism of action of folic acid in reducing NTDs is similarly unclear. Some NTDs occur independently, but some occur in the context of chromosomal anomalies and other Mendelian disorders, such as Meckel-Gruber syndrome (MGS). In babies affected with MGS, a posterior occipital NTD is one of the preeminent signs of this rare autosomal recessive condition.

We know that NTDs occur more frequently in women with a personal or family history of NTD-affected pregnancy. A trend toward reduced endogamy--meaning that Americans are less likely to marry exclusively within their own racial and ethnic group than they were 10 to 20 years ago--may play a role in limiting population-wide genetic vulnerability to NTDs. Emerging evidence also suggests that immune function plays a role in some cases of NTDs.

Differences between folate and folic acid

Although the terms folate and folic acid are often used interchangeably, this terminology requires clarification. Folate, also known as vitamin [B.sub.9], is a water-soluble vitamin. Important natural food sources include liver, legumes, leafy green vegetables, and oranges. (7) Because folate has limited bioavailability in its natural form, obtaining adequate preconception intake from food sources alone is challenging. The bioavailability of folate derived from food varies according to whether the food is raw or cooked, the method of cooking, and the combinations of foods eaten together, among other factors. The estimates of folate bioavailability range widely, from approximately 50% to 80%. (8)

Folic acid, the synthetic form of folate, is used in food fortification and vitamin supplements. It is considerably more bioavailable than natural folate.

Folate and folic acid in the body

Although the human body cannot synthesize folate or folic acid, during periods of chronic supplementation the body can store folates, primarily in the liver and in red blood cells (RBCs). (9,10) Folate stored in RBCs is a particularly important reserve during embryonic development, because it readily yields folate to maternal plasma if folate intake is insufficient during gestation. The first 25 days of gestation are particularly important in this regard. (11) Neural tube closure--which begins on day 18 of embryonic development--is completed by day 26 of gestation, so folic acid cannot reduce NTD risk after that stage of embryonic development. Folic acid intake is therefore vitally important during the preconception period.


Folate/folic acid is also important for processes other than neural tube development. It is critical to many other physiologic processes in overall health and well-being, particularly cardiovascular health. Folate/folic acid is required for the production and maintenance of new cells and is especially crucial during periods of rapid cell division and growth, such as infancy and pregnancy. That is why it is an ingredient in prenatal vitamins intended for use throughout pregnancy. Folate/folic acid is required for DNA synthesis, as it plays an important role in nucleic acid and amino acid metabolism. In purine and pyrimidine synthesis, it is essential for cell division and DNA and RNA synthesis. In addition, folate/folic acid is integral in synthesis of the methyl donor S-adenosylmethionine (SAM). It is used in multiple methylation reactions, including DNA methylation.

After entering the cell, folic acid, possibly with the aid of folate receptors, is involved in the transfer of carbon atoms that are used to synthesize nucleotides or, through the conversion of homocysteine to methionine, for the methylation of a variety of substrates (FIGURE). These processes are regulated by numerous molecules, including enzymes and vitamins other than folic acid, including vitamins [B.sub.6] and [B.sub.12]. The activity of some enzymes, such as methionine synthase, may be influenced by other enzymes, such as methionine synthase reductase. (3) Without adequate folate and folate receptor activity, the appropriate enzyme products that lead to the reduction of homocysteine and to methionine will not be produced, nor will appropriate purine and pyrimidine synthesis occur. (3)

Folic acid deficiencies occur in adults worldwide. On a cellular level, we see impaired cell division and increased levels of homocysteine, which occurs because the enzyme needed to convert homocysteine to methionine is not active. This leads to hyperhomocysteinemia and multiple, related, adverse outcomes, especially in cardiovascular disease.

NTD epidemiology and etiology

Preconception folic acid intake reduces NTDs by 50% to 70%. (12) Folic acid is also associated with reduced risk for other anomalies, including cleft palate and genitourinary abnormalities. (13) Currently in the US, approximately 1 NTD occurs per 1000 deliveries; the incidence rate is 0.1%, although the rates vary by region. In the southeast, the so-called NTD belt, the rate can be as high as 2 to 2.5 per 1000. In the west, rates may be lower than 1 per 1000.

