Subscribe to RSS
DOI: 10.1055/a-2806-3017
Iron Deficiency Screening with Reticulocyte–Hemoglobin Content and 2-Year Neurodevelopmental Outcomes in Extremely Low Birth Weight Infants
Authors
Abstract
Objective
The objective of this study is to assess reticulocyte–hemoglobin (RET–He) and daily iron dosing with 2-year cognitive outcomes.
Study Design
A multicenter retrospective cohort study of 78 infants born between 2014 and 2018 at less than 28 weeks' gestation or less than 1,250 g birth weight throughout level III or IV neonatal intensive care units (NICUs). RET–He measurement, iron supplementation, and the Bayley Scales of Infant and Toddler Development-III (Bayley-III) test were analyzed using multiple linear regression models.
Results
For every 1 mg/kg increase in mean total daily iron supplementation, the Bayley-III cognitive score increased by 2.9 points (95% confidence interval [CI]: 0.4–5.4, p = 0.023). No associations were identified between minimum or maximum RET–He and Bayley-III cognitive outcomes. Infants with a RET–He value < 29 pg tended to be 2.53 times more likely to have a Bayley-III language score below 70 (odds ratio: 2.53, 95% CI: 0.92–6.95, p = 0.071). Thirty-eight out of 78 (38.4%) infants were iron-deficient during their NICU hospitalization, with at least one RET–He < 29 pg.
Conclusion
An association was identified between a higher mean daily iron dose and improved cognitive outcomes for infants, but not between the iron index RET–He and neurodevelopmental outcomes. Iron deficiency remains common among NICU patients undergoing follow-up, suggesting that standard iron dosing may be inadequate for high-risk neonates.
Key Points
-
Higher daily iron dose improves cognitive outcomes.
-
Reticulocyte–hemoglobin level is not associated with neurodevelopmental outcomes.
-
Iron deficiency is common in very low birth weight infants, affecting 38.4%.
Data Availability Statement
These data are original and have not been previously published. Data are not available for sharing outside of the institution.
Contributors' Statement
W.N.H.: Conceptualization, data curation, formal analysis, investigation, methodology, project administration, writing—original draft, writing—review and editing. T.M.B.: Formal analysis, writing—original draft, writing—review and editing. B.O.: Conceptualization, methodology, writing—original draft, writing—review and editing. S.W.: Conceptualization, methodology, writing—original draft, writing—review and editing. R.K.O.: Conceptualization, methodology, writing—original draft, writing—review and editing. T.L.D.: Conceptualization, formal analysis, methodology, project administration, supervision, writing—original draft, writing—review and editing.
Publication History
Received: 12 June 2025
Accepted: 04 February 2026
Article published online:
20 February 2026
© 2026. Thieme. All rights reserved.
Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA
-
References
- 1 Karagülle M, Gündüz E, Şahin Mutlu F, Olga Akay M. Clinical significance of reticulocyte hemoglobin content in the diagnosis of iron deficiency anemia. Turk J Haematol 2013; 30 (02) 153-156
- 2 Georgieff MK. Long-term brain and behavioral consequences of early iron deficiency. Nutr Rev 2011; 69 (suppl 1, suppl 1): S43-S48
- 3 Lorenz L, Arand J, Büchner K. et al. Reticulocyte haemoglobin content as a marker of iron deficiency. Arch Dis Child Fetal Neonatal Ed 2015; 100 (03) F198-F202
- 4 Parodi E, Giraudo MT, Davitto M. et al. Reticulocyte parameters: markers of early response to oral treatment in children with severe iron-deficiency anemia. J Pediatr Hematol Oncol 2012; 34 (06) e249-e252
- 5 Ennis KM, Dahl LV, Rao RB, Georgieff MK. Reticulocyte hemoglobin content as an early predictive biomarker of brain iron deficiency. Pediatr Res 2018; 84 (05) 765-769
