The Effect of Iron Supplements on the Gut Microbiome of Females of Reproductive Age: A Randomized Controlled Trial.

BACKGROUND: Iron deficiency is the most common nutritional deficiency worldwide, particularly for young children and females of reproductive age. Although oral iron supplements are routinely recommended and generally considered safe, iron supplementation has been shown to alter the fecal microbiota in low-income countries. Little is known about the effect of iron supplementation on the fecal microbiota in high-income settings. OBJECTIVES: To assess the effect of oral iron supplementation compared with placebo on the gut microbiome in nonpregnant females of reproductive age in a high-income country. METHODS: A 21-d prospective parallel design double-blind, randomized control trial conducted in South Australia, Australia. Females (18-45 y) were randomly assigned to either iron (65.7 mg ferrous fumarate) or placebo. Fecal samples were collected prior to commencing supplements and after 21 d of supplementation. The primary outcome was microbiota ß-diversity (paired-sample weighted unique fraction metric dissimilarity) between treatment and placebo groups after 21 d of supplementation. Exploratory outcomes included changes in the relative abundance of bacterial taxa. RESULTS: Of 82 females randomly assigned, 80 completed the trial. There was no significant difference between the groups for weighted unique fraction metric dissimilarity (mean difference: 0.003; 95% confidence interval: -0.007, 0.014; P = 0.52) or relative abundance of common bacterial taxa or Escherichia-Shigella (q > 0.05). CONCLUSIONS: Iron supplementation did not affect the microbiome of nonpregnant females of reproductive age in Australia. This trial was registered at clinicaltrials.gov as NCT05033483.

Too Much Too Little: Clarifying the Relationship Between Maternal Iodine Intake and Neurodevelopmental Outcomes.

BACKGROUND: In 2009, the Australian government mandated the fortification of bread salt with iodine. In 2010, pregnant and lactating women were also advised to take an iodine-containing supplement. Our assessment of this policy in an iodine-sufficient population showed that children whose mothers were in the highest and lowest quartiles of iodine intake performed more poorly on early childhood tests of cognition and language than those in the second quartile. However, we did not quantify the iodine intake associated with optimal neurodevelopment. OBJECTIVES: The aim was to establish the iodine intake range in pregnancy associated with optimal child neurodevelopment. METHODS: A prospective cohort study of pregnant women and their young children (n = 699). Iodine intake was assessed by a validated food frequency questionnaire at 16 and 28 wk of gestation. Child neurodevelopment at 18 mo of age was measured using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). The relationship between average iodine intake during pregnancy and child neurodevelopment was assessed using linear regression with fractional polynomials and adjustment for confounders. RESULTS: Mean (SD) iodine intake was similar at study entry and 28 wk, 308 (120) µg/d, with 82% of women taking iodine supplements at study entry. The relationship between iodine intake during pregnancy and Bayley-III cognitive and language scores was curvilinear (P = 0.001 and P = 0.004, respectively), with the lowest Bayley-III scores observed at lower and higher iodine intakes. The inflection point that drove the association between lower iodine intake in pregnancy and poorer child neurodevelopment scores was around 185 µg/d; for the higher pregnancy iodine intakes, language and cognitive scores were negatively affected from ∼350 µg/d to 370 µg/d, respectively. Higher iodine intakes were being driven by supplement use. CONCLUSIONS: Targeted, not blanket, iodine supplementation may be needed for pregnant women with low-iodine intake from food.

Iron-Fortified Foods Are Needed To Meet the Estimated Average Requirement for Iron in Australian Infants Aged 6 to 12 Months.

