Davaasambuu Ganmaa

Randomized Trial of Vitamin D Supplementation and Risk of Acute Respiratory Infection in Mongolia

OBJECTIVE: Observational studies suggest that serum levels of 25-hydroxyvitamin D (25[OH]D) are inversely associated with acute respiratory infections (ARIs). We hypothesized that vitamin D supplementation of children with vitamin D deficiency would lower the risk of ARIs. METHODS: By using cluster randomization, classrooms of 744 Mongolian schoolchildren were randomly assigned to different treatments in winter (January–March). This analysis focused on a subset of 247 children who were assigned to daily ingestion of unfortified regular milk (control; n = 104) or milk fortified with 300 IU of vitamin D3 (n = 143). This comparison was double-blinded. The primary outcome was the number of parent-reported ARIs over the past 3 months. RESULTS: At baseline, the median serum 25(OH)D level was 7 ng/mL (interquartile range: 5–10 ng/mL). At the end of the trial, follow-up was 99% (n = 244), and the median 25(OH)D levels of children in the control versus vitamin D groups was significantly different (7 vs 19 ng/mL; P < .001). Compared with controls, children receiving vitamin D reported significantly fewer ARIs during the study period (mean: 0.80 vs 0.45; P = .047), with a rate ratio of 0.52 (95% confidence interval: 0.31–0.89). Adjusting for age, gender, and history of wheezing, vitamin D continued to halve the risk of ARI (rate ratio: 0.50 [95% confidence interval: 0.28–0.88]). Similar results were found among children either below or above the median 25(OH)D level at baseline (rate ratio: 0.41 vs 0.57; Pinteraction = .27). CONCLUSIONS: Vitamin D supplementation significantly reduced the risk of ARIs in winter among Mongolian children with vitamin D deficiency.

Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data

Objectives To assess the overall effect of vitamin D supplementation on risk of acute respiratory tract infection, and to identify factors modifying this effect. Design Systematic review and meta-analysis of individual participant data (IPD) from randomised controlled trials. Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and the International Standard Randomised Controlled Trials Number registry from inception to December 2015. Eligibility criteria for study selection Randomised, double blind, placebo controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration were eligible for inclusion if they had been approved by a research ethics committee and if data on incidence of acute respiratory tract infection were collected prospectively and prespecified as an efficacy outcome. Results 25 eligible randomised controlled trials (total 11 321 participants, aged 0 to 95 years) were identified. IPD were obtained for 10 933 (96.6%) participants. Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96; P for heterogeneity <0.001). In subgroup analysis, protective effects were seen in those receiving daily or weekly vitamin D without additional bolus doses (adjusted odds ratio 0.81, 0.72 to 0.91) but not in those receiving one or more bolus doses (adjusted odds ratio 0.97, 0.86 to 1.10; P for interaction=0.05). Among those receiving daily or weekly vitamin D, protective effects were stronger in those with baseline 25-hydroxyvitamin D levels <25 nmol/L (adjusted odds ratio 0.30, 0.17 to 0.53) than in those with baseline 25-hydroxyvitamin D levels ≥25 nmol/L (adjusted odds ratio 0.75, 0.60 to 0.95; P for interaction=0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (adjusted odds ratio 0.98, 0.80 to 1.20, P=0.83). The body of evidence contributing to these analyses was assessed as being of high quality. Conclusions Vitamin D supplementation was safe and it protected against acute respiratory tract infection overall. Patients who were very vitamin D deficient and those not receiving bolus doses experienced the most benefit. Systematic review registration PROSPERO CRD42014013953.

Milk consumption and the prepubertal somatotropic axis

BackgroundNutrients, hormones and growth factors in dairy foods may stimulate growth hormone (GH), insulin-like growth factor I (IGF-I), and raise the ratio of IGF-I to its binding protein, IGFBP-3. We conducted pilot studies in Mongolia and Massachusetts to test the extent to which milk intake raised somatotropic hormone concentrations in prepubertal children.MethodsIn Ulaanbaatar, we compared plasma levels before and after introducing 710 ml daily whole milk for a month among 46 10–11 year old schoolchildren. In a randomized cross-over study in Boston, we compared plasma hormone levels of 28 6–8 year old girls after one week of drinking 710 ml lowfat (2%) milk with their hormone levels after one week of consuming a macronutrient substitute for milk.ResultsAfter a month of drinking whole milk, Mongolian children had higher mean plasma levels of IGF-I (p < 0.0001), IGF-I/IGFBP-3 (p < 0.0001), and 75th percentile of GH levels (p = 0.005). After a week of drinking lowfat milk, Boston girls had small and non-significant increases in IGF-1, IGF-1/IGFBP-3 and GH.ConclusionMilk drinking may cause increases in somatotropic hormone levels of prepubertal girls and boys. The finding that milk intake may raise GH levels is novel, and suggests that nutrients or bioactive factors in milk may stimulate endogenous GH production.