Clearly, a disparity exists in this country, with lower rates in multiethnic, multiracial areas, and inadequate preconception intake of folic acid is not the only factor that contributes to NTD. Estimates of preventable cases of NTD that are not related to folic acid are in the range of 6 per 10,000 pregnancies. (14)

How do these numbers affect those of us who provide obstetric care? Consider the example of a woman who has had a pregnancy associated with an NTD such as spina bifida, meningeomyelocele, or anencephaly. Her recurrence risk without intervention is about 1% to 2%. With folic acid, her recurrence risk can be reduced to approximately the baseline 1 in 1000. For a woman who has not had an NTD-affected pregnancy, her occurrence risk of 1 in 1000 can be reduced by 3- to 4-fold. Other causes of NTDs, including chromosomal disorders, cannot be eliminated through folic acid supplementation and fortification. But we can markedly reduce most NTDs that appear to be primarily affected by preconception folate levels.

Timing: The key to maximal benefit

A woman derives the maximal benefit from folic acid when she takes it before conception. Regardless of the characteristics of your obstetric practice, it is virtually impossible to guarantee that patients will be seen before the 26th day of embryonic development. (1) Most of our patients do not present for prenatal care until days or weeks after neural tube closure occurs. It is therefore critical that folate supplementation begins at conception or, optimally, before conception.

Folic acid safety

Pregnant women are generally cautious about taking any medication during pregnancy, and justifiably so. What can we tell them about the safety of folic acid? Fortunately, we have considerable experience on which to base our assertions about safety, because the estimated exposure to a daily dose of 400 mcg exceeds 1 billion person-years. (15)

Unlike fat-soluble vitamins--such as vitamins A, D, E, and K--high folic acid consumption does not present obvious risks. As a water-soluble vitamin, excess amounts are safely excreted in the urine. Folic acid also has a wide therapeutic index, with no substantiated reports of adverse events at daily dosages as high as 15 mg. (16) Folic acid toxicity has not been reported. The FDA-recommended upper limit is 1 mg/d, but women who have had a previous NTD pregnancy or are otherwise believed to be at high risk for an NTD pregnancy are advised to take 4 mg/d, according to the CDC. (12)

Suboptimal folic acid levels: A multifactorial problem

Suboptimal folic acid levels may occur for several reasons. Chief among these is inadequate dietary and supplement intake.


Some evidence suggests that the incidence of folate deficiencies may increase as more people become interested in organic, natural, and therefore nonfortified foods. From the standpoint of folic acid intake, these nonfortified foods represent a step backward. Low-carbohydrate diets may also exacerbate the problem because avoiding bread, pasta, and other fortified grain foods eliminates an important source of folic acid fortification. Women with certain medical conditions that cause impaired absorption and metabolism of nutrients, such as celiac disease or Crohn's disease, or those who have a history of bariatric surgery, are also at risk of absorbing inadequate levels of folic acid.


Certain medications may interfere with and limit the absorption of folate/folic acid. Some of the worst offenders include beta-blockers, calcium-channel blockers, and cholestyramine, which are not commonly prescribed to reproductive-aged women. The antibiotic combination of trimethoprim-sulfamethoxazole is another culprit, although it is typically used on a short-term basis, for example, to treat urinary tract infections. Other drugs that may interfere with folate/folic acid metabolism include antiseizure medications such as phenobarbital, phenytoin, carbamazepine, primidone, and valproic acid; the anti-inflammatory agent sulfasalazine; the anfireflux agent cimetidine; and methotrexate, a chemotherapeutic folate antagonist.


Genetic variants may also affect the metabolism of folic acid. The most common polymorphism involves methylene tetrahydrofolate reductase (MTHFR), an enzyme that is essential in chemical reactions involving folate. The most common MTHFR mutation in the United States is termed C677T, and approximately 10% of the US population is homozygous for this MTHFR polymorphism. (17) Some people with this mutation develop an elevated homocysteine level because enzyme activity is markedly reduced. Elevated homocysteine levels may irritate the blood vessels, leading to an increased likelihood of cardiovascular disease and venous thrombosis for those with this polymorphism. (18) Some reports have also linked it to an increase in NTDs.


