Understanding And Preventing Neural Tube Defects
Neural tube defects (NTDs) are among the most common congenital anomalies in the United States, second only in frequency to congenital heart defects.
Efforts to reduce the prevalence of these devastating abnormalities demonstrates the effectiveness of the translation of basic science and population research to health care practices, and from practice to public policy.
What Are Neural Tube Defects? NTDs are congenital abnormalities that result from the failure of the normal development of brain and spinal cord. The Centers for Disease Control and Prevention (CDC) estimate that, in 2005, the rates for spina bifida and anencephaly, the two most common forms of NTDs, were 18 and 11 cases per 100,000 live births, respectively.1 An estimated 3000 children are born each year in the United States with an NTD.
Normally, the tissue that is to become the central nervous system (the brain and the spinal cord) forms as a flat plate of cells that later folds over on itself to form a closed tube. This normally occurs within four weeks after conception. In children with NTDs, one or both ends of the tube fail to fully close. The result is one or more congenital defects that affect the cranium or the spine.
One common NTD is anencephaly in which the large portions of the brain fail to develop. In other cases, parts of the skull may not form and portions of the brain may extend or herniate through the opening.
Another form of NTD is spina bifida, in which the vertebral column fails to completely surround the spinal cord and the spinal nerves. The meninges (the tissue that surrounds the central spinal cord) may herniate through the opening to form a meningocele. If portions of the spinal cord herniate through the gap, to form a myelomeningocele, the spinal cord and the spinal nerves may be severely and permanently damaged.
These defects are often associated with other congenital neurologic defects. Hydrocephalus (a condition in which excess fluid collects in the brain, compressing normal brain tissue) occurs in 70-90% of cases, and a significant malformation in which a portion of the brain is displaced downward into the neck (the Chiari II malformation) occurs in one-third of children with spina bifida. Each of these causes additional clinical disability depending upon the specific parts of the nervous system that are affected.
Clinical consequences are severe, debilitating, and irreversible. Anencephaly is incompatible with life. Spina bifida with myelomeningocele formation leads to paralysis and loss of sensation with associated urologic, orthopedic, and neurologic consequences requiring multiple operations and life-long medical care.
What Causes NTDs? NTDs, like many other congenital abnormalities, may be caused by genetic factors, exposure to environmental agents, birth injury, or other unidentified reasons.2 Basic and epidemiologic research has suggested that NTDs result from the interaction between multiple environmental factors and a variety of genetic anomalies. This type of interaction between genetics and environment has been referred to as environmental genomics.
Genetic Factors. Both animal models and epidemiologic research have documented the role of genetic factors in producing NTDs.2 No single genetic variant has been shown to be associated with NTDs. In animal models, mutations in more than 200 genes can result in NTDs. In humans, a genetic basis for NTDs is suggested by a higher rate of NTDs in siblings of children with the defect and in second and third degree relatives.
Specific genetic variants in humans associated with NTDs include defects in various genes regulating folate metabolism. Women with either a heterozygous or homozygous defect in methylene-tetrahydofolate-reductace (MTHFR) activity, for example, have significantly higher rates of births with NTDs; those with a homozygous defect have rates 1.8 times that of women with the common form of the gene.
The Role of Folic Acid. The environmental factor most commonly associated with NTDs is folic acid (FA) deficiency. FA is B-vitamin (vitamin B-9) that occurs naturally in green leafy vegetables, oranges, legumes, and beef liver. It is needed for normal cell division because of its role in the synthesis of nucleic acids and other proteins.
Animal experiments in the 1950s demonstrated that rats fed FA antagonists had increased risks of various congenital malformations including NTDs. Subsequent clinical research strongly supported the role of FA deficiency in causing NTDs. Randomized trials and controlled clinical studies have consistently shown that FA dietary supplementation markedly reduces the incidence of NTDs. The British Medical Research Council study of 1991 demonstrated that FA supplementation reduced the rate of recurrent NTD births by 70%.3 A Hungarian study in the 1980s of folate supplementation beginning three months before a planned pregnancy reported a 90% reduction in the primary occurrence of NTDs.4 A recent review of cohort and case-control studies reported significant reductions in NTDs frequency with FA supplementation to levels of only 11% to 65% of groups without supplements.5
The FA deficiency may be the result of either a reduced intake or abnormal metabolism. Some persons may have an absolute FA deficiency whereas others may have genetically determined abnormalities of FA metabolism interfere with FA metabolism. In either case, the result is a functional FA deficiency that, in susceptible persons, may impede normal cell turnover at a critical time in the development of the neural tube so that it is not properly formed.
The mechanism by which FA deficiency leads to NTDs is unclear. It seems likely that the mechanism relates to an interaction between predisposing genetic factors that impede FA utilization and direct nutrient deficiencies. Based on the gene-nutrient interaction model, added folate may either correct for a primary FA deficiency or compensate for genetically-linked defects in FA metabolism. For example, the effects of MTHFR deficiency can be substantially ameliorated by increasing folate intake.
Recommendations for Folic Acid Supplements. The relatively common occurrence of NTDs and the strong evidence for a causal link between NTDs and FA deficiency have led to important changes in health care practices that have focused on increased FA intake. Estimates suggest that if all women in the U.S. for whom FA supplementation was appropriate took supplements, the rate of NTDs could be reduced by 50 to 70%.6
In 1992, the U.S. Public Health Service recommended that all women of childbearing age capable of becoming pregnant consume at least 400 μg of FA to reduce the risk of having a child with a NTD.1 The average folate intake in food by women in the United States is estimated to be 0.2 mg, or half of the recommended daily need.