BACKGROUND: Meeting iron intake recommendations is challenging for infants 6-12 mo, especially breastfed infants. Three-quarters of Australian infants 6-12 mo have iron intakes below the estimated average requirement (7 mg), placing them at risk of iron deficiency. After 6 mo, breastmilk is no longer sufficient to meet the increased demand for iron, and iron-rich complementary foods are recommended. Iron-fortified foods may be a means of improving iron intake in infants, particularly those that are breastfed. OBJECTIVES: The aims of the study were as follows: 1) to examine the effect of milk-type and fortified foods on iron intake and the prevalence of inadequacy in infants 6-12 mo; 2) to model the effect of fixed amounts of iron-fortified infant cereal (IFIC) at 6 levels of iron fortification on total iron intake and the prevalence of inadequacy; and 3) to assess the effect IFIC on the intake of other nutrients in the diet. DESIGN: Secondary analysis of cross-sectional dietary intake data of infants 6-12 mo (n = 286) participating in the Australian Feeding Infants and Toddlers Study (OzFITS) 2021. RESULTS: Median (interquartile range) iron intake was 8.9 (7.5, 10.3); 6.3 (4.5, 8.2); and 2.7 (1.5, 4.4) mg/d in formula-fed, combination-fed, and breastfed infants, respectively. The corresponding prevalence of inadequacy was 19%, 67%, and 96%. Infants who consumed fortified foods had higher median iron intakes than those who did not, 6.2 compared with 1.9 mg/d. Dietary modeling showed that consuming 18 g (300 kJ) of IFIC, fortified at 35 mg/100 g dry weight, reduces the prevalence of inadequacy for iron from 75% to 5% for all infants. CONCLUSIONS: Iron intakes are low in Australian infants, especially for breastfed infants in the second half of infancy. Modeling shows that 300 kJ of IFIC, the current manufacturer-recommended serving, fortified at 35 mg/100 g dry weight, added to infant diets would be an effective means to reduce the prevalence of inadequacy for iron.

Prenatal iodine supplementation and early childhood neurodevelopment: the PoppiE trial - study protocol for a multicentre randomised controlled trial.

INTRODUCTION: Observational studies suggest both low and high iodine intakes in pregnancy are associated with poorer neurodevelopmental outcomes in children. This raises concern that current universal iodine supplement recommendations for pregnant women in populations considered to be iodine sufficient may negatively impact child neurodevelopment. We aim to determine the effect of reducing iodine intake from supplements for women who have adequate iodine intake from food on the cognitive development of children at 24 months of age. METHODS AND ANALYSIS: A multicentre, randomised, controlled, clinician, researcher and participant blinded trial with two parallel groups. Using a hybrid decentralised clinical trial model, 754 women (377 per group) less than 13 weeks' gestation with an iodine intake of ≥165 µg/day from food will be randomised to receive either a low iodine (20 µg/day) multivitamin and mineral supplement or an identical supplement containing 200) µg/day (amount commonly used in prenatal supplements in Australia), from enrolment until delivery. The primary outcome is the developmental quotient of infants at 24 months of age assessed with the Cognitive Scale of the Bayley Scales of Infant Development, fourth edition. Secondary outcomes include infant language and motor development; behavioural and emotional development; maternal and infant clinical outcomes and health service utilisation of children. Cognitive scores will be compared between groups using linear regression, with adjustment for location of enrolment and the treatment effect 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/17/WCHN/187). The results of this trial will be presented at scientific conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04586348.

Effect of Docosahexaenoic Acid (DHA) Supplementation of Preterm Infants on Growth, Body Composition, and Blood Pressure at 7-Years Corrected Age: Follow-Up of a Randomized Controlled Trial.

