Maternal serum unmetabolized folic acid concentration following multivitamin and mineral supplementation with or without folic acid after 12 weeks gestation: A randomized controlled trial.

Pregnant women are advised to take folic acid (FA) supplements before conception and during the first trimester of pregnancy. Many women continue FA supplementation throughout pregnancy, and concerns have been raised about associations between excessive FA intake and adverse maternal and child health outcomes. Unmetabolized folic acid (UMFA) is found in serum after high FA intakes and is proposed as a biomarker for excessive FA intake. We aimed to determine if removing FA from prenatal micronutrient supplements after 12 weeks of pregnancy reduces serum UMFA concentrations at 36 weeks gestation. In this double-blind, randomized controlled trial conducted in South Australia, 103 women with a singleton pregnancy were randomly assigned at 12-16 weeks gestation to take a micronutrient supplement containing no FA or 800 µg/day FA from enrollment until 36 weeks gestation. Ninety women (0 µg/day FA n = 46; 800 µg/day FA n = 44) completed the study. Mean, UMFA concentration was lower in the women randomized to the 0 µg/day group compared to the 800 µg/day FA group, 0.6 ± 0.7 and 1.4 ± 2.7 nmol/L, respectively. The adjusted mean difference (95% CI) in UMFA between the groups was [-0.85 (-1.62, -0.08) nmol/L, p = 0.03]. Maternal serum and red blood cell folate concentrations were lower in the 0 µg/day FA group than in the 800 µg/day group (median 23.2 vs. 49.3 and 1335 vs. 1914 nmol/L, respectively; p < 0.001). Removing FA at 12-16 weeks gestation from prenatal micronutrient supplements reduced the concentration of UMFA at 36 weeks gestation.

The association between dietary intake and cardiometabolic risk factors among obese adolescents in Indonesia.

BACKGROUND AND OBJECTIVE: Poor diets, characterized by excess fat, sugar and sodium intakes, are considered to be one of the most important modifiable risk factors for cardiovascular disease. Diet patterns and intakes during adolescence may persist into adulthood and impact on risk for chronic disease later in life. We aimed to evaluate the dietary intake of obese adolescents and its relationship to cardiometabolic health including lipid status and glycemic control. METHODS AND STUDY DESIGN: This was a cross-sectional study of obese children aged 15 to < 18 years in Yogyakarta, Indonesia. All children had a medical history performed including a physical examination and fasting blood sample. Dietary intake was assessed using a semi-quantitative recall food frequency questionnaire. Multivariable linear regression model was performed to determine the relationship between dietary intakes and cardiovascular disease risks and to adjust for potential confounders. RESULTS: Of 179 adolescents, 101 (57.4%) were male and median age was 16.4 (15.0-17.9) years. The majority of adolescents (98%) had inadequate intake of fibre and exceeded intakes of total fat (65%) and total sugar (36%). There was statistically significant correlation found in the multivariable linear regression analysis between fibre intake and HDL cholesterol after adjusting for potential confounders (ß = 0.165; p = 0.033). CONCLUSIONS: This study demonstrates that there is a high proportion of obese Indonesian adolescents with poor dietary intakes. There was relationship observed between intake of nutrients of concern (fibre) and cardiometabolic risk factor among this sample of obese adolescents. Future research should examine overall dietary patterns in more detail among this population to elucidate the role of poor diet intakes in development of cardiovascular disease risk factors in young people transitioning into adulthood.

Maternal Late-Pregnancy Serum Unmetabolized Folic Acid Concentrations Are Not Associated with Infant Allergic Disease: A Prospective Cohort Study.

