Should We Be Using Rh Immunoglobulin for Bleeding in Early Pregnancy?

Plain-Language Summary: RhD protein is found on the surface of red blood cells. Blood with this protein is called Rh positive. If someone doesn’t have the RhD protein on their red blood cells, they are Rh negative, which is about 15% of people in the United States. During pregnancy, if an Rh-negative person carries an Rh-positive fetus, their body might create antibodies that can harm future Rh-positive pregnancies. This is called sensitization and can lead to severe problems — even death — for the fetus. 

To prevent this, RhD medication is usually given at 28 weeks of pregnancy and after delivery. Once the benefits of giving RhD later in pregnancy were apparent, it also started to be given after miscarriage or abortion. However, new research shows that after an abortion or miscarriage in the first 12 weeks, there isn’t enough fetal blood mixing with maternal blood to cause sensitization. 

Many professional obstetrical organizations no longer recommend RhD for miscarriage and abortions before 12 weeks.

In the middle of the night, sometime in 2015, my patient sat in the ER with bleary eyes, asking if she could go home to her family. She had come in many hours earlier, bleeding in pregnancy and now diagnosed with a miscarriage at 8 weeks gestation. But I couldn’t let her go before finding out her blood type. So she sat, taking up valuable real estate in our busy emergency room, waiting for the results of a test that had an 85% chance of telling her that she would never need Rh immunoglobulin (RhIg).

At that time, it wasn’t clear whether RhIg had value for Rhesus D (RhD) negative patients experiencing bleeding in early pregnancy, so medical organizations in the US and many other high resource countries took a better-safe-than-sorry approach and recommended it. Today, new population-level data and preliminary biological evidence suggest that RhD screening and RhIg treatment in the first trimester of pregnancy can be safely discontinued (1-5).

The Case for RhIg During Pregnancy

RhD sensitization occurs when RhD-negative people are exposed to red blood cells (RBCs) expressing the RhD antigen, most commonly through pregnancy, transfusion, and intravenous drug use (6). Sensitization is a multifactorial process that depends on volume of RBC exposure, ABO blood type compatibility, and other factors (7, 8). Sensitization becomes problematic when a sensitized person is later pregnant with an RhD-positive fetus and produces antibodies which cross the placenta to the fetal circulation, where they bind to fetal RhD-positive RBCs and destroy them. In rare cases, this leads to hemolytic disease of the fetus and newborn (HDFN), which can be characterized by fetal anemia, hydrops fetalis, and stillbirth (9, 10).

Sound clinical evidence from the 1960-80s showed that administering RhIg after an RhD-negative patient is exposed to RhD-positive RBCs dramatically reduces the risk of sensitization. Giving 300mcg of RhIg to RhD-negative patients at 28 weeks of pregnancy and again at delivery has decreased the rates of sensitization from 10% to 0.2%, leading to a drop in the risk of hemolytic disease of fetuses and newborns due to RhD in countries with adequate access to RhIg.

“Indication Creep” of a Public Health Success

The use of RhIg in late pregnancy and after delivery to prevent RhD sensitization has been an unquestionable public health success (7). Professional medical organizations in the US, Canada, and much of Europe aligned around RhIg use and uptake occurred with near-universal fidelity in these high-resource countries.Many of those professional medical organizations also recommended RhIg for threatened, spontaneous, and induced abortion care in the first trimester. However, recommendations for use earlier in pregnancy were based on “indication creep” rather than antecedent studies (11).

The Consequences of Overuse

Efficient use of finite resources is required for truly equitable care. As a product derived from human blood, RhIg certainly qualifies as a finite resource. While intermittent shortages have been an ongoing issue in the US and other high-resource countries, limitations and inequities in access mean that RhD-negative patients in some low-resource countries do not receive a dose of RhIg even when indicated after delivery (12). And while RhIg contamination with Hepatitis C in Germany and Ireland led to improved production methods that have made RhIg extremely safe, we cannot rule out the possibility that at some point in the future some unknown pathogen could find its way into the RhIg supply chain, particularly if production increases to meet widespread demand.

Furthermore, routine RhIg administration at <12 weeks’ gestation costs US healthcare payers up to $313 million per year (13) – not including the ancillary costs to patients for unpaid time off work, travel, and childcare. These costs are particularly burdensome for folks who are paying out of pocket for care, such as the majority having induced abortions, those with high-deductible insurance plans, or those traveling for care.

The patients who must dedicate their time and hard-earned money to those costs inspired our team to revisit the practices of RhD testing and RhIg administration in early pregnancy.

New Research Brings New Clarity

Beginning in 2019, studies of population-level epidemiological and indirect clinical data explored whether RhIg at <12 weeks gestation added value (1-4). Among those studies was the prospective cohort study I conducted with my colleagues at University of Pennsylvania to investigate whether Rh immunoglobulin is beneficial for RhD-negative individuals undergoing induced first-trimester abortion care.

The study included 506 participants, all of whom underwent either a medical or procedural abortion before 12 weeks 0 days’ gestation. Our main objective was to determine how frequently maternal exposure to fetal red blood cells (fRBCs) exceeds the most conservative published threshold for Rh sensitization in induced first-trimester abortion. To measure exposure, we used high-throughput flow cytometry to detect circulating fRBCs in paired maternal blood samples before and after abortion.

