Folic Acid Food Fortification Research Articles

Folic Acid and Placental Pathology

ArticlePlus Click on the links below to access all the ArticlePlus for this article. Please note that ArticlePlus files may launch a viewer application outside of your web browser. https://links.lww.com/EDE/A157 https://links.lww.com/EDE/A158 To the Editor: Placental abruption (premature placental separation from the uterus) and placental infarction (often resulting from microscopic thrombi or clots within placental blood vessels) are associated with increased risks of stillbirth,1 intrauterine growth restriction,1,2 and preterm delivery.1–3 Folate deficiency has been suggested to be associated with placental abruption and infarction (pooled odds ratio = 26; 95% confidence interval = 0.9–736).4 Canadian white flour has been fortified with folic acid since January 1998. We performed an analysis to determine if there was a change in the rate of placental abruption and infarction in relation to folic acid food fortification. We conducted a retrospective population-based study of the monthly prevalence of placental abruption and infarction (calculated by dividing the number of women hospitalized with a diagnosis of either condition in a given month by all women who gave birth to a live-born or stillborn infant >20 weeks’ gestation age within the same month). The exposure of interest was the mandatory folic acid food fortification, with the prefortification period was defined as January 1, 1995, to September 30, 1998 (allowing a lag effect of 9 months for gestation) and postfortification from October 1, 1998, to March 31, 2001. Pregnancies affected by placental abruption or placental infarction were identified using the Canadian Institute for Health Information Discharge Abstract Database, which contains up to 16 diagnoses, coded by International Classification of Diseases, 9th Revision. Codes used are listed in Appendix 1 (available with the electronic version of this letter). Complete data for the province of Quebec and the Northwest Territories, Yukon and Nunavut, were not available and were excluded. A crude prevalence ratio (PR) compared the prevalence of placental abruption in the periods before and during fortification. Poisson regression was used to adjust the PR for maternal age >35 years, as well as the covariates listed in electronic Appendix 1. These analyses were repeated for placental abruption or placental infarction. All patient identifiers were removed before database extraction. Permission to conduct this study was granted by the Research Ethics Board of Mount Sinai Hospital, Toronto. There were 1,159,329 deliveries before fortification and 695,154 in the period thereafter. Participant characteristics are presented in electronic Appendix 2. Monthly prevalences of placental pathologic events are shown in electronic Appendix 3. No change in association with fortification was observed in the risk of placental abruption in either univariate (1.02; 0.99–1.05) or multivariate analyses (1.02; 0.98–1.05) (Table 1). Similar risk estimates were observed for placental abruption or placental infarction separately.TABLE 1: Risk of Placental Abruption or Infarction in Association With Folic Acid Food FortificationWe had no information on maternal weight or cigarette smoking (risk factors for placental disease), folic acid supplement use, or serum folate concentrations. However, since fortification began, red cell folate concentrations have increased by more than 40% among Canadian women,5 and the relative prevalence of folate deficiency declined by more than 85%.6 Our study included nearly all Canadian women who delivered over a 6-year period, with nearly 100% statistical power to detect as little as a 1% change in the prevalence of placental abruption. Thus, it is unlikely that folic acid can prevent abruption or infarction. ACKNOWLEDGMENTS Supported by the physicians of Ontario through the Physicians’ Services Incorporated Foundation, Sunnybrooke and Women's College Foundation, and John Kingdom. Sarah D. McDonald Clinical Epidemiology Unit Ottawa Hospital Ottawa, Ontario, Canada [email protected] Marian J. Vermeulen Institute for Clinical Evaluative Sciences Toronto, Ontario, Canada Joel G. Ray St. Michael's Hospital, University of Toronto Toronto, Ontario, Canada

Sustained Homocysteine-Lowering Effect over Time of Folic Acid-Based Multivitamin Therapy in Stroke Patients despite Increasing Folate Status in the Population