BACKGROUND: The increase in childhood allergic disease in recent decades has coincided with increased folic acid intakes during pregnancy. Circulating unmetabolized folic acid (UMFA) has been proposed as a biomarker of excessive folic acid intake. OBJECTIVE: We aimed to determine if late-pregnancy serum UMFA and total folate concentrations were associated with allergic disease risk in the offspring at 1 y of age in a population at high risk of allergy. METHODS: The cohort consisted of 561 mother-infant pairs from Western Australia. To be eligible the infant had to have a first-degree relative (mother, father, or sibling) with a history of medically diagnosed allergic disease. Maternal venous blood was collected between 36 and 40 wk of gestation. Serum UMFA was measured by LC-tandem MS. Serum total folate was determined using a microbiological method with chloramphenicol-resistant Lactobacillus rhamnosus as the test organism, and was collected between 36 and 40 wk of gestation. UMFA concentrations were measured by tandem MS using stable isotope dilution; folate concentrations were determined using the microbiological method with standardized kits. Infant allergic disease outcomes of medically diagnosed eczema, steroid-treated eczema, atopic eczema, IgE-mediated food allergy, allergen sensitization, and medically diagnosed wheeze were assessed at 1 y of age. RESULTS: Median (IQR) concentrations for UMFA and serum folate were 1.6 (0.6-4.7) and 53.2 (32.6-74.5) nmol/L, respectively. Of the infants, 34.6% had medically diagnosed eczema, 26.4% allergen sensitization, and 14.9% had an IgE-mediated food allergy. In both adjusted and unadjusted models there was little evidence of association between UMFA or serum folate and any of the infant allergy outcomes. CONCLUSIONS: In this cohort of children at high risk of allergic disease there was no association between maternal UMFA or serum folate concentrations measured in late pregnancy and allergic disease outcomes at 1 y of age.

The Inclusion of Folic Acid in Weekly Iron-Folic Acid Supplements Confers no Additional Benefit on Anemia Reduction in Nonpregnant Women: A Randomized Controlled Trial in Malaysia.

BACKGROUND: Weekly iron-folic acid (IFA) supplements are recommended for all menstruating women in countries where anemia prevalence is ≥20%; however, it is unknown whether the inclusion of folic acid in weekly IFA supplements reduces anemia. OBJECTIVES: We examined whether the inclusion of folic acid in weekly IFA supplements conferred any benefit on hemoglobin (Hb) concentration, anemia reduction, or iron status [ferritin and soluble transferrin receptor (sTfR)], over iron alone. METHODS: In this secondary analysis of a randomized controlled trial in Malaysia, n = 311 nonpregnant women (18-45 y old) received 60 mg Fe with either 0, 0.4, or 2.8 mg folic acid once-weekly for 16 wk. Fasting blood was collected at baseline and 16 wk. A generalized linear model (normal distribution with identity link) was used to assess Hb concentration at 16 wk (primary outcome). RESULTS: At baseline, 84% of women had low folate status (plasma folate < 14 nmol/L). At 16 wk, marginal mean (95% CI) Hb was 131 (130, 133), 131 (129, 132), and 132 (130, 133) g/L; ferritin was 58.2 (53.9, 62.5), 56.5 (52.2, 60.9), and 58.0 (53.7, 62.3) µg/L; and sTfR was 5.8 (5.5, 6.1), 5.8 (5.5, 6.1), and 5.9 (5.6, 6.2) mg/L in the 0, 0.4, and 2.8 mg/wk groups, respectively, with no differences between groups (P > 0.05). Baseline plasma folate concentration did not modify the effect of treatment on Hb concentration at 16 wk. Among all women, the risks of anemia [risk ratio (RR): 0.65; 95% CI: 0.45, 0.96; P = 0.03] and iron deficiency based on ferritin (RR: 0.30; 95% CI: 0.20, 0.44; P < 0.001) were lower at 16 wk than at baseline. CONCLUSIONS: Despite the low folate status among these nonpregnant Malaysian women, the inclusion of folic acid in weekly IFA supplements did not reduce anemia or improve iron status, over iron alone. However, the benefits of folic acid for neural tube defect prevention still warrant its retention in weekly IFA supplements.This trial was registered at www.anzctr.org.au as ACTRN12619000818134.

The interaction between energy intake, physical activity and UCP2 -866G/A gene variation on weight gain and changes in adiposity: an Indonesian Nutrigenetic Cohort (INDOGENIC).

The present study aimed to investigate an interaction between energy intake, physical activity and UCP2 gene variation on weight gain and adiposity changes in Indonesian adults. This is a prospective cohort study conducted in 323 healthy adults living in the city of Yogyakarta, Indonesia. Energy intake, physical activity, body weight, BMI, percentage body fat and waist:hip ratio (WHR) were measured at baseline and after 2 years while UCP2 -866G/A gene variation was determined at baseline. We reported that after 2 years subjects had a significant increment in body weight, BMI, body fat and reduction in WHR (all P < 0·05). In all subjects, total energy intake was significantly correlated with changes in body weight (ß = 0·128, P = 0·023) and body fat (ß = 0·123, P = 0·030). Among subjects with the GG genotype, changes in energy intake were positively correlated with changes in body weight (ß = 0·232, P = 0·016) and body fat (ß = 0·201, P = 0·034). These correlations were insignificant among those with AA + GA genotypes (all P > 0·05). In summary, we show that UCP2 gene variation might influence the adiposity response towards changes in energy intake. Subjects with the GG genotype of UCP2 -866G/A gene were more responsive to energy intake, thus more prone to weight gain due to overeating.

