This article reviews the actively evolving clinical practice of Rhesus D (RhD) testing and RhD immune globulin (RhIg) prophylaxis in the context of first trimester bleeding events, including abortion. It summarizes population-level data and indirect biologic studies, while comparing current guidelines for RhD testing and RhIg prophylaxis, highlighting existing discrepancies. Considerations such as cost, access, shortages, and fetal RhD status testing via noninvasive prenatal testing are addressed in this discussion. Although several organizations have updated their clinical guidelines to align with recent evidence against RhIg prophylaxis in early pregnancy, more direct clinical data is needed to develop definitive clinical guidance.
Key points
- •
Rhesus D (RhD) testing and RhD Immune Globulin (RhIg) prophylaxis for first trimester bleeding events is an area of clinical practice that is actively evolving, with recent studies suggesting it is likely unnecessary.
- •
This article reviews these studies and compares current national and international guidelines for RhD testing and prophylaxis in the first trimester.
- •
Considerations including cost, access, and fetal RhD status testing with noninvasive prenatal testing are discussed in the context of first trimester RhIg prophylaxis.
- •
Although several major organizations no longer recommend routine RhD testing and RhIg prophylaxis for first trimester bleeding events, high-quality clinical data is needed to develop more definitive clinical guidance.
- •
Aligning international guidelines will help prevent discrepancies in care and ensure appropriate distribution of this finite human blood product.
| HDFN | hemolytic disease of the fetus and newborn |
| NIPT | noninvasive prenatal testing |
| RANZCOG | Royal Australian and New Zealand College of Obstetricians and Gynecologists |
| RBC | red blood cells |
| Rh | Rhesus |
| Rh− | RhD-negative |
| Rh+ | RhD-posi-tive |
| RhD | Rhesus D |
| RhIg | Rhesus D Immune Globulin |
| SFP | Society of Family Planning |
| SMFM | Society of Maternal Fetal Medicine |
| WHO | World Health Organization |
Introduction
Rhesus D Immune Globulin (RhIg) administration in cases of first-trimester bleeding events is an actively evolving clinical practice. Prior to 2022, Rhesus D (RhD) testing and RhIg prophylaxis in all RhD-negative (Rh−) patients was the standard of care for bleeding events at all gestational ages. This standard was based mostly on expert opinion and indirect evidence. New and emerging evidence from population-level data and indirect biological studies call this standard into question. While direct clinical data remains limited, practice guidelines are quickly evolving to align with the growing population-level and indirect biologic evidence against the benefit of RhIg administration in the first trimester. In 2022, the World Health Organization (WHO) and Society of Family Planning (SFP) updated their guidelines to recommend against Rh testing and RhIg prophylaxis for medical and surgical abortions at less than 12 weeks gestational age. , Several major medical organizations have followed suit. Most recently, in September 2024, the American College of Obstetricians and Gynecologists (ACOG) published a clinical practice update suggesting forgoing routine Rh testing and prophylaxis before 12 weeks. Although several major organizations no longer recommend routine testing and prophylaxis, more high-quality direct clinical data is needed to develop more definitive clinical guidance, align international guidelines to prevent discrepancies in care, and ensure that the medical community is distributing this finite resource appropriately.
Background
The Rhesus (Rh) blood group consists of 49 different Rh antigens, of varying immunogenicity. Rh− refers specifically to the absence of the RhD antigen. In Rh− pregnant patients, exposure to Rh-positive (Rh+) fetal red blood cells (RBCs) during sensitizing events involving fetal-maternal hemorrhage can trigger an immune response. The process of Rh sensitization is dependent on the volume of Rh+ fetal RBC exposure. Once sensitization occurs, maternal antibodies can be reactivated in future Rh+ pregnancies. These antibodies are capable of crossing the placenta, binding to fetal RBCs, and giving rise to hemolytic disease of the fetus and newborn (HDFN), a potentially severe or even fatal condition. It is important to note that RhIg is only effective in blocking sensitization to the RhD antigen, not the other antigens in the Rhesus blood group.
