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Background: Questions remain about the effectiveness, dose, and timing of folic acid in preventing orofacial clefts. Case-control studies report conflicting results. There have been no cohort studies of orofacial clefts and the use of folic acid without other vitamins., Methods: In a prospective cohort of 240,244 women enrolled between 1993 and 1995 in 1 northern and 2 southern provinces in China, we examined the risk of nonsyndromic cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP) in relation to maternal use of 400 μg of folic acid without other vitamins., Results: Daily use of 400 μg of folic acid without other vitamins, started before the last menstrual period (LMP), was associated with reduced risk of CL/P with adjusted rate ratio (aRR) of 0.69 (95% confidence interval = 0.55-0.87). The greatest reduction in risk was observed in the north among daily users who began taking folic acid pills before LMP (aRR = 0.21 [0.10-0.44]); in the south there was marginal reduction in risk (aRR = 0.81 [0.63-1.05]). No evidence of reduced CL/P risk was observed among women who started folic acid pills on or after their LMP. No persuasive evidence for reduction in CP risk was seen with folic acid pill use at any time., Conclusion: Daily maternal consumption of 400 μg of folic acid without other vitamins, started before mother's LMP, was associated with a reduced risk of CL/P in babies born in a high-prevalence region of China.

Background: There are no large randomized trials of the effect of folic acid dosing regimens on blood folate and homocysteine concentrations., Objective: We aimed to evaluate the changes in folate and homocysteine concentrations in response to different folic acid doses and to withdrawal in young women not exposed to other sources of folic acid., Design: Women (n = 1108) were randomly assigned to 1 of 6 intervention groups for which daily intakes of folic acid for 6 mo were 100 microg 1 time/d, 25 microg 4 times/d, 400 microg 1 time/d, 100 microg 4 times/d, 4000 microg 1 time/d, or 4000 microg 1 time/wk. Plasma and red blood cell folate and homocysteine concentrations were measured at baseline; at 1, 3, and 6 mo; and 3 mo after the discontinuation of folic acid., Results: Folate and homocysteine concentrations were not different at baseline between the groups who had the same daily intake of folic acid as a single dose or multiple doses (P = 0.058). Plasma folate concentrations plateaued at 3 mo with 108% (95% CI: 97.7%, 120%), 259% (95% CI: 240%, 279%), 460% (95% CI: 417%, 503%), and 142% (95% CI: 123%, 162%) observed increases for the folic acid groups receiving 100, 400, and 4000 microg/d and 4000 microg/wk, respectively. The rate of reduction in folate concentrations during the 3 mo after cessation of folic acid was dose-dependent-higher intakes were associated with faster reductions., Conclusions: Changes in folate and homocysteine concentrations were unaffected by different dosing schedules. After folic acid cessation, blood folate declined rapidly, which indicated that the intervention-enhanced folate status was rapidly diminished.

Background: Abnormalities of folate and homocysteine metabolism are associated with a number of pediatric and adult disorders. Folate intake and genetic polymorphisms encoding folate-metabolizing enzymes influence blood folate and homocysteine concentrations, but the effects and interactions of these factors have not been studied on a population-wide basis., Objective: The objective was to assess the prevalence of these genetic polymorphisms and their relation to serum folate and homocysteine concentrations., Design: DNA samples from 6793 participants in the third National Health and Nutrition Examination Survey (NHANES III) during 1991-1994 were genotyped for polymorphisms of genes coding for folate pathway enzymes 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C-->T and 1298A-->C, methionine synthase reductase (MTRR) 66A-->G, and cystathionine-beta-synthase 844ins68. The influence of these genetic variants on serum folate and homocysteine concentrations was analyzed by age, sex, and folate intake in 3 race-ethnicity groups., Results: For all race-ethnicity groups, serum folate and homocysteine concentrations were significantly related to the MTHFR 677C-->T genotype but not to the other polymorphisms. Persons with the MTHFR 677 TT genotype had a 22.1% (95% CI: 14.6%, 28.9%) lower serum folate and a 25.7% (95% CI: 18.6%, 33.2%) higher homocysteine concentration than did persons with the CC genotype. Moderate daily folic acid intake (mean: 150 microg/d; 95% CI: 138, 162) significantly reduced the difference in mean homocysteine concentrations between those with the MTHFR 677 CC and TT genotypes. We found a significant interaction between MTHFR 677C-->T and MTRR 66A-->G on serum homocysteine concentrations among non-Hispanic whites., Conclusions: The MTHFR 677C-->T polymorphism was associated with significant differences in serum folate and homocysteine concentrations in the US population before folic acid fortification. The effect of MTHFR 677C-->T on homocysteine concentrations was reduced by moderate daily folic acid intake.

