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1.  Trends in prescription drug abuse and dependence, co-occurrence with other substance use disorders, and treatment utilization: Results from two national surveys 
Addictive behaviors  2008;33(10):1297-1305.
This study examined trends in prescription drug abuse and dependence (sedatives, tranquilizers, opioids, and stimulants), co-occurrence with other substance use disorders and substance abuse treatment utilization among those with diagnoses of prescription drug abuse and dependence in two large, nationally representative, independent samples of adults in the United States in 1991–1992 and 2001–2002.
Two nationally representative cross-sectional samples of civilian noninstitutionalized adults 18 years or older in the United States, of which 52% were women. Data were collected from structured diagnostic interviews using the NIAAA Alcohol Use Disorder and Associated Disabilities Interview Schedule: Diagnostic and Statistical Manual version IV (DSM-IV). National prevalence estimates were derived from the 1991–1992 National Longitudinal Alcohol Epidemiologic Survey (N = 42,862) and the 2001–2002 National Epidemiologic Survey on Alcohol and Related Conditions (N = 43,093).
The past-year prevalence of prescription sedative abuse, sedative dependence, opioid abuse, and opioid dependence increased from 1991–1992 to 2001–2002. The majority of individuals with past-year sedative (56.8%), tranquilizer (89.0%), stimulant (67.9%) and opioid (74.2%) use disorders also met DSM-IV criteria for an additional past-year substance use disorder. The co-occurrence of several forms of prescription drug use disorders and other substance use disorders increased from 1991–1992 to 2001–2002. A minority of individuals with past-year prescription drug abuse and approximately one-half of those with past-year prescription drug dependence utilized substance abuse treatment.
The findings reinforce the importance of continued national monitoring based on the increases in prescription drug abuse and dependence, high co-occurrence with other substance use disorders, and underutilization of substance abuse treatment services.
PMCID: PMC3163593  PMID: 18632211
Epidemiology; DSM-IV; substance use disorders; prescription drugs; substance abuse treatment utilization
2.  Knowledge of folic acid and counseling practices among Ohio community pharmacists 
Pharmacy Practice  2012;10(3):168-172.
To determine knowledge of folic acid use for neural tube defect (NTD) prevention and counseling practices among community pharmacists registered in Ohio.
A cross-sectional study was performed on a random sample (n=500) of community pharmacists registered with the Ohio Board of Pharmacy and practicing in Ohio. A survey previously used by researchers to assess folic acid knowledge and practices among samples of other healthcare provider groups in the United States was adapted with permission for this study. The final tool consisted of 28 questions evaluating the knowledge, counseling practices, and demographics of respondents. The cover letter did not reveal the emphasis on folic acid, and surveys were completed anonymously. The university institutional review board deemed the study exempt.
Of the 122 pharmacists who completed the survey, 116 (95.1%) knew that folic acid prevents some birth defects. Twenty-eight (22.9%) responded that they "always" or "usually" discuss multivitamins with women of childbearing potential, and 19 (15.6%) responded that they "always" or "usually" discuss folic acid supplements. Some gaps in knowledge specific to folic acid were revealed. While 63.1% of pharmacists selected the recommended dose of folic acid intake for most women of childbearing potential, 13.1% could identify the dose recommended for women who have had a previous NTD-affected pregnancy. Respondents identified continuing education programs, pharmacy journals/magazines, and the Internet as preferred avenues to obtain additional information about folic acid and NTD.
This study represents the first systematic evaluation of folic acid knowledge and counseling practices among a sample of pharmacists in the United States. As highly accessible healthcare professionals, community pharmacists can fulfill a vital public health role by counseling women of childbearing potential about folic acid intake. Educational materials may be beneficial in augmenting knowledge of folic acid and facilitating patient education.
PMCID: PMC3780494  PMID: 24155833
Pharmacists; Health Knowledge, Attitudes, Practice; Professional Practice; Health promotion; Folic Acid; Neural Tube Defects; United States
3.  Persistent circulating unmetabolised folic acid in a setting of liberal voluntary folic acid fortification. Implications for further mandatory fortification? 
BMC Public Health  2009;9:295.
Ireland is an example of a country that has extensive voluntary fortification with folic acid. After a public consultation process, in 2006, the Food Safety Authority in Ireland FSAI [1] recommended mandatory fortification. However due to safety considerations this decision is now on hold. Before mandatory fortification goes ahead, existing levels of unmetabolised folic acid and their anticipated increase after fortification needs investigation because of the potential of folic acid to mask pernicious anaemia and possibly accelerate the growth of existing cancers. The aim of this study was to examine the levels of circulatory unmetabolised folic acid in Irish adults (both fasted and un-fasted) and new-born infants (fasted) before the proposed implementation of mandatory folic acid fortification. A secondary aim was to predict the increase in circulatory unmetabolised folic acid levels after fortification.
Study 1. Setting: Irish Blood Transfusion Service (IBTS). Whole blood samples were collected from blood donors (n = 50) attending for routine blood donation sessions (representing the general population). Subjects were not fasted prior to sampling. Study 2. Setting: Coombe Women's and Infant's University Hospital, Dublin. Whole blood samples were collected by venipuncture from mothers (n = 20), and from their infant's umbilical-cords (n = 20) immediately after caesarean section. All women had been fasted for at least 8 hours prior to the surgery. A questionnaire on habitual and recent dietary intakes of folic acid was administered by an interviewer to all subjects. The data collection period was February to April 2006. Serum samples were analysed for plasma folate, plasma folic acid and red cell folate.
Blood Donor Group: Circulatory unmetabolised folic acid was present in 18 out of 20 mothers (fasted) (CI: 68.3%–99.8%) comprising 1.31% of total plasma folate, 17 out of 20 babies (fasted) (CI: 62.1%–96.8%), and 49 out of 50 blood donors (unfasted) (CI: 88.0%–99.9%), comprising 2.25% of total plasma folate,
While the levels of circulatory unmetabolised folic acid reported are low, it is persistently present in women immediately after caesarean section who were fasting indicating that there would be a constant/habitual exposure of existing tumours to folic acid, with the potential for accelerated growth. Mandatory fortification might exacerbate this. This has implications for those with responsibility for drafting legislating in this area.