Even before RhIg was discovered, only about 10% of pregnancies in RhD− patients led to sensitization. Since it was first licensed in 1968, the routine administration of RhIg to RhD− patients in the third trimester (at 28 weeks gestation with or without redosing at 34 weeks gestation) and within 72 hours of delivery has decreased rates of sensitization to less than 0.2%. Notably, rates have not decreased further with the routine administration of RhIg following early pregnancy bleeding events ( Fig. 1 ).
While there is evidence supporting RhIg administration in later pregnancy, the gestational age at which it becomes necessary is unknown. There is increasing data questioning the need for RhIg prophylaxis in the first trimester. In the United States, approximately 6 million pregnancies occur each year, with nearly half experiencing first-trimester bleeding due to induced, spontaneous, or threatened abortion. , Based mostly on expert opinion and indirect evidence of RhIg benefit later in pregnancy, many countries have historically recommended routine testing and subsequent RhIg prophylaxis in all RhD− patients for first trimester bleeding events, including abortion. However, most of the existing evidence comes from older studies with small sample sizes that relied on imprecise measurements of fetal-maternal hemorrhage volume and inaccurate methods of pregnancy dating. These studies also used sharp curettage, which carries an increased risk of bleeding compared with uterine aspiration, the preferred abortion method in modern clinical practice.
In 1971, before RhIg was routinely administered in the first trimester, a cohort study investigated the rate of sensitization in patients with RhD+ live births following spontaneous abortion. They determined a rate of sensitization of 3% based on a single case of sensitization in a patient who required curettage for an incomplete abortion at 16 weeks. The only randomized, controlled study investigating the benefit of RhIg in early pregnancy showed no evidence of sensitization in any RhD− patients or their subsequent RhD+ live births following spontaneous abortion at 8 to 24 weeks, regardless of receiving RhIg or placebo. A 2013 systematic review concluded that there is “insufficient data available to evaluate the practice of anti-D administration in unsensitized Rh− mothers after spontaneous miscarriage” highlighting the lack of evidence to support RhIg administration in early pregnancy.
Limited evidence supporting rhesus D immune globulin administration in first trimester loss
Population Level Data
Several countries do not routinely administer RhIg prophylaxis to Rh− women after first trimester pregnancy loss. A 2019 study compared sensitization rates between 2 countries with different policies but similar abortion rates. The Netherlands has a longstanding policy of forgoing RhIg administration in cases of spontaneous abortions before 10 weeks and induced abortions before 7 weeks gestation. In Canada, RhIg was recommended for all RhD− patients in cases of abortion at any gestational age at the time of the study. Despite a higher prevalence of RhD− patients in the Netherlands, the rate of clinically significant perinatal antibodies was similar (4.03 per 1000) when compared with Canada (4.21 per 100). These findings suggest that universally adopting the Netherlands policy of foregoing RhIg administration in patients with first trimester pregnancy loss is safe.
In fact, Canada updated its guidelines in March 2024 to recommend against RhIg administration in cases of abortion, ectopic pregnancy, or molar pregnancy at less than 8 weeks. As countries continue to adjust their guidelines, there is an opportunity to compare sensitization rates before and after these changes. Additionally, more research is needed to compare rates of sensitization between countries with differing guidelines. These studies could provide valuable supportive evidence to help inform one unified international guideline.
Recent Clinical Data
Compelling but indirect clinical data suggests that RhD testing and RhIg prophylaxis are unnecessary in the first trimester, as the risk of sensitization following any bleeding event at less than 12 weeks likely approaches zero. Newer evidence suggests that the minimum amount of fetomaternal hemorrhage to induce sensitization is 125 fetal RBCs per 5 million total RBCs. A 2020 pilot study utilizing this threshold provides evidence against the routine administration of RhIg in early pregnancy loss. Horvath and colleagues analyzed serum samples from 37 women who underwent uterine aspiration during the first trimester. None of the samples exceeded the estimated sensitization threshold, suggesting that abortion in the first trimester does not expose the maternal circulation to a volume of fetal red blood cells high enough to cause Rh sensitization.
