Hemolytic Disease of the Fetus and Newborn (HDFN)


Hemolytic disease of the fetus and newborn (HDFN) is a rare, immune-mediated blood disorder that affects babies both prenatally and postnatally. In this condition, a mother’s immune system produces antibodies that attack and destroy red blood cells of the fetus or newborn that are incompatible or of a different ABO blood group type or Rhesus (Rh) factor.1 

Incidence and Prevalence of HDFN

Prior to the advent of Rh(D) immunoglobulin (Ig) immunoprophylaxis in 1968, the global incidence of HDFN was estimated at around 1% of all pregnancies, with a 50% mortality rate.1-3 The administration of immunoprophylaxis in Rh(D)-negative mothers at the birth of their Rh(D)-positive babies dropped this global incidence to 0.5% in industrialized countries.1-3 The implementation of routine maternal screening, fetal monitoring, and the administration of antenatal Rh(D) Ig immunoprophylaxis by week 28 further reduced the global incidence of HDFN to 0.1% of all pregnancies in industrialized countries.1-3

Read more about HDFN diagnosis

Rh(D) immunoprophylaxis may not be widely available in developing nations that cannot support the required infrastructure for routine maternal screening, laboratory testing, fetal monitoring, and administration of preventive therapies to reduce HDFN. Timely detection and treatment of maternal alloimmunization is critical in order to lower the occurrence of hyperbilirubinemia and completely eradicate kernicterus among affected neonates. It can lead to long-term good prognosis. However, an estimated 1 to 3 of every 1000 Rh(D)-negative women still develop alloimmunization despite the availability of Rh(D) immunoprophylaxis.1,2,4

A systematic review of the medical literature published in 2023 indicated that the global prevalence of Rh(D)-mediated HDFN affected around 0.047% of all pregnancies, and the global prevalence of K-mediated HDFN affected around 0.006% of all pregnancies.5

Other studies indicate that HDFN affects between 1 in 300 and 1 in 600 live births, with up to 1 in 80 pregnant women exhibiting clinically relevant red blood cell alloantibodies.6-10

Antepartum fetomaternal hemorrhage events account for 1% to 2% of all Rh alloimmunization, with sufficient amounts of fetal blood (~0.1 mL) entering the maternal circulation in 15% to 50% of gestations.1 

Read more about HDFN prognosis

Geographical Factors of HDFN

In the United States between 1996 and 2010, HDFN affected 9810 of 480,245 live births, corresponding to 1695 per 100,000 live births, weighted to the US population. ABO incompatibility contributed to 78.1% of newborns with HDFN, and Rh alloimmunization accounted for 4.3% of newborns with HDFN.11

Race/Ethnicity Factors of HDFN

In the United States, neonates born with HDFN between 1996 and 2010 were more likely to be female, live in the South (compared to the Midwest or West), be African American, and receive treatment at larger or government-run hospitals.11 These findings may indicate the impact of health care disparities on HDFN incidence.

Rh incompatibility varies according to race and ethnicity. Individuals with European ancestry (15%) tend to have Rh(D)-negative blood types more often than individuals with African (5% to 8%), Indian (5%), Asian (1% to 2%), or Native American (1% to 2%) ancestry. Women of European ancestry who are Rh-negative have an 85% chance of having children with men who are Rh-positive.1,6 HDFN occurs with the highest prevalence (30% to 35%) among individuals with Basque ancestry,3 due to the high frequency of the Rh(D)-negative allele in this ethnic group.12

Read more about HDFN etiology

Age Factors of HDFN

Maternal age may play a factor in HDFN incidence because HDFN risk and disease severity increase with subsequent antigen-positive pregnancies due to repeated alloimmunization. In general, older women likely have increased exposure and potential for alloimmunization due to a greater number of pregnancies in their obstetrical history over their lifespan.13 

Read more about HDFN risk factors

Sex Factors of HDFN

Researchers reported that HDFN occurred more frequently in female babies than in male babies between 1996 and 2010 in the United States.11 Ultimately, however, HDFN depends on blood type compatibility between the mother and baby, so it can affect both male and female babies whose blood types differ from the mother without a predisposition for either biological sex.

References

  1. Hall V, Avulakunta ID. Hemolytic diseases of the newborn. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2023. Updated November 22, 2022. Accessed August 23, 2023.
  2. 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
  3. Myle AK, Al-Khattabi GH. Hemolytic disease of the newborn: a review of current trends and prospects. Pediatric Health Med Ther. 2021;12:491-498. doi:10.2147/PHMT.S327032
  4. Koelewijn JM, de Haas M, Vrijkotte TGM, Bonsel GJ, van der Schoot CE. One single dose of 200 μg of antenatal RhIG halves the risk of anti-D immunization and hemolytic disease of the fetus and newborn in the next pregnancy. Transfusion. 2008;48(8):1721-1729. doi:10.1111/j.1537-2995.2008.01742.x
  5. de Winter DP, Kaminski A, Tjoa ML, Oepkes D. Hemolytic disease of the fetus and newborn: systematic literature review of the antenatal landscape. BMC Pregnancy Childbirth. 2023;23(1):12. doi:10.1186/s12884-022-05329-z
  6. Castleman JS, Moise KJ Jr, Kilby MD. Medical therapy to attenuate fetal anaemia in severe maternal red cell alloimmunisation. Br J Haematol. 2021;192(3):425-432. doi:10.1111/bjh.17041
  7. Smith HM, Shirey RS, Thoman SK, Jackson JB. Prevalence of clinically significant red blood cell alloantibodies in pregnant women at a large tertiary-care facility. Immunohematology. 2013;29(4):127-130. doi:10.21307/immunohematology-2019-134
  8. Geifman-Holtzman O, Wojtowycz M, Kosmas E, Artal R. Female alloimmunization with antibodies known to cause hemolytic disease. Obstet Gynecol. 1997;89(2):272-275. doi:10.1016/S0029-7844(96)00434-6
  9. Markham KB, Rossi KQ, Nagaraja HN, O’Shaughnessy RW. Hemolytic disease of the fetus and newborn due to multiple maternal antibodies. Am J Obstet Gynecol. 2015;213(1):68.e1-68.e5. doi:10.1016/j.ajog.2015.01.049
  10. Koelewijn JM, Vrijkotte TGM, van der Schoot CE, Bonsel GJ, de Haas M. Effect of screening for red cell antibodies, other than anti-D, to detect hemolytic disease of the fetus and newborn: a population study in the Netherlands. Transfusion. 2008;48(5):941-952. doi:10.1111/j.1537-2995.2007.01625.x
  11. Yu D, Ling LE, Krumme AA, Tjoa ML, Moise KJ Jr. Live birth prevalence of hemolytic disease of the fetus and newborn in the United States from 1996 to 2010. AJOG Glob Rep. 2023;3(2):100203. doi:10.1016/j.xagr.2023.100203
  12. Flores-Bello A, Mas-Ponte D, Rosu ME, Bosch E, Calafell F, Comas D. Sequence diversity of the Rh blood group system in Basques. Eur J Hum Genet. 2018;26(12):1859-1866. doi: 10.1038/s41431-018-0232-1
  13. Lobato G, Soncini CS. Relationship between obstetric history and Rh(D) alloimmunization severity. Arch Gynecol Obstet. 2008;277(3):245-248. doi:10.1007/s00404-007-0446-x

Reviewed by Debjyoti Talukdar, MD, on 8/28/2023.

READ MORE ON HDFN