Folate Deficiency and Neural Tube Defects in Pregnancy

US Pharm. 2021;46(9):HS-8-HS-12.

ABSTRACT: Folic acid is essential for women’s health and is especially important during pregnancy. Within the first 28 days of pregnancy, the neural tube, which is responsible for the development of the brain and spine, closes. Inadequate concentrations of folate can prevent closure of the neural tube, which can lead to a neural tube defect. To prevent folate deficiency, it is recommended that all women of childbearing age use a prenatal vitamin with at least 400 mcg of folic acid and eat foods that contain folate to maintain adequate concentrations. In 1998, the United States mandated fortification of grained cereals with folate and, as a result, there was a significant reduction in both folate deficiency and neural tube defects among women and their offspring. Despite this initiative, high-risk populations such as minority, obese, and diabetic women remain at an increased risk for folate deficiency.

Nutrition is an essential component of fetal growth and development during the periconceptional phase of pregnancy. Folate supplementation plays a vital role in the development of the neural tube during the first weeks of pregnancy.^1,2 The neural tube is responsible for developing the brain and spinal cord, and without proper closure, neural tissue is left exposed and damaged.^3,4 Neural tube defects occur as a result of tissue damage to the brain and spinal cord. The most common forms of neural tube defects are spina bifida and anencephaly. Folate deficiency increases the risk of neural tube defects, and inadequate concentrations of folate in a pregnant woman can therefore lead to the development of a fetus with congenital defects and malformations.

Folate deficiency is defined as a blood folate concentration <140 ng/mL, and the World Health Organization (WHO) has determined that folate concentrations >400 ng/mL are sufficient to prevent neural tube defects.^5-7 As a result, the U.S Preventive Services Task Force currently recommends that women of childbearing age take ³400 mcg daily of folic acid to prevent neural tube defects.⁸ In addition to folic acid, women are encouraged to eat foods that contain folate, such as green leafy vegetables, fruits, beans, meat, and cereals. Folate supplementation should be taken 1 month prior to and throughout pregnancy to prevent neural tube defects.⁸ Unfortunately, 30% of women of childbearing age still report not taking a prenatal supplement.⁹ Global and national initiatives have been implemented to combat folate deficiency.^10,11 However, despite universal initiatives, folate deficiency is still a concern for women of childbearing age.^12-15 Annually, there are 300,000 babies worldwide born with a neural tube defect, and approximately 3,000 births occur yearly within the United States.¹⁶  

Research has shown that folic acid supplementation could prevent 150,000 to 210,000 neural tube defects annually if women of childbearing age took folate supplementation.¹⁷ Unfortunately, gaps in health literacy, compliance, and health disparities pose a threat to eradicating folate deficiency within the U.S. This article will discuss the importance of folate supplementation, populations that are at an increased risk for folate deficiency, and the role of pharmacists in improving outcomes associated with folate deficiency.

Folate is an essential water-soluble B vitamin required for growth and development of the fetus during pregnancy. It serves as a cofactor during cell division, and when deficient, it can impair cellular growth and replication within a fetus or the placenta.¹⁸ More than 50% of pregnancies in the U.S. are unplanned, and most women do not discover pregnancy until 5 weeks post gestation.^19,20 This is of major concern, since only 34% of pregnant women acknowledge prenatal vitamin use before becoming pregnant, and neural tube defects develop within 28 days post gestation.²¹ Folic acid use before and during the first weeks of pregnancy has been shown to reduce the risk of neural tube defects, and therefore its use is essential in prevention of neural tube defects.^9,22,23

Folate can only be obtained through food sources or through supplements. In an effort to reduce folate deficiency among women of childbearing age, the FDA mandated fortification of all grained cereal products with folic acid in 1998.¹⁰ As a result of this mandate, blood folate concentrations were 149% higher in 2000 than they were prior to 1994, and the incidence of neural tube defects reduced by 35%.^2,24 Despite the drastic impact of this mandate on blood folate concentrations and neural tube defects, folate concentrations of Hispanic American women consistently remain deficient.²⁵ As a result, in 2016 the FDA recommended a voluntary fortification of corn masa flour with folic acid to improve outcomes among Hispanic American women. It was estimated that these efforts would increase daily folic acid consumption and prevent approximately 40 additional neural tube defects yearly among Hispanic American women.²⁵ However, according to the National Health and Nutrition Examination Study (NHANES), the beneficial effect of fortification has yet to significantly impact blood folate concentrations and neural tube defects among Hispanic American women and their offspring. Acculturation, lack of awareness, and access to healthcare are some of the reasons why folate concentrations remain low among Hispanic American women.²⁵

Optimal Supplementation

Major strides have been made in improving outcomes associated with folate deficiency. Despite initiatives and improved outcomes, 22.8% of U.S. women of childbearing age do not maintain blood folate concentrations that are sufficient to prevent neural tube defects.¹⁴ Under-supplementation may be the reason almost 25% of American women are folate deficient. Women who solely supplement with nutrition have been found to have deficient folate concentrations.¹⁵ Therefore, women should be encouraged to supplement folate with both nutrition and a vitamin that contains folic acid. This is a very small lifestyle modification that can make a profound impact on risk reduction of folate deficiency and neural tube defects.