Prenatal alcohol exposure alters methyl metabolism and programs serotonin transporter and glucocorticoid receptor expression in brain.

Prenatal alcohol exposure (PAE) programs the fetal hypothalamic-pituitary-adrenal (HPA) axis, resulting in HPA dysregulation and hyperresponsiveness to stressors in adulthood. Molecular mechanisms mediating these alterations are not fully understood. Disturbances in one-carbon metabolism, a source of methyl donors for epigenetic processes, contributes to alcoholic liver disease. We assessed whether PAE affects one-carbon metabolism (including Mtr, Mat2a, Mthfr, and Cbs mRNA) and programming of HPA function genes (Nr3c1, Nr3c2, and Slc6a4) in offspring from ethanol-fed (E), pair-fed (PF), and ad libitum-fed control (C) dams. At gestation day 21, plasma total homocysteine and methionine concentrations were higher in E compared with C dams, and E fetuses had higher plasma methionine concentrations and lower whole brain Mtr and Mat2a mRNA compared with C fetuses. In adulthood (55 days), hippocampal Mtr and Cbs mRNA was lower in E compared with C males, whereas Mtr, Mat2a, Mthfr, and Cbs mRNA were higher in E compared with C females. We found lower Nr3c1 mRNA and lower nerve growth factor inducible protein A (NGFI-A) protein in the hippocampus of E compared with PF females, whereas hippocampal Slc6a4 mRNA was higher in E than C males. By contrast, hypothalamic Slc6a4 mRNA was lower in E males and females compared with C offspring. This was accompanied by higher hypothalamic Slc6a4 mean promoter methylation in E compared with PF females. These findings demonstrate that PAE is associated with alterations in one-carbon metabolism and has long-term and region-specific effects on gene expression in the brain. These findings advance our understanding of mechanisms of HPA dysregulation associated with PAE.

The role of genes involved in lipolysis on weight loss program in overweight and obese individuals.

The ability of obese people to reduce weight in the same treatment varied. Genetic make up as well as the behavioral changes are important for the successfulness of the program. One of the most proposed genetic variations that have been reported in many intervention studies was genes that control lipolysis process. This review summarizes studies that were done showing the influence of genetic polymorphisms in lipolysis pathway and weight loss in a weight loss treatment program. Some studies had shown that certain enzymes involved in this process were related to successfulness of weight loss program. Single Nucleotide Polymorphism (SNP) in PLIN (11482G>A) and ADRB3 (Trp64Arg) are the most studied polymorphisms that have effect on weight loss intervention. However, those studies were not conclusive because of limited number of subjects used and controversies in the results. Thus, replication and confirmation on the role of those genes in weight loss are important due to their potential to be used as predictors of the results of the program.

Total and high molecular weight adiponectin and ethnic-specific differences in adiposity and insulin resistance: a cross-sectional study.

BACKGROUND: Ethnic-specific differences in insulin resistance (IR) are well described but the underlying mechanisms are unknown. Adiponectin is an insulin sensitizing adipocytokine that circulates as multiple isoforms, with high molecular weight (HMW) adiponectin associated with greatest insulin sensitivity. The objective of this study is to determine if plasma total and HMW adiponectin concentrations underlie ethnic-specific differences in IR. METHODS: Healthy Canadian Aboriginal, Chinese, European, and South Asian adults (N = 634) were assessed for sociodemographics; lifestyle; fasting plasma insulin, glucose, and total and HMW adiponectin; and adiposity measures [BMI, waist circumference, waist-to-hip ratio, percent body fat, and subcutaneous and visceral adipose tissue (quantified by computed tomography)]. The homeostasis model assessment-insulin resistance (HOMA-IR) assessed IR. RESULTS: South Asians had the greatest HOMA-IR, followed by Aboriginals, Chinese, and Europeans (P < 0.001). Plasma total and HMW adiponectin concentrations were lower in Chinese and South Asians than Aboriginal and Europeans (P < 0.05). Total and HMW adiponectin were inversely associated with HOMA-IR (P < 0.001). Ethnicity modified the relationship between HMW adiponectin and HOMA-IR with stronger effects observed in Aboriginals (P = 0.001), Chinese (P = 0.002), and South Asians (P = 0.040) compared to Europeans. This was not observed for total adiponectin (P = 0.431). At mean total adiponectin concentrations South Asians had higher HOMA-IR than Europeans (P < 0.001). CONCLUSIONS: For each given decrease in HMW adiponectin concentrations a greater increase in HOMA-IR is observed in Aboriginals, Chinese, and South Asians than Europeans. Ethnic-specific differences in HMW adiponectin may account for differences in IR.

