Definition

NTDs are abnormalities that can occur in the brain, spine, or spinal canal of a developing embryo and are present at birth.¹ During an embryo's development, specific cells form a neural tube that later becomes the spinal cord, the brain, and the nearby structures (e.g., spinal column) that protect them. The top of the neural tube becomes the brain and the remainder becomes the spinal cord. When the neural tube does not close completely, a hole in the spinal column is left or another type of defect develops.¹ NTDs cover numerous conditions, including spina bifida, encephalocele, and anencephaly. Spina bifida occurs when the neural tube in the cranial region or along the spine does not close by the 28th day of gestation.² Spina bifida can range from mild (no noticeable disability) to severe (limitations in physical movement and function, paralysis, and cognitive deficits). Anencephaly is a more severe NTD that results in the fetus having little to no brain matter; the fetus could also lack part of its skull.^3,4 All infants with anencephaly are stillborn or die soon after birth.¹ NTDs may be isolated, one of multiple congenital abnormalities, or a component of a syndrome that is caused by a single-gene disorder, chromosomal abnormality, or teratogenic exposure.⁵ Although exact proportions are difficult to estimate, studies suggest that a higher proportion of spina bifida and anencephaly cases can be classified as isolated compared with other forms of NTDs, such as encephalocele or iniencephaly.⁶

Prevalence and Burden of Illness

The Centers for Disease Control and Prevention estimate that the average annual prevalence of anencephaly and spina bifida was 6.5 cases per 10,000 live births for the period from 2009 to 2011.⁷ Estimates of total burden of illness require relying on indirect calculations because fetal deaths and elective terminations attributable to NTDs are underreported. The total number of annual cases from health systems without prenatal ascertainment of NTDs for this period is 2,203. Health systems with prenatal ascertainment yield a higher estimate of annual cases for the same period (2,604). The estimated average number of annual live births for the same period is 4,027,880. Anencephaly accounts for 43 percent of NTDs and is incompatible with life.⁷ Infants born with spina bifida can survive with treatment but can have a broad range and degree of disabilities depending on the severity of the defect. Disabilities from spina bifida are based on the level of the lesion and the consequent motor and sensory deficits that occur. Lower lesions are associated with a better prognosis. Paralysis, urinary and fecal incontinence, and ventriculomegaly with placement of a ventricular-peritoneal shunt are common complications.

Etiology and Natural History

The neural plate appears during the third week of fetal development and gives rise to the neural folds that fuse in the midline to form the neural tube. Therefore, defects can occur when one or both sites fail to meet and close. Neural tube closure is usually complete by the end of the 4th week after conception.⁸

The etiology of NTDs is believed to be due to a combination of genetic predisposition and environmental influences.⁹ The specific environmental influences are still under investigation. NTDs occur more frequently in certain families.⁸ Parents with one child with an NTD are at increased risk for having another child with a similar defect (2% to 5%).¹⁰ However, the majority of NTD cases occur in families with no prior history of NTDs.⁹ It may be that certain persons with a genetic predisposition have not yet been exposed to the environmental factors necessary to produce an abnormality in their offspring.¹¹ One of the key environmental influences is intake of folic acid. Low concentrations of folate may limit the number of methyl groups available for DNA replication and methylation. Evidence suggests that parents with a pregnancy complicated by an NTD are more likely to carry a variant in the gene (677C→T mutation) encoding the methylenetetrahydrofolate reductase (MTHFR) enzyme. MTHFR¹² is an enzyme that regulates folate and homocysteine levels. Persons who are homozygous for this gene mutation have lower concentrations of folate,¹³ which can decrease the conversion of homocysteine to methionine and may increase the risk of NTDs.¹² A meta-analysis drawn from Dutch and other international sources suggests that the prevalence of this gene mutation is 9.3 percent (95% confidence interval [CI], 8.1 to 10.4).¹² Estimates for subpopulations in the United States range from 1.2 percent for blacks to 20.7 percent for Hispanics in California, indicating a high degree of variation based on subpopulation.¹⁴ Folic acid may help mitigate the effects of this gene mutation, thereby promoting methionine utilization.¹⁵

Risk Factors

Nonmodifiable risk factors for NTDs include race/ethnicity, female sex of the neonate, and family history of NTDs in a first- or second-degree relative.^9,16 Evidence indicates that certain racial/ethnic groups appear to be at higher risk for NTDs. Both before and after food fortification laws, birth prevalence rates were highest among Hispanics, followed by non-Hispanic whites and non-Hispanic blacks.^17,18 The prevalence of genetic mutations in certain enzymes may differ among these population groups.^19,20 Whether differences between racial/ethnic groups are attributable to genetic or environmental traits is unknown.²¹ Folic acid intake from diet is known to vary by race/ethnicity. For example, Hispanics may be at increased risk for having a baby with NTDs, likely because of lower levels of folic acid in their foods, such as unfortified corn masa products, rather than fortified cereals and pasta.^22-24

