Optimal serum and red blood cell folate concentrations in women of reproductive age for prevention of neural tube defects: World Health Organization guidelines.

Neural tube defects (NTDs) such as spina bifida, anencephaly, and encephalocele are serious birth defects of the brain and spine that occur during the first month of pregnancy when the neural tube fails to close completely. Randomized controlled trials and observational studies have shown that adequate daily consumption of folic acid before and during early pregnancy considerably reduces the risk for NTDs. The U.S. Public Health Service recommends that women capable of becoming pregnant consume 400 µg of folic acid daily for NTD prevention. Furthermore, fortification of staple foods (e.g., wheat flour) with folic acid has decreased folate-sensitive NTD prevalence in multiple settings and is a highly cost-effective intervention.

Folate status and concentrations of serum folate forms in the US population: National Health and Nutrition Examination Survey 2011-2.

Serum and erythrocyte (RBC) total folate are indicators of folate status. No nationally representative population data exist for folate forms. We measured the serum folate forms (5-methyltetrahydrofolate (5-methylTHF), unmetabolised folic acid (UMFA), non-methyl folate (sum of tetrahydrofolate (THF), 5-formyltetrahydrofolate (5-formylTHF), 5,10-methenyltetrahydrofolate (5,10-methenylTHF)) and MeFox (5-methylTHF oxidation product)) by HPLC-MS/MS and RBC total folate by microbiologic assay in US population ≥ 1 year (n approximately 7500) participating in the National Health and Nutrition Examination Survey 2011-2. Data analysis for serum total folate was conducted including and excluding MeFox. Concentrations (geometric mean; detection rate) of 5-methylTHF (37·5 nmol/l; 100 %), UMFA (1·21 nmol/l; 99·9 %), MeFox (1·53 nmol/l; 98·8 %), and THF (1·01 nmol/l; 85·2 %) were mostly detectable. 5-FormylTHF (3·6 %) and 5,10-methenylTHF (4·4 %) were rarely detected. The biggest contributor to serum total folate was 5-methylTHF (86·7 %); UMFA (4·0 %), non-methyl folate (4·7 %) and MeFox (4·5 %) contributed smaller amounts. Age was positively related to MeFox, but showed a U-shaped pattern for other folates. We generally noted sex and race/ethnic biomarker differences and weak (Spearman's r< 0·4) but significant (P< 0·05) correlations with physiological and lifestyle variables. Fasting, kidney function, smoking and alcohol intake showed negative associations. BMI and body surface area showed positive associations with MeFox but negative associations with other folates. All biomarkers showed significantly higher concentrations with recent folic acid-containing dietary supplement use. These first-time population data for serum folate forms generally show similar associations with demographic, physiological and lifestyle variables as serum total folate. Patterns observed for MeFox may suggest altered folate metabolism dependent on biological characteristics.

Iron, folate, and B(12) deficiencies and their associations with anemia among women of childbearing age in a rural area in Northern China.

OBJECTIVE: To assess the prevalence of folate, vitamin B(12), and iron deficiencies and their associations with anemia among women of childbearing age in northern China, an area with a reported high incidence of neural tube defects. METHODS: Plasma folate, vitamin B(12), ferritin, and hemoglobin levels were measured among 1,671 non-pregnant women of childbearing age from Xianghe County, Hebei Province, China in June 2004. RESULTS: Geometric means [95 % confidence interval (CI)] of plasma concentrations were 9.3 (4.0, 21.6) nmol/L for folate, 213.1 (82.4, 550.9) pmol/L for vitamin B(12), 17.4 (1.1, 278.6) microg/L for ferritin, and 129.9 (104.6, 161.4) g/L for hemoglobin (Hb). Approximately 24 % of women had biochemical evidence of folate deficiency (<6.8 nmol/L), 21.4 % were deficient (<148 pmol/L) in vitamin B(12), 30.2 % had iron depletion (<15 microg/L), and anemia (Hb < 120 g/L) was detected among 15.4 % of women. Of the three nutrients, only iron depletion (ferritin < 15 microg/L) was independently associated with anemia (adjusted odds ratio = 6.4, 95 % CI 4.8, 8.6). CONCLUSIONS: Although there were substantial proportions of folate and vitamin B(12) deficiencies among women of childbearing age in northern China, iron deficiency was the most important contributor to anemia.

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.

Molecular dynamics study of anisotropic translational and rotational diffusion in liquid benzene.

