Reduction in Neural-Tube Defects after Folic Acid Fortification in Canada
12 Jul 2007-The New England Journal of Medicine (Massachusetts Medical Society)-Vol. 357, Iss: 2, pp 135-142
TL;DR: Food fortification with folic acid was associated with a significant reduction in the rate of neural-tube defects in Canada, and the decrease was greatest in areas in which the baseline rate was high.
Abstract: 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.
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TL;DR: Overall, the frequency of MPS varies for each population due to differences in ethnic backgrounds and/or founder effects that affect the birth prevalence of each type of M PS, as seen for other rare genetic diseases.
Abstract: The aim of this study was to obtain data about the epidemiology of the different types of mucopolysaccharidoses in Japan and Switzerland and to compare with similar data from other countries. Data for Japan was collected between 1982 and 2009, and 467 cases with MPS were identified. The combined birth prevalence was 1.53 per 100,000 live births. The highest birth prevalence was 0.84 for MPS II, accounting for 55% of all MPS. MPS I, III, and IV accounted for 15, 16, and 10%, respectively. MPS VI and VII were more rare and accounted for 1.7 and 1.3%, respectively. A retrospective epidemiological data collection was performed in Switzerland between 1975 and 2008 (34years), and 41 living MPS patients were identified. The combined birth prevalence was 1.56 per 100,000 live births. The highest birth prevalence was 0.46 for MPS II, accounting for 29% of all MPS. MPS I, III, and IV accounted for 12, 24, and 24%, respectively. As seen in the Japanese population, MPS VI and VII were more rare and accounted for 7.3 and 2.4%, respectively. The high birth prevalence of MPS II in Japan was comparable to that seen in other East Asian countries where this MPS accounted for approximately 50% of all forms of MPS. Birth prevalence was also similar in some European countries (Germany, Northern Ireland, Portugal and the Netherlands) although the prevalence of other forms of MPS is also reported to be higher in these countries. Birth prevalence of MPS II in Switzerland and other European countries is comparatively lower. The birth prevalence of MPS III and IV in Switzerland is higher than in Japan but comparable to that in most other European countries. Moreover, the birth prevalence of MPS VI and VII was very low in both, Switzerland and Japan. Overall, the frequency of MPS varies for each population due to differences in ethnic backgrounds and/or founder effects that affect the birth prevalence of each type of MPS, as seen for other rare genetic diseases. Methods for identification of MPS patients are not uniform across all countries, and consequently, if patients are not identified, recorded prevalence rates will be aberrantly low.
996 citations
TL;DR: The results of the first comparison, involving 6708 births with information on NTDs and other infant outcomes, show a protective effect of daily folic acid supplementation (alone or in combination with other vitamins and minerals) in preventing N TDs compared with no interventions/placebo or vitamin and minerals without folic Acid.
Abstract: Background
It has been reported that neural tube defects (NTD) can be prevented with periconceptional folic acid supplementation. The effects of different doses, forms and schemes of folate supplementation for the prevention of other birth defects and maternal and infant outcomes are unclear.
Objectives
This review aims to examine whether periconceptional folate supplementation reduces the risk of neural tube and other congenital anomalies (including cleft palate) without causing adverse outcomes in mothers or babies. This is an update of a previously published Cochrane review on this topic.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2015). Additionally, we searched the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (31 August 2015) and contacted relevant organisations to identify ongoing and unpublished studies.
Selection criteria
We included all randomised or quasi-randomised trials evaluating the effect of periconceptional folate supplementation alone, or in combination with other vitamins and minerals, in women independent of age and parity.
Data collection and analysis
Two review authors independently assessed the eligibility of studies against the inclusion criteria, extracted data from included studies, checked data entry for accuracy and assessed the risk of bias of the included studies. We assessed the quality of the body of evidence using the GRADE approach.
Main results
Five trials involving 7391 women (2033 with a history of a pregnancy affected by a NTD and 5358 with no history of NTDs) were included. Four comparisons were made: 1) supplementation with any folate versus no intervention, placebo or other micronutrients without folate (five trials); 2) supplementation with folic acid alone versus no treatment or placebo (one trial); 3) supplementation with folate plus other micronutrients versus other micronutrients without folate (four trials); and 4) supplementation with folate plus other micronutrients versus the same other micronutrients without folate (two trials). The risk of bias of the trials was variable. Only one trial was considered to be at low risk of bias. The remaining studies lacked clarity regarding the randomisation method or whether the allocation to the intervention was concealed. All the participants were blinded to the intervention, though blinding was unclear for outcome assessors in the five trials.