Aim: To determine if supplementation of infants born <33 weeks' gestation with higher dose docosahexaenoic acid (DHA) affects growth, body composition, and blood pressure at 7 y corrected age (CA) and if treatment effects differed by infant sex at birth and birth weight strata (<1250 and ≥1250 g). Methods: Seven-year follow-up of an Australian multicenter randomized controlled trial in which 657 infants were fed high-DHA (≈1% total fatty acids) enteral feeds or standard-DHA (≈0.3% total fatty acids) from age 2−4 d until term CA. Seven-year CA outcomes were growth (weight, height), body composition (lean body mass, fat mass, waist, and hip circumference), and blood pressure. Results: There was no effect of high-DHA enteral feeds compared with standard-DHA on growth, body composition, and blood pressure at 7-year CA either overall or in subgroup analysis by sex. There was a significant interaction between high-DHA and birthweight strata on height at 7-y CA (p = 0.03). However, the post-hoc analyses by birthweight strata did not reach significance (p > 0.1). High-DHA group infants were more likely to be classified as obese (relative risk 1.6 (95% CI 1.0, 2.6); p = 0.05). Conclusions: DHA supplementation of premature infants did not affect growth, body composition, or blood pressure at 7-year CA overall by sex and birthweight strata. The finding of a higher risk of obesity in children who receive high-DHA needs to be interpreted with caution due to the small number of children classified as obese.

A randomized, double-blind, placebo-controlled, cross-over trial to evaluate the effect of EstroSense® on 2-hydroxyestrone:16α-hydroxyestrone ratio in premenopausal women.

OBJECTIVES: Some estrogen metabolites are associated with increased breast cancer risk, while others are protective. Research efforts have focused on modifiable factors, including bioactive compounds found in food or supplements, promoting estrogen profiles with anti-cancer properties. EstroSense® is a nutraceutical product with bioactive compounds, including Indole-3-carbinol and green-tea catechins, which may favourably affect estrogen profiles. This study was conducted to determine if EstroSense use, compared to placebo, promotes a higher urinary 2-hydroxyestrone:16α-hydroxyestrone ratio (2-OHE1:16α-OHE1), a biomarker associated with a lowered risk of breast cancer. METHODS: A total of 148 premenopausal women were recruited from British Columbia, Canada to participate in a randomized, double-blind, cross-over, multicentre, placebo-controlled study in which women were randomized to a treatment sequence that consisted of either EstroSense®, followed by placebo or vice-versa. The women were instructed to consume three capsules per day of EstroSense® or the placebo for three menstrual cycles (∼12 weeks). The primary outcome was the measurement of 2-OHE1:16α-OHE1 in casual samples at baseline and after each treatment phase. RESULTS: After 12 weeks of intervention, the mean (95% CI) urinary 2-OHE1:16α-OHE1 was 4.55 (2.69, 6.42) (p<0.001) higher following EstroSense than placebo adjusted for baseline values. CONCLUSIONS: EstroSense use led to markedly higher urinary 2-OHE1:16α-OHE1 than the placebo, a biomarker associated with a lower risk of breast cancer. REGISTRATION: http://clinicaltrials.gov (NCT02385916).

The Australian Feeding Infants and Toddlers Study (OzFITS) 2021: Highlights and Future Directions.

The 2021 Australian Feeding Infants and Toddlers Study (OzFITS 2021) is the first nationwide survey of the feeding practices of children under 2 years. Key Findings: Nearly half of the infants were exclusively breastfed to 4 months, and breastfeeding duration was long, with 68% of infants breastfed to 6 months and 44% breastfed into their second year. Infants were introduced to complementary foods at the appropriate time, between 4 and 6 months. We found a mismatch between the number of recommended servings from each food group in the Australian Dietary Guidelines and the dietary intake of toddlers in our study. Toddlers consumed twice as many fruit servings as recommended, and nearly all consumed discretionary foods despite no allowance for these foods. While most toddlers consumed the recommended dairy serves, they consumed half the recommended servings for other food groups-meats and alternatives, grains, and vegetables. The modeling that informed the Australian Dietary Guidelines did not include an allowance for breastmilk; this needs to be addressed, as a quarter of toddlers in OzFITS 2021 received 30% or more energy from breastmilk. Infants and toddlers met their requirements for most nutrients. One exception was iron, where 90% of older infants and 25% of toddlers had inadequate intakes. Excessive sodium intake was also of concern, with 1 in 3 toddlers exceeding the upper limit of 1000 mg/day. Here, we discuss additional findings, study limitations, gaps in the evidence base, and future directions.

