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RhD alloimmunization: Prevention in pregnant and postpartum patients

RhD alloimmunization: Prevention in pregnant and postpartum patients
Literature review current through: Sep 2023.
This topic last updated: Dec 20, 2022.

INTRODUCTION — RhD-negative individuals who are exposed to D-positive red blood cells (RBCs) are at risk for developing anti-D antibodies. Widespread use of anti-D immune globulin (Rho(D) immune globulin) during pregnancy and postpartum has dramatically reduced, but not eliminated, D alloimmunization caused by fetal RBCs that have gained access to the maternal circulation.

Use of anti-D immune globulin for prevention of D alloimmunization will be discussed here. Related topics (a discussion of the Rh system, diagnosis and management of Rh alloimmunization in pregnancy, in utero transfusion, and neonatal issues) are reviewed in detail separately:

(See "RhD alloimmunization in pregnancy: Overview".)

(See "RhD alloimmunization in pregnancy: Management".)

(See "Intrauterine fetal transfusion of red cells".)

(See "Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management".)

ANTI-D IMMUNE GLOBULIN

Source — Anti-D immune globulin is manufactured from pooled plasma selected for high titers of IgG antibodies to D-positive erythrocytes. Although once produced from the plasma of alloimmunized females, the decreasing prevalence of D alloimmunization has necessitated the use of male donors who undergo repeated injections of D-positive red cells to develop high-titered polyclonal anti-D plasma. This dwindling resource has led to a search for a synthetic anti-D immune globulin, but none are available for clinical use.

Two monoclonal antibodies, BRAD-3 and BRAD-5, have been derived by immortalizing B lymphocyte cell lines from hyperimmunized donors with Epstein-Barr virus. A recombinant polyclonal human anti-D consisting of 25 different monoclonal IgG1 antibodies (rozrolimupab [Sym001]; Symphogen) has also been developed by transfecting Chinese hamster ovary cells with human genes [1,2]. Potential future advantages of a synthetic product over products derived from humans include greater availability and elimination of risks of pathogen transmission and adverse reactions due to impurities in plasma.

Pharmacology and pharmacokinetics

D-antibody suppression

300 micrograms – A single 300 microgram dose (1 microgram = 5 international units) contains sufficient anti-D to suppress the immune response to 15 mL of D-positive fetal red blood cells (RBCs) (or 30 mL fetal D-positive whole blood).

50 micrograms – A single 50 microgram dose contains sufficient anti-D to suppress the immune response to 2.5 mL of D-positive fetal RBCs (or 5 mL fetal whole blood).

Positive titers from passive immunization

Mean half-life – The mean half-life of anti-D immune globulin is 24 days and approximately the same for intravenous or intramuscular injection. However, peak serum levels are achieved faster after intravenous injection.

Duration of a positive titer – In most patients, a low antibody titer (≤4) can be detected in maternal serum for several weeks after administration [3]; higher titers have been reported in case reports [4]. In a small proportion of patients, highly sensitive assays have detected residual anti-D antibody as long as 95 days after a routine antepartum injection [5] and possibly as long as 180 days [6]. Fifteen to 20 percent of patients who receive anti-D immune globulin at 28 weeks of gestation will have a low titer (≤4) at term.

Persistence of the antibody can result in a positive direct antiglobulin test in the newborn but does not have adverse clinical effects. In one study, 20 percent of newborns whose mothers received anti-D immune globulin at 34 weeks of gestation had a positive direct antiglobulin test, but hemoglobin and bilirubin levels were similar to controls [7].

Mechanism of action — The mechanism whereby anti-D immune globulin prevents D alloimmunization is unproven. Possibilities include rapid macrophage-mediated clearance of anti-D-coated RBCs and/or down-regulation of antigen-specific B cells before an immune response occurs [8,9]. A significant number of D antigen sites on fetal RBCs in the maternal circulation are not bound by passive anti-D immune globulin; therefore, epitope masking is probably not the reason anti-D responses are prevented by prophylaxis.

