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From Medscape Medical News
High Plasma Folate Levels in Pregnancy May Increase Asthma Risk for Offspring
March 4, 2010 (New Orleans, Louisiana) — Children of mothers with high plasma folate levels during pregnancy appear to have an increased risk of developing asthma by the age of 3 years, according to a sampling from the Norwegian Mother and Child Cohort (NMCC) study presented in a poster session here at the American Academy of Allergy, Asthma and Immunology 2010 Annual Meeting.
"Norway provides a unique opportunity to address the question of possible deleterious consequences of high folate intake during pregnancy because the food supply there is not fortified with folates," said investigational team member Stephanie London, MD, DrPH, from the Epidemiology Branch and Laboratory of Respiratory Biology at the National Institute of Environmental Health Sciences in Durham, North Carolina.
"It's one of the few places where you can look at whether the supplementation, which is clearly good from the point of view of decreasing birth defects, could potentially also have some adverse effects," she added.
Recent Studies Question Folic Effects
Previous research has consistently shown that the periconceptional intake of folic acid reduces the risk for neural tube defects in infants, leading to the increased use of these supplements and to the fortification of foods with folic acid in the United States and other countries.
However, a recent study showed that high dietary supplementation with folic acid and other methyl donors in pregnant mice led to allergic asthma phenotypes, through epigenetic changes, in offspring.
In another study recently conducted by Dr. London's research team, an association was found between folate supplements used during early pregnancy and an increased risk for respiratory disease in children up to the age of 18 months.
For this study, they examined data on 507 mothers from the population-based NMCC who had plasma folate levels measured during their second trimester of pregnancy, and who had children with asthma at the age of 3 years. The folate levels of 1455 mothers of healthy controls were also measured. All children were born between July 1, 2002 and June 30, 2004.
"The age of 3 isn't a perfect phenotype because that's early to diagnose asthma, but that was the age that the kids were at the time of the study," explained Dr. London.
A Linear Increase Found
Results showed that mothers in the top quintile of plasma folate had children with an increased risk for asthma at age 3 (adjusted odds ratio [OR], 1.66; 95% confidence interval [CI], 1.16 - 2.37), relative to mothers in the bottom quintile.
In addition, the investigators found "a trend of linear increase across quintiles" (P = 0.007). Children of mothers with folate levels between the 70th and 95th percentiles had an OR of 1.34 (95% CI, 1.03 - 1.73), whereas children of mothers with levels above the 95th percentile had an OR of 1.44 (95% CI, 1.08-1.93).
"In other words, as the mother's folate level increased, so did the risk of asthma in their child," said Dr. London.
"Overall, this study showed small effects, but it definitely doesn't mean that people shouldn't use folates," she noted. "It just raises the possibility that, as a population, maybe we're reaching folate repletion. It's also possible that there could be a double-edged sword to folate supplementation; certainly it's looking like that may be the case in some cancer studies. However, at this stage, I wouldn't want to be quoted as saying that we should rethink how much folate people are getting."
The investigators next plan to follow-up with these children to "an age when asthma can be more reliably diagnosed," and through to age 7. They've received funding to assess the epigenetic effects of folate supplementation. "In these women, we're going to be looking at cord blood DNA, and looking at whether the patterns of methylation are different according to folate levels and asthma status in the child," explained Dr. London.
Caution Urged
"The findings were consistent with literature from animal models where folic acid could possibly lead to a higher risk for asthma," said Juan Celedón, MD, DrPH, associate professor of medicine at Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts.
"However, I think that there are some cautions with this study," added Dr. Celedón, who was not involved in the research. "First, you can't diagnose asthma until the age of 6, so further follow-up of those kids is needed. Second, they did not measure any objective markers of allergy. And third, they didn't show a mechanism. All that said, the findings are very intriguing,"
"We just need to be very cautious in this area," he told Medscape Allergy & Clinical Immunology. "A woman takes folic acid to protect against neural tube defects and it's been very, very effective for that. I think we need to be extraordinarily careful and need to assess this thoroughly before we can begin to make any recommendations [for] current practice in regard to changing or even reducing folic acid during pregnancy."
This study was funded by the Norwegian Research Council. The NMCC study was funded by the Norwegian Ministry of Health and a grant from the National Institute of Environmental Health Sciences/National Institutes of Health. Dr. London and Dr. Celedón have disclosed no relevant financial relationships.
