BACKGROUND:Pregestational diabetes increases the risk of adverse outcomes including congenital malformations, stillbirth, developmental disabilities, and maternal morbidity. Periconceptional glycemic control and folic acid (FA) supplementation are 2 of the most effective birth defects prevention strategies. OBJECTIVES:The objectives are to describe the proportion of and risk factors for diabetes and prediabetes and assess the association of folate status and diabetes among a nationally representative sample of nonpregnant women of reproductive age (WRA). METHODS:WRA (12‒49 y) from the NHANES 2011‒March 2020 (n = 3731) were included. Diabetes status was defined by glycated hemoglobin (HbA1c) ≥6.5%, fasting plasma glucose (FPG) ≥126 mg/dL, or self-report. Prediabetes was defined as HbA1c ≥5.7 <6.5% or FPG ≥100 <126 mg/dL. The associations were assessed by multivariate regression models. RESULTS:Among all WRA, 32.3% [95% confidence interval (CI): 30.0%, 34.7%] had prediabetes and 5.3% (95% CI: 4.4%, 6.3%) had diabetes [1.8% undiagnosed, 95% CI: 1.4%, 2.3%; 3.1% diagnosed but uncontrolled (HbA1c ≥5.7), 95% CI: 2.5, 4.0; 0.4% diagnosed but controlled (HbA1c<5.7), 95% CI: 0.2, 0.6]. The prevalence of diabetes was associated with increased age, BMI, serum pyrazino-s-triazine, an oxidation form of 5'-methyltetrahydrofolate (MeFox), and red blood cell (RBC) folate concentrations (all P < 0.0001) but not unmetabolized FA. Among WRA ≥35 y, 10.5% (95% CI: 8.5%, 12.8%) had diabetes and 40.3% (95% CI: 37.1%, 43.5%) had prediabetes. In adjusted regression models, diabetes was associated with altered folate metabolism [i.e., high (>90th %) RBC folate concentrations with lower (<400 μg/d) FA intake; adjusted odds ratio 2.28 (95% CI: 1.23, 4.24)]. Among those with diabetes, high serum MeFox and RBC folate concentrations were lower with euglycemia. CONCLUSIONS:Diabetes and prediabetes were common among WRA. Diabetes was associated with high RBC folate concentration and high MeFox despite low FA intake; however, these associations were reduced among those with good glycemic control. Screening for and preventing the progression of prediabetes, diagnosis, and glycemic control among those with diabetes has the potential to prevent adverse outcomes.

BACKGROUND:Malaria is an infectious disease transmitted by female Anopheles mosquitoes, with ongoing transmission in over 80 countries. The malaria parasite requires folate for survival and growth; antifolate antimalarial medications used for prevention and treatment target enzymes in folate metabolism as their mechanism of action. Periconceptional folic acid (synthetic form of folate) supplementation (400 μg/day) is the standard of care for neural tube defect prevention. Concerns have been raised about the potential effects of folic acid (including above the tolerable upper intake level (UL) >1.0 mg/day) in the context of malaria prevention and treatment, including the efficacy of antimalarial medications. Examining the potential impact of folic acid on malaria risk and severity amongst people taking antifolate antimalarial medications may inform public health programmes in malaria-endemic areas. OBJECTIVES:To examine the effects of folic acid supplementation on the risk and severity of malaria infection amongst people taking antifolate antimalarials and living in areas with malaria endemicity. PREVENTION:Amongst uninfected people taking antifolate antimalarial medications for malaria prevention, does folic acid supplementation increase susceptibility or severity of malaria infection? TREATMENT:Amongst people with malaria infection who are being treated with antifolate antimalarial drugs, does folic acid supplementation reduce parasite clearance or increase the risk of treatment failure? SEARCH METHODS:We searched databases including CENTRAL, MEDLINE, Embase, CINAHL, Scopus, and trial registries (September 13, 2024), grey literature, and reference searches to identify additional studies. SELECTION CRITERIA:Randomised trials evaluating the effects of folic acid supplementation (alone or in combination with iron or other vitamins and minerals) amongst individuals taking antifolate antimalarial medications in malaria-endemic areas. DATA COLLECTION AND ANALYSIS:Primary outcomes included uncomplicated malaria or severe malaria, parasite clearance, and treatment failure. Cochrane RoB 2 was used to evaluate the risk of bias. Certainty of evidence was assessed using GRADE for primary outcomes. We performed meta-analyses using random-effects models for all outcomes. MAIN RESULTS:Eight trials with 3486 participants were included: three malaria prevention trials and five malaria treatment trials. Most treatment trials included folic acid doses above the UL (> 1.0 mg/d); one trial included 400 μg per day. Antifolate antimalarials included sulfadoxine-pyrimethamine (SP; five trials), sulfisoxazole plus pyrimethamine (one trial), atovaquone-proguanil (one trial), and proguanil (one trial). Some studies had unclear or high risk of bias due to missing outcome data. Malaria prevention Comparison 1: Folic acid (alone or in combination with other vitamins and minerals) + antifolate antimalarials versus placebo/no folic acid + antifolate antimalarial medications. Data for primary outcomes, uncomplicated and severe malaria, were not reported. One trial reported laboratory parasitaemia; there was little to no difference in malaria parasitaemia amongst pregnant women receiving folic acid (with iron) and antifolate antimalarials compared to iron and antifolate antimalarials (Risk Ratio (RR) 1.21; 95% CI 0.56 to 2.62; P = 0.63; 1 trial, 643 individuals). Comparisons 2-4: No studies reported data for Comparisons 2-4. Malaria treatment Comparison 1: Folic acid (alone or in combination with other vitamins and minerals) + antifolate antimalarial medications versus placebo/no folic acid with antifolate antimalarials. People receiving folic acid (alone or with iron) and antifolate antimalarials were less likely to clear malaria parasites (day 3) compared to individuals who did not receive folic acid (RR 0.89; 95% CI 0.84 to 0.95, 4 trials, 929 individuals, moderate-certainty evidence); and had increased risk of treatment failure on day 7 (RR 2.12; 95% CI 1.41 to 3.19, 4 trials, 1062 individuals, moderate-certainty evidence), day 14 (RR 1.97; 95% CI 1.44 to 2.70, 3 trials; 891 individuals; moderate-certainty evidence), and day 28 (RR 1.35; 95% CI 1.21 to 1.51; 4 trials; 1012 individuals, moderate-certainty evidence). Comparison 2: Folic acid alone + antifolate antimalarials versus placebo/no folic acid + antifolate antimalarial medication. Folic acid supplementation with antifolate antimalarials likely had lower parasite clearance (day 3) (RR 0.87; 95% CI 0.79 to 0.96, 2 trials, 229 individuals, moderate certainty of the evidence), and increased treatment failure (day 7: RR 2.58; 95% CI 0.89 to 7.45; P = 0.08; 2 trials; 344 individuals, moderate-certainty evidence; day 14: RR 4.15; 95% CI 0.92 to 18.65; P = 0.06; 1 trial; 173 individuals, moderate-certainty evidence; and day 28: RR 1.47; 95% CI 0.86 to 2.49; P = 0.16; 2 trials; 294 individuals, moderate-certainty evidence), compared to no folic acid and antifolate antimalarials. Comparison 3: Folic acid with iron + antifolate antimalarial medication versus placebo/no folic acid with iron + antifolate antimalarial medication. People receiving folic acid with iron and antifolate antimalarials were less likely to clear malaria parasites (day 3: RR 0.90; 95% CI 0.83 to 0.98; P = 0.02; 2 trials; 700 individuals, moderate-certainty evidence), and had increased treatment failure (day 7: RR 1.96; 95% CI 1.05 to 3.65; P = 0.03; 2 trials; 718 individuals; day 14: RR 1.90; 95% CI 1.35 to 2.67; 2 trials; 718 individuals; day 28: RR 1.17; 95% CI 0.79 to 1.74; 2 trials; 578 individuals; all moderate-certainty evidence), compared to iron and antifolate antimalarials. Comparison 4: No studies reported data. AUTHORS' CONCLUSIONS:Malaria prevention: None of the included trials reported primary outcomes. Malaria treatment: People who received folic acid supplementation (alone or with iron) and antifolate antimalarial treatment were less likely to clear malaria parasitaemia (day 3), and had increased treatment failure (days 7, 14, 28). Most of the included trials provided folic acid with doses above the tolerable UL (> 1.0 mg). One trial included folic acid at a dose of 400 μg/d (recommended dose for preventing neural tube defects) and showed little to no difference in parasite clearance or treatment failure.

