Overview

Definition

Hemolytic disease of the fetus and newborn (HDFN) is hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia of the fetus or newborn of varying degrees of severity due to maternal IgG antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins against fetal RBC surface antigens.

• Also known as alloimmune HDFN or erythroblastosis fetalis
• Antigens involved: 
  • ABO
  • Rhesus (Rh) factor (most commonly the D antigen)
  • Minor red cell antigens (Kell, Duffy, Kidd antigens)

Epidemiology

• Rh incompatibility remains the most common cause of HDFN worldwide.
• In the United States, 15% of the population is Rh negative.
• HDFN due to ABO mismatch occurs when the mother is blood type O+ (has anti-A and anti-B antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins): 
  • Jaundice (hyperbilirubinemia) more frequently seen versus hemolysis
  • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview is less severe in ABO incompatibility in most cases compared to sensitized Rh incompatibility. 
• Recognition of the increased risk factors for maternal exposure to RBC antigens has significantly improved the prevention and management of HDFN.
• Current Rhogam recommendations, when followed, can reduce RhD alloimmunization to 0.2% in mothers at risk.

Etiology

• Maternal antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins must be of the IgG class to cross the placenta Placenta The placenta consists of a fetal side and a maternal side, and it provides a vascular communication between the mother and the fetus. This communication allows the mother to provide nutrients to the fetus and allows for removal of waste products from fetal blood. Placenta, Umbilical Cord, and Amniotic Cavity.
• Maternal antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins (to fetal antigens) that are formed depend on the blood group and result in different types of HDFN:
  • ABO hemolytic disease:
    • Major blood groups: A, B, AB, O
    • A and/or B antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins are naturally produced against the antigens that are not innately present (e.g., type O has anti-A and anti-B antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins). 
    • Seen in 15% of pregnancies 
  • RhD hemolytic disease:
    • Rh (positive or negative based on the expression of D antigen in RBCs)
    • RhD negative status is due to the absence or alteration of the RHD gene.
    • HDFN usually occurs during the 2nd exposure when the antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins involved are IgG.
  • Minor blood groups (33 total blood group systems Blood group systems There are 29 blood group systems, among which the ABO group is the most important. Blood groups are determined by antigens that are surface markers on the RBC and consist of proteins and carbohydrates. Blood Group Systems), such as:
    • Kell (anti-Kel-1 antibody: a rare but severe cause of HDFN, which is life threatening)
    • Duffy
    • Kidd
• Other risk factors for maternal exposure to incompatible RBC antigens:
  • Known fetal-maternal hemorrhage (FMH):
    • Placental abruption and other placental bleeding or injury
    • Delivery of a previous infant
    • Previous infant with HDFN
    • Fetal surgery
  • Possible FMH events that may have gone unappreciated:
    • Ectopic pregnancy Ectopic pregnancy Ectopic pregnancy refers to the implantation of a fertilized egg (embryo) outside the uterine cavity. The main cause is disruption of the normal anatomy of the fallopian tube. Ectopic Pregnancy
    • Spontaneous or induced abortion
    • Abnormal placental insertion
    • Fetal demise
    • Amniocentesis and chorionic villus sampling
    • Maternal abdominal trauma
    • Fetal version maneuvers
  • Maternal history with possible transfusion (if it occurred in childhood, the mother may not know the history):
    • Survivor of childhood cancer
    • History of surgery, especially cardiac or other major surgery
    • Prolonged hospital stay as a child
    • Splenectomy without a known cause

Pathophysiology

During pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care, fetal RBCs move across the placenta Placenta The placenta consists of a fetal side and a maternal side, and it provides a vascular communication between the mother and the fetus. This communication allows the mother to provide nutrients to the fetus and allows for removal of waste products from fetal blood. Placenta, Umbilical Cord, and Amniotic Cavity into the maternal circulation:

• Usually at low volumes (< 15 mL)
• Greater risk of FMH and larger volumes (10–150 mL) closer to delivery or under certain circumstances
• Incompatibility of antigens expressed on the fetal RBCs leads to the formation of maternal antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins.
• Type of incompatibility can impact the outcome (ranges from mild to severe anemia and sequela).