PMCID: PMC2734856  PMID: 19689788
4.  Folic acid handling by the human gut: implications for food fortification and supplementation123 
Background: Current thinking, which is based mainly on rodent studies, is that physiologic doses of folic acid (pterylmonoglutamic acid), such as dietary vitamin folates, are biotransformed in the intestinal mucosa and transferred to the portal vein as the natural circulating plasma folate, 5-methyltetrahydrofolic acid (5-MTHF) before entering the liver and the wider systemic blood supply.
Objective: We tested the assumption that, in humans, folic acid is biotransformed (reduced and methylated) to 5-MTHF in the intestinal mucosa.
Design: We conducted a crossover study in which we sampled portal and peripheral veins for labeled folate concentrations after oral ingestion with physiologic doses of stable-isotope–labeled folic acid or the reduced folate 5-formyltetrahydrofolic acid (5-FormylTHF) in 6 subjects with a transjugular intrahepatic porto systemic shunt (TIPSS) in situ. The TIPSS allowed blood samples to be taken from the portal vein.
Results: Fifteen minutes after a dose of folic acid, 80 ± 12% of labeled folate in the hepatic portal vein was unmodified folic acid. In contrast, after a dose of labeled 5-FormylTHF, only 4 ± 18% of labeled folate in the portal vein was unmodified 5-FormylTHF, and the rest had been converted to 5-MTHF after 15 min (postdose).
Conclusions: The human gut appears to have a very efficient capacity to convert reduced dietary folates to 5-MTHF but limited ability to reduce folic acid. Therefore, large amounts of unmodified folic acid in the portal vein are probably attributable to an extremely limited mucosal cell dihydrofolate reductase (DHFR) capacity that is necessary to produce tetrahydrofolic acid before sequential methylation to 5-MTHF. This process would suggest that humans are reliant on the liver for folic acid reduction even though it has a low and highly variable DHFR activity. Therefore, chronic liver exposure to folic acid in humans may induce saturation, which would possibly explain reports of systemic circulation of unmetabolized folic acid. This trial was registered at as NCT02135393.
PMCID: PMC4095662  PMID: 24944062
5.  Circulating Unmetabolized Folic Acid: Relationship to Folate Status and Effect of Supplementation 
There are increasing concerns that exposure to unmetabolized folic acid, which results from folic acid intakes that overwhelm the liver's metabolic capacity, may be associated with adverse effects. In this paper, we examined the folic acid status of women of reproductive age in relation to dietary intake and the effect of folic acid supplementation (1.1 mg or 5 mg). Plasma unmetabolized folic acid was not significantly correlated with folate intake estimated by food frequency questionnaire or biomarkers. The proportion of women with detectable levels of unmetabolized folic acid increased from 65% to 100% after twelve weeks of supplementation (P < 0.05); however, the increase in concentrations did not reach statistical significance and the effect was not sustained. Moreover, there were no significant differences between the two doses. This suggests that there are mechanisms by which the body adapts to high folic acid intakes to limit exposure to unmetabolized folic acid.
PMCID: PMC3317000  PMID: 22529856
6.  Folic acid fortification and public health: Report on threshold doses above which unmetabolised folic acid appear in serum 
BMC Public Health  2007;7:41.
All flour in the USA is fortified with folic acid at a level of 140 μg/100 g which is estimated to supply an extra 100 μg daily to the average diet. Some researchers have advocated that this be increased to double and even four times this amount. Based on previous research these higher levels are likely to lead to the appearance of unmetabolised vitamin in the circulation, which may have safety implications for sub-groups of the population. The UK and the Republic of Ireland will likely introduce mandatory fortification also in the next year or so.
The aim of this study was to capture the short-term effect of folic acid fortification on unmetabolised folic acid in serum after chronic consumption of folic acid.
After pre-saturation with 400 μg folic acid supplements daily for 14-weeks, healthy folate replete adults (n = 20) consumed folic acid fortified bread, at three different levels (400 μg, 200 μg, 100 μg) over a period of one week each. The dose was administered in two-equal sized slices consumed at 09.00 hrs and 13.00 hrs. Serum samples for total folate and folic acid were collected at baseline, after 14-weeks of supplementation, and pre and post (at 1, 2, 3 and 4 hours) each dose tested.
Unmetabolised folic acid was detected after the 14-week supplementation period. Folic acid was not detected in either the 200 μg or 100 μg (current US regime) doses tested but was present at the highest level (400 μg) tested.
Our findings suggest that persons exposed to the current US fortification programme supplying an average of 100 μg per day or less are unlikely to have unmetabolised folic acid in serum. It also seems that daily consumption of the higher level of 200 μg or less is unlikely to be problematic. Increasing the level however to 400 μg on the other hand is likely to lead to unmetabolised folic acid appearance.
PMCID: PMC1839088  PMID: 17378936
7.  Urinary Concentrations of Metabolites of Pyrethroid Insecticides in the General U.S. Population: National Health and Nutrition Examination Survey 1999–2002 
Environmental Health Perspectives  2010;118(6):742-748.
Pyrethroid insecticides are the most commonly used residential insecticides in the United States.
Our objective was to assess human exposure via biomonitoring to pyrethroid insecticides in a representative sample of the general U.S. population ≥ 6 years of age.
By using isotope-dilution high-performance liquid chromatography/electrospray chemical ionization/tandem mass spectrometry, we measured five urinary metabolites of pyrethroid insecticides in 5,046 samples collected as a part of the 1999–2002 National Health and Nutrition Examination Survey (NHANES). Univariate, multivariate, and Pearson correlation analyses were performed using SUDAAN and SAS software, incorporating the appropriate sample weights into the analyses. Multivariate analyses included age, sex, race/ethnicity, creatinine, fasting status, and urine collection time as covariates.