Adverse birth outcomes (ABOs) cause significant infant morbidity and mortality in resource-limited settings. Many of the maternal risk factors associated with ABOs can be prevented. We present the prevalence, trends, and risk factors of selected ABOs from a hospital-based birth defects surveillance program in Kampala, Uganda. We analyzed data for all mothers with singleton deliveries collected from four urban hospitals between 2015 and 2022. Prevalence of preterm birth [PTB], low birth weight [LBW], small for gestational age [SGA], and stillbirth [SB] and maternal HIV seroprevalence were calculated among 222,427 births. SB was defined as infant born without life ≥ 28 weeks of gestation, LBW as term live birth weighing < 2500 g and PTB as live birth born < 37 weeks of gestation. Time trends of ABOs by maternal HIV status and age were computed using quasi-Poisson regression model and presented graphically. Risk factor associations were estimated using robust Poisson models adjusting for infant sex, hospital of delivery, and birth year. Prevalence of PTB, LBW, SGA, and SB were 14.8

INTRODUCTION:Congenital heart defects, orofacial clefts, and neural tube defects share similar modifiable risk factors. The prevalence and trends of risk factors for these selected birth defects were assessed among nonpregnant, nonlactating women of reproductive age (aged 12-49 years) in the U.S. METHODS:Cross-sectional data from the National Health and Nutrition Examination Survey 2007-March 2020 were analyzed in fall 2024. Demographics, BMI, household food security, folic acid supplement use, usual intake of dietary folate and vitamin B12, concentrations for serum and red blood cell folate, serum vitamin B12, serum cotinine (smoking exposure), and diabetes status were reported. Weighted percentages of prevalence of risk factors with 95% CIs were calculated using the survey package in R to account for clustered sampling. RESULTS:Among 5,374 women of reproductive age, approximately 66.4% (95% CI=64.3, 68.4) had at least 1 known modifiable risk factor: 6.7% (95% CI=5.7, 7.6) reported very low food security, 33.8% (95% CI=32.2, 35.4) had obesity, 4.8% (95% CI=4.0, 5.5) had diabetes, 18.8% (95% CI=17.2, 20.4) had smoking exposure, and 19.5% (95% CI=17.8, 21.1) had red blood cell folate concentrations below the threshold (748 nmol/L) for optimal neural tube defect prevention. Over the time studied, the percentage of women of reproductive age with at least 1 risk factor rose from 65.3% (95% CI=62.1, 68.4) to 69.5% (95% CI=65.4, 73.9; p=0.08). CONCLUSIONS:Approximately 2 of 3 women of reproductive age in the U.S. have pre-existing modifiable risk factors for birth defects. Implementation of preconception health care could help reduce the prevalence of known risk factors and improve birth outcomes.