Equilibrium NPT and NVT molecular dynamics simulations were performed on liquid benzene over an extended range of temperature (from 260 to 360 K) using the COMPASS force field. Densities and enthalpies of vaporization (from cohesive energy densities) were within 1% of experiment at all temperatures. tumbling and spinning rotational diffusion coefficients, D(perpendicular) and D(parallel), computed as a function of temperature, agreed qualitatively with the results of earlier reported experimental and computational investigations. Generally, it was found that D(parallel)/D(perpendicular) approximately 1.4-2.5 and the activation energy for tumbling was significantly greater than for spinning about the C6 axis [Ea(D(perpendicular)) = 8.1 kJ mol(-1) and Ea(D(parallel)) = 4.5 kJ mol(-1)]. Calculated translational diffusion coefficients were found to be in quantitative agreement with experimental values at all temperatures [deviations were less than the scatter between different reported measurements]. In addition, translational diffusion coefficients were computed in the molecule-fixed frame to yield values for Dxy (diffusion in the plane of the molecule) and Dz (diffusion perpendicular to the plane). It was found that the ratio Dxy/Dz approximately 2.0, and that the two coefficients have roughly equal activation energies. This represents the first atomistic molecular dynamics study of translational diffusion in the molecular frame.

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.

Folic acid supplements during pregnancy and risk of miscarriage.

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

[Preventing neural tube defects with periconceptional folic acid supplementation: a population-based intervention program in the China].

OBJECTIVES: To evaluate the effectiveness of periconceptional use of 400 microgram folic acid only on the prevention of neural tube defects (NTDs). METHOD: As part of a public health campaign in areas of high (North) and low (South) NTDs prevalence in the China during 1993 and 1995, 130 142 pill takers and 117 689 non-pill takers were recruited. Women were asked to begin taking a pill containing only 400 microgram of folic acid daily from the time of their premarital examination until the end of the first trimester of pregnancy. The outcomes of these pregnancies were ascertained through 1996. RESULTS: We identified 102 NTDs among offspring of pill takers and 173 NTDs among offspring of non-pill takers. The NTDs rate in offspring of non-pill takers was 4.8 per thousand (16/3 318) and 1.0 per thousand (28/28 625) in the south; while the rate in pill takers was 1.0 per thousand (13/13 012) in the north and 0.6 per thousand in the south. The greatest reduction in risk occurred among the fetuses or infants of a subgroup of women in the northern region with periconceptional use who took pills more than 80 percent of the time (reduction in risk, 85 percent as compared with the fetuses or infants of women who registered before their last menstrual period and who took no folic acid; 95 percent confidence interval, 62 to 94 percent). In the southern region the reduction in risk among the fetuses or infants of women with periconceptional use of folic acid was also significant (reduction in risk, 41 percent; 95% confidence interval, 3 to 64 percent). CONCLUSION: Periconceptional intake of supplements containing only 400 microgram folic acid can reduce the risk for NTDs in areas of high and low NTDs prevalence.

Prevention of neural-tube defects with folic acid in China. China-U.S. Collaborative Project for Neural Tube Defect Prevention.

BACKGROUND AND METHODS: Periconceptional administration of folic acid can reduce a woman's risk of having a fetus or infant with a neural-tube defect. As part of a public health campaign conducted from 1993 to 1995 in an area of China with high rates of neural-tube defects (the northern region) and one with low rates (the southern region), we evaluated the outcomes of pregnancy in women who were asked to take a pill containing 400 microg of folic acid alone daily from the time of their premarital examination until the end of their first trimester of pregnancy. RESULTS: Among the fetuses or infants of 130,142 women who took folic acid at any time before or during pregnancy and 117,689 women who had not taken folic acid, we identified 102 and 173, respectively, with neural-tube defects. Among the fetuses or infants of women who registered before their last menstrual period and who did not take any folic acid, the rates of neural-tube defects were 4.8 per 1000 pregnancies of at least 20 weeks' gestation in the northern region and 1.0 per 1000 in the southern region. Among the fetuses or infants of the women with periconceptional use of folic acid, the rates were 1.0 per 1000 in the northern region and 0.6 per 1000 in the southern region. The greatest reduction in risk occurred among the fetuses or infants of a subgroup of women in the northern region with periconceptional use who took folic acid pills more than 80 percent of the time (reduction in risk, 85 percent as compared with the fetuses or infants of women who registered before their last menstrual period and who took no folic acid; 95 percent confidence interval, 62 to 94 percent) [corrected]. In the southern region the reduction in risk among the fetuses or infants of women with periconceptional use of folic acid was also significant (reduction in risk, 41 percent; 95 percent confidence interval, 3 to 64 percent). CONCLUSIONS: Periconceptional intake of 400 microg of folic acid daily can reduce the risk of neural-tube defects in areas with high rates of these defects and in areas with low rates.