Racial/ethnic differences persist through childhood. In a study of the prevalence of spina bifida among children and adolescents in 10 regions of the United States, the estimated prevalence in 2002 was 3.1 cases per 10,000 (95% CI, 3.0 to 3.3) among non-Hispanic white children and adolescents, 1.9 (95% CI, 1.7 to 2.2) among non-Hispanic black children and adolescents, 3.6 (95% CI, 3.4 to 3.8) among Hispanic children and adolescents, and 1.8 (95% CI, 1.5 to 2.2) among all other children and adolescents.¹⁶ Possible reasons for these differences include differential birth prevalence and survival probability.

Among other risk factors, high maternal body mass index (BMI) is an independent risk factor for lower serum folate²⁵ and NTDs.²⁶ Because as many as 56 percent of women in the United States ages 20 to 39 years are overweight or obese, this risk factor is widely relevant to primary care practice.²⁷ Undiagnosed and pregestational (type 1 or 2) diabetes are also risk factors for NTDs.^28,29 In addition, women with epilepsy who take certain antiepileptic medications, such as valproic acid or carbamazepine, are at increased risk of spina bifida (1% to 2% and 0.5%, respectively).³⁰ Another medication associated with NTDs is warfarin.³¹ Malabsorption of micronutrients, including dietary folate (e.g., due to bariatric surgery),³² or maternal heat exposure (e.g., from a sauna, hot tub, fever, or electric blanket)³³ also elevate the risk of NTDs.

A study of the proportion of NTDs attributable to known risk factors, modifiable or otherwise, found that the factors responsible for the greatest proportion of cases included maternal Hispanic ethnicity, obesity, low dietary folate intake, female sex of the neonate, and lack of folic acid supplementation.⁹

Rationale for Intervention

NTDs are among the most common congenital major anomalies in the United States.³⁴ NTDs occur very early in pregnancy, with no or only limited chance for complete recovery. Prevention is the only medical solution. Periconceptional folic acid supplementation is a primary prevention intervention that can be implemented in primary care settings.

Although often used interchangeably, the term “folate” refers to the water-soluble B vitamin (B₉) that occurs in many chemical forms, including naturally in foods, while “folic acid” is the term applied to the synthetic form of folate that is found in supplements and added to fortified foods.³⁵ Folic acid supplementation is usually provided as a single vitamin or part of a multivitamin.

Intervention Strategies

The main approaches in the United States to achieving adequate folate concentrations in women who are capable of becoming pregnant are ensuring a healthy diet that includes foods fortified with folic acid, providing folic acid supplements, and providing a combination of supplements and a folic acid–rich diet.³⁶ Although other risk factors for NTDs exist, such as diabetes, obesity, and family history, prevention measures have focused primarily on promoting folic acid consumption through diet and supplements.

In 1998, the U.S. Food and Drug Administration required the addition of folic acid to all enriched cereal grain products sold in the United States.³⁷ The rate of NTDs has dropped since food fortification laws were implemented.^7,18,38,39

Dietary Measures and Biomarkers of Folic Acid Intake

Several measures are used to assess the adequacy of dietary folic acid consumption: recommended daily allowance (RDA), dietary folic equivalent (DFE), and estimated average requirement (Table 1).

Table 1

Measures and Definitions.

Another approach is to use red blood cell (RBC) or serum folate concentration as a biomarker for folic consumption. Plasma or serum concentration of folate reflects transient levels of folate found in circulation. RBC concentration is thought to be a more accurate measure because it reflects body stores of folate. There is no stated threshold value for plasma or serum concentration to determine deficiency as it relates to the risk of NTD. The World Health Organization recommends an RBC folate concentration greater than 400 ng/mL (906 nmol/L) in women of reproductive age to achieve the greatest reduction of NTDs.⁴⁰ Although folate concentrations have traditionally been assessed using microbiological and protein-binding assays, newer assays are being developed but are not yet standardized.⁴¹ Consequently, current assays do not produce comparable results and may lead to inaccurate assessments of folate status. Folate status reflects both dietary intake and absorption. The question of how much natural food folate or folic acid intake is necessary to achieve adequate RBC folate concentration has not yet been resolved.^40,42

Sources of Folate and Folic Acid

Women can consume folate by eating foods rich in folate, such as dark green leafy vegetables, oranges, orange juice, and legumes. Women can consume folic acid, the synthetic derivative of folate, by eating food fortified with folic acid, such as cereals, grains, and pasta products, or by taking a dietary supplement or multivitamin containing folic acid of varying doses. Manufacturers are mandated in the United States to fortify cereal grain products (e.g., grains and pastas) that are labeled as “enriched”—a mandatory addition of folic acid at 0.14 mg per 100 g of grain product.⁴³ Other cereals and related products such as ready-to-eat cereals may be voluntarily fortified, but their folic acid content can change because the level is not mandated.

