Erythroblastosis Fetalis: When Immunity Turns Against the Fetus

June 4, 2025

Erythroblastosis Fetalis, also known as hemolytic disease of the fetus and newborn (HDFN), is a largely preventable condition. It’s a serious and potentially life-threatening disease that occurs when there’s an “incompatibility” between the blood types of a mother and the fetus. In short, the mother’s body identifies the baby’s red blood cells (RBCs) as foreign and begins to destroy them.

Because of modern advances in prenatal care, and particularly, in Rh immunoprophylaxis, this condition has almost been eradicated in well-resourced healthcare settings. In other parts of the world, with poor access to antenatal screening and preventive treatment, erythroblastosis fetalis remains a threat to the health of newborns.

Pathophysiology of Erythroblastosis Fetalis

Most cases of erythroblastosis are because of Rh(D) and ABO incompatibilities, with the underlying mechanism being: immune-mediated hemolysis.

This hemolysis (breakdown of red blood cells) is due to incompatibility between maternal and fetal blood types. The problem begins when fetal RBCs carrying antigens inherited from the father enter the maternal bloodstream. This can happen during delivery, miscarriage, trauma, or invasive procedures like amniocentesis. Once this exposure occurs, the maternal immune system may recognize these antigens as foreign and produce antibodies against them.

Rh(D) Incompatibility:

The Rh factor refers to a group of proteins on the surface of RBCs, the most important of which is the D antigen. If it’s present, you’re Rh-positive. If not, you’re Rh-negative.

If an Rh-negative mother is carrying an Rh-positive fetus, her immune system may recognize the D antigen as foreign. The first exposure typically doesn’t cause harm. The maternal immune system makes IgM antibodies, which are large and don’t cross the placenta.
In later pregnancies, though, re-exposure causes a switch to IgG antibodies.¹ These cross the placenta, bind to fetal red blood cells, and mark them for destruction. This leads to hemolysis and progressively worsening anemia in the fetus.
To compensate, the fetal bone marrow speeds up RBC production, pushing out immature RBCs, erythroblasts, into the circulation. Hence the name: erythroblastosis fetalis.
If hemolysis is severe, the fetal heart struggles to keep up with the oxygen demands. This can lead to high-output heart failure, fluid buildup in the organs and tissues (hydrops fetalis), and intrauterine death.

Image describing sensitisation process of Rh-incompatibility, which can lead to Erythroblastosis Fetalis in later pregnancies — First exposure to Rh+ fetal blood sensitizes an Rh− mother, prompting anti-Rh antibody production. In future pregnancies, these antibodies can cross the placenta, attacking fetal RBCs and causing hemolysis. (Image Courtesy: Betts, J. G., Young, K. A., Wise, J. A., Johnson, E., Poe, B., Kruse, D. H., Korol, O., Johnson, J. E., Womble, M., & DeSaix, P. (2013). Anatomy and physiology (Section 18.6). Available from OpenStax. Licensed under CC by 4.0)

ABO Incompatibility:

ABO-related hemolytic disease works similarly but is usually milder. Mothers with type O blood naturally carry anti-A and anti-B antibodies that can sometimes cross the placenta and destroy fetal red cells with A or B blood. However, ABO antigens are less densely expressed on fetal red cells, making this form typically less severe than Rh-mediated HDFN.

Other Blood Group Antibodies:

And it’s not just Rh and ABO. Rare cases of HDFN can be triggered by antibodies to Kell, Duffy, or Kidd antigens. Some, like anti-Kell, are especially concerning because they inhibit red cell production at the bone marrow level, leading to more severe anemia.²

Comparison of hemolytic disease mechanisms caused by ABO, Rh, and other minor red blood cell antigens.

Prevalence of Erythroblastosis Fetalis

Erythroblastosis fetalis affects around 1–2% of pregnancies worldwide (translating to roughly 1,695 cases per 100,000 live births), but the numbers vary dramatically based on the type of incompatibility.³

ABO incompatibility is common, showing up in 15–25% of pregnancies, but most remain mild and fewer than 1% evolve into clinically significant disease.
Rh incompatibility, on the other hand, is rare overall, but the effects are often more severe.

The introduction of Rh immunoglobulin (RhoGAM) dramatically dropped Rh-induced HDFN from 99 to 44 cases per 100,000 live births in countries with routine screening, and mortality has been cut by nearly two-thirds.

But in regions with limited healthcare resources, across sub-Saharan Africa, South Asia, and parts of Latin America, Rh incompatibility remains a major concern. In Pakistan, for example, an estimated 270,000 Rh-incompatible pregnancies occur annually, still as many as 87% of affected women don’t receive prophylaxis.⁴ This is a reflection of real-world inequities: limited healthcare infrastructure, gaps in antenatal screening, and poor access to Rh immunoglobulin continue to put newborns at risk.

