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Hemolytic Disease of the Fetus and Newborn

Hemolytic disease of the fetus and newborn Newborn An infant during the first 28 days after birth. Physical Examination of the Newborn (HDFN), also known as erythroblastosis fetalis, is caused by maternal IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis antibody destruction of the fetal RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology. Rhesus (Rh) blood group incompatibility (frequently triggered by D antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination) and ABO incompatibility are common causes. In Rh incompatibility, an RhD-negative mother carries an RhD-positive baby; thus, 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: Types and Functions form against antigens when fetal RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology cross into the maternal circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment. In ABO incompatibility, commonly, a mother with blood type O has existing 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: Types and Functions to A and B antigens. The affected baby can suffer from 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 leading to severe 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, hydrops Hydrops Cholecystitis fetalis, cardiac Cardiac Total Anomalous Pulmonary Venous Return (TAPVR) complications, and fetal demise. If the pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care is affected by Rh incompatibility, antenatal surveillance Surveillance Developmental Milestones and Normal Growth is done to determine the need for intrauterine transfusion and early delivery. Postnatal treatment includes close monitoring, phototherapy Phototherapy Treatment of disease by exposure to light, especially by variously concentrated light rays or specific wavelengths. Hyperbilirubinemia of the Newborn for 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 exchange transfusion in severe cases. For RhD-negative mothers, maternal sensitization can be prevented by using anti-D immunoglobulin (RhoGAM). Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual's condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas is excellent with 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, blood type screening Screening Preoperative Care, and availability of RhD immune globulin.

Last updated: Mar 30, 2021

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Definition

Hemolytic disease of the fetus and newborn Newborn An infant during the first 28 days after birth. Physical Examination of the 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 Newborn An infant during the first 28 days after birth. Physical Examination of the Newborn of varying degrees of severity due to maternal IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis 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: Types and Functions against fetal RBC surface antigens.

  • Also known as alloimmune HDFN or erythroblastosis fetalis
  • Antigens involved: 
    • ABO
    • Rhesus (Rh) factor (most commonly the D antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination)
    • 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: Types and Functions): 
    • 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 ( hyperbilirubinemia Hyperbilirubinemia A condition characterized by an abnormal increase of bilirubin in the blood, which may result in jaundice. Bilirubin, a breakdown product of heme, is normally excreted in the bile or further catabolized before excretion in the urine. Jaundice) 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 and Types is less severe in ABO incompatibility in most cases compared to sensitized Rh incompatibility. 
  • Recognition of the increased risk factors for maternal exposure Exposure ABCDE Assessment 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: Types and Functions must be of the IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis class to cross the placenta Placenta A highly vascularized mammalian fetal-maternal organ and major site of transport of oxygen, nutrients, and fetal waste products. It includes a fetal portion (chorionic villi) derived from trophoblasts and a maternal portion (decidua) derived from the uterine endometrium. The placenta produces an array of steroid, protein and peptide hormones (placental hormones). 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: Types and Functions (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: Types and Functions 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: Types and Functions). 
      • Seen in 15% of pregnancies 
    • RhD hemolytic disease:
      • Rh (positive or negative based on the expression of D antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination in RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology)
      • RhD negative status is due to the absence or alteration of the RHD gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics.
      • HDFN usually occurs during the 2nd exposure Exposure ABCDE Assessment 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: Types and Functions involved are IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis.
    • 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 Exposure ABCDE Assessment to incompatible RBC antigens:
    • Known fetal-maternal hemorrhage (FMH):
      • Placental abruption Placental Abruption Premature separation of the normally implanted placenta from the uterus. Signs of varying degree of severity include uterine bleeding, uterine muscle hypertonia, and fetal distress or fetal death. Antepartum Hemorrhage 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 Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care
      • Spontaneous or induced abortion Abortion Expulsion of the product of fertilization before completing the term of gestation and without deliberate interference. Spontaneous Abortion
      • Abnormal placental insertion
      • Fetal demise
      • Amniocentesis Amniocentesis Percutaneous transabdominal puncture of the uterus during pregnancy to obtain amniotic fluid. It is commonly used for fetal karyotype determination in order to diagnose abnormal fetal conditions. Polyhydramnios 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):
Blood types chart

