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Drugs, pregnancy & lactation: folic acid and cardiac abnormalities.

When most physicians and patients hear about folic acid, they automatically think about its role in preventing spina bifida and other neural tube defects. But there are now more than 20 years of data that point toward a larger role for folic acid in preventing common, and in some cases devastating, congenital heart defects.

The various published studies leave little doubt that folic acid can significantly reduce the risk for many common cardiac malformations, but other questions remain. For instance, what is the minimum dose for protection? And should health authorities around the world consider recommending a much higher dose of folic acid for short-term use in pregnant women and those trying to conceive?

Early research on cardiac malformations

One of the early studies showing the promise of folic acid beyond neural tube defects was published in 1996. The randomized, double-blind controlled trial in Hungary compared the effect of periconceptional multivitamin supplements containing 0.8 mg of folic acid versus trace element supplements on neural tube defects and other congenital abnormalities. The multivitamin supplement group had a significant reduction in urinary tract abnormalities, and in the rate of sporadic cardiovascular malformations, specifically ventricular septal defects (Am J Med Genet. 1996 Mar 15;62 [2]: 179-83).

In 2004, the same researchers confirmed their results using a controlled, cohort trial that matched pregnant women from regional antenatal care clinics who did not take vitamin supplements to pregnant women who did take supplements containing 0.8 mg folic acid. The results were similar. From a total of 3,056 offspring evaluated, 31 congenital cardiovascular malformations occurred in the group with folic acid supplementation, compared with 50 in the group without, for a 40% lower risk overall, although the main impact was seen among ventricular septal defects (Birth Defects Res A Clin Mol Teratol. 2004 Nov;70[11]:853-61).

Our own group examined the evidence in a meta-analysis published in 2006 and found significant support for an expanded role for folic acid (J Obstet Gynaecol Can. 2006 Aug;28[8]:680-9).

The major issue with the available studies is the lack of highest-quality evidence. While some of the studies were randomized trials, you can no longer conduct a true randomized design and withhold folic acid from women; it's simply not ethical knowing what we know about the preventive benefits of folic acid for neural tube defects. But the literature--which includes quality cohort and case-controlled studies--is convincing.

High dose best?

While some studies have shown a protective effect of folic acid in congenital heart defects at low levels, such as the 0.8 mg used in the early Hungarian studies, other studies indicate that more is better.

A review of 13 studies published in the Lancet shows that for every 0.1-mg/day increase in folic acid intake in women aged 20-35 years, there is a corresponding 0.94-ng/mL increase in serum folate concentrations and that translates into reduced risk of defects, at least in terms of neural tube defects (Lancet. 2001 Dec 15;358[9298]:2069-73).

Most recently, some of the same researchers that published the early reports out of Hungary on protection against congenital heart defects showed evidence that a variety of congenital heart defects could be reduced with folic acid supplementation of between 3 mg and 6 mg daily (Eur J Obstet Gynecol Reprod Biol. 2015 Jul 9;193:34-9).

The study evaluated 3,567 infants with various congenital heart defects and 5,395 matched controls. The researchers excluded women taking multivitamins that contained folic acid and stratified the women taking folic acid alone into three subgroups: those who took folic acid anytime during pregnancy, those who took it during the "critical period" for development of malformations based on medical records and self-reported information, and those who took it during the "critical period" based on medical records alone.

During the study period, there was only one type of folic acid tablet available in Hungary--a 3-mg tablet. On average, the daily dose was 5.6 mg.

Most women began folic acid supplementation around 6-11 weeks' gestation, coinciding with their first prenatal visit. There was a significant drop in the prevalence of cases with ventricular septal defect (odds ratio, 0.57), tetralogy of Fallot (OR, 0.53), d-transposition of great arteries (OR, 0.47), and atrial septal defect secundum (OR, 0.63) when pregnant women took high doses of folic acid during the critical period for congenital heart defect development.

Overall, the researchers concluded that about 40% of severe congenital heart defects could be prevented using high doses of folic acid during the critical period.

This is a significant reduction for a common and serious problem among pregnant women. While it's true that there are more surgical solutions available today, cardiac malformations are still a major source of morbidity and mortality among children, and it can be the motivation for parents to terminate a pregnancy in cases where there are serious, complicated malformations.

Prevention is always the best option, and this research suggests, once again, that folic acid may offer even more benefits.

The study also shows that there was no clear difference in reduction of congenital heart defects based on either a 3-mg or 6-mg dose, except with atrial septal defect secundum. In that case, the 3-mg dose reduced risk by only 10%, compared with more than 40% at 6 mg. But the researchers were quick to point out that more research is needed to look at the dose-response relationship.

The 5.6-mg average daily dose is significant because it is far above the 0.4-mg level recommended by the Centers for Disease Control and Prevention and the level frequently prescribed for pregnant women--0.8 mg to 1 mg.

We know that some women may benefit from more folic acid, such as women who have previously given birth to a child with neural tube defects. But there are more subgroups that could benefit from higher doses of folic acid, including women taking antifolate medications such as anti-epileptic drugs, methotrexate, and sulfonamides. Women who don't consume enough vegetables and don't take a multivitamin could benefit from high doses, as would obese women, smokers, and women with diabetes.

For years the concern has been that folic acid at higher levels could increase the risk for certain cancers, but the evidence there is uncertain. Additionally, that risk would be triggered only after years of exposure, while the benefits of high-dose folic acid could be achieved in a matter of months. I don't think the evidence of harm is convincing enough to stop us from considering that high-dose folic acid could be used in the general population.

One of the encouraging aspects of using folic acid to prevent congenital heart defects is that the critical window for influencing malformations is larger than with neural tube defects. While folic acid must be given in the first 28 days of pregnancy to have a benefit, the window of opportunity is 1-2 months longer for cardiac malformations.

The bottom line is that high-dose folic acid to prevent congenital heart defects is a target ripe for further research. While randomized controlled trials aren't possible, there are plenty of high-quality studies that could be conducted to provide clinicians with the information they need to prevent these devastating malformations.

BY GIDEON KOREN, M.D.

Dr. Koren is professor of pharmacology and pharmacy at the University of Toronto. He is the founding director of the Motherisk Program. He received grant support to conduct studies on folic acid from Duchesnay. He has been a consultant to several companies that produce vitamins in the context of pregnancy, including Bayer. Email him at obnews@frontlinemedcom.com.

Caption: DR. KOREN

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Title Annotation:OBSTETRICS
Author:Koren, Gideon
Publication:OB GYN News
Date:Oct 1, 2015
Words:1284
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