Vitamin D Levels in Black Americans and the Association With Left Ventricular Remodeling and Incident Heart Failure With Preserved Ejectin Fraction: The Jackson Heart Study.

BACKGROUND: In observational studies, a lower serum vitamin D3 concentration has been associated with an increased risk of cardiovascular disease. However, the associations between serum vitamin D3 levels and left ventricular (LV) structure and heart failure with preserved ejection fraction (HFpEF) have not been well-characterized among Black Americans. The prevalence of vitamin D3 deficiency is higher among Black Americans than in other race/ethnicity groups. We hypothesized that serum vitamin D3 levels are associated with LV concentric remodeling and incident HFpEF in Black Americans. METHODS AND RESULTS: Among 5306 Black Americans in the Jackson Heart Study cohort, we investigated the relationships between serum vitamin D3 levels and LV structure and function, evaluated with echocardiography, and incident HF hospitalization, categorized as either HF with reduced EF (HFrEF; an EF of <50%) or HFpEF (an EF of ≥50%). After adjustment for possible confounding factors, lower vitamin D3 levels were associated with greater relative wall thickness (ß for 1 standard deviation [SD] increase -0.003, 95% confidence interval -0.005 to -0.000). Over a median follow-up period of 11 years (range 10.2-11.0 years), 340 participants developed incident HF (7.88 cases per 1000 person-years), including 146 (43%) HFrEF and 194 (57%) HFpEF cases. After adjustment, higher serum vitamin D3 levels were associated with decreased hazard for HF overall (hazard ratio for 1 SD increase 0.88, 95% confidence interval 0.78-0.99) driven by a significant association with HFpEF (hazard ratio for 1 SD increase 0.84, 95% confidence interval 0.71-0.99). CONCLUSIONS: In this community-based Black American cohort, lower serum vitamin D3 levels were associated with LV concentric remodeling and an increased hazard for HF, mainly HFpEF. Further investigation is required to examine whether supplementation with vitamin D3 can prevent LV concentric remodeling and incident HFpEF in Black Americans.

Cost-effectiveness of Contemporary Statin Use Guidelines With or Without Coronary Artery Calcium Assessment in African American Individuals.

Importance: Clinical and economic consequences of statin treatment guidelines supplemented by targeted coronary artery calcium (CAC) assessment have not been evaluated in African American individuals, who are at increased risk for atherosclerotic cardiovascular disease and less likely than non-African American individuals to receive statin therapy. Objective: To evaluate the cost-effectiveness of the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guideline without a recommendation for CAC assessment vs the 2018 ACC/AHA guideline recommendation for use of a non-0 CAC score measured on one occasion to target generic-formulation, moderate-intensity statin treatment in African American individuals at risk for atherosclerotic cardiovascular disease. Design, Setting, and Participants: A microsimulation model was designed to estimate life expectancy, quality of life, costs, and health outcomes over a lifetime horizon. African American-specific data from 472 participants in the Jackson Heart Study (JHS) at intermediate risk for atherosclerotic cardiovascular disease and other US population-specific data on individuals from published sources were used. Data analysis was conducted from November 11, 2018, to November 1, 2019. Main Outcomes and Measures: Lifetime costs and quality-adjusted life-years (QALYs), discounted at 3% annually. Results: In a model-based economic evaluation informed in part by follow-up data, the analysis was focused on 472 individuals in the JHS at intermediate risk for atherosclerotic cardiovascular disease; mean (SD) age was 63 (6.7) years. The sample included 243 women (51.5%) and 229 men (48.5%). Of these, 178 of 304 participants (58.6%) who underwent CAC assessment had a non-0 CAC score. In the base-case scenario, implementation of 2013 ACC/AHA guidelines without CAC assessment provided a greater quality-adjusted life expectancy (0.0027 QALY) at a higher cost ($428.97) compared with the 2018 ACC/AHA guideline strategy with CAC assessment, yielding an incremental cost-effectiveness ratio of $158 325/QALY, which is considered to represent low-value care by the ACC/AHA definition. The 2018 ACC/AHA guideline strategy with CAC assessment provided greater quality-adjusted life expectancy at a lower cost compared with the 2013 ACC/AHA guidelines without CAC assessment when there was a strong patient preference to avoid use of daily medication therapy. In probability sensitivity analyses, the 2018 ACC/AHA guideline strategy with CAC assessment was cost-effective compared with the 2013 ACC/AHA guidelines without CAC assessment in 76% of simulations at a willingness-to-pay value of $100 000/QALY when there was a preference to lose 2 weeks of perfect health to avoid 1 decade of daily therapy. Conclusions and Relevance: A CAC assessment-guided strategy for statin therapy appears to be cost-effective compared with initiating statin therapy in all African American individuals at intermediate risk for atherosclerotic cardiovascular disease and may provide greater quality-adjusted life expectancy at a lower cost than a non-CAC assessment-guided strategy when there is a strong patient preference to avoid the need for daily medication. Coronary artery calcium testing may play a role in shared decision-making regarding statin use.