Background and Aims: It is uncertain what impact increasing voluntary folate fortification may be having on the statistical power of randomized trials testing the homocysteine hypothesis of atherothrombosis. The objective of this study was to determine whether there has been a change in folate status between 1998 and 2002 in stroke patients randomized into the VITAmins TO Prevent Stroke (VITATOPS) Study at a single center in Perth, Australia, and what impact this may have had on the magnitude of the homocysteine-lowering effect achieved over time with folic acid-based multivitamin therapy. Methods: We conducted a randomized, double-blind, placebo-controlled study involving 285 patients with stroke or transient ischemic attack who were recruited between 1998 and 2002 and randomized to long-term folic acid 2.0 mg/day, pyridoxine 25 mg/day and cobalamin 0.5 mg/day (active VITATOPS medication) or placebo. Fasting plasma total homocysteine, red cell folate, serum cobalamin and serum pyridoxine levels were measured at baseline and 6 months, and the change in blood levels over 4 time quartiles and differences in levels between the two randomized treatments were examined. Results: Between 1998 and 2002, there was a significant rise in baseline mean red cell folate levels over 4 time quartiles among the entire stroke cohort (723.3, 780.1, 922.6 and 1,023.7 nmol/l in the first, second, third and fourth quartiles, respectively; p < 0.0001), but this was not associated with a spontaneous reduction in mean baseline total homocysteine levels during the same time period (12.7, 14.3, 12.1 and 12.8 µmol/l in the first, second, third and fourth quartiles, respectively; p = 0.55). The homocysteine-lowering effect of the active VITATOPS trial medication at 6 months after randomization also did not change significantly between 1998 and 2002 (difference between randomized groups: –4.1, –4.1, –3.1 and –3.6 µmol/l in the first, second, third and fourth quartiles, respectively; p = 0.56). Conclusions: The homocysteine-lowering effect of the active VITATOPS trial medication has not attenuated significantly in the past 5 years despite increasing voluntary fortification of foods with folic acid as reflected by a progressive rise in baseline folate status. These data suggest that in the continuing absence of a program of mandatory folate fortification of food in populations served by centers participating in the VITATOPS trial, the study will remain adequately powered to test the homocysteine-lowering hypothesis for which it was designed.

Wine Consumption and Epithelial Ovarian Cancer

Wine Consumption and Epithelial Ovarian Cancer

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Birth defects in Arkansas: is folic acid fortification making a difference?

Since 1998, fortification of grain products with folic acid has been mandated in the United States, in an effort to reduce the prevalence of neural tube defects (NTDs). Published reports have shown a reduction in the prevalence of spina bifida since fortification was mandated, but no published studies have reported a reduction in birth defects, other than NTDs, that are postulated to be associated with folic acid deficiency. This study was performed to determine if fortification has reduced the prevalence of NTDs and other birth defects in Arkansas. Using data from the Arkansas Reproductive Health Monitoring System, prevalences were computed for thirteen specific birth defects with prior evidence supporting a protective effect of folic acid or multivitamins. Prevalences were calculated using data for live births to Arkansas residents for 1993-2000. Exposure to folic acid fortification was classified by birth year as "pre-fortification" (1993-1995), "transition" (1996-1998) or "post-fortification" (1999-2000). Logistic regression analysis was used to compute crude and adjusted prevalence odds ratios comparing the identified time periods. Prevalences decreased between the pre- and post-fortification periods for spina bifida, orofacial clefts, limb reduction defects, omphalocele, and Down syndrome, but only the decrease in spina bifida was statistically significant (prevalence odds ratio 0.56; 95% confidence interval, 0.37, 0.83). In Arkansas, the prevalence of spina bifida has decreased since folic acid fortification of foods was implemented. Similar studies by other birth defects surveillance systems are needed to confirm a preventive effect of fortification for malformations other than spina bifida.

Use of folic acid supplementation and risk for dizygotic twinning

Background An increase in dizygotic twinning rate after folic acid supplementation has previously been described, but in a recent study from China, no such effect was seen. Aims To further investigate the association between use of folic acid supplement and dizygotic twinning. Study design Using the Swedish Medical Birth Registry, the rate of dizygotic twinning among infants of women who reported the use of folic acid was studied, taking a number of confounders into consideration. Comparisons were made with all women recorded in the register. Outcome measure Unlike-sexed twin pairs were used as representatives of dizygotic twinning. Results A number of confounders for the association between folic acid use and twinning were identified and taken into consideration. Women who were immigrants (who used less folic acid and had slightly lower twinning rates than women born in Sweden) and women who reported subfertility problems or treatment for subfertility (who had a high use of folic acid and a high twinning rate) were excluded, and adjustment was then made for year of birth, maternal age, parity, and smoking in early pregnancy. Folic acid use and twinning risk increased with maternal age and decreased with parity. Smokers used less folic acid than nonsmokers. Concomitant use of other drugs was no important confounder except for those used at subfertility. The odds ratio (OR) for dizygotic twinning after folic acid supplementation was then 1.71 (95%CI=1.21–2.42) and for the years 2000–2001 even 2.09 (95%CI=1.39–3.12). Conclusion There is an increase in twinning rate after folic acid supplementation in a Western population which should be taken into consideration when folic acid supplementation or food fortification is recommended.

