Maternal Folate Intake during Pregnancy and Childhood Asthma

Folate, a type of water-soluble vitamin B and a cofactor (as tetrahydrofolates) in the transfer of one-carbon moieties, has a key role in amino acid metabolism, purine and pyrimidine synthesis, and formation of S-adenosylmethionine (1). Folic acid is a synthetic form of folate used in nutritional supplements and food fortification, whereas folate is a generic term referring to all derivatives of folic acid.

Folate deficiency during conception and pregnancy is associated with neonatal neural tube defects (NTDs), such as anencephaly and spina bifida. In 1992, the U.S. Public Health Service recommended that all women of reproductive age consume 400 μg of folic acid per day to prevent NTDs (2). In the United States, mandatory fortification of enriched cereal grain products with folic acid was authorized by the Food and Drug Administration in 1996 and was fully implemented in 1998. The prevalence of NTDs has been significantly reduced in the United States and in other countries adopting folic acid food fortification programs (3).

DNA methylation is catalyzed by enzymes that transfer methyl groups (methyl-transferases) from the methyl agent S-adenosylmethionine to cytosine. In humans, methyl donors for DNA methylation are mostly derived from dietary methyl donors such as folate (4). Because DNA methylation may affect immune responses and asthma pathogenesis, there has been understandable interest in examining a potential link between prenatal folate status and childhood asthma in epidemiologic studies. Such interest was further increased in 2008, when it was reported that gestational dietary supplementation with methyl donors (at doses that would be equivalent to high to very high in humans) led to allergic airway disease (AAD) in mice (5).

In industrialized countries, the “asthma epidemic” preceded folic acid food fortification programs or widespread use of prenatal folic acid. Consistent with this ecologic observation and on the basis of a critical review of findings from epidemiologic studies published until 2013, we (6) and others (7) found no evidence of moderate or strong effects of prenatal folate status on asthma inception. However, we acknowledged that there were insufficient data to exclude weak or modest effects of prenatal folate on the development of childhood asthma (6).

In a study published in this issue of the Journal (pp. 221–228), Parr and colleagues aimed to prospectively examine the relation between maternal total folate intake (dietary and supplemental) during pregnancy and childhood asthma at age 7 years in a large Norwegian population-based cohort (8). In a previous case-control study nested within the same cohort, there was a significant linear (e.g., dose–response) association between maternal plasma folate in the second trimester of pregnancy and asthma at age 3 years among 1,962 participating children (9). In the current study, the same investigative group found that children born to mothers with the highest total folate intake from diet and supplements at a gestational age of ∼22 weeks (fifth quintile [≥578 μg/d]) had a 23% higher risk of asthma (defined either by use of asthma medications or by maternal report of a physician’s diagnosis) at age 7 years than those born to mothers with the lowest total folate intake (first quintile [≤146 μg/d]) at the same gestational age (95% confidence interval for relative risk, 1.06–1.44). Unlike their prior findings at age 3 years, there was no dose–response relationship, and thus the authors postulate a threshold effect for prenatal folate on asthma at school age. Of note, however, they report no significant association between total folate intake and maternal report of eczema or allergy symptoms. Moreover, there was no significant association between maternal plasma folate levels and childhood asthma in a subset of 2,681 participants (including 127 subjects with asthma). Although the authors state that their negative findings for plasma folate are explained by limited statistical power, there was no trend for a positive association similar to that reported for total maternal folate intake (relative risk for highest quartile vs. lowest quartile of plasma folate, 0.97; 95% confidence interval, 0.54–1.76; P = 0.99).

The modest association between maternal total folate intake at midpregnancy and childhood asthma observed in this study is somewhat consistent with findings from two recent retrospective studies. In a retrospective cohort study of mother–child dyads in Tennessee, a folic acid prescription in the first trimester only or in the first trimester and beyond was associated with a 20% increased risk of asthma (defined by healthcare use or use of medications for asthma) in children aged 4.5 to 6 years (10). In another database-driven study, use of a high dose of folic acid (5 mg) during pregnancy was associated with a 34% increased risk of any use of asthma medications in children aged 8 years and older (11). Of note, total estimate of maternal intake of folate or plasma folate was not available in either of those two previous studies.

The study conducted by Parr and colleagues has several strengths, including large sample size (including 1,901 children with asthma) and a reasonably accurate estimate of total folate intake from both diet and supplements (given no folic acid fortification program in Norway) (8). However, findings from this study must be cautiously interpreted because of inability to exclude confounding by healthcare use or other unmeasured variables, misclassification of asthma and (particularly) atopy, negative findings for total folate intake and atopy or plasma folate and asthma, and nongeneralizability to either underserved populations in developed nations or residents of developing countries (who may have limited dietary intake of folate). Such cautious interpretation is further warranted by the recent retraction of the article reporting an association between high gestational intake of methyl donors and AAD (“experimental asthma”) in mice, due to nonreplication of the original findings for airway responsiveness (12). To date, no murine study has specifically examined folate supplementation during pregnancy and AAD.

In spite of all the limitations outlined above, the study by Parr and colleagues raises the question of whether prenatal total intake of folate exceeding current recommendations (400 μg/d) slightly increases the risk of childhood asthma (8). Until this question is further examined in longitudinal studies that account for bias by healthcare use and other confounders, include measures of plasma or (preferably) red blood cell folate, and assess objective measures of asthma and atopy (e.g., lung function and allergy skin testing), there is no rationale for changing existing recommendations for total folate intake or altering folic acid fortification programs, both of which have been proven to prevent NTDs.