Deep Learning for Automatic Calcium Scoring in CT: Validation Using Multiple Cardiac CT and Chest CT Protocols.

Background Although several deep learning (DL) calcium scoring methods have achieved excellent performance for specific CT protocols, their performance in a range of CT examination types is unknown. Purpose To evaluate the performance of a DL method for automatic calcium scoring across a wide range of CT examination types and to investigate whether the method can adapt to different types of CT examinations when representative images are added to the existing training data set. Materials and Methods The study included 7240 participants who underwent various types of nonenhanced CT examinations that included the heart: coronary artery calcium (CAC) scoring CT, diagnostic CT of the chest, PET attenuation correction CT, radiation therapy treatment planning CT, CAC screening CT, and low-dose CT of the chest. CAC and thoracic aorta calcification (TAC) were quantified using a convolutional neural network trained with (a) 1181 low-dose chest CT examinations (baseline), (b) a small set of examinations of the respective type supplemented to the baseline (data specific), and (c) a combination of examinations of all available types (combined). Supplemental training sets contained 199-568 CT images depending on the calcium burden of each population. The DL algorithm performance was evaluated with intraclass correlation coefficients (ICCs) between DL and manual (Agatston) CAC and (volume) TAC scoring and with linearly weighted κ values for cardiovascular risk categories (Agatston score; cardiovascular disease risk categories: 0, 1-10, 11-100, 101-400, >400). Results At baseline, the DL algorithm yielded ICCs of 0.79-0.97 for CAC and 0.66-0.98 for TAC across the range of different types of CT examinations. ICCs improved to 0.84-0.99 (CAC) and 0.92-0.99 (TAC) for CT protocol-specific training and to 0.85-0.99 (CAC) and 0.96-0.99 (TAC) for combined training. For assignment of cardiovascular disease risk category, the κ value for all test CT scans was 0.90 (95% confidence interval [CI]: 0.89, 0.91) for the baseline training. It increased to 0.92 (95% CI: 0.91, 0.93) for both data-specific and combined training. Conclusion A deep learning calcium scoring algorithm for quantification of coronary and thoracic calcium was robust, despite substantial differences in CT protocol and variations in subject population. Augmenting the algorithm training with CT protocol-specific images further improved algorithm performance. © RSNA, 2020 See also the editorial by Vannier in this issue.

The Dietary Fructose:Vitamin C Intake Ratio Is Associated with Hyperuricemia in African-American Adults.

Background: A high fructose intake has been shown to be associated with increased serum urate concentration, whereas ascorbate (vitamin C) may lower serum urate by competing with urate for renal reabsorption. Objective: We assessed the combined association, as the fructose:vitamin C intake ratio, and the separate associations of dietary fructose and vitamin C intakes on prevalent hyperuricemia. Methods: We conducted cross-sectional analyses of dietary intakes of fructose and vitamin C and serum urate concentrations among Jackson Heart Study participants, a cohort of African Americans in Jackson, Mississippi, aged 21-91 y. In the analytic sample (n = 4576), multivariable logistic regression was used to examine the separate associations of dietary intakes of fructose and vitamin C and the fructose:vitamin C intake ratio with prevalent hyperuricemia (serum urate ≥7 mg/dL), after adjusting for age, sex, smoking, waist circumference, systolic blood pressure, estimated glomerular filtration rate, diuretic medication use, vitamin C supplement use, total energy intake, alcohol consumption, and dietary intake of animal protein. Analyses for individual dietary factors (vitamin C, fructose) were adjusted for the other dietary factor. Results: In the fully adjusted model, there were 17% greater odds of hyperuricemia associated with a doubling of the fructose:vitamin C intake ratio (OR: 1.17; 95% CI: 1.08, 1.28), 20% greater odds associated with a doubling of fructose intake (OR: 1.20; 95% CI: 1.08, 1.34), and 13% lower odds associated with a doubling of vitamin C intake (OR: 0.87; 95% CI: 0.78, 0.97). Dietary fructose and the fructose:vitamin C intake ratio were more strongly associated with hyperuricemia among men than women (P-interaction ≤ 0.04). Conclusion: Dietary intakes of fructose and vitamin C are associated with prevalent hyperuricemia in a community-based population of African Americans.

