Before the discovery of the correlation of folic acid deficiency and neural tube defects (NTDs), NTDs were one of the most common birth defects in the United States. Once the necessity of adequate levels of prenatal folic acid intake was identified, the U.S. government implemented mandatory fortification of certain affordable foods in 1998. This fortification health mandate decreased the incidence of NTDs dramatically, as women of all races, ethnicities, and socioeconomic statuses not only learned the importance of folic acid for neurological development but also gained access to affordable folate. The exact etiology of NTDs and their relationship to folic acid metabolism are still unknown, and some researchers raise concerns of theoretical risks with excess folate consumption. Nevertheless, the discovery of folic acid and the implementation of widespread preventive measures against NTDs are notable examples of public health success in education and disease reduction in the United States. Considering the commonality of NTDs and the debilitating conditions they cause, they present an important public health issue. The discovery that linked prenatal folic acid intake to NTDs and the subsequent legislation were public health victories. The 1990 Nutrition Labeling and Education Act called for reproductive-aged women to take folic acid supplements to reduce the occurrence of NTDs, making folic acid a preventive measure against NTDs. This article will discuss the importance of the discovery of the relationship between folic acid and NTDs, the historical context of NTDs, the current knowledge of NTDs, and the public health response to NTDs using folic acid.

Keywords: NTDs, folic acid, birth defects


Despite public health intervention, neural tube defects (NTDs) are common in the United States (Duke Molecular Physiology Institute, 2019). The estimated annual number of cases of NTD births in the United States is roughly 2,660 (Data & Statistics on Birth Defects, 2018). NTDs originate from a malformation of embryogenesis that starts with the neural tube cells, which begin to form the spinal cord, brain, and protective structures such as the vertebrae during the first month of pregnancy, often before a woman even knows she is pregnant (About Neural Tube Defects, 2018). The fetal neural tube cells fuse to form the neural plate, which then develops into the neural tube which is the precursor for the brain and spinal cord (About Neural Tube Defects, 2018). When the cells forming the neural tube fail to close correctly, they form a defect in the spinal column, cord, or brain, which leads to an open or closed NTD (Duke Molecular Physiology Institute, 2019).

There are three types of NTDs: anencephaly, encephalocele, and spina bifida (About Neural Tube Defects, 2018). The severity of NTDs depends on the location and extent of the defect. Anencephaly is the most severe NTD, as it involves a defect of the top of the neural tube that results in babies born missing most or part of the brain, and thus, these types of NTDs are incompatible with life (About Neural Tube Defects, 2018). Encephaloceles refer to cases with a defect at the base of the skull, which results in a sac-like protrusion of the brain (About Neural Tube Defects, 2018). Symptoms of encephaloceles vary based on the size and location of the protrusion (About Neural Tube Defects, 2018). Spina bifida is the most common NTD of the three, and its incidence was most affected by folic acid fortification. This article will focus mostly on spina bifida.

Spina bifida presents as spina bifida occulta, meningocele, or myelomeningocele (Centers for Disease Control and Prevention [CDC], 2019). Spina bifida occulta is the mildest form because it does not usually cause disabilities and appears only as a small, often unnoticeable, gap in the vertebrae (CDC, 2019). Meningoceles are sacs filled with cerebrospinal fluid that protrude between vertebrae, but the spinal cord and nerves remain intact (CDC, 2019). Myelomeningoceles are a more severe form of spina bifida in which the spinal cord, nerves, and cerebrospinal fluid herniate through a part of the spine, resulting in damage to the entrapped segments (CDC, 2019). These damages to the nervous system can cause severe disabilities such as paraplegia, extremity weakness, numbness, and loss of bladder or bowel control (CDC, 2019).

Background and Importance of Scientific Discovery

In 1991, The Lancet published clinical research on the impact of folic acid consumption compared to other vitamins in preventing NTDs in women who had already given birth to a child with an NTD (MRC Vitamin Study Research Group, 1991). The study suggested that folic acid supplementation around the time of conception had a positive impact on reducing the chance of an NTD pregnancy. Women received a folic acid dose; a mixture of vitamins A, D, B1, B2, B6, and C; both supplements; or no supplement. The folic acid had a 72% protective effect against NTD pregnancies compared to the other groups (MRC Vitamin Study Research Group, 1991). Soon after, Czeizel and Dudás (1992) presented data on folic acid supplementation reducing NTDs in all pregnant women and not just at-risk women. Similarly, the study suggested that folic acid supplements reduce the incidence of NTDs among all women of childbearing capacity (Czeizel & Dudás, 1992). Following the publication of these studies, the CDC (1992) released a statement that strongly recommended the use of folic acid in reducing the number of cases of NTDs. Based on the knowledge that neural tube development occurs in the first month of pregnancy, a woman’s folic acid levels must be adequate prior to conception, unlike other prenatal vitamins. Thus, the U.S. government mandated cereal grain products be fortified with folic acid or folate in 1998 to reach the target group of reproductive-aged women (Williams et al., 2015).