Elevated rates of severe neural tube defects in a high-prevalence area in northern China.

In the northern provinces of China, the birth prevalence rate of neural tube defects (NTDs) is among the highest in the world-at about 6 per 1,000 births in rural areas. A unique population-based birth defects surveillance system in which photographs are taken of infants with selected external birth defects was implemented in two provinces in northern China and two provinces in southern China where NTD rates approximate those in the United States. In the period from March 1992 through December 1993, 660 infants with NTDs were identified by the surveillance project from a birth cohort of 251,567. We compared data from the two surveillance areas in China with data from a low-prevalence area in the United States to determine if the pattern of NTD types differs. Based on birth prevalence rates of NTDs from the Metropolitan Atlanta Congenital Defects Program, the observed to expected ratios for two types of NTDs are markedly increased at 80.8 for craniorachischisis and 25.0 for iniencephaly. Rates of these two NTDs in the southern provinces are increased to a lesser degree with observed to expected ratios of 7.1 for craniorachischisis and 2.7 for iniencephaly. The pattern of NTDs in northern China shows an increase in types that are rare in low-prevalence areas such as metropolitan Atlanta. Increased awareness of varying patterns of NTDs in different populations may have important implications for identifying etiologic and pathogenetic mechanisms of NTDs.

Nuclear energy facilities and cancers.

Workers employed in the nuclear energy industry and members of the general public living near nuclear facilities are exposed to low levels of ionising radiation as a result of the routine operation of these facilities. For the purposes of radiological protection, it is assumed that low doses of radiation confer a small increased risk of cancer upon the exposed individual and this is a major consideration in setting dose limits for workers and the general public. Quantitative estimates of radiation risk have been derived from epidemiological studies of groups exposed, on average, to high or moderate doses of radiation (such as the Japanese atomic bomb survivors), and appropriate assumptions are made for the application of such estimates to low dose conditions. There have been claims that the risks of cancer in nuclear industry workers, in their children, and in populations living around nuclear facilities have been grossly underestimated. Substantial evidence is now available from the epidemiological study of these groups. Studies of nuclear industry workforces demonstrate that currently accepted risk estimates are at about the right level, although a positive trend of leukaemia mortality with radiation dose, of a magnitude which is compatible with predictions, can be detected in the most statistically powerful workforce studies. The hypothesis that irradiation of fathers before the conception of their children materially increases the risk of childhood leukaemia has been largely discounted since it is biologically implausible and has found no support in studies using data independent of the study which generated the hypothesis. Increased levels of childhood leukaemia have occurred near certain nuclear facilities in the United Kingdom, but it is most unlikely that these are related to exposure to ionising radiation. Recent evidence suggests that these excesses are caused by a rare response to an infectious agent, which is enhanced under the unusual conditions of population mixing found in these communities. Similar excesses of childhood leukaemia have been found in other communities which have experienced unusual population mixing, but are not near nuclear facilities.

How far investigations for occult metastases in breast cancer aid the clinician.

This retrospective study aimed to assess the usefulness and clinical importance of current, commonly used, diagnostic staging procedures in breast cancer. The analysis comprises all 398 women clinically staged I-III (UICC criteria), and irradiated with radical intent in the Professorial Unit of Radiotherapy at the Middlesex Hospital over a ten-year period (1978-1987). The routine initial screening in this institution included the following staging investigations within 4 weeks of referral: 99mTc MDP bone scan; chest X-ray; liver function tests (including serum alkaline phosphatase) and liver ultrasound scan. Further enquiry and examination of the patient, clear progression of disease, additional radiographs or a recommended repeat interval scan provided sufficient additional information to confirm metastatic disease. The overall rate of detection of metastatic disease at three months was 29/389 (7.4%) for skeletal scintigraphy, 10/386 (2.6%) for chest radiographs, 8/271 (2.9%) for liver ultrasound and 3/347 (0.8%) for serum alkaline phosphatase. In total 37/398 (9.3%) of patients were confirmed to have metastatic disease by three months. Skeletal scintigraphy alone appears to identify 78% (29/37) of those with detectable metastatic disease at 3 months. Skeletal scintigraphy and liver ultrasound will identify 95% (35/37).

Metastatic carcinoma in the cervical lymph nodes from an occult primary: a conservative approach to the role of radiotherapy.