Maternal intake of vitamin E and birth defects, national birth defects prevention study, 1997 to 2005.

BACKGROUND: In a recent study, high maternal periconceptional intake of vitamin E was found to be associated with risk of congenital heart defects (CHDs). To explore this association further, we investigated the association between total daily vitamin E intake and selected birth defects. METHODS: We analyzed data from 4525 controls and 8665 cases from the 1997 to 2005 National Birth Defects Prevention Study. We categorized estimated periconceptional energy-adjusted total daily vitamin E intake from diet and supplements into quartiles (referent, lowest quartile). Associations between quartiles of energy-adjusted vitamin E intake and selected birth defects were adjusted for demographic, lifestyle, and nutritional factors. RESULTS: We observed a statistically significant association with the third quartile of vitamin E intake (odds ratio [OR], 1.17; 95% confidence interval [CI], 1.01-1.35) and all CHDs combined. Among CHD sub-types, we observed associations with left ventricular outflow tract obstruction defects, and its sub-type, coarctation of the aorta and the third quartile of vitamin E intake. Among defects other than CHDs, we observed associations between anorectal atresia and the third quartile of vitamin E intake (OR, 1.66; 95% CI, 1.01-2.72) and hypospadias and the fourth quartile of vitamin E intake (OR, 1.42; 95% CI, 1.09-1.87). CONCLUSION: Selected quartiles of energy-adjusted estimated total daily vitamin E intake were associated with selected birth defects. However, because these few associations did not exhibit exposure-response patterns consistent with increasing risk associated with increasing intake of vitamin E, further studies are warranted to corroborate our findings.

Hypospadias and maternal intake of phytoestrogens.

Experimental data indicate that gestational exposures to estrogenic compounds impact risk of hypospadias. We examined whether risk of hypospadias (i.e., a congenital malformation in which the opening of the penile urethra occurs on the ventral side of the penis) was associated with maternal intake of phytoestrogens, given their potential impact on estrogen metabolism. The analysis included data on mothers of 1,250 hypospadias cases and 3,118 controls who delivered their infants from 1997 to 2005 and participated in the National Birth Defects Prevention Study, a multistate, population-based, case-control study. After adjustment for several covariates, high intakes of daidzein, genistein, glycetin, secoisolariciresinol, total isoflavones, total lignans, and total phytoestrogens were associated with reduced risks; odds ratios comparing intakes ≥90th percentile with intakes between the 11th and 89th percentiles ranged from 0.6 to 0.8. For example, the odds ratio for total phytoestrogen intake was 0.7 (95% confidence interval: 0.5, 1.0). This study represents the first large-scale analysis of phytoestrogen intake and hypospadias. The observed associations merit investigation in additional populations before firm conclusions can be reached.

Maternal occupational exposure to polycyclic aromatic hydrocarbons and congenital heart defects among offspring in the national birth defects prevention study.