ABO incompatibility:

• Maternal blood group O is at the highest risk: 
  • Fetal blood group A or B
  • Maternal anti-A or anti-B IgG target antigens on the fetal RBCs and cause hemolysis → jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice (more common) and usually mild anemia
• Innate, with no sensitization/prior exposure needed 
• Milder form of HDFN
• Anti-A antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins > anti-B antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins

Rhesus incompatibility:

• Setting: RhD-negative mother and RhD-positive fetus
• Prior sensitization needs to occur:
  • 1st pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care: Mother develops IgM antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins (cannot cross the placenta Placenta The placenta consists of a fetal side and a maternal side, and it provides a vascular communication between the mother and the fetus. This communication allows the mother to provide nutrients to the fetus and allows for removal of waste products from fetal blood. Placenta, Umbilical Cord, and Amniotic Cavity) at the 1st exposure to an Rh-incompatible fetus.
  • The 1st pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care will not be affected.
  • Subsequent pregnancies result in maternal anti-D IgG that can cross the placenta Placenta The placenta consists of a fetal side and a maternal side, and it provides a vascular communication between the mother and the fetus. This communication allows the mother to provide nutrients to the fetus and allows for removal of waste products from fetal blood. Placenta, Umbilical Cord, and Amniotic Cavity and target the RBC RhD antigen of the subsequent fetus.
  • More severe hemolysis causing severe anemia, hydrops, cardiac failure, and severe jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice 
  • In rare situations, a woman may have been sensitized prior to her 1st pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care (e.g., blood transfusion in her childhood).

Clinical Presentation

Fetus (in utero)

Ultrasound (US) may show evidence of immune hydrops fetalis, a life-threatening condition in which fetuses have abnormal fluid build-up in the body. The US findings of immune hydrops fetalis may include:

• Polyhydramnios Polyhydramnios Polyhydramnios is a pathological excess of amniotic fluid. Common causes of polyhydramnios include fetal anomalies, gestational diabetes, multiple gestations, and congenital infections. Patients are often asymptomatic but may present with dyspnea, extremity swelling, or abdominal distention. Polyhydramnios
• Enlarged placenta Placenta The placenta consists of a fetal side and a maternal side, and it provides a vascular communication between the mother and the fetus. This communication allows the mother to provide nutrients to the fetus and allows for removal of waste products from fetal blood. Placenta, Umbilical Cord, and Amniotic Cavity
• Hepatomegaly
• Splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly
• Cardiomegaly
• Generalized edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema (including scalp edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema, pleural effusion Pleural Effusion Pleural effusion refers to the accumulation of fluid between the layers of the parietal and visceral pleura. Common causes of this condition include infection, malignancy, autoimmune disorders, or volume overload. Clinical manifestations include chest pain, cough, and dyspnea. Pleural Effusion, ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites)

Newborn Newborn A neonate, or newborn, is defined as a child less than 28 days old. A thorough physical examination should be performed within the first 24 hours of life to identify abnormalities and improve outcomes by offering timely treatment. Physical Examination of the Newborn

Mild-to-moderate disease:

• No or mild anemia (normal hemoglobin is 19.9 + 2.2 g/dL at birth)
• Jaundice in the 1st 24 hours of life

Severe disease:

• Severe anemia (< 10 g/dL)
• Significant jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice in the 1st 24 hours of life
• Kernicterus (a rare condition where high levels of unconjugated bilirubin deposit in parts of the brain leading to encephalopathy) 
• Hepatosplenomegaly
• Ascites
• Edema 
• Shock Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of Shock

Diagnosis

General principles

It is important to identify the potential risk factors for unknown sensitization and prior history of HDFN during pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care. Potential blood incompatibilities include:

• ABO incompatibility: 
  • Most anti-A and anti-B antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins are IgM; therefore, a majority do not cross the placenta Placenta The placenta consists of a fetal side and a maternal side, and it provides a vascular communication between the mother and the fetus. This communication allows the mother to provide nutrients to the fetus and allows for removal of waste products from fetal blood. Placenta, Umbilical Cord, and Amniotic Cavity.
  • As such, ABO incompatibility is more of a concern postnatally.
• RhD incompatibility: 
  • Associated with severe risk of HDFN 
  • Only incompatibility that has prophylaxis available; thus, antenatal diagnosis is important
• Other erythrocyte antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins capable of causing HDFN:
  • Duffy
  • Kell
  • Kidd
• Incompatibility with minor blood groups: generally, if a red cell IgG antibody is identified, best to proceed and evaluate for hemolytic disease