Introduction:We assessed the risk of adverse pregnancy and birth outcomes and birth defects among women living with HIV (WLHIV) on antiretroviral therapy (ART) and HIV-negative women.Methods:We analyzed data on live births, stillbirths, and spontaneous abortions during 2015-2021 from a hospital-based birth defects surveillance system in Kampala, Uganda. ART regimens were recorded from hospital records and maternal self-reports. Using a log-binomial regression model, we compared the prevalence of 16 major external birth defects and other adverse birth outcomes among WLHIV on ART and HIV-negative women.Results:A total of 203,092 births were included from 196,373 women of whom 15,020 (7.6%) were WLHIV on ART. During pregnancy, 15,566 infants were primarily exposed to non-nucleoside reverse transcriptase inhibitor-based ART (n = 13,614; 87.5%). After adjusting for maternal age, parity, and number of antenatal care visits, WLHIV on non-nucleoside reverse transcriptase inhibitor were more likely than HIV-negative women to deliver preterm (adjusted prevalence ratio [aPR] = 1.27, 95% confidence interval: 1.21 to 1.32), post-term (aPR = 1.23, 95% CI: 1.16 to 1.32), or small for gestational age infants (aPR = 1.35, 95% CI: 1.30 to 1.40). Spina bifida was more prevalent among infants born to WLHIV on ART periconceptionally compared with HIV-negative women (aPR = 2.45, 95% CI: 1.27 to 4.33). The prevalence of the other selected birth defects was similar between infants from WLHIV on ART and HIV-negative women.Conclusions:In Uganda, WLHIV on ART were more likely than HIV-negative women to experience selected adverse birth outcomes. Further surveillance of maternal ART exposure, including by drug class and ART regimen, is needed to monitor and prevent adverse birth outcomes in WLHIV.

BACKGROUND AND AIMS:In clinical populations, vitamin B12 deficiency has been associated with adverse metabolic health (e.g., gestational diabetes). Population-level data among women of reproductive age could inform screening and interventions. The objective of this analysis was to examine the prevalence of adverse metabolic characteristics (elevated adiposity and central adiposity, hypertension, elevated glycated hemoglobin [HbA1c]) and associations of vitamin B12 status with metabolic characteristics in women as part of a population-based biomarker survey in Southern India. METHODS:Participants (n = 980 women 15-40 y; not pregnant or lactating) were assessed for total vitamin B12, holotranscobalamin, methylmalonic acid, homocysteine, and HbA1c. Categorical anthropometry assessments and bioelectrical impedance analysis (e.g., whole body (WF%) and trunk (TF%) fat) were assessed among adults (≥18 y). Linear and binomial regressions were used to examine associations of vitamin B12 status with metabolic characteristics. RESULTS:Overall, 25 % of participants had HbA1c ≥5.7 % (HbA1c ≥5.7-<6.5 %: 20.0 %; ≥6.5 %: 5.0 %), and 18.6 % had hypertension (Stage 1: 16.4 %; Stage 2: 2.2 %). Among adults, 23.4 % had body mass index of (BMI) 25.0-<30.0 kg/m2, 9.6 % had BMI ≥30.0 kg/m2, 13.4 % had elevated waist circumference (WC; >88.9 cm), and 20.8 % had elevated waist-hip ratio (WHR; ≥0.85 cm). Overall, higher vitamin B12 concentrations were associated with lower BMI and WC. Among adults, higher vitamin B12 concentrations were associated with lower WF% and TF%; and lower prevalence of overweight (BMI ≥25.0 kg/m2) and elevated WC, WHR, and WF%. Similarly, vitamin B12 <148 pmol/L was associated with higher BMI and WC overall and, among adults, higher WF% and TF%, and increased overweight (BMI ≥25.0 kg/m2; prevalence ratio: 1.31; 95 % confidence interval: 1.09-1.58), and elevated WC (>88.9 cm; 1.85 [1.32-2.60]), WHR (≥85.0; 1.38 [1.07-1.78]), WF% (>35 %; 1.29 [1.10-1.51]), and TF% (>35 %; 1.25 [1.06-1.49]). CONCLUSIONS:The burden of adverse metabolic characteristics was substantial in this population of young, apparently healthy women. Among those with vitamin B12 <148 pmol/L there was increased central adiposity and overweight status. Evaluating vitamin B12 and metabolic outcomes prospectively could inform screening and interventions to improve women's health. REGISTRATION NUMBER:NCT04048330.

BACKGROUND:Maternal folate and vitamin B12 deficiency can lead to serious adverse pregnancy outcomes. There are no nationally representative estimates on folate and vitamin B12 status among women of reproductive age (WRA) in Malawi. OBJECTIVE:We assessed folate and vitamin B12 status among nonpregnant WRA in Malawi and predicted the risk of folate-sensitive neural tube defects (NTDs) were they to become pregnant. METHODS:Using data from the cross-sectional, nationally representative 2015-2016 Malawi Micronutrient Survey, we calculated the proportion of folate and vitamin B12 deficiency and insufficiency by demographic characteristics among 778 nonpregnant WRA (15-49 years). We predicted NTD prevalence using red blood cell (RBC) folate distributions and a published Bayesian model of the association between RBC folate and NTD risk. Analyses accounted for complex survey design. RESULTS:Among WRA, 8.5% (95% CI: 6.2, 11.6) and 13.3% (10.0, 17.4) had serum (<7 nmol/L) and RBC folate (<305 nmol/L) deficiency, respectively. The proportion of vitamin B12 deficiency (<148 pmol/L) and insufficiency (≤221 pmol/L) was 11.8% (8.6, 16.0) and 40.6% (34.1, 47.4), respectively. RBC folate insufficiency (<748 nmol/L, defined as the concentration associated with the threshold for elevated NTD risk: >8 cases per 10,000 births) was widespread: 81.4% (75.0, 86.4). The predicted NTD risk nationally was 24.7 cases per 10,000 live births. RBC folate insufficiency and higher predicted NTD risk were more common among WRA living in urban areas or with higher education. CONCLUSIONS:These findings highlight the importance of nutritional and NTD surveillance in Malawi and the opportunity for improving folate and vitamin B12 nutrition among Malawian WRA.

