A Predictive Model for Thiamine Responsive Disorders Among Infants and Young Children: Results from a Prospective Cohort Study in Lao People's Democratic Republic.

OBJECTIVE: To develop a predictive model for thiamine responsive disorders (TRDs) among infants and young children hospitalized with signs or symptoms suggestive of thiamine deficiency disorders (TDDs) based on response to therapeutic thiamine in a high-risk setting. STUDY DESIGN: Children aged 21 days to <18 months hospitalized with signs or symptoms suggestive of TDD in northern Lao People's Democratic Republic were treated with parenteral thiamine (100 mg daily) for ≥3 days in addition to routine care. Physical examinations and recovery assessments were conducted frequently for 72 hours after thiamine was initiated. Individual case reports were independently reviewed by three pediatricians who assigned a TRD status (TRD or non-TRD), which served as the dependent variable in logistic regression models to identify predictors of TRD. Model performance was quantified by empirical area under the receiver operating characteristic curve. RESULTS: A total of 449 children (median [Q1, Q3] 2.9 [1.7, 5.7] months old; 70.3% exclusively/predominantly breastfed) were enrolled; 60.8% had a TRD. Among 52 candidate variables, those most predictive of TRD were exclusive/predominant breastfeeding, hoarse voice/loss of voice, cyanosis, no eye contact, and no diarrhea in the previous 2 weeks. The area under the receiver operating characteristic curve (95% CI) was 0.82 (0.78, 0.86). CONCLUSIONS: In this study, the majority of children with signs or symptoms of TDD responded favorably to thiamine. While five specific features were predictive of TRD, the high prevalence of TRD suggests that thiamine should be administered to all infants and children presenting with any signs or symptoms consistent with TDD in similar high-risk settings. The usefulness of the predictive model in other contexts warrants further exploration and refinement. TRIAL REGISTRATION: Clinicaltrials.gov NCT03626337.

Risk factors for anaemia among women and their young children hospitalised with suspected thiamine deficiency in northern Lao PDR.

Anaemia among women and young children remains a major public health concern. This secondary study describes the anaemia prevalence among young hospitalised children and their mothers in northern Lao People's Democratic Republic and explores possible nutritional causes and risk factors for anaemia. Hospitalised children (ages 21 days to <18 months) with clinical symptoms suggestive of thiamine deficiency disorders were eligible along with their mothers. Venous blood was collected for determination of haemoglobin, ferritin, soluble transferrin receptor (sTfR), retinol-binding protein (RBP), erythrocyte glutathione reductase activation coefficient (EGRac), thiamine diphosphate (ThDP) and acute phase proteins. Risk factors for anaemia were modelled using minimally adjusted logistic regression controlling for age. Haemoglobin results were available for 436 women (mean ± SD age 24.7 ± 6.4 years; 1.6% pregnant) and 427 children (4.3 ± 3.5 months; 60.3% male). Anaemia prevalence (Hb < 120 g/L for nonpregnant women and <110 g/L for pregnant women and children) was 30.7% among women and 55.2% among children. In bivariate analyses, biomarkers significantly associated with anaemia in women were ferritin, sTfR, RBP, EGRac and ThDP. Other risk factors for women were lower BMI, mid-upper arm circumference < 23.5 cm, lower education, lower socioeconomic index, food insecurity, Hmong ethnicity, not/rarely having attended antenatal care, not having taken antenatal iron-containing supplements and not meeting minimum dietary diversity. Risk factors for anaemia among children were older age, male sex, stunting, sTfR, ThDP and alpha-1-acid-glycoprotein. Anaemia was common among women and their hospitalised children and was associated with micronutrient deficiencies and socioeconomic, dietary and health care-seeking risk factors, suggesting that multiple strategies are required to prevent anaemia among women and children.

Traditional prenatal and postpartum food restrictions among women in northern Lao PDR.