Naturally occurring food folate is 1.7 times less bioavailable than folic acid.³⁵ Since the 1998 U.S. Food and Drug Administration requirement to fortify enriched cereal grain products, the national incidence of babies born with NTDs has decreased.^7,18,38,39 However, it remains challenging for most women to consume the recommended daily intake of 0.4 mg of folic acid from diet alone. In the United States, women age 19 years or older have a median daily intake of 0.117 mg of folic acid per day from mandatorily fortified food.⁴⁴ Data from the 2007 to 2012 National Health and Nutrition Examination Survey (NHANES) suggest that 48.4 percent of U.S. women of childbearing age (95% CI, 46.3 to 50.6) reported consuming folic acid from mandatorily fortified foods only.⁴⁵ In another study of pregnant women in North Carolina (n=2,247), only 60 percent met folic acid recommendations from diet alone.⁴⁶ Additionally, populations that do not consume mandatorily fortified foods (e.g., those on gluten-free or Atkins diets) are not protected by mandatory food fortification.

Folic acid intake from diet varies by race/ethnicity. Some investigators reported on decreased dietary folic acid intake among Mexican American women, who may be at increased risk because of lower levels of consumption of fortified foods, such as cereals and pastas, as a result of their corn masa–based diets.^22-24 Dietary supplements, including multivitamins, contain large amounts of folic acid, and U.S. adults commonly use supplements.⁴⁷ Supplements containing folic acid in the United States generally contain 400 to 800 μg of folic acid. However, doses up to 1,000 μg are permitted without a prescription.

More than 28 percent of 2007 to 2012 NHANES participants reported using a dietary supplement containing folic acid (>71% not taking folic acid daily).⁴⁵ Of those who took a supplement containing folic acid, about half (14.6 % of all women) took one that contained less than the daily recommended dose of 400 μg.⁴⁵ The Pregnancy Risk Assessment Monitoring System (PRAMS) data for 2009 report that only 30 percent of women reported taking a multivitamin, prenatal vitamin, or folic acid supplement daily 1 month before conception (70% were not taking folic acid daily).⁴⁸

Blood folate data from NHANES have documented improvements in the folate status of the U.S. population after food fortification was implemented.⁴⁹ The prevalence of low serum folate (<10 nmol/L) among U.S. women of childbearing age (ages 15 to 44 years) declined from 32.2 percent in the prefortification period (1988 to 1994) to 5.5 percent in the postfortification period (1999 to 2010). These changes have been accompanied by a decline in the prevalence of NTDs from 10.7 cases per 10,000 live births before fortification (1995 to 1996) to 7.0 cases after fortification (1999 to 2011).⁷ Other countries such as Canada, South Africa, Costa Rica, Chile, Argentina, and Brazil have also reported reductions in the rate of NTDs following the introduction of food fortification.⁵⁰

Consumption of Folate and RBC Folate Concentration

A systematic review and Bayesian meta-analysis explored the extent to which consumption of natural folate translates to an increase in RBC and serum folate concentrations. The review excluded studies in settings with folic acid consumption through supplements or fortification that did not include an adequate washout period.⁵¹ Six studies of nonpregnant, nonlactating females ages 12 to 49 years with RBC concentrations assessed with microbiological assay contributed to the analysis. The authors found that a 10 percent increase in natural food folate intake can increase RBC folate concentration by approximately 6 percent (95% credible interval [CrI], 4 to 9). Using the model, the authors estimated that in a population with a mean natural food folate intake of 450 μg DFE/day, the mean RBC folate concentration would be approximately 1,070 nmol/L (95% CrI, 770 to 1,440). For every 10 percent increase in natural food folate intake, the authors reported that serum/plasma folate concentration could increase by approximately 7 percent (95% CrI, 1 to 12).