We detected 3-phenoxybenzoic acid (3PBA), a metabolite common to many pyrethroid insecticides, in more than 70% of the samples. The least-squares geometric mean (LSGM) concentration (corrected for covariates) of 3PBA and the frequency of detection increased from 1999–2000 (0.292 ng/mL) to 2001–2002 (0.318 ng/mL) but not significantly. Non-Hispanic blacks had significantly higher LSGM 3PBA concentrations than did non-Hispanic whites and Mexican Americans in the 2001–2002 survey period and in the combined 4-year survey periods but not in the 1999–2000 survey period. Children had significantly higher LSGM concentrations of 3PBA than did adolescents in both NHANES periods and than adults in NHANES 1999–2000. Cis- and trans-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid were highly correlated with each other and with 3PBA, suggesting that urinary 3PBA was derived primarily from exposure to permethrin, cypermethrin, or their degradates.
Pyrethroid insecticide exposure in the U.S. population is widespread, and the presence of its metabolites in the urine of U.S. residents indicates that children may have higher exposures than adolescents and adults.
PMCID: PMC2898848  PMID: 20129874
general population; insecticide; NHANES; pyrethroid; 3-phenoxybenzoic acid; urine
8.  Trends in Alcohol Services Utilization from 1991-1992 to 2001-2002: Ethnic Group Differences in the U.S. Population 
During the early 1990s in the U.S., changes to the provision and financing of alcohol treatment services included reductions in inpatient treatment services and in private sector spending for treatment. We investigated trends in alcohol services utilization over the 10-year period from 1991-1992 to 2001-2002 among U.S. Whites, Blacks and Hispanics.
Data come from two household surveys of the U.S. adult population. The 1991-1992 National Longitudinal Alcohol Epidemiologic Survey (NLAES) and the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) conducted face-to-face interviews with a multistage cluster sample of individuals 18 years of age and older in the continental United States. Treatment utilization represented both total utilization and the use of alcohol services. Data analyses were prevalence rates and multivariate logistic regressions for lifetime utilization with drinkers and individuals with alcohol use disorders (AUD).
From 1991-1992 to 2001-2002, drinking-related emergency room and human services use increased for drinkers, while total utilization and the use of private health professional services and mutual aid decreased for individuals with AUDs. In drinkers and individuals with AUDs, Blacks and Hispanics were less likely than Whites to use private health professional care. Hispanics with AUDs were less likely than Whites with AUDs to use alcohol or drug programs. Ethnicity interacted with alcohol severity to predict alcohol services utilization. At higher levels of alcohol severity, Blacks and Hispanics were less likely than Whites to ever use treatment and to use alcohol services (i.e., human services for Hispanic drinkers, mental health services for Blacks with AUDs, and mutual aid for Hispanics with AUDs).
Our findings showed increases from 1991-1992 to 2001-2002 in alcohol services utilization for drinkers, but reductions in utilization for individuals with AUDs. Blacks and Hispanics, particularly those at higher levels of alcohol severity, underutilized treatment services compared to Whites. These utilization trends for Blacks and Hispanics may reflect underlying disparities in health care access for minority groups, and language and logistical barriers to utilizing services.
PMCID: PMC3143282  PMID: 21575015
Alcohol Services; Treatment Utilization; Ethnicity; National Trends
9.  Effects of Folic Acid Supplementation on Serum Folate and Plasma Homocysteine Concentrations in Older Adults: A Dose-Response Trial 
American Journal of Epidemiology  2010;172(8):932-941.
The authors’ objective in this study was to estimate the changes in serum folate and homocysteine concentration that resulted from 6 weeks of supplementation with folic acid. A randomized, double-blind, placebo-controlled, dose-response trial with a parallel-group design was conducted. A total of 133 participants aged 60–90 years (70% female, 19% nonwhite) were assigned to receive 0, 100, 400, 1,000, or 2,000 μg/day of folic acid for 6 weeks. Data were collected in the United States between June and September 1996. At baseline, median serum folate and plasma homocysteine concentrations were 5.7 ng/mL (interquartile range (25th–75th percentiles), 4.1–7.8) and 8.3 μmol/L (interquartile range, 7.1–10.0), respectively. As the folic acid dose increased, serum folate levels increased (P-trend < 0.001). There was no dose-response relation with homocysteine level among all participants. In analyses restricted to persons with the lowest serum folate concentration (<4.5 ng/mL) at baseline, there was a trend (P = 0.06) toward decreased homocysteine levels with increasing folic acid dose. In healthy, older adults with adequate folate status, folic acid supplementation is not beneficial for homocysteine reduction. However, for older adults with low serum folate levels, supplementation will improve folate status and may be beneficial for lowering homocysteine concentrations.
PMCID: PMC2984248  PMID: 20847105
adult; dietary supplements; folic acid; homocysteine
10.  Circulating folic acid in plasma: relation to folic acid fortification 
The implementation of folic acid fortification in the United States has resulted in unprecedented amounts of this synthetic form of folate in the American diet. Folic acid in circulation may be a useful measure of physiologic exposure to synthetic folic acid, and there is a potential for elevated concentrations after fortification and the possibility of adverse effects.
We assessed the effect of folic acid fortification on circulating concentrations of folic acid and 5-methyltetrahydrofolate in the Framingham Offspring Cohort.
This is a cross-sectional study that used plasma samples from fasting subjects before and after fortification. Samples were measured for folate distribution with the use of an affinity-HPLC method with electrochemical detection.
Among nonsupplement users, the median concentration of folic acid in plasma increased from 0.25 to 0.50 nmol/L (P < 0.001) after fortification, and among supplement users the median increased from 0.54 to 0.68 nmol/L (P = 0.001). Among nonsupplement users, the prevalence of high circulating folic acid (≥85th percentile) increased from 9.4% to 19.1% (P = 0.002) after fortification. Among supplement users, the prevalence of high circulating folic acid increased from 15.9% to 24.3% (P = 0.02). Folic acid intake and total plasma folate were positively and significantly related to high circulating folic acid after adjustment for potential confounding factors (P for trend < 0.001).
Folic acid fortification has resulted in increased exposure to circulating folic acid. The biochemical and physiologic consequences of this are unknown, but these findings highlight the need to understand the effects of chronic exposure to circulating folic acid.
PMCID: PMC3763811  PMID: 18779294
11.  Clinical Utility of Folic Acid Testing for Patients with Anemia or Dementia 
Serum folic acid tests are routinely ordered by physicians for evaluating anemia and sometimes ordered for evaluating dementia and altered mental status.