Culturally determined food restrictions are common among pregnant and postpartum women in Asia. This study aimed to describe perinatal dietary restrictions, factors associated with food avoidances and attainment of minimum dietary diversity (MDD-W) among women in Lao PDR. Mother-child (aged 21 days to <18 months) dyads (n = 682) were enrolled into a cohort study in northern Lao PDR and interviewed at one time point postpartum. During pregnancy and postpartum, 1.6% and 97% of women reported following dietary restrictions, respectively. Cluster analysis identified four distinct postpartum dietary patterns: most restrictive (throughout first 2 months postpartum); least restrictive; 2 weeks highly restrictive and 1 month highly restrictive, followed by 19%, 15%, 5% and 62% of women, respectively. Greater maternal age, gravidity and higher household socioeconomic status were associated with allowing more diverse foods, while women from food insecure households followed more restrictive diets for longer. Women belonging to the Hmong ethnic group followed a highly restrictive diet of white rice and chicken for the first month postpartum. MDD-W was achieved by 10% of women restricting their diet at the time of the interview compared with 17% of women who were consuming their normal diet (p = 0.04). Postpartum dietary restrictions are widespread among women in northern Lao PDR. These highly restrictive diets, low dietary diversity and food insecurity likely contribute to micronutrient deficiencies in women that may have important consequences for their breastfed infants through reduced breastmilk micronutrient content, which requires further exploration. Culturally appropriate strategies to increase micronutrient intakes among women should be considered.

Effects of Daily Zinc, Daily Multiple Micronutrient Powder, or Therapeutic Zinc Supplementation for Diarrhea Prevention on Physical Growth, Anemia, and Micronutrient Status in Rural Laotian Children: A Randomized Controlled Trial.

OBJECTIVES: To evaluate the optimal zinc supplementation strategy for improving growth and hematologic and micronutrient status in young Laotian children. STUDY DESIGN: In total, 3407 children aged 6-23 months were randomized to receive either daily preventive zinc tablets (7 mg/d), high-zinc, low-iron micronutrient powder (10 mg/d zinc, 6 mg/d iron, and 13 other micronutrients), therapeutic zinc supplementation for diarrhea (20 mg/d for 10 days per episode), or daily placebo powder; all were followed for ~9 months. Anthropometry, hemoglobin, zinc, and iron status were assessed at baseline and endline. Analyses were by intention-to-treat, using linear and modified Poisson regression. RESULTS: At baseline, mean (±SD) age was 14.2 ± 5.1 months and stunting and anemia prevalence were 37.9% and 55.6%, respectively. At endline, zinc deficiency in the preventive zinc (50.7%) and micronutrient powder (59.1%) groups were significantly lower than in the therapeutic zinc (79.2%) and control groups (78.6%; P < .001), with no impact on stunting (37.1%-41.3% across the groups, P = .37). The micronutrient powder reduced iron deficiency by 44%-55% compared with other groups (P < .001), with no overall impact on anemia (P = .14). Micronutrient powder tended to reduce anemia by 11%-16% among children who were anemic at baseline (P = .06). CONCLUSIONS: Despite improving zinc status, preventive zinc and micronutrient powder had no impact on growth. The micronutrient powder improved iron status and tended to reduce anemia among the subset of previously anemic children. TRIAL REGISTRATION: ClinicalTrials.govNCT02428647.

Assessment of Erythrocyte Transketolase, Whole Blood Thiamine Diphosphate, and Human Milk Thiamine Concentrations to Identify Infants and Young Children Responding Favorably to Therapeutic Thiamine Administration: Findings from the Lao Thiamine Study, a Prospective Cohort Study.