Background Vitamin B-12 deficiency is a major public health problem worldwide, with the highest burden in elderly people, pregnant women, and young children. Due to its role in DNA synthesis and methylation, folate metabolism, and erythropoiesis, vitamin B-12 supplementation during pregnancy may confer longer-term benefits to maternal and child health outcomes. Objectives To evaluate the benefits and harms of oral vitamin B-12 supplementation during pregnancy on maternal and child health outcomes. Search methods We searched the Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP) on 2 June 2023, and reference lists of retrieved studies. Selection criteria Randomised controlled trials (RCTs), quasi-RCTs, or cluster-RCTs evaluating the effects of oral vitamin B-12 supplementation compared to placebo or no vitamin B-12 supplementation during pregnancy. Data collection and analysis We used standard Cochrane methods. Four review authors independently assessed trial eligibility. Two review authors independently extracted data from included studies and conducted checks for accuracy. Three review authors independently assessed the risk of bias of the included studies using the Cochrane RoB 1 tool. We used GRADE to evaluate the certainty of evidence for primary outcomes. Main results The review included five trials with 984 pregnant women. All trials were conducted in low- and middle-income countries, including India, Bangladesh, South Africa, and Croatia. At enrolment, 26% to 51% of pregnant women had vitamin B-12 deficiency (less than 150 pmol/L), and the prevalence of anaemia (haemoglobin less than 11.0 g/dL) ranged from 30% to 46%. The dosage of vitamin B-12 supplementation varied from 5 mu g/day to 250 mu g/day, with administration beginning at 8 to 28 weeks' gestation through to delivery or three months' postpartum, and the duration of supplementation ranged from 8 to 16 weeks to 32 to 38 weeks. Three trials, involving 609 pregnant women, contributed data for meta-analyses of the effects of vitamin B-12 supplementation compared to placebo or no vitamin B-12 supplementation. Maternal anaemia: there may be little to no difference for maternal anaemia by intervention group, but the evidence is very uncertain (70.9% versus 65.0%; risk ratio (RR) 1.08, 95% confidence interval (CI) 0.93 to 1.26; 2 trials, 284 women; very low-certainty evidence). Maternal vitamin B-12 status: vitamin B-12 supplementation during pregnancy may reduce the risk of maternal vitamin B-12 deficiency compared to placebo or no vitamin B-12 supplementation, but the evidence is very uncertain (25.9% versus 67.9%; RR 0.38, 95% CI 0.28 to 0.51; 2 trials, 272 women; very low-certainty evidence). Women who received vitamin B-12 supplements during pregnancy may have higher total vitamin B12 concentrations compared to placebo or no vitamin B-12 supplementation (mean difference (MD) 60.89 pmol/L, 95% CI 40.86 to 80.92; 3 trials, 412 women). However, there was substantial heterogeneity (I-2 = 85%). Adverse pregnancy outcomes: the evidence is uncertain about the effect on adverse pregnancy outcomes, including preterm birth (RR 0.97, 95% CI 0.55 to 1.74; 2 trials, 340 women; low-certainty evidence), and low birthweight (RR 1.50, 95% CI 0.93 to 2.43; 2 trials, 344 women; low-certainty evidence). Two trials reported data on spontaneous abortion (or miscarriage); however, the trials did not report quantitative data for meta-analysis and there was no clear definition of spontaneous abortion in the study reports. No trials evaluated the effects of vitamin B-12 supplementation during pregnancy on neural tube defects. Infant vitamin B-12 status: children born to women who received vitamin B-12 supplementation had higher total vitamin B-12 concentrations compared to placebo or no vitamin B-12 supplementation (MD 71.89 pmol/L, 95% CI 20.23 to 123.54; 2 trials, 144 children). Child cognitive outcomes: three ancillary analyses of one trial reported child cognitive outcomes; however, data were not reported in a format that could be included in quantitative meta-analyses. In one study, maternal vitamin B-12 supplementation did not improve neurodevelopment status (e.g. cognitive, language (receptive and expressive), motor (fine and gross), social-emotional, or adaptive (conceptual, social, practical) domains) in children compared to placebo (9 months, Bayley Scales of Infant and Toddler Development Third Edition (BSID-III); 1 trial; low-certainty evidence) or neurophysiological outcomes (72 months, event-related potential measures; 1 trial; low-certainty evidence), though children born to women who received vitamin B-12 supplementation had improved expressive language domain compared to placebo (30 months, BSID-III; 1 trial; low-certainty evidence). Authors' conclusions Oral vitamin B-12 supplementation during pregnancy may reduce the risk of maternal vitamin B-12 deficiency and may improve maternal vitamin B-12 concentrations during pregnancy or postpartum compared to placebo or no vitamin B-12 supplementation, but the evidence is very uncertain. The effects of vitamin B-12 supplementation on other primary outcomes assessed in this review were not reported, or were not reported in a format for inclusion in quantitative analyses. Vitamin B-12 supplementation during pregnancy may improve maternal and infant vitamin B-12 status, but the potential impact on longer-term clinical and functional maternal and child health outcomes has not yet been established.