To determine the utility of routine folic acid testing for patients with anemia or dementia/altered mental status in the era of folic acid fortification.
Retrospective analysis of consecutive folic acid tests performed on adults over a 4-month period; chart review of patients without anemia.
Measurements and Main Results
Serum folic acid level, mean corpuscular volume (MCV), and hematocrit. We reviewed 1,007 folic acid tests performed on 980 patients. The average age was 63.8 years, and 62% of the tests were from outpatient facilities. Only 4 (0.4%) patients had folic acid levels <3 ng/mL, while 10 (1%) patients had levels of 3–4 ng/mL (borderline). Thirty-five percent of the folic acid tests were performed on patients who were not anemic; most of these were ordered to evaluate dementia or altered mental status and folic acid level was normal in all these patients. Only 7% of the patients tested had a macrocytic anemia; these patients were more likely than those without macrocytic anemia to have low folic acid levels (2.8% vs 0.4%, p < .03).
Low serum folic acid levels were rarely detected in a series of patients being evaluated for anemia, dementia, or altered mental status. The test should be reserved for patients with macrocytic anemia and those at high risk for folic acid deficiency.
PMCID: PMC2517884  PMID: 18414954
folic acid, anemia, dementia
12.  A comprehensive evaluation of food fortification with folic acid for the primary prevention of neural tube defects 
Periconceptional use of vitamin supplements containing folic acid reduces the risk of a neural tube defect (NTD). In November 1998, food fortification with folic acid was mandated in Canada, as a public health strategy to increase the folic acid intake of all women of childbearing age. We undertook a comprehensive population based study in Newfoundland to assess the benefits and possible adverse effects of this intervention.
This study was carried out in women aged 19–44 years and in seniors from November 1997 to March 1998, and from November 2000 to March 2001. The evaluation was comprised of four components: I) Determination of rates of NTDs; II) Dietary assessment; III) Blood analysis; IV) Assessment of knowledge and use of folic acid supplements.
The annual rates of NTDs in Newfoundland varied greatly between 1976 and 1997, with a mean rate of 3.40 per 1,000 births. There was no significant change in the average rates between 1991–93 and 1994–97 (relative risk [RR] 1.01, 95% confidence interval [CI] 0.76–1.34). The rates of NTDs fell by 78% (95% CI 65%–86%) after the implementation of folic acid fortification, from an average of 4.36 per 1,000 births during 1991–1997 to 0.96 per 1,000 births during 1998–2001 (RR 0.22, 95% CI 0.14–0.35). The average dietary intake of folic acid due to fortification was 70 μg/day in women aged 19–44 years and 74 μg/day in seniors. There were significant increases in serum and RBC folate levels for women and seniors after mandatory fortification. Among seniors, there were no significant changes in indices typical of vitamin B12 deficiencies, and no evidence of improved folate status masking haematological manifestations of vitamin B12 deficiency. The proportion of women aged 19–44 years taking a vitamin supplement containing folic acid increased from 17% to 28%.
Based on these findings, mandatory food fortification in Canada should continue at the current levels. Public education regarding folic acid supplement use by women of childbearing age should also continue.
PMCID: PMC524178  PMID: 15450123
13.  Trends in Folic Acid Awareness and Behavior in the United States: The Gallup Organization for the March of Dimes Foundation Surveys, 1995–2005 
Maternal and Child Health Journal  2006;10(Suppl 1):177-182.
Objective: To summarize changes in folic acid awareness, knowledge, and behavior among women of childbearing age in the United States since the U.S. Public Health Service (USPHS) 1992 folic acid recommendation and later fortification. Methods: Random-digit dialed telephone surveys were conducted of approximately 2000 women (per survey year) aged 18–45 years from 1995–2005 in the United States. Results: The percentage of women reporting having heard or read about folic acid steadily increased from 52% in 1995 to 84% in 2005. Of all women surveyed in 2005, 19% knew folic acid prevented birth defects, an increase from 4% in 1995. The proportion of women who reported learning about folic acid from health care providers increased from 13% in 1995 to 26% in 2005. The proportion of all women who reported taking a vitamin supplement containing folic acid increased slightly from 28% in 1995 to 33% in 2005. Among women who were not pregnant at the time of the survey in 2005, 31% reported taking a vitamin containing folic acid daily compared with 25% in 1995. Conclusions: The percentage of women taking folic acid daily has increased modestly since 1995. Despite this increase, the data show that the majority of women of childbearing age still do not take a vitamin containing folic acid daily. Health care providers and maternal child health professionals must continue to promote preconceptional health among all women of childbearing age, and encourage them to take a vitamin containing folic acid daily.
PMCID: PMC1592142  PMID: 16823638
Multivitamin use; Folic acid consumption; Childbearing age women
14.  Determination of unmetabolized folic acid in human plasma using affinity HPLC12345 
Background: Folic acid (FA) fortification of food created the need to determine whether fortification elevated concentrations of unmetabolized FA in plasma and whether this form of the vitamin in blood is associated with adverse health outcomes.
Objective: The objective of this research was to devise a simple, rapid method for the measurement of unmetabolized plasma FA in epidemiologic studies.
Design: We previously used the affinity/HPLC with electrochemical detection method to measure folate distribution in human plasma and red blood cells (RBCs). We modified this method with the inclusion of synthetic ethyltetrahydrofolate as an internal standard and with the use of 2 affinity columns connected in parallel to the analytic column through a switching valve to allow one column to be loaded while the other column was eluted into the analytic column.
Results: We identified FA and 5-methyltetrahydrofolate (5-mTHF) by retention time and characteristic response across the channels of the electrochemical detector. Limits of detection were 0.034 pmol for 5-mTHF and 0.027 pmol for FA per injection, and the recovery was 92.2% (5-mTHF) and 98.9% (FA). CVs for samples were 8.1% (within day) and 6.8% (between day) for 5-mTHF and 3.2% (within day) and 5.9% (between day) for FA. Total folate with the use of this method correlated highly (r2 = 0.98, P < 0.001) with values from the microbial assay. The run time for the method was 30 min per sample. Researchers can use this method with longer run times to measure the distribution of folate forms in RBCs.