Major ABO blood groups with the respective antigens and 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: Types and Functions based on blood type

Image: “ABO blood type” by InvictaHOG. License: Public Domain

Pathophysiology

During pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care, fetal RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology move across the placenta Placenta A highly vascularized mammalian fetal-maternal organ and major site of transport of oxygen, nutrients, and fetal waste products. It includes a fetal portion (chorionic villi) derived from trophoblasts and a maternal portion (decidua) derived from the uterine endometrium. The placenta produces an array of steroid, protein and peptide hormones (placental hormones). Placenta, Umbilical Cord, and Amniotic Cavity into the maternal circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment:

  • 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 RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology 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: Types and Functions.
  • Type of incompatibility can impact the outcome (ranges from mild to severe 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 and Types and sequela).

ABO incompatibility:

  • Maternal blood group O Blood group O Blood Group Systems is at the highest risk: 
    • Fetal blood group A Blood group A Blood Group Systems or B
    • Maternal anti-A or anti-B IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis target antigens on the fetal RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology 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 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 and Types
  • Innate, with no sensitization/prior exposure Exposure ABCDE Assessment 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: Types and Functions > 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: Types and Functions

Rhesus incompatibility:

  • Setting: RhD-negative mother and RhD-positive fetus
  • Prior sensitization needs to occur:
    • 1st pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care: Mother develops IgM IgM A class of immunoglobulin bearing mu chains (immunoglobulin mu-chains). Igm can fix complement. The name comes from its high molecular weight and originally being called a macroglobulin. Immunoglobulins: Types and Functions 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: Types and Functions (cannot cross the placenta Placenta A highly vascularized mammalian fetal-maternal organ and major site of transport of oxygen, nutrients, and fetal waste products. It includes a fetal portion (chorionic villi) derived from trophoblasts and a maternal portion (decidua) derived from the uterine endometrium. The placenta produces an array of steroid, protein and peptide hormones (placental hormones). Placenta, Umbilical Cord, and Amniotic Cavity) at the 1st exposure Exposure ABCDE Assessment to an Rh-incompatible fetus.
    • The 1st pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care will not be affected.
    • Subsequent pregnancies result in maternal anti-D IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis that can cross the placenta Placenta A highly vascularized mammalian fetal-maternal organ and major site of transport of oxygen, nutrients, and fetal waste products. It includes a fetal portion (chorionic villi) derived from trophoblasts and a maternal portion (decidua) derived from the uterine endometrium. The placenta produces an array of steroid, protein and peptide hormones (placental hormones). Placenta, Umbilical Cord, and Amniotic Cavity and target the RBC RhD antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination of the subsequent fetus.
    • More severe hemolysis causing severe 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 and Types, hydrops Hydrops Cholecystitis, cardiac failure Cardiac failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart 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 The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care (e.g., blood transfusion in her childhood).
First pregnancy with rhesus incompatibility

Rh incompatibility, 1st pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care:
Mother is Rh negative and baby is Rh positive in the 1st pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care, which triggers Triggers Hereditary Angioedema (C1 Esterase Inhibitor Deficiency) 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: Types and Functions ( IgM IgM A class of immunoglobulin bearing mu chains (immunoglobulin mu-chains). Igm can fix complement. The name comes from its high molecular weight and originally being called a macroglobulin. Immunoglobulins: Types and Functions). This scenario does not affect Affect The feeling-tone accompaniment of an idea or mental representation. It is the most direct psychic derivative of instinct and the psychic representative of the various bodily changes by means of which instincts manifest themselves. Psychiatric Assessment the 1st baby.

Image by Lecturio.
Second, dangerous pregnancy with rhesus incompatibility

Rh incompatibility, 2nd pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care:
While the 1st-born baby is not affected, by this time, IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis 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: Types and Functions have developed, which attack the baby if Rh positive. This scenario can lead to hydrops Hydrops Cholecystitis fetalis, hypoxia Hypoxia Sub-optimal oxygen levels in the ambient air of living organisms. Ischemic Cell Damage, and death.