Background: Folate and vitamin B12 are important biomarkers of nutritional status of populations. Objectives: This study aims to estimate folate and vitamin B12 usual intakes among United States adults and examine folate and vitamin B12 biomarker status by intake source. Methods: We analyzed data for United States adults aged >19 y from National Health and Nutrition Examination Survey 2007-2018 (n = 31,128), during which time voluntary corn masa flour (CMF) fortification was started. Usual intake was estimated using the National Cancer Institute method. Folate intake included folate from natural foods and folic acid from 4 sources: enriched cereal grain products (ECGPs), CMF, ready-to-eat cereals (RTEs), and folic acid-containing supplements (SUP). Vitamin B12 intake was mainly from food and supplements. Results: The median natural food folate intake (222 & mu;g dietary folate equivalents (DFE)/d) was below the estimated average requirement (EAR) of 320 & mu;g DFE/d. The proportions of those who consumed folic acid from ECGP/CMF only, ECGP/CMF + RTE, ECGP/CMF + SUP, and ECGP/CMF + RTE + SUP were 50%, 18%, 22%, and 10%, respectively. Median usual folic acid intakes (& mu;g/d) were 236 (IQR: 152, 439) overall and 134, 313, 496, and 695 in the ECGP/CMF only, ECGP/CMF + RTE, ECGP/CMF + SUP, and ECGP/CMF + RTE + SUP folic acid consumption groups, respectively. Overall, 2.0% (95% CI: 1.7%, 2.3%) of adults, all of whom used folic acid supplements, consumed greater than the tolerable upper intake level (UL) of 1000 & mu;g/ d folic acid. The median usual vitamin B12 intake (& mu;g/d) was 5.2 for vitamin B12 supplement nonusers and 21.8 for users. Consumption of RTE and/or supplements with folic acid was associated with higher serum and red blood cell folate concentrations. Vitamin B12 supplement users had significantly higher serum vitamin B12 concentrations. Conclusions: Folic acid fortification plays a critical role in helping United States adults meet the folate EAR. At current fortification levels, United States adults who do not consume supplements do not have the usual folic acid intake exceeding the UL.

Background: RBC folate concentrations are monitored at the population level, with a recommended threshold for optimal neural tube defect (NTD) prevention. A corresponding threshold for serum folate has not been established.Objectives: This study aimed to estimate the serum folate insufficiency threshold corresponding to the RBC folate threshold for NTD prevention and examine how this threshold is modified by vitamin B12 status.Methods: Participants were women (15-40 y; not pregnant or lactating; n = 977) from a population-based biomarker survey in Southern India. RBC folate and serum folate were measured via microbiologic assay. RBC folate deficiency (<305 nmol/L) and insufficiency (<748 nmol/L), serum vitamin B12 deficiency (<148 pmol/L) and vitamin B12 insufficiency (<221 pmol/L), elevated plasma MMA (>0.26 mu mol/L), elevated plasma homocysteine (>10.0 mu mol/L), and elevated HbA1c (>= 6.5%) were evaluated. Bayesian linear models were used to estimate unadjusted and adjusted thresholds.Results: Compared with adequate vitamin B12 status, the estimated serum folate threshold was higher in participants with serum vitamin B12 deficiency (72.5 vs. 28.1 nmol/L) or vitamin B12 insufficiency (48.7 vs. 24.3 nmol/L) and elevated MMA (55.6 vs. 25.9 nmol/L). The threshold was lower in participants with elevated HbA1c (HbA1c >= 6.5% vs. <6.5%; 21.0 vs. 40.5 nmol/L).Conclusions: The estimated serum folate threshold for optimal NTD prevention was similar to previous reports (24.3 vs. 25.6 nmol/L) among participants with sufficient vitamin B12 status. However, this threshold was more than 2-fold higher in participants with vitamin B12 deficiency and substantially higher across all indicators of insufficient vitamin B12 status (<221 pmol/L, elevated MMA, combined B12, impaired vitamin B12 status), and lower in participants with elevated HbA1c. Findings suggest a serum folate threshold for NTD prevention may be possible in some settings; however, it may not be appropriate in populations with high prevalence of vitamin B12 insufficiency. Am J Clin Nutr 2023;xx:xx-xx.This trial was registered at https://clinicaltrials.gov as NCT04048330.

Background Limited diagnostic capabilities, resources and health worker skills have deterred the advancement of birth defects surveillance systems in most low- and middle-income countries (LMICs). Empowering health workers to identify and diagnose major external birth defects (BDs) is crucial to establishing effective hospital-based BD surveillance. Makerere University-Johns Hopkins University (MU-JHU) Research Collaboration BD Surveillance System consists of three diagnostic levels: (1) surveillance midwives, (2) MU-JHU clinical team, and (3) U.S. Centers for Disease Control and Prevention (CDC) birth defects subject matter experts (SMEs) who provide confirmatory diagnosis. The diagnostic concordance of major external BDs by surveillance midwives or MU-JHU clinical team with CDC birth defects SMEs were estimated. Methods Study staff went through a series of trainings, including birth defects identification and confirmation, before surveillance activities were implemented. To assess the diagnostic concordance, we analyzed surveillance data from 2015 to 2021 for major external BDs: anencephaly, iniencephaly, encephalocele, spina bifida, craniorachischisis, microcephaly, anophthalmia/microphthalmia, anotia/microtia, cleft palate alone, cleft lip alone, cleft lip with cleft palate, imperforate anus, hypospadias, talipes equinovarus, limb reduction, gastroschisis, and omphalocele. Positive predictive value (PPV) as the proportion of BDs diagnosed by surveillance midwives or MU-JHU clinical team that were confirmed by CDC birth defects SMEs was computed. PPVs between 2015 and 2018 and 2019–2021 were compared to assess the accuracy of case diagnosis over time. Results Of the 204,332 infants examined during 2015–2021, 870 infants had a BD. Among the 1,245 BDs identified, 1,232 (99.0%) were confirmed by CDC birth defects SMEs. For surveillance midwives, PPV for 7 of 17 BDs was > 80%. For the MU-JHU clinical team, PPV for 13 of 17 BDs was > 80%. Among surveillance midwives, PPV improved significantly from 2015 to 2018 to 2019–2021, for microcephaly (+ 50.0%), cleft lip with cleft palate (+ 17.0%), imperforate anus (+ 30.0%), and talipes equinovarus (+ 10.8%). Improvements in PPV were also observed among MU-JHU clinical team; however, none were significant. Conclusion The diagnostic accuracy of the midwives and clinical team increased, highlighting that BD surveillance, by front-line health care workers (midwives) in LMICs is possible when midwives receive comprehensive training, technical support, funding and continuous professional development.