BACKGROUND: There is evidence in experimental model systems that exposure to polycyclic aromatic hydrocarbons (PAHs) results in congenital heart defects (CHDs); however, to our knowledge, this relationship has not been examined in humans. Therefore, we conducted a case-control study assessing the association between estimated maternal occupational exposure to PAHs and CHDs in offspring. METHODS: Data on CHD cases and control infants were obtained from the National Birth Defects Prevention Study for the period of 1997 to 2002. Exposure to PAHs was assigned by industrial hygienist consensus, based on self-reported maternal occupational histories from 1 month before conception through the third month of pregnancy. Logistic regression was used to evaluate the association between maternal occupational PAH exposure and specific CHD phenotypic subtypes among offspring. RESULTS: The prevalence of occupational PAH exposure was 4.0% in CHD case mothers (76/1907) and 3.6% in control mothers (104/2853). After adjusting for maternal age, race or ethnicity, education, smoking, folic acid supplementation, and study center, exposure was not associated with conotruncal defects (adjusted odds ratio [AOR], 0.98; 95% confidence interval [CI], 0.58-1.67), septal defects (AOR, 1.28; 95% CI, 0.86-1.90), or with any isolated CHD subtype. CONCLUSIONS: Our findings do not support an association between potential maternal occupational exposure to PAHs and various CHDs in a large, population-based study. For CHD phenotypic subtypes in which modest nonsignificant associations were observed, future investigations could be improved by studying populations with a higher prevalence of PAH exposure and by incorporating information on maternal and fetal genotypes related to PAH metabolism. Birth Defects Research (Part A), 2012.

Maternal occupational exposure to organic solvents during early pregnancy and risks of neural tube defects and orofacial clefts.

OBJECTIVES: Though toxicological experiments demonstrate the teratogenicity of organic solvents in animal models, epidemiologic studies have reported inconsistent results. Using data from the population-based National Birth Defects Prevention Study, the authors examined the relation between maternal occupational exposure to aromatic solvents, chlorinated solvents and Stoddard solvent during early pregnancy and neural tube defects (NTDs) and orofacial clefts (OFCs). METHODS: Cases of NTDs (anencephaly, spina bifida and encephalocoele) and OFCs (cleft lip ± cleft palate and cleft palate alone) delivered between 1997 and 2002 were identified by birth defect surveillance registries in eight states; non-malformed control infants were selected using birth certificates or hospital records. Maternal solvent exposure was estimated by industrial hygienist review of self-reported occupational histories in combination with a literature-derived exposure database. ORs and 95% CIs for the association between solvent class and each birth defect group and component phenotype were estimated using multivariable logistic regression, adjusting for maternal age, race/ethnicity, education, pre-pregnancy body mass index, folic acid supplement use and smoking. RESULTS: The prevalence of exposure to any solvent among mothers of NTD cases (n = 511), OFC cases (n = 1163) and controls (n = 2977) was 13.1%, 9.6% and 8.2%, respectively. Exposure to chlorinated solvents was associated with increased odds of NTDs (OR = 1.96, CI 1.34 to 2.87), especially spina bifida (OR = 2.26, CI 1.44 to 3.53). No solvent class was strongly associated with OFCs in these data. CONCLUSIONS: The findings suggest that maternal occupational exposure to chlorinated solvents during early pregnancy is positively associated with the prevalence of NTDs in offspring.

Lack of periconceptional vitamins or supplements that contain folic acid and diabetes mellitus-associated birth defects.

OBJECTIVE: The purpose of this study was to examine the risk of birth defects in relation to diabetes mellitus and the lack of use of periconceptional vitamins or supplements that contain folic acid. STUDY DESIGN: The National Birth Defects Prevention Study (1997-2004) is a multicenter, population-based case-control study of birth defects (14,721 cases and 5437 control infants). Cases were categorized into 18 types of heart defects and 26 noncardiac birth defects. We estimated odds ratios for independent and joint effects of preexisting diabetes mellitus and a lack of periconceptional use of vitamins or supplements that contain folic acid. RESULTS: The pattern of odds ratios suggested an increased risk of defects that are associated with diabetes mellitus in the absence vs the presence of the periconceptional use of vitamins or supplements that contain folic acid. CONCLUSION: The lack of periconceptional use of vitamins or supplements that contain folic acid may be associated with an excess risk for birth defects due to diabetes mellitus.

Hypospadias and intake of nutrients related to one-carbon metabolism.

