Iron Status in Infants with HDFN

Fast Facts

Iron is contraindicated for infants with HDFN unless a ferritin test shows a true deficiency.

Normal Lab Values: 25-200 ng/mL for newborns. 50-200 ng/mL for 1-5 months of age.

One of the common misconceptions is that babies with HDFN need iron supplements to fix their anemia. This is false. Iron supplements will not help infants with Hemolytic Disease of the Fetus and Newborn (HDFN), and can actually be dangerous in some instances. Regardless of the specific antibody (anti-D, anti-K, anti-c, anti-E, etc), the infant can still be at risk. Medical literature has shown that infants with HDFN do not have iron deficiency anemia, but hemolytic anemia. When the red blood cells are destroyed by the antibodies, the iron in the baby's blood is stored in the body and recycled, leading to a build up of iron and iron overload for the majority of babies with HDFN. "Iron therapy is contraindicated in most cases of hemolytic anemia. The reason is that iron released from RBCs in most hemolytic anemias is reused and iron stores are not reduced 1." Infants with hemolytic anemia have normal iron stores, or high iron stores if they have had an intrauterine transfusion (IUT). One study found that 70% of babies with HDFN had iron overload at birth and none were iron deficient at birth. At 1 month of age, 50% of the infants still had iron overload, and 18% continued to have iron overload at 3 months 2. It is not just babies who have received IUTs who are at risk. "In addition to transfusions for alloimmune HDFN, the haemolysis itself can also contribute to iron overload in alloimmune HDFN 2". Multiple articles say that babies with HDFN are at risk for iron overload and should not be supplemented without a ferritin test first. "Therefore, we advise to measure iron status, and we discourage the use of iron supplementation in the first 3 months of life in neonates with alloimmune HDFN 2". Some authors suggest that all babies who have received IUTs be evaluated for high ferritin levels 3. If the ferritin does come back highly elevated, chelation therapy may be used to reduce the amount of iron in the blood and to reduce or reverse liver damage 4, 5. Inappropriate administration of iron in infants with HDFN can result in iron overload 9 and adverse events such as cholestasis 16, portal hypertension, coagulopathy abnormal liver enzymes, free-radical damage 17, liver damage, or death.

For additional articles, see our additional reading by topic page.

Treatments for Anemia

“Top-up” Transfusions

Elevated levels of circulating maternal antibodies in the neonatal circulation in conjunction with suppression of the fetal bone marrow production of red cells often results in the need for neonatal red cell “top-up” transfusions after discharge from the nursery. This results in a 1- to 3-month period in which up to 75% of these infants may need “top-up” red cell transfusions6. Weekly reticulocyte counts and hematocrit levels should be assessed until a rising reticulocyte count is noted for at least 2 consecutive weeks. The threshold-for-transfusion includes a hematocrit value of less than 30% in the symptomatic infant or less than 20% in the asymptomatic infant have been suggested by some experts. Typically, only one neonatal transfusion is required, although a maximum of up to three has been reported.


Erythropoietin has been in use since the 1990s as an adjunct treatment for late anemia and to increase a reduced reticulocyte count. In limited single-arm studies and case reports, erythropoietin has been shown to be safe 7, 8 and may reduce the need for transfusion in neonates with HDFN 9, 10, 11, 12, 13. In one 6-week study of 20 infants with HDFN due to anti-D, the “number of erythrocyte transfusions was significantly lower than that of the control group (1.8 versus 4.2). The reticulocyte counts and Hb levels rose earlier in the treatment group" 14. This may also be a treatment option for children whose parents object to the use of blood products for religious reasons 15. For additional articles relating to erythropoietin, see our additional reading by topic page.

Folic Acid

Active hemolysis consumes folate; folate is a key ingredient in erythropoiesis. As a result, folic acid is frequently prescribed for infants with HDFN in order to encourage the creation of new RBCs. Various approaches supplement folic acid at a dosage between 50 µg/day and 300µg/day for 3 months 16.