Healthcare Disparities

Healthcare disparities within the minority community are directly proportional to the outcomes observed in babies born of minority mothers. Hispanic mothers are more likely to birth a baby with a neural tube defect than non-Hispanic white and black mothers.^2,25 Williams et al evaluated the incidence of spina bifida within women of childbearing age and reported an incidence of 4.18 per 10,000 births among Hispanic mothers versus 3.37 and 2.90 per 10,000 births among non-Hispanic white and black mothers, respectively.²⁴

Hispanic and black American women are also more likely to have folate deficiency when compared with non-Hispanic white American women. The Boston Birth Cohort conducted a study to assess folic acid supplementation and folate concentrations in more than 7,000 low-income, urban mothers and found that fewer than 5% of the women had used folic acid supplementation prior to their pregnancy.¹³ Study participants were mostly black American (50%) and Hispanic American (27%) women, and only 58% of study participants used prenatal vitamins throughout each trimester. It was also found that even after conception, black and Hispanic women had lower blood folate concentrations (28.2 nmol/L, 30.4 nmol/L, and 34.2 nmol/L) and folate deficiency (12.2%, 8.1%, and 5.1%) when compared with white women. Despite mandates, this population of women struggles with obtaining sufficient folate supplementation. Research has shown that women must supplement with folic acid and folate-rich foods to maintain adequate concentrations of folate.¹⁵ Therefore, in the absence of increased awareness of concomitant supplementation, folate concentrations may remain deficient among minority women. Unfortunately, awareness is just one of many barriers that have a negative impact on minority women.

According to a 2017 March of Dimes survey, 53% and 34% of Hispanic and black American women, respectively, reported that access and healthcare cost had a direct impact on prenatal care.²¹ This may play a major role in minority women not obtaining resources needed to prevent folate deficiency. In addition to cost and access, forgetfulness, adverse effects, and the overall perception of prenatal supplements have been cited as reasons some minority women may not take prenatal supplements.²⁶ There is a consistent trend in nonpregnant minority women of childbearing age who are not taking or are not taking sufficient amounts of folate supplementation to prevent neural tube defects. This is a key population to target for tailored initiatives to bring awareness to the severity of folate deficiency and the preventable consequence of neural tube defects.

In addition to race, socioeconomic status, marital status, and level of education also have a direct correlation on the risk of folate deficiency and a neural tube defect. Caucasian women, married women, and women with higher incomes are more likely to have better outcomes with neural tube defects and with taking folate supplementation.⁹ The advice of a healthcare provider is impactful; during the 1999–2004 NHANES study, 47.4% of women stated that they took a supplement based on a healthcare provider’s recommendation when compared with 16.1% of pregnant women who took it based on their own decision.²⁵ Pharmacists can play a pivotal role in combating folate deficiency by identifying women who are at most risk for folate deficiency and providing direct education on the importance of folate supplementation and proper use of folate supplements.

Obesity

Obesity is a common risk factor among many disease states, and it is an important risk factor for folate deficiency. The risk of neural tube defects is increased by twofold in women who are obese.²⁷ Unlike minority women, obese women are at an increased risk of folate deficiency due to inadequate absorption of folate, which is a water-soluble vitamin, rather than a lack of supplementation. Studies have shown that most obese women consume folate supplementation; however, their blood folate concentrations remain deficient.²⁸ Despite adequate supplementation, obese women remain at an increased risk for folate deficiency and birthing a child with a neural tube defect. Obese women are five to 10 times more likely to birth a baby with spina bifida and are six times more likely to have serum folate concentrations <14.9 nmol/L.^29,30 Fortunately, weight loss may be key to reducing folate deficiency among obese women. Without a change in their folate intake, weight loss has been shown to increase folate levels in obese women.³⁰ Therefore, women of childbearing age should be encouraged to lose weight and to maintain adequate folate supplementation to reduce their risk of folate deficiency during pregnancy.