Efficacy — Prior to the development of anti-D immune globulin, approximately 16 percent of D-negative pregnant people became alloimmunized after two births of D-positive ABO-compatible infants [10]. This rate fell to 1 to 2 percent with routine postpartum administration of a single dose of anti-D immune globulin and was further reduced to 0.1 to 0.3 percent with the addition of routine antenatal administration in the third trimester [11-13]. In a meta-analysis of randomized trials comparing postpartum anti-D prophylaxis with no treatment/placebo, treatment within 72 hours of birth dramatically lowered the incidence of D alloimmunization in a subsequent pregnancy (relative risk [RR] 0.12, 95% CI 0.07-0.23) [14]. A subsequent meta-analysis found a further reduction in alloimmunization when prophylaxis was administered both antepartum and postpartum versus only postpartum, but the wide confidence interval could not exclude the possibility of no or minimal benefit (RR 0.42, 95% CI 0.15-1.17; two trials, 3902 participants) [15].

D alloimmunization has not been completely eliminated because of [16]:

Failure to administer anti-D immune globulin in accordance with medical society guidelines, and

Unsuspected fetomaternal bleeding early in gestation, before administration of third-trimester prophylaxis

In a study of anti-D globulin utilization worldwide, a total of 4 million doses were administered annually, falling short of the estimated 13 million doses required for antenatal and postpartum prophylaxis that would be needed in all RhD-negative patients who delivered RhD-positive infants [17]. The lack of adequate prophylaxis worldwide has led to an estimated 114,100 fetal/neonatal deaths annually, with many additional cases of long-term disability due to kernicterus [18].

Safety

Overall risks and adverse reactions — There is no evidence that maternal administration of anti-D immune globulin results in any significant risk of fetal anemia, enhancement of maternal primary immune response to D-positive RBCs, adverse obstetric outcome, reduced maternal response to postpartum rubella immunization, or short- or long-term harm to the fetal immune system [19,20].

Serious adverse reactions are rare: From 1990 to 2000, 2.9 million doses of one manufacturer's anti-D immune globulin were administered, and the manufacturer received only 11 reports of adverse events possibly related to the drug [20].

Risk of infection and allergic reactions

Protection from transmission of viruses – Plasma units for making anti-D immune globulin are tested for antibodies to hepatitis C virus, human immunodeficiency viruses, hepatitis B virus, and parvovirus B19. Only units that test negative are used.

In addition, most anti-D immune globulin is processed by Cohn cold ethanol fractionation followed by viral-clearance ultrafiltration. This process is highly effective for removing viral particles, such as hepatitis A and C, parvovirus B12, and human immunodeficiency virus [21,22].

Protection from allergic reactions – Allergic reactions to anti-D immune globulin are rare. Anti-D immune globulin prepared by Cohn cold ethanol fractionation followed by viral-clearance ultrafiltration (eg, HyperRHO S/D, RhoGAM, BayRho-D) must be administered intramuscularly because trace amounts of IgA and other plasma proteins in the product could cause severe hypersensitivity and anaphylactic reactions if administered intravenously to patients with antibodies to IgA. (See "Intravenous immune globulin: Adverse effects", section on 'Preparation'.)

Anti-D immune globulin prepared by ion exchange chromatography isolation (eg, Rhophylac, WinRho SDF) are purer and can be given either intravenously or intramuscularly.

Intramuscular and intravenous preparations are equally effective [23].

Protection from diseases caused by prions – There is no evidence that anti-D immune globulin administration can transmit prions associated with Creutzfeldt-Jakob disease (CJD). Available epidemiologic studies suggest that a history of preceding transfusion does not increase the risk of developing CJD. However, human-to-human transmission of prion diseases can occur under special circumstances, and low levels of infectivity have been noted when whole blood, serum, or buffy coat derived from patients with CJD is inoculated into animals. Therefore, as a precaution, all anti-D immune globulin used in the United Kingdom is manufactured from plasma from the United States. (See "Creutzfeldt-Jakob disease" and "Variant Creutzfeldt-Jakob disease".)

Protection from mercury – Thimerosal, a mercury preservative used to prevent bacterial and fungal contamination, had been used in anti-D immune globulin products in the past, but the US Food and Drug Administration mandated its removal from these products in 2001.

Risk of spurious blood glucose test results — The liquid formulation of WinRho SDF contains maltose, which can result in falsely high blood glucose levels with certain types of blood glucose testing systems [24]. Due to the potential for falsely elevated glucose readings, only testing systems that are glucose-specific should be used to monitor blood glucose levels in patients recently receiving WinRho SDF Liquid.

