Iron supplementation and the risk of bronchopulmonary dysplasia in extremely low gestational age newborns

Abstract

Background: The aim of this study was to determine the relationship between iron exposure and the development of bronchopulmonary dysplasia (BPD).

Methods: A secondary analysis of the PENUT Trial dataset was conducted. The primary outcome was BPD at 36 weeks gestational age and primary exposures of interest were cumulative iron exposures in the first 28 days and through 36 weeks' gestation. Descriptive statistics were calculated for study cohort characteristics with analysis adjusted for the factors used to stratify randomization.

Results: Of the 941 patients, 821 (87.2%) survived to BPD evaluation at 36 weeks, with 332 (40.4%) diagnosed with BPD. The median cohort gestational age was 26 weeks and birth weight 810 g. In the first 28 days, 76% of infants received enteral iron and 55% parenteral iron. The median supplemental cumulative enteral and parenteral iron intakes at 28 days were 58.5 and 3.1 mg/kg, respectively, and through 36 weeks' 235.8 and 3.56 mg/kg, respectively. We found lower volume of red blood cell transfusions in the first 28 days after birth and higher enteral iron exposure in the first 28 days after birth to be associated with lower rates of BPD.

Conclusions: We find no support for an increased risk of BPD with iron supplementation.

Trial registration number: NCT01378273. https://clinicaltrials.gov/ct2/show/NCT01378273 IMPACT: Prior studies and biologic plausibility raise the possibility that iron administration could contribute to the pathophysiology of oxidant-induced lung injury and thus bronchopulmonary dysplasia in preterm infants. For 24-27-week premature infants, this study finds no association between total cumulative enteral iron supplementation at either 28-day or 36-week postmenstrual age and the risk for developing bronchopulmonary dysplasia.

Figure 1. The relationship between iron exposure in the first 28-days and diagnosis of bronchopulmonary dysplasia (BPD) at 36 weeks’.

In both Figure 1A (enteral iron exposure) and 1B (parenteral iron exposure), the analyzed cohort was separated into those patients who had no iron exposure with the remainder divided into quartiles based on total iron exposure. Groups are ordered from lowest exposure (far left, no iron) to greatest exposure (far right, greatest quartile of exposure). An inverse relationship exists between enteral iron exposure and diagnosis of BPD at 36 weeks’ (1A) whereas a weak direct relationship exists between escalating parenteral iron exposure and diagnosis of BPD at 36 weeks’ (1B).

Figure 2:. Variation in enteral iron exposure in the first 28-days by recruitment site

The study cohort was separated into those patients who had no enteral iron exposure in the first 28-days with the remaining patients divided into quartiles by total exposure in mg per kg. Deidentified PENUT Trial sites (1 through 19) are noted on the far left and number of patients recruited at each site at the far right. Significant site to site variation in exposure to enteral iron is seen in the first 28-days, with some sites (#3, #7, #11, 17) having a majority of recruited patients not receiving any enteral iron in the first 28-days after birth.