Background: Neural tube defects are serious birth defects of the brain and spinal cord. Up to 70% of neural tube defects can be prevented by the consumption of folic acid by women before and early during pregnancy., Objective: The objective was to examine folic acid intake in women of childbearing age in the United States., Design: We analyzed nutrient intake data reported by 1685 nonpregnant women aged 15-49 y who participated in the National Health and Nutritional Examination Survey, 2001-2002., Results: The adjusted geometric mean consumption of folic acid from fortified foods was 128 microg/d (95% CI: 123, 134 microg/d) in nonpregnant women. Eight percent (95% CI: 5.8%, 11.0%) of nonpregnant women reported consuming >or=400 microg folic acid/d from fortified foods. This proportion was lower among non-Hispanic black women (5.0%) than among non-Hispanic white (8.9%) or Hispanic (6.8%) women. A smaller percentage of non-Hispanic black (19.1%) and Hispanic (21%) women than of non-Hispanic white women (40.5%) consumed >or=400 microg folic acid from supplements, fortified foods, or both, in addition to food folate, as recommended by the Institute of Medicine to reduce the frequency of neural tube defects., Conclusions: Most nonpregnant women of childbearing age in the United States reported consuming less than the recommended amount of folic acid. The proportion with low daily folic acid intake was significantly higher in non-Hispanic black and Hispanic women than in non-Hispanic white women. At the present level of folic acid fortification, most women need to take a folic acid-containing dietary supplement to achieve the Institute of Medicine recommendation.

Background: In the United States and Canada, folic acid fortification of enriched grain products was fully implemented by 1998. The resulting population-wide reduction in blood homocysteine concentrations might be expected to reduce stroke mortality if high homocysteine levels are an independent risk factor for stroke., Methods and Results: In this population-based cohort study with quasi-experimental intervention, we used segmented log-linear regression to evaluate trends in stroke-related mortality before and after folic acid fortification in the United States and Canada and, as a comparison, during the same period in England and Wales, where fortification is not required. Average blood folate concentrations increased and homocysteine concentrations decreased in the United States after fortification. The ongoing decline in stroke mortality observed in the United States between 1990 and 1997 accelerated in 1998 to 2002 in nearly all population strata, with an overall change from -0.3% (95% CI, -0.7 to 0.08) to -2.9 (95% CI, -3.5 to -2.3) per year (P=0.0005). Sensitivity analyses indicate that changes in other major recognized risk factors are unlikely to account for the reduced number of stroke-related deaths in the United States. The fall in stroke mortality in Canada averaged -1.0% (95% CI, -1.4 to -0.6) per year from 1990 to 1997 and accelerated to -5.4% (95% CI, -6.0 to -4.7) per year in 1998 to 2002 (P< or =0.0001). In contrast, the decline in stroke mortality in England and Wales did not change significantly between 1990 and 2002., Conclusions: The improvement in stroke mortality observed after folic acid fortification in the United States and Canada but not in England and Wales is consistent with the hypothesis that folic acid fortification helps to reduce deaths from stroke.

Objective: The United States food supply has been fortified with folic acid since 1998. Information about folate levels early in pregnancy before the fortification is limited. This study examined the associations between serum folate at first prenatal visit and maternal race/ethnicity, age, vitamin use, and body mass index., Study Design: This cross-sectional study assessed serum folate levels among 9421 women who entered prenatal care in 1999 and 2000 in southern California. Information on race/ethnicity, vitamin use, weight, height, and age was obtained from surveys and birth certificates., Results: After adjustment for vitamin use, the strongest predictor of serum folate level, being in the lowest folate quartile (< or = 16 ng/mL) was related independently to being of black, Hispanic, or Asian/Pacific Islander race/ethnicity, being younger age, and being overweight or obese., Conclusion: After food fortification with folic acid, differences in serum folate values in pregnant women by maternal race/ethnicity, age, and body mass index persisted.

Objectives: To evaluate the effectiveness of policies and recommendations on folic acid aimed at reducing the occurrence of neural tube defects., Design: Retrospective cohort study of births monitored by birth defect registries., Setting: 13 birth defects registries monitoring rates of neural tube defects from 1988 to 1998 in Norway, Finland, Northern Netherlands, England and Wales, Ireland, France (Paris, Strasbourg, and Central East), Hungary, Italy (Emilia Romagna and Campania), Portugal, and Israel. Cases of neural tube defects were ascertained among liveborn infants, stillbirths, and pregnancy terminations (where legal). Policies and recommendations were ascertained by interview and literature review., Main Outcome Measures: Incidences and trends in rates of neural tube defects before and after 1992 (the year of the first recommendations) and before and after the year of local recommendations (when applicable)., Results: The issuing of recommendations on folic acid was followed by no detectable improvement in the trends of incidence of neural tube defects., Conclusions: Recommendations alone did not seem to influence trends in neural tube defects up to six years after the confirmation of the effectiveness of folic acid in clinical trials. New cases of neural tube defects preventable by folic acid continue to accumulate. A reasonable strategy would be to quickly integrate food fortification with fuller implementation of recommendations on supplements.