A Systematic Review of Vitamin D during Pregnancy and Postnatally and Symptoms of Depression in the Antenatal and Postpartum Period from Randomized Controlled Trials and Observational Studies.

Depression is a common mood disorder associated with childbirth and is hypothesized to be affected by low vitamin D. This systematic review identified two randomized controlled trials (RCT) of vitamin D supplementation for the treatment or prevention of depressive symptoms in the perinatal period, as well as 18 observational studies of vitamin D exposure and depression in the antenatal and postnatal periods. Both RCTs claimed an improvement in depressive symptoms in the vitamin D group, although the sample sizes were too small to draw firm conclusions. The case-control and cohort studies had mixed findings and were limited by study quality. There were inconsistent results within the few studies with a more robust methodology or within samples restricted to women likely to have depression. The current evidence is inconclusive due to the poor quality and heterogeneity of studies, likely contributing to the contradictory findings. Given there are already numerous RCTs of prenatal vitamin D supplementation, we recommend adding an appropriate measure of depression in the perinatal period to assist in resolving the uncertainty.

Usual Nutrient Intake Distribution and Prevalence of Inadequacy among Australian Children 0-24 Months: Findings from the Australian Feeding Infants and Toddlers Study (OzFITS) 2021.

(1) Background: Breastmilk provides all the nutrition an infant requires between 0−6 months. After that, complementary foods are needed to meet the child's increasing energy and nutrient requirements. Inadequate energy and nutrient intake may lead to growth faltering, impaired neurodevelopment, and increased disease risk. While the importance of early life nutrition is well recognized, there are few investigations assessing the nutritional adequacy of Australian children <24 months. Here, we describe usual energy and nutrient intake distributions, including the prevalence of inadequate intakes and exceeding the upper limit (UL), in a national sample of Australian children 6− 24 months and infants < six months who had commenced solids and/or formula. (2) Methods: Dietary intakes were assessed using a one-day food record for 976 children with a repeat one-day record in a random subset. (3) Results: Based on the Nutrient Reference Values for Australia and New Zealand, children's intakes were above the Adequate Intake or Estimated Average Requirement for most nutrients. Exceptions were iron and zinc where the prevalence of inadequacy was estimated to be 90% and 20%, respectively, for infants aged 6−11.9 months. Low iron intake was also observed in one quarter of toddlers 12−24 months. On average, children consumed 10% more energy than predicted based on Estimated Energy Requirements, and ~10% were classified as overweight based on their weight for length. One third of toddlers exceeded the tolerable upper limit for sodium and consumed > 1000 mg/day. Of the children under six months, 18% and 43% exceeded the UL for vitamin A (retinol) and zinc. (4) Conclusions: Compared to nutrient reference values, diets were sufficient for most nutrients; however, iron was a limiting nutrient for infants aged 6−11.9 months and toddlers 12−24 months potentially putting them at risk for iron deficiency. Excessive sodium intake among toddlers is a concern as this may increase the risk for hypertension.

The Australian Feeding Infants and Toddlers Study (OzFITS) 2021: Study Design, Methods and Sample Description.

