Rh incompatibility

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

The prevention of RhD sensitization in Rh-negative mothers carrying an Rh-positive fetus is the primary management objective. It involves immunoprophylaxis via the administration of Rho(D) immune globulin to at-risk women.

If sensitization does occur, the window for primary prevention is effectively closed and Rh immunoprophylaxis is no longer appropriate. Actions then involve fetal and maternal surveillance for, and management of, fetal anemia or hydrops.

Prevention of RhD sensitization

Immunoprophylaxis with Rho(D) immune globulin is highly effective in preventing sensitization of Rh-negative mothers carrying an Rh-positive fetus.[21][24][44] It has been instrumental in the dramatic reduction in death from Rh incompatibility. Rho(D) immune globulin is a blood product containing a high titer of antibodies to Rh antigens of red blood cells. Its precise mechanism of action is unknown, but it may work by neutralizing Rh-positive fetal red blood cells in the maternal blood, thus reducing the risk of sensitization. Administration is efficacious by either the intramuscular or intravenous route.[45] Anti-Rh antibodies persist for more than 3 months after one dose.

A prerequisite for immunoprophylaxis is knowledge of the maternal rhesus status.[44] All pregnant women should be tested at the time of the first prenatal visit for RhD type, and screened for the presence of anti-D antibodies, to identify unsensitized RhD-negative patients who are potential candidates for immunoprophylaxis.[21][44] Rho(D) immune globulin is not given to an RhD-negative mother who is already sensitized to the RhD antigen.

Eligible candidates should receive routine prenatal and postpartum administration of Rho(D) immune globulin, as described below. In addition, the risk of sensitization can be reduced by administering Rho(D) immune globulin to women in situations in which fetomaternal hemorrhage (FMH) is likely, such as miscarriage, chorionic villus sampling, and amniocentesis.[46] Multiple clinical guidelines describing RhD sensitization prevention strategies have been published, including those from the American College of Obstetricians and Gynecologists, and the International Federation of Gynecology and Obstetrics/International Confederation of Midwives.[21][44]

Routine postpartum administration of Rho(D) immune globulin

RhD sensitization occurs in approximately 16% of pregnancies among RhD-negative women.[44] Postpartum administration of Rho(D) immune globulin reduces this risk to approximately 1.5%, and is the most effective intervention to prevent Rh incompatibility in subsequent pregnancies.[21][44]

Following birth, newborns from RhD-negative women should have their Rh factor determined from umbilical-cord blood.[44] If the infant is confirmed to be RhD-positive, all RhD-negative women who are not known to be sensitized should receive Rho(D) immune globulin (intravenously or intramuscularly) within 72 hours of delivery.[21][27][44]

Guidelines vary on the dose of Rho(D) immune globulin that should be administered, and can depend on the size of the FMH, the brand of Rho(D) immune globulin used, and affordability.[44] A prophylactic dose of 1500 IU (equivalent to 300 micrograms) of Rho(D) immune globulin is commonly given in high-income countries and can prevent RhD sensitization after exposure to up to 30 mL of RhD-positive fetal whole blood or 15 mL of fetal red cells.[21][44][47] On rare occasions, delivery-associated FMH may be greater than 30 mL. Circumstances such as traumatic deliveries, cesarean sections, manual removal of the placenta, delivery of twins, and unexplained hydrops fetalis are more likely to be associated with a large FMH. Accordingly, several guidelines, including those from the American College of Obstetricians and Gynecologists, and from the British Society for Haematology, recommend that RhD-negative women who give birth to RhD-positive infants should undergo additional testing to assess the volume of FMH and guide the amount of Rho(D) immune globulin required to prevent sensitization.[21][34][48] However, at no time should Rho(D) immune globulin treatment be delayed pending the results of quantitative FMH testing.[49]

If Rho(D) immune globulin is not given within 72 hours of delivery, it should be given as soon as the need is recognized, for up to 28 days after delivery.[27]

Routine prenatal administration of Rho(D) immune globulin

Building on the efficacy of postpartum Rho(D) immune globulin administration, the risk of RhD sensitization in Rh-negative women carrying an Rh-positive baby has been shown to be further reduced (to approximately 0.5%) by the introduction of routine prenatal administration.[44][50]