Background: Since fortification of cereal grain products with synthetic folic acid (FA) became mandatory in January 1998, women in the United States who have become pregnant have been exposed to a higher level of FA than women who became pregnant previously. Some studies have suggested that increased FA consumption might increase the risk of multiple gestation pregnancies., Methods: Women who had a live birth in Kaiser Foundation Health Plan hospitals from January 1, 1994 through December 31, 2000; all multiple births; and the use of ovulation-inducing drugs were ascertained from electronic databases. Medical records of a sample of women with multiple births who did not use ovulation-inducing drugs were reviewed to determine whether they used assisted reproductive technology. Exposure to FA-fortified foods was based on date of delivery., Results: The rate of multiple births increased from 13.6 to 14.8 per 1000 live births from 1994 through 2000. The percentage of women who had a multiple birth and who filled a prescription for an ovulation-inducing drug in the 12 months before delivery increased from a low of 6.6% in 1994 to a high of 14.9% in 2000. After excluding women using ovulation-inducing drugs, the increased rate of multiple births was no longer observed., Conclusions: While the rates of multiple births have increased since FA fortification became mandatory, this increase can be explained by the increased use of ovulation-inducing drugs. Our findings show no relationship between food fortification with FA and the rates of multiple births in this large, managed health care population.

Background: Neural tube defect (NTD) rates can be lowered by increased consumption of folic acid (FA) by women before and during early pregnancy. The crude proportion of reproductive-aged women taking FA supplements has been used to predict a decline of the NTD rate in the general population. In this study we examine the potential error in using the crude proportion to predict NTD risk reduction, and offer an alternative method., Methods: The crude proportion measures the number of women taking FA. It ignores the substantial variability by maternal age in the probability of giving birth. Age-specific fertility rates (ASFRs) reflect the probability that a woman in a specific age group will give birth in a given year. In this study, we show how to calculate a proportion weighted by ASFRs to predict a decline in the NTD rate, and to assess the effectiveness of FA consumption in preventing NTDs., Results: Our results show that a crude proportion of 50% of women (15-49 years old) taking FA is associated with a range of 24-77% in weighted proportions. Assuming a 40% risk reduction from taking 400 microg of FA daily, the expected NTD rate decline could vary from 9.6% to 30.6%, depending on the age distribution of women taking FA., Conclusions: The ASFR-weighted proportion estimates the proportion of babies born to women taking FA, as opposed to the crude proportion of women taking FA. We recommend using the ASFR-weighted proportion to predict an NTD rate decline and measure the success of FA education campaigns. We found that when women in high-fertility age groups increased their FA consumption, the decline in the NTD rate was greater than when women in low-fertility age groups did so. Our findings suggest that the more efficient approach to NTD prevention is to focus on women with a higher probability of giving birth. For example, by focusing on <50% of women of childbearing age (20-34 years), as much as 76% of the maximum NTD rate reduction can be achieved.

Since January 2000 the Chilean Ministry of Health has required the fortification of wheat flour with folic acid (FA) at a concentration of 2.2 mg FA/kg in order to reduce the risk of neural tube defects (NTD) in newborns. This policy was expected to result in a mean additional intake of approximately 400 microg FA/d. We assessed the effectiveness of the FA flour fortification program on bread folate content and on blood folate concentration in women of childbearing age in Santiago, Chile. The prefortification folate status of 751 healthy women of reproductive age was assessed. The folate content of 100 bread samples bought at retail bakeries was measured, average wheat flour consumption was estimated and postfortification FA dietary intake was calculated. The effect of flour fortification on blood folate concentration in this group of women (n = 605) was evaluated in a follow-up study. Blood folate concentrations of the 605 women in the follow-up group increased (P < 0.0001) following fortification. Before fortification the mean serum and red blood cell folate concentrations were 9.7 +/- 4.3 and 290 +/- 102 nmol/L, respectively, compared with 37.2 +/- 9.5 and 707 +/- 179 nmol/L postfortification, respectively. The mean FA content of bread was 2020 +/- 940 micro g/kg. The median FA intake of the group evaluated postfortification was 427 microg/d (95% CI 409-445) based on an estimated intake of 219 g/d (95% CI 201-229) of wheat flour, mainly as bread. Fortification of wheat flour substantially improved folate status in a population of women of reproductive age in Chile. The effect of the FA fortification program on the occurrence of NTD is currently being assessed.