Image by Lecturio.

Clinical Presentation

Fetus (in utero)

Ultrasound (US) may show evidence of immune hydrops Hydrops Cholecystitis fetalis, a life-threatening condition in which fetuses have abnormal fluid build-up in the body. The US findings of immune hydrops Hydrops Cholecystitis 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 A highly vascularized mammalian fetal-maternal organ and major site of transport of oxygen, nutrients, and fetal waste products. It includes a fetal portion (chorionic villi) derived from trophoblasts and a maternal portion (decidua) derived from the uterine endometrium. The placenta produces an array of steroid, protein and peptide hormones (placental hormones). 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 Cardiomegaly Enlargement of the heart, usually indicated by a cardiothoracic ratio above 0. 50. Heart enlargement may involve the right, the left, or both heart ventricles or heart atria. Cardiomegaly is a nonspecific symptom seen in patients with chronic systolic heart failure (heart failure) or several forms of cardiomyopathies. Ebstein’s Anomaly
  • 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 An infant during the first 28 days after birth. 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 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

Severe disease:

  • Severe 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 and Types (< 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 Kernicterus A term used pathologically to describe bilirubin staining of the basal ganglia; brain stem; and cerebellum and clinically to describe a syndrome associated with hyperbilirubinemia. Clinical features include athetosis, muscle spasticity or hypotonia, impaired vertical gaze, and deafness. Nonconjugated bilirubin enters the brain and acts as a neurotoxin, often in association with conditions that impair the blood-brain barrier (e.g., sepsis). This condition occurs primarily in neonates, but may rarely occur in adults. Hyperbilirubinemia of the Newborn (a rare condition where high levels of unconjugated bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism deposit in parts of the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification leading to encephalopathy Encephalopathy Hyper-IgM Syndrome
  • Hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus
  • 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
  • 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 
  • 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
Newborn with hydrops fetalis

Hydrops Hydrops Cholecystitis fetalis in a newborn Newborn An infant during the first 28 days after birth. Physical Examination of the Newborn, born to a Rhesus negative mother without proper prevention:
Note the 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.

Image: “Le nouveau né en EN Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum hydrops Hydrops Cholecystitis foetalis” by Service de Gynécologie Obstétrique, Hôpital Militaire d’instruction Mohammed V, Avenue des Far Hay Riad, Rabat, Maroc. License: CC BY 2.0

Diagnosis

General principles

It is important to identify the potential risk factors for unknown sensitization and prior history of HDFN during pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and 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: Types and Functions are IgM IgM A class of immunoglobulin bearing mu chains (immunoglobulin mu-chains). Igm can fix complement. The name comes from its high molecular weight and originally being called a macroglobulin. Immunoglobulins: Types and Functions; therefore, a majority do not cross the placenta Placenta A highly vascularized mammalian fetal-maternal organ and major site of transport of oxygen, nutrients, and fetal waste products. It includes a fetal portion (chorionic villi) derived from trophoblasts and a maternal portion (decidua) derived from the uterine endometrium. The placenta produces an array of steroid, protein and peptide hormones (placental hormones). 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 Prophylaxis Cephalosporins 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: Types and Functions capable of causing HDFN:
    • Duffy
    • Kell
    • Kidd
  • Incompatibility with minor blood groups: generally, if a red cell IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis antibody is identified, best to proceed and evaluate for hemolytic disease