Most women with NTD-affected pregnancies do not have clinical folate deficiency. Polymorphisms for folate-pathway enzymes have been identified but cannot fully account for the 70% decrease in risk associated with folic acid supplementation. This observation led to a hypothesis that a folateo receptor autoantibody could cause fetal abnormalities by impeding folic acid transport and binding to cellular components during embryonic development.

Immunologic processes have been linked to an outcome that has essentially the same effect as folate deficiency. It is possible that folate levels are adequate but the vitamin does not bind to its receptor, perhaps because of folic acid/folate receptor antibodies. The net result would be that not enough folate enters this metabolic process, leading to a de facto folate deficiency. In a small pilot study with results published in The New England Journal of Medicine in 2004, serum was taken from 12 women with current or prior NTD-affected pregnancies (index) and 24 controls (20 with unaffected current or prior pregnancies, 4 nulligravid). The serum was analyzed for autoantibodies by incubation with human placental folate receptors radiolabeled with folic acid. Serum from 9 of 12 (75%) index women and 2 of 20 (10%) controls contained autoantibodies to folate receptors (P<.001), suggesting that serum from women with NTD-complicated pregnancies contained autoantibodies that bind folate receptors, blocking cellular uptake of folate. (17) One possible interpretation of the findings is that autoantibodies to folate receptors increase during pregnancy, at least in some subpopulations of women. Is the relationship causal? Do women with autoantibodies benefit from a higher level of supplementation? We don't yet know, but these findings strongly suggest that in addition to genetic issues, immunologic issues may also affect NTD risk.

Forms of folate/folic acid

Folic acid is a synthetic, stable form of folate that does not occur in nature but is the primary form used in food fortification and supplementation. Folate is the naturally occurring form found in foods. Dietary folates are a mixture of a variety of isomers of the 5-methyltetrahydrofolate polyglutamates. Folate is also available as a synthetic derivative--L-5-methyl-THF (L-MTHF). L-MTHF also has possible uses in fortifying foods and as a supplement.

Currently, it is not clear that 1 form of folate has an advantage over another. Much of the available outcomes data is based on the use of folic acid, while other beneficial outcomes have been demonstrated in association with folate levels. Advantages of L-MTHE if they exist, may reflect that folate is the naturally occurring form and the only form actually found in plasma. Folate is more effectively transported into peripheral tissues. Homeostatic mechanisms prevent accumulation of excess levels, regardless of how much is taken. Folate is also less vulnerable to the influences that some polymorphisms and drugs may exert on absorption/metabolism. And folate is what is measured in studies, especially those demonstrating a decreased risk for NTD when higher serum levels of folate are present.

L-MTHF was investigated as an alternative to folic acid supplementation, with results published in the American Journal of Clinical Nutrition in 2006. This was a double-blind, randomized controlled trial in which 144 healthy nonpregnant women from 19 to 33 years of age were randomized to receive 400 mcg folic acid, 416 mcg [6S]-5-MTHF (which provides a serum level equivalent to 400 mcg folic acid), 208 mcg [6S]-5-MTHE or placebo. RBC and plasma folate concentrations were measured at baseline and at 4-week intervals, up to 24 weeks. Plasma folate concentrations plateaued after 12 weeks in all groups. The mean RBC folate concentration was greater than 906 nmol/L, the cut-point for NTD risk reduction, in only 2 groups: participants taking 400 mcg folic acid or those taking 416 mcg [6S]-5-MTHE The slope of the increase over time was greater with 416 mcg [6S]-5-MTHF than with 400 mcg folic acid for RBC (P<.001) and plasma folate (P<.05). The investigators concluded that 416 mcg [6S]-5-MTHF was more effective than 400 mcg folic acid in improving folate status in these women. Perhaps more important, the L-MTHF delivered higher levels of serum folate--levels associated with NTD risk reduction--faster than folic acid. (11)


Folic acid use has been shown to reduce the risk for NTDs, but the exact mechanism of action is not yet fully understood. Polymorphisms are present in a subset of the population at greatest risk for NTD-affected pregnancy. Folic acid is favored over dietary folate because of its superior bioavailability. However, a synthetic form of folate, L-MTHE provides serum levels of folate comparable to those found with folic acid supplementation and may offer some advantages over folic acid.