Congenital heart defects are among the most common congenital anomalies and are the leading cause of infant death due to congenital anomalies. Except for a few known measures, effective primary prevention is not yet feasible for most heart anomalies. Recent reports have associated the use of multivitamin supplements around the time of conception and during early pregnancy with a reduced risk for heart defects in the offspring. We review and discuss the evidence and suggest a framework for further investigation in this area.

Background: Periconceptional folic acid use reduces the risk of neural tube defects and possibly other birth defects. The effectiveness of two interventions to increase the use of multivitamins among women of childbearing ages was evaluated., Methods: Quasi-experimental interrupted time series design with a nonequivalent control group. Participants included female members of Kaiser Foundation Health Plan aged 18 to 39 years residing in the three geographic service areas of California under study from 1998 through 2000. The central component of the direct mail/pharmacy information intervention was the mailing of "starter kits" of 100 multivitamins, while the provider education intervention used primary care providers to deliver the study message. Main outcomes included the use of multivitamins containing folic acid at least four times per week ("regularly"), intention to use multivitamins regularly, and knowledge and attitudes about multivitamins. Outcomes were measured via telephone interviews of nonpregnant women of childbearing age., Results: A total of 3438 women were interviewed. There was a small but significant increase in the percentage of women using multivitamins in the direct mail/pharmacy information intervention group at the beginning of the intervention period (p =0.006), but this increase was not sustained after the interventions ended. No other significant change was observed., Conclusions: Despite our ability to reach many women of childbearing age with multiple messages about regularly using multivitamins, only a small temporary increase was found in the percentage of women using multivitamins who received the messages in the mail. Other interventions and further evaluation of the impact of food fortification with folic acid should be considered.

Background: Folic acid supplements are recommended for women of childbearing age to prevent neural tube defects in their offspring. Results of some studies, however, suggest an increase in multiple births associated with use of vitamin supplements that contain folic acid during pregnancy. Our aim was to assess this association., Methods: We used data from a population-based cohort study from which we assessed the occurrence of multiple births in women (n=242015) who had participated in a campaign to prevent neural tube defects with folic acid supplements (400 microg per day) in China. Folic acid use was ascertained before pregnancy outcome was known. We studied the relation between multiple births and any use of folic acid pills before or during early pregnancy; additionally, we investigated mechanisms by which folic acid could potentially affect the occurrence of multiple births by examining pill-taking at three time periods: before ovulation, around the time of fertilisation, and after conception., Findings: 1496 (0.62%) multiple births occurred in a cohort of 242015 women who had registered with the study between October, 1993, and September, 1995, and who had a pregnancy not affected by a birth defect; the rate of multiple births in women who did and did not take folic acid before or during early pregnancy was 0.59% and 0.65%, respectively (rate ratio 0.91; 95% CI 0.82-1.00)., Interpretation: Our findings suggest that consumption of folic acid supplements during pregnancy is not associated with an increased occurrence of multiple births.

Background: Folic acid intake is the most important predictor of blood folate concentrations among nonpregnant women, but the reporting of folic acid-containing supplement use is subject to error., Objective: We assessed the effect of reporting error of supplement use on blood folate concentrations., Design: Data from the third National Health and Nutrition Examination Survey were analyzed. Respondents to that survey were asked twice about supplement use: ie, during the household interview, to recall use in the previous month, and during the physical examination, to recall use in the previous 24 h. To examine the effect of error reporting, we classified women (aged 15-44 y) into 5 groups according to supplement use in the previous month (nonusers, those ingesting < 400 micro g/d, and those ingesting >or= 400 micro g/d) and in the 24 h before the physical examination (yes or no). We expected nonappreciable differences in red blood cell (RBC) folate concentration by status of 24-h recall within the same category of previous-month use because RBC folate reflects long-term average consumption. We calculated covariate-adjusted means of serum and RBC folate concentrations., Results: Among women who reported average daily use of >or= 400 micro g folic acid in the previous month, the adjusted mean RBC folate was 436.5 nmol/L (95% CI: 406.7, 466.3 nmol/L) in those who did not take the supplement in the previous 24 h and 519.7 nmol/L (95% CI: 496.2, 543.2 nmol/L) in those who did do so (P < 0.01). This significant difference indicates apparently erroneous reporting of supplement use in the previous month by some participants., Conclusion: The effect of reporting error on blood folate concentrations is important in interpreting survey results, evaluating health education campaigns, and identifying populations needing special education programs.