The results of the first comparison involving 6708 births with information on NTDs and other infant outcomes, show a protective effect of daily folic acid supplementation (alone or in combination with other vitamins and minerals) in preventing NTDs compared with no interventions/placebo or vitamins and minerals without folic acid (risk ratio (RR) 0.31, 95% confidence interval (CI) 0.17 to 0.58); five studies; 6708 births; high quality evidence). Only one study assessed the incidence of NTDs and showed no evidence of an effect (RR 0.07, 95% CI 0.00 to 1.32; 4862 births) although no events were found in the group that received folic acid. Folic acid had a significant protective effect for reoccurrence (RR 0.34, 95% CI 0.18 to 0.64); four studies; 1846 births). Subgroup analyses suggest that the positive effect of folic acid on NTD incidence and recurrence is not affected by the explored daily folic acid dosage (400 µg (0.4 mg) or higher) or whether folic acid is given alone or with other vitamins and minerals. These results are consistent across all four review comparisons.
There is no evidence of any preventive or negative effects on cleft palate (RR 0.73, 95% CI 0.05 to 10.89; three studies; 5612 births; low quality evidence), cleft lip ((RR 0.79, 95% CI 0.14 to 4.36; three studies; 5612 births; low quality evidence), congenital cardiovascular defects (RR 0.57, 95% CI 0.24 to 1.33; three studies; 5612 births; low quality evidence), miscarriages (RR 1.10, 95% CI 0.94 to 1.28; five studies; 7391 pregnancies; moderate quality evidence) or any other birth defects (RR 0.94, 95% CI 0.53 to 1.66; three studies; 5612 births; low quality evidence). There were no included trials assessing the effects of this intervention on neonatal death, maternal blood folate or anaemia at term.
Authors' conclusions
Folic acid, alone or in combination with vitamins and minerals, prevents NTDs, but does not have a clear effect on other birth defects.
600 citations
TL;DR: Nations considering fortification should be cautious and stimulate further research to identify the effects, good and bad, caused by a high intake of folic acid from fortified food or dietary supplements.
Abstract: Fortification of food with folic acid to reduce the number of neural tube defects was introduced 10 y ago in North America. Many countries are considering whether to adopt this policy. When fortification is introduced, several hundred thousand people are exposed to an increased intake of folic acid for each neural tube defect pregnancy that is prevented. Are the benefits to the few outweighed by possible harm to some of the many exposed? In animals, a folic acid-rich diet can influence DNA and histone methylation, which leads to phenotypic changes in subsequent generations. In humans, increased folic acid intake leads to elevated blood concentrations of naturally occurring folates and of unmetabolized folic acid. High blood concentrations of folic acid may be related to decreased natural killer cell cytotoxicity, and high folate status may reduce the response to antifolate drugs used against malaria, rheumatoid arthritis, psoriasis, and cancer. In the elderly, a combination of high folate levels and low vitamin B-12 status may be associated with an increased risk of cognitive impairment and anemia and, in pregnant women, with an increased risk of insulin resistance and obesity in their children. Folate has a dual effect on cancer, protecting against cancer initiation but facilitating progression and growth of preneoplastic cells and subclinical cancers, which are common in the population. Thus, a high folic acid intake may be harmful for some people. Nations considering fortification should be cautious and stimulate further research to identify the effects, good and bad, caused by a high intake of folic acid from fortified food or dietary supplements. Only then can authorities develop the right strategies for the population as a whole.
583 citations
Cites background from "Reduction in Neural-Tube Defects af..."
...We do not challenge the established benefits of fortification with folic acid in the prevention of neural tube defects (2, 3), but we would like to ask a different question: Is the benefit to the relatively few mothers and children sufficient justification for exposing the entire population to an increased intake of folic acid? It has been estimated by the SACN that 77–162 NTD pregnancies would be pre-...
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TL;DR: Primary prevention of congenital anomalies in the population based on controlling environmental risk factors is a crucial policy priority, including preconceptional care and whole population approaches.