(1) Background: Caregiver feeding practices during the first two years of a child's life influence nutrition, growth, and development, as well as long term taste preferences and dietary patterns. Suboptimal feeding practices lead to poorer health outcomes, such as obesity, that persist into adulthood. Although the importance of early life nutrition is well-established, there are no Australia-wide surveys of dietary intakes of children under two years of age. The 2021 Australian Feeding Infants and Toddlers Study (OzFITS) aims to fill this gap. This paper describes the methods and study sample of OzFITS 2021. (2) Methods: OzFITS 2021 is a cross-sectional study of children aged 0 to 23.9 months of age and their caregiver across Australia. Data were collected between April 2020 and April 2021. A telephone-based survey was completed with a caregiver to obtain information on child and caregiver characteristics and feeding practices. For exclusively breastfed infants, the number of breastfeeds in a 24 h period was reported. Dietary intakes for mixed fed children were estimated using a one-day food record, with 30% of caregivers completing a second food record on a non-consecutive day. (3) Results: We enrolled 1140 caregiver and child dyads. Of those eligible to complete a food record, 853 (87%) completed the food record. Compared to the Australian population, caregivers were more likely to be university-educated (>75%), married or in a de facto relationship (94%), and have a household income >$100,000/y (60%). (4) Conclusions: OzFITS 2021 is the first national study to examine food and nutrient intake in Australian children aged under 2 years. The study will provide information on breastfeeding rates and duration, use of breast milk substitutes, and timing of solid food introduction. Dietary intake data will allow the comparison of core food groups and discretionary food intake to Australian guidelines and estimate the prevalence of inadequate intake of key nutrients, like iron. Healthcare practitioners and policymakers can use the study findings as a source of evidence to inform the next iteration of infant feeding guidelines.

Dog Tales: Mindful Dog Interactions Evoke Similar Experiences to Dog Assisted Mindfulness Meditations.

Stay-at-home regulations in response to COVID-19 have put humans at increased risk of loneliness. Some studies support dog ownership as a protection against loneliness, while other studies have suggested the lockdowns can be used to reflect upon the similar restrictions owners impose on their pets on a daily basis. This study evaluated two novel ways to enrich the lives of pet dogs in the home, while also providing benefits to owners. It was hypothesized that a six-week Dog Assisted Mindfulness (DAM) intervention and a Dog Interactions (DI) intervention would positively impact owner-rated loneliness, mindfulness, and owner-dog emotional attachment, compared to a control group. Seventy-three participants were randomly assigned to each group. Mixed methods ANOVAs found no significant main effects of group, nor any group × time interaction effects. Qualitative analyses revealed common experiences among participants in the two active interventions, including enhanced owner-dog connection, and feelings of relaxation, happiness and engagement both during and after participating in the weekly activities. There was also an added benefit of 'dog happiness' in the interactions group. Future studies should investigate this in a more objective manner and in the meantime, regular owner-dog interactions should be encouraged, especially during times of extended lockdown.

Thiamine supplementation holds neurocognitive benefits for breastfed infants during the first year of life.

Women reliant on mostly rice-based diets can have inadequate thiamine intake, placing breastfed infants at risk of thiamine deficiency and, in turn, physical and cognitive impairments. We investigated the impact of maternal thiamine supplementation doses on infants' cognitive, motor, and language development across the first year. In this double-blind, four-parallel-arm, randomized controlled trial, healthy mothers of exclusively breastfed newborn infants were recruited in Kampong Thom, Cambodia. At 2 weeks postnatal, women (n = 335) were randomized to one of four treatment groups to consume one capsule/day with varying amounts of thiamine for 22 weeks: 0, 1.2, 2.4, and 10 mg. At 2, 12, 24, and 52 weeks of age, infants were assessed with the Mullen Scales of Early Learning (MSEL) and the Caregiver Reported Early Development Instrument (CREDI). Multiple regression and mixed effects modeling suggest that by 6 months of age, the highest maternal thiamine dose (10 mg/day) held significant benefits for infants' language development, but generally not for motor or visual reception development. Despite having achieved standardized scores on the MSEL that approximated U.S. norms by 6 months, infants showed a significant drop relative to these norms in both language domains following trial completion, indicating that nutritional interventions beyond 6 months may be necessary.

Baseline Hemoglobin, Hepcidin, Ferritin, and Total Body Iron Stores are Equally Strong Diagnostic Predictors of a Hemoglobin Response to 12 Weeks of Daily Iron Supplementation in Cambodian Women.

