Maternal Folate Supplementation Culprit in Childhood Asthma?

Dr. Harriott's Comment:

If you know someone who is pregnant, please share this information with them. Typically, folate supplementation has been recommended as part of prenatal vitamins for years to prevent congenital developmental spinal disorders, such as spina bifida. OB's will likely continue to recommend supplementation. However, with a 66% increase in asthma risk, this is a conversation an expectant mother wants to have with her OB regarding supplementation levels and timing. Apparently, the recommendations are still a work in progress.

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AAAAI: Folate-Asthma Link Depends on Timing

By Crystal Phend, Senior Staff Writer, MedPage Today
Published: March 03, 2010
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

NEW ORLEANS -- High folate levels in utero may increase a child's future asthma risk, while those in the child's early years make little difference, according to two studies reported here.

In a Norwegian cohort, second trimester maternal folate levels over 17.84 nmol/L -- a level that might be expected with supplementation -- were associated with 66% elevated risk of the child having asthma at age 3 years (95% CI 16% to 237%).

This appeared to be a dose-dependent relationship (P<0.01), said Siri E. Haberg, MD, PhD, of the Norwegian Institute of Public Health in Oslo, who presented the results at the American Academy of Allergy, Asthma & Immunology meeting.Action Points
Explain to interested patients that high folate levels in utero may increase a child's future asthma risk, while those in the child's early years make little difference, according to two studies reported here.


Note that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
In an American cohort, children's own folate levels at age 4 held little correlation with development of asthma by age 6, according to a second group led by Adesua Y. Okupa, MD, of the University of Wisconsin at Madison.

Timing may be important, Haberg noted.

Any mild deleterious effects on asthma risk from folate use wouldn't outweigh the benefit of preventing life-threatening congenital defects, said Haberg's co-author Stephanie J. London, MD, DrPH, of the U.S. National Institute of Environmental Sciences in Research Triangle Park, N.C.

Women of childbearing age should not stop taking folic acid supplements -- recommended to prevent neural tube defects -- based on these observational results, agreed Stanley J. Szefler, MD, of National Jewish Health in Denver, who was not involved in either study.

But the findings seem to fit with emerging evidence in animal studies that more is not always better, he said.

"Giving too much folate can also have effects on DNA methylation, which may trigger off genes to work maybe the way you don't want them to," Szefler told MedPage Today.

There may be an optimal level of folate to maximize neurological and congenital development of an infant, but minimize harmful epigenetic effects, he said.

Until studies determine what that is, women should take the amount deemed necessary but avoid taking excessive amounts, Szefler recommended.

Haberg's group analyzed outcomes for 507 children with athsma and 1,455 without it at age 3, all of whose mothers had provided blood samples at around 18 weeks' gestation as part of the larger, population-based Norwegian Mother and Child Study.

Norway is a good place to look for folate effects because it does not fortify the food supply with folic acid and thus has a greater range of levels among the population, London noted.

Overall, women in the highest folate quintile had the significant 66% elevated risk of their child having asthma as a toddler, after adjustment for maternal atopy, smoking, and other confounders.

Those in the intermediate quintiles conferred 16% to 48% higher adjusted risk to their child as well compared with the lowest 5.54-nmol/L and under group, although only significant for the third quintile with folate levels of 7.68 to 10.60 nmol/L.

In a sensitivity analysis of 422 women not on folic acid supplements at the time of their second trimester blood test, the adjusted risk of asthma in the child rose again with folate exposure in utero (P=0.011). The adjusted odds were significant for women over the 70th percentile (odds ratio 1.34 at 7.297 to 15.835 nmol/L) and those over the 95th percentile (OR 1.44 for above 15.835 nmol/L).

Okupa's study was an analysis of the prospective Childhood Origins of Asthma study of a high-risk birth cohort.

Among 220 kids with folate measured at age 4, 30% developed asthma and 49% were positive for allergic sensitization by age 6 years.

Allergies appeared to be more common in children with higher folate levels (P=0.01), whereas asthma showed no such association (P=0.81). Adjustment for socioeconomic status and other confounders didn't impact these results.

"It is possible that there is a critical period where folic acid supplement dosages may be manipulated to maximize neuroprotective effects yet minimize the adverse respiratory effects," Okupa said at the session where she presented the results.

Haberg's group cautioned that, despite adjustment for important variables, confounding remained a possible explanation for the modest effects seen in their study. The study was also limited by follow-up only to 3 years at this point, which may not be old enough to establish a diagnosis of asthma, Haberg said in an interview.

Szefler noted that folate levels fluctuate from day to day based on diet, so a single blood measurement may not have accurately conveyed exposure.

"It's very hard to make those comparisons," he said in an interview. "Right now there's not a standard level that you should have."

Okupa's study was funded by the National Institutes of Health and the National Institute of Allergy and Infectious Diseases.

Okupa reported no conflicts of interest.

London's study was supported by the Norwegian Research Council. The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health Division of Intramural Research, NEIHS/NIH, NIH/NINDS, and the Norwegian Research Council/FUGE.

Szefler reported no relevant conflicts of interest.


Primary source: American Academy of Allergy, Asthma & Immunology
Source reference:
Haberg SE, et al "Maternal folate levels in pregnancy and asthma at 3 years of age" AAAAI 2010; Abstract 505.

Additional source: American Academy of Allergy, Asthma & Immunology
Source reference:
Okupa AY, et al "Relationships among folate, allergic sensitization, wheezing, and asthma" AAAAI 2010; Abstract 217.