Altered glutathione homeostasis in heart augments cardiac lipotoxicity associated with diet-induced obesity in mice.

Obesity-related cardiac lipid accumulation is associated with increased myocardial oxidative stress. The role of the antioxidant glutathione in cardiac lipotoxicity is unclear. Cystathionine ß-synthase (Cbs) catalyzes the first step in the trans-sulfuration of homocysteine to cysteine, which is estimated to provide ∼50% of cysteine for hepatic glutathione biosynthesis. As cardiac glutathione is a reflection of the liver glutathione pool, we hypothesize that mice heterozygous for targeted disruption of Cbs (Cbs(+/-)) are more susceptible to obesity-related cardiolipotoxicity because of impaired liver glutathione synthesis. Cbs(+/+) and Cbs(+/-) mice were fed a high fat diet (60% energy) from weaning for 13 weeks to induce obesity and had similar increases in body weight and body fat. This was accompanied by increased hepatic triglyceride but no differences in hepatic glutathione levels compared with mice fed chow. However, Cbs(+/-) mice with diet-induced obesity had greater glucose intolerance and lower total and reduced glutathione levels in the heart, accompanied by lower plasma cysteine levels compared with Cbs(+/+) mice. Higher triglyceride concentrations, increased oxidative stress, and increased markers of apoptosis were also observed in heart from Cbs(+/-) mice with diet-induced obesity compared with Cbs(+/+) mice. This study suggests a novel role for Cbs in maintaining the cardiac glutathione pool and protecting against cardiac lipid accumulation and oxidative stress during diet-induced obesity in mice.

Vitamin D deficiency in South-East Asian children: a systematic review.

OBJECTIVE: To describe the prevalence and determinants of vitamin D deficiency (VDD) among healthy children aged between 0 and 18 years living in South-East Asia (SEA). DESIGN: We systematically searched Ovid MEDLINE and Ovid EMBASE for observational studies assessing VDD among healthy children in the SEA region as the primary or secondary outcome from database inception to 6 April 2021. PubMed was used for e-pubs and publications not indexed in Medline. Publications that included abstracts in English were included. We performed a systematic review to describe the prevalence of VDD in SEA children. RESULTS: Our initial search identified 550 publications with an additional 2 publications from manual screening. Of those, 21 studies from 5 different countries (Thailand, Indonesia, Vietnam, Malaysia and Cambodia) were summarised and included in forest plots. The prevalence of VDD (<50 nmol/L) ranged from 0.9% to 96.4%, with >50% of newborns having VDD, and severe VDD (<30 nmol/L) ranged from 0% to 55.8%. Female sex and urban living were the most common determinants of VDD. CONCLUSIONS: VDD among healthy children living in the SEA region is common. Efforts to detect VDD and the implementation of preventive measures, including education on safe sun exposure and oral vitamin D supplementation or food fortification, should be considered for key target groups, including adolescent females and pregnant and lactating women to improve the vitamin D status of newborns. PROTOCOL REGISTRATION NUMBER: This study is registered with PROSPERO (CRD42020181600).

Vitamin D status in breast cancer cases following chemotherapy: A pre and post observational study in a tertiary hospital in Yogyakarta, Indonesia.