Conclusion: This updated method allows efficient analysis of folate forms in human plasma and tissues without the loss of sensitivity or precision.
PMCID: PMC3127506  PMID: 21593489
15.  Evaluation of the Dutch general exemption level for voluntary fortification with folic acid 
Food & Nutrition Research  2012;56:10.3402/fnr.v56i0.5443.
Fortification with folic acid was prohibited in the Netherlands. Since 2007, a general exemption is given to fortify with folic acid up until a maximum level of 100 µg/100 kcal. This maximum level was based on a calculation model and data of adults only. The model requires parameters on intake (diet, supplements, energy) and on the proportion of energy that may be fortified. This study aimed to evaluate the model parameters considering the changing fortification market. In addition, the risk of young children exceeding the UL for folic acid was studied.
Folic acid fortified foods present on the Dutch market were identified in product databases and by a supermarket inventory. Together with data of the Dutch National Consumption Survey-Young Children (2005/2006) these inventory results were used to re-estimate the model parameters. Habitual folic acid intake of young children was estimated and compared to the UL for several realistic fortification scenarios.
Folic acid fortified foods were identified in seven different food groups. In up to 10% of the population, the proportion of energy intake of folic acid fortified foods exceeded 10% – the original model parameter. The folic acid intake from food supplements was about 100 µg/day, which is lower than the intake assumed as the original model parameter (300 µg). In the scenarios representing the current market situation, a small proportion (<5%) of the children exceeded the UL.
The maximum fortification level of 100 µg/100 kcal is sufficiently protective for children in the current market situation. In the precautionary model to estimate the maximum fortification levels, subjects with high intakes of folic acid from food and supplements, and high energy intakes are protected from too high folic acid intakes. Combinations of high intakes are low in this population. The maximum levels should be monitored and revised with increasing fortification and supplementation practices.
PMCID: PMC3319366  PMID: 22481899
folic acid; voluntary fortification; maximum safe fortification levels; evaluation; Dutch fortification policy
16.  Possible Relationship of Folic Acid Supplementation and Improved Flow-Mediated Dilation in Premenopausal, Eumenorrheic Athletic Women 
The purpose of this study was to determine if six weeks of folic acid supplementation would improve brachial artery endothelial-dependent flow-mediated dilation in eumenorrheic female runners with previously normal serum folate levels. This was a prospective, double-blinded, randomized pilot study with convenience sampling. Sixteen eumenorrheic subjects who were not taking birth control pills and who ran at least 20 miles/week were randomly assigned to 10 mg/day of folic acid supplementation or placebo for at least 6 weeks. Serum folate levels and brachial artery measurements were made during the early follicular phase of the menstrual cycle, in a sedentary state, following an 8 hour fast; a standard ultrasound technique was used. The brachial artery vasodilator response to reactive hyperemia was similar between the folic acid (6.6% ± 0.8%, mean ± SE) and placebo groups (6.5% ± 0.7%) at baseline. After six weeks, there was a significantly higher change in flow-mediated dilation for the folic acid group (3.5% ± 0.6%) compared to the placebo group (0.1% ± 0.2%) (p = 0.01). Serum folate levels also increased significantly in the folic acid group following six weeks of folic acid supplementation. This study demonstrates that brachial artery flow-mediated dilation improves significantly in eumenorrheic female runners with previously normal serum folate levels after 6 weeks of supplementation with folic acid.
Key pointsFolic acid improves FMD in eumenorrheic runners.Folic acid improves FMD in women runners.
PMCID: PMC3737801  PMID: 24150565
Premenopause; regular menstruation; endothelial function; folate; flow-mediated vasodilation
17.  Neural Tube Defects and Maternal Folate Intake Among Pregnancies Conceived After Folic Acid Fortification in the United States 
Rates of neural tube defects have decreased since folic acid fortification of the food supply in the United States. The authors’ objective was to evaluate the associations between neural tube defects and maternal folic acid intake among pregnancies conceived after fortification. This is a multicenter, case-control study that uses data from the National Birth Defects Prevention Study, 1998–2003. Logistic regression was used to compute crude and adjusted odds ratios between cases and controls assessing maternal periconceptional use of folic acid and intake of dietary folic acid. Among 180 anencephalic cases, 385 spina bifida cases, and 3, 963 controls, 21.1%, 25.2%, and 26.1%, respectively, reported periconceptional use of folic acid supplements. Periconceptional supplement use did not reduce the risk of having a pregnancy affected by a neural tube defect. Maternal intake of dietary folate was not significantly associated with neural tube defects. In this study conducted among pregnancies conceived after mandatory folic acid fortification, the authors found little evidence of an association between neural tube defects and maternal folic acid intake. A possible explanation is that folic acid fortification reduced the occurrence of folic acid-sensitive neural tube defects. Further investigation is warranted to possibly identify women who remain at increased risk of preventable neural tube defects.
PMCID: PMC3139973  PMID: 18953063
folic acid; neural tube defects
18.  Does early onset of non-medical use of prescription drugs predict subsequent prescription drug abuse and dependence? Results from a national study 
Addiction (Abingdon, England)  2007;102(12):1920-1930.
The present study examined the associations between early onset of non-medical use of prescription drugs (NMUPD) (i.e. sedatives, tranquilizers, opioids, stimulants) and the development of prescription drug abuse and dependence in the United States.
Data were collected from structured diagnostic interviews using the National Institute on Alcohol Abuse and Alcoholism (NIAAA) Alcohol Use Disorder and Associated Disabilities Interview Schedule: Diagnostic and Statistical Manual version IV (DSM-IV).
National prevalence estimates were derived from the 2001–2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC, n = 43 093).
A nationally representative cross-sectional sample of civilian non-institutionalized adults aged 18 years or older in the United States, of whom 52% were women, 71% white, 12% Hispanic, 11% African American, 4% Asian and 2% Native American or of other racial background.
