Rh Incompatibility 

Updated: Aug 05, 2022
Author: Leon Salem, MD, MS; Chief Editor: Bruce M Lo, MD, MBA, CPE, RDMS, FACEP, FAAEM, FACHE 


Practice Essentials

The Rh factor (ie, Rhesus factor) is a red blood cell surface antigen that was named after the monkeys in which it was first discovered. Rh incompatibility, also known as Rh disease, is a condition that occurs when a woman with Rh-negative blood type is exposed to Rh-positive blood cells, leading to the development of Rh antibodies.

Rh incompatibility can occur by 2 main mechanisms. The most common type occurs when an Rh-negative pregnant mother is exposed to Rh-positive fetal red blood cells secondary to fetomaternal hemorrhage during the course of pregnancy from spontaneous or induced abortion, trauma,[1]  invasive obstetric procedures, or normal delivery. Rh incompatibility can also occur when an Rh-negative female receives an Rh-positive blood transfusion. In part, this is the reason that blood banks prefer using blood type "O negative" or "type O, Rh negative," as the universal donor type in emergency situations when there is no time to type and crossmatch blood.

The most common cause of Rh incompatibility is exposure from an Rh-negative mother by Rh-positive fetal blood during pregnancy or delivery. As a consequence, blood from the fetal circulation may leak into the maternal circulation, and, after a significant exposure, sensitization occurs leading to maternal antibody production against the foreign Rh antigen.

Once produced, maternal Rh immunoglobulin G (IgG) antibodies persist for life and may cross freely from the placenta to the fetal circulation, where they form antigen-antibody complexes with Rh-positive fetal erythrocytes and eventually are destroyed, resulting in a fetal alloimmune-induced hemolytic anemia.[2]  Although the Rh blood group systems consist of many antigen subtypes (eg, D, C, c, E, e), the D antigen is the most immunogenic; therefore, it most commonly is involved in Rh incompatibility.

Recommendations for screening for Rh incompatibility are available from the US Preventive Services Task Force.[3]


The amount of fetal blood necessary to produce Rh incompatibility varies. In one study, less than 1 mL of Rh-positive blood was shown to sensitize volunteers with Rh-negative blood. Conversely, other studies have suggested that 30% of persons with Rh-negative blood never develop Rh incompatibility, even when challenged with large volumes of Rh-positive blood. Once sensitized, it takes approximately one month for Rh antibodies in the maternal circulation to equilibrate in the fetal circulation. In 90% of cases, sensitization occurs during delivery. Therefore, most firstborn infants with Rh-positive blood type are not affected because the short period from first exposure of Rh-positive fetal erythrocytes to the birth of the infant is insufficient to produce a significant maternal IgG antibody response.

The risk and severity of sensitization response increases with each subsequent pregnancy involving a fetus with Rh-positive blood. In women who are prone to Rh incompatibility, the second pregnancy with an Rh-positive fetus often produces a mildly anemic infant, whereas succeeding pregnancies produce more seriously affected infants who ultimately may die in utero from massive antibody-induced hemolytic anemia.

Risk of sensitization depends largely upon the following 3 factors:

  1. Volume of transplacental hemorrhage

  2. Extent of the maternal immune response

  3. Concurrent presence of ABO incompatibility

The incidence of Rh incompatibility in the Rh-negative mother who is also ABO incompatible is reduced dramatically to 1-2% and is believed to occur because the mother's serum contains antibodies against the ABO blood group of the fetus. The few fetal red blood cells that are mixed with the maternal circulation are destroyed before Rh sensitization can proceed to a significant extent. 

Rh incompatibility is only of medical concern for females who are pregnant or plan to have children in the future. Rh-positive antibodies circulating in the bloodstream of an Rh-negative woman otherwise have no adverse effects.


United States statistics

Only 15% of the population lack the Rh erythrocyte surface antigen and are considered Rh-negative. The vast majority (85%) of individuals are considered Rh positive. Rh sensitization occurs in approximately 1 per 1000 births to women who are Rh negative. The Southwest United States has an incidence approximately 1.5 times the national average, which likely is caused by immigration factors and limited access to medical care, since blood typing is a routine part of prenatal care. Even so, only 17% of pregnant women with Rh-negative blood who are exposed to Rh-positive fetal blood cells ever develop Rh antibodies.

Race-related demographics

Approximately 15-20% of White patients, as opposed to 5-10% of Black patients, have the Rh-negative blood type.

Among individuals of Asian and American Indian descent, the incidence of Rh-negative blood type is less than 5%.


Factors that influence an Rh-negative pregnant female's chances of developing Rh incompatibility include the following:

  • Ectopic pregnancy

  • Placenta previa

  • Placental abruption

  • Abdominal/pelvic trauma

  • In utero fetal death

  • Any invasive obstetric procedure (eg, amniocentesis)

  • Lack of prenatal care

  • Spontaneous abortion



During the course of Rh incompatibility, the fetus is primarily affected. The binding of maternal Rh antibodies produced after sensitization with fetal Rh-positive erythrocytes results in fetal autoimmune hemolysis. As a consequence, large amounts of bilirubin are produced from the breakdown of fetal hemoglobin and are transferred via the placenta to the mother where they are subsequently conjugated and excreted by the mother. However, once delivered, low levels of glucuronyl transferase in the infant preclude the conjugation of large amounts of bilirubin and may result in dangerously elevated levels of serum bilirubin and severe jaundice.