OBJECTIVES: To observe pre- and post-treatment vitamin D level and its association with treatment and concomitant factors in breast cancer patients treated with chemotherapy. METHODS: We performed a pre-post observational analysis that nested in an ongoing prospective cohort study of breast cancer patients at Dr. Sardjito General Hospital, Yogyakarta, Indonesia. 136 subjects were recruited from the main study. Information on subjects' socio-demographic characteristics clinical status, and tumour profile was assessed at baseline. Number of chemotherapy cycles and chemotherapy-induced nausea vomiting (CINV) were also recorded. Vitamin D concentration was measured using ELISA methods at baseline and post-treatment. Vitamin D level of <20 ng/ml and <12 ng/ml were defined as deficiency and severe deficiency. Correlation between socio-demographic and clinical profile with baseline vitamin D was tested using Spearman correlation. Paired t-test was used to evaluate changes in post-treatment vitamin D concentration. The odds ratio for a subject to experience post-treatment vitamin D decrease was assessed based on number of chemotherapy cycles and CINV severity. RESULTS: The mean vitamin D level before chemotherapy was very low (8.80±3.64 ng/ml) in the whole panel. Higher AST level were associated with lower vitamin D level at baseline (r = -0.188, p = 0.028). Severe deficiency was found in 82.4% subjects at baseline and the rate increased to 89.0% after chemotherapy. Eighty-five cases showed a decrease level whereas 51 showed a slight improvement. Overall, a significant decrease of the vitamin D level was observed after chemotherapy (median change 3.13±4.03 ng/ml, p <0.001). Subjects who received >6 cycles of chemotherapy were less likely to experience a decreased level of post-treatment vitamin D (OR = 0.436, 95% CI = 0.196-0.968, p = 0.039). CONCLUSIONS: Indonesian breast cancer patients showed pre-existing severe vitamin D deficiency and deterioration of vitamin D after chemotherapy. Future research is needed to explore its implication towards patients' survival in the local setting. Evidence-based approach also needs to be taken to address this modifiable condition, including increasing awareness of the importance of maintaining vitamin D sufficiency both in patients and the general population.

Estimated Choline Intakes and Dietary Sources of Choline in Pregnant Australian Women.

(1) Background: Despite the postulated importance of choline during pregnancy, little is known about the choline intake of Australians during pregnancy. In this study, we estimated dietary intakes of choline in early and late pregnancy, compared those intakes to recommendations, and investigated food sources of choline in a group of pregnant women in Australia. (2) Methods: 103 pregnant women enrolled in a randomized controlled trial. In early pregnancy (12−16 weeks gestation) and late pregnancy (36 weeks gestation), women completed a food frequency questionnaire designed to assess dietary intake over the previous month. (3) Results: Choline intakes and sources were similar in early and late pregnancy. Median choline intake in early pregnancy was 362 mg/day. Of the women, 39% and 25% had choline intakes above the Australian National Health and Medical Research Council (NHMRC) adequate intake (AI) of >440 mg/day and the European Food Safety Authority (EFSA) AI of >480 mg/day for choline in pregnancy, respectively. Eggs, red meat, nuts, legumes, and dairy accounted for 50% of choline intake, with eggs being the most significant contributor at 17%. (4) Conclusions: Few pregnant women in our study met the AI recommended by the NHMRC and EFSA. In Australia, choline intake in pregnancy may need to be improved, but further work to define choline requirements in pregnancy is required.

Associations of the FTO rs9939609 variant with discrete body fat depots and dietary intake in a multi-ethnic cohort.

The fat mass and obesity associated (FTO) gene has been implicated with obesity and dietary intake predominantly in European populations. We assessed the association between the FTO rs9939609 variant with body fat distribution and dietary intake in a multi-ethnic population. Aboriginal, Chinese, European and South Asian participants living in Canada (n = 706) were assessed for body fat and inner-abdominal fat using imaging techniques, dietary intake and genotyped for the FTO rs9939609 variant. Linear regression was used to study the associations between the minor allele of the variant and measures of adiposity and dietary intake. Minor allele frequencies were: Aboriginals (17%), Chinese (17%), Europeans (39%) and South Asians (31%). The rs9939609 variant was associated with intake of dietary macronutrients in Aboriginals and Europeans only. In the total population, there were positive associations between the rs9939609 minor allele and greater fat mass (0.94 ± 0.56 kg, P = 0.045), per cent body fat (0.7 ± 0.4%, P = 0.031), relative greater subcutaneous abdominal adipose tissue (4.9 ± 2.8%, P = 0.039) and percent daily calories from fat (0.4 ± 0.2%, P = 0.064). Our findings suggest that the FTO rs9939609 minor allele may be associated with dietary intake in adults and is positively associated with regional fat deposition.