- 6 Wang Y, Wu Y, Li T, Wang X, Zhu C. Iron metabolism and brain development in premature infants. Front Physiol 2019; 10: 463
- 7 Chmielewska A, Dziechciarz P, Gieruszczak-Białek D. et al. Effects of prenatal and/or postnatal supplementation with iron, PUFA or folic acid on neurodevelopment: update. Br J Nutr 2019; 122 (s1): S10-S15
- 8 Luciano R, Romeo DM, Mancini G. et al. Neurological development and iron supplementation in healthy late-preterm neonates: a randomized double-blind controlled trial. Eur J Pediatr 2022; 181 (01) 295-302
- 9 Agostoni C, Buonocore G, Carnielli VP. et al; ESPGHAN Committee on Nutrition. Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr 2010; 50 (01) 85-91
- 10 German KR, Vu PT, Comstock BA. et al. Enteral iron supplementation in extremely preterm infants and its positive correlation with neurodevelopment; post hoc analysis of the PENUT randomized controlled trial. J Pediatr 2021; 238: 102-109.e8
- 11 German KR, Vu PT, Neches S, Juul SE. Comparison of two markers of iron sufficiency and neurodevelopmental outcomes. Early Hum Dev 2021; 158: 105395
- 12 Brugnara C, Zurakowski D, DiCanzio J, Boyd T, Platt O. Reticulocyte hemoglobin content to diagnose iron deficiency in children. JAMA 1999; 281 (23) 2225-2230
- 13 Auerbach M, Brugnara C, Staffa S. Measuring reticulocyte hemoglobin content as a marker for iron deficiency and response to therapy represents a paradigm shift in care. Blood 2020; 136 (Suppl. 01) 42-43
- 14 Ohls RK, Christensen RD, Kamath-Rayne BD. et al. A randomized, masked, placebo-controlled study of darbepoetin alfa in preterm infants. Pediatrics 2013; 132 (01) e119-e127
- 15 Kling PJ. Iron nutrition, erythrocytes, and erythropoietin in the NICU: erythropoietic and neuroprotective effects. Neoreviews 2020; 21 (02) e80-e88
- 16 Evaluating iron status and the risk of anemia in young infants using erythrocyte parameters. Pediatric Research [Internet]. Accessed February 17, 2023 at: https://www.nature.com/articles/pr2012162
- 17 Christensen RD, Henry E, Bennett ST, Yaish HM. Reference intervals for reticulocyte parameters of infants during their first 90 days after birth. J Perinatol 2016; 36 (01) 61-66
- 18 Al-Ghananim RT, Nalbant D, Schmidt RL, Cress GA, Zimmerman MB, Widness JA. Reticulocyte hemoglobin content during the first month of life in critically ill very low birth weight neonates differs from term infants, children, and adults. J Clin Lab Anal 2016; 30 (04) 326-334
- 19 Long H, Yi JM, Hu PL. et al. Benefits of iron supplementation for low birth weight infants: a systematic review. BMC Pediatr 2012; 12: 99
- 20 Steinmacher J, Pohlandt F, Bode H, Sander S, Kron M, Franz AR. Randomized trial of early versus late enteral iron supplementation in infants with a birth weight of less than 1301 grams: neurocognitive development at 5.3 years' corrected age. Pediatrics 2007; 120 (03) 538-546
- 21 Brugnara C, Laufer MR, Friedman AJ, Bridges K, Platt O. Reticulocyte hemoglobin content (CHr): early indicator of iron deficiency and response to therapy. Blood 1994; 83 (10) 3100-3101
- 22 Bahr TM, Tan S, Smith E, Baserga MC, Christensen RD, Ohls RK. Serum ferritin values do not correlate with reticulocyte hemoglobin content (RET-He) in extremely low gestational age neonates. J Perinatol 2023; 43: 1368-1373
- 23 Juul S, German K. Iron supplementation for infants in the NICU: what preparation, how much, and how long is optimal?. Semin Fetal Neonatal Med 2025; 30 (01) 101612
- 24 Armstrong C. AAP reports on diagnosis and prevention of iron deficiency anemia. Pediatrics 2010
- 25 Zamora TG, Guiang III SF, Widness JA, Georgieff MK. Iron is prioritized to red blood cells over the brain in phlebotomized anemic newborn lambs. Pediatr Res 2016; 79 (06) 922-928
