Neural tube defects (NTDs)
Spina bifida
Anencephaly
Encephalocele
Rates of NTDs
Associated causes of NTDs
Public health recommendations for folic acid preventable birth defects
Fortification of foods in the U.S.
Professional recommendations on folic acid consumption
Folic acid and other birth defects

Neural tube defects (NTDs)

During embryonic development, the neural plate undergoes a change in shape to create an infolding and closure to form the neural tube, the structure that develops into the brain, spinal cord and spine. Neural tube closure occurs between 22 and 28 days after conception. When the neural tube does not form correctly and does not completely close, a serious birth defect can develop called a neural tube defect (NTD). NTDs occur very early in pregnancy, even before most women know they are pregnant.

These serious malformations -- which include spina bifida, anencephaly, and encephalocele -- are among the most commonly observed birth defects in humans and constitute a major cause of infant mortality and serious disability.

Neural tube defects affect approximately 3,000 pregnancies per year in the U.S.

Spina bifida

Spina bifida is the most common NTD and occurs when the spinal column fails to close completely during early development, allowing the spinal cord to be exposed and open to possible damage.  

• Spina bifida may cause leg paralysis, bladder and bowel problems, hydrocephalus, and/or other serious health complications.
• The severity of the disability depends on the size and location of the opening on the spine. Usually, the larger defects and those higher on the spine cause more disability.
• Children born with this condition usually need surgery in the first few days of life to close the defect.
• Most people with spina bifida need to use a wheelchair or leg braces throughout their life.

Anencephaly

Anencephaly is an incomplete or severely underdeveloped skull with the brain partially or completely absent.

• Unfortunately, this birth defect is always fatal with death occurring before birth or shortly thereafter.

Encephalocele

Encephalocele is an opening in the skull that allows some of the brain to protrude outside the skull, covered only with a membrane (meninges).

• Depending on the severity of the defect, encephalocele can result in varying degrees of mental disability or may be fatal.

Rates of NTDs

• Each year approximately 3,000 pregnancies in the United States are affected by a NTD (Centers for Disease Control and Prevention 1991-2002).
• The rate of spina bifida in the U.S. for 2002 was 20.13 per 100,000 live births (Lary & Edmonds 1996).
• The prevalence of spina bifida varies among states (higher in the east than in the west) as well as among different ethnic groups, with Hispanics having the highest and Asians and Pacific Islanders having the lowest rates (Lary & Edmonds 1996).
• The rate of anencephaly in the U.S. for 2002 was 9.55 per 100,000 live births (Centers for Disease Control and Prevention 2004).
• In Florida, 97 children and their families were affected by spina bifida, anencephaly or encephalocele in 2001. This corresponds to a rate of 4.7 per 10,000 live births (Florida Department of Health 1997-2001).

Associated causes of NTDs

Most NTDs occur as isolated defects, rather than in association with other malformations. While the latter are sometimes due to single gene defects, chromosomal abnormalities, or teratogenic agents, the cause of isolated NTDs is not fully understood. It is assumed, however, to be multifactorial, that is the result of an interplay between genetic and environmental factors.   Several factors have been associated with an increased risk for NTDs (Centers for Disease Control and Prevention 1999, Frey & Hauser 2003, Cabrera et al. 2005):

• Low folate status or intake
• Previous NTD-affected pregnancy
• Use of certain medications, including anticonvulsants and folic acid antagonist medications
• Maternal hyperthermia during early pregnancy (e.g., febrile disease or hot tub use)
• Maternal obesity and diabetes
• Race/ethnicity (Mexican-American women living in the U.S. who were born in Mexico may be at higher risk)
• Low socioeconomic status
• Exposure to fumonisin B1, a mycotoxin found as a contaminant in corn

Public health recommendations for folic acid preventable birth defects

There is substantial evidence that periconceptional (before conception and during early pregnancy) use of folic acid reduces the incidence of neural tube defects (NTDs). Research has shown that up to 70 percent of NTDs could be prevented if all women who can become pregnant consume 400 micrograms of folic acid from at least a month before conception through the first trimester of pregnancy. Click here to learn more about the research supporting folic acid and birth defect prevention.