GUIDELINES FOR PREVENTION OF ANTI-D ALLOIMMUNIZATION (UNITED STATES) — The author agrees with the American College of Obstetricians and Gynecologists (ACOG) approach to prevention of D alloimmunization in D-negative pregnant people, which is described in the following sections [25]. This approach is generally similar to that in other countries, with minor differences in available drug preparations, third-trimester timing of administration, and pregnancy complications warranting prophylaxis [26]. (See 'Society guideline links' below.)

General approach when the fetus is, or may be, D antigen positive

Screen at the first prenatal visit – All D-negative pregnant people should undergo an antibody screen at the first prenatal visit of each pregnancy. The blood test is accurate and inexpensive and, if antibodies are identified (screen-positive), interventions are available for predicting the risk for hemolytic disease of the fetus and newborn (HDFN) as well as diagnosing and treating severe fetal anemia. (See "RhD alloimmunization in pregnancy: Overview".)

Antibody screen-positive patients – D-negative patients who screen positive for anti-D antibodies should not receive anti-D immune globulin: It is not effective once alloimmunization to the D antigen has occurred and will not prevent a rise in maternal titer.

Antibody screen-negative patients – D-negative patients with a negative anti-D antibody screen are candidates for anti-D immune globulin at:

28 weeks of gestation. (See 'Standard prophylaxis at 28 or 28 plus 34 weeks of gestation' below.)

After delivery of a D-positive newborn. (See 'Prophylaxis after delivery' below.)

After an antepartum event associated with an increased risk of fetomaternal bleeding. The quality of evidence supporting a risk of alloimmunization from pregnancy complications is variable, and discussed below. (See 'Selective prophylaxis for pregnancy complications associated with fetomaternal bleeding' below.)

Use of paternal typing or cell-free DNA for targeted antepartum prophylaxis — D-negative pregnant people who are carrying a D-negative fetus do not benefit from anti-D immune globulin; therefore, knowledge of the fetal D antigen status is useful clinically.

Fetal D-negative antigen status determined by paternal typing — Routine paternal D antigen typing is not a standard of care. However, if both biologic mother and father of the fetus are known with certainty to be D-negative, then antenatal anti-D immune globulin may be omitted since the fetus must be D-negative [25,27]. We recommend documenting assurance of paternity and absence of use of a donor egg from a D-positive egg donor. A meta-analysis revealed a median incidence of 3 percent for nonpaternity in pregnancy [28].

Fetal D-negative status known based on evaluation of cell-free DNA

Test performance – The feasibility of using cfDNA circulating in maternal plasma to determine fetal RHD genotype and guide administration of prophylaxis has been shown in several studies [29-34]. Testing is performed after 11 weeks of gestation. The odds of correctly identifying RHD-positive and RHD-negative fetuses increases significantly with gestational age after 11 weeks, so testing is best avoided earlier in pregnancy [35]. In a meta-analysis of 30 studies of cfDNA for RHD determination (n = 10,290 tests), sensitivity was 99.3 percent (95% CI 98.2-99.7) and specificity was 98.4 percent (95% CI 96.4-99.3) for pregnancies tested in the first and second trimesters; sensitivity with real-time quantitative PCR was higher than with conventional PCR [36].

Disadvantages – Selective administration of anti-D immune globulin based on cfDNA results has the potential to increase the number of cases of D alloimmunization when compared with universal antenatal prophylaxis because of the possibility of a false-negative result. A false-negative result (an RHD-positive fetus incorrectly identified as RHD-negative) is of concern since antepartum anti-D immune globulin would be omitted and could potentially result in antepartum alloimmunization. If antepartum prophylaxis is based on cfDNA results, it has been estimated that 1:86,000 D-negative females would have a future pregnancy affected by HDFN that could have been prevented by universal antepartum prophylaxis [30]. One additional case of fetal or neonatal loss or developmental problems would occur per 860,000 D-negative pregnant people. The risk is extremely low because most alloimmunization develops as a result of delivery, and newborn cord blood testing, if performed, would detect fetuses falsely genotyped as RHD-negative, enabling postpartum maternal administration of anti-D immune globulin.

Inconclusive and false-positive (an RHD-negative fetus incorrectly identified as RHD-positive) cfDNA results are not a major concern because antepartum anti-D immune globulin would be administered.

