Is a Lower Dose of More Bioavailable Iron (18-mg Ferrous Bisglycinate) Noninferior to 60-mg Ferrous Sulfate in Increasing Ferritin Concentrations While Reducing Gut Inflammation and Enteropathogen Detection in Cambodian Women? A Randomized Controlled Noninferiority Trial.

BACKGROUND: Global guidelines recommend untargeted iron supplementation for women in regions of anemia prevalence ≥40%, such as Cambodia. However, the potential harms of untargeted iron on the gut have not been rigorously studied in women and likely vary depending on iron dose and form. OBJECTIVES: We investigated if a lower dose of a highly bioavailable iron amino acid chelate was as effective as the standard dose of iron salts in increasing ferritin concentrations and whether any differences were observed in gut inflammation or enteropathogen detection. METHODS: A double-blind, randomized placebo-controlled noninferiority trial was conducted in Cambodia. Nonpregnant women (n = 480, 18-45 y) were randomly assigned to 60-mg ferrous sulfate, 18-mg ferrous bisglycinate, or placebo for 12 wk. Nonfasting blood and stool specimens were collected at baseline and 12 wk. Ferritin and fecal calprotectin were measured with an ELISA. A molecular assay was used to detect 11 enteropathogens in a random subset of n = 100 women. Generalized linear mixed-effects models were used to estimate the adjusted mean difference in ferritin concentrations at 12 wk (primary outcome), as compared with our 'a priori' noninferiority margin of 20 µg/L. RESULTS: Baseline anemia and iron deficiency prevalence was low (17% and 6%, respectively). The adjusted mean difference in ferritin concentrations between the iron groups was 14.6 (95% confidence interval [CI]: 7.6, 21.6) µg/L. Mean ferritin concentration at 12 wk was higher in the ferrous sulfate (99 [95% CI: 95, 103] µg/L, P < 0.001) than in ferrous bisglycinate (84 [95% CI: 80, 88] µg/L) and placebo groups (78 [95% CI: 74, 82] µg/L). No differences in fecal calprotectin concentrations or enteropathogen detection were observed across groups at 12 wk. CONCLUSIONS: Ferrous bisglycinate (18-mg) was not as effective as ferrous sulfate (60-mg) in increasing ferritin concentrations and did not differentially influence biomarkers of gut health in this predominantly iron-replete population of Cambodian women. This trial was registered at clinicaltrials.gov registry as NCT04017598.

Pilot implementation of a monitoring and enforcement system for the International Code of Marketing of Breast-milk Substitutes in Cambodia.

Globally, monitoring and enforcement mechanisms for the World Health Organization's International Code of Marketing of Breast-milk Substitutes are often lacking. The Cambodian government adopted the Code as the national standard in Sub-Decree 133 on Marketing of Products for Infant and Young Child Feeding. Following the formation of a multisectoral Oversight Board and development of detailed guidance documents for the implementation and enforcement of Sub-Decree 133, a 7-month pilot was conducted in 2017 to trial a monitoring system in four urban areas of Cambodia. The pilot included training of monitors from the Ministries of Health and Commerce, screening for violations at retail locations and health facilities, testing reporting mechanisms, and taking actions against violators. During the pilot, 85 national- and subnational-level monitors were trained, 392 site visits were made, 2,377 monitoring checklists were completed, and 11 warning letters were issued to violators. Half of the completed checklists (52.9%) indicated Code violations, yet monitors submitted zero violation reports. The pilot revealed modifications needed to the monitoring system: integrate monitor trainings into existing ministry training curricula for sustainability; enhance targeting of monitors for Sub-Decree training; delineate clear roles and responsibilities for the national and subnational levels; simplify monitoring checklists and violation reports; and improve integration of monitoring activities into routine ministry operations. Before the Sub-Decree 133 monitoring and enforcement system is implemented throughout Cambodia, revisions must be made to ensure the viability of this system. Challenges and lessons learned can also guide Code monitoring efforts being undertaken by other countries.

Predictors of breast milk substitute feeding among newborns in delivery facilities in urban Cambodia and Nepal.