BACKGROUND: The WHO recommends daily iron supplementation for all women in areas where the population-level anemia prevalence is ≥40%, despite the fact that hemoglobin (Hb) concentration is generally considered to be a poor prognostic indicator of iron status. OBJECTIVES: In this secondary analysis, we investigated the predictive power of ten baseline hematological biomarkers towards a 12-week Hb response to iron supplementation. METHODS: Data were obtained from a randomized controlled trial of daily iron supplementation in 407 nonpregnant Cambodian women (18-45 years) who received 60 mg elemental iron as ferrous sulfate for 12 weeks. Ten baseline biomarkers were included: Hb, measured with both a hematology analyzer and a HemoCue; inflammation-adjusted ferritin; soluble transferrin receptor; reticulocyte Hb; hepcidin; mean corpuscular volume; inflammation-adjusted total body iron stores (TBIS); total iron binding capacity; and transferrin saturation. Receiver operating characteristic (ROC) curves from fitted logistic regression models were used to make discrimination comparisons and variable selection methods were used to construct a multibiomarker prognostic model. RESULTS: Only 25% (n = 95/383) of women who completed the trial experienced a 12-week Hb response ≥10 g/L. The strongest univariate predictors of a Hb response were Hb as measured with a hematology analyzer, inflammation-adjusted ferritin, hepcidin, and inflammation-adjusted TBIS (AUCROC = 0.81, 0.83, 0.82, and 0.82, respectively), and the optimal cutoffs to identify women who were likely to experience a Hb response were 117 g/L, 17.3 µg/L, 1.98 nmol/L, and 1.95 mg/kg, respectively. Hb as measured with a hematology analyzer, inflammation-adjusted ferritin, and hepcidin had the best combined predictive ability (AUCROC=0.86). Hb measured with the HemoCue had poor discrimination ability (AUCROC = 0.65). CONCLUSIONS: Baseline Hb as measured with a hematology analyzer was as strong a predictor of Hb response to iron supplementation as inflammation-adjusted ferritin, hepcidin, and inflammation-adjusted TBIS. This is positive given that the WHO currently uses the population-level anemia prevalence to guide recommendations for untargeted iron supplementation.

Dietary Riboflavin Intake and Riboflavin Status in Young Adult Women Living in Metro Vancouver, Canada.

BACKGROUND: Nutrition surveys suggest that <10% of Canadian adults have inadequate riboflavin intakes. However, biochemical riboflavin deficiency [erythrocyte glutathione reductase activity coefficient (EGRac) ≥1.40] has been reported in 41% of young adult women living in Metro Vancouver. Canadian Chinese ethnicity comprise >25% of Vancouver's population and are postulated to have poorer riboflavin status than those of European ethnicity because they could be less likely to consume dairy products and fortified wheat. OBJECTIVES: The objectives of this study were to determine dietary riboflavin intake and food sources, and to assess the association between riboflavin intake and status in young women of European (n = 107) and Chinese (n = 91) ethnicities living in Metro Vancouver, Canada. METHODS: This was a cross-sectional study conducted in women (aged 19-45 y). Women were healthy, not pregnant or breastfeeding, of European or Chinese ethnicities, and not taking riboflavin-containing supplements for the past 4 mo. Dietary riboflavin intake was assessed using the past-year Diet History Questionnaire II, and riboflavin status (EGRac) was measured in fasting venous blood samples. RESULTS: Only 7% of participants had dietary riboflavin intakes below the Estimated Average Requirement (0.9 mg/d), but 40% of women had biochemical riboflavin deficiency (EGRac ≥1.40). Although more Canadian women of European ethnicity than Chinese ethnicity had biochemical riboflavin deficiency (46% and 34%; P < 0.001), median dietary riboflavin intake did not differ (1.73 and 1.82 mg/d; P = 0.587). Dairy products and vegetables contributed the most to riboflavin intake. Energy-adjusted dietary riboflavin intake was inversely associated with EGRac (B = -0.04, 95% CI: -0.07, -0.01). However, after further adjustment the relation was not significant. CONCLUSIONS: Overall, women of reproductive age living in Metro Vancouver, Canada, had a low prevalence of inadequate dietary riboflavin intake despite the high prevalence of apparent biochemical riboflavin deficiency.

