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Background In 1998, folic acid fortification of a large variety of cereal products became mandatory in Canada, a country where the prevalence of neural-tube defects was historically higher in the eastern provinces than in the western provinces. We assessed changes in the prevalence of neural-tube defects in Canada before and after food fortification with folic acid was implemented.
Methods The study population included live births, stillbirths, and terminations of pregnancies because of fetal anomalies among women residing in seven Canadian provinces from 1993 to 2002. On the basis of published results of testing of red-cell folate levels, the study period was divided into prefortification, partial-fortification, and full-fortification periods. We evaluated the relationship between baseline rates of neural-tube defects in each province and the magnitude of the decrease after fortification was implemented.
Results A total of 2446 subjects with neural-tube defects were recorded among 1.9 million births. The prevalence of neural-tube defects decreased from 1.58 per 1000 births before fortification to 0.86 per 1000 births during the full-fortification period, a 46% reduction (95% confidence interval, 40 to 51). The magnitude of the decrease was proportional to the prefortification baseline rate in each province, and geographical differences almost disappeared after fortification began. The observed reduction in rate was greater for spina bifida (a decrease of 53%) than for anencephaly and encephalocele (decreases of 38% and 31%, respectively).
Conclusions Food fortification with folic acid was associated with a significant reduction in the rate of neural-tube defects in Canada. The decrease was greatest in areas in which the baseline rate was high.
We conducted our study to assess changes in the prevalence of neural-tube defects associated with food fortification with folic acid throughout Canada. Since there was known to be a geographical gradient in the prevalence of neural-tube defects at birth, with higher rates in the eastern provinces than in the western provinces,4 we also tested the hypothesis that the magnitude of the effect of folic acid fortification would vary directly with the baseline rate of the defect.
Methods
Study Subjects
The study population included live births, stillbirths, and terminations of pregnancies because of fetal anomalies among women residing in 7 of the 10 Canadian provinces and none of the territories from 1993 to 2002. Denominator numbers were provided by provincial vital-statistics offices. The total numbers of live births and stillbirths recorded in each participating province are shown in Table 1. In the province of Quebec, many high-risk pregnancies in the Outaouais region are referred to hospitals situated in the province of Ontario. Since outcomes from these pregnancies were unavailable, we excluded all births from the Outaouais region, which represented less than 5% of the total births in the province.
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The neural-tube defects of subjects were classified according to the nomenclature proposed by Nevin and Weatherall.5 The main categories were anencephaly (including acrania, craniorachischisis, and exencephaly), spina bifida or meningomyelocele (including a spinal defect not otherwise specified), iniencephaly, encephalocele, and any neural-tube defect not otherwise specified. We excluded subjects with occult spinal dysraphism, including spina bifida occulta, thickened filum terminale, diastematomyelia, caudal regression syndrome, intradural lipoma, lipomeningomyelocele, split notochord, and other forms of myelodysplasia. This category of mainly caudal defects may be embryologically distinct from myelomeningocele,6 and a substantial proportion of persons with such defects are diagnosed late in childhood or even adulthood.7 Ethical approvals and authorizations to review medical records were obtained in accordance with provincial jurisdictions.
Folate Supplementation
The level of fortification with folic acid in Canada is 0.15 mg per 100 g of flour or cornmeal (U.S. level, 0.14 mg per 100 g) and 0.20 to 0.27 mg per 100 g of pasta (the same as the U.S. level). In the United States, but not in Canada, the level of fortification for rice is 0.154 mg per 100 g up to a maximum of 0.308 mg per 100 g; the level for corn grits and farina is 0.15 mg per 100 g. Breakfast cereals may be enriched up to 400 µg per serving in the United States and up to 60 µg per serving in Canada. Results of biochemical tests in a large Ontario laboratory have shown that red-cell folate levels in the population started to increase in April 1997 and reached a plateau in February 1999.8 Given this finding and assuming that there is no beneficial effect of folic acid after the first trimester of pregnancy,9 we considered that all term births before September 30, 1997, occurred during the prefortification period, those between October 1, 1997, and March 31, 2000, occurred during the partial-fortification period, and those after March 31, 2000, occurred during the full-fortification period. Thus, term births in the full-fortification period were conceived after the mother had been exposed to full fortification for at least 5 months, which was assumed to be sufficient to attain an equilibrium in folate status.10 A large proportion of pregnancies affected by neural-tube defects were terminated or were preterm births. Therefore, to prevent any classification bias, a theoretical birth date was calculated for each subject, assuming a gestation of 40 weeks (the date of the birth or abortion minus the length of gestation in weeks plus 40 weeks).