Background:Women of reproductive age are at an increased risk of anemia and micronutrient deficiencies. Evidence supports the role of periconceptional nutrition in the development of neural tube defects (NTDs) and other pregnancy complications. Vitamin B12 deficiency is a risk factor for NTDs and may modify folate biomarkers that predict NTD risk at the population level. There is an interest in mandatory fortification with vitamin B12 and folic acid for anemia and birth defect prevention. However, there are limited population-representative data needed to inform policy and guidelines.Objectives:This randomized trial will be conducted to evaluate the efficacy of quadruple-fortified salt (QFS; iron, iodine, folic acid, vitamin B12) in 1,000 households in Southern India.Methods:Women 18 to 49 y who are not pregnant or lactating and reside within the catchment area of our community-based research site in Southern India will be screened and invited to participate in the trial. After informed consent, women and their households will be randomized to receive one of the following 4 interventions: 1) double-fortified salt (DFS; iron, iodine), 2) DFS + folic acid (iron, iodine, folic acid), 3) DFS + vitamin B12 (iron, iodine, vitamin B12), or 4) DFS + folic acid and vitamin B12 (QFS; iron, iodine, folic acid, vitamin B12) for 12 mo. Structured interviews will be conducted by trained nurse enumerators to collect sociodemographic, anthropometric, dietary, health, and reproductive history data. Biological samples will be collected at baseline, midpoint, and endpoint. Whole blood will be analyzed for hemoglobin using Coulter Counter. Total vitamin B12 will be measured by chemiluminescence; red blood cell folate and serum folate will be evaluated using the World Health Organization-recommended microbiologic assay.Conclusions:The results of this randomized trial will help to evaluate the efficacy of QFS to prevent anemia and micronutrient deficiencies. Clinical trial registration numbers: NCT03853304 and Clinical Trial Registry of India REF/2019/03/024479.Registration number:NCT03853304 and REF/2019/03/024479.

There are 3 major folic acid intake sources in the US—enriched cereal grain products (ECGP), ready-to-eat cereals (RTE), and folic acid containing supplements (SUP), generating 4 mutually exclusive consumption groups. This study aims to describe the contribution of these sources to folic acid intakes above the tolerable upper intake level (UL, 1000 mg/d), and their impact on red blood cell (RBC) folate and serum vitamin B12 concentrations. We used data for nonpregnant US adults (≥19 y) from the National Health and Nutrition Examination Survey (NHANES) 2007–2018 (n = 31,128); serum vitamin B12 data were only available for 2011–2014 (n = 9,298). Median usual intake was estimated from two 24-h dietary recalls using the National Cancer Institute (NCI) method. Statistical analyses accounted for complex survey design using appropriate weights. The proportions of those who consumed folic acid from ECGP only, ECGP +RTE, ECGP +SUP, and ECGP +RTE +SUP were 50%, 18%, 22%, and 10%, and the median modelled usual folic acid intakes (mg/d) were 126 (interquartile range (IQR): 92,168), 308 (IQR: 267, 360), 490 (IQR: 347, 586), and 687 (IQR: 577, 767), respectively. Overall, 1.97% (95% CI: 1.96%, 1.98%) of adults consumed >UL. Adults who did not consume SUP did not have intakes >UL. The median usual vitamin B12 intake was 6.4 (IQR: 4.1, 11.7) mg/d. Consumption of RTE and/or SUP was associated with higher RBC folate concentrations (nmol/L) (ECGP only: 976 [95% CI: 963, 989], ECGP +RTE: 1130 [95% CI: 1110, 1150], ECGP +SUP: 1307 [95% CI: 1283, 1332], ECGP +RTE +SUP: 1467 [95% CI: 1439, 1495]). Serum vitamin B12 concentrations (pmol/L) were 350 (95% CI: 343, 356; ECGP only), 380 (95% CI: 366, 393; ECGP +RTE), 456 (95% CI: 440, 473; ECGP +SUP), and 485 (95% CI: 462, 509; ECGP +RTE +SUP). RBC folate deficiency (<305 nmol/L) was < 2% and vitamin B12 deficiency (<148 pmol/L) was < 6% across all folic acid consumption groups. Folate and vitamin B12 deficiencies are low in the US population. At current fortification levels, US adults who do not consume supplements do not have usual folic acid intake exceeding the UL. Vitamin B12 intake among most US adults meets the recommended daily allowance (2.4 mg/d). This project was conducted with no specific support..