Use in the United States – The use of cfDNA to select appropriate candidates for antepartum prophylaxis is not standard practice in the United States, but the test is commercially available. Some authorities have argued in favor of using it routinely on an ethical basis since the universal prophylaxis approach subjects patients to the costs and consequences of a drug treatment that has no benefit if the fetus is D-negative [37,38].

A 2019 cost analysis using the current cfDNA assay available in the United States failed to find fetal RHD genotyping to be cost-effective as compared with a policy of universal administration of antenatal anti-D immune globulin [39]. ACOG does not recommend the use of cell-free DNA for fetal RHD testing to determine the need for antenatal anti-D immune globulin [25]. They do, however, state that as the cost of the assay in the United States declines, this practice may become an attractive strategy.

The test methodology and performance of cfDNA for determining fetal RHD status are reviewed separately. (See "RhD alloimmunization in pregnancy: Management", section on 'Cell-free DNA testing'.)

Use outside of the United States – The National Institute for Health and Care Excellence in England recommends noninvasive fetal RHD genotype as a cost-effective option to guide antenatal prophylaxis with anti-D immune globulin if the overall cost of testing is £24 or less [40]. An Australian study concluded that noninvasive RHD genotyping was an economically sound option for Australia [41].

In several countries (eg, Denmark, the Netherlands, Sweden, England, France, Finland) fetal RHD determination is performed routinely in D-negative pregnant patients and administration of antenatal anti-D immune globulin is avoided when an RHD-negative fetus is identified. Over one-third of D-negative pregnant patients appropriately avoided antenatal anti-D immune globulin in large studies from Denmark [33] and Sweden [34].

Postnatal cord blood typing is no longer performed in the Netherlands and Denmark [33]: Postnatal prophylaxis is administered based on the prenatal fetal RHD screening result, given the low rate of false negatives (0.03 percent [95% CI 0.01-0.06 percent] in the Netherlands [42]).

Standard prophylaxis at 28 or 28 plus 34 weeks of gestation

Screening — Antibody rescreening at 28 weeks will detect the rare patient who has become alloimmunized in the interval since the first screen. The United States Preventive Services Task Force and ACOG recommend obtaining an antibody screen prior to anti-D immune globulin administration at 28 weeks, unless the biologic father is known with certainty to be D-negative [25,43]. In countries where cfDNA testing for fetal RHD status is performed early in pregnancy, third-trimester maternal anti-D antibody screening can be omitted if the cfDNA findings suggested that the fetus is D-negative.

Administration of anti-D immune globulin

Single dose regimen: 28 weeks – A single dose of 300 micrograms of anti-D immune globulin is administered in the United States. For patient convenience, it can be administered during the office visit when the maternal antibody screen is drawn and before results are available. Ideally, the injection is given after the sample is drawn; however, slow absorption from an intramuscular injection site should prevent detection of passively acquired antibody in maternal serum if the injection is given shortly before blood drawing. In the rare case of a newly positive antibody screen, administration of a single dose of anti-D immune globulin before test results are available would not worsen fetal anemia.

Two dose regimen: 28 and 34 weeks – Some other countries use a two-dose regimen. For example, in the United Kingdom, 100 micrograms of anti-D immune globulin are administered at 28 and 34 weeks of gestation [44]. In Canada, 100 to 120 micrograms are administered at 28 and 34 weeks [27]. A network meta-analysis found that the two-dose 28 and 34 week regimen of 300 micrograms was more effective than a single dose of 300 micrograms at 28 weeks for reducing the incidence of D-negative postpartum mothers with serum positive for anti-D antibody after delivery of a D-positive fetus [45]. A cost analysis was not performed.

Selective prophylaxis for pregnancy complications associated with fetomaternal bleeding

Indications — In the United States, anti-D immune globulin is given to any D-negative nonalloimmunized pregnant person who has an event potentially associated with placental trauma or disruption of the fetomaternal interface and whose fetus is or may be D-positive. Fetal red blood cells (RBCs) have been detected in the circulation of patients exposed to the pregnancy events described below and alloimmunization has been reported in such individuals [27,46-48], although the precise risk of alloimmunization associated with these events is less clear than the risk after delivery. The following events should be considered for prophylaxis:

Pregnancy loss or termination at <20 weeks – Natural (spontaneous) pregnancy loss at <20 weeks of gestation has been associated with a 1.5 to 2.0 percent risk of alloimmunization while induced pregnancy loss (pregnancy termination) at <20 weeks has been associated with a 4 to 5 percent risk of alloimmunization [49]. Anti-D immune globulin has traditionally been administered to such patients, but this approach has become controversial [50].

