Iron supplementation in preterm and low-birth-weight infants: a systematic review of intervention studies

Context: Enteral iron supplementation in preterm infants is recommended to supply sufficient iron for growth and development without increasing the risk of iron overload. However, the current recommendations date from 2010 and are based on limited evidence. Objective: This systematic review aimed to investigate the effects of enteral iron supplementation on iron status, growth, neurological development, and adverse clinical outcomes in preterm (<37 weeks' gestation) and low-birth-weight (LBW, <2500 g) infants. Data sources: The PubMed/Medline and Cochrane Library databases were searched to 31 October 2018. Data extraction: Of the 684 records identified, 27 articles, describing 18 randomized controlled trials (RCTs) plus 4 non-randomized interventions, were included. Using the Cochrane Collaboration's criteria, study quality was found to be poor to fair overall. Results: Most articles (23/27) reported iron status indices; supplementation for >= 8 weeks resulted in increased hemoglobin and ferritin concentrations and a reduction in iron deficiency and anemia. No article reported on iron overload. Growth-related parameters reported in 12 articles were not affected by supplementation. Among the 7 articles on neurological development, a positive effect on behavior at 3.5 and 7 years was observed in one Swedish RCT. No association was found between supplementation and adverse clinical outcomes in the 9 articles reporting on studies in which such data was collected. Conclusions: Long-term iron supplementation appears to result in improved iron status and a reduction in iron deficiency and anemia in preterm and LBW infants. However, high-quality evidence regarding the long-term effects of supplementation on functional health outcomes is lacking. Iron overload has largely been ignored. Well-designed, long-term, dose-response RCTs are required to ascertain the optimal dose and delivery method for the provision of dietary iron in preterm infants, with consideration of short- and long-term health effects.