In September 1992, the U.S. Public Health Service (USPHS) recommended that all women capable of becoming pregnant should consume 400 microg of folic acid/day on an ongoing basis to reduce their risk for having a pregnancy affected by spina bifida and anencephaly (i.e., neural tube defects [NTDs]). The recommendation was preceded a year earlier by a CDC recommendation for women at high risk (i.e., those women who have had an earlier pregnancy affected by an NTD). The 1991 CDC recommendation stated that women at high risk should plan subsequent pregnancies and consume 4,000 microg/day of folic acid from the time they begin trying to become pregnant through the first trimester of pregnancy to reduce their risk. The 1992 USPHS recommendation specified that women at high risk should follow the general population recommendation for consumption of 400 microg/day when not trying to become pregnant.

Background: Although taking supplements that contain 400 microg of folic acid before and during early pregnancy reduces a woman's risk for having a baby with a neural-tube defect (NTD), the effects of such supplements on other pregnancy outcomes remain unclear. We examined whether the use of such supplements affects the occurrence of miscarriage., Methods: Participants were women in China who had taken part in a recent folic acid campaign to prevent NTDs and who had registered in this campaign before they became pregnant for the first time. We examined the risk for miscarriage among women who had confirmed pregnancies and who had or had not taken pills containing only 400 microg of folic acid before and during early pregnancy., Results: The overall rate of miscarriage was 9.1% (2155/23806). The rates of miscarriage among women who had and had not taken folic acid pills before and during the first trimester were 9.0% and 9.3%, respectively (risk ratio 0.97 [95% CI 0.84-1.12]). The distributions of gestational age at pregnancy diagnosis and at miscarriage were similar for both groups of women., Interpretation: In this population-based study of a cohort of women whose use of folic acid supplements while pregnant had been previously documented and who had been pregnant for the first time, we found no evidence that daily consumption of 400 microg of folic acid before and during early pregnancy influenced their risk for miscarriage.

Context: Daily consumption of 400 microg of folic acid before conception and during early pregnancy dramatically reduces the occurrence of neural tube defects (NTDs). Before food fortification, however, only an estimated 29% of US reproductive-aged women were taking a supplement containing 400 microg of folic acid daily. The US Food and Drug Administration authorized addition of folic acid to enriched grain products in March 1996, with compliance mandatory by January 1998., Objective: To evaluate the impact of food fortification with folic acid on NTD birth prevalence., Design, Setting, and Population: National study of birth certificate data for live births to women in 45 US states and Washington, DC, between January 1990 and December 1999., Main Outcome Measure: Birth certificate reports of spina bifida and anencephaly before fortification (October 1995 through December 1996) compared with after mandatory fortification (October 1998 through December 1999)., Results: The birth prevalence of NTDs reported on birth certificates decreased from 37.8 per 100 000 live births before fortification to 30.5 per 100 000 live births conceived after mandatory folic acid fortification, representing a 19% decline (prevalence ratio [PR], 0.81; 95% confidence interval [CI], 0.75-0.87). During the same period, NTD birth prevalence declined from 53.4 per 100 000 to 46.5 per 100 000 (PR, 0.87; 95% CI, 0.64-1.18) for women who received only third-trimester or no prenatal care., Conclusions: A 19% reduction in NTD birth prevalence occurred following folic acid fortification of the US food supply. However, factors other than fortification may have contributed to this decline.

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.

The results of the British Medical Research Council's randomized controlled trial proved that folic acid can prevent spina bifida and anencephaly. The trial provided critical scientific data upon which to base public health policy for preventing folic acid-preventable spina bifida and anencephaly. Within weeks of publication of the results, the Centers for Disease Control and Prevention in the US developed and issued guidelines for women who had had a pregnancy affected by spina bifida or anencephaly. A year later, the US Public Health Service issued the recommendation that all women of child-bearing age who are capable of becoming pregnant should consume 0.4 mg of folic acid per day. The Public Health Service needed a year to make inferential judgements about dose, target groups, safety, timing of ingestion, and existing and proposed vitamin and drug policies and regulations. Current policy discussions concern whether to permit manufacturers of vitamins or food products to claim that folic acid will prevent folic acid-preventable spina bifida and anencephaly and whether to allow a food staple to be fortified with folic acid.

Investigates the relation of folic acid supplementation to the occurrence of miscarriage during early pregnancy in China. Determination of the overall rate of clinically recognized miscarriage; Absence of evidence for related effects of folic acid.