Since 2019, some medical organizations have become more selective about administering anti-D immune globulin after events very early in pregnancy. While some organizations use ≥12 weeks (84 days) gestation as a threshold for anti-D immune globulin administration, others use 70 or 77 days as the threshold. In addition, some suggest the use of anti-D immune globulin after surgical procedures ≤70 days but not after medically induced pregnancy termination ≤70 days. (See "Overview of pregnancy termination", section on 'Alloimmunization prevention'.)

Although the D antigen is detectable on embryonic RBCs by 38 days after conception (ie, 7+3 weeks of gestation) [51], the volume of RBCs in early gestation is low and an increased risk for D-alloimmunization has not been documented when anti-D immune globulin was omitted in patients with very early losses/terminations. Available evidence of the safety of omitting prophylaxis is sparse:

In a 2020 prospective cohort study that performed pre- and post-procedure flow cytometry in 37 patients at 5+6 to 11+3 weeks of gestation undergoing uterine aspiration for natural (spontaneous) pregnancy loss or pregnancy termination, fetal RBC counts in the maternal circulation increased after the procedure but remained below the threshold calculated by the authors for potentially inducing alloimmunization [52]. Limitations of this study, in addition to its small size, include that the spontaneous pregnancy loss group may have already expelled the fetus before the aspiration and thus was at lower risk for a fetomaternal bleeding from the procedure; the authors' calculations used a theoretical sensitizing dose based on previous studies of 0.1 mL and assumed a maternal blood volume of 4 L; and no follow-up testing was performed to determine whether any patients became alloimmunized.

More data are needed regarding risk of alloimmunization in a large population of D-negative females who do not receive anti-D immune globulin and are tested for D antibodies pre- and six weeks post-early pregnancy loss. The author of this topic suggests administration of anti-D immune globulin after a natural (spontaneous) pregnancy loss or induced pregnancy loss (medical or surgical pregnancy termination) at any gestational age because of a lack of sufficient evidence to identify with certainty those patients who are not at risk for alloimmunization, which has lifelong consequences.

In a 2020 practice bulletin on medication abortion up to 70 days of gestation, ACOG recommended administration of anti-D immune globulin if indicated [53]. In a 2018 practice bulletin on early pregnancy loss (ie, miscarriage or spontaneous abortion <13+0 weeks), ACOG stated anti-D immune globulin should be considered, especially in losses that are later in the first trimester, and they recommended anti-D immune globulin for patients who undergo surgical management of their miscarriage since their risk of alloimmunization is higher [54]. In the 2017 practice bulletin on prevention of RhD alloimmunization, ACOG suggested consideration of anti-D immune globulin in cases of spontaneous first-trimester miscarriage, especially those later in the first trimester, but recommended anti-D immune globulin for patients who undergo instrumentation for their miscarriage and patients who undergo pregnancy termination (medical or surgical) [25].

In 2022, the World Health Organization recommended against ant-D immune globulin after both medical and surgical abortion at <12 weeks [55]. This recommendation was based, in part, on a meta-analysis including one small study of unsensitized individuals with natural (spontaneous) pregnancy loss published in 1972 [56] and another small trial of individuals with either spontaneous or induced pregnancy loss also published in 1972 [57] that found that the frequency of antibody formation after an event at <12 weeks was less in patients who received anti-D immune globulin prophylaxis, but the difference was not statistically significant (1.2 versus 4.4 percent; RR 0.27, 95% CI 0.03-2.15, very low quality evidence); the frequency of alloimmunization in a subsequent pregnancy was not known [55].

In 2022, a committee consensus from the Society of Family Planning stated that RhD testing and administration were not recommended prior to 12 weeks of gestation for patients undergoing spontaneous, medication, or uterine aspiration abortion [58]. For patients prior to 12 weeks of gestation undergoing sharp curettage, although not recommended, anti-D immune globulin administration could be considered at patient request as part of a shared decision-making process, discussing the patient’s future fertility desires in the context of existing data.