  1. 1. Schick, Paul. Hemolytic Anemia Treatment & Management. Medscape
  2. 2. Rath ME, Smits-Wintjens VE, Oepkes D, Walther FJ, Lopriore E. Iron status in infants with alloimmune haemolytic disease in the first three months of life. Vox Sang. 2013;105(4):328–333. doi:10.1111/vox.12061
  3. 3. Yilmaz S, Duman N, Ozer E, et al. A case of rhesus hemolytic disease with hemophagocytosis and severe iron overload due to multiple transfusions. J Pediatr Hematol Oncol.
  4. 4. Yalaz M, Bilgin BS, Köroğlu OA, et al. Desferrioxamine treatment of iron overload secondary to RH isoimmunization and intrauterine transfusion in a newborn infant. Eur J Pediatr. 2011;170(11):1457–1460. doi:10.1007/s00431-011-1521-7
  5. 5. Khdair-Ahmad F, Aladily T, Khdair-Ahmad O, Badran EF. Chelation therapy for secondary neonatal iron over load: Lessons learned from rhesus hemolytic disease. Turk J Pediatr. 2018;60(3):335–339. doi:10.24953/turkjped.2018.03.018
  6. 6.Saade GR, Moise KJ, Belfort MA, Hesketh DE, Carpenter RJ. Fetal and neonatal hematologic parameters in red cell alloimmunization: predicting the need for late neonatal transfusions. Fetal Diagn Ther. 1993;8:161-4.
  7. 7. Donato H, Bacciedoni V, García C, Schvartzman G, Vain N. Tratamiento de la anemia hiporregenerativa tardía de la enfermedad hemolítica del recién nacido con eritropoyetina recombinante [Recombinant erythropoietin as treatment for hyporegenerative anemia following hemolytic disease of the newborn]. Arch Argent Pediatr. 2009;107(2):119–125. doi:10.1590/S0325-00752009000200005
  8. 8. Alvarez Domínguez E, Pérez Fernández JM, Figueras Aloy J, Carbonell Estrany X. Tratamiento con eritropoyetina para la anemia tardía tras enfermedad hemolítica del recién nacido [Erythropoietin treatment for late anaemia after haemolytic disease of the newborn]. An Pediatr (Barc). 2010;73(6):334–339. doi:10.1016/j.anpedi.2010.09.002
  9. 9. Rath ME, Smits-Wintjens VE, Walther FJ, Lopriore E. Hematological morbidity and management in neonates with hemolytic disease due to red cell alloimmunization. Early Hum Dev. 2011;87(9):583–588. doi:10.1016/j.earlhumdev.2011.07.010
  10. 10. Manoura A, Korakaki E, Hatzidaki E, et al. Use of recombinant erythropoietin for the management of severe hemolytic disease of the newborn of a K0 phenotype mother. Pediatr Hematol Oncol. 2007;24(1):69–73. doi:10.1080/08880010601001453
  11. 11. Zuppa AA, Cardiello V, Alighieri G, et al. Anti-Rh(c), "little c," isoimmunization: the role of rHuEpo in preventing late anemia. J Pediatr Hematol Oncol. 2013;35(6):e269–e271. doi:10.1097/MPH.0b013e318271f5b0
  12. 12. Alaqeel AA. Hyporegenerative anemia and other complications of rhesus hemolytic disease: to treat or not to treat is the question. Pan Afr Med J. 2019;32:120. Published 2019 Mar 14. doi:10.11604/pamj.2019.32.120.17757
  13. 13. Dhodapkar KM, Blei F. Treatment of hemolytic disease of the newborn caused by anti-Kell antibody with recombinant erythropoietin. J Pediatr Hematol Oncol. 2001;23(1):69–70. doi:10.1097/00043426-200101000-00018
  14. 14. Ovali F, Samanci N, Dağoğlu T. Management of late anemia in Rhesus hemolytic disease: use of recombinant human erythropoietin (a pilot study). Pediatr Res. 1996;39(5):831–834. doi:10.1203/00006450-199605000-00015
  15. 15. Lakatos L, Csáthy L, Nemes E. "Bloodless" treatment of a Jehovah's Witness infant with ABO hemolytic disease. J Perinatol. 1999;19(7):530–532. doi:10.1038/
  16. 16. Ree IMC, Smits-Wintjens VEHJ, van der Bom JG, van Klink JMM, Oepkes D, Lopriore E. Neonatal management and outcome in alloimmune hemolytic disease. Expert Rev Hematol. 2017;10(7):607–616. doi:10.1080/17474086.2017.1331124
  17. 17. Berger HM, Lindeman JH, van Zoeren-Grobben D, Houdkamp E, Schrijver J, Kanhai HH. Iron overload, free radical damage, and rhesus haemolytic disease. Lancet. 1990;335(8695):933–936. doi:10.1016/0140-6736(90)90997-j