Based on substantial scientific evidence, in September 1992, the U.S. Public Health Service recommended that:

•  All women of childbearing age in the United States who are capable of becoming pregnant should consume 400 micrograms of folic acid per day for the purpose of reducing their risk of having a pregnancy affected with spina bifida or other NTDs.

•  Women who have had a previous NTD-affected pregnancy also should consume 400 micrograms of folic acid daily, unless they are planning a pregnancy, in which case they should consult their physician about consuming 4 milligrams (4,000 micrograms) of folic acid every day for NTD recurrence prevention.

To assist women in getting adequate levels of folic acid for NTD risk reduction, the Food and Drug Administration issued a regulation in 1996 requiring that by January 1998 all enriched cereal grain products be fortified with folic acid to reduce the risk of neural tube defects in newborns. Fortification (140 micrograms folic acid per 100 grams cereal grain product) began in 1996 and the process was essentially complete by mid-1997.

In 1998 the Institute of Medicine issued the following recommendation as part of the Dietary Reference Intakes for folate:

•  Women capable of becoming pregnant consume 400 micrograms of folate daily from supplements, fortified foods, or both in addition to consuming food folate from a varied diet.

Different organizations, as well as federal and state agencies -- including the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Institute of Medicine, the American College of Medical Genetics, the Teratology Society, and the American Academy of Pediatrics -- have issued statements regarding folic acid supplementation and fortification. They have all followed essentially the same recommendations of the Public Health Service.

The general consensus today can be summarized as follows:

Prevention of first occurrence:

•  All women of childbearing age who are capable of becoming pregnant should take 400 micrograms of synthetic folic acid daily while consuming a healthy diet that includes folate-rich foods.

•  Since neural tube closure occurs between 22 and 28 days after conception, which is before the recognition of pregnancy by most women, and because approximately 50 percent of pregnancies are unplanned, NTD prevention will be best achieved by adequate folic acid intake by all women of childbearing age who are sexually active and capable of becoming pregnant.

•  Although not all occurrences of NTDs can be prevented with folic acid, the CDC estimates a 50-70% reduction in NTDs if recommendations for adequate folic acid intake for women were followed.

Prevention of recurrences:

• Women with a previous pregnancy resulting in a fetus with an NTD should take a separate supplement of 4 milligrams (4,000 micrograms) of folic acid daily, starting 1 month before conception and throughout the first 3 months of pregnancy.
• Women should be advised not to attempt to achieve these doses of folic acid by taking over-the-counter or prescription multivitamins with folic acid because of the possibility of ingesting harmful levels of other vitamins, for example, vitamin A.
• It should be noted that 4 milligrams (4,000 micrograms) of folic acid did not prevent all recurrences of NTDs in an intervention study. Therefore, high-risk patients should be cautioned that folic acid supplementation does not preclude the need for counseling or consideration of prenatal testing for NTDs.

Fortification of foods in the U.S.

The Food and Drug Administration (FDA) requires that food manufacturers fortify all enriched cereal grain products with folic acid effective January 1, 1998. The fortification level is 140 micrograms folic acid per 100 grams of cereal grain food. This regulation affects enriched foods including flour, breads, rolls, pasta, rice, cornmeal, instant oatmeal, crackers, baked goods (e.g., cookies, cakes), and mixed foods containing these foods (e.g., soups with rice or pasta, certain convenience and frozen foods, etc.). Cereal grain foods were chosen for fortification because they are consumed widely by the target age group (women of childbearing age).