Testing the mother

• Blood type (ABO)
• Rh status: reflex antibody screening (RhD-negative mothers only)
  • Negative anti-D antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Mother is not sensitized.
  • Positive anti-D antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Mother has been sensitized. 
• Antibody screening for other erythrocyte antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins (e.g., anti-Kell) for all mothers:
  • Identify the antibody, if detected.
  • IgM antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins do not cross the placenta Placenta The placenta consists of a fetal side and a maternal side, and it provides a vascular communication between the mother and the fetus. This communication allows the mother to provide nutrients to the fetus and allows for removal of waste products from fetal blood. Placenta, Umbilical Cord, and Amniotic Cavity and do not cause HDFN.
  • Get antibody titers of any antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins known to cause HDFN → higher titers = higher risk for HDFN

Testing the father

• If maternal antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins are detected, the father should be tested for the antigen in question.
• If the father is negative, the infant will not have the antigen:
  • No risk for HDFN 
  • Proceed with routine care.
• If the father is positive (or unknown), the infant may have the antigen:
  • Infant could be at risk for HDFN
  • Attempt to determine if the father is heterogenous (infant could be at risk) vs. homogenous (infant is at risk).
  • Attempt to determine the fetal genotype.

Testing the fetus

• Attempt to determine the fetal genotype (and subsequently HDFN risk) via:
  • Maternal serum
  • Amniocentesis
• Monitor fetus at risk using US (determine the presence of hydrops fetalis) and maternal antibody titers (rise in titers indicates active hemolysis).
• Monitor for the development of fetal anemia via:
  • US doppler assessment of the fetal middle cerebral artery (MCA)
    • ↑ Peak systolic velocity (PSV) in the MCA indicates “cephalization of flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure”
    • “Cephalization of flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure” indicates fetal anemia and that the infant is attempting to shunt blood flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure to its most critical organ, the brain.
    • ↑ MCA-PSV means ↓ HbF
  • Cordocentesis to obtain a fetal blood sample and measure hemoglobin

Postnatal evaluation

• Newborn Newborn A neonate, or newborn, is defined as a child less than 28 days old. A thorough physical examination should be performed within the first 24 hours of life to identify abnormalities and improve outcomes by offering timely treatment. Physical Examination of the Newborn physical exam to determine hemolysis:
  • Respiratory status: tachypnea, distress (can have pleural effusion Pleural Effusion Pleural effusion refers to the accumulation of fluid between the layers of the parietal and visceral pleura. Common causes of this condition include infection, malignancy, autoimmune disorders, or volume overload. Clinical manifestations include chest pain, cough, and dyspnea. Pleural Effusion and pulmonary hypoplasia Pulmonary hypoplasia Pulmonary hypoplasia is the lack of normal fetal development of the pulmonary parenchyma. The condition is characterized by a decreased number of alveoli and bronchial generations. Oligohydramnios is a notable cause, but conditions that restrict lung development or lead to fetal lung compression can also result in pulmonary hypoplasia. Pulmonary Hypoplasia)
  • Cardiac: murmur
  • Pallor
  • Jaundice (common, but not present at birth in normal/healthy babies)
  • Hepatosplenomegaly, ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites
• Look for evidence of significant hemolysis:
  • CBC: ↓ hemoglobin after birth 
  • ↑ Indirect bilirubin levels
  • ↑ Reticulocyte count (often)
  • Coomb’s test (+ direct or indirect test)
  • Peripheral smear: ↓ RBCs, macrocytosis, reticulocytosis

Management

Prevention

RhD incompatibilities are the only forms of alloimmunization that can be prevented.