Folic Acid Food Fortification in Canada

Folic Acid Food Fortification in Canada

Folic acid food fortification in Canada.

By January 1998, most Canadian cereal grains (e.g., white flour) were being fortified with folic acid, with a large percentage being fortified by mid-1997. This was in compliance with both American and Canadian mandatory fortification deadlines of January and November 1998, respectively. It was estimated that between 0.1 to 0.2 mg of additional synthetic folic acid per day would be provided through this initiative, the goal of which was to lower the rate of neural tube defects (NTD). The current report outlines some of the changes to the health status of Canadians in relation to its folic acid food fortification initiative.

Folic Acid Food Fortification in Canada

Folic Acid Food Fortification in Canada

Folic Acid Food Fortification in Canada

Folic Acid Food Fortification in Canada

Effect of folic acid fortification of foods on folate intake in female smokers with cervical dysplasia

Objective We investigated the effect of folic acid fortification of enriched cereal grains on folate intake in women of predominantly childbearing age at high risk for cervical cancer. Methods Subjects in this cross-sectional study were 77 women randomized between November 1999 and December 2000 in the Women's Intervention to Stay Healthy (WISH), a clinical trial evaluating the effect of a tobacco control intervention on the progression of cervical dysplasia. All subjects were cigarette smokers, had a previously abnormal Papanicolaou test, and were positive for high-risk human papillomavirus at entry. Dietary intake was assessed with food-frequency questionnaires completed at the baseline visit for WISH. The effect of folic acid fortification on folate intake was assessed by using pre- and postfortification folate databases to estimate folate intake. Results Mean folate intake assessed with the postfortification database was 63% higher than intake assessed with the prefortification database: 417 versus 256 μg/d of dietary folate equivalents ( P < 0.0001). The proportion of subjects below the estimated average requirement for folate was smaller after fortification than before fortification: 40.3% versus 75.3% ( P < 0.0001). Several foods, including white bread, cheese dishes, spaghetti, and rice, became major sources of folate as a result of fortification. Conclusions Folic acid fortification resulted in an increased intake of folate in these subjects. However, even with fortification, folate intake in a large proportion of these women remained below recommended levels. These results should be considered before decisions regarding future levels of folic acid fortification are made.

Effect of folic acid fortification of food on homocysteine-related mortality

Background In 1998, the Food and Drug Administration mandated the fortification of food products with folic acid. The effect of this rule on mortality associated with homocysteine levels in patients with coronary artery disease is unknown. Methods We studied 2481 consecutive patients with coronary artery disease who underwent coronary angiography between 1994 and 1999, and who had baseline homocysteine measurements and at least 2 years of follow-up. Patients were divided into prefortification (1994 to 1997, n = 1595) and postfortification (1998 to 1999, n = 886) groups, as well as classified based on baseline homocysteine levels (normal to low, intermediate, and high). Homocysteine levels were measured by fluorescence polarization immunoassay. Mortality was determined by telephone survey or from a national Social Security database or hospital records. Results After implementation of the fortification rule, median homocysteine levels declined from 13.8 to 12.3 μmol/L ( P <0.001), and the proportion of patients with high homocysteine levels (>15 μmol/L) decreased from 41% (n = 650) to 28% (n = 249) ( P <0.001). Overall, homocysteine was a modest risk factor for mortality (adjusted relative risk [RR] = 1.03 per μmol/L; 95% confidence interval [CI]: 1.01 to 1.05; P = 0.006). There was no significant interaction between fortification status and homocysteine category with mortality ( P for interaction = 0.85). Two-year mortality was reduced minimally (7.8% [n = 124] to 7.2% [n = 64]; RR = 0.93; 95% CI: 0.68 to 1.27; P = 0.63; adjusted RR = 0.97; 95% CI: 0.68 to 1.40), but was consistent with the expectation of a modest reduction in homocysteine levels. Conclusion Homocysteine is an independent, graded risk factor for mortality. Homocysteine levels decreased modestly after the fortification of food with folic acid, but the effects on mortality were minor and likely attributable to other factors, indicating the need for more aggressive measures to reduce homocysteine-associated cardiovascular risk.

