Hemolytic Disease of the Fetus and Newborn (HDFN)

Hemolytic disease of the fetus and newborn (HDFN), an immune-mediated blood disorder affecting fetuses and neonates, develops when the blood group types of mother and baby are incompatible. The most frequent types of incompatibility are due to ABO and rhesus (Rh) factor red cell antigens.¹ HDFN is primarily characterized by 2 hallmark signs: anemia and hyperbilirubinemia.²

Diagnosis of HDFN

The diagnosis and management of HDFN are based on the results of maternal and fetal laboratory testing and fetal radiographic monitoring.³ If maternal red cell antibodies are detected through indirect antibody testing and/or the newborn has a positive direct antibody test (DAT) result, a diagnosis of HDFN can be confirmed.²

A comprehensive obstetric and medical history of the expectant mother is also required to identify past events that may have predisposed the mother to fetomaternal hemorrhage, putting the pregnancy at risk for HDFN.²

Read more about HDFN risk factors

Maternal Testing

All pregnant women should undergo blood type screening, including ABO and Rh factor testing.³

Risk stratification can be based on red blood cell antibody titers, or strength, but these assays are relatively subjective. Antibody titers commonly considered as indicating risk for significant fetal anemia range between 1:16 and 1:32.³ However, when antibody titers are used to assess risk for HDFN, the surface red cell antigen in question must be considered. For example, because Kell blood group antigens are present on early red cell precursors, even a relatively low maternal anti-K titer, such as 1:8, may be associated with severe hypoproliferative anemia.³

Read more about HDFN testing

Fetal Testing

Direct fetal genotyping can be used to assess fetal blood group antigen expression and predict risk for HDFN when the mother is sensitized. Invasive procedures, such as chorionic villus sampling and amniocentesis, or a noninvasive methodology like cell free fetal (cff) DNA testing in samples of maternal blood are used for prenatal testing.³

After 16 to 24 weeks, fetal anemia is monitored with middle cerebral artery (MCA) Doppler velocity measurements every 2 weeks for risk stratification. Fetal MCA Doppler measurements that exceed 1.5 multiples of the mean suggest moderate-to-severe fetal anemia due to HDFN, which is confirmed via invasive cordocentesis to assess the fetal hematocrit. Intrauterine transfusion is recommended when the fetal hematocrit is below 30%.³ 

Read more about HDFN prognosis

Paternal Testing

The father (in cases of assured paternity) can undergo testing for blood group and phenotype to predict the likelihood of fetal inheritance of the relevant paternal red cell antigens.⁴ A fetus has a 50% chance of antigen inheritance when testing identifies paternal heterozygosity for the relevant antigen.³

Read more about HDFN genetics 

Differential Diagnosis of HDFN

HDFN must be considered in neonates with early, severe, or prolonged postnatal jaundice. Fetal or neonatal anemia in HDFN results from hemolysis. Hemolytic anemia is characterized by bone marrow reactivity, indicated by reticulocytosis and the production of immature erythrocytes and erythroblasts that circulate in the peripheral blood.² 

Defects in Erythrocyte Membrane Proteins or Erythrocyte Enzyme Metabolism

The differential diagnosis must include conditions that cause non-immune-mediated hemolysis and congenital hemolytic anemias resulting from defects in either erythrocyte membrane proteins or erythrocyte enzyme metabolism.^2,5 Disorders that cause erythrocyte membrane defects include hereditary spherocytosis, hereditary elliptocytosis, and hereditary stomatocytosis (a group of conditions).^2,5 The conditions most commonly associated with erythrocyte enzyme defects that lead to hemolytic anemia include glucose-6-phosphate dehydrogenase (G6PD) deficiency and pyruvate kinase deficiency.^2,5 Pyruvate kinase deficiency is the most common autosomal recessive, metabolic, enzyme-related glycolytic disorder that leads to hemolytic anemia. The condition is inherited in an autosomal-recessive pattern.⁶

Defective Enzymes

Ultra-rare conditions that may also lead to hemolytic anemia involve defects in the following enzymes⁵:

• Glucose phosphate isomerase
• Phosphofructokinase
• Adenylate kinase
• Triosephosphate isomerase
• Phosphoglycerate kinase
• Hexokinase
• Pyrimidine 5′-nucleotidase

Congenital Dyserythropoietic Anemia

Providers should consider congenital dyserythropoietic anemia (CDA) on the list of differential diagnoses. CDA is an inherited blood disorder of erythrocyte development that manifests as moderate-to-severe anemia and sometimes develops before birth.^5,7