Mildly affected infants may have little or no anemia and may exhibit only hyperbilirubinemia secondary to the continuing hemolytic effect of Rh antibodies that have crossed the placenta.

Moderately affected infants may have a combination of anemia and hyperbilirubinemia/jaundice.

In severe cases of fetal hyperbilirubinemia, kernicterus develops. Kernicterus is a neurologic syndrome caused by deposition of bilirubin into central nervous system tissues. Kernicterus usually occurs several days after delivery and is characterized by loss of the Moro (ie, startle) reflex, posturing, poor feeding, inactivity, a bulging fontanelle, a high-pitched shrill cry, and seizures. Infants who survive kernicterus may go on to develop hypotonia, hearing loss, and mental retardation.

A very serious life-threatening condition observed in infants affected by Rh incompatibility is erythroblastosis fetalis, which is characterized by severe hemolytic anemia and jaundice. The most severe form of erythroblastosis fetalis is hydrops fetalis, which is characterized by high output cardiac failure, edema, ascites, pericardial effusion, and extramedullary hematopoiesis. Newborns with hydrops fetalis are extremely pale with hematocrits usually less than 5. Hydrops fetalis often results in death of the infant shortly before or after delivery and requires an emergent exchange transfusion if there is to be any chance of infant survival.


Emergent delivery of an infant with hydrops fetalis should be as nontraumatic as possible. Ideally, a neonatologist who is prepared to perform an exchange transfusion should attend to the infant immediately.[4]





Obtain the following history:

  • History of prior blood transfusion

  • Rh blood type of the mother

  • Rh blood type of the father (55% of Rh-positive men are genetically heterozygous for the Rh antigen and, therefore, produce Rh-negative offspring when mating with Rh-negative women 50% of the time.)

  • Previous pregnancies, including spontaneous and elective abortions

  • Previous administration of Rh IgG (RhoGAM)

  • Mechanism of injury in cases of maternal trauma during pregnancy

  • Presence of vaginal bleeding and/or amniotic discharge

  • Previous invasive obstetric procedures, such as amniocentesis, cordocentesis, chorionic villous sampling, or ectopic pregnancy

Note that a large fetal-maternal hemorrhage may occur without symptoms and with little or no evidence of trauma. Therefore, a high index of suspicion is warranted and a low threshold for treatment is indicated.

Physical Examination

Evaluation of the vital signs and primary survey of the airway and cardiovascular system are indicated to ensure maternal stability.

A thorough pelvic examination is required.

In situations in which abdominal and/or pelvic trauma is a consideration, inspect for evidence of bruising that may suggest the possibility of significant fetomaternal hemorrhage.

When an infant with an Rh-negative mother is delivered in the emergency department, a thorough physical examination of the infant must be performed after initial stabilization, and a neonatal clinician must be consulted immediately.

Physical findings may vary from mild jaundice to extreme pallor and anemia with hydrops fetalis.



Diagnostic Considerations

Potential reasons for postpartum clinical failures include the following:

  • Failure to type the patient's blood during the ED visit

  • Failure to administer Rh IgG when indicated

  • Error in typing the mother's or infant's blood

  • Unrecognized fetomaternal hemorrhage

  • Inadequate Rh IgG dosage for the volume of fetomaternal hemorrhage

Other conditions to consider in patients with suspected Rh incompatibility include the following:

  • ABO incompatibility

  • Autoimmune hemolytic anemia

  • Microangiopathic hemolytic anemia

  • Spherocytosis

  • Hereditary enzyme deficiencies

  • Alpha thalassemia

  • Chronic fetomaternal hemorrhage

  • Twin-twin transfusion

  • Erythroblastosis fetalis

  • Hydrops fetalis



Laboratory Studies

Prenatal emergency care

Determination of Rh blood type is required in every pregnant female.[5, 6]

In a pregnant woman with Rh-negative blood type, the Rosette screening test often is the first test performed. The Rosette test can detect alloimmunization caused by very small amounts of fetomaternal hemorrhage. When a high clinical suspicion of large fetomaternal hemorrhage is present (>30 mL blood), the Kleihauer-Betke acid elution test can be performed. The Kleihauer-Betke test is a quantitative measurement of fetal red blood cells in maternal blood, and it can be valuable for determining if additional amounts of Rh IgG should be administered. The amount of Rh IgG required for treatment after sensitization is at least 20 mcg/mL of fetal RBCs.

Point-of-care blood tests have become available for use in the emergency department and have been shown to have very high sensitivity and specificity in determining Rh status.[7]

Obtaining maternal Rh antibody titers can be helpful for future follow-up care of pregnant females who are known to be Rh negative and may be initiated from the ED. High levels of maternal Rh antibodies suggest that Rh sensitization has occurred, and further studies, such as amniocentesis and/or cordocentesis, may be necessary to evaluate the health of the fetus.