Statistical Analysis
Prevalence rates for neural-tube defects were calculated as the sum of subjects with the defect in live births, stillbirths, and induced abortions, divided by the number of total live births and stillbirths. Confidence intervals of rates, ratios, and differences were calculated by an exact method. The chi-square test and the Cochran–Armitage test for linear trend in proportions were performed, with the statistical significance level set at 0.05 in two-sided tests. The relationship between the baseline rate of neural-tube defects in each province and the magnitude of the decrease after fortification began was modeled by testing a series of linear, exponential, and power functions. A weight equal to the inverse of the variance of the estimated difference in rate was assigned to each observation. A constraint was that we assumed that no risk reduction would be observed in situations in which the baseline rate of neural-tube defects was 0.6 per 1000 births or less. We based this assumption on data regarding residual risk observed in several regions in China in which women received daily supplementation of folic acid at a dose of 400 µg.11 The predicted residual error sum square coefficient and the coefficient of determination were used to assess statistical fit and to select the best model. The data were analyzed with the use of SAS software, version 8.1 (SAS Institute).
Results
Study Subjects
During the study period, we identified 2446 subjects with neural-tube defects. The distribution of subjects according to diagnostic category and pregnancy outcome is shown in Table 2. Of pregnancies affected by neural-tube defects, 60% were terminated after prenatal diagnosis. Spina bifida was the most frequently recorded anomaly (53% of total subjects), with anencephaly representing approximately a third of subjects with neural-tube defects (34%). The overall ratio of anencephaly to spina bifida was 0.65, and there was no significant variation of this ratio during the study years.
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We found that food fortification with folic acid was associated with a significant reduction in neural-tube defects in Canada. Furthermore, the risk reduction appeared greatest in regions in which the rates were highest before the fortification program was implemented.
Achieving a high level of identification of subjects with neural-tube defects in a geographically defined population was possible in seven provinces, representing 55% of the total births in the country. Previous reports regarding Canadian data have showed similar reductions in rates.2,12,13,14,15,16 Our study extends those observations with the use of standard methods to obtain a comprehensive assessment from the Atlantic to the Pacific coasts and multiple sources for identification of subjects. Published data from Ontario16 were used to complement the observations in the other seven Canadian provinces, as indicated in Figure 2. Validation studies performed in Quebec and British Columbia, the two largest participating provinces, have indicated a high level of identification of subjects with neural-tube defects, equal to or higher than 92%, with no substantial change during the study years.17,18,19
A marked decrease in prevalence rates was observed from 1997 through 2000, corresponding to the initiation of food fortification in Canada. Distribution of fortified food started at the beginning of 1997, and by the end of that year, the entire milling industry had adopted fortification in anticipation of the coming mandatory requirements in the United States and Canada.2 This finding was also consistent with the observed increase in red-cell folate levels in the population of Ontario.8 In Newfoundland, a nutritional survey showed no significant change in dietary habits from 1997 through 2001, with the average daily intake of naturally occurring folate remaining the same at the end of the period as it was at the beginning.12
In contrast to the reduction in rates of neural-tube defects observed after dietary fortification, there was no significant change in the prevalence rate between 1993 and 1997, when expert committees and Health Canada recommended daily folic acid supplementation with or without multivitamins for pregnant women.2 Other data suggest that these recommendations were not routinely followed. Health surveys that were performed periodically in Quebec showed no substantial change in the use of vitamin supplements among nonpregnant women between the ages of 18 and 40 years during the period from 1987 through 1998.2 During the period of our study, results from two surveys among pregnant women in Quebec showed no substantive change in the use of vitamin supplements either before conception (27.5% in 1997–1998 and 31.6% in 1999–2000) or before the 12th week of pregnancy (36.0% in 1997–1998 and 30.6% in 1999–2000).20,21 Among a random sample of nonpregnant women of reproductive age in Greater Vancouver, only 25.7% reported taking daily vitamins in 1998–1999.22