Introducing breast milk substitutes (BMS) in the first days after birth can increase infant morbidity and reduce duration and exclusivity of breastfeeding. This study assessed determinants of BMS feeding among newborns in delivery facilities in Phnom Penh, Cambodia, and Kathmandu Valley, Nepal. Cross-sectional surveys were conducted among mothers upon discharge from health facilities after delivery: 304 mothers in Kathmandu Valley and 306 mothers in Phnom Penh participated. On the basis of a conceptual framework for prelacteal feeding, multivariable logistic regression was used to identify factors associated with BMS feeding prior to facility discharge. In both Phnom Penh and Kathmandu Valley, feeds of BMS were reported by over half of mothers (56.9% and 55.9%, respectively). Receiving a health professional's recommendation to use BMS increased the odds of BMS feeding in both Kathmandu Valley and Phnom Penh (odds ratio: 24.87; confidence interval [6.05, 102.29]; odds ratio: 2.42; CI [1.20, 4.91], respectively). In Kathmandu Valley, recommendations from friends/family and caesarean delivery were also associated with BMS use among mothers. Early initiation of breastfeeding and higher parity were protective against the use of BMS in Kathmandu Valley. Breastfeeding support from a health professional lowered the odds of BMS feeding among newborns. Exposure to BMS promotions outside the health system was prevalent in Phnom Penh (84.6%) and Kathmandu Valley (27.0%) but was not associated with BMS feeds among newborns. Establishment of successful breastfeeding should be prioritized before discharging mothers from delivery facilities, and health professionals should be equipped to support and encourage breastfeeding among all new mothers.

Prevalence, duration, and content of television advertisements for breast milk substitutes and commercially produced complementary foods in Phnom Penh, Cambodia and Dakar, Senegal.

Promotion of breast milk substitutes (BMS) and inappropriate marketing of commercially produced complementary foods (CPCF), including through television, can negatively influence infant and young child feeding. The World Health Organization International Code of Marketing of Breast-milk Substitutes and subsequent relevant World Health Assembly (WHA) resolutions prohibit such advertising and require manufacturers and distributors to comply with its provisions; however, such regulations at national level may vary. Advertisements require Ministry of Health approval in Cambodia but are not regulated in Senegal. Television stations were monitored for 13 months in Phnom Penh and for 3 months in Dakar to assess advertisements for BMS and CPCF. Ten television channels (out of 16) in Phnom Penh and four (out of 20) in Dakar aired advertisements for BMS. Three and five channels, respectively, aired advertisements for CPCF. All BMS advertised in Phnom Penh were for children over 1 year of age. BMS products for children 6+ months of age and 1+ years of age were advertised in Dakar. Average air time for BMS advertisements was 189.5 min per month in Phnom Penh and 29.7 min in Dakar. Air time for CPCF advertisements averaged 3.2 min per month and 13.6 min, respectively. Fewer than half of BMS advertisements and three quarters of CPCF advertisements explicitly stated an age of use for products. Nutrition and health claims were common across BMS advertisements. This study illustrates the need to adopt, regulate, monitor, and enforce legislation prohibiting BMS promotion, as well as to implement regulations to prevent inappropriate promotion of CPCF.

Effect of enhanced homestead food production on anaemia among Cambodian women and children: A cluster randomized controlled trial.

