Folic acid supplementation and cardiovascular disease: the state of the art

Bazzano LA . Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana . USA. Am J Med Sci. 2009 Jul

High levels of homocysteine, a non-protein-forming, sulfur-containing amino acid, have been associated with elevated cardiovascular risk in observational studies. Support for the homocysteine hypothesis comes from 2 primary lines of epidemiologic evidence, observational studies, such as case control and cohort studies, and studies of genetic variation. On the basis of unequivocally supportive epidemiologic data, a series of large randomized controlled trials of homocysteine lowering through folic acid supplementation were launched. The recently reported results of the 3 large, randomized clinical trials (SEARCH, WENBIT, WAFACS) in combination with those previously reported (CHAOS-2, VISP, NORVIT, HOPE-2) effectively rule out the possibility of large effect on risk of coronary heart disease, stroke, and all-cause mortality. Although the potential for prevention of atherosclerotic cardiovascular disease in adults through folic acid supplementation has not yet been substantiated, folic acid supplementation prenatally may reduce congenital heart defects in offspring.

Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial

Albert CM , Cook NR , Gaziano JM , Zaharris E , MacFadyen J , Danielson E , Buring JE , Manson JE . Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 900 Commonwealth Ave E, Boston, Massachusetts USA. JAMA. 2008 May

CONTEXT: Recent randomized trials among patients with preexisting cardiovascular disease (CVD) have failed to support benefits of B-vitamin supplementation on cardiovascular risk. Observational data suggest benefits may be greater among women, yet women have been underrepresented in published randomized trials. OBJECTIVE: To test whether a combination of folic acid, vitamin B6, and vitamin B12 lowers risk of CVD among high-risk women with and without CVD. DESIGN, SETTING, AND PARTICIPANTS: Within an ongoing randomized trial of antioxidant vitamins, 5442 women who were US health professionals aged 42 years or older, with either a history of CVD or 3 or more coronary risk factors, were enrolled in a randomized, double-blind, placebo-controlled trial to receive a combination pill containing folic acid, vitamin B6, and vitamin B12 or a matching placebo, and were treated for 7.3 years from April 1998 through July 2005. INTERVENTION: Daily intake of a combination pill of 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12. MAIN OUTCOME MEASURES: A composite outcome of myocardial infarction, stroke, coronary revascularization, or CVD mortality. RESULTS: Compared with placebo, a total of 796 women experienced a confirmed CVD event (406 in the active group and 390 in the placebo group). Patients receiving active vitamin treatment had similar risk for the composite CVD primary end point (226.9/10,000 person-years vs 219.2/10,000 person-years for the active vs placebo group; relative risk [RR], 1.03; 95% confidence interval [CI], 0.90-1.19; P = .65), as well as for the secondary outcomes including myocardial infarction (34.5/10,000 person-years vs 39.5/10,000 person-years; RR, 0.87; 95% CI, 0.63-1.22; P = .42), stroke (41.9/10,000 person-years vs 36.8/10,000 person-years; RR, 1.14; 95% CI, 0.82-1.57; P = .44), and CVD mortality (50.3/10,000 person-years vs 49.6/10,000 person-years; RR, 1.01; 95% CI, 0.76-1.35; P = .93). In a blood substudy, geometric mean plasma homocysteine level was decreased by 18.5% (95% CI, 12.5%-24.1%; P < .001) in the active group (n = 150) over that observed in the placebo group (n = 150), for a difference of 2.27 micromol/L (95% CI, 1.54-2.96 micromol/L). CONCLUSION: After 7.3 years of treatment and follow-up, a combination pill of folic acid, vitamin B6, and vitamin B12 did not reduce a combined end point of total cardiovascular events among high-risk women, despite significant homocysteine lowering.

Pregnancy intentions and folic acid supplementation exemplars: findings from the Central Pennsylvania Women's Health Study

Parrott R , Volkman JE , Hillemeier MM , Weisman CS , Chase GA , Dyer AM . Department of Communication Arts & Sciences, The Pennsylvania State University, University Park, Pennsylvania, USA.J Health Commun. 2009 Jun 

One Healthy People 2010 objective is that 80% of women in the United States start a pregnancy with optimal levels of folic acid. This often requires women to use folic acid supplements preconceptionally to get adequate levels. Efforts to achieve the objective have resulted in a suboptimal floor effect at less than 50% of women. We advance a framework based on exemplification theory, identifying supplementation as an additive action in which two role models exemplify folic acid supplementation among women of reproductive age able to become pregnant (n = 1,258). The women were participants in Phase I of the Central Pennsylvania Women's Health Study (CePAWHS). One exemplar identified represents the positive habits aligned with supplementers considering a pregnancy sometime in their future, while the other resides in the exemplification of positive habits aligned with supplementers not considering a pregnancy sometime in their future but still able to become pregnant. Among women not considering a future pregnancy, daily green salad consumption, weekly fish consumption, having had a health care visit in the past year, and having had any ob/gyn visit in the past 2 years resulted in increased odds of folic acid supplement use in a multivariable model. In the same model, an increase in age resulted in increased odds of folic acid supplement use. Among women considering a future pregnancy, not smoking cigarettes, having higher levels of psychosocial stress, and having higher levels of interaction social support resulted in increased odds of folic acid supplement use in a multivariable model. In the same model, those who have had a health care visit in the past year, as well as those who have received pregnancy planning counseling, were also more likely to use a folic acid supplement. Implications for strategic communication are considered.