Routine prenatal antibody screening should be obtained at 28 weeks of gestation before administration of Rho(D) immune globulin (to identify women who have become sensitized before 28 weeks of gestation).[21][27][34][51] If anti-D antibodies are identified, it should be determined whether this presence is immune-mediated or passive (e.g., as a result of previous Rho(D) immune globulin treatment). If RhD antibodies are passive, then the woman should continue to be offered prophylaxis with Rho(D) immune globulin; however, if they are present because of sensitization, prophylaxis is not beneficial, and management should proceed in accordance with protocols for RhD-sensitized pregnancies.[21]

Prophylactic prenatal Rho(D) immune globulin should be offered to unsensitized RhD-negative women, whether the fetal blood type is unknown or known to be Rh-positive.[21][27] The American College of Obstetricians and Gynecologists recommends that a single dose be offered at 28 weeks of gestation, while other guidelines recommend either a single dose at around 28 weeks, or two doses at around 28 and 34 weeks of gestation.[21][27][34][44]

Noninvasive estimation of fetal Rh status is now possible via the analysis of cell-free DNA in maternal plasma, and this method may be acceptable for sensitized patients who refuse amniocentesis.[33] Some countries recommend employing this technique in the first trimester, to allow targeted prenatal RhD immunoprophylaxis (i.e., only where the fetus is RhD-positive); however, the American College of Obstetricians and Gynecologists does not recommend the routine use of this approach on the grounds of cost-effectiveness.[21][44] When paternity is certain, rhesus testing of the baby’s father may be offered as a means of determining fetal RhD status.[27][33]

Routine prenatal Rho(D) immune globulin prophylaxis should be administered regardless of, and in addition to, any Rho(D) immune globulin that may have been given for a potentially sensitizing event (see below).[34] In the past, it has been recommended that a second dose of Rho(D) immune globulin should be administered to women who have not given birth at 40 weeks; however, the current guidelines suggest that this is generally not required, provided that the prenatal injection was given no earlier than 28 weeks' gestation.[21][27]

Administration of Rho(D) immune globulin following potentially sensitizing events

In RhD-negative, previously unsensitized women, a variety of events associated with potential placental trauma or disruption of the fetomaternal interface can lead to sensitizing FMH during pregnancy. Rho(D) immune globulin can help minimize the risk of such sensitization, and if indicated, should be administered as soon as possible after the event, ideally within 72 hours.[27][34] If Rho(D) immune globulin is not given within 72 hours, it should be given as soon as the need is recognized, for up to 28 days after the potentially sensitizing event.[27] For sensitizing events occurring after 20 weeks of pregnancy, the magnitude of FMH should be assessed, and further doses of Rho(D) immune globulin administered if required.[34][49]

Miscarriage/abortion and intrauterine fetal death

Guidelines for the administration of Rho(D) immune globulin following miscarriage/abortion vary and local protocols should be followed.[21][27][34][44][49][52] The American College of Obstetricians and Gynecologists states that in the case of spontaneous first-trimester miscarriage or abortion in RhD-negative women, the risk of sensitization is very low so routine Rh testing and Rh immunoprophylaxis is not recommended. However, Rh testing and administration of Rho(D) immune globulin may be considered on an individual basis, according to patient preferences.[21][25] It recommends that Rho(D) immune globulin should be given to unsensitized RhD-negative women who have a pregnancy termination (either medical or surgical); or who experience fetal death in the second or third trimester.[21][25]

Guidelines from the International Federation of Gynecology and Obstetrics/International Confederation of Midwives note that because an intrauterine fetal death may have been caused by a large FMH, it may be useful to perform a Kleihauer–Betke test, to determine the size of the hemorrhage, and thus the dose of Rho(D) immune globulin needed.[44]

Ectopic pregnancy

Several guidelines recommend the administration of Rho(D) immune globulin for all cases of ectopic pregnancy in unsensitized RhD-negative women.[21][27][44]

Molar pregnancy

In a complete molar pregnancy, sensitization to RhD should not occur, due to the absence of fetal organ development. However, the situation is different in a partial molar pregnancy. Because differentiating between the forms of molar pregnancy may be difficult, it is generally advised to administer Rho(D) immune globulin to all unsensitized RhD-negative women with a molar pregnancy.[21][44]

Invasive procedures (e.g., chorionic villus sampling, amniocentesis)

Most countries recommend administration of Rho(D) immune globulin following invasive diagnostic procedures, such as chorionic villus sampling or amniocentesis, in unsensitized RhD-negative women when the fetuses could be RhD-positive.[21][27][34][44]