BACKGROUND Anemia is an important public health problem, and accurate estimates may inform policy and programs. Although hemoglobin assessment of venous blood via automated hematology analyzers (AHA) is recommended, most population-based surveys are based on analysis of capillary blood via portable hemoglobinometers to estimate anemia prevalence. OBJECTIVE To evaluate screening methods for hemoglobin and anemia assessment using paired venous samples. DESIGN Participants were women of reproductive age (15-40y) who were not pregnant or lactating. Paired venous whole blood samples (n = 896) were analyzed for hemoglobin (Hb) via portable hemoglobinometer (HemoCue 301) and Coulter Counter AHA. Anemia and severe anemia were defined as Hb <12.0 and <8.0 g/dL, respectively. Bland-Altman methods were used to assess level of agreement for Hb results (mean difference, standard deviation of differences, limits of agreement). Diagnostic accuracy parameters (sensitivity, specificity, positive predictive value, negative predictive value, accuracy) were calculated to evaluate HemoCue performance compared to the AHA reference, overall and by sociodemographic, nutritional, and metabolic characteristics. RESULTS The estimated anemia prevalence was significantly lower via HemoCue vs. AHA (36.3% vs. 41.6%; p-value <0.0001). The HemoCue had 84.4% accuracy for anemia screening and 98.8% for severe anemia, compared to the AHA reference. The HemoCue had 74.8% sensitivity and 91.2% specificity, compared to AHA. HemoCue sensitivity was higher in WRA with iron deficiency (SF<15.0 μg/L 81.6% vs. SF ≥15.0 μg/L: 41.3%), and lower in WRA with metabolic risk factors, including overweight (BMI≥25.0 kg/m2; 63.9% vs. 78.8%), or elevated CRP (CRP>1.0 mg/L: 67.2% vs. ≤1.0 mg/L: 82.9%), trunk fat (TF>35%: 62.7% vs. ≤35%: 80.1), or whole-body fat (WBF >35%: 63.9% vs. ≤35%: 80.3%). CONCLUSION Findings suggest that women with anemia may be incorrectly identified as not anemic via portable hemoglobinometer, and the anemia prevalence may be underestimated at the population level. Registration number: NCT04048330.

Inadequate maternal choline intake during pregnancy has been associated with adverse pregnancy and child health outcomes – and has been identified as a potential risk factor for neural tube defects. However, there is limited data on biomarkers of choline metabolism in women of reproductive age (WRA), and few representative population-level data from India. The objective of this analysis was to examine biomarkers of choline metabolism and their correlates in WRA, as part of a population-based biomarker survey in Southern India. Participants were WRA (15–40y; n = 980) who were not pregnant or lactating. Free choline, betaine, dimethylglycine, methionine, and trimethylamine N-oxide concentrations were evaluated via liquid chromatography tandem mass spectrometry. Linear regression models were used to examine sociodemographic (e.g., age, parity), dietary (e.g., frequency of animal source food intake), and anthropometric (e.g., body mass index [BMI], waist circumference, waist-hip ratio) correlates of biomarkers of choline metabolism, including betaine concentrations and betaine to choline ratio (B:C). Betaine concentrations (GM: 44.2 μmol/L [95% CI: 43.4, 45.0]) were 4-fold higher compared to free choline (11.1μmol/L [10.9, 11.2]) levels, with an average B:C of 4.0 [3.9, 4.1]. Increased age (β: −0.01 [SE: 0.002], P < 0.0001), multiparity (multiparous/primiparous vs. nulliparous, P < 0.0001), and increased frequency of animal source food intake (poultry, p = 0.004; red meat, p = 0.01), were associated with lower B:C. Higher BMI (betaine: β: −0.004 [SE: 0.002], p = 0.02; B:C: β: −0.02 [SE: 0.002], P < 0.0001), waist circumference (betaine: −0.002 [0.001], p = 0.02; B:C: −0.01 [0.001], P < 0.0001), and waist-hip ratio (betaine: −0.31 [0.15], p = 0.04; B:C: −1.02 [0.16], P < 0.0001), were also associated with lower betaine concentrations and B:C. In this population, higher BMI and central adiposity were associated with lower betaine concentrations and B:C. Findings from this biomarker survey will inform prospective research on the role of choline biomarkers in the health and nutritional requirements of WRA. Centers for Disease Control and Prevention (5U01DD001007), University of South Carolina Disability Research and Dissemination Center; Cornell DNS; NIH T32DK007158 (HMG); NIH 5T32HD087137 (AF).

Background: Women of reproductive age (WRA) are at increased risk for anemia and iron deficiency. However, there is limited population-level data in India, which could help inform evidence-based rec-ommendations and policy.Aims: To conduct a population-based biomarker survey of anemia, iron deficiency, and inflammation in WRA in Southern India. Methods: Participants were WRA (15-40 y) who were not pregnant or lactating. Blood samples (n = 979) were collected and analyzed for hemoglobin (Hb), serum ferritin (SF), soluble transferrin receptor (sTfR), C-reactive protein (CRP), and alpha-1 acid glycoprotein (AGP). Anemia and severe anemia were defined as Hb < 12.0 and < 8.0 g/dL. Serum ferritin was adjusted for inflammation using BRINDA methods. Iron deficiency was defined as SF < 15.0 mu g/L, iron insufficiency was defined as SF < 20.0 and < 25.0 mu g/L, and iron deficiency anemia was defined as Hb < 12.0 g/dL and SF < 15.0 mu g/L. Inflammation was defined as CRP > 5.0 mg/L or AGP > 1.0 g/L. Restricted cubic spline regression models were also used to determine if alternative SF thresholds should be used t to classify iron deficiency. Results: A total of 41.5% of WRA had anemia, and 3.0% had severe anemia. Findings from spline analyses suggested a SF cut-off of < 15.0 mu g/L, consistent with conventional cut-offs for iron deficiency. 46.3% of WRA had SF < 15.0 mu g/L (BRINDA-adjusted: 61.5%), 55.0% had SF < 20.0 mu g/L (72.7%), 61.8% had SF < 25.0 mu g/L (81.0%), and 30.0% had IDA (34.5%). 17.3% of WRA had CRP > 5.0 mg/L and 22.2% had AGP > 1.0 g/L. The prevalence of ID (rural vs. urban: 49.1% vs. 34.9%; p = 0.0004), iron insufficiency (57.8% vs. 43.8%; p = 0.0005), and IDA (31.8% vs. 22.4%; p = 0.01) were significantly higher in rural areas, although CRP levels were lower and there were no differences in elevated CRP or AGP. Conclusions: The burden of anemia and iron deficiency in this population was substantial, and increased after adjusting for inflammation, suggesting potential to benefit from screening and interventions. (C) 2022 The Author(s). Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism.