Multivitamin Supplementation: No Decrease in Autosomal Trisomy

Several studies of the rates of autosomal trisomies (including Down syndrome) have failed to show decreased incidence since folic acid fortification of foods was introduced in 1998. Now, a new study from the Centers for Disease Control …

Folate and homocysteine levels in pregnancy

This study aims to determine serum folate and plasma homocysteine levels in healthy pregnant women following a live birth and compare them with healthy non-pregnant women. Fifty healthy gravid multiparous women are included in the study and 25 normal non-pregnant female subjects act as controls (group I). The pregnant women are divided into two groups according to interpregnancy interval: group II (six months or less); group III (18–24 months). Venous blood samples are analysed for red blood cell folate and homocysteine, vitamin B12, serum folate and albumin, and serum aminotransferases (ALT and AST). There was a significant decrease in red cell folate and serum folate in group II compared to the control group (P<0.001). Serum vitamin B12 showed no significant difference. Plasma homocysteine and serum albumin showed significant decreases in both groups II and III compared to the control group. (P<0.001) There was significant positive correlation between homocysteine and serum albumin in the three studied groups. (r=0.42, P<0.001; r=0.45, P<0.001; r=0.51, P<0.001, respectively). There was significant negative correlation between red cell folate and homocysteine in the three studied groups. (r=–0.48, P<0.001; r=–0.53, P<0.001; r=–0.49, P<0.001, respectively). Two cases in group II showed signs of intrauterine growth retardation. The results suggest that pregnant females with short interpregnancy intervals are more likely to develop folate deficiency. Educational strategies are required to increase folate awareness among women to promote the benefits of folic acid supplementation. Mandatory folate fortification of foods should be defined and monitored.

Association between folic acid food fortification and congenital orofacial clefts

By January 1998, most of Canada's cereal grain products were being fortified with folic acid. Among 336,963 women who underwent antenatal maternal serum screening, the prevalence of orofacial clefts did not change from before (1.15 per 1000) to after (1.21 per 1000) food fortification (prevalence ratio, 1.06; 95% confidence interval, 0.86–1.30).

Folic acid food fortification is associated with a decline in neuroblastoma.

Neuroblastoma, an embryonic tumor, is the second most common pediatric tumor and is the most prevalent extracranial solid tumor in children. Results of previous studies have suggested that maternal vitamin intake may decrease the risk of several childhood cancers. In January 1997, Canada began fortifying flour with folic acid for the prevention of neural tube defects. The effect of folic acid fortification on the rate of neuroblastoma in offspring is not known. We investigated the rates of neuroblastoma (<1 year), acute lymphoblastic leukemia, and hepatoblastoma registered by the Pediatric Oncology Group of Ontario, which captures 95% of all pediatric cancers in Ontario, before and after the introduction of folate fortification. An interventional time series analysis showed that the incidence of neuroblastoma declined from 1.57 cases per 10,000 births before to 0.62 case per 10,000 births after folic acid fortification (P <.0001). The crude incidence rate ratio (0.40; 95% confidence interval, 0.25-0.64) remained significant after adjustment for both age and disease stage at diagnosis (adjusted incidence rate ratio, 0.38; 95% confidence interval, 0.23-0.62). In contrast, there was no significant change in the rate of infant acute lymphoblastic leukemia (incidence rate ratio, 0.97; 95% confidence interval, 0.41-2.27) or hepatoblastoma (incidence rate ratio, 0.81; 95% confidence interval, 0.35-1.89). Folic acid fortification was associated with a 60% reduction in neuroblastoma but was not associated with any change in the rate of infant acute lymphoblastic leukemia or hepatoblastoma. Further investigation is needed into the role of metabolism in the formation and prevention of neuroblastoma and other embryonically determined cancers.