Postnatal emergency care

Immediately after the birth of any infant with an Rh-negative mother in the ED or prehospital setting, examine blood from the umbilical cord of the infant for ABO blood group and Rh type, measure hematocrit and hemoglobin levels, perform a serum bilirubin analysis, obtain a blood smear, and perform a direct Coombs test.

A positive direct Coombs test result confirms the diagnosis of antibody-induced hemolytic anemia, which suggests the presence of ABO or Rh incompatibility.

Elevated serum bilirubin measurements, low hematocrit, and elevated reticulocyte count from the neonate can help determine if an early exchange transfusion is necessary.

An emergent exchange transfusion, preferably performed in a neonatal intensive care setting with experience in this procedure, is required in infants born with erythroblastosis fetalis, hydrops fetalis, or kernicterus.

Other testing

Perform fetal monitoring in cases of suspected fetal distress. Abnormal fetal heart tones and ultrasonographic evidence of fetal or placental injury are indications of worsening fetal condition requiring emergent delivery, ideally in a center specializing in high-risk obstetric care.

Imaging Studies

In the ED, ultrasonography of a pregnant female with suspected Rh incompatibility is limited to pelvic ultrasonography. Fetal ascites and soft tissue edema are definite signs of severe involvement.

Once hydrops fetalis has developed, the sonographic evidence includes scalp edema, cardiomegaly, hepatomegaly, pleural effusion, and ascites.



Prehospital Care

When possible, prehospital care personnel should direct their efforts on stabilization of the mother and infant, followed by immediate transport to a facility specializing in high-risk obstetric and neonatal care.

Emergency Department Care

ED care of the pregnant woman with Rh-negative blood and a suspected fetomaternal hemorrhage varies depending on the presentation of the patient and the gestational age of the fetus.

If the mother has Rh-negative blood and has not been sensitized previously, administer human anti-D immune globulin (Rh IgG or RhoGAM) and refer the woman for further evaluation.

If the mother has been sensitized previously, as determined by elevated level of maternal Rh antibodies, administration of Rh IgG is of no value. In this situation, prompt referral to a center that specializes in high-risk obstetrics is warranted.

When an infant with Rh incompatibility is delivered in the ED, a more aggressive approach is required, centering on respiratory and hemodynamic stabilization of the infant and determining the need for an emergent exchange transfusion and phototherapy.

Stress the importance of early prenatal care to each pregnant female who presents to the ED. Early administration of Rh IgG in conjunction with early prenatal care is the best means to prevent Rh incompatibility

Referrals and consultations

After administering Rh IgG in the ED, promptly refer the Rh-negative pregnant mother of an Rh-positive fetus to an institution equipped for high-risk obstetric care.

Refer every pregnant female with Rh incompatibility to a medical center specializing in high-risk obstetric care.



Medication Summary

Rh IgG, first released for general use in 1968, has been remarkably successful in the prevention of Rh incompatibility. In the Rh-negative mother, the preparation is administered after a suspected fetomaternal hemorrhage. The exact mechanism by which passive administration of Rh IgG prevents Rh immunization is unknown. The most likely hypothesis is that the Rh immune globulin coats the surface of fetal RBCs containing Rh antigens. These exogenous antibody-antigen complexes cross the placenta before they can stimulate the maternal endogenous immune system B cells to produce IgG antibodies.

Since Rh IgG became the standard of care in the United States, the risk of Rh incompatibility has been reduced from 10-20% to less than 1%. Because of its short half-life, Rh IgG routinely is administered once at 28 weeks' gestation and again within 72 hours after birth to all Rh-negative pregnant females as a part of routine prenatal and postnatal care.[8, 9]

The current recommendation is that every Rh-negative nonimmunized woman who presents to the ED with antepartum bleeding or potential fetomaternal hemorrhage should receive 300 mcg of Rh IgG IM. For every 30 mL of fetal whole blood exposed to maternal circulation, 300 mcg of Rh IgG should be administered. A lower 50-mcg dose preparation of Rh IgG is available and recommended for Rh-negative females who have termination of pregnancy in the first trimester when fetomaternal hemorrhage is believed to be minimal.

The results of an epidemiologic study by Pegoraro et al, which estimated the worldwide number of pregnancies involving an Rh(D)-negative mother and an Rh(D)-positive fetus, suggested that about 50% of women around the globe who need immunoprophylaxis do not receive it.[10]

Blood derived product

Class Summary

This agent is effective in preventing Rh isoimmunization.

Human anti-D immune globulin (RhoGAM, BayRho-D, Rhophylac, HyperRho)

Suppresses immune response of nonsensitized Rh O (D) negative mothers exposed to Rh O (D) positive blood from the fetus as a result of a fetomaternal hemorrhage, abdominal trauma, amniocentesis, abortion, full-term delivery, or transfusion accident. Should be administered if the patient is Rh negative, unless the father also is Rh negative.