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HDFN & Anemia After Birth

Fast Facts

Anemia: An inadequate amount of red blood cells.

Normal Lab Values: Hemoglobin at 0-6 months of age 12.7-18.3 g/dL (females) and 15.7-18.6 g/dL (males). Hematocrit at 0-6 months of age 37.4-55.9% (females) and 43.4-56.1% (males).

Anemia is an inadequate amount of red blood cells. Anemia is commonly evaluated by checking the child’s hemoglobin or hematocrit levels. If the hemoglobin or hematocrit level is low, the child is considered to be anemic.

Maternal alloantibodies which have crossed into the fetal circulation remain and can attach to the infant’s red blood cells for up to 12 weeks after birth. For this reason, follow-up in newborns whose cord blood confirms the presence of maternal antibodies is essential until the hemoglobin is increasing without a blood transfusion for at least two consecutive weeks, even in the absence of visible indications of anemia. Improperly monitored and untreated anemia can lead to heart failure and death in infants who are several weeks old.

There are 3 kinds of anemia that an infant with HDFN can have:

  • Early onset anemia: Anemia that is present within the first 2 weeks of birth.
  • Delayed onset anemia: Anemia that occurs at 2-12 weeks of age.
  • Hyporegenerative anemia: Anemia that occurs when the bone marrow is suppressed (due to specific antibodies like anti-K and anti-M, or due to blood transfusions).

A common misconception is that if a woman has low titers, or if her baby is not anemic at birth, then her baby will not develop anemia later. This is false. Sadly there are victims of HDFN who are lost around 3 or 4 weeks of age due to delayed onset anemia that was not properly monitored for – monitoring must continue after hospital discharge. Delayed onset anemia is the kind that occurs most often in infants with HDFN and can be monitored by hemoglobin checks every 1-2 weeks. In the first 2-6 weeks of life, many infants have a natural drop in hemoglobin levels. This drop, combined with the effects of the antibodies, leads to many babies needing their first transfusion when they are between 2 and 6 weeks old.

Before discharge a follow up appointment should be scheduled with a pediatric hematologist or other provider. The discharging physician should alert the family pediatrician or pediatric hematologist of the follow up care plan. Pediatricians and parents should be aware that affected infants may develop significant anemia until 12 weeks of life, especially if they received IUTs during pregnancy. Parents should be educated on the physical signs of anemia and when to return to the hospital if the infant deteriorates between appointments.

Early onset anemia

Early onset anemia is anemia that is present at birth or before week 2. This anemia, caused by antibody mediated hemolysis, may be detected during a cord blood sample, or as part of other follow up testing. Infants who are in the NICU may struggle with feeding, failure to thrive, or cardiovascular complications. For these infants it is often not a matter of if they will need a transfusion, but when. Correcting the anemia early (at higher hemoglobin levels) may reduce stress on the infant’s body, reduce prematurity issues, and help improve latch for oral feeds. Infants with early onset anemia will have an elevated bilirubin, and a normal or elevated reticulocyte count 1. It is important to note that while early onset anemia occurs within the first 2 weeks of life, it does not resolve within the first two weeks of life. Early onset anemia can become hyporegenerative anemia and all infants with early onset anemia must be monitored weekly until the hemoglobin is increasing without intervention for 2-3 weeks in a row.

Delayed Onset Anemia

Delayed onset anemia is anemia that presents between 2-12 weeks of life. This anemia is still caused by antibody mediated hemolysis and may be worsened by a natural decline of hemoglobin levels. It is not uncommon for infants to need their first transfusion at 2-4 weeks of age. Infants with delayed onset anemia may have a normal or elevated bilirubin count, along with a normal or high reticulocyte count 1. Delayed onset anemia can happen to all infants with HDFN regardless of which antibody the mother has, even if the fetus was not treated with IUTs. Treatment options for infants with delayed onset anemia include folic acid, blood transfusion, and erythropoietin 2, 3.

Hyporegenerative Anemia

Hyporegenerative anemia is a unique form of anemia due to HDFN that happens due to a combination of factors. Antibody mediated hemolysis is still in play, however bone marrow suppression either by IUTs and transfusions, or by specific antibody action is a major factor. Antibodies such as anti-Kell and anti-M are known to cause bone marrow suppression making it harder for the infant to regenerate blood cells destroyed by maternal antibodies. These infants usually have a normal bilirubin level along with a low reticulocyte count, and may also have erythropoietin deficiency 4.

Tests for Anemia

Tests for anemia include a hemoglobin or hematocrit count, and a reticulocyte count (retic).
Hemoglobin is a protein in red blood cells that carries oxygen. A blood test can tell how much hemoglobin you have in your blood and is used as an indicator of anemia (common in the USA). The normal pediatric hemoglobin range for infants age 0-6 months is 12.7 – 18.3 g/dL for females and 14.7 – 18.6 g/dL for males.
Hematocrit is a blood test that measures the percentage of the volume of whole blood that is made up of red blood cells and is used as an indicator of anemia. The normal hematocrit range for infants 0-6 months is 37.4 – 55.9% for females, and 43.4 – 56.1% for males.
The retic is a measure of how many immature blood cells are in the blood stream. These are future RBCs and can give an idea of how quickly a baby is making new blood to replace what the antibodies are destroying. A reticulocyte count can be used to decide if a top up transfusion is needed or if another hemoglobin check in a couple days will suffice. If the retic shows little to no production of new blood cells, it can be boosted with medication (erythropoietin).
You can read more about testing on our Infant testing 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 transfusions 5. 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 onset anemia and hyporegenerative anemia to increase a reduced reticulocyte count. In limited single-arm studies and case reports, erythropoietin has been shown to be safe 2, 6 and may reduce the need for transfusion in neonates with HDFN 7, 8, 9, 10, 11. 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” 3. This may also be a treatment option for children whose parents object to the use of blood products for religious reasons 12. 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 13.

Treatments for anemia range from folic acid (to replenish the folate that is used up when producing new red blood cells), to erythropoietin (to boost the reticulocyte count), to blood transfusions.


Iron is not considered an acceptable treatment for hemolytic anemia – most infants with HDFN have iron overload. See Iron Status in Infants with HDFN for more information.


  1. 1. Delaney M, Matthews DC. Hemolytic disease of the fetus and newborn: managing the mother, fetus, and newborn. Hematology Am Soc Hematol Educ Program. 2015;2015:146–151. doi:10.1182/asheducation-2015.1.146
  2. 2. 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
  3. 3. 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
  4. 4. Zwiers C, van Kamp I, Oepkes D, & Lopriore E. Intrauterine transfusion and non-invasive treatment options for hemolytic disease of the fetus and newborn – review on current management and outcome, Expert Review of Hematology. 10:4,337-344, DOI: 10.1080/17474086.2017.1305265
  5. 5.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.
  6. 6. 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
  7. 7. 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
  8. 8. 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
  9. 9. 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
  10. 10. 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
  11. 11. 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
  12. 12. 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/sj.jp.7200223
  13. 13. 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
  14. 14. 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


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