Continuing Education Activity

Rho(D) immune globulin (RhIG) is a medication used to manage and treat Rh-negative pregnancies and immune thrombocytopenic purpura. It is in the immune globulin biological class of drugs. This activity reviews the indications, action, and contraindications for RhIG as a valuable agent in managing RhIG in preventing hemolytic disease of the newborn and immune thrombocytopenic purpura and other disorders when applicable. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, monitoring, relevant interactions) pertinent for healthcare team members in managing patients with Rh-negative pregnancies, immune thrombocytopenic purpura, and related conditions.

Objectives:

• Identify the mechanism of action and administration of Rho(D) immune globulin.
• Describe the adverse effects and contraindications of Rho(D) immune globulin.
• Review the appropriate monitoring and toxicity of Rho(D) immune globulin.
• Outline the importance of collaboration and coordination among the interprofessional team to enhance patient care when dosing and monitoring warfarin to improve patient outcomes for those receiving Rho(D) immune globulin.

Indications

Rho(D) immune globulin (anti-D immune globulin or RhIG) is a commercial biological antibody derived from human plasma that targets red blood cells (RBCs) positive for the Rh(D) antigen (also referred to as the D antigen). When a blood type is described as positive (A+, B+, AB+, O+), the individual has RBCs that are positive for the D antigen and are thus Rh-positive.

RhIG is known for its use in preventing hemolytic disease of the fetus and neonate, which is the result of transplacental passage of anti-D antibodies due to previous exposure to an incompatible Rh blood type of either a previous pregnancy or received blood products. If the Rh-negative mother forms anti-D antibodies, this is known as Rhesus (Rh) isoimmunization. These maternally-derived anti-D antibodies may cross the placenta and target Rh-positive fetal RBCs for destruction resulting in hemolysis. This hemolytic disease may have devastating effects on the fetus, depending on the severity of the immune response.     

Several trademark names for RhIG products exist in the United States. Although Rho(D) immune globulin is a specific brand name, it is the common parlance used to refer to all RhIG products. Careful examination of the product insert is necessary to establish the associated indications and other unique characteristics. 

Indications for RhIG vary by manufacturer. An FDA-approved RhIG product exists for each of the following indications:

1. Immune thrombocytopenic purpura (ITP)

   • Rh(D)-positive, non-splenectomized

     • Chronic ITP in children and adults
     • Acute ITP in children
     • Improving platelet counts secondary to HIV infection
2. Rh isoimmunization suppression 

   • Rh(D)-negative, non-sensitized patient with Rh-incompatible fetus

     • Prophylaxis in the following clinical situations: 
     • Routine antepartum and postpartum mothers
     • Obstetric complications (ectopic pregnancy, threatened abortion, fetal demise in second or third trimesters)
     • Spontaneous or induced abortions
     • Following invasive obstetric procedures [1]
     • Abdominal trauma involving fetal-maternal hemorrhage 
   • Incompatible transfusions of Rh(D)-positive RBCs in Rh(D)-negative individuals [2]

Possible non-FDA-approved uses of RhIG:

1. Anti-D alloimmunization prophylaxis after platelet transfusion of Rh-positive individuals to Rh-negative patients with acute leukemia due to possible RBC residual in platelet concentrates.[3] [Level 3]

Mechanism of Action

The mechanism of action for patients receiving RhIG in immune thrombocytopenic purpura treatment is not entirely understood. Prevention of Rh isoimmunization appears to be an immunologic blockade of Fc receptors (RcR) within the reticuloendothelial system (RES); other immunomodulatory effects are also possible. Intravenous infusion of anti-D into an Rh-positive recipient leads to antibody coating of the circulating erythrocytes, which are eventually cleared primarily by the spleen. Clearance of sensitized erythrocytes by the RES results in increased platelet counts and reduced bleeding.[4][5]

The mechanism by which RhIG prevents isoimmunization is not completely understood but is likely to suppress the immune response and antibody formation in Rh-incompatible individuals (Rh-negative exposed to Rh-positive RBCs). If administration occurs within 72 hours of full-term delivery, the incidence decreases from 12% or 13% to 1% or 2%. The chances of isoimmunization drop to less than 1% with the administration schedule at 28 weeks gestation and within 72-hours postpartum.[2][6] 

Administration

Administration of RhIG for prevention of Rh isoimmunization is achieved by either intramuscular (IM) or intravenous (IV) injection, depending on the indication and manufacturer recommendations. During pregnancy, a single dose should be given prophylactically at weeks 26 to 28 and again within 72 hours of delivery of an Rh-positive infant.