Testing the mother

  • Blood type (ABO)
  • Rh status: reflex antibody screening Screening Preoperative Care (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: Types and Functions: 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: Types and Functions: Mother has been sensitized. 
  • Antibody screening Screening Preoperative Care 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: Types and Functions (e.g., anti-Kell) for all mothers:
    • Identify the antibody, if detected.
    • IgM IgM A class of immunoglobulin bearing mu chains (immunoglobulin mu-chains). Igm can fix complement. The name comes from its high molecular weight and originally being called a macroglobulin. Immunoglobulins: Types and Functions 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: Types and Functions do not cross the placenta Placenta A highly vascularized mammalian fetal-maternal organ and major site of transport of oxygen, nutrients, and fetal waste products. It includes a fetal portion (chorionic villi) derived from trophoblasts and a maternal portion (decidua) derived from the uterine endometrium. The placenta produces an array of steroid, protein and peptide hormones (placental hormones). 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: Types and Functions 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: Types and Functions are detected, the father should be tested for the antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination in question.
  • If the father is negative, the infant will not have the antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination:
    • No risk for HDFN 
    • Proceed with routine care.
  • If the father is positive (or unknown), the infant may have the antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination:
    • 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 Genotype The genetic constitution of the individual, comprising the alleles present at each genetic locus. Basic Terms of Genetics.

Testing the fetus

  • Attempt to determine the fetal genotype Genotype The genetic constitution of the individual, comprising the alleles present at each genetic locus. Basic Terms of Genetics (and subsequently HDFN risk) via:
    • Maternal serum
    • Amniocentesis Amniocentesis Percutaneous transabdominal puncture of the uterus during pregnancy to obtain amniotic fluid. It is commonly used for fetal karyotype determination in order to diagnose abnormal fetal conditions. Polyhydramnios
  • Monitor fetus at risk using US (determine the presence of hydrops Hydrops Cholecystitis fetalis) and maternal antibody titers (rise in titers indicates active hemolysis).
  • Monitor for the development of fetal 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 and Types via:
    • US doppler Doppler Ultrasonography applying the doppler effect, with frequency-shifted ultrasound reflections produced by moving targets (usually red blood cells) in the bloodstream along the ultrasound axis in direct proportion to the velocity of movement of the targets, to determine both direction and velocity of blood flow. Ultrasound (Sonography) assessment of the fetal middle cerebral artery Middle cerebral artery The largest of the cerebral arteries. It trifurcates into temporal, frontal, and parietal branches supplying blood to most of the parenchyma of these lobes in the cerebral cortex. These are the areas involved in motor, sensory, and speech activities. Cerebrovascular System: Anatomy (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 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 and Types and that the infant is attempting to shunt blood flow Blood flow Blood flow refers to the movement of a certain volume of blood through the vasculature over a given unit of time (e.g., mL per minute). Vascular Resistance, Flow, and Mean Arterial Pressure to its most critical organ, the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification.
      • ↑ MCA-PSV means ↓ HbF
    • Cordocentesis to obtain a fetal blood sample and measure hemoglobin
Ultrasound of fetus with hdfn

Diagnosis of hemolytic disease of the fetus and newborn Newborn An infant during the first 28 days after birth. Physical Examination of the Newborn
A: ultrasound image of the head of the fetus showing 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 (arrow); B: ultrasound showing 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 (arrow) on a sagittal Sagittal Computed Tomography (CT) section of the abdomen; C: sinusoidal fetal heart-rate pattern seen in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with severe 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 and Types

Image: “Serious materno-fetal alloimmunization” by Service de Gynécologie Obstétrique, Hôpital Militaire d’instruction Mohammed V, Avenue des Far Hay Riad, Rabat, Maroc. License: CC BY 2.0