Sex differences in the association of vitamin D and metabolic risk factors with carotid intima-media thickness in obese adolescents.

BACKGROUND: It has been shown that vitamin D is associated with obesity and the development of atherosclerosis. Less is known about this association among adolescents with obesity. OBJECTIVES: To determine the association of vitamin D level and metabolic risk factors with carotid intima-media thickness (CIMT) among obese adolescents. METHODS: We conducted a cross-sectional study among obese children aged 15 to 17 years in Yogyakarta, Indonesia. The association of vitamin D and other metabolic risk factors (triglyceride, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), and insulin resistance using homeostasis model assessment of insulin resistance (HOMA-IR)) with CIMT was explored by multivariable linear regression models. RESULTS: Out of 156 obese adolescents, 55.8% were boys. Compared to girls, boys had higher BMI z-score, waist circumference, and HDL-cholesterol. After adjustment for age, sex and second-hand smoke exposure, high HOMA-IR, total cholesterol, LDL-cholesterol and triglyceride levels were associated with higher odds of elevated CIMT. In analyses stratified by sex, a similar trend was observed in boys, while none of the risk factors were associated with CIMT in girls. We observed no association between vitamin D and CIMT. CONCLUSIONS: Hyperinsulinemia, higher total cholesterol and LDL cholesterol were associated with greater odds of elevated CIMT among obese adolescent boys.

Risk of metabolic syndrome and early vascular markers for atherosclerosis in obese Indonesian adolescents.

Background: The prevalence of childhood obesity has increased in low- and middle-income countries, including Indonesia. It is important to identify risk factors for cardiovascular disease in obese adolescents in this region.Aim: To assess the risk of metabolic syndrome and early vascular markers for atherosclerosis in obese Indonesian adolescentsMethods: A cross-sectional study was undertaken in obese high school students aged 15-<18 years in Yogyakarta, Indonesia. All eligible adolescents were interviewed about their medical history, were physically examined and had a fasting blood sample taken. Arterial stiffness was measured during systole and diastole blood pressure, endothelial dysfunction was estimated using flow-mediated dilation (FMD) and arterial wall thickness using carotid artery intima-media thickness (CIMT).Results: A total of 4268 students were screened, 298 (7%) of whom were classified as obese. Of those, 229 had blood samples taken, 173 had FMD performed and 156 had CIMT examination. Adolescents with a higher body mass index or BMI Z-score (>3.0) had a significantly poorer lipid profile, insulin level and homeostasis model assessment of insulin resistance (HOMA-IR) than those with a lower BMI Z-score. There were no significant differences for early vasculature markers for atherosclerosis between these two groups.Conclusion: The prevalence of risks of cardiovascular disease in obese adolescents was significant. The higher the BMI Z-score, the higher the risks of cardiovascular disease. Interventions to reduce obesity and its cardiovascular disease morbidities are urgently needed in low- and middle-income countries.Abbreviations: BMI; body mass index; CIMT, carotid artery intima-media thickness; CDC, Centers for Disease Control and Prevention; FMD flow-mediated dilation; HDL high-density lipoprotein cholesterol; HbA1c haemoglobin A1c; HOMA-IR, homeostasis model assessment of insulin resistance; IOTF, International Obesity Task Force; LDL, low-density lipoprotein cholesterol; WHO, World Health Organization.

Study protocol for a randomised controlled trial evaluating the effect of folic acid supplementation beyond the first trimester on maternal plasma unmetabolised folic acid in late gestation.

