A pre-pregnancy year of folic acid sharply lowers risk of very premature birth
A woman who takes folate long before conception is half as likely to deliver before 32 weeks of gestation and 70% less likely to deliver before 28 weeks, a study finds. Full term is about 40 weeks.
By Thomas H. Maugh II
May 12, 2009
Taking folic acid supplements for a year before conception reduces the risk of very premature birth by at least 50%, researchers reported Monday.
Shorter courses of the supplement were not as effective, according to the study of nearly 35,000 women reported in the Public Library of Science journal PLoS Medicine.
Folic acid's effectiveness in reducing the risk of neural-tube and other birth defects -- even without such a long course -- is long established. The discovery that it can also reduce the risk of preterm birth "is very significant," said Dr. Diane Ashton, deputy medical director of the March of Dimes Birth Defects Foundation, who was not involved in the study.
The finding reinforces the recommendation that "all women of child-bearing age should take multivitamin supplements," she said.
Only 35% to 40% of such women do take supplements, according to surveys conducted by the March of Dimes and other groups.
Preterm births -- before 37 full weeks of gestation -- account for about 13% of U.S. deliveries and are associated with vision impairment, mental retardation and cerebral palsy in children, and diabetes and cardiovascular disease as they grow older.
The earlier the delivery, the higher the risk of such complications.
Previous research had shown that women who deliver prematurely have lower-than-normal levels of folate in their blood. Small trials of folic acid supplements to prevent premature birth have given mixed results.
Dr. Radek Bukowski and his colleagues at the University of Texas Medical Branch at Galveston were able to screen a much larger number of women by piggybacking their research onto a National Institutes of Health study that was testing methods of screening for Down's syndrome.
"It was such a large data set, with so much information, that we were able to answer this question as well," Bukowski said.
The women were questioned during the first trimester of pregnancy about their health behaviors, including use of supplements.
The researchers found that for women who had been taking folate for at least a year before conception, the risk of birth between 28 and 32 weeks was reduced by 50%.
The risk of birth between 20 and 28 weeks was reduced by 70%.
The latter reduction is particularly significant, Ashton said, because researchers had previously found no way to reduce the proportion of preterm babies born so early.
The supplementation had no effect on the risk of preterm birth after 32 weeks, the researchers found. And beginning supplementation around the time of conception did little to reduce preterm births, even though such timing does reduce the risk of neural-tube defects.
The scientists do not know why this is so.
The U.S. has required since 1998 that flour and similar products be fortified with folic acid. Beyond that, health authorities recommend that women of childbearing age -- whether or not they plan to become pregnant -- consume an additional 400 micrograms per day.
There has been recent debate about whether even higher amounts would be more beneficial -- although some critics believe that higher amounts could mask vitamin B12 deficiency and might raise the risk of certain cancers.
But studies such as this one, Bukowski said, suggest that "dose is not as important as duration."
Preconceptional Folate Supplementation and the Risk of Spontaneous Preterm Birth: A Cohort Study
Radek Bukowski1*, Fergal D. Malone2, Flint T. Porter3, David A. Nyberg4, Christine H. Comstock5, Gary D. V. Hankins1, Keith Eddleman6, Susan J. Gross7, Lorraine Dugoff8, Sabrina D. Craigo9, Ilan E. Timor-Tritsch10, Stephen R. Carr11, Honor M. Wolfe12, Mary E. D'Alton13
1 University of Texas Medical Branch, Department of Obstetrics and Gynecology, Galveston, Texas, United States of America, 2 Royal College of Surgeons in Ireland, Department of Obstetrics and Gynecology, Dublin, Ireland, 3 University of Utah, Salt Lake City, Utah, United States of America, 4 The Fetal & Women's Center of Arizona, Scottsdale, Arizona, United States of America, 5 William Beaumont Hospital, Fetal Imaging Department, Royal Oak, Michigan, United States of America, 6 Mount Sinai Medical Center, Department of Obstetrics and Gynecology, New York, New York, United States of America, 7 Montefiore Medical Center--Albert Einstein College of Medicine, Department of Obstetrics & Gynecology and Women's Health, Bronx, New York, United States of America, 8 University of Colorado Health Sciences Center, Department of Obstetrics and Gynecology, Denver, Colorado, United States of America, 9 Tufts-New England Medical Center, Department of Obstetrics and Gynecology, Boston, Massachusetts, United States of America, 10 New York University Medical Center, School of Medicine, Department of Obstetrics and Gynecology, New York, New York, United States of America, 11 Brown University/Women & Infants' Hospital, Department of Obstetrics and Gynecology, Providence, Rhode Island, United States of America, 12 University of North Carolina at Chapel Hill, Department of Obstetrics and Gynecology, Chapel Hill, North Carolina, United States of America, 13 Columbia University Medical Center, Department of Obstetrics and Gynecology, Maternal-Fetal Medicine, New York, New York, United States of America
Low plasma folate concentrations in pregnancy are associated with preterm birth. Here we show an association between preconceptional folate supplementation and the risk of spontaneous preterm birth.
Methods and Findings
In a cohort of 34,480 low-risk singleton pregnancies enrolled in a study of aneuploidy risk, preconceptional folate supplementation was prospectively recorded in the first trimester of pregnancy. Duration of pregnancy was estimated based on first trimester ultrasound examination. Natural length of pregnancy was defined as gestational age at delivery in pregnancies with no medical or obstetrical complications that may have constituted an indication for delivery. Spontaneous preterm birth was defined as duration of pregnancy between 20 and 37 wk without those complications. The association between preconceptional folate supplementation and the risk of spontaneous preterm birth was evaluated using survival analysis. Comparing to no supplementation, preconceptional folate supplementation for 1 y or longer was associated with a 70% decrease in the risk of spontaneous preterm delivery between 20 and 28 wk (41 [0.27%] versus 4 [0.04%] spontaneous preterm births, respectively; HR 0.22, 95% confidence interval [CI] 0.08--0.61, p = 0.004) and a 50% decrease in the risk of spontaneous preterm delivery between 28 and 32 wk (58 [0.38%] versus 12 [0.18%] preterm birth, respectively; HR 0.45, 95% CI 0.24--0.83, p = 0.010). Adjustment for maternal characteristics age, race, body mass index, education, marital status, smoking, parity, and history of prior preterm birth did not have a material effect on the association between folate supplementation for 1 y or longer and spontaneous preterm birth between 20 and 28, and 28 to 32 wk (adjusted HR 0.31, 95% CI 0.11--0.90, p = 0.031 and 0.53, 0.28--0.99, p = 0.046, respectively). Preconceptional folate supplementation was not significantly associated with the risk of spontaneous preterm birth beyond 32 wk. The association between shorter duration (<1 y) of preconceptional folate supplementation and the risk of spontaneous preterm birth was not significant after adjustment for maternal characteristics. However, the risk of spontaneous preterm birth decreased with the duration of preconceptional folate supplementation (test for trend of survivor functions, p = 0.01) and was the lowest in women who used folate supplementation for 1 y or longer. There was also no significant association with other complications of pregnancy studied after adjustment for maternal characteristics.
Preconceptional folate supplementation is associated with a 50%--70% reduction in the incidence of early spontaneous preterm birth. The risk of early spontaneous preterm birth is inversely proportional to the duration of preconceptional folate supplementation. Preconceptional folate supplementation was specifically related to early spontaneous preterm birth and not associated with other complications of pregnancy.
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