PURPOSE: We examined whether hypospadias is associated with maternal intake of folic acid containing vitamin/mineral supplements or dietary intake of nutrients related to one-carbon metabolism (folate, choline, vitamins B12 and B6, thiamine, riboflavin, methionine and zinc). MATERIALS AND METHODS: The study included births from October 1997 to December 2003 that were part of the National Birth Defects Prevention Study. Diet was assessed by food frequency questionnaire during maternal telephone interviews. Analyses included 915 cases with second or third degree hypospadias (urethra opened at the penile shaft, scrotum or perineum) and 2,266 male, liveborn, nonmalformed controls. All ORs and 95% CIs were estimated from logistic regression models that included several potential confounders. Nutrient based analyses also included energy intake. RESULTS: Hypospadias risk was not associated with supplement use (adjusted ORs were 1.2, 95% CI 0.9-1.6 for intake beginning in the month before or the first month of pregnancy and 1.1, 95% CI 0.8-1.4 for intake beginning in the second or third month, relative to no intake). Among women who took supplements reduced hypospadias risk was associated with higher dietary intakes of choline, methionine and vitamin B12. The respective ORs (CIs) for the highest vs lowest quartiles were 0.7 (0.5-1.1), 0.6 (0.4-0.9) and 0.7 (0.5-1.0). Among women who did not take supplements increased risk of hypospadias was associated with higher vitamin B12 intake. The OR (CI) for the highest vs lowest quartile was 3.1 (1.1-9.0). CONCLUSIONS: This study suggests an association of hypospadias with intake of certain nutrients related to one-carbon metabolism.

Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics.

Prevention of congenital cardiovascular defects has been hampered by a lack of information about modifiable risk factors for abnormalities in cardiac development. Over the past decade, there have been major breakthroughs in the understanding of inherited causes of congenital heart disease, including the identification of specific genetic abnormalities for some types of malformations. Although relatively less information has been available on noninherited modifiable factors that may have an adverse effect on the fetal heart, there is a growing body of epidemiological literature on this topic. This statement summarizes the currently available literature on potential fetal exposures that might alter risk for cardiovascular defects. Information is summarized for periconceptional multivitamin or folic acid intake, which may reduce the risk of cardiac disease in the fetus, and for additional types of potential exposures that may increase the risk, including maternal illnesses, maternal therapeutic and nontherapeutic drug exposures, environmental exposures, and paternal exposures. Information is highlighted regarding definitive risk factors such as maternal rubella; phenylketonuria; pregestational diabetes; exposure to thalidomide, vitamin A cogeners, or retinoids; and indomethacin tocolysis. Caveats regarding interpretation of possible exposure-outcome relationships from case-control studies are given because this type of study has provided most of the available information. Guidelines for prospective parents that could reduce the likelihood that their child will have a major cardiac malformation are given. Issues related to pregnancy monitoring are discussed. Knowledge gaps and future sources of new information on risk factors are described.

Maternal caffeine consumption and risk of cardiovascular malformations.

BACKGROUND: The physiologic effects and common use of caffeine during pregnancy call for examination of maternal caffeine consumption and risk of birth defects. Epidemiologic studies have yielded mixed results, but such studies have grouped etiologically different defects and have not evaluated effect modification. METHODS: The large sample size and precise case classification of the National Birth Defects Prevention Study allowed us to examine caffeine consumption and specific cardiovascular malformation (CVM) case groups. We studied consumption of caffeinated coffee, tea, soda, and chocolate to estimate total caffeine intake and separately examined exposure to each caffeinated beverage. Smoking, alcohol, vasoactive medications, folic acid supplement use, and infant gender were evaluated for effect modification. Maternal interview reports for 4,196 CVM case infants overall and 3,957 control infants were analyzed. RESULTS: We did not identify any significant positive associations between maternal caffeine consumption and CVMs. For tetralogy of Fallot, nonsignificant elevations in risk were observed for moderate (but not high) caffeine intake overall and among nonsmokers (ORs of 1.3 to 1.5). Risk estimates for both smoking and consuming caffeine were less than the sum of the excess risks for each exposure. We observed an inverse trend between coffee intake and risk of atrial septal defect; however, this single significant pattern of association might have been a chance finding. CONCLUSIONS: Our study found no evidence for an appreciable teratogenic effect of caffeine with regard to CVMs.

Are encephaloceles neural tube defects?