For any known or suspected maternal exposure to Rh-positive RBCs or any incompatible Rh-positive blood product received, RhIG should be administered within 72 hours and dosed accordingly to the amount of RBC exposure per manufacturer guidelines. In pregnant women, RhIG should be administered every 12 weeks from the first injection to maintain a sufficient quantity of passively acquired anti-D antibodies.  

Administration of RhIG for immune thrombocytopenic purpura is via IV infusion only.[7] There is a risk of complement system activation when IM-only preparations are given intravenously and should always be avoided in patients with immune thrombocytopenic purpura. Peak serum levels are achieved faster with IV administration; however, the half-life is approximately the same (24 days) for IV and IM administration. Dosages are expressed in micrograms or international units (IUs). The conversion scale is 1 microgram = 5 IUs. The presence of RhIG can persist for months after administration and varies by the individual immune response.[8]

Adverse Effects

The most common adverse effects include[9]:

• Chills
• Headache
• Asthenia
• Fever
• Dizziness
• Infection
• Hypertension
• Vasodilation
• Drowsiness
• Shivering
• Diaphoresis 
• Pallor
• Decreased hemoglobin in patients with immune thrombocytopenic purpura
• Increased lactate dehydrogenase  
• Decreased haptoglobins
• Increased serum bilirubin
• Abdominal and back pain
• Antibody development (positive anti-C antibody test)
• Injection site reaction - erythema, discomfort, mild pain 
• Hyperkinetic muscle activity 

The most serious adverse interactions include[10]:

• Disseminated intravascular coagulation
• Intravascular hemolysis (immune thrombocytopenic purpura patients)
• Acute renal insufficiency
• Clinically compromising anemia
• Death

Contraindications

The FDA-labeled contraindications for RhIG vary by manufacturer but include the following:

1. A hemolytic reaction may result if given to Rh-positive patients; RhIG should be avoided in these individuals. 
2. Patients with a history of severe hypersensitivity or anaphylaxis to any human immune globulin product.
3. Patients with preexisting hemolysis, autoimmune hemolytic anemia, or high risk for hemolysis.
4. RhIG products may contain a small quantity of IgA and should be avoided in IgA deficient individuals with antibodies against IgA.

Monitoring

According to published monitoring parameters on Rh(D) immune globulin, if indicated for the alloimmunization prophylaxis, after administration, patients should be monitored for at least 20 minutes to watch for any signs of systemic reactions.  

If using RhIG to treat immune thrombocytopenic purpura, the black-box warning recommends closely monitoring patients for at least 8 hours to rule out any evidence of intravascular hemolysis. While most patients will be asymptomatic, signs and symptoms to be mindful of in a minority of patients include fever, back pain, shaking chills, and discolored urine or hematuria, which may indicate hemolysis.[10]

Recommended labs for monitoring before treatment initiation include complete blood count (baseline anemia assessment and degree of hemolysis), differential and PBS review (evidence of hemolysis, infection), direct antiglobulin test and antibody screen, reticulocyte count, urinalysis, serum creatinine, and BUN.[10]

Recommended labs to monitor following treatment include complete blood count (1 to 3 days after infusion if first administration), urinalysis 1 to 2 hours after treatment (dipstick only, unless positive for blood), serum creatinine (only if posttreatment hemoglobin decreased greater than 1 g/dL), and BUN (only if posttreatment hemoglobin decreased greater than 1 g/dL).[10]

If intravascular hemolysis is suspected, monitor plasma hemoglobin, LDH, haptoglobin, and plasma bilirubin (direct and indirect).  

Toxicity

Severe and life-threatening toxicities are rare with RhIG treatments. In the event of an overdose in immune thrombocytopenic purpura, patients should be closely monitored to check that the hemoglobin doesn't decrease by more than 1.2 g/dL.[11]

In the suppression of Rh isoimmunization, hemolytic reactions can occur in the case of incompatible blood transfusions after very large doses of RhIG.

Patients should be monitored closely for signs and symptoms of hemolysis with the initiation of supportive treatment at the start of symptoms.