Randomized trial of vitamin D supplementation for winter-related atopic dermatitis in children

BACKGROUND Epidemiologic and preclinical data, and a small randomized trial in Boston, suggest that vitamin D supplementation may improve winter-related atopic dermatitis (AD). OBJECTIVE To determine the effect of vitamin D supplementation on winter-related AD. METHODS We performed a randomized, double-blind, placebo-controlled trial of Mongolian children with winter-related AD (clinicaltrials.gov identifier: NCT00879424). Baseline eligibility included age 2 to 17 years, AD score 10 to 72 using the Eczema Area and Severity Index (EASI), and winter-related AD (eg, history of AD worsening during the fall-to-winter transition). Subjects were enrolled in Ulaanbaatar during winter and randomly assigned to oral cholecalciferol (1000 IU/day) versus placebo for 1 month. All children and parents received emollient and patient education about AD and basic skin care. The main outcomes were changes in EASI score and in Investigators Global Assessment. RESULTS The 107 enrolled children had a mean age of 9 years (SD 5), and 59% were male. Their median age of AD onset was 3 months (interquartile range 2 months to 1 year) and mean EASI score at baseline 21 (SD 9). One-month follow-up data were available for 104 (97%) children. Compared with placebo, vitamin D supplementation for 1 month produced a clinically and statistically significant improvement in EASI score (adjusted mean change: -6.5 vs -3.3, respectively; P = .04). Moreover, change in Investigators Global Assessment favored vitamin D over placebo (P = .03). There were no adverse effects in either group. CONCLUSION Vitamin D supplementation improved winter-related AD among Mongolian children, a population likely to have vitamin D deficiency in winter.

Vitamin D, tuberculin skin test conversion, and latent tuberculosis in Mongolian school-age children: a randomized, double-blind, placebo-controlled feasibility trial

BACKGROUND By modulating immune function, vitamin D might increase innate immunity and inhibit the growth of initial bacterial invasion and protect against tuberculosis infection. OBJECTIVE We examined the effect of vitamin D supplementation on tuberculin skin test (TST) conversion. DESIGN A double-blind, placebo-controlled study was conducted in 120 Mongol schoolchildren. We estimated the prevalence of latent tuberculosis infection at baseline and examined the effect of vitamin D (800 IU/d) on serum concentrations of 25-hydroxyvitamin D [25(OH)D] and TST conversion. RESULTS At baseline, the mean (±SD) 25(OH)D concentration was 7 ± 4 ng/mL, and all concentrations were <20 ng/mL. Vitamin D supplementation increased serum 25(OH)D by a mean of 12.7 ng/mL compared with placebo (P < 0.0001). At baseline, 16 children in the vitamin D group and 18 in the placebo group were TST positive (P = 0.7). Over 6 mo, TSTs converted to positive in 5 (11%) children receiving vitamin D compared with 11 (27%) receiving placebo (RR: 0.41; 95% CI: 0.16, 1.09; P = 0.06). Only one TST conversion occurred among those whose serum 25(OH)D concentration increased to >20 ng/mL, whereas 8 TST conversions occurred in those whose final 25(OH)D concentration remained <10 ng/mL (P = 0.05). The mean increase in stature was 2.9 ± 1.6 cm in the vitamin D group and 2.0 ± 1.7 cm in the placebo group (95% CI: 2.16, 2.81; P < 0.003). CONCLUSIONS Vitamin D supplementation for 6 mo had significant favorable effects on serum 25(OH)D concentrations and on growth in stature. A trend was seen toward fewer TST conversions in the vitamin D group. This trial was registered at clinicaltrials.gov as NCT01244204.

Randomized trial of fortified milk and supplements to raise 25-hydroxyvitamin D concentrations in schoolchildren in Mongolia

