Folic acid use and nonsyndromic orofacial clefts in China: a prospective cohort study.

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.

Teratology: from science to birth defects prevention.

One of the goals of birth defects research is to better understand risk or preventive factors for birth defects so that strategies for prevention can be developed. In this article, we have selected four areas of birth defects research that have led to the development of prevention strategies. These areas include rubella virus as a cause of congenital rubella syndrome, folic acid as a preventive factor for neural tube defects, cytomegalovirus infection as a cause of birth defects and developmental disabilities, and alcohol as a cause of fetal alcohol spectrum disorders. For each of these areas, we review key clinical and research findings that led to the identification of the risk or preventive factor, milestones in the development of prevention strategies, and the progress made thus far toward prevention.

Folate status and homocysteine response to folic acid doses and withdrawal among young Chinese women in a large-scale randomized double-blind trial.

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.

Prevalence and effects of gene-gene and gene-nutrient interactions on serum folate and serum total homocysteine concentrations in the United States: findings from the third National Health and Nutrition Examination Survey DNA Bank.

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.

Birth defects among infants born to women who received anthrax vaccine in pregnancy.

In response to bioterrorism threats, anthrax vaccine has been used by the US military and considered for civilian use. Concerns exist about the potential for adverse reproductive health effects among vaccine recipients. This retrospective cohort evaluated birth defects, in relation to maternal anthrax vaccination, among all infants born to US military service women between 1998 and 2004. Department of Defense databases defined maternal vaccination and infant diagnoses; multivariable regression models described potential associations between anthrax vaccination and birth defects in liveborn infants. Among 115,169 infants born to military women during this period, 37,140 were born to women ever vaccinated against anthrax, and 3,465 were born to women vaccinated in the first trimester of pregnancy. Birth defects were slightly more common in first trimester-exposed infants (odds ratio = 1.18, 95% confidence interval: 0.997, 1.41) when compared with infants of women vaccinated outside of the first trimester, but this association was statistically significant only when alternative referent groups were used. Although the small observed association may be unlikely to represent a causal relation between vaccination in early pregnancy and birth defects, this information should be considered when making decisions about administering anthrax vaccine to pregnant women.

Race-ethnicity differences in folic acid intake in women of childbearing age in the United States after folic acid fortification: findings from the National Health and Nutrition Examination Survey, 2001-2002.

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.

Improvement in stroke mortality in Canada and the United States, 1990 to 2002.

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.

Do racial and ethnic differences in serum folate values exist after food fortification with folic acid?

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.

Sex and congenital malformations: an international perspective.

The study evaluated the sex distribution of major isolated malformations and common trisomies among a large and geographically varied sample. Eighteen registries from 24 countries contributed cases, which were centrally reviewed and classified in three clinical types as isolated, associated, or syndromic. We selected cases of 26 major defects (n = 108,534); trisomy 21, 18, and 13 (n = 30,114); other syndromes (n = 2,898); and multiple congenital anomalies (n = 24,197), for a total of 165,743 cases. We observed a significant deviation of sex distribution (compared to a sex ratio of 1.06 or male proportion of 51.4%) for 24 of the 29 groups (a male excess in 16, a female excess in 8), and in 8 of such groups these estimates varied significantly across registries. A male excess was noted for two left obstructive cardiac defects (hypoplastic left heart and coarctation of the aorta) and a female excess for all the main types of neural tube defects. A male excess was seen for omphalocele but not gastroschisis. For neural tube defects the female excess tended to be stronger in areas with historically high prevalence for these defects. For 15 of the 26 birth defects the sex distribution differed among isolated, associated, and syndromic cases. Some of these epidemiologic commonalities are consistent with known or putative developmental processes. Further, the geographic variation for some defects may reflect local prevalence rates and risk factors. Finally, the findings underscore the need for clinical classification (e.g., into isolated, multiple, syndromes) in studies of birth defects.

International retrospective cohort study of neural tube defects in relation to folic acid recommendations: are the recommendations working?

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.

Food fortification with folic acid and rate of multiple births, 1994-2000.

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.

Can we ensure the safe use of known human teratogens? Introduction of generic isotretinoin in the US as an example.

