Iron deficiency at neonatal intensive care unit discharge in very preterm infants

Abstract Introduction: ID is the most common micronutrient deficiency worldwide. Preterm infants are especially vulnerable to ID due to low iron stores at birth, rapid post-natal growth, and frequent blood testing performed during hospital stay. Untreated ID in infancy may result in permanent neurodevelopmental impairments that cannot be reversed by later iron supplementation. Thus, it is universally recommended to start preterm infants on prophylactic iron supplementation at 2-3 weeks of chronological age. Our group has shown previously that ID is common in preterm infants at 4-6 months of corrected age despite prophylactic iron supplementation started during neonatal stay. However, literature on ID in preterm infants during neonatal intensive care unit (NICU) stay is scarce. While several risk factors are known in term infants, maternal and neonatal risk factors that predict ID at NICU discharge in preterm infants remains underexplored. The primary objective of this study was to study the incidence of ID at NICU discharge in VP infants and explore associated risk factors. Methods: A retrospective population-based cohort study was conducted at the IWK Health Centre in Halifax, Nova Scotia, Canada. All very preterm infants born < 31 weeks GA to mothers who resided in the province of Nova Scotia, Canada during the period of 2005-2018 were included. Infants with severe congenital malformations, chromosomal anomalies, or who died prior to outcome assessment were excluded. Data regarding the presence of ID as well as neonatal and antenatal variables were extracted. All infants received prophylactic iron supplementation at a dose of 2-4 mg/kg/day starting at 2-4 weeks chronological age. Serum ferritin (SF) levels were monitored every 2-4 weeks. Supplemental iron dosage was further adjusted to a maximum of 6 mg/kg/day based on SF levels. ID was defined as SF < 50 ug/l at discharge. Univariate analysis was performed to compare infants with and without ID. Variables with a p value of < 0.2 on univariate analysis underwent backward stepwise multivariable logistic regression analysis to identify independent predictors of ID. Variables with a p-value < 0.05 were retained. Results: A total of 258 very preterm infants were studied (GA <31 wks, 56.2% male). Of these, 80 infants (31%) were ID (mean ferritin 34.7 ug/l) at NICU discharge. Mean birth weight, gestational age, apgar score, length of hospital stay, feeding type (partial or exclusively breastfed vs exclusively formula fed) and neonatal morbidities including bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis, and culture positive sepsis were comparable between the two groups. A significantly lower number of infants in the ID group were diagnosed with hemodynamically significant patent ductus arteriosus (Odds Ratio (OR): 0.4, Confidence Intervals (CI): 0.2-0.8, p=0.01). Further, infants in the ID group received a significantly lower number of blood transfusions during NICU stay compared to infants without ID (median (interquartile range, (IQR): 1(2), p=0.04). Infants born to mothers with gestational hypertension and/or who underwent a cesarean section had a higher incidence of ID (OR: 2.4 (1.2-4.7), p=0.02 and OR: 1.8 (1.1-3.3), p=0.05, respectively). Other antenatal variables such as maternal age and maternal morbidities (i.e., obesity, smoking, diabetes, anemia) were statistically comparable between the two groups. Multivariable logistic regression revealed that gestational hypertension was the only independent predictor of ID at NICU discharge (OR: 2.6 (1.3-5.1), p=0.007). Conclusion: ID is common in very preterm infants at NICU discharge despite prophylatic iron supplementation started early on. Preterm infants born to mothers with gestational hypertension are significantly more likely to be iron deficient at NICU discharge compared to those without gestational hypertension. A possible explanation for this finding could be that gestational hypertension impairs placental iron transport to neonates which, in combination with preterm birth, significantly enhances ID risk. Gestational hypertension has been linked to elevated maternal hepcidin levels, which may also play a potential role in promoting ID in preterm infants. Findings from this study suggest that this subpopulation of very preterm infants may receive benefit from more rigorous monitoring of iron stores during NICU stay and after discharge.