BACKGROUND The optimal public health strategy for maintaining 25-hydroxyvitamin D [25(OH)D] concentrations in schoolchildren in Mongolia is unknown. OBJECTIVE The objective was to compare the effectiveness of different supplement and fortified milk regimens to increase 25(OH)D concentrations in Mongolian schoolchildren. DESIGN Twenty-one classrooms of 579 children aged 9-11 y were randomized to interventions with an equivalent content of vitamin D(3): 1) a one-time seasonal supplement of 13,700 IU, 2) 300 IU/d from supplements, 3) 300 IU/d from fortified ultra-high-temperature pasteurized milk from the United States, 4) 300 IU/d from fortified pasteurized Mongolian milk, or 5) unfortified pasteurized Mongolian milk (control). RESULTS In January, the mean (±SD) serum 25(OH)D concentration was 8 ± 4 ng/mL (20 ± 10 nmol/L), and 98% of the children had a concentration <20 ng/mL (50 nmol/L). In March, concentrations were 8 ± 4 ng/mL after unfortified milk, 20 ± 6 ng/mL after fortified Mongolian milk, 29 ± 10 ng/mL after fortified US milk, 21 ± 6 ng/mL after daily supplements, and 12 ± 4 ng/mL after seasonal supplements (each greater than unfortified milk, P < 0.01). Seasonal supplementation was less effective than was daily supplementation (P < 0.0001). Despite consuming daily supplements or fortified milk, 41% of the children still had concentrations <20 ng/mL (50 nmol/L). Children with lower baseline 25(OH)D concentrations experienced slightly larger 25(OH)D responses to intervention than did children with higher concentrations (P = 0.002). CONCLUSIONS In this population with extremely low vitamin D concentrations, delivery of 300 IU vitamin D/d via supplements or in fortified milk improved 25(OH)D concentrations but failed to raise concentrations uniformly to >20 ng/mL (50 nmol/L). The daily low-dose intervention was superior to the seasonal larger-dose intervention. Higher doses may be needed to prevent deficiency in schoolchildren in Mongolia and at other northern latitudes. This trial is registered at clinicaltrials.gov as NCT00886379.

High-Dose Vitamin D3 During Tuberculosis Treatment in Mongolia: A Randomised Controlled Trial

Rationale: Existing trials of adjunctive vitamin D in the treatment of pulmonary tuberculosis (PTB) are variously limited by small sample sizes, inadequate dosing regimens, and high baseline vitamin D status among participants. Comprehensive analyses of the effects of genetic variation in the vitamin D pathway on response to vitamin D supplementation are lacking. Objectives: To determine the effect of high‐dose vitamin D3 on response to antimicrobial therapy for PTB and to evaluate the influence of single‐nucleotide polymorphisms (SNPs) in vitamin D pathway genes on response to adjunctive vitamin D3. Methods: We conducted a clinical trial in 390 adults with PTB in Ulaanbaatar, Mongolia, who were randomized to receive four biweekly doses of 3.5 mg (140,000 IU) vitamin D3 (n = 190) or placebo (n = 200) during intensive‐phase antituberculosis treatment. Measurements and Main Results: The intervention elevated 8‐week serum 25‐hydroxyvitamin D concentrations (154.5 nmol/L vs. 15.2 nmol/L in active vs. placebo arms, respectively; 95% confidence interval for difference, 125.9‐154.7 nmol/L; P < 0.001) but did not influence time to sputum culture conversion overall (adjusted hazard ratio, 1.09; 95% confidence interval, 0.86‐1.36; P = 0.48). Adjunctive vitamin D3 accelerated sputum culture conversion in patients with one or more minor alleles for SNPs in genes encoding the vitamin D receptor (rs4334089, rs11568820) and 25‐hydroxyvitamin D 1&agr;‐hydroxylase (CYP27B1: rs4646536) (adjusted hazard ratio ≥ 1.47; P for interaction ≤ 0.02). Conclusions: Vitamin D3 did not influence time to sputum culture conversion in the study population overall. Effects of the intervention were modified by SNPs in VDR and CYP27B1. Clinical trial registered with www.clinicaltrials.gov (NCT01657656).

Vitamin D deficiency in reproductive age Mongolian women: a cross sectional study.

Vitamin D production is critical not only for rickets prevention but for its role in several chronic diseases of adulthood. Maternal vitamin D status also has consequences for the developing fetus. This study assessed the prevalence of vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D]<20ng/ml) and insufficiency [25(OH)D=20-29ng/ml] in spring, among reproductive age Mongolian women. Blood was drawn in March and April, 2009 from 420 Mongolian women, 18-44 years of age. Serum 25(OH)D concentrations were measured, anthropometric measurements were performed and information was collected by interview on lifestyle, dietary and reproductive factors. Logarithm-transformed 25(OH)D levels were compared across risk factor categories by analysis of variance. Linear regression analysis was used to assess the independent associations of factors with vitamin D status. Cutaneous vitamin D3 synthesis was assessed between December and July using a standard 7-dehydrocholesterol ampoule model. The vast majority of women 415 (98.8%) had serum 25(OH)D<20ng/ml (50nmol/l) with an additional 4 women (<1%) in the insufficient range (20-29ng/ml); only one women (0.2%) had sufficient levels (>30ng/ml or 75nmol/l). 25(OH)D concentrations were positively and independently associated with educational status and use of vitamin D supplements, but not with other demographic, lifestyle, reproductive, or anthropometric factors. 25(OH)D levels were not associated with dietary factors in this population, as there is little access to foods containing vitamin D in Mongolia. No production of previtamin D3 was observed until March and was maximally effective in April and was sustained through July. These data suggest that the prevalence of vitamin D deficiency in spring among reproductive age women in Mongolia is high. Given the lack of naturally vitamin D-rich food in the diet and limited use of vitamin D supplements, food fortification and/or supplementation with vitamin D should be considered among these women.

