Condition Definition

NTDs are major congenital malformations of the brain, spinal cord, and overlying tissues that develop during the first few weeks of gestation as a result of abnormal closure of the embryonic neural tube. The most common NTDs are anencephaly, encephalocele, and spina bifida.^{1, 4–7} Anencephaly occurs when the cranial portion of the neural tube does not close; affected infants are born without parts of the brain and skull. Encephaloceles occur when defects along the cranium allow portions of the brain and meninges to protrude. Spina bifida is a diverse group of spinal NTDs that vary in severity from myelomeningocele (protrusion of spinal cord and meninges through a spinal defect) to meningocele (protrusion of meninges through a spinal defect) and spina bifida occulta (spinal defect without any protrusion).⁸ Spinal anomalies (e.g., spina bifida) can also co-occur with cranial anomalies (e.g., anencephaly and encephalocele).

Prevalence and Burden of Disease

Based on 2010-2014 data from 39 U.S. population-based birth defects surveillance programs, the Centers for Disease Control and Prevention (CDC) estimated that anencephaly occurred in 2.5 out of 10,000 live births in the United States, encephalocele in 1 out of 10,000, and spina bifida in 3.9 out of 10,000.⁹ Estimates of the total burden of NTDs must rely on indirect calculations because of underreporting of pregnancy terminations and fetal deaths. In U.S. studies, from 1988-2000, 30 to 80 percent of pregnancies complicated by spina bifida and anencephaly were terminated after early diagnosis.¹⁰ Using databases that included all prenatally diagnosed NTDs in 1999-2000 regardless of eventual pregnancy outcome, at least 3,000 pregnancies per year in the United States were estimated to be affected by NTDs.¹¹

NTDs result in a range of disabilities and death in affected children depending on location and severity of the defect(s). Anencephaly is incompatible with life. Children with encephaloceles have a 50 percent mortality rate, and the majority of survivors have developmental deficits.¹² Disabilities from spina bifida are based on the location of the lesion; the lower the lesion within the spine, the better the prognosis. Common disabilities for survivors of NTDs are paralysis, urinary and fecal incontinence, and ventriculomegaly with placement of ventricular-peritoneal shunts.^13–15 Some cases of myelomeningocele can be repaired prenatally via fetal surgery to close the NTD during the second trimester of pregnancy, and this appears to improve infant outcomes during the first year of life.¹⁶ The CDC estimated that the total lifetime cost of caring for an infant born with spina bifida is $791,900 based on 2014 dollars.¹⁷ About 18 percent of infants diagnosed with spina bifida in Florida between 1998 and 2007 had more than three hospitalizations in their first year of life.¹⁸ Among children with spina bifida recruited between ages 8 and 15 years old in 2006 in the U.S. Midwest, significant impacts on physical and social quality of life were found, and these increased over time.¹⁹

Etiology

The neural plate appears at the fifth week of gestation (3 weeks after fertilization) and has completed formation and closure by the sixth week of gestation (28 days after fertilization).²⁰ Failures in this process are irreversible. Many biological functions are necessary for the neural tube to close properly.²¹ The etiology of NTDs is multifactorial and includes a variety of genetic predispositions and environmental factors. The genetic predispositions are likely polygenic in nature involving multiple gene-gene and gene-environmental interactions, many of which have yet to be identified.²¹

Although often used interchangeably, the term “folate” refers to the water-soluble B vitamin (B₉) that occurs in many chemical forms, including naturally in many foods, while “folic acid” is the term applied to the synthetic form of folate that is found in supplements and added to fortified foods.⁷ Most NTDs are likely caused by low concentrations of folate stored in the body, which may be due to inadequate dietary intake, poor intestinal absorption, medication use that antagonizes folic acid, and genetic factors that impair folate metabolism. These are called folate-sensitive NTDs and are preventable by consuming adequate amounts of folic acid daily. High levels of folic acid supplementation (4 mg) have been found to reduce the risk of recurrent NTDs by more than 70 percent, and even more modest levels of folic acid supplementation (0.4 mg) reduce the first occurrence of NTDs.²² The mechanism by which folate reduces the risk of NTDs is not well understood but is likely related to its role in nucleotide synthesis, which is especially important for the rapidly dividing cells in the embryonic neural tube.²³ Without an adequate supply of nucleotides to facilitate deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) replication, the development of neural folds could be impaired. Adequate maternal folate status is important in preventing NTDs, but folic acid supplementation may also prevent NTDs in some individuals with normal folate concentrations who may not metabolize folate in an optimal manner. Furthermore, suboptimal folate status may disproportionately increase the risk of NTDs in specific groups of individuals who have a genetic susceptibility.²⁰ For example, certain polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene (e.g., 677C>T) have been associated with lower folate concentrations and a higher risk of NTDs than in the absence of these polymorphisms.^24–26 MTHFR is involved in folate metabolism and the transfer of methyl groups used in the synthesis of nucleotides and other substrates including converting homocysteine to methionine. Folic acid supplementation may be particularly important for individuals with these types of genetic predispositions.²⁷ However, folic acid supplementation at 0.4 mg increases blood folate concentrations, reaching the optimal red blood cell (RBC) folate concentration threshold after 3 to 6 months of supplementation across all MTHFR genotypes.^{28, 29}