RBC Folate Concentration and NTDs

Findings from two large epidemiological studies support RBC folate concentration as a key prevention strategy for NTDs. Daly and colleagues reassessed the findings of a large case-control study of pregnant women in Ireland presenting for antenatal care in three clinics in Dublin between 1986 and 1990.⁵² The investigators analyzed blood samples from 86 cases and 266 controls (normal live births) in a 1:3 ratio for RBC and plasma folate concentrations. Cases and controls were not matched for maternal or gestational age, but both characteristics were similar between the two groups. Median gestational age at the time the samples were collected was 15 weeks. Using an overall NTD rate of 1.9 cases/1,000 births, Daly estimated the risk of NTDs with RBC and plasma folate levels as continuous variables and at different threshold levels. After adjustment for maternal covariates in logistic regression models, dose-response effects were determined for both plasma and RBC folate levels. In assessing RBC folate levels, an eight-fold difference in the risk of NTDs was found among women with RBC concentrations less than 340 nmol/L (150 ng/mL) compared with those with levels of 906 nmol/L (400 ng/mL) or higher (p<0.001). Notably, the study was conducted in a relatively homogeneous population in Ireland. Blood specimens were obtained at a median of 15 gestational weeks, which is well beyond the time of neural tube closure. Thus, the dose-response effects as summarized may not fully reflect the periconceptional relationship between RBC folate concentration and the risk of NTDs.

In an effort to determine the optional RBC folate concentration to reduce NTDs, Crider and associates⁴² reviewed data from two population-based Chinese cohorts prior to food fortification programs: more than 240,000 participants (1993 to 1995) in a community-based study of folate supplementation⁵³ (400 μg/day) and 1,194 participants (2003 to 2005) in the population-based Folic Acid Dosing Trial.^54,55 Nonpregnant women without plans to conceive (intrauterine device in place) were randomized to one of four dosage regimens: 100 μg/day, 400 μg/day, 4,000 μg/day, or 4,000 μg/week. Measurement of RBC folate concentration and MTHFR genotyping were performed at baseline and at 1, 3, and 6 months after supplementation. Crider and colleagues initially analyzed data from the Folic Acid Dosing Trial to assess the association between the length of time that women consumed folic acid supplementation and RBC folate concentration, adjusted for the presence of the MTHFR genotype. Findings from this initial model were then used to estimate RBC folate concentrations in the community-based cohort based on participants' report of daily folate supplementation (i.e., pill consumption) to determine the association between RBC folate concentration, folate supplementation, and risk of NTDs. Subsequently, the model was applied to U.S. women using published estimates from NHANES. Estimates of the association between RBC folate concentration and risk of NTDs were consistent with those published in the earlier work by Daly et al. A substantially lower risk of NTDs was seen with RBC concentrations of 1,180 nmol/L (95% uncertainty interval, 1,050 to 1,340 nmol/L). Also, similar to Daly, RBC folate concentration near 1,200 nmol/L was associated with a substantial reduction in NTDs (5.8/10,000 live births). The relative consistency with the earlier estimates by Daly support the potential use of RBC folate concentration in assessing the risk of NTDs and could inform future health policies.

Folic Acid Consumption and Pregnancy Intention

Planning or intention to have a baby influences folic acid consumption. Women who plan to get pregnant are more likely to take folic acid prior to becoming pregnant.^56-59 However, half of all pregnancies in the United States are unplanned,^60,61 which presents a challenge in terms of promoting folic acid consumption for women who are not planning to but may become pregnant. Interventions to increase use in this group require messaging to encourage women to take folic acid “just in case” they get pregnant. Alternatively, public health campaigns can promote folic acid use as a method of maintaining good health overall, but these campaigns do not appear to have lowered the prevalence of NTDs.²¹ Few studies have assessed which messaging approach is more effective for women who are not intending to but could become pregnant.^62-65 However, formative studies^64,65 suggest targeting messages for planners (women who are planning to become pregnant in the next 2 years) and nonplanners (women who do not plan to become pregnant in the next 2 years). For the latter, messages should be focused on promoting a woman's overall health and well-being and how to have a healthy lifestyle (e.g., taking a multivitamin).

Promoting Folic Acid Consumption

Public health campaigns have been effective in increasing awareness, knowledge, and use of folic acid.⁶⁶ Although knowledge about the benefits and sources of folic acid increased postcampaign, campaigns have had less effect on women's understanding of the correct timing for taking folic acid supplements.⁶⁶ In addition to increasing public folic acid awareness through campaigns, women are increasingly learning about folic acid in the clinical setting. From 1995 to 2008, the proportion of women who reported learning about folic acid from their health care providers increased from 13 to 33 percent, according to U.S. national surveys conducted by the March of Dimes.⁶⁷ Of women surveyed in 2008, 32 percent reported that their health provider discussed the benefits of folic acid.⁶⁷ However, only 12 percent of women reported that their health care provider advised them that folic acid needs to be taken before pregnancy.⁶⁷ Although preconception guidelines from the American College of Obstetricians and Gynecologists exist,⁶⁸ preconception care has yet to become standard practice among health care providers. Providers need to promote and initiate the idea of preconceptional health to help ensure women are as healthy as they can be before they become pregnant.⁶⁹