How is Rh‑D (Rhd) status assessed and what are the management recommendations for Rh‑negative individuals, especially regarding blood transfusion and Rh immunoglobulin prophylaxis during pregnancy?

Rh-D Status Assessment and Management

Determining Rh-D Status

Rh-D status is determined through standard serological blood typing, and for pregnant Rh-negative women, cell-free fetal DNA testing from maternal plasma can determine fetal RhD status with 97.2% sensitivity and 96.8% specificity, or exceeding 99% accuracy when performed after 11 weeks gestation. 1

• This non-invasive prenatal testing allows targeted administration of RhIg only when the fetus is RhD-positive, avoiding unnecessary treatment in approximately 40% of Rh-negative pregnancies where the fetus is also Rh-negative 1
• Standard cord blood serological testing after delivery confirms newborn RhD status and determines need for postpartum prophylaxis 1

Management for Rh-Negative Individuals in Pregnancy

Standard Prophylaxis Protocol

All Rh-negative pregnant women should receive RhIg at 28 weeks gestation and within 72 hours after delivery of an Rh-positive infant, reducing alloimmunization rates from 1.8% to 0.1-0.2%. 1

• The standard dose is 300 mcg (1500 IU) for both antepartum and postpartum administration 2
• Postpartum RhIg alone reduces alloimmunization from 13-17% to 1-2%, and adding the antenatal dose at 28 weeks provides the additional reduction to 0.1-0.2% 1
• The 72-hour window is critical for optimal effectiveness, though delayed administration up to 28 days postpartum still provides some benefit and is preferable to no administration 1

Early Pregnancy Events Requiring RhIg

For spontaneous or induced abortion, vaginal bleeding, or threatened abortion at <12 weeks gestation, administer 50 mcg RhIg within 72 hours; if unavailable, use the standard 300 mcg dose. 1

This recommendation is based on several critical facts:

• Fetal red blood cells display RhD antigens from as early as 6 weeks gestation, making maternal sensitization physiologically possible even in very early pregnancy 1, 3
• Fetomaternal hemorrhage occurs in 48% of threatened abortions, 36% of complete abortions, and 22% of incomplete abortions 1
• No randomized controlled trials demonstrate that withholding RhIg in first trimester is safe 1
• As little as 0.03-0.1 mL of Rh-positive red blood cells can trigger primary alloimmunization 3

Common pitfall to avoid: Do not assume early gestational age eliminates risk—fetal RBCs with D-antigen are present from 6 weeks onward, and bleeding severity does not reliably predict hemorrhage volume 1

Obstetric Complications and Procedures

Administer 300 mcg (1500 IU) RhIg within 72 hours for any potentially sensitizing event including: 1, 2

• Amniocentesis or chorionic villus sampling
• External cephalic version
• Abdominal trauma (28% of pregnant patients with minor trauma show fetomaternal hemorrhage) 1
• Antepartum hemorrhage or placental bleeding at any gestational age
• Ectopic pregnancy or hydatidiform mole
• Intrauterine fetal death

Excessive Fetomaternal Hemorrhage

When fetomaternal hemorrhage exceeds 15 mL of fetal RBCs, administer 300 mcg (1500 IU) plus an additional 20 mcg per mL of Rh-positive fetal RBCs in excess of 15 mL if quantified, or an additional 300 mcg dose if excess bleeding cannot be quantified. 2

• Quantitative testing for fetomaternal hemorrhage should be considered for significant placental trauma 1
• The standard 300 mcg dose covers up to 15 mL of fetal Rh-positive RBCs 2

Management for Rh-Negative Individuals Receiving Blood Transfusions

For Rh-negative individuals inadvertently transfused with Rh-positive blood products, administer 20 mcg (100 IU) RhIg per 2 mL of transfused Rh-positive whole blood or per 1 mL of Rh-positive RBCs within 72 hours of exposure. 2

Special Consideration for Platelet Transfusions

For Rh-negative children (particularly girls) and women of childbearing age receiving platelet transfusions from Rh-positive donors, prevention of RhD alloimmunization should be considered either through exclusive use of Rh-negative platelets or via anti-D immunoprophylaxis. 4

• Platelets do not express Rh antigens, but contaminating RBCs in platelet preparations are sufficient to induce Rh sensitization in 7.8-19% of exposed Rh-negative cancer patients 4
• A dose of 25 mg (125 IU) of anti-D immunoglobulin protects against 1 mL of RBCs 4
• Intravenous preparations (such as WinRho SDF) are preferable in thrombocytopenic patients 4

Administration Routes and Practical Considerations

RhIg can be administered intravenously or intramuscularly for suppression of Rh isoimmunization; for large doses exceeding 5 mL, divide into multiple intramuscular injection sites. 2

• Critical warning: Do not confuse micrograms (mcg) with International Units (IU) when calculating doses—miscalculations could result in significant overdose or underdose (1 mcg = 5 IU) 2
• Do not administer subcutaneously into fatty tissue 2
• Ensure intramuscular injection reaches muscle; consider intravenous administration if this is uncertain 2

Safety Profile and Contraindications

RhIg is a pooled biological blood product derived from human plasma that carries rare but serious risks including intravascular hemolysis, though current preparations show no recent evidence of viral transmission. 5

Contraindications include: 2

• History of anaphylactic or severe systemic reaction to human immune globulin products
• IgA deficiency with antibodies against IgA and history of hypersensitivity
• Never administer to the newborn infant—only to the Rh-negative mother

Important safety considerations:

• May cause hemolysis by coating fetal Rh-positive red cells, with rare cases of intravascular hemolysis, disseminated intravascular coagulation, and renal failure 5
• FDA black box warning exists for fatal intravascular hemolysis in ITP treatment (does not apply to pregnancy prophylaxis) 2
• May not be acceptable to certain populations such as Jehovah's Witnesses who refuse blood products 5

Clinical Scenarios Requiring Special Attention

Unknown Blood Type in Urgent Situations

When RhD testing could delay abortion care or pose logistical barriers, counsel patients on implications of unknown blood type but prioritize completing the abortion; if testing is unavailable and clinically indicated, administer RhIg as the risks of administration are low compared to potential consequences of sensitization. 1

Supply Shortages

During RhIg shortages, prioritize postpartum patients and antenatal patients at later gestational ages, as approximately 90% of fetomaternal hemorrhage and alloimmunization events occur during delivery itself. 1, 3

• Equivalent RhIg products may be substituted if the typically used brand is unavailable 1
• Pregnant women at 28 weeks gestation should still be prioritized for available doses 1

Understanding the Immunization Timeline

Most sensitization (approximately 90%) occurs at delivery, but antepartum exposure increases with gestational age from 7% in first trimester to 29% in third trimester. 3

• Primary immune response varies, with only 60% of exposed individuals developing detectable antibodies 3
• Antibodies may not be immediately detectable; post-exposure testing should occur at least 4 weeks after exposure 3
• Silent sensitization can occur without any identified precipitating event 3
• Individual variation is substantial—40% of exposed individuals never develop antibodies even with repeated exposures 3