Over the years, the impact of folic acid supplementation and mandatory folic acid fortification in the United States became visible in statistical data. Data were collected between 1995 and 2011 to compare the prevalence of NTDs before folic acid fortification in 1998 with prevalence of NTDs after folic acid fortification (Williams et al., 2015). Prevalence estimates included nationwide data and considered maternal race and ethnicity (Williams et al., 2015). The years post-mandate presented an estimated 28% reduction in the prevalence of anencephaly and spina bifida across all racial and ethnic groups (Williams et al., 2015). Although this reduction is significant, it is it not incredibly high. This could be due to unknown etiologic factors that contribute to NTDs, perhaps genetic. It could also be related to supplement dosage levels being lower than they should be, or women not eating the anticipated amount of supplemented foods.

Fortification not only reduced the incidence of NTDs, but also reduced health care costs. As NTDs cause crippling disablement, the lifetime cost of living with spina bifida is estimated to be US$560,000, and the cost of the fatal anencephaly is estimated to be US$5,415 (Grosse et al., 2008). Based on these costs, given an estimated 1,300 cases prevented, the decrease in NTD births between 1999 and 2011 saved roughly US$508 million annually (Williams et al., 2015). Thus, mandatory folic acid fortification appears to be an effective public health preventive measure.

Before the discovery and implementation of folate mandation as a preventive measure against NTDs, the occurrence of NTDs was roughly one in every 1,000 births in the United States (Pediatrics Committee on Genetics, 1999). Of these NTD cases, more than a third of the pregnancies were aborted either spontaneously or electively, and the annual incidence of NTD births was roughly 2,500 infants (Pediatrics Committee on Genetics, 1999). After the discovery of the need for folic acid supplementation, NTDs appear in roughly 3,000 pregnancies in the United States annually—a much smaller statistic than in one of every 1,000 births (March of Dimes, 2018).

Understanding the Etiology and Perceptions of NTDs Before the Discovery of Folate

Before the discovery of the impact of folic acid on NTDs, researchers addressed the impact of environmental factors on congenital deformities. Animal studies suggested that X-ray, UV light, mechanical shaking, and temperature and chemical changes all contributed to central nervous system congenital defects, including NTDs (Record & McKeown, 1949). Other studies proposed genetic patterns of etiology, such as Khoury, Erickson, and James (1982) who suggested that NTDs have appeared more commonly with other congenital defects rather than on their own—a concept known as heterogeneous causality (Khoury et al., 1982). As siblings of a child with an NTD were more likely to also be born with an NTD, researchers considered this a sign of genetic inheritance; however, the pattern of inheritance was unidentifiable (Khoury et al., 1982). Similar environmental and genetic factors are still researched today, as the etiology of NTDs is still unknown.

Understanding the Etiology and Perceptions of NTDs After the Discovery of Folate

Although the exact etiological cause of NTDs is still vague and unknown, identifying insufficient folic acid intake as a contributor to NTDs sheds light on the risk factors of NTDs. Folic acid itself plays an integral role in fetal development as it is essential for the production of nucleic acids and DNA (Cabrera, Hill, Etheredge, & Finnell, 2004). Folate also plays an integral role in the metabolism of amino acids and is required for healthy, rapid cell division, which occurs early in pregnancy (Office of Dietary Supplements, 2019). Impaired folate function, whether through folate deficiency or through disabled folate uptake, can lead to megaloblastic anemia—a condition resulting from impaired DNA synthesis that results in cell growth without division (Office of Dietary Supplements, 2019). Megaloblastic anemia and disrupted nucleic acid synthesis most likely affect neural tube cell division and formation during the first month of pregnancy, which leads to NTDs through the previously discussed pathways of development.