Persistence of vitamin B12 insufficiency among elderly women after folic acid food fortification

Objective To estimate the associated risk of folate and vitamin B12 (B12) insufficiency, as well as vitamin repletion, following folic acid food fortification. Design Retrospective cross-sectional study over a 5-year period. Setting Two large laboratory databases in the provinces of Ontario and British Columbia, Canada. Participants Canadian women aged 65 years and over who underwent concomitant clinical testing of serum folate and B12 during the pre-fortification period of January 1996 to December 1997 in Ontario (n = 733) and British Columbia (n = 3839), and in the near-complete post-fortification period of January 1998 to December 2000 in Ontario (n = 4415) and British Columbia (n = 6677). Measurements Geometric mean concentrations of serum folate and B12 before and after folate fortification. Prevalence ratios (PR) were used to separately compare the post- and pre-fortification period rates of folate deficiency (below 6.0 nmol/L); B12 insufficiency (below 150 pmol/L); and B12 insufficiency in combination with supraphysiological concentrations of serum folate (above 45 nmol/L). Results The mean baseline folate and B12 concentrations were similar between provinces. Using the combined provincial data, the mean serum folate concentration increased by 64% after fortification, from 14.8 to 24.2 nmol/L ( p < 0.001). The average B12 concentration increased from 280 to 300 pmol/L, which was more pronounced in BC ( p < 0.001) than in Ontario ( p = 0.16). The prevalence of folate deficiency declined from 6.3% to 0.88% after fortification (PR 0.14, 95% confidence interval [CI] 0.11-0.18), while the decline in B12 deficiency was less pronounced (PR 0.78, 95% CI 0.71-0.86). The prevalence of combined B12 insufficiency with supraphysiological concentrations of serum folate increased from 0.09% pre-fortification to 0.61% post (PR 7.0, 95% CI 2.6-19.2). Conclusions The introduction of folic acid food fortification was associated with a substantial improvement in the folate status of Canadian women aged 65 years and older, paralleled by a large decline in the rate of folate deficiency. Improvement in the B12 status of these women was far less pronounced. Because the prevalence of combined B12 insufficiency and supraphysiological concentrations of serum folate may have increased with folic acid food fortification, consideration should be given to confirming this finding, and possibly, to the addition of B12 to folate fortified foods. Sponsorship Public Health Branch, Ontario Ministry of Health and Long Term Care. Potential conflict of interest None

Prevalence of trisomy 21 following folic acid food fortification.

Polymorphisms of maternal genes responsible for normal folate metabolism may be associated with an increased risk of fetal trisomy 21. By January 1998, most of Canada's flour was being fortified with folic acid. We investigated whether the prevalence of antenatally and postnatally detected trisomy 21 changed before and after folic acid food fortification. A total of 218,977 women underwent second trimester maternal serum screening for trisomy 21 in the 48 months before fortification and 117,986 women were screened in the 29 months after fortification. There were 375 identified cases of trisomy 21 before fortification (1.71 per 1,000), compared to 201 cases thereafter (1.70 per 1,000) for a crude prevalence ratio (PR) of 0.99 (95% confidence interval [CI] 0.84-1.18). The associated risk of trisomy 21 did not change after adjustment for mean maternal age (adjusted PR 0.99 [95% CI 0.82-1.19]). Similarly, no significant decline in the monthly prevalence of trisomy 21 was observed using autoregressive integrated moving average time series analysis (P = 0.24). In conclusion, we failed to observe a decline in the occurrence of trisomy 21 following folic acid food fortification.

Association of neural tube defects and folic acid food fortification in Canada

Ray JG, Meier C, Vermeulen MJ, Boss S, Wyatt PR, Cole DE. Lancet 2002;360(9350):2047–8. (http://www.thelancet.com) The following abstracts from leading journals have been selected on the basis of their importance to the practice of obstetrics and gynecology.

The Prevention of Congenital Anomalies with Periconceptional Folic Acid Supplementation

Large randomized trials have demonstrated the critical role of folic acid supplementation in the prevention of neural tube defects. Since 1992, a number of national and international professional societies have released guidelines recommending folic acid supplementation of at least 0. 4 mg/day for all women of childbearing age or women planning pregnancies, and 4 mg/day for women with a previous infant with a neural tube defect. Furthermore, a reduction in the incidence of congenital cardiac and urologie anomalies has been demonstrated in some studies following periconceptional folic acid supplementation. There is growing evidence of a possible role of folic acid supplementation in the prevention of other congenital anomalies, including cardiac defects. Since 1998, mandatory fortification of certain foods with folate has been associated with at least a 54% reduction in the incidence of open neural tube defects, yet rates of periconceptional folic acid use remain suboptimal, especially in minority women. Innovative strategies in educating women, health-care providers, and pharmacists on the benefits of folic acid supplementation need to be explored. Mandatory folate fortification of foods needs to be defined and monitored.