The results addressed our main objective and left us with many questions and ideas for further research. While we found variation in fRBC counts between individuals, baseline and postabortion fRBC counts were strongly correlated within individuals and no participant with fRBC counts below the threshold prior to abortion crossed above the threshold after treatment. In other words, induced abortion in the first trimester—whether by medication or procedure— does not appear to be a risk factor for RhD sensitization.

Better Evidence, Better Guidelines, Better Practices

I am pleased to report that the World Health Organization (WHO), Society of Family Planning (SFP), Royal College of Obstetricians and Gynecologists (RCOG), and the American College of Obstetricians and Gynecologists (ACOG) have all updated their recommendations regarding Rh testing and RhIg treatment at less than 12 weeks of gestation to reflect the new evidence. However, some national and international guidelines still depart from this growing consensus.

This research is just the beginning of what I hope will be a team effort in our scientific community to develop universal, evidence-based guidelines for RhIg in various pregnancy scenarios. Meanwhile, let’s make the most of a critical and finite resource by discontinuing its use in first trimester pregnancy loss and abortion care.

This blog is written by its author and represents the author’s opinion and information. GenBioPro does not provide and this blog should not be considered GenBioPro’s medical advice or recommendations on clinical practice. GenBioPro’s sole recommendations are provided in the Full Prescribing Information for its products. Prescribers should review Full Prescribing Information for any product and exercise their independent clinical judgement in the care of their patients.

With respect to RH Immunoglobulin, prescribers should note that the Prescribing Information for mifepristone tablet, 200 mg, provides the following: “5.5 Rhesus Immunization: The use of Mifepristone tablets, 200 mg is assumed to require the same preventive measures as those taken prior to and during surgical abortion to prevent rhesus immunization.”

References

1. Horvath S, Tsao P, Huang ZY, et al. The concentration of fetal red blood cells in first-trimester pregnant women undergoing uterine aspiration is below the calculated threshold for Rh sensitization. Contraception. 2020;102(1):1-6. doi: 10.1016/j.contraception.2020.02.011.

2. Horvath S, Huang Z-Y, Koelper NC, et al. Induced Abortion and the Risk of Rh Sensitization. JAMA. 2023;330(12):1167-74. doi: 10.1001/jama.2023.16953.

3. Wiebe ER, Campbell M, Aiken AR, Albert A. Can we safely stop testing for Rh status and immunizing Rh-negative women having early abortions? A comparison of Rh alloimmunization in Canada and the Netherlands. Contraception X. 2019;1:100001.

4. Hollenbach SJ, Cochran M, Harrington A. “Provoked” feto-maternal hemorrhage may represent insensible cell exchange in pregnancies from 6 to 22 weeks gestational age. Contraception. 2019;100(2):142-6. doi: 10.1016/j.contraception.2019.03.051.

5. Urbaniak S, Greiss M. RhD haemolytic disease of the fetus and the newborn. Blood Reviews. 2000;14(1):44-61.

6. DelBaugh RM, and the BEST Collaborative. Why Do People Still Make Anti-D Over 50 Years after the introduction of Rho(D) Immune Globulin? A NEST Collaborative Study Presented on Behalf of the RADAR Study Investigators. Transfusion. 2025. doi: 10.1111/trf.18202.

7. Klein HG, Anstee DJ. Mollison’s blood transfusion in clinical medicine. Chichester, West Sussex, UK: Wiley-Blackwell; 2014.

8. Yazer M, Triulzi D, Sperry J, Corcos A, Seheult J. Rate of RhD-alloimmunization after the transfusion of RhD-positive red blood cell containing products among injured patients of childbearing age: single center experience and narrative literature review. Hematology. 2021;26(1):321-7. doi: 10.1080/16078454.2021.1905395.

9. ACOG Clinical Practice Update: Rh D Immune Globulin Administration After Abortion or Pregnancy Loss at Less Than 12 Weeks of Gestation. Obstet Gynecol. 2024;144(6):e140-e143. doi: 10.1097/AOG.0000000000005733.

10. Practice Bulletin No. 181: Prevention of Rh D Alloimmunization. Obstet Gynecol. 2017;130(2):e57-e70. doi: 10.1097/AOG.0000000000002232.

11. Sperling JD, Dahlke JD, Sutton D, Gonzalez JM, Chauhan SP. Prevention of RhD Alloimmunization: A Comparison of Four National Guidelines. Am J Perinatol. 2018;35(2):110-9. Epub 20170914. doi: 10.1055/s-0037-1606609.

12. Pegoraro V, Urbinati D, Visser GH, et al. Hemolytic disease of the fetus and newborn due to Rh (D) incompatibility: A preventable disease that still produces significant morbidity and mortality in children. PloS One. 2020;15(7):e0235807.

13. Horvath S, Wang L, Calo W, Yazer MH. Economic analysis of foregoing Rh immunoglobulin for bleeding in pregnancy <12 weeks gestation. Contraception. 2024;139:110530. doi: 10.1016/j.contraception.2024.110530.

14. Yazer MH, Panko G, Holcomb JB, Kaplan A, Leeper C, Seheult JN, et al. Not as “D” eadly as once thought–the risk of D-alloimmunization and hemolytic disease of the fetus and newborn following RhD-positive transfusion in trauma. Hematology. 2023;28(1):2161215.