To examine the associations of iron status with metabolic health outcomes in women of reproductive age (WRA), as part of a population-based biomarker survey in Southern India. Participants were WRA (15–40 y; n = 980) who were not pregnant or lactating (2017–2018). Blood samples were analyzed for hemoglobin (Hb; Coulter Counter) and glycated hemoglobin (HbA1c; nephelometry). Serum ferritin (SF) was measured by electrochemiluminescence; soluble transferrin receptor, C-reactive protein, and alpha-1 acid glycoprotein were analyzed via immuno-based assays (Roche). Anthropometric and blood pressure measurements were collected in triplicate. Bioelectrical impedance analysis (BC-418 MA) was used to estimate whole body (WF%) and trunk (TF%) fat in women ≥ 18y. Anemia was defined as Hb < 12.0 g/dL. SF was adjusted for inflammation using Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) methods; iron deficiency (ID) was defined as SF < 15.0 µg/L. Linear and binomial regression were used to examine associations of iron status with metabolic outcomes. A total of 41.5% of WRA had anemia, and 46.3% had ID (61.5%; BRINDA-adjusted). A total of 23.3% of adults were overweight (BMI: 25.0-<30.0 kg/m2) and 9.6% had obesity (BMI ≥ 30.0 kg/m2). Waist circumference (WC; ≥88.9 cm) and waist-hip ratio (WHR; ≥0.85) were elevated in 13.4% and 20.8% of women, and 25.0% had elevated HbA1c (≥6.5%: 5.0%; ≥5.7-<6.5%: 20.0%). Higher Hb concentrations were associated with increased BMI (β: 0.42 [SE: 0.09]; p < 0.01), WC (0.77 [0.21]; p < 0.01), and WF% (0.89 [0.17]; p < 0.01). Higher SF levels were associated with higher WF% (β: 0.79 [SE: 0.32]; p = 0.01) and TF% (0.92 [0.39]; p = 0.02), and elevated WC (RR: 1.20 [95% CI: 1.02–1.42]). Iron status was not significantly associated with HbA1c or blood pressure. The burden of adverse metabolic outcomes was substantial in this population. Higher iron status was associated with higher BMI and central adiposity. Evaluating iron status and metabolic outcomes in future studies could help inform screening and interventions to improve the health of WRA. Centers for Disease Control and Prevention (5U01DD001007), University of South Carolina Disability Research and Dissemination Center; Consejo Nacional de Ciencia y Tecnología (CEGL); NIH 5T32HD087137 (AF); NIH T32DK007158 (HMG).

BACKGROUND:Cognitive health is a public health concern among older adults. Dietary supplement (SUP) use is common and concerns have been raised about high folic acid intake among those with vitamin B-12 deficiency and exacerbation of poor cognitive performance (PCP). OBJECTIVES:We evaluated SUP use, usual folic acid intake, and blood folate and vitamin B-12 concentrations in relation to cognitive performance. METHODS:We used NHANES 2011-2014 data on adults aged ≥60 y (n = 2867) and estimated total usual folic acid intake from diet and supplements, vitamin B-12 intake from SUPs, blood folates, vitamin B-12 concentrations, vitamin B-12 insufficiency (≤258 pmol/L), high folate (serum folate ≥59 nmol/L or RBC folate ≥1609 nmol/L), and PCP (<34 on the Digit Symbol Substitution Test). We assessed folate distributions adjusted for multiple variables, including renal function. RESULTS:Compared with persons without PCP, adults with PCP were less likely to use supplements containing folic acid (mean ± SEE: 34.4% ± 2.4%) or vitamin B-12 (mean ± SEE: 47.5% ± 1.6%). Among vitamin B-12-insufficient adults, 18.0% ± 1.6% (mean ± SEE) reported taking a vitamin B-12 supplement. Among participants with high folate and insufficient vitamin B-12 concentrations, 34.3% ± 11.5% (mean ± SEE) reported taking vitamin B-12-containing supplements. Persons with high folate and normal vitamin B-12 concentrations had lower odds of PCP [aOR (adjusted odds ratio): 0.61; 95% CI: 0.45, 0.83] than persons with normal folate and vitamin B-12. Persons with high folate and normal methylmalonic acid (MMA) had lower odds of PCP (OR: 0.56; 95% CI: 0.40, 0.78) than those with normal folate and MMA concentrations. After adjustment for renal function, elevated risk of PCP was attenuated among persons with high folate and MMA. Concurrent high folate and insufficient vitamin B-12 concentrations were not associated with PCP. CONCLUSIONS:Differential associations between vitamin B-12 and MMA highlight the need to consider renal function in studies of high folate and low vitamin B-12 status. Consumption of vitamin B-12 supplements concurrent with low vitamin B-12 status may indicate vitamin B-12 malabsorption.