A comparison of migrants to, and women born in, urban Mongolia: demographic, reproductive, anthropometric and lifestyle characteristics.

BACKGROUND Mongolia has experienced vast migration from rural to urban areas since the 1950s. We hypothesized that women migrating to Ulaanbaatar, the capital, would differ in factors related to future chronic disease risk compared with women who were born in Ulaanbaatar. METHODS Premenopausal mothers (aged <44 years) of children attending two schools (one in the city centre and one in the outskirts) in Ulaanbaatar were recruited for the study. During April and May 2009, 420 women were interviewed about migration, reproductive history and lifestyle factors and anthropometric measurements were taken. RESULTS Women born in (n=178) and outside (n=242) Ulaanbaatar were similar in education and marital status, but the latter appeared to have a more traditional lifestyle including being more likely to have lived as a nomadic herder (22.3% vs 5.6%; p<0.001) and to currently live in a traditional yurt or ger (40.1% vs 29.2%). Ever-use of hormonal contraception was more common in women born outside Ulaanbaatar (52.1% vs 38.2%; p=0.005) and their age at first live birth was older (26.0% vs 20.8% for ≥ 25 vs <25 years). Although the number of pregnancies was similar, the number of live births was greater for those born outside Ulaanbaatar (p=0.002). Women born in Ulaanbaatar were more likely to have smoked cigarettes (24.7% vs 11.2%; p<0.001). Women born outside Ulaanbaatar were more likely to consume the traditional meat and dairy diet. CONCLUSION Rural migrants to Mongolias capital have retained a traditional lifestyle in some, but not all, respects. Internal migrant populations may provide the opportunity to assess the effect of changes in isolated risk factors for subsequent chronic disease.

Vitamin D supplementation and growth in urban Mongol school children: Results from two randomized clinical trials

Background Symptomatic vitamin D deficiency is associated with slowed growth in children. It is unknown whether vitamin D repletion in children with asymptomatic serum vitamin D deficiency can restore normal growth. Objective We tested the impact of vitamin D-supplementation on serum concentrations of 25-hydroxyvitamin D [25(OH)D] and short-term growth in Mongol children, with very low serum vitamin D levels in winter. Design We conducted two randomized, double-blind, placebo-controlled trials in urban school age children without clinical signs of rickets. The Supplementation Study was a 6-month intervention with an 800 IU vitamin D3 supplement daily, compared with placebo, in 113 children aged 12–15 years. A second study, the Fortification Study, was a 7-week intervention with 710 ml of whole milk fortified with 300 IU vitamin D3 daily, compared with unfortified milk, in 235 children aged 9–11 years. Results At winter baseline, children had low vitamin D levels, with a mean (±SD) serum 25-hydroxyvitamin D [25(OH)D] concentration of 7.3 (±3.9) ng/ml in the Supplementation Study and 7.5 (±3.8) ng/ml in the Fortification Study. The serum levels increased in both vitamin D groups—by 19.8 (±5.1) ng/ml in the Supplementation Study, and 19.7 (±6.1) ng/ml in the Fortification Study. Multivariable analysis showed a 0.9 (±0.3 SE) cm greater increase in height in the vitamin-D treated children, compared to placebo treated children, in the 6-month Supplementation Study (p = 0.003). Although the children in the 7-week Fortification Study intervention arm grew 0.2 (±0.1) cm more, on average, than placebo children this difference was not statistically significant (p = 0.2). There were no significant effects of vitamin D supplements on differences in changes in weight or body mass index in either trial. For the Fortification Study, girls gained more weight than boys while taking vitamin D 3 (p-value for interaction = 0.03), but sex was not an effect modifier of the relationship between vitamin D3 and change in either height or BMI in either trial. Conclusions Correcting vitamin D deficiency in children with very low serum vitamin D levels using 800 IU of vitamin D3 daily for six months increased growth, at least in the short-term, whereas, in a shorter trial of 300 IU of D fortified milk daily for 7 weeks did not.