There is inconsistent evidence on the efficacy of agriculture programmes at improving women and children's anaemia and nutritional status. The primary aim of this study was to evaluate the impact of a nutrition-sensitive enhanced homestead food production (EHFP) programme on anaemia in women (18-45 years) and children (6-59 months) in rural Cambodia. Secondary outcomes were women's micronutrient status and women and children's anthropometry. In this cluster-randomized controlled trial, 900 households from 90 villages (clusters) were randomized to either (a) home gardens and behaviour change communication (BCC) on nutrition, hygiene, women's empowerment, and marketing (EHFP); (b) home gardens plus fishponds and BCC (EHFP + F); or (c) control (no intervention). Haemoglobin concentration and anthropometry were measured in women and children at baseline and at 22 months. Venous blood samples were collected in a subset of women (n = 450) at baseline and at 22 months. Generalized linear mixed effect models with repeated measures were used to evaluate the difference across groups and the change from baseline to end of study. Ninety clusters, 552 women, and 754 children completed the trial. Compared with control, we found a statistically significant impact on anaemia prevalence in children (-14.0 percentage points; P = 0.02) and retinol binding protein concentrations in women (difference in difference: 0.34; P = 0.02) randomized to EHFP and EHFP + F groups, respectively. No other statistically significant effects on anaemia, nutritional biomarker concentrations, or anthropometry were observed. Future research is needed to examine longer term impacts of EHFP on anthropometry in women and children and into the nutritional causes of anaemia among children in Cambodia.

Effect of enhanced homestead food production and aquaculture on dietary intakes of women and children in rural Cambodia: A cluster randomized controlled trial.

The Cambodian diet is low in nutrient-dense animal-source foods. Enhanced homestead food production (EHFP) and aquaculture, which increase availability of nutrient-dense foods, are promising interventions to improve dietary intake. This study examined the effect of EHFP with or without aquaculture on dietary intake and prevalence of inadequate intake of select nutrients among women and children living in rural Cambodia, compared to controls. In a registered, cluster randomized controlled trial in Prey Veng, Cambodia, 10 households in each of 90 villages (n = 900) were randomized by village to receive EHFP, EHFP plus aquaculture, or control. After 22-month intervention, 24-hr dietary recalls (24HRs) were collected from mothers aged 18-50 years (n = 429) and their children aged 6 months-7 years (n = 421), reported by their mothers. Usual intake distributions (generated using 24HRs and repeat 24HRs on a subsample) were used to estimate prevalence of inadequate intake. Compared to controls, women in the EHFP group had significantly higher zinc (+1.0 mg/d) and Vitamin A (+139 retinol activity equivalents/d) intakes, and women in the EHFP plus aquaculture group had significantly higher iron (+2.7 mg/d), Vitamin A (+191 retinol activity equivalents/d), and riboflavin (+0.17 mg/d) intakes. Women in the EHFP plus aquaculture group also had significantly lower prevalence of inadequate iron (-7%, at 10% bioavailability), Vitamin A (-19%), and riboflavin (-17%) intakes, compared to controls. No significant differences in intakes or nutrient adequacy were observed among children or between EHFP and EHFP plus aquaculture groups. The biological importance of the small differences in nutrient intakes among women remains to be established.

Comparison of four immunoassays to measure serum ferritin concentrations and iron deficiency prevalence among non-pregnant Cambodian women and Congolese children.

BACKGROUND: Global standardization of ferritin assays is lacking, which could have direct implications on the accurate measurement and comparability of ferritin concentration and iron deficiency (ID) prevalence rates in at-risk populations. METHODS: We measured serum ferritin concentrations using four immunoassays: the s-ELISA and the AxSYM™ analyzer were compared among 420 non-pregnant Cambodian women; the Centaur® XP analyzer, s-ELISA, and AxSYM™ analyzer were compared among a subset of 100 Cambodian women; and the s-ELISA and the Elecsys® 2010 analyzer were compared among 226 Congolese children aged 6-59 months. RESULTS: Median ferritin concentrations (adjusted for inflammation) ranged between 48 and 91 µg/L among Cambodian women and between 54 and 55 µg/L among Congolese children. ID prevalence ranged from 2% to 10% among Cambodian women and 5% to 7% among Congolese children. Bias between methods varied widely (-9 to 45 µg/L) among women, and was 43 µg/L among children. Bias was lower when ferritin values outside of the s-ELISA measurement range (>250 µg/L) were excluded. CONCLUSIONS: The observed differences in ferritin concentrations likely reflect different ferritin isoforms, antibodies, and calibrators used across assays and by different laboratories. However, despite differences in ferritin concentrations, ID prevalence was relatively similar and low across all methods.

