Formula Feeding Significantly Increases Risk of Iron Deficiency in Very Preterm Infants during the First 4-6 Months of Life

Introduction: Iron deficiency (ID) early in life is associated with adverse neurodevelopmental and behavioural outcomes later in life. Preterm infants are considered at increased risk of developing ID due to their relative lack of iron stores, accelerated growth during the first few weeks of life and multiple phlebotomies received while in hospital. Breast fed (BF) preterm infants are considered at particularly increased risk of ID due to the lower iron content of breast milk. Therefore, iron supplementation is routinely recommended for these infants. However, the supplemental iron requirements of formula fed (FF) preterm infants are generally deemed to be lower due to the presence of iron in formulas. The Canadian Pediatric Society recommends no additional iron supplementation for preterm infants with a birth weight <2kg if they are primarily FF with iron-rich formula. The American Academy of Pediatrics makes no general recommendation for iron supplementation in infants fed primarily with iron-rich formula.

The primary objective of this study was to investigate how feeding type influences the iron status of very preterm infants at 4-6-months corrected age (CA). A secondary objective was to further explore the risk factors associated with ID in the FF group.

Methods: A retrospective population-based cohort study was conducted at IWK Health using the Perinatal Follow-Up Program database, a provincial database containing relevant clinical information for all very preterm infants (<31 weeks gestational age) born in the province of Nova Scotia, Canada. All very preterm infants born in Nova Scotia from 2005-2018 were included. Infants with severe congenital malformations, chromosomal anomalies and/or hemolytic anemias were excluded. Information about presence of ID, feeding type, iron intake from formula, and supplemental iron therapy at 4-6-month follow-up was extracted, as were neonatal variables. ID was defined as serum ferritin <20 and <12 mcg/L at 4-and 6-months CA, respectively. Variables were compared between the FF and BF groups using chi square and unpaired t-tests. The FF group was further divided into ID and non-ID groups, which were compared using similar analysis techniques.

Results: A total of 392 infants were studied (gestational age: 23-30 weeks; 55.75% male). Of these, 285 were exclusively FF with iron-rich formula and 107 were exclusively or partially BF. Mean birth weight, gestational age and neonatal variables were comparable between the two groups. Mean iron intake from formula in the FF group was 1.66 mg/kg/day. An elemental iron intake of ≥ 2mg/kg/day was obtained from formula alone in only 20.4% of FF infants. FF infants were also less likely to receive additional iron supplements (Table 1). However, mean total daily iron intake (from formula and supplements) was higher in the FF group. Despite this, 36.8% of infants in FF group developed ID versus 20.6% in BF group (p=0.002).

Table 2 shows key characteristics of ID and non-ID FF infants. Mean gestational age and birth weight were both lower in the ID group. The ID group also had a higher percentage of infants born <1100g (p=0.01). More babies in the ID group received at least one blood transfusion (Odds:1.1-3.0). Other neonatal variables were comparable between the two groups. ID infants had a higher daily formula intake, daily iron intake from formula and total daily iron intake combined from formula and supplements.

Conclusion: Most very preterm infants fail to receive elemental iron of 2mg/kg/day from formula alone. ID is significantly more prevalent in FF infants than BF infants despite higher iron intake overall. A possible explanation for this finding could be that the bioavailability of iron from formula is lower than from breast milk. Breast milk contains lactoferrin, which aids iron absorption. Thus, iron from breast milk may be better absorbed than iron from formula. Our observations suggest the need to revisit the international recommendations for iron supplementation in FF very preterm infants. Lower gestational age, lower birth weight and need for blood transfusions were associated with ID in FF infants. Plausibly, blood transfusions may lead clinicians to withhold necessary iron supplementation for fear of iron overload in these infants, leading to unintentional ID. We suggest that optimal iron supplementation in this population should be guided by a risk adapted strategy.

No relevant conflicts of interest to declare.