Bleeding and abdominal trauma in pregnancy

Rho(D) immune globulin is recommended for RhD-negative women who experience prenatal hemorrhage after 20 weeks of gestation; some guidelines also suggest Rho(D) immune globulin should be considered in certain cases of bleeding earlier in gestation.[21][34][44]

Rho(D) immune globulin should be administered to RhD-negative women who have experienced abdominal trauma.[21][27][34][44]

Quantitative testing for FMH may be considered following events potentially associated with placental trauma and disruption of the fetomaternal interface (e.g., placental abruption, blunt trauma to the abdomen, cordocentesis, placenta previa with bleeding).[27] There is a substantial risk of FMH over 30 mL with such events.[27]

External cephalic version in breech presentation

Some guidelines recommend administration of Rho(D) immune globulin for unsensitized RhD-negative patients following external cephalic version.[21][27][34] Quantitative testing for FMH may also be considered.[27]

Verbal or written consent must be obtained prior to administration of Rho(D) immune globulin.

Management following RhD sensitization

If antibody screening identifies anti-D antibodies in an RhD-negative pregnant woman, and assessments conclude that their presence is active, not passive, the patient should be considered sensitized, and specialist obstetric advice should be sought.[49] Rh immunoprophylaxis is no longer given.[32] Fortunately, initial sensitization in a first affected pregnancy is often mild.

The initial management of an RhD-sensitized pregnancy involves the determination of the paternal rhesus status. If paternity is certain, and the father is RhD-negative, no further assessment/intervention is necessary. All children from a homozygous RhD-positive father, and 50% from a heterozygous RhD-positive father, will be RhD-positive.[32] In the case of a heterozygous RhD-positive, or unknown, paternal genotype, the fetal antigen type should be assessed (by amniocentesis or noninvasive analysis of maternal blood).[32] In the case of an RhD-positive fetus, management involves fetal and maternal surveillance for signs of fetal anemia and hydrops.

Quantitation of maternal antibody titer is performed serially to document worsening disease and identify the need for additional fetal testing and/or treatment. The American College of Obstetricians and Gynecologists states that a critical titer (titer associated with a significant risk for severe hemolytic disease of the fetus and newborn, and hydrops) is considered to be between 1:8 and 1:32 in most centers.[32] If the initial antibody titer is 1:8 or less, the patient may be monitored with titer assessment every 4 weeks.[32] However, serial titers are not adequate for monitoring fetal status when the mother has had a previously affected fetus or neonate.[32]

In a center with trained personnel and when the fetus is at an appropriate gestational age, Doppler measurement of peak systolic velocity in the fetal middle cerebral artery is an appropriate noninvasive means to monitor pregnancies complicated by RhD sensitization.[32] Fetal ultrasound assessment is also employed.

Most cases of rhesus sensitization causing serious hemolytic disease in the fetus are the result of incompatibility with respect to the D antigen.[32] However, over 30 antigenic variants have been identified, and care of patients with sensitization to non-RhD antigens that are known to cause hemolytic disease should be the same as that for patients with D sensitization.[32] A possible exception is Kell sensitization.[32]

Fetal therapy

The goal of fetal therapy is to correct severe anemia, ameliorate tissue hypoxia, prevent (or reverse) fetal hydrops, and avoid fetal death.

If fetal blood is Rh-negative, or if middle cerebral artery blood flow or amniotic bilirubin levels remain normal in an Rh-positive fetus, the pregnancy can continue to term untreated. If fetal blood is Rh-positive or of unknown Rh status, and middle cerebral artery flow or amniotic bilirubin levels are elevated, suggesting fetal anemia, the fetus can be given intravascular intrauterine blood transfusions by a specialist at an institution equipped to care for high-risk pregnancies. [Figure caption and citation for the preceding image starts]: Intraperitoneal transfusion; the echogenic needle tip is visualized in the pocket of ascitesThe Ottawa Hospital; used with consent of the patient [Citation ends]. com.bmj.content.model.Caption@123ab991

Neonatal therapy

Neonates with erythroblastosis are immediately evaluated by a pediatrician to determine the need for exchange transfusion, phototherapy, or intravenous immune globulin (IVIG). IVIG is used in some clinical practice as it has been shown to reduce the need for exchange transfusion in neonates with proven hemolytic disease due to Rh and/or ABO incompatibility and to decrease the duration of hospitalization and phototherapy.[53][54] However, there is an overall lack of evidence to support its use for the treatment of alloimmune hemolytic disease.[55][56] [ ] [Evidence C]

Use of this content is subject to our disclaimer