P1.210: The Secondary Outcomes from a Clinical Trial Comparing Two Doses of Enteral Iron Supplementation in Preterm Infants

Background: Iron deficiency is associated with impaired learning and developmental outcomes in children. Preterm infants are especially susceptible to iron deficiency due to several factors including low iron stores at birth, rapid growth, and iron loss from phlebotomy. Current guidelines recommend 2-6 mg/kg/day of enteral iron supplementation, though the optimal dose remains unclear. Auditory neural myelination and processing, measured by auditory brainstem response (ABR) latency, is affected by iron deficiency, inflammation, infections, and other factors. Ferritin, an iron storage protein, is highly regulated by iron concentration in the body and can be used to represent iron status. Cord blood ferritin level < 76 ng/mL is negatively associated with neurobehavioral outcomes. Evaluating the impact of enteral iron dosage on ABR latency, iron storage, inflammatory conditions, and growth outcomes will inform clinical practices for preterm infants.

Methods: This single site randomized double-blind dosage comparison clinical trial tested the impact of two different enteral iron doses on gut microbiota. Very low birth weight infants were assigned to 2 mg/kg/day or 6 mg/kg/day of enteral iron starting at ≥ 14 days and full feeds (150-160 ml/kg/day) until 36+6/7 weeks or discharge. Primary outcomes were the changes in beneficial and pathogenic bacterial abundances. Secondary outcomes reported in this abstract include ferritin levels, growth, ABR latency at 36 weeks, intestinal inflammation and leakage using stool and urine biomarkers, and clinical diagnoses. Adverse events were compared between the groups.

Results: 162 infants were enrolled at 28.8±2.8 weeks and 1083 ± 279 g (Table 1). No significant differences were found between iron groups for major comorbidities including retinopathy of prematurity, necrotizing enterocolitis, and bronchopulmonary dysplasia. At 4 weeks of age, median ferritin levels were significantly higher in the high-dose group (192 [116-316] vs 123 [60-238], p=0.003) (Figure 1). There was greater proportion of infants with 4-week ferritin levels < 76 ng/ml in the low-dose group (32% vs 5%, p< 0.001). Among infants with 4-week ferritin levels < 100 ng/mL, ferritin levels did not improve at 6 and 8 weeks despite increasing total iron dose by 2 mg/kg/day. There were no differences in 36-week ABR latencies, weight z-scores at birth, 4, 6, and 8 weeks, and the occurrences of adverse events between dose groups. No association was found between 36-week ABR latency and 4-week ferritin levels.

Conclusion: Preterm infants receiving 2 mg/kg/day of oral iron had significantly lower ferritin levels at 4 weeks than those receiving 6 mg/kg/day. Increasing iron dose at 4, 6, and 8 weeks in response to low ferritin levels did not improve iron storage. These findings suggest early administration of higher-dose iron is necessary to maintain an adequate iron storage; however, future research needs to determine the clinically significant postnatal ferritin levels in preterm infants to guide iron management.