A study comparing folate levels in women of childbearing age before and after the implementation of food fortification in Ontario found geometric mean levels of red-cell folate of 527 nmol per liter before food fortification and 741 nmol per liter after fortification was implemented, with serum vitamin B12 levels remaining unchanged.23 On the basis of the increase in serum folate levels reported in Ontario, it was estimated that the fortification program increased daily folic acid consumption by 150 µg.24 However, in blood samples collected at prenatal clinics in Newfoundland, there was a marked increase in serum folate and a slight but significant increase in serum vitamin B12 levels from 1992–1996 to 1998–2002, suggesting that dietary changes or increased consumption of vitamin supplements may have contributed to the substantial reduction in the rate of neural-tube defects observed in this province after food fortification was implemented.13
A previous study assessed the effect of folic acid fortification in the United States, using eight population-based surveillance systems that identified subjects with neural-tube defects that had been diagnosed prenatally.25 In that study, the combined prevalence rate of anencephaly and spina bifida was 1.06 per 1000 births in 1995–1996, before fortification, and 0.76 per 1000 births in 1999–2000, after fortification was implemented, a 28% reduction. This decrease is less than the one we report in Canada: 46% for all neural-tube defects and 48% for anencephaly and spina bifida combined. The higher baseline rate in Canada may have contributed to the difference, but other factors could also play a role, including differences in ethnic distribution, eating habits, use of vitamin supplements, and the prevalence of other risk factors for neural-tube defects, such as maternal obesity and diabetes.26,27
We found a greater reduction in rates in regions with a higher baseline prevalence of neural-tube defects than in regions with a lower prevalence. The greatest reduction in birth prevalence was observed in Newfoundland and Labrador, which had a difference in rate of 3.80 per 1000 births, as compared with British Columbia, which had a difference in rate of 0.21 per 1000 births. These results are consistent with the findings of a study in China showing a more pronounced effect of prenatal folic acid supplementation in the northern part of the country, where the baseline rate of neural-tube defects (4.9 per 1000 births) was higher than that in the southern part (1.0 per 1000 births). Ultimately, a birth prevalence of 0.6 neural-tube defects per 1000 births was observed among women who received daily supplementation of 400 µg of folic acid in both regions.11
A simple linear function best represented the relationship between the baseline prevalence of neural-tube defects in a region and the magnitude of the decrease in the rate after fortification was implemented. This model might be used to predict the effect of a food-fortification program providing an average level of additional daily intake of 150 µg of folic acid, as estimated in Canada.24 In Canada, the current rate of neural-tube defects ranges from 0.7 to 1.3 per 1000 births, with an average of 0.9 per 1000 births. Since not all cases of neural-tube defects can be prevented, the potential for further improvement would be smaller than that reported in our study but might be as much as 30% for a residual risk of 0.6 per 1000 births. Validation of our model is warranted in other settings.
Marked reductions in rates of neural-tube defects have occurred across Canada after fortification of food with folic acid was implemented. Decisions regarding the optimal level of food fortification and the types of foods to be enriched must take into account both safety, especially for seniors who may have unrecognized B12 deficiency,28 and the goal of maximizing the reduction in neural-tube defects.
Supported by a grant (MOP-57904) from the Canadian Institutes of Health Research.
No potential conflict of interest relevant to this article was reported.
We thank Health Canada and the Public Health Agency of Canada for logistic assistance and Martine Six and Manale Ouakki at the Quebec University Hospital Research Centre for their help in the collection and analysis of data.
Source Information
From Laval University, Quebec, QC (P.D.W., F.T.); the University of British Columbia, Vancouver (M.I.V.A.); British Columbia Ministry of Health, Victoria (S.-H.U.); Alberta Health and Wellness, Calgary (R.B.L., B.S.); the University of Manitoba, Winnipeg (J.A.E.); Dalhousie University, Halifax, NS (M.C.V.H.); the IWK Health Centre, Halifax, NS (P.Z.); Health Science Centre, St. John's, NL (M.C., B.F.); Food Directorate, Health Canada, Ottawa (N.S.L.) — all in Canada; and Robert Stempel School of Public Health, Florida International University, Miami (T.N.).
Address reprint requests to Dr. De Wals at the Département de Médecine Sociale et Préventive, Université Laval, Pavillon de l'Est, Local 1110, 2180, Chemin Sainte-Foy, Quebec, QC G1K 7P4, Canada, or at philippe.dewals{at}msp.ulaval.ca.
References
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