American Academy of Allergy, Asthma and Immunology (AAAAI) 2010 Annual Meeting: Abstract 505. Presented February 28, 2010.
Deborah Brauser has disclosed no relevant financial relationships.
"Norway provides a unique opportunity to address the question of possible deleterious consequences of high folate intake during pregnancy because the food supply there is not fortified with folates," said investigational team member Stephanie London, MD, DrPH, from the Epidemiology Branch and Laboratory of Respiratory Biology at the National Institute of Environmental Health Sciences in Durham, North Carolina.
"It's one of the few places where you can look at whether the supplementation, which is clearly good from the point of view of decreasing birth defects, could potentially also have some adverse effects," she added.
Recent Studies Question Folic Effects
Previous research has consistently shown that the periconceptional intake of folic acid reduces the risk for neural tube defects in infants, leading to the increased use of these supplements and to the fortification of foods with folic acid in the United States and other countries.
However, a recent study showed that high dietary supplementation with folic acid and other methyl donors in pregnant mice led to allergic asthma phenotypes, through epigenetic changes, in offspring.
In another study recently conducted by Dr. London's research team, an association was found between folate supplements used during early pregnancy and an increased risk for respiratory disease in children up to the age of 18 months.
For this study, they examined data on 507 mothers from the population-based NMCC who had plasma folate levels measured during their second trimester of pregnancy, and who had children with asthma at the age of 3 years. The folate levels of 1455 mothers of healthy controls were also measured. All children were born between July 1, 2002 and June 30, 2004.
"The age of 3 isn't a perfect phenotype because that's early to diagnose asthma, but that was the age that the kids were at the time of the study," explained Dr. London.
A Linear Increase Found
Results showed that mothers in the top quintile of plasma folate had children with an increased risk for asthma at age 3 (adjusted odds ratio [OR], 1.66; 95% confidence interval [CI], 1.16 - 2.37), relative to mothers in the bottom quintile.
In addition, the investigators found "a trend of linear increase across quintiles" (P = 0.007). Children of mothers with folate levels between the 70th and 95th percentiles had an OR of 1.34 (95% CI, 1.03 - 1.73), whereas children of mothers with levels above the 95th percentile had an OR of 1.44 (95% CI, 1.08-1.93).
"In other words, as the mother's folate level increased, so did the risk of asthma in their child," said Dr. London.
"Overall, this study showed small effects, but it definitely doesn't mean that people shouldn't use folates," she noted. "It just raises the possibility that, as a population, maybe we're reaching folate repletion. It's also possible that there could be a double-edged sword to folate supplementation; certainly it's looking like that may be the case in some cancer studies. However, at this stage, I wouldn't want to be quoted as saying that we should rethink how much folate people are getting."
The investigators next plan to follow-up with these children to "an age when asthma can be more reliably diagnosed," and through to age 7. They've received funding to assess the epigenetic effects of folate supplementation. "In these women, we're going to be looking at cord blood DNA, and looking at whether the patterns of methylation are different according to folate levels and asthma status in the child," explained Dr. London.
Caution Urged
"The findings were consistent with literature from animal models where folic acid could possibly lead to a higher risk for asthma," said Juan Celedón, MD, DrPH, associate professor of medicine at Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts.
"However, I think that there are some cautions with this study," added Dr. Celedón, who was not involved in the research. "First, you can't diagnose asthma until the age of 6, so further follow-up of those kids is needed. Second, they did not measure any objective markers of allergy. And third, they didn't show a mechanism. All that said, the findings are very intriguing,"
"We just need to be very cautious in this area," he told Medscape Allergy & Clinical Immunology. "A woman takes folic acid to protect against neural tube defects and it's been very, very effective for that. I think we need to be extraordinarily careful and need to assess this thoroughly before we can begin to make any recommendations [for] current practice in regard to changing or even reducing folic acid during pregnancy."
This study was funded by the Norwegian Research Council. The NMCC study was funded by the Norwegian Ministry of Health and a grant from the National Institute of Environmental Health Sciences/National Institutes of Health. Dr. London and Dr. Celedón have disclosed no relevant financial relationships.
American Academy of Allergy, Asthma and Immunology (AAAAI) 2010 Annual Meeting: Abstract 505. Presented February 28, 2010.
Authors and Disclosures
Journalist
Deborah Brauser
is a freelance writer for Medscape.Deborah Brauser has disclosed no relevant financial relationships.
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