The prescription of known teratogenic medications requires a careful balance between allowing women access to medications that they might need and avoiding unnecessary exposure to these medications during pregnancy because of their devastating fetal effects. Isotretinoin, a potent human teratogen, is of particular concern because of its widespread use among reproductive-aged women and the dramatic increase in use from 1992 through 2000. A revised risk management system was implemented in 2002 because of concerns about the continued occurrence of isotretinoin-exposed pregnancies. However, the recent approval of three generic versions of isotretinoin in the US has further complicated risk management and raises concerns that use might increase further if the lower cost of generics serves to increase accessibility. There are now four separate isotretinoin risk management systems in the US, each with its own distinct packaging, though the requirements for and substance of each are identical. Some additional concrete steps could be taken to minimise any unnecessary use of isotretinoin and help allow an adequate assessment of the current risk management systems. In addition to being familiar with and following all aspects of the current risk management system, physicians could choose to limit the use of isotretinoin to those who meet the labelled indications in order to reduce the number of exposed pregnancies. All four companies currently marketing isotretinoin in the US could jointly and voluntarily establish a consolidated, mandatory registration and follow-up of all women of reproductive potential who receive an isotretinoin prescription. Mandatory registration has many challenges, but it could allow a clear accounting of the total number of women for whom follow-up information is and is not available. Although the companies cannot be legally compelled to use a consolidated approach, the use of a single registry for the originator's product and all generic brands would allow identification of duplicates and also avoid the confusion that is introduced by providing materials that not only look different, but also have different addresses, contact information and names for participation in follow-up surveys. This is particularly important because women might take more than one version of isotretinoin during a single course of therapy or might receive a different programme's materials from their doctor than from the pharmacy. Though the introduction of generic versions of isotretinoin further complicates risk management, the companies marketing isotretinoin have an opportunity to work together to demonstrate their commitment to both limit the occurrence of exposed pregnancies and conduct a meaningful evaluation of the occurrence of pregnancies exposed to isotretinoin.

Autosomal trisomy and maternal use of multivitamin supplements.

Recent reports suggest that women carrying certain polymorphisms of folate genes associated with suboptimal folate status might be at increased risk for having a child with Down syndrome or other autosomal trisomies, and hypothesized that maternal use of multivitamin supplements might reduce such risk. To evaluate this hypothesis, we examined data from a population-based case-control study, and contrasted cases of Down syndrome, trisomy 18, and trisomy 13, with unaffected controls. Periconceptional multivitamin use, compared to no such use, was associated with an odds ratio (OR) of 0.9 (95% confidence interval [CI], 0.6-1.3) for having a pregnancy affected by an autosomal trisomy. The OR was 0.8 (95% CI, 0.5-1.3) for Down syndrome and 1.4 (95% CI, 0.5-3.6) for trisomies 13 and 18, with little variation by maternal race or age. Periconceptional multivitamin use was not associated with a major reduction in the risk for common autosomal trisomies.

Vitamin supplements and the risk for congenital anomalies other than neural tube defects.

Randomized trials, supported by many observational studies, have shown that periconceptional use of folic acid, alone or in multivitamin supplements, is effective for the primary prevention of neural tube defects (NTDs). Whether this is true also for other congenital anomalies is a complex issue and the focus of this review. It is useful to consider the evidence not only for specific birth defects separately but, importantly, also for all birth defects combined. For the latter, the Hungarian randomized clinical trial indicated, for periconceptional multivitamin use, a reduction in the risk for all birth defects (odds ratio (OR) = 0.53, 95% confidence interval (CI) = 0.35-0.70), even after excluding NTDs (OR = 0.53, 95% CI = 0.38-0.75). The Atlanta population-based case-control study, the only large observational study to date on all major birth defects, also found a significant risk reduction for all birth defects (OR = 0.80, 95% CI = 0.69-0.93) even after excluding NTDs (OR = 0.84, 95% CI = 0.72-0.97). These and other studies also evaluated specific anomalies, including those of the heart, limb, and urinary tract, as well as orofacial clefts, omphalocele, and imperforate anus. For cardiovascular anomalies, two studies were negative, whereas three, including the randomized clinical trial, suggest a possible 25-50% overall risk reduction, more marked for some conotruncal and septal defects. For orofacial clefts, six of seven case-control studies suggest an apparent reduced risk, which could vary by cleft type and perhaps, according to some investigators, by pill dosage. For limb deficiencies, three case-control studies and the randomized trial estimated approximately a 50% reduced risk. For urinary tract defects, three case-control studies and the randomized trial reported reduced risks, as did one study of nonsyndromic omphalocele. All these studies examined multivitamin supplement use. With respect to folic acid alone, a reduced rate of imperforate anus was observed among folic acid users in China. We discuss key gaps in knowledge, possible avenues for future research, and counseling issues for families concerned about occurrence or recurrence of these birth defects.

Consumption of folic acid-fortified bread improves folate status in women of reproductive age in Chile.

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.

Do multivitamin or folic acid supplements reduce the risk for congenital heart defects? Evidence and gaps.

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.

A population-based birth defects surveillance system in the People's Republic of China.

We describe a unique birth defects surveillance system in the People's Republic of China. The system was instituted in March 1992 as a component of an evaluation of the effectiveness of a public health campaign using periconceptional folic acid supplementation to prevent neural tube defects, and currently surveys birth cohorts of approximately 150 000 infants per year. Local health care providers collect information in the form of detailed written descriptions and photographs of affected infants. The system allows for detection of birth defects at the local level with later definitive classification and coding; however, information is limited to structural anomalies that are visible on physical examination. This birth defects surveillance system provides an extensive database of infants with major and minor external structural anomalies, including the unique feature of a photographic record for most cases. These data can be used for aetiological studies, descriptive epidemiology and identification of unusual trends.