Causes & Risk Factors of Erythroblastosis Fetalis

The root cause of erythroblastosis fetalis is that the mother’s immune system becomes sensitized to fetal red blood cell antigens and begins producing antibodies that target the fetus’s red cells for destruction. This can occur due to several risk factors:

Rh-negative mother carrying an Rh-positive fetus (the most common cause of severe HDFN)
Previous sensitizing events, including:
- Birth of a Rh-positive infant
- Miscarriage or abortion
- Invasive prenatal procedures (amniocentesis or chorionic villus sampling)
- Abdominal trauma during pregnancy
Ethnicity: Rh-negative status is more common in Caucasians (15–16%) than Asians (<1%)⁵
Inadequate or missed administration of anti-D immunoglobulin after a sensitizing event
Multiparity, especially without Rh prophylaxis

Clinical Presentation of Erythroblastosis Fetalis

The signs and symptoms of Erythroblastosis fetalis depend on how early it’s detected and how severe the RBC breakdown is.

Before Birth (Prenatal Signs):

In the womb, the degree of hemolysis determines the severity of clinical signs:

Mild cases may be asymptomatic or result in mild anemia.
Moderate to severe cases lead to:
- Fetal anemia
- Hepatosplenomegaly from extramedullary hematopoiesis
- Ascites, pleural effusion, and subcutaneous edema (signs of hydrops fetalis)⁶
- Cardiac failure due to high-output physiology

Image of a newborn immediately after delivery showing abdominal distension because of ascites, and then a reduction in ascites becuase of drainage — Abdominal distension due to ascites a. Immediately after birth b. After drainage of ascites in the delivery room (Image courtesy: Nourkami-Tutdibi, N., Geipel, M., Meyberg-Solomayer, G. et al. Hydrops fetalis with isolated massive ascites in a preterm neonate with rhesus disease. Wien Med Wochenschr 172, 290–291 (2022). Available from Springer. Licensed under CC by 4.0)

After Birth (Newborn Signs):

In the absence of prophylaxis, symptoms often emerge within the first hours after delivery.

Pallor and jaundice within the first 24 hours
Irritability, poor feeding, or unusual sleepiness
Tachycardia and tachypnea
Hepatosplenomegaly
If left untreated,it can lead to Kernicterus (brain damage from severe jaundice)⁷

What is Kernicterus?

The destruction of fetal RBCs floods the system with unconjugated bilirubin, a yellow pigment that’s toxic at high levels. This buildup can cross the blood-brain barrier and cause permanent brain damage.
Warning signs include:

Poor feeding
High-pitched or inconsolable crying
Floppy limbs (hypotonia) progressing to stiffness (hypertonia)
Seizures, lethargy, or arching of the back (opisthotonus)

Bilirubin levels above 20 mg/dL in term infants are a medical emergency. Without treatment, kernicterus can cause hearing loss, cerebral palsy, or developmental delays.⁸

An elaborate table listing all the differences between ABO and Rh incompatibility induced HDFN — Key Differences in Hemolytic Disease of the Fetus and Newborn (HDFN): Rh vs. ABO Incompatibility. While ABO mismatch is more common, it’s typically milder, unlike Rh incompatibility, which poses a greater risk of severe disease.

Hydrops Fetalis vs. Erythroblastosis Fetalis

Though often used interchangeably, these two terms refer to distinct, but sometimes connected conditions:

Erythroblastosis fetalis (HDFN) is a blood disorder caused by maternal antibodies attacking fetal red blood cells. This immune response leads to anemia, and in severe cases, can progress to hydrops fetalis.

Hydrops fetalis is a clinical syndrome marked by abnormal fluid accumulation in two or more fetal compartments, such as the abdomen, lungs, skin, or around the heart.⁹. While severe HDFN can cause hydrops, not all hydrops is immune-mediated.

In fact, thanks to widespread Rh prophylaxis, immune hydrops now accounts for only 10–15% of cases. The majority (85–90%) are non-immune hydrops, often linked to cardiac anomalies, infections, chromosomal disorders, or other conditions.

Diagnosis & Treatment of Erythroblastosis Fetalis

Prenatal Screening:

Diagnosis begins with maternal blood typing and antibody screening in the first trimester of every pregnancy.

Blood type and Rh status
Antibody screen (to detect maternal alloimmunization)

If the mother is Rh-negative:

The father’s Rh status is checked.
- Father Rh-negative? The fetus cannot be Rh-positive → no risk.
- Father Rh-positive or unknown? The fetus may be at risk → Close monitoring.
Remember that an unsensitized (with a negative antibody screen) Rh-negative mother is always a candidate for Rh immunoprophylaxis (anti-D immunoglobulin), given at 28 weeks and within 72 hours after delivery.

Antibody Monitoring:

If maternal alloantibodies (especially anti-D) are present:

Antibody titers are monitored regularly (usually every 2–4 weeks).
If titers rise above a critical threshold (commonly 1:16), fetal monitoring is intensified.

Fetal Monitoring:

To evaluate fetal anemia:

Doppler ultrasound is used to measure middle cerebral artery peak systolic velocity (MCA-PSV).¹⁰Myle, A. K., & Al-Khattabi, G. H. (2021). Hemolytic Disease of the Newborn: A Review of Current Trends and Prospects. Pediatric health, medicine and therapeutics, 12, 491–498. https://doi.org/10.2147/PHMT.S327032
- Increased flow velocity = decreased blood viscosity = anemia
- It’s non-invasive and remarkably reliable.