Folic acid supplementation and spontaneous preterm birth: adding grist to the mill?

 Callaway L , Colditz PB , Fisk NM . School of Medicine , The University of Queensland , Brisbane , Queensland , Australia . PLoS Med. 2009 May 

Preterm birth is increasing, and complicates 12% of deliveries in the United States . It is the dominant cause of neonatal mortality. Preterm birth also accounts for one in three children with vision impairment, one in five with mental retardation, and almost half with cerebral palsy. Babies born weighing under 2,500 g are at heightened risk in adulthood of diabetes and cardiovascular disease. These short- and long-term sequelae make the prevention of preterm birth a public health priority.

Higher serum folate levels are associated with a lower risk of atopy and wheeze

Matsui EC , Matsui W . Division of Pediatric Allergy and Immunology, Johns Hopkins School of Medicine, Baltimore ,  USA . J Allergy Clin Immunol. 2009 Jun 

BACKGROUND: Folic acid is known to be associated with inflammatory diseases, but the relationship between folic acid and allergic diseases is unclear. OBJECTIVES: The purpose of the study was to examine the relationship between serum folate levels and markers of atopy, wheeze, and asthma. METHODS: Data were obtained from the 2005-2006 National Health and Nutrition Examination Survey in which serum folate and total IgE levels were measured in 8083 subjects 2 years of age and older. A high total IgE level was defined as greater than 100 kU/L. Allergen-specific IgE levels were measured for a panel of 5 common aeroallergens. Atopy was defined as at least 1 positive allergen-specific IgE level. Doctor-diagnosed asthma and wheeze in the previous 12 months were assessed by means of questionnaire. RESULTS: Serum folate levels were inversely associated with total IgE levels (P < .001). The odds of a high total IgE level, atopy, and wheeze decreased across quintiles of serum folate levels, indicating a dose-response relationship between serum folate levels and these outcomes. Each of these associations remained statistically significant after adjusting for age, sex, race/ethnicity, and poverty index ratio. Adjusted odds ratios associated with the fifth quintile of folate relative to the first quintile were as follows: high IgE level, 0.70 (95% CI, 0.53-0.92); atopy, 0.69 (95% CI, 0.57-0.85); and wheeze, 0.60 (95% CI, 0.44-0.82). Higher folate levels were also associated with a lower risk of doctor-diagnosed asthma, but this finding was not statistically significant (odds ratio for fifth quintile vs first quintile, 0.84 [95% CI, 0.70-1.02]). CONCLUSIONS: Serum folate levels are inversely associated with high total IgE levels, atopy, and wheeze.

Blood folate levels: the latest NHANES results 

McDowell MA , Lacher DA , Pfeiffer CM , Mulinare J , Picciano MF , Rader JI , Yetley EA , Kennedy-Stephenson J , Johnson CL . Centers for Disease Control and Prevention National Center for Health Statistics  Hyattsville , Maryland  USA . NCHS Data Brief. 2008 May 

Data from the National Health and Nutrition Examination Surveys. Very large increases in blood folate levels of the U.S. population occurred between 1988-1994 and 1999-2000. Small fluctuations in blood folate levels occurred over the time period 1999-2006. The median red blood cell (RBC) folate level of the U.S. population 4 years of age and older was 266 ng/mL in 2005-2006. The median serum folate level of the U.S. population 4 years of age and older was 12.2 ng/mL in 2005-2006. In 2005-2006, the prevalence of low RBC folate (less than 140 ng/mL) among U.S. women of childbearing age (15-45 years) was 4.5%. In 2005-2006, the prevalence of low serum folate (less than 3 ng/mL) among U.S. women of childbearing age was 0.5%. Folate is an essential vitamin for good health. Women of childbearing age are among the population subgroups that have been shown previously to have low blood folate levels. Low blood folate levels are associated with an increased risk of neural tube birth defects. Beginning in 1998, the Food and Drug Administration (FDA) required the addition of folic acid (a form of folate) to all enriched breads, cereals, flours, corn meal, pasta products, rice, and other cereal grain products sold in the United States . Blood folate data from the National Health and Nutrition Examination Surveys (NHANES) have documented improvements in the folate status of the U.S. population after folate fortification was implemented. Red blood cell (RBC) folate measures long-term folate intake and low levels are associated with adverse health effects. Serum folate reflects recent folate intake and low levels are an early indicator of inadequate folate status. Pre- and postfortification blood folate levels of the U.S. population 4 years of age and older and prevalence of low blood folate among women of childbearing age (15-45 years) are reported. All material appearing in this report is in the public domain and may be reproduced or copied without permission; citation as to source, however, is appreciated.