Background: There is limited information on relationships among biomarkers of thiamine status (whole blood thiamine diphosphate [ThDP], erythrocyte transketolase activity coefficient [ETKac], and human milk thiamine [MTh]) and clinical manifestations of thiamine deficiency. Objectives: This study aimed to explore correlations among these biomarkers and thiamine responsive disorders (TRDs), a diagnosis based on favorable clinical response to thiamine. Methods: Hospitalized infants and young children (aged 21 d to <18 mo) with respiratory, cardiac, and/or neurological symptoms suggestive of thiamine deficiency were treated with parenteral thiamine (100 mg daily) for ≥3 d alongside other treatments and re-examined systematically. Clinical case reports were reviewed by 3 pediatricians, who determined TRD or non-TRD status. Children in a community comparison group were matched by age, sex, and residence. Venous whole blood ThDP and MTh were determined by high-performance liquid chromatography fluorescence detection and ETKac in washed erythrocytes by ultraviolet spectrophotometry. Associations between biomarkers were assessed using Spearman correlations, and biomarker cutoffs predictive of TRD and ETKac >1.25 were explored using area under the receiver operating characteristic curve framework. Results: Thiamine biomarkers were available for 287 hospitalized children and 228 community children (mean age 4.7 mo; 59.4% male). Median (interquartile range [IQR]) ThDP and ETKac were 66.9 nmol/L (IQR: 41.4, 96.9 nmol/L) and 1.25 nmol/L (IQR: 1.11, 1.48 nmol/L), respectively, among hospitalized children, and 64.1 nmol/L (IQR: 50.0, 85.3 nmol/L) and 1.22 nmol/L (IQR: 1.12, 1.37 nmol/L) among 228 community children (P > 0.05 for both). Forty-five percent of breastfeeding mothers of infants <6 mo had MTh <90 µg/L. ThDP and ETKac, but not MTh, were significantly different between 152 children with TRD and 122 without TRD, but overlapping distributions undermined prediction of individual responses to thiamine. Conclusions: Although ETKac, ThDP, and MTh are useful biomarkers of population thiamine status, none of the biomarkers reliably identified individual children with TRD. ThDP is more practical for population assessment because preparing washed erythrocytes is not required.This trial was registered at clinicaltrials.gov as NCT03626337.

Nutrition and health-seeking practices during pregnancy and lactation and potential strategies to increase micronutrient intakes among women in northern Lao PDR.

Access to and utilisation of antenatal care (ANC) is important for optimising health and nutrition during pregnancy. This study aimed to assess adherence to and factors associated with ANC and antenatal supplement use among Laotian women, and consider culturally appropriate strategies to increase micronutrient intakes. Mother-child (aged 21 d to <18 months) dyads (n 699) enrolled in a hospital-based prospective cohort study with the community comparison group in Luang Prabang province were interviewed about their antenatal history, supplement use, household sociodemographic and dietary practices, including postpartum food avoidances. Ninety percent of women (mean age 24⋅7 ± 6⋅3 years) reported receiving ANC during their pregnancy, with the majority reporting four to seven contacts, while 84⋅6 and 17⋅3 % reported supplement use during pregnancy and lactation, respectively. Adequate ANC contacts (≥8) and supplement use was more likely among women with complete primary education and from higher socioeconomic status households, and less likely among women belonging to ethnic minority populations and those who delivered their child at home. All women continued to consume salt while adhering to postpartum food avoidances; however, 58⋅5 and 38⋅7 % of habitual consumers restricted fish and soy sauces, respectively. Eighty-six percent of women reported they would be willing to take supplements when adhering to postpartum dietary restrictions. Overall, women's reported ANC attendance and antenatal supplement use was suboptimal. Understanding predictors of and barriers to ANC and supplement use may help implement effective public health strategies to improve adherence. Alongside targeted supplementation, salt fortification with micronutrients may be a viable population-wide intervention that needs further evaluation.

Effects of therapeutic zinc supplementation for diarrhea and two preventive zinc supplementation regimens on the incidence and duration of diarrhea and acute respiratory tract infections in rural Laotian children: A randomized controlled trial.