Enhancing Healthcare Team Outcomes

Several RhIG products are currently available in the United States. Although there are multiple brand names, they all have similar clinical indications and dosing but differ significantly in specific attributes. Pharmacists can play an essential role in ensuring the safe administration of these products by guiding clinicians on the use and timing of RhIG therapy. This is one example of the kind of interprofessional activity that must accompany RhIG therapy, with clinicians, mid-level practitioners, specialists, nurses, and pharmacists working and communicating collaboratively to achieve optimal patient outcomes while minimizing adverse effects. [Level 5]

The recommendation is to delay live vaccine administration until at least 12 weeks after the last dose of RhIG. However, according to CDC guidelines, postpartum vaccination of rubella-susceptible women with rubella or MMR vaccine should not be delayed during the last trimester or delivery. It should be serologically tested 6 to 8 weeks post-vaccination to ensure that seroconversion has occurred.

If RhIG is inadvertently omitted after delivery, it should be given as soon as possible within the first 72 hours. Partial protection can be achieved when administered with 13 days of birth and may provide some benefit as much as 28 days after delivery; the longer the delay, the less protective.[12][13] [Level 2] [Level 3]

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Kim YA, Makar RS. Detection of fetomaternal hemorrhage. Am J Hematol. 2012 Apr;87(4):417-23. [PubMed: 22231030]

2.

Bowman JM. The prevention of rh-immunization. Can Fam Physician. 1977 Dec;23:60-8. [PMC free article: PMC2379019] [PubMed: 20469282]

3.

Villalba A, Santiago M, Freiria C, Montesinos P, Gomez I, Fuentes C, Rodriguez-Veiga R, Fernandez JM, Sanz G, Sanz MA, Carpio N, Solves P. Anti-D Alloimmunization after RhD-Positive Platelet Transfusion in RhD-Negative Women under 55 Years Diagnosed with Acute Leukemia: Results of a Retrospective Study. Transfus Med Hemother. 2018 May;45(3):162-166. [PMC free article: PMC6006613] [PubMed: 29928170]

4.

Ware RE, Zimmerman SA. Anti-D: mechanisms of action. Semin Hematol. 1998 Jan;35(1 Suppl 1):14-22. [PubMed: 9523745]

5.

Crow AR, Lazarus AH. The mechanisms of action of intravenous immunoglobulin and polyclonal anti-d immunoglobulin in the amelioration of immune thrombocytopenic purpura: what do we really know? Transfus Med Rev. 2008 Apr;22(2):103-16. [PubMed: 18353251]

6.

Crowther C, Middleton P. Anti-D administration after childbirth for preventing Rhesus alloimmunisation. Cochrane Database Syst Rev. 2000;1997(2):CD000021. [PMC free article: PMC7061351] [PubMed: 10796089]

7.

Costumbrado J, Mansour T, Ghassemzadeh S. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Dec 11, 2022. Rh Incompatibility. [PubMed: 29083656]

8.

Bussel JB, Graziano JN, Kimberly RP, Pahwa S, Aledort LM. Intravenous anti-D treatment of immune thrombocytopenic purpura: analysis of efficacy, toxicity, and mechanism of effect. Blood. 1991 May 01;77(9):1884-93. [PubMed: 1850307]

9.

Hong F, Ruiz R, Price H, Griffiths A, Malinoski F, Woloski M. Safety profile of WinRho anti-D. Semin Hematol. 1998 Jan;35(1 Suppl 1):9-13. [PubMed: 9523744]

10.

Despotovic JM, Lambert MP, Herman JH, Gernsheimer TB, McCrae KR, Tarantino MD, Bussel JB. RhIG for the treatment of immune thrombocytopenia: consensus and controversy (CME). Transfusion. 2012 May;52(5):1126-36; quiz 1125. [PMC free article: PMC3427798] [PubMed: 21981825]

11.

Cheung E, Liebman HA. Anti-RhD immunoglobulin in the treatment of immune thrombocytopenia. Biologics. 2009;3:57-62. [PMC free article: PMC2726056] [PubMed: 19707396]

12.

Samson D, Mollison PL. Effect on primary Rh immunization of delayed administration of anti-Rh. Immunology. 1975 Feb;28(2):349-57. [PMC free article: PMC1445805] [PubMed: 804437]

13.

Fung Kee Fung K, Eason E, Crane J, Armson A, De La Ronde S, Farine D, Keenan-Lindsay L, Leduc L, Reid GJ, Aerde JV, Wilson RD, Davies G, Désilets VA, Summers A, Wyatt P, Young DC., Maternal-Fetal Medicine Committee, Genetics Committee. Prevention of Rh alloimmunization. J Obstet Gynaecol Can. 2003 Sep;25(9):765-73. [PubMed: 12970812]

Disclosure: Athina Yoham declares no relevant financial relationships with ineligible companies.

Disclosure: Damian Casadesus declares no relevant financial relationships with ineligible companies.