(1.) Czeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med. 1992;327:1832-1835.

(2.) MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet. 1991;338:131-137.

(3.) Botto LD, Moore CA, Khoury MJ, et al. Neural-tube defects. N Engl J Med. 1999;341:1509-1519.

(4.) U.S. Preventive Services Task Force (USPSTF). Folic acid for the prevention of neural tube defects, folicacid/folicacidrs.htm. Accessed August 6, 2009.

(5.) CDC. Spina bifida and anencephaly before and after folic acid mandate: United States, 1995-1996 and 1999 2000. MMWR Morb Mortal Wkly Rep. 2004;53;362-365.

(6.) Mills J. Signore C. Neural tube defect rates before and after food fortification with folic acid. Birth Defects Res (Part A). 2004;70:844-845.

(7.) Brown JE, Jacobs DR Jr, Hartman TJ, et al. Predictors of red cell folate level in women attempting pregnancy, JAMA. 1997;277:548-552.

(8.) Winkels RM, Brouwer IA, Siebelink E, et al. Bioavailability of food folates is 80% of that of folic acid. Am J Clin Nutr. 2007;85:465-473.

(9.) Gregory JF 3rd, Williamson J, Liao JF, et al. Kinetic model of folate metabolism in nonpregnant women consuming [2H2]folic acid: isotopic labeling of urinary folate and the catabolite para-acetamidobenzoylglutamate indicates slow, intake-dependent, turnover of folate pools. J Nutr. 1998;128:1896-1906.

(10.) Gregory JF 3rd, Caudill MA, Opalko FI, et al. Kinetics of folate turnover in pregnant women (second trimester) and nonpregnant controls during folic acid supplementation: stable-isotopic labeling of plasma folate, urinary folate and folate catabolites shows subtle effects of pregnancy on turnover of folate pools. J Nutr. 2001;131:1928-1937.

(11.) Lamers Y, Prinz-Langenohl R, Bramswig S, et al. 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. 2000;84:156-161.

(12.) Centers for Disease Control and Prevention (CDC). Effectiveness in disease and injury prevention use of folic acid for prevention of spina bifida and other neural tube defects--1983-1991. MMWR Morb Mortal Wkly Rep. 1991;40:513-516.

(13.) Hall JG. Folic acid: the opportunity that still exists. CMAJ. 2000;162:1571-1572.

(14.) Berry RJ, Li D, Erickson JD, et al. Prevention of neural-tube defects with folic acid in China. China-U.S. Collaborative Project for Neural Tube Defect Prevention. N Engl J Med. 1999;341:1485-1490.

(15.) Oakley GP. Inertia on folic acid fortification: public health malpractice. Teratology. 2002;66:44-54.

(16.) Hardman JG, Limbird LE, Gilman AG. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw Hill; 2001.

(17.) Frosst P, Blom HL Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10: 111-113.

(18.) Varga EA, Sturm AC, Misita CP, et al. Cardiology patient pages. Homocysteine and MTHFR mutations: relation to thrombosis and coronary artery disease. Circulation. 2005;111:e289-e293. Accessed July 30, 2009.

Lee P. Shulman, MD

Anna Ross Lapham Professor and Chief

Division of Reproductive Genetics

Department of Obstetrics and Gynecology

Medical Director, Graduate Program in Genetic Counseling

Co-Director, Northwestern Ovarian Cancer Early Detection and Prevention Program

Feinberg School of Medicine of Northwestern University

Chicago, Illinois


Lee P. Shulman, MD, receives grant/ research support from Bayer HealthCare Pharmaceuticals. He is a consultant for and is on the speakers bureaus of Bayer HealthCare Pharmaceuticals, Ortho-McNeil Pharmaceutical, Inc., Barr Laboratories/Duramed, and Schering-Plough.
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Author:Shulman, Lee P.
Publication:OBG Management
Geographic Code:1USA
Date:Sep 1, 2009
Previous Article:Foreword.
Next Article:An update on the epidemiologic data related to folic acid intake and neural tube defects.

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