A higher percentage of individuals who began using prescription drugs non-medically at or before 13 years of age were found to have developed prescription drug abuse and dependence versus those individuals who began using at or after 21 years of age. Multivariate logistic regression analyses indicated that the odds of developing any life-time prescription drug abuse among non-medical users was reduced by approximately 5% with each year non-medical use was delayed [adjusted odds ratio (AOR) = 0.95, 95% CI = 0.94, 0.97], and that the odds of developing any life-time prescription drug dependence were reduced by about 2% with each year onset was delayed (AOR = 0.98, 95% CI = 0.96, 1.00) when controlling for relevant covariates.
The results of this study indicate that early onset of NMUPD was a significant predictor of prescription drug abuse and dependence. These findings reinforce the importance of developing prevention efforts to reduce NMUPD and diversion of prescription drugs among children and adolescents.
PMCID: PMC2377405  PMID: 17916222
DSM-IV drug use disorders; non-medical use; prescription drug abuse; prescription drug dependence; prescription drug initiation
19.  Estimates of contraceptive failure from the 2002 National Survey of Family Growth 
Contraception  2007;77(1):10-21.
In 2001, the U.S. government’s Healthy People 2010 initiative set a goal of reducing contraceptive failure during the first year of use from 13% in 1995 to 7% by 2010. We provide updated estimates of contraceptive failure for the most commonly used reversible methods in the United States, as well as an assessment of changes in failure rates from 1995 to 2002.
Study design
Estimates are obtained using the 2002 National Survey of Family Growth (NSFG), a nationally representative sample of U.S. women containing information on their characteristics, pregnancies, and contraceptive use. We also use the 2001 Abortion Patient Survey to correct for underreporting of abortion in the NSFG. We measure trends in contraceptive failure between 1995 and 2002, provide new estimates for several population subgroups, examine changes in subgroup differences since 1995, and identify socioeconomic characteristics associated with elevated risks of failure for three commonly used reversible contraceptive methods in the U.S.: the pill, male condom and withdrawal.
In 2002, 12.4% of all episodes of contraceptive use ended with a failure within 12 months after initiation of use. Injectable and oral contraceptives remain the most effective reversible methods used by women in the U.S., with probabilities of failure during the first 12 months of use of 7% and 9%, respectively. The probabilities of failure for withdrawal (18%) and the condom (17%) are similar. Reliance on fertility-awareness-based methods results in the highest probability of failure (25%). Population subgroups experience different probabilities of failure, but the characteristics of users that may predict elevated risks are not the same for all methods.
There was no clear improvement in contraceptive effectiveness between 1995 and 2002. Failure rates remain high for users of the condom, withdrawal and fertility-awareness methods, but for all methods, the risk of failure is greatly affected by socioeconomic characteristics of the users.
PMCID: PMC2811396  PMID: 18082661
Contraception; Contraceptive Methods; Contraceptive Effectiveness; Contraceptive Failure; National Survey of Family Growth; NSFG
20.  Epidemiology of neural tube defects 
Saudi Medical Journal  2014;35(Suppl 1):S29-S35.
To find the prevalence of neural tube defects (NTDs), and compare the findings with local and international data, and highlight the important role of folic acid supplementation and flour fortification with folic acid in preventing NTDs.
This is a retrospective study of data retrieved from the medical records of live newborn infants admitted to the Neonatal Intensive Care Unit (NICU), Security Forces Hospital (SFH), Riyadh, Saudi Arabia with NTDs spanning 14 years (1996-2009). All pregnant women on their first antenatal visit to the primary care clinic were prescribed folic acid 0.5 mg daily, or 5 mg if there is a family history of NTD. The pre-fortification prevalence is compared to post-fortification, before and after excluding syndromic, genetic, and chromosomal causes. The results were compared with reports from other parts of Saudi Arabia and internationally, through a literature search using MEDLINE.
The prevalence of NTDs during the period was 1.2 per 1000 live births. The pre-fortification of flour with folic acid prevalence was 1.46 per 1000 live births. The post-fortification prevalence was 1.05 (p=0.103). After excluding syndromic, genetic, and chromosomal causes from calculation of the prevalence, there was a significant reduction in the prevalence, from 1.46 to 0.81 per 1000 live births (p=0.0088). Syndromic, genetic, and chromosomal causes were identified in 20 cases (19.4%). Only 2% of mothers received preconception folic acid, and only 10% of them received it during the first 4 weeks of gestation.
Despite the implementation of fortification of flour with folic acid since 2001, the prevalence of NTDs in the Kingdom of Saudi Arabia is still high. This is due to the impact of genetic, syndromic, and chromosomal causes of NTD not preventable by folic acid. Other factors like unplanned pregnancy and lack of awareness of the role of folic acid in preventing nonsyndromic causes, play a significant role.
PMCID: PMC4362102  PMID: 25551108
21.  A Cost-Effectiveness Analysis of Folic Acid Fortification Policy in the United States 
Public health nutrition  2008;12(4):10.1017/S1368980008002565.
To quantify the health and economic outcomes associated with changes in folic acid consumption following fortification of enriched grain products in the United States.
Cost-effectiveness analysis.
Annual burden of disease, quality-adjusted-life-years (QALYs), and costs were projected for four steady-state strategies: no fortification or fortifying with 140, 350, or 700 micrograms (mcg) folic acid per 100 grams (g) enriched grain. The analysis considered four health outcomes: neural tube defects (NTDs); myocardial infarctions (MIs); colon cancers; and B-12 deficiency maskings.
U.S. adult population subgroups defined by age, gender, and race/ethnicity, with folate intake distributions from the National Health and Nutrition Examination Surveys (1988-1992 and 1999-2000), and reference sources for disease incidence, utility, and economic estimates.
The greatest benefits from fortification were predicted in MI prevention, with 16,862 and 88,172 cases averted per year in steady state for the 140-mcg and 700-mcg fortification levels, respectively. These projections were 6,261 and 38,805 for colon cancer and 182 and 1,423 for NTDs, while 15 to 820 additional B-12 cases were predicted. Compared with no fortification, all post-fortification strategies provided QALY gains and cost savings for all subgroups, with predicted population benefits of 266,649 QALYs gained and $3.6 billion saved in the long run by changing the fortification level from 140-mcg/100-g enriched grain to 700-mcg/100-g.