Postnatal evaluation

  • Newborn Newborn An infant during the first 28 days after birth. Physical Examination of the Newborn physical exam to determine hemolysis:
    • Respiratory status: tachypnea Tachypnea Increased respiratory rate. Pulmonary Examination, 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 Hypoplasia Hypoplastic Left Heart Syndrome (HLHS))
    • Cardiac Cardiac Total Anomalous Pulmonary Venous Return (TAPVR): murmur
    • Pallor
    • 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 (common, but not present at birth in normal/healthy babies)
    • Hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus, 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 Indirect Bilirubin Liver Function Tests levels
    • Reticulocyte Reticulocyte Immature erythrocytes. In humans, these are erythroid cells that have just undergone extrusion of their cell nucleus. They still contain some organelles that gradually decrease in number as the cells mature. Ribosomes are last to disappear. Certain staining techniques cause components of the ribosomes to precipitate into characteristic ‘reticulum’ (not the same as the endoplasmic reticulum), hence the name reticulocytes. Erythrocytes: Histology count (often)
    • Coomb’s test (+ direct or indirect test)
    • Peripheral smear: ↓ RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology, 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: Types and Functions
    • 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: Types and Functions at 28 weeks.
    • Give RhoGAM (anti-D immunoglobulin):
      • At 28 weeks gestation (the time fetal RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology express D antigens)
      • Within 72 hours of birth
      • After amniocentesis Amniocentesis Percutaneous transabdominal puncture of the uterus during pregnancy to obtain amniotic fluid. It is commonly used for fetal karyotype determination in order to diagnose abnormal fetal conditions. Polyhydramnios 
      • 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 Miscarriage Spontaneous abortion, also known as miscarriage, is the loss of a pregnancy before 20 weeks’ gestation. However, the layperson use of the term “abortion” is often intended to refer to induced termination of a pregnancy, whereas “miscarriage” is preferred for spontaneous loss. Spontaneous Abortion):
    • Measures fetal hemoglobin (HbF) transferred from a fetus to the mother’s bloodstream
    • Helps decide the additional dosage Dosage Dosage Calculation of RhoGAM, if needed
Hdfn prevention

Prevention of sensitization using anti-D immunoglobulins Immunoglobulins 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: Types and Functions (RhoGAM):
Anti-D binds Rh negative antigens in the mother’s circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment to avoid sensitization and development of immune response/formation of 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: Types and Functions versus Rh negative.

Image by Lecturio.

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 Threshold Minimum voltage necessary to generate an action potential (an all-or-none response) Skeletal Muscle Contraction indicative of ↓ hemoglobin, check for 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 and Types:
    • Mild 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 and Types:
      • Serial US monitoring 
      • Delivery at term or when there is adequate lung maturity
    • Severe 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 and Types
      • Confirm severe 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 and Types (hemoglobin < 10 g/dL).
      • ≤ 35 weeks gestational age Gestational age The age of the conceptus, beginning from the time of fertilization. In clinical obstetrics, the gestational age is often estimated as the time from the last day of the last menstruation which is about 2 weeks before ovulation and fertilization. Pregnancy: Diagnosis, Physiology, and Care: intrauterine transfusion of packed RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology (negative for involved antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination 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 Gestational age The age of the conceptus, beginning from the time of fertilization. In clinical obstetrics, the gestational age is often estimated as the time from the last day of the last menstruation which is about 2 weeks before ovulation and fertilization. Pregnancy: Diagnosis, Physiology, and Care: Consider delivery.
  • Other considerations:
    • If preterm delivery anticipated:
      • Assess maturity of the fetal lung.
      • Consider glucocorticoid steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors for lung maturity.
    • Prepare for delivery where obstetric, maternal-fetal medicine, and pediatric support is available.

Management of the affected newborn Newborn An infant during the first 28 days after birth. Physical Examination of the 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 Lethargy A general state of sluggishness, listless, or uninterested, with being tired, and having difficulty concentrating and doing simple tasks. It may be related to depression or drug addiction. Hyponatremia
      • Irritability
      • Respiratory distress
    • Monitor:
      • Bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism 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 Resuscitation The restoration to life or consciousness of one apparently dead. . Neonatal Respiratory Distress Syndrome
    • 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 and Types:
      • Exchange transfusion for severely affected newborns ( 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, hydrops Hydrops Cholecystitis fetalis) to reduce hemolysis and improve oxygenation
      • Simple transfusion is an option for newborns without circulatory collapse.
      • Iron supplementation Iron Supplementation Iron Deficiency Anemia with RBC transfusion (based on severity)
    • Hyperbilirubinemia Hyperbilirubinemia A condition characterized by an abnormal increase of bilirubin in the blood, which may result in jaundice. Bilirubin, a breakdown product of heme, is normally excreted in the bile or further catabolized before excretion in the urine. Jaundice:
      • Phototherapy Phototherapy Treatment of disease by exposure to light, especially by variously concentrated light rays or specific wavelengths. Hyperbilirubinemia of the Newborn
      • Careful fluid management
      • Possible exchange transfusion 
      • For severe cases: IV immunoglobulin Iv Immunoglobulin Dermatomyositis ( IVIg IVIG Dermatomyositis), which can block RBC antibody receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors, leading to a decrease in hemolysis
Jaundice phototherapy