• RhD-negative women with negative anti-D antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: 
  • Recheck antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins at 28 weeks.
  • Give RhoGAM (anti-D immunoglobulin):
    • At 28 weeks gestation (the time fetal RBCs express D antigens)
    • Within 72 hours of birth
    • After amniocentesis 
    • After chorionic villus sampling
    • If other risks of FMH are suspected (as listed above)
• Kleihauer-Betke (KB) test considered in cases of potential FMH (i.e., bleeding or miscarriage):
  • Measures fetal hemoglobin (HbF) transferred from a fetus to the mother’s bloodstream
  • Helps decide the additional dosage of RhoGAM, if needed

Management of the affected fetus

• Individuals at risk of HDFN should undergo recommended fetal monitoring Fetal monitoring The primary goals of antepartum testing and monitoring are to assess fetal well-being, identify treatable situations that may cause complications, and evaluate for chromosomal abnormalities. These tests are divided into screening tests (which include cell-free DNA testing, serum analyte testing, and nuchal translucency measurements), and diagnostic tests, which provide a definitive diagnosis of aneuploidy and include chorionic villus sampling (CVS) and amniocentesis. Antepartum Testing and Monitoring.
• When MCA-PSV reaches the threshold indicative of ↓ hemoglobin, check for anemia:
  • Mild anemia:
    • Serial US monitoring 
    • Delivery at term or when there is adequate lung maturity
  • Severe anemia: 
    • Confirm severe anemia (hemoglobin < 10 g/dL).
    • ≤ 35 weeks gestational age: intrauterine transfusion of packed RBCs (negative for involved antigen and cytomegalovirus Cytomegalovirus CMV is a ubiquitous double-stranded DNA virus belonging to the Herpesviridae family. CMV infections can be transmitted in bodily fluids, such as blood, saliva, urine, semen, and breast milk. The initial infection is usually asymptomatic in the immunocompetent host, or it can present with symptoms of mononucleosis. Cytomegalovirus, leukodepleted, and irradiated)
    • > 35 weeks gestational age: Consider delivery.
• Other considerations:
  • If preterm delivery anticipated:
    • Assess maturity of the fetal lung.
    • Consider glucocorticoid steroids for lung maturity.
  • Prepare for delivery where obstetric, maternal-fetal medicine, and pediatric support is available.

Management of the affected newborn

• Mild HDFN:
• ABO incompatibility results in jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice and mild hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia.
  • Watch for the following symptoms:
    • Worsening jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice
    • Poor feeding 
    • Lethargy
    • Irritability
    • Respiratory distress
  • Monitor:
    • Bilirubin levels (and treat accordingly, see management below)
    • Hemoglobin, if clinically indicated
• Severe HDFN (as seen in RhD incompatibility and Kell alloimmunization):
  • High-risk delivery team available for resuscitation
  • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview:
    • Exchange transfusion for severely affected newborns (shock, hydrops fetalis) to reduce hemolysis and improve oxygenation
    • Simple transfusion is an option for newborns without circulatory collapse.
    • Iron supplementation with RBC transfusion (based on severity)
  • Hyperbilirubinemia:
    • Phototherapy
    • Careful fluid management
    • Possible exchange transfusion 
    • For severe cases: IV immunoglobulin (IVIg), which can block RBC antibody receptors, leading to a decrease in hemolysis

Prognosis

• Prognosis is excellent if there is access to prenatal care Prenatal care Prenatal care is a systematic and periodic assessment of pregnant women during gestation to assure the best health outcome for the mother and her fetus. Prenatal care prevents and identifies maternal and fetal problems that adversely affect the pregnancy outcome. Prenatal Care, ABO blood type screening at birth, and with the use of Rhogam in Rh-negative mothers.
• Rarer forms of HDFN due to minor blood groups, particularly Kell, can cause severe and often fatal anemia.