In 1996, the U.S. Preventive Services Task Force recommended that these women take a FA-containing supplement.7 The recommendation that all women capable of becoming pregnant was based on the observations that FA supplements were required very early in pregnancy, often before a women knows she was pregnant, and because of a high proportion of pregnancies are unplanned. Daily intake of 4 mg of FA is recommended for women who have had a previous pregnancy with an NTD or who are taking certain drugs that interfere with FA metabolism.
Limited Adherence to Recommendations. In practice, adherence to these guidelines is limited. A 2007 survey supported by the March of Dimes Foundation8 reported that only 40% of all women who were surveyed reported daily use of folate-containing supplement, although 81% reported an awareness of the need for FA supplements. Rates were lowest among women who were nonwhite (36%), had less than a high school education (29%), or had incomes under $25,000 per year (32%). Reasons commonly given for not taking a daily supplement include forgetting (33%), lack of recognition of a need or reason (32%) and the reliance on a balanced diet (12%).
Similarly, fresh fruit and vegetable consumption is low. In Tennessee in 2007, only 29% of surveyed adults with incomes over $75,000 reported eating fruits and vegetables five or more times per day; for those with incomes under $15,000, only 17% did so.9
Role of Access. One reason for low FA consumption is the difficulty in purchasing fresh foods in the local neighborhood. One study by the New York City Department of Health reported that only 3% of markets in the poorer areas of Manhattan – that is, areas with the highest populations of at-risk women -- carried fresh leafy vegetables.12 These data are consistent with other findings that the local food environment impacts intake.11 Data collected in Memphis demonstrated that the density of neighborhood convenience stores, which typically do not sell fresh fruits and vegetables, is highly associated with obesity among African Americans.12
Impact on Other Health Conditions. Improved nutrition in general and folate supplementation also improve other health conditions. Healthy eating is a main counter to obesity and the related cardiovascular diseases and diabetes. Folate supplements reduce the prevalence of cardiovascular and urinary tract congenital abnormalities as well as the incidence of NTDs.4
Limitations of Folate Supplementation. Although FA supplements can substantially reduce the occurrence of NTDs, they are ineffective in certain populations. For example, FA supplementation in not effective in the Latino population living in California.2 This suggests that certain populations may have genetic variations in FA responsiveness or have predominantly other causes of NTDs.
The Role of Public Policy in Nutrition. Thus, although the evidence is strong and the recommendations are clear, most women do not, in practice, have FA intakes adequate to reduce the risk of NTDs. The importance of NTDs coupled with the effectiveness of FA and the ineffectiveness of voluntary supplementation have led to a series of public policy interventions designed to reduce the prevalence of FA deficiency in the general population. Public policy interventions have been proposed or implemented to address a variety of nutritional issues. Many are related to obesity and cardiovascular disease, including proposals to tax unhealthy foods13, restrictions on food served in public schools14, bans on transfat use, and the requirement for food labeling in restaurants.15
Mandatory Cereal Fortification. As of January 1998, the U.S. Food and Drug Administration required fortification of enriched cereal grains with 140 μg of folate per 100g of flour16 (with an exception allowed for “organic” foods), a level that would increase daily FA intake by 0.1 mg. The CDC estimated that this fortification resulted in a 26% fall in the rate of NTDs between 1995-6 (before the regulation) and 1999-2000 (after the fortification requirement).17 Red blood cell folate levels doubled between 1988-94 and 1999-2000. Both findings are generally attributed mostly to fortification rather than to supplementation efforts, and indicate the mandatory public health actions were effective, efficient and inexpensive.
Educational Campaigns. Public health education campaigns have been successful in increasing the awareness of the importance and use of FA supplementation. One program in the Netherlands, for example, increased awareness by pregnant women from 28% to 78% and the use of supplements from 8% to 63% over three years.18
Policies to Improve Access to FA. Other public policy interventions have been designed to facilitate eating natural sources of FA, namely leafy green vegetables. The response in New York suggests that broadly-based policy interventions can be developed and implemented to successfully improve nutrition and, hopefully, reduce the prevalence of NTDs and other nutrition-based diseases.
In an effort to increase the local availability of fresh fruits and vegetables, New York instituted a series of innovative policies. These included the licensing of 1000 “Green Carts” that may sell only fresh fruits and vegetables in neighborhoods that have low consumption levels. The program also funds microloans and technical assistance for cart operators.19
A related initiative is “Health Bucks”, a program in which food stamp recipients receive a Health Buck worth $2 for each $5 in food stamps spent at a farmer’s market.20 These vouchers can then be used at the farmer’s market to purchase additional fruits and vegetables. Between 2008 and 2009, food stamp purchases at greenmarkets more than doubled.21
Other publicly supported programs also were started. New York City’s Fresh Retail Expansion to Support Health (FRESH) program includes millions of dollars in tax and real estate benefits and zoning allowances (including a reduction in the minimum parking requirements) for the development of full-line grocery stores in 45 low-income and underserved communities; to qualify, stores must commit a minimum of 500 square feet to the sale of fresh fruits and vegetables.22 A state- funded program also provides, free of charge, fresh fruits and vegetables to students in selected schools as a snack (and not part of the regular meal service) during the school day. Although these programs do not specifically target pregnancy-related folate requirements, they will by design impact this important population.
Other Public Policy Interventions. Other interventions to improve nutrition and FA consumption have also been suggested. Examples include limiting the number of fast food restaurants through zoning regulations as passed in Los Angeles.23