The Homozygous Hemoglobin EE Genotype and Chronic Inflammation Are Associated with High Serum Ferritin and Soluble Transferrin Receptor Concentrations among Women in Rural Cambodia.

BACKGROUND: Ferritin and soluble transferrin receptor (sTfR) concentrations are commonly used to assess iron deficiency (ID); however, they are influenced by multiple factors. OBJECTIVES: We assessed associations between numerous variables and both ferritin and sTfR concentrations in Cambodian women and compared ID prevalence through the use of study-generated correction factors (CFs) for ferritin with those from a published meta-analysis. METHODS: Venous blood from 450 women (aged 18-45 y) was assessed for hemoglobin (Hb), ferritin, sTfR, retinol binding protein, folate, vitamin B-12, C-reactive protein, α-1 acid glycoprotein (AGP), and genetic Hb disorders. Linear regression was used to calculate geometric mean ratios (95% CIs) for ferritin and sTfR concentrations. RESULTS: The variant Hb EE genotype was associated with 50% (14%, 96%) and 51% (37%, 66%) higher geometric mean ferritin and sTfR concentrations, respectively, than was the normal Hb AA genotype; a 1-g/L increase in AGP was associated with 99% (50%, 162%) and 48% (33%, 64%) higher concentrations in the same variables, respectively. ID prevalence in nonpregnant women (n = 420) was 2% (n = 9) with the use of ferritin <15 µg/L and 18% (n = 79) with the use of sTfR >8.3 mg/L as criteria. ID prevalence with the use of sTfR was higher in women with the Hb EE genotype (n = 17; 55%) than in those with the Hb AA genotype (n = 20; 10%); and in women with the Hb AA genotype and chronic inflammation (n = 10; 18%) than in that group of women without chronic inflammation (n = 10; 7%) (P < 0.05). No differences in ID prevalence were found with the use of ferritin between women with Hb EE and AA genotypes (P = 1.0) or by chronic inflammation status (P = 0.32). There were no differences in mean ferritin concentrations among all 450 women when study-generated CFs were compared with those from the meta-analysis (P = 0.87). CONCLUSIONS: Compared with sTfR, ferritin concentrations appear to reflect more accurately true ID in rural Cambodian women. The CFs from a published meta-analysis were appropriate for use in this population with a high prevalence of Hb disorders and inflammation.

The effect of oral iron with or without multiple micronutrients on hemoglobin concentration and hemoglobin response among nonpregnant Cambodian women of reproductive age: a 2 x 2 factorial, double-blind, randomized controlled supplementation trial.

Background: Despite a high prevalence of anemia among nonpregnant Cambodian women, current reports suggest that iron deficiency (ID) prevalence is low. If true, iron supplementation will not be an effective anemia reduction strategy.Objective: We measured the effect of daily oral iron with or without multiple micronutrients (MMNs) on hemoglobin concentration in nonpregnant Cambodian women screened as anemic.Design: In this 2 × 2 factorial, double-blind, randomized trial, nonpregnant women (aged 18-45 y) with hemoglobin concentrations ≤117 g/L (capillary blood) were recruited from 26 villages in Kampong Chhnang province and randomly assigned to receive 12 wk of iron (60 mg; Fe group), MMNs (14 other micronutrients; MMN group), iron plus MMNs (Fe+MMN group), or placebo capsules. A 2 × 2 factorial intention-to-treat analysis with the use of a generalized mixed-effects model was used to assess the effects of iron and MMNs and the interaction between these factors. Results: In July 2015, 809 women were recruited and 760 (94%) completed the trial. Baseline anemia prevalence was 58% (venous blood). Mean (95% CI) hemoglobin concentrations at 12 wk in the Fe, MMN, Fe+MMN, and placebo groups were 121 (120, 121), 116 (116, 117), 123 (122, 123), and 116 (116, 117) g/L, with no iron × MMN interaction (P = 0.66). Mean (95% CI) increases in hemoglobin were 5.6 g/L (3.8, 7.4 g/L) (P < 0.001) among women who received iron (n = 407) and 1.2 g/L (-0.6, 3.0 g/L) (P = 0.18) among women who received MMNs (n = 407). The predicted proportions (95% CIs) of women with a hemoglobin response (≥10 g/L at 12 wk) were 19% (14%, 24%), 9% (5%, 12%), 30% (24%, 35%), and 5% (2%, 9%) in the Fe, MMN, Fe+MMN, and placebo groups, respectively.Conclusions: Daily iron supplementation for 12 wk increased hemoglobin in nonpregnant Cambodian women; however, MMNs did not confer additional significant benefit. Overall, ∼24% of women who received iron responded after 12 wk; even fewer would be likely to respond in the wider population. This trial was registered at clinicaltrials.gov as NCT02481375.