Low-dose thiamine supplementation of lactating Cambodian mothers improves human milk thiamine concentrations: a randomized controlled trial.

BACKGROUND: Infantile beriberi-related mortality is still common in South and Southeast Asia. Interventions to increase maternal thiamine intakes, and thus human milk thiamine, are warranted; however, the required dose remains unknown. OBJECTIVES: We sought to estimate the dose at which additional maternal intake of oral thiamine no longer meaningfully increased milk thiamine concentrations in infants at 24 wk postpartum, and to investigate the impact of 4 thiamine supplementation doses on milk and blood thiamine status biomarkers. METHODS: In this double-blind, 4-parallel arm randomized controlled dose-response trial, healthy mothers were recruited in Kampong Thom, Cambodia. At 2 wk postpartum, women were randomly assigned to consume 1 capsule, containing 0, 1.2 (estimated average requirement), 2.4, or 10 mg of thiamine daily from 2 through 24 weeks postpartum. Human milk total thiamine concentrations were measured using HPLC. An Emax curve was plotted, which was estimated using a nonlinear least squares model in an intention-to-treat analysis. Linear mixed-effects models were used to test for differences between treatment groups. Maternal and infant blood thiamine biomarkers were also assessed. RESULTS: In total, each of 335 women was randomly assigned to1 of the following thiamine-dose groups: placebo (n = 83), 1.2 mg (n = 86), 2.4 mg (n = 81), and 10 mg (n = 85). The estimated dose required to reach 90% of the maximum average total thiamine concentration in human milk (191 µg/L) is 2.35 (95% CI: 0.58, 7.01) mg/d. The mean ± SD milk thiamine concentrations were significantly higher in all intervention groups (183 ± 91, 190 ± 105, and 206 ± 89 µg/L for 1.2, 2.4, and 10 mg, respectively) compared with the placebo group (153 ± 85 µg/L; P < 0.0001) and did not significantly differ from each other. CONCLUSIONS: A supplemental thiamine dose of 2.35 mg/d was required to achieve a milk total thiamine concentration of 191 µg/L. However, 1.2 mg/d for 22 wk was sufficient to increase milk thiamine concentrations to similar levels achieved by higher supplementation doses (2.4 and 10 mg/d), and comparable to those of healthy mothers in regions without beriberi. This trial was registered at clinicaltrials.gov as NCT03616288.

Assessment of salt intake to consider salt as a fortification vehicle for thiamine in Cambodia.

Thiamine deficiency is a public health issue in Cambodia. Thiamine fortification of salt has been proposed; however, the salt intake of lactating women, the target population, is currently unknown. We estimated salt intakes among lactating women (<6 months postpartum) using three methods: repeat observed-weighed intake records and 24-h urinary sodium excretions (n = 104), and household salt disappearance (n = 331). Usual salt intake was estimated by adjusting for intraindividual intakes using the National Cancer Institute method, and a thiamine salt fortification scenario was modeled using a modified estimated average requirement (EAR) cut-point method. Unadjusted salt intake from observed intakes was 9.3 (8.3-10.3) g/day, which was not different from estimated salt intake from urinary sodium excretions, 9.0 (8.4-9.7) g/day (P = 0.3). Estimated salt use from household salt disappearance was 11.3 (10.7-11.9) g/person/day. Usual (adjusted) salt intake from all sources was 7.7 (7.4-8.0) g/day. Assuming no stability losses, a modeled fortification dose of 275 mg thiamine/kg salt could increase thiamine intakes from fortified salt to 2.1 (2.0-2.2) mg/day, with even low salt consumers reaching the EAR of 1.2 mg/day from fortified salt alone. These findings, in conjunction with future sensory and stability research, can inform a potential salt fortification program in Cambodia.