Folic acid fortification has improved folate status in the United States. Red blood cell folate concentrations in women aged 15-44 years were reported to be 2-3 times higher after fortification compared to pre-fortification (Centers for Disease Control and Prevention 2000).  This increase in folate status coincided with a 26-27% reduction in the number of neural tube defects in the U.S. (Centers for Disease Control and Prevention 2004), which is significant yet far short of the estimated reduction in NTD incidence of 50%-70% based on observational and intervention studies for women taking supplements containing folic acid. Folic acid fortification also has been associated with significant reductions in NTD rates in Canada (Mills & Signore 2004) and Chile (Lopez-Camelo et al. 2005).  

Professional recommendations on folic acid consumption

Folic acid recommendations are strongly supported by health professional organizations. The following professional organizations have released recommendations on folic acid consumption, folic acid fortification or statements of support for the 1992 U.S. Public Health Service (USPHS) recommendation for folic acid supplementation for women.

American Academy of Pediatrics (AAP) - http://www.aap.org/advocacy/washing/folic498.htm

American College of Obstetricians and Gynecologists (ACOG) -   ACOG provides recommendations on folic acid in line with the USPHS in its "Guidelines for Women's Health Care" (2002), second edition and "Guidelines for Perinatal Care" (2002), fifth edition.   These publications are available from the ACOG bookstore. Access at www.acog.org.  

American College of Medical Genetics (ACMG) - http://www.acmg.net/resources/policies/Folic_Acid_2004.pdf

American College of Preventive Medicine - http://www.acpm.org/ajpm1561.pdf

American Medical Association (AMA) - http://www.ama-assn.org/apps/pf_new/pf_online?f_n=browse&doc=policyfiles/HnE/H-440.898.HTM

Association of Women's Health, Obstetric and Neonatal Nurses (AWHONN) - http://www.awhonn.org/awhonn/?pg=875-4730-7170

Teratology Society - http://teratology.org/pubs/folicacid.pdf

Folic acid and other birth defects

The benefits of folic acid consumption may extend well beyond neural tube defects. Studies have reported a significant association between folic acid intake and reduced risk for other birth defects, including orofacial clefts, heart defects, urinary tract defects, and limb deficiencies. Click here for more information.

References

Cabrera, R.M., Hill, D.S., Etheredge, A.J., Finnell, R.H. (2005) Investigations into the Etiology of Neural Tube Defects.   Birth Defects Research (Part C) 72:330-334.

Centers for Disease Control and Prevention. (2000) Folate status in women of childbearing age-United States. 1999. MMWR 49:962-965.

Centers for Disease Control and Prevention.   National Center for Health Statistics.   Trends in Spina Bifida and Anecephalus in the United States, 1991-2002.  
http://www.cdc.gov/nchs/products/pubs/pubd/hestats/spine_anen.htm. Accessed March 15, 2005.

Centers for Disease Control and Prevention.   Preventing Neural Tube Birth Defects: A Prevention Model and Resources Guide, 1999.

Centers for Disease Control and Prevention.   (2004) Spina Bifida and Anencephaly Before and After Folic Acid Mandate -- United States. 2004. MMWR 53:362-365

Florida Department of Health, Florida Birth Defects Registry, 1997 - 2001. Personal communication.

Frey, L. & Hauser, W. A. (2003) Epidemiology of Neural Tube Defects.   Epilepsia, 44(Suppl. 3):4-13.

Lary J.M. & Edmonds, L.D. (1996) Prevalence of spina bifida at birth-- United States, 1983-1990: a comparison of two surveillance systems.   MMWR 45(ss-2), 15-26.

Lopez-Camelo J.S., Orioli I.M., da Graca Dutra, M., Nazer-Herrera, J., Rivera, N., Ojeda, M.E., Canessa, A., Wettig, E., Fontannaz, A.M., Mellado, C., Castilla, E.E. (2005) Reduction of birth prevalence rates of neural tube defects after folic acid fortification in Chile. American Journal of Medical Genetics Part A. Published online: 21 April 2005.

Mills, J.L., Signore, D. (2004) Neural tube defect rates before and after food fortification with folic acid. Birth Defects Research (Part A). 70:844-845.