This study indicates that the health and economic gains of folic acid fortification far outweigh the losses for the U.S. population, and that increasing the level of fortification deserves further consideration to maximize net gains.
PMCID: PMC3856722  PMID: 18590584
Cost-effectiveness analysis; folic acid fortification; prenatal and maternal nutrition; health policy
Prenatal folic acid supplements reduce the risk of neural tube defects in children, but it has not been determined whether they protect against other neurodevelopmental disorders.
To examine the association between maternal use of prenatal folic acid supplements and the subsequent risk of autistic disorder in children.
Design, Setting, and Patients
The study sample of 85,176 was derived from the population-based, prospective Norwegian Mother and Child Cohort Study (MoBa). The children were born in 2002–08. By the end of follow-up on March 31st, 2012, the age range was 3.3–10.2 years and the mean age 6.4 years. The exposure of primary interest was use of folic acid from 4 weeks before to 8 weeks after the start of pregnancy. The start of pregnancy was defined as the first day of the last menstrual period before conception. Relative risks of ASD were estimated by odds ratios (ORs) with 95% confidence intervals (CIs) in a logistic regression analysis. Analyses were adjusted for maternal education level, year of birth, and parity.
Main Outcome Measure
Specialist-confirmed diagnosis of autistic disorder.
To date, 114 children in the study sample have been diagnosed with autistic disorder. In children whose mothers took folic acid, 0.10% (64/61,042) had autistic disorder, compared with 0.21% (50/24,134) in those unexposed to folic acid. The adjusted OR for autistic disorder in children of folic acid users was 0.61 (95% CI, 0.41–0.90). Similar analyses for prenatal fish oil supplements showed no such association with autistic disorder, even though fish oil use was associated with the same maternal characteristics as folic acid use.
Prenatal folic acid supplements around the time of conception were associated with a lower risk of autistic disorder in the MoBa cohort.
PMCID: PMC3908544  PMID: 23403681
23.  Prevalence and Trends of Urinary Incontinence in Adults in the United States, 2001 to 2008 
The Journal of urology  2011;186(2):589-593.
We estimate trends in the prevalence of urinary incontinence in the adult population of the United States from 2001 through 2008 before and after adjusting for other potential associated factors.
Materials and Methods
We analyzed data on 17,850 adults 20 years old or older who participated in the 2001 to 2008 cycles of the National Health and Nutrition Examination Survey. Any urinary incontinence was defined as a positive response to questions on urine leakage during physical activity, before reaching the toilet and during nonphysical activity. During this period changes in demographic and clinical factors associated with urinary incontinence included age, race/ethnicity, obesity, diabetes and chronic medical conditions (prostate disease in men). Age standardized prevalence estimates and prevalence ORs of urinary incontinence trends were determined using adjusted multivariate models with appropriate sampling weights.
The age standardized prevalence of urinary incontinence in the combined surveys was 51.1% in women and 13.9% in men. Prevalence in women increased from 49.5% in 2001 to 2002, to 53.4% in 2007 to 2008 (Ptrend = 0.01) and in men from 11.5% to 15.1%, respectively (Ptrend = 0.01). In women increased prevalence was partially explained by differences in age, race/ethnicity, obesity, diabetes and select chronic diseases across the survey periods. After adjustment the prevalence OR for 2007 to 2008 vs 2001 to 2002 decreased from 1.22 (95% CI 1.03–1.45) to 1.16 (95% CI 0.99–1.37). in men adjustment for potentially associated factors did not explain the increasing prevalence of urinary incontinence.
The age standardized prevalence of urinary incontinence increased in men and women from 2001 through 2008. Decreasing obesity and diabetes may lessen the burden of urinary incontinence, especially in women.
PMCID: PMC3197263  PMID: 21684555
urinary incontinence; risk factors; epidemiology; female; male
24.  Contemporary Issues Surrounding Folic Acid Fortification Initiatives 
The impact of folate on health and disease, particularly pregnancy complications and congenital malformations, has been extensively studied. Mandatory folic acid fortification therefore has been implemented in multiple countries, resulting in a reduction in the occurrence of neural tube defects. However, emerging evidence suggests increased folate intake may also be associated with unexpected adverse effects. This literature review focuses on contemporary issues of concern, and possible underlying mechanisms as well as giving consideration the future direction of mandatory folic acid fortification. Folate fortification has been associated with the presence of unmetabolized folic acid (PteGlu) in blood, masking of vitamin B12 deficiency, increased dosage for anti-cancer medication, photo-catalysis of PteGlu leading to potential genotoxicity, and a role in the pathoaetiology of colorectal cancer. Increased folate intake has also been associated with twin birth and insulin resistance in offspring, and altered epigenetic mechanisms of inheritance. Although limited data exists to elucidate potential mechanisms underlying these issues, elevated blood folate level due to the excess use of PteGlu without consideration of an individual’s specific phenotypic traits (e.g. genetic background and undiagnosed disease) may be relevant. Additionally, the accumulation of unmetabolized PteGlu may lead to inhibition of dihydrofolate reductase and other enzymes. Concerns notwithstanding, folic acid fortification has achieved enormous advances in public health. It therefore seems prudent to target and carefully monitor high risk groups, and to conduct well focused further research to better understand and to minimize any risk of mandatory folic acid fortification.
PMCID: PMC4287316  PMID: 25580388
mandatory folic acid fortification; synthetic folic acid; adverse effects; public health
25.  Preconceptional Folate Supplementation and the Risk of Spontaneous Preterm Birth: A Cohort Study 
PLoS Medicine  2009;6(5):e1000061.
In an analysis of a cohort of pregnant women, Radek Bukowski and colleagues describe an association between taking folic acid supplements and a reduction in the risk of preterm birth.
Low plasma folate concentrations in pregnancy are associated with preterm birth. Here we show an association between preconceptional folate supplementation and the risk of spontaneous preterm birth.