Risk Factors

In addition to insufficient maternal folate, other risk factors for NTDs include, but are not limited to, a history of previous pregnancy affected by NTDs or a history of NTDs in a first- or second-degree relative; poorly controlled pregestational diabetes³⁰ or risk for diabetes such as previous gestational diabetes;³¹ maternal obesity;³² malabsorption caused by bariatric procedures; use of folic acid antagonists such as methotrexate, carbamazepine, and valproic acid;³³ specific genetic syndromes (e.g., trisomy 13 and 18); maternal fever in the first trimester;³⁴ low dietary folate intake; and lack of folic acid supplementation.³⁵ For diabetes and obesity, these effects may be due in part to genetic differences in glucose homeostasis and the subsequent impact on finely tuned processes in the developing embryo.³⁶ Socioeconomic risk factors such as maternal education levels, lower income, and lower income of community of residence have been associated with NTDs in some but not all studies.^{37, 38} Socioeconomic factors may affect risk as a result of impacts on nutritional status, including supplementation patterns.³⁹

Risk of NTDs has been found to be higher in certain ethnic groups such as First Nation groups in Canada and Hispanic persons in California.^{40, 41} This finding may be related to a higher risk of genetic polymorphisms among these groups of persons but may also be due to differential folic acid intake. Folic acid fortification of U.S. grain products was found to result in consistent reductions in NTDs across racial and ethnic groups.^{42, 43}

Rationale for Intervention

NTDs are the second most common group of serious congenital anomalies in the United States, accounting for significant infant morbidity and mortality and costs to affected individuals, their families, and their communities. Many of these NTDS are caused by low folate concentrations in the body. Because NTDs occur very early in pregnancy, often before the pregnancy is even known, and usually results in limited or no chance of complete recovery, strategies that enhance folic acid uptake before pregnancy offer the best chance of prevention.

Intervention Strategies

Two approaches to enhancing folic acid update before pregnancy are available; one relies on folate fortification of the general food supply, and the other relies on individually directed folate supplementation. In keeping with the USPSTF’s focus on strategies for prevention that are feasible or relevant for primary care, the focus of this report is on individually directed folate supplementation. However, trends in food fortification provide important context.

In 1998, the U.S. Food and Drug Administration mandated the addition of folic acid to specific enriched cereal grain products. At that time, an immediate drop in the prevalence of NTDs was noted which has been maintained since that time.⁴² In 2016, the U.S. Food and Drug Administration began allowing corn masa flour to be voluntarily fortified with folic acid to address known disparities in folic acid intake and NTDs among Hispanic persons. Some experts predict that if there were mandated fortification of corn masa flour, an additional 40 NTDs per year would be prevented in the United States.⁴⁴ Continued surveillance and comparisons of RBC folate concentrations before and after voluntary fortification of masa may help shed light on the effects of masa fortification. One analysis comparing 1 year of data (2017 to 2018) with prior years (2011 to 2016) found no statistically significant differences in RBC folate concentration in Hispanic women of reproductive age but did find that RBC folate concentration increased significantly among lesser acculturated Hispanic women consuming enriched cereal grain products only.⁴⁵

Other potential strategies to prevent NTDs could include reduction of preconception obesity, better control of preconception diabetes, and avoidance of preconception folic acid antagonists. Questions persist regarding the optimal intake of folic acid given food supplementation, individualization of folic acid recommendations based on genetic variants, minimal effective dose, tolerable upper intake, and optimal ways to measure folate concentrations in the body.^{46, 47} Questions also persist about potential harms. One proposed potential harm of folic acid supplementation is masking of vitamin B12 deficiency because of a compensatory effect on macrocytic anemia. This compensatory effect has been theorized to lead to a delay in the diagnosis and treatment of vitamin B12 deficiency, thereby causing irreversible neurologic injury. However, a population study using U.S. National Health and Nutrition Examination Survey data measuring serum B12 levels before (1991–1994) and after (2001–2006) food fortification found a lower risk of laboratory-diagnosed B12 deficiency after fortification.⁴⁸ Some experts have been concerned about the potential association of folic acid supplementation during pregnancy and autism diagnosis in the resulting children and increase in maternal cancer risk.^{49, 50}