Oral Vitamin A Supplementation for Prevention of Bronchopulmonary Dysplasia in Extremely Preterm Infants: A Dose-Response Meta-Analysis

Abstract

Introduction: Bronchopulmonary dysplasia (BPD) affects 40% of infants <28 weeks gestation. Vitamin A deficiency is common in preterm infants and linked to impaired lung development. Intramuscular vitamin A reduces BPD but is painful. Oral vitamin A may be an alternative, but optimal dosing is unknown.

Methods: We performed a systematic review and one-stage dose-response meta-analysis. Databases: PubMed, Scopus, Embase. Inclusion: RCTs of oral vitamin A supplementation (any dose, ≥14 days) in infants <29 weeks gestation. Primary outcome: BPD at 36 weeks postmenstrual age. Secondary: retinopathy of prematurity (ROP), mortality. Restricted cubic splines modeled dose-response.

Results: Seven RCTs (n=2,106 infants) with doses from 1,500 to 10,000 IU/kg/day were included. Overall BPD incidence was 34% in supplemented vs. 42% in placebo (RR 0.81, 95% CI 0.72–0.91). Dose-response analysis showed a U-shaped curve: maximum benefit at 5,000 IU/kg/day (RR 0.68). Doses >7,500 IU/kg/day showed no additional benefit and trend toward increased ROP (RR 1.15, p=0.09). Mortality unchanged (RR 0.92). No hypervitaminosis A cases reported.

Discussion: Oral vitamin A reduces BPD with an optimal therapeutic window around 5,000 IU/kg/day. The U-shaped response suggests toxicity at high doses, possibly interfering with retinoid signaling. Intramuscular formulation remains more studied, but oral route is acceptable for infants with feeding tolerance.

Conclusions: Oral vitamin A at 5,000 IU/kg/day is effective and safe for BPD prevention in extremely preterm infants. Higher doses provide no added benefit and may increase ROP risk.