Differential Diagnosis

• Thalassemia Thalassemia Thalassemia is a hereditary cause of microcytic hypochromic anemia and results from a deficiency in either the α or β globin chains, resulting in hemoglobinopathy. The presentation of thalassemia depends on the number of defective chains present and can range from being asymptomatic to rendering the more severely affected patients to be transfusion dependent. Thalassemia: genetic hemoglobinopathies with variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables presentations that affect globin chains. More common non-immune hydrops fetalis can be due to genetic causes leading to fluid overload, including other forms of severe anemia such as thalassemia major (rare form with a complete lack of alpha chains). 
• Hereditary spherocytosis Hereditary Spherocytosis Hereditary spherocytosis (HS) is the most common type of hereditary hemolytic anemia. The condition is caused by a cytoskeletal protein deficiency in the RBC membrane. This results in loss of membrane stability and deformability of the RBC, giving the cell its spherical shape (spherocyte). Hereditary Spherocytosis: a relatively common, usually autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia due to a defect in the membrane protein. Newborns with this condition usually present with anemia and neonatal jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice. Peripheral blood smear shows microspherocytes.
• Glucose-6-phosphate dehydrogenase deficiency Glucose-6-phosphate Dehydrogenase Deficiency Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a type of intravascular hemolytic anemia. The condition is inherited in an X-linked recessive manner. Patients have episodic hemolysis due to an oxidative stressor that causes damage to red blood cells, which lack sufficient NADPH to protect them from oxidative injury. Glucose-6-phosphate Dehydrogenase (G6PD) Deficiency: an intravascular hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia, which is inherited in an X-linked recessive manner. Patients have episodic hemolysis due to an identified oxidative stressor that causes damage to RBCs that lack enough NADPH NADPH Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5'-phosphate (nmn) coupled by pyrophosphate linkage to the 5'-phosphate adenosine 2. Pentose Phosphate Pathway. Newborns with oxidative stress can present with anemia. Peripheral smear shows microspherocytes and “bite cells.”
• Congenital TORCH infection: TORCH stands for toxoplasmosis Toxoplasmosis Toxoplasmosis is an infectious disease caused by Toxoplasma gondii, an obligate intracellular protozoan parasite. Felines are the definitive host, but transmission to humans can occur through contact with cat feces or the consumption of contaminated foods. The clinical presentation and complications depend on the host's immune status. Toxoplasma/Toxoplasmosis, others ( syphilis Syphilis Syphilis is a bacterial infection caused by the spirochete Treponema pallidum pallidum (T. p. pallidum), which is usually spread through sexual contact. Syphilis has 4 clinical stages: primary, secondary, latent, and tertiary. Syphilis, varicella-zoster virus Varicella-Zoster Virus Varicella-zoster virus (VZV) is a linear, double-stranded DNA virus in the Herpesviridae family. Varicella-zoster infections are highly contagious and transmitted through aerosolized respiratory droplets or contact with infected skin lesions. Varicella-Zoster Virus/Chickenpox, parvovirus B19 Parvovirus B19 Primate erythroparvovirus 1 (generally referred to as parvovirus B19, B19 virus, or sometimes erythrovirus B19) ranks among the smallest DNA viruses. Parvovirus B19 is of the family Parvoviridae and genus Erythrovirus. In immunocompetent humans, parvovirus B19 classically results in erythema infectiosum (5th disease) or "slapped cheek syndrome." Parvovirus B19, and human immunodeficiency virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview), rubella Rubella Rubella (also known as German measles or three-day measles) is caused by a single-stranded, positive-sense RNA virus of the Togaviridae family. Rubella only infects humans and spreads prenatally via vertical transmission or postnatally via droplet contact. Congenital rubella is associated with a classic triad of symptoms: cataracts, cardiac defects, and deafness. Infection in children and adults may be mild and present with constitutional symptoms along with a viral exanthem. Rubella Virus, cytomegalovirus Cytomegalovirus CMV is a ubiquitous double-stranded DNA virus belonging to the Herpesviridae family. CMV infections can be transmitted in bodily fluids, such as blood, saliva, urine, semen, and breast milk. The initial infection is usually asymptomatic in the immunocompetent host, or it can present with symptoms of mononucleosis. Cytomegalovirus, and herpes simplex. These infections are associated with fetal loss, stillbirth, intrauterine growth retardation, fetal anemia, jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, and hepatosplenomegaly. History, blood tests for infection based on clinical suspicion, and typical examination findings of the different infections aid in pointing to the diagnosis.
• Gilbert syndrome: most common inherited disease associated with bilirubin glucuronidation. Unconjugated hyperbilirubinemia results from a UGT1A1 mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations. In contrast with HDFN, the baby has normal hematocrit, reticulocyte count, and peripheral smear.