Thiamine fortification strategies in low- and middle-income settings: a review.

Thiamine (vitamin B1 ) is an essential micronutrient in energy metabolism and cognitive and neurological health. Thiamine deficiency disorders (TDDs) have a range of clinical presentations that result in various morbidities and can be fatal if not promptly recognized and treated, especially in infants. To intervene, thiamine intakes by breastfeeding mothers and others at risk of thiamine deficiency should be increased to ensure adequate thiamine intake. Although thiamine fortification programs have a long history in high-income countries, there are few mandatory fortification programs to address TDDs in low- and middle-income countries (LMICs), particularly in the regions of greatest concern, South and Southeast Asia. This review highlights essential aspects for consideration in the development of a mandatory fortification program in LMICs, including an overview of the data required to model fortification dosing schemes, available thiamine fortificants, and potential fortification vehicles, as well as identifies current knowledge gaps.

Perspective: Weekly Iron and Folic Acid Supplementation (WIFAS): A Critical Review and Rationale for Inclusion in the Essential Medicines List to Accelerate Anemia and Neural Tube Defects Reduction.

Weekly iron and folic acid supplementation (WIFAS) is among the 8 key effective actions for improving adolescent nutrition included by the WHO in the 2018 guidelines. However, at present WIFAS in the WHO-recommended formulation is not included in the Model Essential Medicines List (MEML), limiting the potential for countries to import, produce, and prioritize this formulation as part of their national supply management and procurement plans for medicines. The WHO WIFAS guideline presents evidence that the formulation reduces anemia, but not that folic acid reduces neural tube defects (NTDs), because sufficient evidence was unavailable at the time of the last review. Recently, a 3-arm, parallel-group, randomized, double-blind, placebo-controlled folic acid efficacy trial on WIFAS was conducted to address this evidence gap. The study population included 331 women (18-45 y old), randomly assigned to 3 treatment groups, including a supplement with 60 mg Fe as ferrous fumarate and either 0 mg, 0.4 mg, or 2.8 mg of folic acid, to be consumed once weekly for 16 wk, followed by a 4-wk washout period. In this article we critically review how the outcomes of this folic acid efficacy trial, and how the evidence generated, could potentially be used to inform WHO WIFAS guidelines for the potential inclusion of this formulation on the MEML, and how this, in turn, may affect product availability. If the new evidence on weekly folic acid is assessed as adequately reducing the risk of NTDs, a guideline revision could be warranted and WIFAS could be presented to the MEML for the dual benefits of anemia reduction and NTD prevention. This inclusion could enable acceleration of implementing policies and programs to contribute to global anemia and NTD reduction efforts.

Modeling thiamine fortification: a case study from Kuria atoll, Republic of Kiribati.

In 2014, there was an outbreak of beriberi on Kuria, a remote atoll in Kiribati, a small Pacific Island nation. A thiamine-poor diet consisting mainly of rice, sugar, and small amounts of fortified flour was likely to blame. We aimed to design a food fortification strategy to improve thiamine intakes in Kuria. We surveyed all 104 households on Kuria with a pregnant woman or a child 0-59 months. Repeat 24-h dietary recalls were collected from 90 men, 17 pregnant, 44 lactating, and 41 other women of reproductive age. The prevalence of inadequate thiamine intakes was >30% in all groups. Dietary modeling predicted that rice or sugar fortified at a rate of 0.3 and 1.4 mg per 100 g, respectively, would reduce the prevalence of inadequate thiamine intakes to <2.5% in all groups. Fortification is challenging because Kiribati imports food from several countries, depending on price and availability. One exception is flour, which is imported from Fiji. Although resulting in less coverage than rice or sugar, fortifying wheat flour with an additional 3.7 mg per 100 g would reduce the prevalence of inadequacy to under 10%. Kiribati is small and has limited resources; thus, a regional approach to thiamine fortification is needed.

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.