Efficacy Endpoints: Primary: Rhesus Rh D alloimmunization; Secondary: Kleihauer-Betke test, neonatal jaundice
Harm Endpoints: Anemia requiring transfusion, renal failure, disseminated intravascular coagulopathy (DIC), death
Who was studied: >4,500 Rh-negative un-sensitized women
Narrative: Alloimmunization occurs when a Rh negative (Rh-) mother develops anti-Rh antibodies after being exposed to Rh positive (Rh+) blood during pregnancy or in the immediate intra-partum period with a Rh+ fetus. Maternal Rh antibodies are capable of crossing the placenta, entering the fetal circulation of a subsequent pregnancy, and attacking fetal Rh+ red blood cells. This can lead to severe complications such as massive hemolysis, profound anemia, and high output fetal cardiac failure (hydrops fetalis).
Anti-Rh immunoglobulin (aka Anti-Rh, Anti-Rh-D, Anti-D) quickly binds to fetal Rh+ red blood cells entering the maternal circulation and prevents them from sensitizing the mother’s immune system. Post-partum prophylaxis with Rh IgG has made the immune-mediated complications of Rhesus disease incredibly rare (Clarke and Hussey 1994; Crowther and Middleton 1997). Routine ante-partum administration of Rh immunoglobulin (Rhogam) to Rh- women, on the other hand, has the hypothesized role of preventing alloimmunization during pregnancy in the setting of occult fetal-maternal hemorrhage, thus preventing the aforementioned postpartum complications with Rh+ fetuses in future pregnancies.
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 of gestation to prevent transplacental fetal blood exposure and maternal alloimmunization. Infusion of anti-D in Rh-negative pregnant women did not yield a significant change in alloimmunization rates during pregnancy, at delivery, or 12 months post-partum. Secondary outcomes showed a small but significant reduction in the chance of a positive Kleihauer-Betke test during pregnancy and at delivery. No differences were seen in neonatal jaundice. These findings were derived from low or very low quality data. The trials did not examine alloimmunization or other outcomes in future pregnancies.
Adverse effects of Rh immunoglobulin, including clinically-significant anemia, renal failure, pulmonary edema, DIC, and death, were not reported in these trials. Separate studies suggest adverse events to be exceedingly rare (MacKenzie et al 2004, e.g.).
Overall, this is a fairly well-performed systematic review and meta-analyses limited by mostly low quality evidence. Given the consistently demonstrated outcomes, potential patient-centered benefits, and lack of demonstrated or likely harm, we recommend consideration of the intervention (YELLOW), pending more definitive research.
Caveats: This latest Cochrane update by McBain et al from 2015 yielded one new trial in progress but no new published results to include since the prior article (Crowther and Middleton 2009). Therefore, data and conclusions remain unchanged. Methods were adjusted the prior publication to formally describe risk of bias using GRADE criteria.
Maternal alloimmunization (the development of anti-Rh antibodies) has been widely accepted as a surrogate marker for potential fetal morbidity and mortality (Kim and Makar 2012). This is supported by population-based studies showing a marked decrease in rhesus disease since the routine administration of post-partum anti-D immunoglobulin (Clarke and Hussey 1994). The referenced Cochrane review did not show a significant difference in this outcome (low quality evidence).
The clinical accuracy and importance of the secondary outcome - a positive Kleihauer-Betke (measurement of fetal hemoglobin in maternal blood) - is much less certain (Duckett and Constantine 1997). The test is at best a weak proxy for potential alloimmunization in future pregnancies,and as such, is two steps removed from a patient-centered outcome.
The first trial included in the systematic review showed non-significant trends toward reduced alloimmunization using a 100 mcg dose. The second trial failed to show any benefit with a 50 mcg dose. This dose response mirrors what has been seen in postpartum administration. Reporting data for the higher-dose trials separately would yield 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 this systematic review showing only a trend toward benefit. Additionally, the included trials suffer from relatively poor quality, lacking placebo controls, absence of true blinding, and appropriate randomization.
Adverse events from Rho were not reported in the included trials of this review, but literature on the treatment of idiopathic thrombocytopenia (ITP) reports them to be exceedingly rare (Cooper 2009). 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. It remains unclear how well estimates of harm equate in these two populations.
Given to Rh-negative women during the third trimester, anti-Rh IgG 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-Rh IgG 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, considering the cost of treatment may be on the order of $USD100-1,000. 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.
Analysis I.2: Positive Kleihauer-Betke at birth of a Rh positive infant
Intervention 73/599 = 12.2%
Control 119/590 = 20.2%
RRR = 39.6%
ARR = 7.98%
NNT = 12.5
X100/60 (for all pregnancies not just Rh+) = 20.8
Analysis I.4: Immunization in pregnancy *NON SIGNIFICANT
Intervention 5/1879 = 0.3%
Control 13/2023 = 0.6%
RRR = 58.6%
ARR = 0.4%
NNT = 265.6
Analysis I.5: Immunization after birth of a Rh positive infant *NON SIGNIFICANT
Intervention 5/1112 = 0.4%
Control 13/1185 = 1.1%
RRR = 59.0%
ARR = 0.6%
NNT = 154.5
X100/60 = 257.4
Analysis I.6: Immunization at 2-12 months *NON SIGNIFICANT
Intervention 6/985 = 0.6%
Control 16/1063 = 1.5%
RRR = 59.5%
ARR = 0.9%
NNT = 111.6
X100/60 = 186.0
“This result became statistically significant when calculated as a risk difference (RD) across the two randomised controlled trials (RD -0.01, 95% CI -0.01 to 0.00).”
Analysis I.9: Neonatal Jaundice *NON SIGNIFICANT
Intervention 1/927 = 0.1%
Control 4/955 = 0.4%
RRR = 74.2%
ARR = 0.3%
NNT = 321.6
Author: Gary Green, MD
Published/Updated: February 8, 2018
The title bar is color-coded with our overall recommendation.