The 2023 powered follow-up multicenter prospective cohort study supports forgoing RhIg prophylaxis in early pregnancy. They measured the volume of fetal RBCs in paired maternal blood samples before and after first trimester abortion in 506 participants and found that in 99.8% of participants, post-abortion fetal RBC volume was below the threshold. Notably, the only patient whose post-abortion RBC volume exceeded the threshold reported prior bleeding during pregnancy and exceeded the threshold before and after the procedure. While more direct, high-quality clinical data is needed, these results strongly suggest that medication and procedural abortions are not associated with an increased risk of sensitization before 12 weeks.
Other considerations
Given the latest data, it is important to consider the burdens associated with continuing to screen all patients with first trimester bleeding events and administering RhIg to all patients found to be RhD−. These include nationwide shortages of this finite blood product, costs to patients and health care systems, difficulties with access to care, and the risks associated with injection. Furthermore, advancements in noninvasive prenatal testing (NIPT) for fetal RhD antigen status along with a promising new treatment for rare cases of sensitization, should be included in this discussion.
Shortages, Overuse, and Equitable Access
It is important to consider shortages and disparities in access when discussing how and when to best distribute RhIg. The medical community has a responsibility to allocate this finite blood product equitably, ensuring that as many patients as possible who need it, receive it. Although the smaller 50 μg (250 IU) dose has long been considered sufficient to prevent sensitization in early pregnancy, many health systems still administer the 300 (1500 IU) microgram dose. This overuse in high-income countries has consequences for low-resource settings. Internationally, accessing RhIg at delivery and at 28 weeks gestation, when there is strong direct evidence of its benefit, can be challenging.
Pegoraro and colleagues conducted a study to quantify the discrepancy in RhIg prophylaxis between high and low-income countries. They compared the doses of RhIg that are needed to achieve adequate prophylaxis to those that are actually administered. Their results suggest that half of women around the world who require prophylaxis do not receive it. To achieve postpartum prophylaxis alone, which has the highest quality evidence in preventing HDFN, more than 2.5 million additional doses would be needed outside of high-income countries. These results are likely due to a complex interaction between availability, awareness, and affordability. It is the responsibility of the international health care community to ensure that the available supply is administered equitably and in alignment with high quality direct evidence.
There have been periodic shortages of RhIg internationally and in the United States. Shortages result from several factors including increased demand, limited number of manufacturers, and production challenges. In March 2024, the American Society of Health System Pharmacists began reporting a shortage of RhIg in the US due to shortage of an active ingredient and manufacturing issues, anticipating that the shortage would be present through at least the end of calendar year 2024. It is important to be good stewards of this finite resource derived from human blood and prioritize its use in settings that offer the most benefit. Several organizations, including ACOG, have issued practice advisories to address proper distribution when shortages are present. In the setting that triaging RhIg becomes necessary, ACOG recommends prioritizing postpartum patients, then the 28-week antepartum dose. The Society of Maternal Fetal Medicine (SMFM), one of the few organizations whose guidelines still recommend RhIg prophylaxis at all gestational ages, similarly specifies prioritizing postpartum and antenatal patients at later gestational ages when the supply is limited. Additionally, ACOG recommends consideration of NIPT to determine fetal Rh(D) antigen status (see below). As shortages continue, the existing disparities will become more apparent. This highlights the importance of aligning international guidelines to prioritize appropriate distribution and utilization of RhIg.
Cost and Access
In the US alone, as much as $313 million dollars is spent on RhD testing and RhIg administration in first trimester bleeding events annually. A 2024 economic analysis of forgoing RhIg testing and prophylaxis for bleeding events at less than 12 weeks’ gestation determined that it could save US health care payers $5.5 million/100,000 pregnancies. Abortion care is paid for directly by patients up to 69% of the time. Thus, costs associated with any additional, unnecessary testing can negatively impact access to care. Omitting unnecessary testing in this patient population offers the most high-value care.
