Vitamin D supplementation for prevention of vitamin D deficiency in preterm and low birth weight infants.

RATIONALE: Infants born prematurely or low birth weight (LBW) are at increased risk of vitamin D deficiency, poor bone health and rickets. Uncertainty exists regarding the need, dose and duration of vitamin D supplementation in preterm and LBW infants. OBJECTIVES: To evaluate the benefits and harms of vitamin D (daily cumulative dose ≥ 200 IU) for prevention of vitamin D deficiency in preterm and low birth weight infants. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and trials registries, together with reference checking of related studies and included studies. The latest search date was February 2026. ELIGIBILITY CRITERIA: Randomised controlled trials (RCTs), cluster- or quasi-RCTs of vitamin D supplementation versus no supplementation or placebo, or higher versus lower dose in preterm (< 37 weeks' gestational age) and term LBW infants. We excluded studies that enrolled infants with rickets. OUTCOMES: Our outcomes of interest were: vitamin D deficiency (vitamin D level < 30 nmol/L); vitamin D insufficiency or deficiency (≤ 50 nmol/L); vitamin D excess (≥ 250 nmol/L); osteopenia of prematurity; bone mineral content; nutritional rickets; and hypercalcaemia. RISK OF BIAS: We used the Cochrane risk of bias tool (RoB 1) to assess bias in the RCTs. SYNTHESIS METHODS: We synthesised results for each outcome using meta-analysis where possible, with a fixed-effect model, using risk ratio (RR), risk difference (RD), number needed to treat for an additional beneficial outcome (NNTB) or an additional harmful outcome (NNTH), mean difference or standardised mean difference (SMD) with 95% confidence intervals (CI). We used GRADE to assess the certainty of evidence for each outcome. INCLUDED STUDIES: We included 34 studies (5012 infants). Eleven studies (1514 infants) compared vitamin D supplementation versus no supplementation in preterm infants. Twenty-five studies (1546 infants) compared higher- versus lower-dose vitamin D supplementation in preterm infants. One study enrolled 2079 term LBW infants. SYNTHESIS OF RESULTS: We assessed most of the studies at high risk of bias, downgrading the evidence to moderate or low. Many subgroup analyses were underpowered due to insufficient data. Vitamin D supplementation versus no supplementation in preterm infants Vitamin D supplementation probably reduces the risk of vitamin D deficiency (RR 0.20, 95% CI 0.12 to 0.35; RD -0.28, 95% CI -0.36 to -0.21; NNTB 4, 95% CI 3 to 5; 4 studies, 385 infants; moderate-certainty evidence); and may reduce the risk of vitamin D insufficiency or deficiency (RR 0.46, 95% CI 0.38 to 0.58; RD -0.38, 95% CI -0.47 to -0.29; NNTB 3, 95% CI 2 to 4; 4 studies, 385 infants; low-certainty evidence) up to discharge/term-corrected age. Radiological evidence of osteopenia of prematurity, bone mineral content, and secondary hyperparathyroidism were not reported. Vitamin D supplementation versus no supplementation in low birth weight term and near-term infants A single study compared weekly vitamin D3 at 35 μg from seven days to six months of age versus placebo. Vitamin D supplementation probably reduces vitamin D deficiency (RR 0.21, 95% CI 0.13 to 0.34; RD -0.30, 95% CI -0.38 to -0.23; NNTB 3, 95% CI 3 to 4; 453 infants; moderate-certainty evidence); and probably reduces vitamin D insufficiency or deficiency (RR 0.59, 95% CI 0.50 to 0.70; RD -0.30, 95% CI -0.39 to -0.21; NNTB 3, 95% CI 3 to 5; 453 infants; moderate-certainty evidence) at six months of age. Vitamin D excess, osteopenia of prematurity, bone mineral content, secondary hyperparathyroidism, and hypercalcaemia were not reported. Higher-dose vitamin D (≥ 800 IU/day) supplementation versus lower-dose vitamin D (200 to < 800 IU/day) supplementation in preterm infants Higher- versus lower-dose vitamin D supplementation in preterm infants probably reduces vitamin D deficiency (RR 0.15, 95% CI 0.07 to 0.31; RD -0.13, 95% CI -0.17 to -0.09; NNTB 8, 95% CI 6 to 13; 11 studies; 672 infants; moderate-certainty evidence); and may reduce vitamin D insufficiency or deficiency (RR 0.37, 95% CI 0.28 to 0.48; RD -0.25, 95% CI -0.31 to -0.20; NNTB 4, 95% CI 3 to 5; 11 studies; 683 infants; low-certainty evidence) up to term-corrected age. However, higher- versus lower-dose vitamin D supplementation in preterm infants probably increases vitamin D excess (RR 5.76, 95% CI 1.09 to 30.3; RD 0.04, 95% CI 0.01 to 0.08; NNTH 25, 95% CI 13 to 100; 5 studies; 395 infants; moderate-certainty evidence). Higher- versus lower-dose vitamin D supplementation may result in little to no difference in radiological evidence of osteopenia of prematurity (RR 0.85, 95% CI 0.48 to 1.50; 7 studies, 447 infants; low-certainty evidence), and bone mineral content (SMD 0.13, 95% CI -0.22 to 0.49; 4 studies, 124 infants; low-certainty evidence). It probably reduces secondary hyperparathyroidism up to term-corrected age (RR 0.46, 95% CI 0.31 to 0.67; I² = 31%; RD -0.17, 95% CI -0.25 to -0.09; NNTB 6, 95% CI 4 to 11; 6 studies, 409 infants;moderate-certainty evidence). We are uncertain if it affects hypercalcaemia up to term-corrected age (RR 1.10, 95% CI 0.16 to 7.45; RD 0.00, 95% CI -0.03 to 0.03; 6 studies, 418 infants; very low-certainty evidence). AUTHORS' CONCLUSIONS: Vitamin D supplementation (≥ 200 IU/day) in preterm infants probably reduces the risk of vitamin D deficiency and vitamin D insufficiency or deficiency up to discharge/term-corrected age. Vitamin D supplementation in term LBW infants probably reduces the risk of vitamin D deficiency and insufficiency or deficiency up to six months of age. We are uncertain of any other effects on bone health, growth, or morbidities. Higher doses (≥ 800 IU/day) compared to lower doses (< 800 IU/day) probably reduce the risk of vitamin D deficiency and vitamin D insufficiency or deficiency, but probably increase vitamin D excess up to discharge/term-corrected age. Higher versus lower doses in preterm infants may result in little to no difference in radiological evidence of osteopenia of prematurity and bone mineral content, and probably reduces secondary hyperparathyroidism. We are uncertain if a higher dose versus a lower dose in preterm infants affects hypercalcaemia. FUNDING: This Cochrane review had no dedicated funding. REGISTRATION: Protocol available via DOI 10.1002/14651858.CD011529.