Methods and Findings
In a cohort of 34,480 low-risk singleton pregnancies enrolled in a study of aneuploidy risk, preconceptional folate supplementation was prospectively recorded in the first trimester of pregnancy. Duration of pregnancy was estimated based on first trimester ultrasound examination. Natural length of pregnancy was defined as gestational age at delivery in pregnancies with no medical or obstetrical complications that may have constituted an indication for delivery. Spontaneous preterm birth was defined as duration of pregnancy between 20 and 37 wk without those complications. The association between preconceptional folate supplementation and the risk of spontaneous preterm birth was evaluated using survival analysis. Comparing to no supplementation, preconceptional folate supplementation for 1 y or longer was associated with a 70% decrease in the risk of spontaneous preterm delivery between 20 and 28 wk (41 [0.27%] versus 4 [0.04%] spontaneous preterm births, respectively; HR 0.22, 95% confidence interval [CI] 0.08–0.61, p = 0.004) and a 50% decrease in the risk of spontaneous preterm delivery between 28 and 32 wk (58 [0.38%] versus 12 [0.18%] preterm birth, respectively; HR 0.45, 95% CI 0.24–0.83, p = 0.010). Adjustment for maternal characteristics age, race, body mass index, education, marital status, smoking, parity, and history of prior preterm birth did not have a material effect on the association between folate supplementation for 1 y or longer and spontaneous preterm birth between 20 and 28, and 28 to 32 wk (adjusted HR 0.31, 95% CI 0.11–0.90, p = 0.031 and 0.53, 0.28–0.99, p = 0.046, respectively). Preconceptional folate supplementation was not significantly associated with the risk of spontaneous preterm birth beyond 32 wk. The association between shorter duration (<1 y) of preconceptional folate supplementation and the risk of spontaneous preterm birth was not significant after adjustment for maternal characteristics. However, the risk of spontaneous preterm birth decreased with the duration of preconceptional folate supplementation (test for trend of survivor functions, p = 0.01) and was the lowest in women who used folate supplementation for 1 y or longer. There was also no significant association with other complications of pregnancy studied after adjustment for maternal characteristics.
Preconceptional folate supplementation is associated with a 50%–70% reduction in the incidence of early spontaneous preterm birth. The risk of early spontaneous preterm birth is inversely proportional to the duration of preconceptional folate supplementation. Preconceptional folate supplementation was specifically related to early spontaneous preterm birth and not associated with other complications of pregnancy.
Editors' Summary
Most pregnancies last about 40 weeks, but sometimes the new family member arrives early. Every year, half a million babies in the United States (12.5% of all babies) are born prematurely (before 37 completed weeks of pregnancy). Sadly, premature babies are more likely to die than full-term babies and many have short- and/or long-term health problems. Premature babies often have breathing problems, they are susceptible to life-threatening infections, and they are more likely to have learning and developmental disabilities than those born on time. The severity of these health problems depends on the degree of prematurity—preterm babies born between 34 and 36 weeks of pregnancy rarely develop severe disabilities, but a quarter of babies born before 28 weeks of pregnancy develop serious lasting disabilities and half have learning and behavioral problems. Although doctors have identified some risk factors for early delivery (for example, smoking), it is impossible to predict who will have an early birth and there is no effective way to prevent preterm births.
Why Was This Study Done?
Some researchers think that folate supplements may prevent preterm births. Folate (folic acid), a vitamin found in leafy green vegetables, fruits, and dried beans, helps to prevent neural tube birth defects. Consequently, women are encouraged to take folic acid supplements throughout (and preferably before) pregnancy and many governments now mandate that bread, pasta, and other grain products be fortified with folic acid to help women get sufficient folate. There is some evidence that women who deliver early have less folate in their blood than women who deliver at term. Furthermore, folate supplementation during pregnancy has increased the length of pregnancy in some but not all clinical trials. A possible explanation for these mixed results is that the duration of pregnancy reflects conditions in the earliest stages of pregnancy or before conception and that folate supplementation needs to start before conception to reduce the risk of preterm birth. In this study, the researchers test this idea by analyzing data collected from nearly 35,000 pregnant women enrolled in a study that was originally designed to investigate screening for Down's syndrome.
What Did the Researchers Do and Find?
During the first three months of their pregnancy, the women were asked whether they had taken folate supplements before conception. The duration of each pregnancy was estimated from ultrasound measurements taken early in the pregnancy and from the time of delivery. During the study, 1,658 women had spontaneous preterm deliveries before 37 weeks and 160 delivered before 32 weeks. After allowing for other maternal characteristics that might have affected the likelihood of preterm delivery, the risk of spontaneous preterm delivery between 20 and 28 weeks was 70% lower in women who took folate supplements for more than a year before becoming pregnant than in women who didn't take a supplement. Long-term folate supplementation also reduced the risk of preterm delivery between 28 and 32 weeks by 50% but did not affect the risk of preterm birth beyond 32 weeks. Folate supplementation for less than a year before conception did not reduce the risk of preterm birth, and folate supplementation was not associated with any other complications of pregnancy.
What Do These Findings Mean?
These findings show that folate supplementation for a year or more before conception is associated with a 50%–70% decrease in early (but not late) spontaneous preterm births and that the longer a woman takes folate supplements before becoming pregnant, the lower her risk of a preterm birth. Although the researchers allowed for maternal characteristics that might have affected the duration of pregnancy, it is possible that folate supplementation may not be responsible for the reduction in preterm birth risk seen in this study. For example, taking folate supplements may be a marker of healthy behavior and the women taking the supplements might have been doing something else that was reducing their risk of preterm birth. However, despite this and other limitations of this study, these findings suggest that long-term folate supplementation before conception is worth investigating further as a potential way to prevent preterm births.
Additional Information
Please access these Web sites via the online version of this summary at
This study is further discussed in a PLoS Medicine Perspective by Nicholas Fisk
The MedlinePlus encyclopedia contains a page on premature babies (in English and Spanish); MedlinePlus provides links to other information on premature babies (in English and Spanish)
The US National Institute of Child Health and Human Development provides information on preterm labor and birth
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on preterm birth and on folic acid (in English and Spanish)
The Nemours Foundation, another nonprofit organization for child health, also provides information on premature babies (in English and Spanish)
The US Office of Dietary Supplements has a fact sheet on folate
PMCID: PMC2671168  PMID: 19434228

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