This retrospective study examines the results of treatment for cervical lymph node metastases from an unknown primary epithelial cancer of squamous cell or anaplastic histology. The analysis covers a series of 87 consecutive unselected patients at the Middlesex Hospital, London, in the years between 1954 and 1986. Fifty-eight patients received radiation therapy with a view to cure, 25 patients were treated with radiotherapy to a palliative dose, 1 patient only had a radical neck dissection, and 3 patients received no treatment apart from excision biopsy. In contrast to common practice in the United States, only a single patient received prophylactic radiation to the nasopharynx as part of the initial therapy. Overall actuarial survival for all patients (87) at 2 years was 43% and at 5 years 33%, and in the radically treated group (58) it was 52% and 40%, respectively. Only 6 of the 87 patients (7%) subsequently revealed a primary tumor above the clavicles. Overall disease control above the clavicles was achieved in 53% (46/87), but was 64% (37/58) in the radically treated group. Guidelines for radiation therapy are discussed in view of these results.

A microcomputer-based vital records data base with interactive graphic assessment for states and localities.

Vital records data bases describe large populations over long periods of time, yet their organization and size often preclude or discourage their use. We constructed a microcomputer-based data base of all singleton births in Massachusetts, 1975-84. The original data were stored in 700,000 records, each 174 bytes long, occupying a total of over 120 megabytes (MB). By removing redundant information and unique identifiers, and packing the data, we store 21 fields of this information in a 16-byte record resulting in a data base of 11.1 MB, a saving of over 90 percent of disk space. By using programs written expressly for this data base, we can display a birth weight frequency plot of the entire data set in under 65 seconds on an IBM-compatible PC-AT. Comparable assessments in SAS-PC took over 105 minutes and in main frame SAS on an AS-9000 took over 37 CPU seconds. Implementing similar systems for state registries on births, deaths, cancers, and birth defects potentially offers investigators easy access to vast stores of information and would enable public health officials to produce timely reports, initiate a variety of surveillance activities, and respond rapidly to residents' inquiries about clusters and anomalous disease patterns.

Metastatic adenocarcinoma in the cervical lymph nodes from an occult primary.

Cervical lymph node metastases as the only site of disease is a rare presentation of an adenocarcinoma of unknown primary origin. This retrospective analysis examines the records of ten consecutive patients at the Middlesex Hospital with this diagnosis between 1954 and 1986. The diagnostic protocol employed and the results of radical treatment are evaluated. Nine patients received radiation therapy with intent to cure, and one patient had a radical neck dissection. Overall actuarial survival for all patients (10) at 2 years was 23% and at 5 years 0%. Only two of the 10 patients subsequently revealed a primary tumour--both below the clavicles. Disease control above the clavicles was not achieved in a single patient despite radical treatment.

First interim progress report on the second British Institute of Radiology Fractionation Study: short versus long overall treatment times for radiotherapy of carcinoma of the laryngopharynx.

Preliminary data from a second British Institute of Radiology Fractionation Trial comparing short (less than or equal to 4 weeks) and long (greater than 4 weeks) overall treatment times are reported. The intake of patients ran from January, 1975 to December, 1985 when 611 patients with carcinoma of the laryngo-pharynx were registered in this prospective, randomized, multicentre clinical trial. No significant differences have, so far, been demonstrated between the two arms of the trial with respect to observed survival rates, tumour-free or laryngectomy-free rates. Further long-term follow-up is continuing.

Periconceptional use of multivitamins and the occurrence of neural tube defects.

We studied the association between multivitamin use during the periconceptional period and the occurrence of neural tube defects using data from the Atlanta Birth Defects Case-Control Study. There were 347 babies with neural tube defects who were live born or stillborn to residents of metropolitan Atlanta from 1968 through 1980. The 2829 control-babies born without birth defects were randomly selected through birth certificates. Periconceptional multivitamin use was defined as reported use for each of the three months before conception through the first three months of pregnancy. Mothers who reported not using multivitamins any time during the six-month period were defined as nonusers. Fourteen percent of mothers reported periconceptional multivitamin use and 40% reported nonuse. Multivitamin users were different from nonusers in a number of demographic, health-related, and life-style characteristics. We found an overall apparent protective effect of periconceptional multivitamin use on the occurrence of neural tube defects, with a crude estimated relative risk of 0.40 (95% confidence interval, 0.25 to 0.63). At this time, it is not possible to determine whether this apparently lower risk is the direct result of multivitamin use or the result of other characteristics of women who use multivitamins.