Vitamin D supplementation for preventing infections in children under five years of age.
Vitamin D is a micronutrient important for bone growth and immune function. Deficiency can lead to rickets and has been linked to various infections, including respiratory infections. The evidence on the effects of supplementation on infections in children has not been assessed systematically.



To evaluate the role of vitamin D supplementation in preventing pneumonia, tuberculosis (TB), diarrhoea, and malaria in children under five years of age. This includes high-, middle-, and low-income countries.



We searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Library, MEDLINE, EMBASE, LILACS, the WHO International Clinical Trials Registry Platform (ICTRP; http://www.who.int/ictrp/en/) , ClinicalTrials.gov and the ISRCTN registry (http://www.isrctn.com/) up to 16 June 2016.



We included randomized controlled trials (RCTs) that evaluated preventive supplementation of vitamin D (versus placebo or no intervention) in children under five years of age.



Two review authors independently screened the titles and abstracts, extracted the data, and assessed the risk of bias of included trials.



Four trials met the inclusion criteria, with a total of 3198 children under five years of age, and were conducted in Afghanistan, Spain, and the USA. Prevalence of vitamin D deficiency varied widely in these populations (range: 73.1% in Afghanistan, 10 to 12% in USA, and 6.2% in Spain). The included trials evaluated mortality (two trials), pneumonia incidence (two trials), diarrhoea incidence (two trials), hospitalization (two trials), and mean serum vitamin D concentrations (four trials).We do not know whether vitamin D supplementation impacts on all-cause mortality because this outcome was underpowered due to few events (risk ratio (RR) 1.43, 95% confidence interval (CI) 0.54 to 3.74; one trial, 3046 participants, low quality evidence).For pneumonia, episodes of 'radiologically confirmed' first or only episode of pneumonia were little different in the supplemented and unsupplemented group (Rate Ratio: 1.06, 95% confidence interval (CI) 0.89 to 1.26; two trials, 3134 participants, moderate quality evidence), and similarly for children with confirmed or unconfirmed pneumonia (RR 0.95, 95% CI 0.87 to 1.04; one trial, 3046 participants). In these two trials there were no obvious differences between supplemented and unsupplemented children regarding episodes of diarrhoea.In the single large trial from Afghanistan, the trial authors reported that vitamin D supplementation was associated with an increase in repeat episodes of pneumonia confirmed by chest radiograph (RR 1.69, 95% CI 1.28 to 2.21; one trial, 3046 participants), but not reflected in the outcome of confirmed or unconfirmed pneumonia (RR 1.06, 95% CI 1.00 to 1.13; one trial, 3046 participants).For hospital admission measured in one small trial, there was no difference detected (RR 0.86, 95% CI 0.20 to 3.62; one trial, 88 participants; very low quality evidence).The mean serum vitamin D concentrations were higher in supplemented compared to unsupplemented children at the end of supplementation (MD 7.72 ng/mL, 95% CI 0.50 to 14.93; four trials, 266 participants, low quality evidence). These results were driven primarily by two smaller trials with large magnitudes of effect. In the other two bigger trials, serum vitamin D concentrations were elevated in the intervention group for most of the trial duration but not at the end of supplementation. This may be due to time elapsed at measurement from the last dose, incomplete compliance, or increased need of vitamin D with infant age.We did not find any trial that reported on the incidence of TB, malaria or febrile illness, duration of pneumonia, duration of diarrhoea, severity of infection, and cause-specific mortality (due to TB, diarrhoea, or malaria).



Evidence from one large trial did not demonstrate benefit of vitamin D supplementation on the incidence of pneumonia or diarrhoea in children under five years. To our knowledge, trials that evaluated supplementation for preventing other infections, including TB and malaria, have not been performed.
Departments of Epidemiology and Nutrition, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA, USA, 02115.
Mohammad Y
MY
Yakoob
Rehana A
RA
Salam
Farhan R
FR
Khan
Zulfiqar A
ZA
Bhutta
D002675:Child, Preschool; D003967:Diarrhea / Q000453:epidemiology / Q000517:prevention & control*; D006801:Humans; D015994:Incidence; D007223:Infant; D008288:Malaria / Q000517:prevention & control; D011014:Pneumonia / Q000453:epidemiology / Q000517:prevention & control*; D016032:Randomized Controlled Trials as Topic; D014397:Tuberculosis, Pulmonary / Q000517:prevention & control; D014807:Vitamin D / Q000008:administration & dosage* / Q000097:blood; D014808:Vitamin D Deficiency / Q000453:epidemiology; D014815:Vitamins / Q000008:administration & dosage*
D014815:Vitamins; D014807:Vitamin D