Invasive prenatal diagnostic or therapeutic procedures – Prenatal invasive diagnostic and therapeutic procedures that may be associated with fetomaternal bleeding include, but are not limited to, chorionic villus sampling, amniocentesis/amnioinfusion, fetal blood sampling, fetoscopy/fetoscopic surgery, and multifetal reduction [59]. In D-negative patients giving birth to D-positive infants, pooled data before widespread anti-D immune globulin prophylaxis suggested that the procedure-related risk of alloimmunization after second-trimester amniocentesis was 1 percent in the absence of anti-D immune globulin prophylaxis (overall risk during pregnancy 2.5 percent versus 1.5 percent in similar patients not undergoing amniocentesis) [60].

Blunt abdominal trauma and external cephalic version – Blunt abdominal trauma (eg, fall, intimate partner violence, motor vehicle crash) or external cephalic version may result in fetomaternal bleeding, possibly related to clinical or subclinical placental abruption [61,62]. The frequency of such bleeding and risk of alloimmunization are unknown, given the variability in, and difficulty of, quantifying trauma.

Ectopic pregnancy – Fetomaternal bleeding has been documented in patients with an ectopic (extrauterine) pregnancy [63]. It may be transplacental or may result from absorption of fetal blood by the maternal peritoneum. The frequency of such bleeding and risk of alloimmunization are unknown.

Threatened abortion – The exact etiology of bleeding in patients with threatened abortion and a live fetus generally cannot be determined. It is frequently attributed to marginal separation of the placenta, which could result in fetomaternal bleeding [64]. Because of the theoretic risk of alloimmunization, anti-D immune globulin is administered to patients with significant clinical bleeding, not just spotting, since 20 to 40 percent of pregnant people experience spotting and alloimmunization in these individuals is rare. The actual risk of alloimmunization is unknown.

An incidental finding of a subchorionic hematoma on ultrasound examination is not an indication for antepartum prophylaxis in the absence of vaginal bleeding.

Fetal death in the second or third trimester – Fetal demise can be an immunizing event when caused by massive fetomaternal hemorrhage or occult abruption (see "Spontaneous massive fetomaternal hemorrhage"). The frequency of such bleeding and risk of alloimmunization are unknown.

Antepartum bleeding in the second or third trimester – The risk of fetomaternal bleeding in patients with antepartum vaginal bleeding is probably higher with placental abruption than placenta previa, but data are sparse. The frequency of such bleeding and risk of alloimmunization are unknown.

Hydatidiform mole – A complete mole does not contain fetal RBCs, but prophylaxis after evacuation is suggested because fetal RBCs are present in partial molar pregnancies. In addition, sometimes it is initially difficult to determine whether the patient had a molar pregnancy, a missed abortion, or a partial mole with fetal absorption.

Administration of anti-D immune globulin

First trimester – Because the RBC mass of the first-trimester fetus is small (mean RBC volume at 8 and 12 weeks is 0.33 mL and 1.5 mL, respectively), a 50 microgram dose of anti-D immune globulin can be used for first-trimester events and protects against a fetomaternal bleed of 2.5 mL RBCs; however, there is no harm in giving the standard 300 microgram dose, which is more readily available.

The fetoplacental blood volume at 20 weeks of gestation is approximately 30 mL [65]. Given the small fetal blood volume before 20 weeks, it is unnecessary to quantify the amount of fetomaternal bleeding to determine whether more than one dose of anti-D immune globulin is needed.

Second and third trimesters and postpartum – The standard 300 microgram dose is recommended.

When anti-D immune globulin is indicated after 20 weeks of gestation, quantifying the volume of fetomaternal bleeding should generally be performed to detect pregnancies with fetomaternal bleeding >15 mL of RBCs (30 mL whole blood), which would necessitate more than one dose of anti-D immune globulin [27]. (See 'Testing for fetomaternal bleeding' below.)

Monitoring and repeat dosing in patients with ongoing bleeding — No data are available to guide decisions about repeat doses of anti-D immune globulin in patients at risk for recurrent fetomaternal bleeding, such as in a pregnancy complicated by chronic placental abruption with ongoing intermittent vaginal bleeding. As discussed above, the half-life of anti-D immune globulin is approximately three weeks. (See 'Pharmacology and pharmacokinetics' above.)

Given the pharmacokinetics of anti-D immune globulin, we agree with the ACOG recommendation to monitor the maternal antibody titer every three weeks in patients with recurrent antepartum bleeding who received prophylaxis [25]:

If the result is positive, indicating that anti-D immune globulin from the previous dose of prophylaxis is still present, no additional treatment is necessary.