Read more about HDFN signs and symptoms

Various Hemoglobinopathies

Hemoglobinopathies including alpha thalassemias and beta globin variants that contribute to disorders such as sickle cell anemia (HbSS) and various subtypes of sickle cell disease (HbSE, HbSC, HbS/β-thalassemia) must be ruled out with newborn screening, peripheral blood smear analysis, confirmatory hemoglobin electrophoresis, and in some cases, maternal and paternal hemoglobin electrophoresis.^2,8

Gilbert Syndrome

Gilbert syndrome is an autosomal-recessive disorder of bilirubin metabolism within the liver, in which decreased glucuronidation of unconjugated bilirubin leads to unconjugated hyperbilirubinemia and recurrent episodes of jaundice.^1,2,9

Read more about HDFN clinical features

Congenital Infections

Fetal or neonatal infections passed from mother to fetus during gestation may cause signs and symptoms similar to those of HDFN, such as fetal anemia, fetal death, congenital anomalies, and organ diseases.^10,11 Congenital infections that affect the nervous system of fetuses and neonates include^10,11:

• Parvovirus B19 infection, which can result in severe fetal anemia and hydrops fetalis
• Cytomegalovirus infection, which may cause spontaneous abortion, prematurity,  intrauterine growth restriction, or stillbirth during pregnancy and petechiae, jaundice, hepatosplenomegaly, microcephaly, sensorineural hearing loss, chorioretinitis, optic atrophy, or other neurologic impairments in surviving neonates
• Syphilis, which can manifest as hydrops fetalis, hepatomegaly, ascites, placental thickening, and elevated MCA Doppler velocity measurements
• Toxoplasmosis (infection with the parasite Toxoplasma gondii), which can manifest as neonatal fever, hepatosplenomegaly, jaundice, anemia, lymphadenopathy, and spinal fluid abnormalities¹⁰ as well as chorioretinitis, intracranial calcifications, hydrocephalus or microcephaly, nystagmus, severe intrauterine growth restriction, and prematurity

Other Conditions

Other conditions that cause neonatal jaundice and hyperbilirubinemia that should be included in the differential diagnosis of HDFN include¹:

• Physiologic jaundice
• Prematurity 
• Breast milk and breastfeeding jaundice
• Sepsis
• Birth trauma
• Hypothyroidism 

References

1. Hall V, Avulakunta ID. Hemolytic diseases of the newborn. StatPearls [Internet}. Updated November 22, 2022. Accessed September 2, 2023. 
2. Ross MB, de Alarcón P. Hemolytic disease of the fetus and newborn. NeoReviews. 2013;14(2):e83-e88. doi:10.1542/neo.14-2-e83
3. Delaney M, Matthews DC. Hemolytic disease of the fetus and newborn: managing the mother, fetus, and newborn. Hematology. 2015;2015(1):146-151. doi:10.1182/asheducation-2015.1.146
4. Basu S, Kaur R, Kaur G. Hemolytic disease of the fetus and newborn: current trends and perspectives . Asian J Transfus Sci. 2011;5(1):3-7. doi:10.4103/0973-6247.75963
5. Fattizzo B, Giannotta JA, Cecchi N, Barcellini W. Confounding factors in the diagnosis and clinical course of rare congenital hemolytic anemias. Orphanet J Rare Dis. 2021;16:415. doi:10.1186/s13023-021-02036-4
6. Enegela OA, Anjum F. Pyruvate kinase deficiency. StatPearls [Internet]. Updated April 27, 2023. Accessed September 2, 2023. 
7. Congenital dyserythropoietic anemia. MedlinePlus. Accessed September 2, 2023.
8. Hemoglobinopathies: current practices for screening, confirmation and follow-up. Centers for Disease Control and Prevention. December 2015. Accessed September 2, 2023.
9. Thoguluva Chandrasekar V, Faust TW, John S. Gilbert syndrome. StatPearls [Internet]. Updated February 6, 2023. Accessed September 2, 2023. 
10. Curcio AM, Shekhawat P, Reynolds AS, Thakur KT. Neurologic infections during pregnancy. Handb Clin Neurol. 2020;172:79-104. doi:10.1016/B978-0-444-64240-0.00005-2
11. Auriti C, Bucci S, De Rose DU, et al. Maternal–fetal infections (cytomegalovirus, Toxoplasma, syphilis): short-term and long-term neurodevelopmental outcomes in children infected and uninfected at birth. Pathogens. 2022;11(11):1278. doi:10.3390/pathogens11111278

Reviewed by Kyle Habet, MD, on 9/7/2023.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.