BACKGROUND: Diarrhea and respiratory tract infections are leading causes of childhood morbidity and mortality. This individually randomized, double-blind placebo-controlled trial was designed to evaluate the effects of different zinc supplementation regimens on the incidence and duration of diarrhea and acute lower (ALRI) and upper (AURI) respiratory tract infections among rural Laotian children. The study included 3407 children, 6-23 months at enrollment. METHODS: Children were randomized to one of four study groups: therapeutic zinc supplements for diarrhea treatment (20 mg/d for 10 days with each episode; TZ), daily preventive zinc tablets (7 mg/d; PZ), daily multiple micronutrient powder (10 mg/d zinc, 6 mg/d iron and 13 other micronutrients; MNP), or daily placebo powder for 9 months. Incidence and duration of diarrhea (≥3 liquid stools/24 hours), ALRI (persistent cough with wheezing, stridor or chest in-drawing) and AURI (purulent nasal discharge with cough) were assessed by parental report during weekly home visits and analyzed using negative binomial models. RESULTS: Baseline mean age was 14.2 ± 5.1 months, and 71% had low plasma zinc (<65 µg/dL). Overall diarrhea incidence (0.61 ± 0.01 episodes/100 days at risk) and duration (2.12 ± 0.03 days/episode) did not differ by study group. Age modified the impact of the interventions on diarrhea incidence (P = 0.06) and duration (P = 0.01). In children >18 months, TZ reduced diarrhea incidence by 24% vs MNP (P = 0.035), and 36% vs Control (P = 0.004), but there was no difference with PZ. This patterned remained when analyses were restricted to diarrhea episode occurring after the first treatment with TZ. Also, in children >18 months, TZ reduced diarrhea duration by 15% vs PZ (P = 0.03), and 16% vs Control (P = 0.03), but there was no difference with MNP. There were no overall effects of study group on incidence of ALRI (overall mean 0.005 ± 0.001 episodes/100 days, P = 0.14) or AURI (overall mean 0.09 ± 0.01 episodes/100 days, P = 0.72). CONCLUSIONS: There was no overall impact of TZ, PZ or MNP on diarrhea, ALRI and AURI. However, in children >18 months, TZ significantly reduced both the duration of diarrhea episodes and the incidence of future diarrhea episodes compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02428647.

Establishing a case definition of thiamine responsive disorders among infants and young children in Lao PDR: protocol for a prospective cohort study.

INTRODUCTION: Diagnosis of infantile thiamine deficiency disorders (TDD) is challenging due to the non-specific, highly variable clinical presentation, often leading to misdiagnosis. Our primary objective is to develop a case definition for thiamine responsive disorders (TRD) to determine among hospitalised infants and young children, which clinical features and risk factors identify those who respond positively to thiamine administration. METHODS AND ANALYSIS: This prospective study will enrol 662 children (aged 21 days to <18 months) seeking treatment for TDD symptoms. Children will be treated with intravenous or intramuscular thiamine (100 mg daily for a minimum of 3 days) alongside other interventions deemed appropriate. Baseline assessments, prior to thiamine administration, include a physical examination, echocardiogram and venous blood draw for the determination of thiamine biomarkers. Follow-up assessments include physical examinations (after 4, 8, 12, 24, 36, 48 and 72 hours), echocardiogram (after 24 and 48 hours) and one cranial ultrasound. During the hospital stay, maternal blood and breast-milk samples and diet, health, anthropometric and socio-demographic information will be collected for mother-child pairs. Using these data, a panel of expert paediatricians will determine TRD status for use as the dependent variable in logistic regression models. Models identifying predictors of TRD will be developed and validated for various scenarios. Clinical prediction model performance will be quantified by empirical area under the receiver operating characteristic curve, using resampling cross validation. A frequency-matched community-based cohort of mother-child pairs (n=265) will serve as comparison group for evaluation of potential risk factors for TRD. ETHICS AND DISSEMINATION: Ethical approval has been obtained from The National Ethics Committee for Health Research, Ministry of Health, Lao PDR and the Institutional Review Board of the University of California Davis. The results will be disseminated via scientific articles, presentations and workshops with representatives of the Ministry of Health. TRIAL REGISTRATION NUMBER: NCT03626337.