INTRODUCTION: Taking folic acid containing supplements prior to and during early pregnancy reduces the risk of neural tube defects. Neural tube defects occur prior to 28 days postconception, after which, there is no proven benefit of continuing to take folic acid. However, many women continue to take folic acid containing supplements throughout the pregnancy. At higher intakes, folic acid is not converted to its active form and accumulates in circulation as unmetabolised folic acid (UMFA). Recently, concerns have been raised about possible links between late gestation folic acid supplementation and childhood allergy, metabolic disease and autism spectrum disorders. We aim to determine if removing folic acid from prenatal micronutrient supplements after 12 weeks gestation reduces circulating levels of maternal UMFA at 36 weeks gestation. METHODS AND ANALYSIS: This is a parallel-design, double-blinded randomised controlled trial. Women ≥12 and <16 weeks' gestation with a singleton pregnancy and able to give informed consent are eligible to participate. Women (n=100; 50 per group) will be randomised to receive either a micronutrient supplement containing 0.8 mg of folic acid or a micronutrient supplement without folic acid daily from enrolment until delivery. The primary outcome is plasma UMFA concentration at 36 weeks gestation. Secondary outcomes include red blood cell folate and total plasma folate concentration. We will assess whether there is a difference in mean UMFA levels at 36 weeks gestation between groups using linear regression with adjustment for baseline UMFA levels and gestational age at trial entry. The treatment effect will be described as a mean difference with 95% CI. ETHICS AND DISSEMINATION: Ethical approval has been granted from the Women's and Children's Health Network Research Ethics Committee (HREC/19/WCHN/018). The results of this trial will be presented at scientific conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12619001511123.

Long-term exposure to PM2.5 and fasting plasma glucose in non-diabetic adolescents in Yogyakarta, Indonesia.

BACKGROUND: Indonesia is facing serious air pollution. However, very few studies have been conducted to examine the health risks of air pollution in Indonesia, particularly for adolescents. OBJECTIVE: To assess the association between long-term exposure to ambient particles with a diameter of <2.5 µm (PM2.5) and fasting plasma glucose (FPG) in adolescents. METHODS: A cross-sectional study was conducted in 482 adolescents aged 14-18 years in Yogyakarta, Indonesia in 2016. We finally included 469 (97.30%) participants who had no missing data for data analysis. We collected individual data on socio-demographics, behavioral habits, and health information through standardized questionnaires. Satellite-based PM2.5 concentrations from 2013 to 2016 were assigned based on participants' residential addresses. The association between PM2.5 and FPG was examined using a generalized linear regression model while FPG was modeled as a continuous variable. An ordered logistic regression model was used to assess the relationship between PM2.5 and FPG categories. RESULTS: Every 1 µg/m³ increase in PM2.5 was associated with a 0.34 mg/dL [95 confidence interval (95% CI): 0.08 mg/dL, 0.59 mg/dL] increase in FPG levels. Comparing with the low FPG level (under 86 mg/dL), every 1 µg/m³ increase in PM2.5 was associated with a 10.20% (95% CI: 1.60%, 19.80%) increase in the odds of impaired fasting glucose (IFG) (100-125 mg/dL). Stratified analyses indicated greater effects on participants with hypertension [odds ratio (OR) = 1.30, 95% CI: 1.09, 1.57] and those had higher physical activities (OR = 1.36, 95% CI: 1.09, 1.57). Adolescents' sex, obesity status and different cutoff points of FPG did not modify the association between the exposure to PM2.5 and FPG levels. CONCLUSION: Long-term exposure to PM2.5 was associated with increased FPG levels in Indonesian non-diabetic adolescents.

Weekly iron-folic acid supplements containing 2.8 mg folic acid are associated with a lower risk of neural tube defects than the current practice of 0.4 mg: a randomised controlled trial in Malaysia.

INTRODUCTION: Weekly iron-folic acid (IFA) supplements are recommended for all menstruating women in countries where anaemia prevalence is >20%. Anaemia caused by folate deficiency is low worldwide, and the need to include folic acid is in question. Including folic acid might reduce the risk of a neural tube defect (NTD) should a woman become pregnant. Most weekly supplements contain 0.4 mg folic acid; however, WHO recommends 2.8 mg because it is seven times the daily dose effective in reducing NTDs. There is a reluctance to switch to supplements containing 2.8 mg of folic acid because of a lack of evidence that this dose would prevent NTDs. Our aim was to investigate the effect of two doses of folic acid, compared with placebo, on red blood cell (RBC) folate, a biomarker of NTD risk. METHODS: We conducted a three-arm double-blind efficacy trial in Malaysia. Non-pregnant women (n=331) were randomised to receive 60 mg iron and either 0, 0.4, or 2.8 mg folic acid once weekly for 16 weeks. RESULTS: At 16 weeks, women receiving 0.4 mg and 2.8 mg folic acid per week had a higher mean RBC folate than those receiving 0 mg (mean difference (95% CI) 84 (54 to 113) and 355 (316 to 394) nmol/L, respectively). Women receiving 2.8 mg folic acid had a 271 (234 to 309) nmol/L greater mean RBC folate than those receiving 0.4 mg. Moreover, women in the 2.8 mg group were seven times (RR 7.3, 95% CI 3.9 to 13.7; p<0.0001) more likely to achieve an RBC folate >748 nmol/L, a concentration associated with a low risk of NTD, compared with the 0.4 mg group. CONCLUSION: Weekly IFA supplements containing 2.8 mg folic acid increases RBC folate more than those containing 0.4 mg. Increased availability and access to the 2.8 mg formulation is needed. TRAIL REGISTRATION NUMBER: This trial is registered with the Australian New Zealand Clinical Trial Registry (ACTRN12619000818134).