Median Urinary Iodine Concentrations Are Indicative of Adequate Iodine Status among Women of Reproductive Age in Prey Veng, Cambodia.

Iodine deficiency disorders are estimated to affect over 1.9 million people worldwide. Iodine deficiency is especially serious for women during pregnancy and lactation because of the negative consequences for both mother and infant. The aim of this cross-sectional study was to determine the median urinary iodine concentration (UIC) as a population-level indicator of iodine status among rural women farmers of reproductive age (18-45 years) in the province of Prey Veng, Cambodia. A total of 450 women provided a spot morning urine sample in 2012. Of those women, 93% (n = 420) were non-pregnant and 7% (n = 30) were pregnant at the time of collection. UIC was quantified using the Sandell-Kolthoff reaction with modifications. The median UIC of non-pregnant (139 µg/L) and pregnant women (157 µg/L) were indicative of adequate iodine status using the WHO/UNICEF/ICCIDD epidemiological criteria for both groups (median UIC between 100-199 and 150-249 µg/L, respectively). We conclude that non-pregnant and pregnant women in rural Prey Veng, Cambodia had adequate iodine status based on single spot morning urine samples collected in 2012. More research is warranted to investigate iodine status among larger and more representative populations of women in Cambodia, especially in light of recent policy changes to the national program for universal salt iodization.

Effect of micronutrient sprinkles on reducing anemia: a cluster-randomized effectiveness trial.

OBJECTIVE: To evaluate the effectiveness of Sprinkles alongside infant and young child feeding (IYCF) education compared with IYCF education alone on anemia, deficiencies in iron, vitamin A, and zinc, and growth in Cambodian infants. DESIGN: Cluster-randomized effectiveness study. SETTING: Cambodian rural health district. PARTICIPANTS: Among 3112 infants aged 6 months, a random subsample (n = 1350) was surveyed at baseline and 6-month intervals to age 24 months. INTERVENTION: Daily micronutrient Sprinkles alongside IYCF education vs IYCF education alone for 6 months from ages 6 to 11 months. MAIN OUTCOME MEASURES: Prevalence of anemia; iron, vitamin A, and zinc deficiencies; and growth via biomarkers and anthropometry. RESULTS: Anemia prevalence (hemoglobin level <11.0 g/dL [to convert to grams per liter, multiply by 10.0]) was reduced in the intervention arm compared with the control arm by 20.6% at 12 months (95% CI, 9.4-30.2; P = .001), and the prevalence of moderate anemia (hemoglobin level <10.0 g/dL) was reduced by 27.1% (95% CI, 21.0-31.8; P < .001). At 12 and 18 months, iron deficiency prevalence was reduced by 23.5% (95% CI, 15.6-29.1; P < .001) and 11.6% (95% CI, 2.6-17.9; P = .02), respectively. The mean serum zinc concentration was increased at 12 months (2.88 µg/dL [to convert to micromoles per liter, multiply by 0.153]; 95% CI, 0.26-5.42; P = .03). There was no statistically significant difference in the prevalence of zinc and vitamin A deficiencies or in growth at any time. CONCLUSIONS: Sprinkles reduced anemia and iron deficiency and increased the mean serum zinc concentration in Cambodian infants. Anemia and zinc effects did not persist beyond the intervention period. TRIAL REGISTRATION anzctr.org.au Identifier: ACTRN12608000069358.