Besides a prior NTD-affected pregnancy, other trends in maternal health and NTD risk appear in maternal insulin-dependent diabetes, use of certain anti-seizure medications, medically diagnosed obesity, exposure to high temperatures during early pregnancy, being of certain minority racial or ethnic status, and lower socioeconomic status (Burke, 1999). Current literature lacks an understanding of how these health problems factor into NTD risk. However, these factors appear to correlate with an increased risk of bearing a child with an NTD. After the discovery of folate correlation with risk of NTDs, researchers began looking into vitamin B12 deficiency as well. Low B12 levels lead to pernicious anemia which causes degeneration of the nervous system, similar to how low folate levels lead to megaloblastic anemia (Cabrera et al., 2004). However, there is much academic debate surrounding low levels of maternal vitamin B12 as a potential risk factor for NTDs (Cabrera et al., 2004). Some studies found a correlation between low levels of B12 and increased risk of NTDs, whereas others found no correlation between vitamin B12 intake and NTDs (Cabrera et al., 2004). Although the exact etiological cause of NTDs is still unknown, the discovery of folic acid opened doorways for more research into other dietary, environmental, and genetic causes.

Impact of Folate Discovery on the Public Health Response to NTDs

Soon after the release of published studies on the positive impact of folic acid on reducing NTDs, the U.S. government mandated folate fortification of enriched cereal or grain products. This was a true victory in the public health realm because it made folic acid more physically and financially accessible for the target population of women in their reproductive years, because women could consume the necessary dose of folic acid from cheap sources like cereal rather than buying supplemental pills. Furthermore, assuming that fortified grains are part of most women’s diets in America, mandated fortification ensured adequate folic acid levels in women who were not expecting to become pregnant. After the mandate, incidence of NTD pregnancies decreased among all racial and ethnic groups, suggesting that the mandate positively impacted a massive amount of the intended population. However, Hispanic populations still present a higher prevalence of NTDs compared to other racial and ethnic groups, so the beneficial outcome is not shared to the same extent (Williams et al., 2015). Williams et al. (2015) propose dietary differences, including differences in primary grain consumption, in Hispanic populations or genetic differences that affect folic acid uptake could be accountable for the elevated rates of NTDs among Hispanic populations. Suggested interventions to reduce this disparity include fortifying corn masa flour to the same level of cereal grain fortification (Williams et al., 2015).

Not only did the folic acid mandate make folate easily accessible and affordable, but it also increased the awareness of the importance of prenatal vitamins and sparked educational initiatives to inform potential mothers of NTD risk factors. For example, the CDC published a pamphlet directed toward women interested in NTD prevention. In its debrief, the CDC (1998) outlined three steps to effectively advocate for birth defect prevention: mobilizing the community, making a plan for action, and testing the materials and methods on the community. The nonprofit organization “March of Dimes,” which supports maternal and infant health initiatives, now outlines the ins and outs of NTDs, with a focus on preventive measures (March of Dimes, 2018). The discovery of folic acid as a preventive measure allowed for a successful public health response in areas of both health and educational impact.


The discovery of maternal folic acid intake correlating to NTDs revolutionized prenatal care. This article presents the folic acid mandate in a very positive way, but like many health initiatives, there are also potential risks of any mass campaign. Researchers worry that excessive levels of folic acid, also known as vitamin B9, may mask vitamin B12 deficiency, leading to pernicious anemia and subsequent nervous system degeneration; however, this theoretical consideration has yet to be proven (Crider, Bailey, & Berry, 2011). Another group proposed high folate intake might be linked to cancer, but there is not enough evidence or data for this either (Crider et al., 2011). Another concern is that fortification allows excess folic acid intake, and the health effects of excess intake are unknown (Crider et al., 2011). Although these concerns are important to investigate, they currently lack scientific evidence to solidify their validity. The discovery of folic acid changed the public’s perception by increasing awareness for the importance of prenatal vitamins and supplements, and offered a preventive measure against NTDs. With this understanding, and the overall unknown etiology of folic acid, it would be ideal for more research to be conducted to find out the etiological cause of NTDs.


The mandate of folic acid fortification exemplifies how a public health initiative can improve population health. NTDs present a widespread threat to infant health throughout the United States. Researchers linked low levels of maternal folic acid intake to NTDs, thus identifying a heavily contributing risk factor. In response to this identified cause, the U.S. government used public health initiatives to make a mass appeal to the general public through mandatory folate fortification and spreading awareness of the importance of prenatal vitamins. In the years after the implementation of the folate mandate, the noticeable decline of incidence of NTDs in the United States strongly reflects the success of this scientific discovery and subsequent public health initiatives.


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