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Efficacy Endpoints: Rhesus Rh D alloimmunization, Rhesus disease
Harm Endpoints: Anemia requiring transfusion, renal failure, DIC, death
Narrative: • Alloimmunization, in which a Rh negative mother develops anti-Rh antibodies after being exposed to Rh positive blood during pregnancy or in the immediate intra-partum period, can lead to severe complications in future pregnancies. Rh antibodies are capable of crossing the placenta, entering the fetal circulation, and attacking fetal (Rh-positive) red blood cells. This can lead to massive hemolysis, profound anemia, and high output fetal cardiac failure (hydrops fetalis). Post-partum administration of Rh immunoglobulin prophylaxis has made these immune-mediated complications incredibly rare. Routine ante-partum administration of Rh immunoglobulin has the additional hypothesized role of preventing alloimmunization during pregnancy due to occult fetal-maternal hemorrhage.
This review included two relatively low quality trials involving over 4,500 Rh-negative unsensitized women. The studies examined the efficacy of IgG anti-D antibodies given at 28 and 34 weeks gestation to prevent transplacental fetal blood exposure and maternal alloimmunization. Infusion of anti-D in Rh-negative pregnant women significantly reduced the chance of a positive Kleihauer-Betke test at delivery. There was a non-significant trend towards reducing alloimmunization during pregnancy, at delivery, and up to 12 months post partum.
Adverse effects of Rh immunoglobulin, including clinically-significant anemia, renal failure, pulmonary edema, DIC, and death, appear to be exceedingly rare.
Caveats: • Maternal alloimmunization (the development of anti-Rh antibodies) has been widely accepted as a surrogate marker for potential fetal morbidity and mortality. This is supported by population-based studies showing a marked decrease in rhesus disease since the routine administration of post-partum anti-D immunoglobulin. While we feel that maternal alloimmunization has been validated as a surrogate marker and outcome measure, the clinical accuracy and importance of a positive Kleihauer-Betke or similar test is much less certain. The test is at best a weak proxy for potential alloimmunization,, and as such, is two steps removed from a patient-important outcome.
One of the review’s two cited studies showed non-significant trends toward reduced alloimmunization using a 100 mcg dose, while the other failed to show benefit with a 50 mcg dose. This dose response mirrors what has been seen in postpartum administration. Reporting data for the higher-dose study separately suggests a NNT for preventing alloimmunization of 213. This is roughly consistent with other non-randomized trials excluded by the Cochrane review but often cited as supporting data in obstetric guidelines. In general, the data for antepartum prophylaxis is less robust than that for postpartum women, with the systematic review showing only a trend toward benefit. Additionally, the review’s included studies suffer from relatively poor quality, lacking placebo controls, true blinding, and full randomization.
Adverse events from anti-D are exceedingly rare. Nearly all reports of significant events occur in the treatment of idiopathic thrombocytopenia (ITP). It should be noted that the doses used in ITP (up to 200 mcg/kg) are much higher than those used for the prevention of rhesus disease, and many ITP regimens require multiple doses. Therefore, it is not clear how well estimates of harm equate in these two populations. The available data on the use of anti-D in pregnancy suggests that significant adverse events are vanishingly rare, though these outcomes were not recorded in the trials involved in this study.
When administered to Rh-negative women during the third trimester, anti-D immunoglobulin may have a role in reducing Rhesus disease in future pregnancies. Given the excellent safety profile of the intervention, the risk to benefit ratio suggests that the use of anti-D immunoglobulin in the third trimester may be a reasonable option in regions with sufficient resources and access to the drug. However, we believe that the lack of conclusive quantitative evidence has brought the cost effectiveness of unproven antepartum therapy into question,. High-quality, randomized, placebo-controlled trials should be performed to assess whether either routine or event-based administration of anti-D immunoglobulin adds importantly to the routine use of the drug in the post-partum period.
Author: Gary Green, MD and Dan Runde, MD
Published/Updated: January 8, 2013
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