Effect of once weekly folic acid supplementation on erythrocyte folate concentrations in women to determine potential to prevent neural tube defects: a randomised controlled dose-finding trial in Malaysia.

INTRODUCTION: Folic acid (0.4 mg) taken prior to and during early pregnancy reduces the risk of neural tube defects (NTDs). Because these birth defects occur early in pregnancy, before women may know they are pregnant, many countries have mandated the addition of folic acid to food staples. In countries where fortification is not possible, and weekly iron folic acid programmes exist to reduce anaemia, the WHO recommends that 2.8 mg (7×0.4 mg) folic acid be given instead of the current weekly practice of 0.4 mg. Currently, there is a lack of evidence to support if the 2.8 mg folic acid per week dose is sufficient to raise erythrocyte folate concentrations to a level associated with a reduced risk of a NTD-affected pregnancy. We aim to conduct a three-arm randomised controlled trial to determine the effect of weekly folic acid with iron on erythrocyte folate, a biomarker of NTD risk. METHODS AND ANALYSIS: We will recruit non-pregnant women (n=300; 18-45 years) from Selangor, Malaysia. Women will be randomised to receive either 2.8, 0.4 or 0.0 (placebo) mg folic acid with 60 mg iron weekly for 16 weeks, followed by a 4-week washout period. The primary outcome will be erythrocyte folate concentration at 16 weeks and the mean concentration will be compared between randomised treatment groups (intention-to-treat) using a linear regression model adjusting for the baseline measure. ETHICS AND DISSEMINATION: Ethical approval was obtained from the University of British Columbia (H18-00768) and Universiti Putra Malaysia (JKEUPM-2018-255). The results of this trial will be presented at scientific conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBERS: ACTRN12619000818134 and NMRR-19-119-45736.

The Interaction between Coffee: Caffeine Consumption, UCP2 Gene Variation, and Adiposity in Adults-A Cross-Sectional Study.

BACKGROUND: Coffee is suggested as an alternative option for weight loss but the relationship between coffee consumption and adiposity in population-based studies is still controversial. Therefore, this study was aimed at evaluating the relationship between coffee intake and adiposity in adults and to test whether uncoupling protein 2 (UCP2) gene variation was able to affect this relationship. METHODS: This was a cross-sectional study conducted in male and female adults living in the urban area of Yogyakarta, Indonesia. Adiposity was determined based on body weight, body mass index (BMI), percent body fat, and waist and hip circumference. Data on coffee consumption and other dietary components were collected using a semiquantitative food frequency questionnaire along with other caffeine-containing beverages such as tea, chocolate, and other beverages. The -866 G/A UCP2 gene variation was analyzed using polymerase chain reaction-restriction fragment length polymorphism. The correlation between coffee intake and adiposity was tested using linear regression test with adjustment for sex, age, energy intake, table sugar intake, and total caffeine intake. RESULTS: In all subjects, coffee intake was inversely correlated with body weight (ß = -0.122, p=0.028), BMI (ß = -0.157, p=0.005), and body fat (ß = -0.135, p=0.009). In subjects with AA + GA genotypes, coffee intake was inversely correlated with body weight (ß = -0.155, p=0.027), BMI (ß = -0.179, p=0.010), and body fat (ß = -0.148, p=0.021). By contrast, in subjects with GG genotype, coffee intake was not correlated with body weight (ß = -0.017, p=0.822), BMI (ß = -0.068, p=0.377), and body fat (ß = -0.047, p=0.504). CONCLUSION: We showed that coffee intake was negatively correlated with adiposity, and this was independent of total caffeine intake. Additionally, we showed that the -866 G/A UCP2 gene variation influences the relationship between coffee intake and adiposity.