Confirmation & Treatment:

If MCA-PSV suggests moderate to severe anemia:

Diagnosis can be confirmed via cordocentesis (fetal blood sampling via the umbilical vein) to:
- Confirm hemoglobin levels
- Crossmatch for possible intrauterine transfusion (IUT)

IUT is the gold standard for severe fetal anemia:

Rh-negative, antigen-negative blood is directly transfused to the fetus.
May be repeated every 1–3 weeks until:
- The fetus is stable
- Or it’s safe to deliver

Delivery:

Timing depends on a balance:

Fetal lung maturity
Severity of anemia
Response to transfusions

Delivery is planned accordingly—sometimes early, often with steroids for lung maturity if preterm.

Postnatal Assessement:

Once the baby is born, if HDFN is suspected or confirmed:

Direct Coombs test (DAT): Confirms the presence of maternal antibodies attached to neonatal RBCs.
Complete blood count (CBC) and reticulocyte count: Assesses anemia and marrow response
Serum bilirubin levels: Evaluates the severity of jaundice
Peripheral smear: Reveals nucleated RBCs and polychromasia
ABO and Rh typing of both mother and infant should be reviewed.

Management & Treatment:

In mild cases of jaundice:

Phototherapy: First-line treatment for hyperbilirubinemia. It converts unconjugated bilirubin into excretable isomers.¹¹

In severe cases, though, exchange transfusion and IVIG are urgently needed.

Exchange Transfusion: For severe anemia or rapidly rising bilirubin. It replaces antibody-coated cells and lowers bilirubin quickly
Intravenous immunoglobulin (IVIG): May reduce hemolysis by blocking Fc receptors in the neonatal reticuloendothelial system. This prevents immune cells from recognizing and destroying red cells that are tagged with maternal antibodies.
Supportive care, including hydration and feeding support

Emerging Treatments:

Nipocalimab, a monoclonal antibody that blocks IgG transfer across the placenta shows promise in reducing the need for intrauterine transfusions.¹² Advances in noninvasive prenatal testing (NIPT) and improvements in transfusion tools are also making care safer and more targeted.

Prevention of Erythroblastosis Fetalis

The most effective strategy is preventing maternal sensitization using Rh immunoglobulin (RhIg).

Routine prophylaxis: Given at 28 weeks of gestation and within 72 hours postpartum¹³
After sensitizing events: Following miscarriage, trauma, invasive procedures (amniocentesis, chorionic villus sampling), or abdominal trauma
Maternal counseling: Emphasizing the importance of completing prophylaxis and seeking care after any pregnancy complications

Cases still occur due to missed or delayed doses, late prenatal care, or sensitization to non-D Rh antigens (e.g., anti-c, anti-E), which RhIg doesn’t cover.

Prognosis & Follow Up

Erythroblastosis fetalis has become a preventable and treatable condition in much of the world. With proper prevention and treatment:

Survival rates exceed 90–95%
Early detection and management yield excellent outcomes
Infants who experienced severe disease require:
- Serial monitoring for late anemia and jaundice
- Hearing assessment (kernicterus risk)
- Developmental follow-up if severe hyperbilirubinemia occurred
For sensitized mothers, all future pregnancies require close monitoring regardless of fetal blood type.

Conclusion

Once a devastating diagnosis, Erythroblastosis fetalis has now changed to an easily preventable condition. The widespread use of Rh immunoglobulin represents one of obstetric medicine’s greatest success stories, dramatically reducing both incidence and mortality.
Recent discoveries like placental antibody-blocking therapies and noninvasive genotyping signals a shift toward more precise, less invasive care. With new clinical tools in hand, the focus has now turned to access, equity, and global implementation: ensuring that every fetus at risk receives timely, effective intervention, wherever they are.

Refrences

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Myle, A. K., & Al-Khattabi, G. H. (2021). Hemolytic Disease of the Newborn: A Review of Current Trends and Prospects. Pediatric health, medicine and therapeutics, 12, 491–498. https://doi.org/10.2147/PHMT.S327032
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Myle, A. K., & Al-Khattabi, G. H. (2021). Hemolytic Disease of the Newborn: A Review of Current Trends and Prospects. Pediatric health, medicine and therapeutics, 12, 491–498. https://doi.org/10.2147/PHMT.S327032
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Myle, A. K., & Al-Khattabi, G. H. (2021). Hemolytic Disease of the Newborn: A Review of Current Trends and Prospects. Pediatric health, medicine and therapeutics, 12, 491–498. https://doi.org/10.2147/PHMT.S327032
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Myle, A. K., & Al-Khattabi, G. H. (2021). Hemolytic Disease of the Newborn: A Review of Current Trends and Prospects. Pediatric health, medicine and therapeutics, 12, 491–498. https://doi.org/10.2147/PHMT.S327032
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Myle, A. K., & Al-Khattabi, G. H. (2021). Hemolytic Disease of the Newborn: A Review of Current Trends and Prospects. Pediatric health, medicine and therapeutics, 12, 491–498. https://doi.org/10.2147/PHMT.S327032
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