Image of 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: newborn Newborn An infant during the first 28 days after birth. Physical Examination of the Newborn undergoing phototherapy Phototherapy Treatment of disease by exposure to light, especially by variously concentrated light rays or specific wavelengths. Hyperbilirubinemia of the Newborn

Image: “ 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 phototherapy Phototherapy Treatment of disease by exposure to light, especially by variously concentrated light rays or specific wavelengths. Hyperbilirubinemia of the Newborn” by Martin Pot. License: CC BY 3.0

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

  • Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas 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 Screening Preoperative Care 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 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 and Types.

Differential Diagnosis

  • Thalassemia: genetic hemoglobinopathies with variable 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: a relatively common, usually autosomal dominant hemolytic anemia due to a defect in the membrane protein. Newborns with this condition usually present with anemia and neonatal jaundice. Peripheral blood smear shows microspherocytes.
  • Glucose-6-phosphate dehydrogenase deficiency: an intravascular 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. Newborns with oxidative stress can present with anemia. Peripheral smear shows microspherocytes and “bite cells.”
  • Congenital Congenital Chorioretinitis 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 Immunodeficiency Chédiak-Higashi Syndrome 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), rubella Rubella An acute infectious disease caused by the rubella virus. The virus enters the respiratory tract via airborne droplet and spreads to the lymphatic system. 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 Herpes Simplex A group of acute infections caused by herpes simplex virus type 1 or type 2 that is characterized by the development of one or more small fluid-filled vesicles with a raised erythematous base on the skin or mucous membrane. It occurs as a primary infection or recurs due to a reactivation of a latent infection. Congenital TORCH Infections. These infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease are associated with fetal loss, stillbirth, intrauterine growth retardation Growth Retardation Failure of a fetus to attain expected growth. Fetal Alcohol Spectrum Disorder, fetal 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 and Types, 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 Hepatosplenomegaly Cytomegalovirus. History, blood tests for infection based on clinical suspicion, and typical examination findings of the different infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease aid in pointing to the diagnosis.
  • Gilbert syndrome Gilbert syndrome A benign familial disorder, transmitted as an autosomal dominant trait. It is characterized by low-grade chronic hyperbilirubinemia with considerable daily fluctuations of the bilirubin level. Jaundice: most common inherited disease associated with bilirubin Bilirubin A bile pigment that is a degradation product of heme. Heme Metabolism glucuronidation. Unconjugated hyperbilirubinemia Unconjugated hyperbilirubinemia Hyperbilirubinemia of the Newborn 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 Hematocrit The volume of packed red blood cells in a blood specimen. The volume is measured by centrifugation in a tube with graduated markings, or with automated blood cell counters. It is an indicator of erythrocyte status in disease. For example, anemia shows a low value; polycythemia, a high value. Neonatal Polycythemia, reticulocyte Reticulocyte Immature erythrocytes. In humans, these are erythroid cells that have just undergone extrusion of their cell nucleus. They still contain some organelles that gradually decrease in number as the cells mature. Ribosomes are last to disappear. Certain staining techniques cause components of the ribosomes to precipitate into characteristic ‘reticulum’ (not the same as the endoplasmic reticulum), hence the name reticulocytes. Erythrocytes: Histology count, and peripheral smear.

References

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  7. Moise, K. (2020). RhD alloimmunization: Prevention in pregnant and postpartum patients. UpToDate. Retrieved March 16, 2021, from https://www.uptodate.com/contents/rhd-alloimmunization-prevention-in-pregnant-and-postpartum-patients
  8. Ross, M., de Alarcón, P. Hemolytic disease of the fetus and newborn. Neo Reviews. https://neoreviews.aappublications.org/content/14/2/e83

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