Abortion care via telemedicine and self-managed abortion rates are increasing. An increasing number of patients need access to a safe abortion without unnecessary barriers. Requiring in-person care, and potentially travel across state lines, for RhD testing and RhIg prophylaxis could prevent some patients from accessing a safe abortion. The priority for all health care providers is that patients can access safe and affordable care. While patients should be counseled on all potential complications associated with home abortion care, including forgoing RhD testing and prophylaxis, current evidence suggest that the risk of sensitization in induced abortions at less than 12 weeks’ gestational age are very low and should not prevent any patient from receiving desired abortion care.
Injection Risks
Historically, there have been outbreaks of hepatitis C associated with the administration of contaminated RhIg. Although today’s supply is thoroughly screened for known pathogens and considered very safe, there is a small risk of infection with any human blood product, including the risk of new bloodborne pathogens that may not be immediately detectable in the future. Injection risks include adverse drug reactions (headache, fever, chills), hemolysis, and hypersensitivity reactions. There have even been rare case reports of disseminated intravascular coagulation associated with RhIg administration. While there is strong evidence that this product is safe and effective when administered at 28 weeks gestation and within 72-h postpartum, it is important to more carefully weigh these minimal risks when considering the lack of evidence supporting its use in early pregnancy.
Detecting Fetal Rhesus D Status with Noninvasive Prenatal Testing
Recent studies of NIPT to determine fetal Rh(D) antigen status are important to review as they have the potential to enhance first trimester risk assessment for sensitization. Fetal RBC antigen genotyping using cell-free DNA from maternal plasma has high sensitivity and specificity for determining fetal Rh(D) antigen status. This could preserve RhIg, a limited blood product, to patients who really need it while avoiding unnecessary treatment for those who don’t. The Royal Australian and New Zealand College of Obstetricians and Gynecologists (RANZCOG) has standardized NIPT testing at over 11 weeks gestation for RhD− patients, forgoing RhIg administration altogether if the fetus is determined to be RhD−. Several European countries have adopted this as standard practice , , . US health systems are also beginning to offer this alternative testing. A 2019 systematic review determined that NIPT is sufficiently accurate to detect fetal RhD status in RhD− patients, which could lead to a considerable reduction in unnecessary treatment.
A Promising New Treatment for Rare Cases of Sensitization
New and exciting developments investigating potential treatments for sensitization also warrant attention. Traditionally, management of HDFN has relied on invasive interventions, such as intrauterine transfusions, that require access to specialty care and pose risks to the fetus. Recent trials investigating nipocalimab, a monoclonal antibody targeting the neonatal Fc receptor, offer a promising, less invasive alternative in managing this rare occurrence. Phase II clinical trial data showed that a statistically significant number (54%, n = 7/13) of participants at high risk for recurrent early-onset HDFN achieved a live birth at or after 32 weeks’ gestation without intrauterine transfusions, compared with the historic reference point of 10%. No cases of fetal hydrops occurred. While more high-quality clinical data is needed, these findings highlight the potential for nipocalimab to delay and prevent fetal anemia in rare cases where sensitization occurs. If nipocalimab proves effective in managing HDFN, the perceived tolerable risk of sensitization following first trimester bleeding events might be further reduced, providing support to recent updates in clinical guidelines.
Current practice guidelines
US Guidelines
In light of recent evidence, ACOG updated their guidelines in September 2024 to suggest foregoing RhIg at less than 12 weeks gestation but continues to allow for administration following a risk-benefit discussion and shared decision-making with the patient. This is similar to the SFP, National Abortion Federation, and Planned Parenthood guidelines which recommend forgoing routine Rh testing and RhIg prophylaxis for patients undergoing abortion at less than 12 weeks gestation. However, the SMFM continues to recommend testing and prophylaxis at all gestational ages, when clinically feasible, due to lack of direct clinical evidence disproving its benefit. This leaves health care providers having to navigate conflicting recommendations. All US guidelines recommend administering the smaller 50 μg (250 IU) dose, when it is determined to be necessary at less than 12 weeks. While shared decision making should be implemented in all patient care settings, it should not replace the need for clear, aligned guidelines. This situation is further complicated by the shortage of RhIg in the US, additional barriers to abortion access in the post- Dobbs era, cost, and the inequities associated with the use of RhIg in early pregnancy ( Table 1 ).