Diabetes

Diabetic women are at a twofold to fourfold increased risk for birthing a baby with a birth defect.³¹ Excess glucose has been shown to decrease the expression of Pax3, a gene required for neural tube closure, and to increase the risk of neural tube defects.³² Women with preexisting diabetes who do not take a prenatal vitamin containing folic acid are at high risk for birth defects. The American Diabetes Association recommends 400 mcg of folic acid daily in nonpregnant women with pre-existing diabetes and 600 mcg daily for women who are pregnant or who plan to become pregnant.³³ Women with diabetes should be on optimized glucose-lowering therapy to manage hyperglycemia and should follow a low-carb diet that contains folate-rich foods to reduce risk of neural tube defects.

Nondiabetic women may be at an increased risk for gestational diabetes if too much folate is consumed.³⁴ The number of women who are consuming too much folate is just as prevalent as the number of women who are not taking prenatal vitamins before pregnancy. The Boston Birth Cohort data reported that 23% of the women enrolled had an elevated serum-folate concentration.¹³ Therefore, a healthy median should be maintained among nondiabetic women to ensure that folate is consumed in the right amount to reduce their risk of gestational diabetes.

Antiepileptics

Women who take valproic acid and carbamazepine are at an increased risk for birthing a baby with a neural tube defect. The use of antiepileptic medications increases the risk of a neural tube defect by two-fold.³⁵ Other antiepileptics are less likely to cause neural tube defects, and as a result, women taking valproic acid or carbamazepine should be changed to an alternative agent if they plan to or become pregnant. If an alternative agent is not an option, women on valproic acid and/or carbamazepine should take 4 mg of folic acid daily before and during pregnancy to reduce their risk of neural tube defects.³⁶

Role of the Pharmacist

Pharmacists currently provide an array of preventative services (e.g., lipid screening, glucose screening, heart failure monitoring) to improve outcomes among patients at an increased risk for many chronic diseases.^37-39 Pharmacist-directed educational initiatives have had a positive impact on increasing awareness of folate deficiency among women of childbearing age.^40,41 Murphy et al completed a study in college women to determine whether educating on the importance of folic acid would cause a change in behavior to increase use of folic acid at 1 month and 12 months following a 30-minute education session.^40,41 They found a statistically significant increase in awareness of the importance of folate supplementation and in the use of folic-acid supplementation at 1 month; however, by the 12th month, most of the women were found to have discontinued use of folic acid.

Campaigns that consistently motivate women to be compliant with taking folate supplementation, engage women to remain vigilant with use of supplementation, and promote awareness of folate deficiency and its subsequent birth defects are key to further reducing folate deficiency. Pharmacists possess the clinical knowledge required to provide counseling opportunities for women at an increased risk for folate deficiency; however, fewer than 25% of pharmacists actually counsel patients on folate supplementation.⁴² Recommendations provided during a pharmacist-patient counseling session could make a profound impact on patients since most women take a prenatal vitamin after a healthcare professional’s recommendation.^21,25 Patients are also twice as likely to visit their pharmacist than their primary-care provider.⁴³ Recurrent interactions and trust between pharmacists and patients open the door to endless opportunities for engagement, motivation, and education to foster awareness in at-risk populations.

Pharmacists are readily visible and accessible to provide education and counseling opportunities to patients. Outreach opportunities that target minority and college communities may be both educational and influential to women of childbearing age. Pharmacists can provide educational brochures, host informational sessions, disseminate surveys to assess and promote awareness, and identify high-risk women during prescription verification for counseling. By seeking optimal opportunities to identify and counsel patients who are at an increased risk for folate deficiency, pharmacists can continue to improve outcomes to reduce folate deficiency and neural tube defects.

Conclusion

Folate deficiency is a preventable condition with detrimental consequences. The fortification of foods has drastically reduced folate deficiency and the incidence of neural tube defects since 1998. Unfortunately, only 34% of women actually take a prenatal vitamin before pregnancy, and minority, obese, and diabetic women are at an increased risk of developing folate deficiency and birthing a baby with a neural tube defect despite fortification of foods.^9,21 Physiology, access to healthcare, financial burden, social barriers, and/or lack of awareness may all play a role in the lack of improved outcomes among these target populations. To reduce neural tube defects, consistent attention should be brought to the importance of folate supplementation before pregnancy and assurance of proper folate supplementation to maintain adequate blood concentrations. Pharmacists are readily accessible, trusted, and knowledgeable to provide opportunities that profoundly impact outcomes. Initiatives tailored to high-risk populations can further reduce risk of folate deficiency and neural tube defects.

The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.

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