OBJECTIVE: Encephalocele is classified as a neural tube defect, but questions have been raised regarding whether its epidemiological characteristics are similar to those of other neural tube defects. DESIGN: We compared characteristics of temporal trends in, and the impact of folic acid grain fortification on, the prevalence of encephalocele, spina bifida, and anencephaly using data from the Metropolitan Atlanta Congenital Defects Program, a population-based birth defects surveillance system. Prevalences of encephalocele, spina bifida, and anencephaly were compared by maternal age, gender, race, birth weight, ascertainment period (1968-1981, 1982-1993, or 1994-2002), and fortification period (1994-1996 [prefortification] and 1998-2002 [postfortification]) using prevalence ratios with 95% confidence intervals. Temporal trends were assessed using Poisson and negative binomial regression models. RESULTS: Prevalence rates of encephalocele (n = 167), spina bifida (n = 650), and anencephaly (n = 431) were 1.4, 5.5, and 3.7 per 10 000 live births, respectively. Encephalocele was similar to anencephaly in showing an increased prevalence among girls and multiple gestation pregnancies and to spina bifida and anencephaly in an annual prevalence decrease between 1968 and 2002 (-1.2% for encephalocele, -4.2% for spina bifida, and -3.6% for anencephaly). With fortification, prevalence decreased for spina bifida but not significantly for encephalocele or anencephaly. CONCLUSIONS: Encephalocele shows more similarities to spina bifida or anencephaly than it shows differences with respect to characteristics, temporal trend, and impact of fortification. Additional studies should be done to explore the etiologic heterogeneity of encephalocele using better markers of folate status and a wider range of risk factors.

Trends in twinning rates in metropolitan Atlanta before and after folic acid fortification.

OBJECTIVE: To examine whether trends in rates of twinning in metropolitan Atlanta increased after folic acid fortification. STUDY DESIGN: Live births to residents of 5 metropolitan Atlanta counties during the period 1990-2001 were identified from the state of Georgia's vital records. Rates of twinning and rate ratios were computed for the periods before and after fortification with folic acid. RESULTS: Of the 510,000 singleton and twin births in metropolitan Atlanta during the study period, 7168 (1.43%) represented twin pregnancies. Overall, the rate of twinning increased 18% (P < .001)from the prefortification to postfortification period. As compared with the rate of twinning during the prefortification period, that during the postfortification period increased by 23% (OR 1.23, 95% CI 1.7, 1.28) among women over 30 years but showed no increase among women <30 years of age (OR 1.02, CI 0.94, 1.10). Among women >30, there was an increasing rate of twinning throughout the prefortification period (4.9%). There was no upward trend in twinning rates among women younger than 30 years prior to fortification. CONCLUSION: Increasing trends of twinning were observed only in women older than 30 years, but these trends began prior to folic acid fortification and reached a plateau in recent years. Further elucidation of the possible relationship between folic acid and twinning will need to account for the use of fertility treatments by older women.

Do multivitamin supplements attenuate the risk for diabetes-associated birth defects?

OBJECTIVE: To evaluate whether the risk for birth defects associated with maternal diabetes is attenuated by use of multivitamin supplements during the periconceptional period. METHODS: In the population-based Atlanta Birth Defects Case-Control Study, we identified case infants who had nonsyndromic birth defects that were reported to be associated with diabetes (n = 3278) and were born during 1968-1980 to residents of metropolitan Atlanta. Controls were infants without birth defects (n = 3029). Maternal diabetes was defined as reported diabetes with onset before the date of birth of the index infant, and periconceptional use of multivitamins was defined as reported regular use of multivitamin supplements from 3 months before pregnancy through the first 3 months of pregnancy. RESULTS: Offspring of mothers with diabetes had an increased risk for selected birth defects. However, the increased risk was limited to offspring of mothers who had diabetes and had not taken multivitamins during the periconceptional period (odds ratio: 3.93; 95% confidence interval: 1.79-8.63). Offspring of mothers who had diabetes and had taken multivitamins during the periconceptional period had no increased risk for birth defects (odds ratio: 0.15; 95% confidence interval: 0.00-1.99). CONCLUSIONS: Periconceptional use of multivitamin supplements may reduce the risk for birth defects among offspring of mothers with diabetes.

Folic acid supplements during early pregnancy and likelihood of multiple births: a population-based cohort study.

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.