Abstract: EUROCAT (European Surveillance of Congenital Anomalies) is the network of population-based registers of congenital anomaly in Europe, with a common protocol and data quality review, covering 1.5 million annual births in 22 countries. EUROCAT recorded a total prevalence of major congenital anomalies of 23.9 per 1,000 births for 2003-2007. 80% were livebirths. 2.5% of livebirths with congenital anomaly died in the first week of life. 2.0% were stillbirths or fetal deaths from 20 weeks gestation. 17.6% of all cases were terminations of pregnancy following prenatal diagnosis (TOPFA). Thus, congenital anomalies overwhelmingly concern children surviving the early neonatal period, who have important medical, social or educational needs. The prevalence of chromosomal anomalies was 3.6 per 1,000 births, contributing 28% of stillbirths/fetal deaths from 20 weeks gestation with congenital anomaly, and 48% of all TOPFA. Congenital heart defects (CHD) were the most common non-chromosomal subgroup, at 6.5 per 1,000 births, followed by limb defects (3.8 per 1,000), anomalies of urinary system (3.1 per 1,000) and nervous system defects (2.3 per 1,000). In 2004, perinatal mortality associated with congenital anomaly was 0.93 per 1,000 births, and TOPFA 4.4 per 1,000 births, with considerable country variation. Primary prevention of congenital anomalies in the population based on controlling environmental risk factors is a crucial policy priority, including preconceptional care and whole population approaches.
503 citations
Cites background from "Reduction in Neural-Tube Defects af..."
...Many countries outside Europe have introduced mandatory folic acid fortification of staple foods [ 12 ], in order to overcome the problems associated with prevention by supplementation....
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TL;DR: The history, effect, concerns, and future directions of folic acid food fortification programs are highlighted.
Abstract: Periconceptional intake of folic acid is known to reduce a woman's risk of having an infant affected by a neural tube birth defect (NTD). National programs to mandate fortification of food with folic acid have reduced the prevalence of NTDs worldwide. Uncertainty surrounding possible unintended consequences has led to concerns about higher folic acid intake and food fortification programs. This uncertainty emphasizes the need to continually monitor fortification programs for accurate measures of their effect and the ability to address concerns as they arise. This review highlights the history, effect, concerns, and future directions of folic acid food fortification programs.
467 citations
References
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TL;DR: Evaluated the outcomes of pregnancy in women who were asked to take a pill containing 400 μg of folic acid alone daily from the time of their premarital examination until the end of their first trimester of pregnancy, and identified 102 and 173 women with neural-tube defects.
Abstract: Background Periconceptional use of multivitamins containing folic acid can reduce a woman's risk of having a baby with a neural-tube defect. Methods As part of a public health campaign conducted from 1993 to 1995 in an area of China with high rates of neural-tube defects (the northern region) and one with low rates (the southern region), we evaluated the outcomes of pregnancy in women who were asked to take a pill containing 400 μg of folic acid alone daily from the time of their premarital examination until the end of their first trimester of pregnancy. Results Among the fetuses or infants of 130,142 women who took folic acid at any time before or during pregnancy and 117,689 women who had not taken folic acid, we identified 102 and 173, respectively, with neural-tube defects. Among the fetuses or infants of women who registered before their last menstrual period and who did not take any folic acid, the rates of neural-tube defects were 4.8 per 1000 pregnancies of at least 20 weeks' gestation in the nort...
1,254 citations
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TL;DR: The results of randomized trials indicate that at least half the cases of neural-tube defects could be prevented if women consumed sufficient amounts of the B vitamin folic acid before conception and during early pregnancy.
Abstract: Each year spina bifida and anencephaly, the two most common forms of neural-tube defects, occur in 1 in 1000 pregnancies in the United States1 and an estimated 300,000 or more newborns worldwide.2 Although these severe conditions have been recognized since antiquity, never before has progress been so fast and substantive, particularly in the area of prevention. The results of randomized trials indicate that at least half the cases of neural-tube defects could be prevented if women consumed sufficient amounts of the B vitamin folic acid before conception and during early pregnancy.3,4 Elsewhere in this issue of the Journal, Berry . . .
945 citations
TL;DR: Periconceptional intake of 400 microg of folic acid daily can reduce the risk of neural-tube defects in areas with high rates of these defects and in areas of China with low rates.
Abstract: BACKGROUND AND METHODS
Periconceptional administration of folic acid can reduce a woman's risk of having a fetus or infant with a neural-tube defect. As part of a public health campaign conducted from 1993 to 1995 in an area of China with high rates of neural-tube defects (the northern region) and one with low rates (the southern region), we evaluated the outcomes of pregnancy in women who were asked to take a pill containing 400 microg of folic acid alone daily from the time of their premarital examination until the end of their first trimester of pregnancy.
RESULTS
Among the fetuses or infants of 130,142 women who took folic acid at any time before or during pregnancy and 117,689 women who had not taken folic acid, we identified 102 and 173, respectively, with neural-tube defects. Among the fetuses or infants of women who registered before their last menstrual period and who did not take any folic acid, the rates of neural-tube defects were 4.8 per 1000 pregnancies of at least 20 weeks' gestation in the northern region and 1.0 per 1000 in the southern region. Among the fetuses or infants of the women with periconceptional use of folic acid, the rates were 1.0 per 1000 in the northern region and 0.6 per 1000 in the southern region. The greatest reduction in risk occurred among the fetuses or infants of a subgroup of women in the northern region with periconceptional use who took folic acid pills more than 80 percent of the time (reduction in risk, 85 percent as compared with the fetuses or infants of women who registered before their last menstrual period and who took no folic acid; 95 percent confidence interval, 62 to 94 percent) [corrected]. In the southern region the reduction in risk among the fetuses or infants of women with periconceptional use of folic acid was also significant (reduction in risk, 41 percent; 95 percent confidence interval, 3 to 64 percent).
CONCLUSIONS
Periconceptional intake of 400 microg of folic acid daily can reduce the risk of neural-tube defects in areas with high rates of these defects and in areas with low rates.
641 citations
TL;DR: In seniors with low vitamin B-12 status, high serum folate was associated with anemia and cognitive impairment when vitamin B -12 status was normal; when it was normal, however, high Serum folatewas associated with protection against cognitive impairment.
Abstract: Background : Historic reports on the treatment of pernicious anemia with folic acid suggest that high-level folic acid fortification delays the diagnosis of or exacerbates the effects of vitamin B-12 deficiency, which affects many seniors. This idea is controversial, however, because observational data are few and inconclusive. Furthermore, experimental investigation is unethical. Objective : We examined the relations between serum folate and vitamin B-12 status relative to anemia, macrocytosis, and cognitive impairment (ie, Digit Symbol-Coding score 210 nmol/L-the maximum of the reference range for serum vitamin B-12-replete participants with normal creatinine. Results : After control for demographic characteristics, cancer, smoking, alcohol intake, serum ferritin, and serum creatinine, low versus normal vitamin B-12 status was associated with anemia [odds ratio (OR) : 2.7; 95% CI : 1.7, 4.2], macrocytosis (OR : 1.8; 95% CI : 1.01, 3.3), and cognitive impairment (OR : 2.5; 95% CI : 1.6,3.8). In the group with a low vitamin B-12 status, serum folate >59 nmol/L (80th percentile), as opposed to ≤59 nmol/L, was associated with anemia (OR : 3.1; 95% CI : 1.5, 6.6) and cognitive impairment (OR : 2.6; 95% CI : 1.1, 6.1). In the normal vitamin B-12 group, ORs relating high versus normal serum folate to these outcomes were < 1.0 (f interaction < 0.05), but significantly < 1.0 only for cognitive impairment (0.4; 95% CI : 0.2, 0.9). Conclusion : In seniors with low vitamin B-12 status, high serum folate was associated with anemia and cognitive impairment. When vitamin B-12 status was normal, however, high serum folate was associated with protection against cognitive impairment.
562 citations
TL;DR: Because as many as 10% of women may be obese periconceptionally, the observed twofold increased risk is relevant to the population burden of NTDs.
Abstract: Objective. —To investigate the risk for neural tube defect (NTD)—affected pregnancies among obese women (ie, women with a body mass index [BMI] >29 kg/ m 2 ) compared with women of average prepregnancy weight. Design. —Population-based case-control study. Setting. —All hospitals in 55 of 58 counties in California. Participants. —In-person interviews were conducted with mothers of 538 (88% of eligible) NTD cases (including fetuses and infants electively terminated, stillborn, or born alive) and with mothers of 539 nonmalformed controls (88%) within an average of 5 months from the term delivery date. Main Outcome Measures. —The risk of an NTD-affected pregnancy among obese women. Results. —Compared with women whose BMI was less than or equal to 29 kg/ m 2 , an increased risk for NTD-affected pregnancy was observed among obese women (odds ratio, 1.9; 95% confidence interval, 1.3 to 2.9). The increased risk was not attributable to maternal nonuse of a vitamin containing folic acid, diabetes, use of diet pills, lower dietary folate intake, or an NTD-pregnancy history. Adjustment for maternal age, education, gravidity, use of vitamins, and use of alcohol did not change the odds ratio. The risk associated with maternal obesity was greater for spina bifida and for other less prevalent NTDs than for anencephaly. Conclusion.—Because as many as 10% of women may be obese periconceptionally, the observed twofold increased risk is relevant to the population burden of NTDs. ( JAMA . 1996;275:1093-1096)
342 citations