If the result is negative, then the patient may not be protected. In these cases, a test to evaluate the volume of fetal RBCs in the maternal circulation is obtained and a repeat dose of 300 micrograms of anti-D immune globulin is administered, with additional dosing if indicated by the results of testing for fetomaternal bleeding.

Prophylaxis after delivery

Postpartum dosing — An appropriate dose of anti-D immune globulin should be administered to nonalloimmunized D-negative patients within 72 hours of delivery of a D-positive newborn [25,27]. We recommend cord blood typing, even if prenatal cfDNA testing suggested that the fetus is RHD-negative.

The 300 microgram dose of anti-D immune globulin is adequate to protect against maternal alloimmunization from as much as 15 mL fetal RBCs (30 mL D-positive fetal whole blood). Rarely, maternal testing reveals fetomaternal bleeding exceeding this volume, so additional doses need to be administered, as discussed below. (See 'Testing for fetomaternal bleeding' below.)

Alternatively, a lower dose of anti-D immune globulin can be given postpartum (eg, 100 to 120 micrograms), with routine testing for fetomaternal bleeding and administration of additional drug if more than 5 to 6 mL of fetal RBCs are detected.

Testing for fetomaternal bleeding — We suggest routinely testing all D-negative patients for excessive fetomaternal bleeding after delivery to ensure that they receive an adequate dose of anti-D immune globulin [25,66,67]. The incidence of fetomaternal bleeding greater than 20 to 30 mL at delivery is estimated to be approximately 1 in 200 to 300 deliveries [68-70], which is at the limit of effective prophylaxis from a single 300 microgram dose of anti-D immune globulin. Fetomaternal bleeding greater than 80 mL and greater than 150 mL is estimated to occur in 1 in 1000 deliveries and 1 in 5000 deliveries, respectively [68]; risk factors (eg, cesarean delivery) will only identify 50 percent of these cases [10].

Rosette test – The rosette test [71] is a qualitative, yet sensitive test for fetomaternal bleeding. We suggest performing this test as an initial screen. A standard dose of anti-D immune globulin is given to patients with a negative test. The test is designed to give a negative result when the amount of fetomaternal bleeding is small (<2 mL or 0.04 percent fetal cells) and thus will not necessitate additional doses of anti-D immune globulin; few cases require confirmatory quantitative testing.

When the rosette test is positive, a Kleihauer-Betke test or flow cytometry is recommended to determine the percentage of fetal RBCs in the maternal blood [72]. (See "Spontaneous massive fetomaternal hemorrhage", section on 'Kleihauer-Betke assay' and "Spontaneous massive fetomaternal hemorrhage", section on 'Flow cytometry'.)

Calculating the amount of anti-D immune globulin required – The percentage of fetal RBCs determined by the Kleihauer-Betke test or flow cytometry is multiplied by 50 to estimate the volume of the fetomaternal bleeding (50 is the factor used to represent the average maternal blood volume of 5 liters). This product is then divided by 30 (the amount of fetomaternal bleeding covered by one vial of 300 micrograms of anti-D immune globulin) to determine the number of vials of anti-D immune globulin that should be administered. Consultation with a blood bank pathologist is advised to calculate the total dose. (See 'Dosing for large fetomaternal hemorrhages' below.)

Note: Individuals with hereditary persistence of fetal hemoglobin will have a high proportion of fetal hemoglobin that is not due to fetomaternal bleeding. (See "Spontaneous massive fetomaternal hemorrhage", section on 'Measuring the volume of FMH'.)

Dosing for large fetomaternal hemorrhages — Since the calculation for determining fetomaternal bleeding depends upon an estimation of the maternal blood volume, which is not directly measured, the transfusion service (blood bank) should be consulted if a large fetomaternal hemorrhage occurs. When the College of American Pathologists evaluated laboratory accuracy of anti-D immune globulin dose calculation among laboratories participating in proficiency testing, they found that 9 percent recommended a dose of anti-D immune globulin that was too low and 11 percent recommended a dose that was too high [73]. (See "Spontaneous massive fetomaternal hemorrhage".)

General recommendations:

Because of the risk of underdosing, the Association for the Advancement of Blood & Biotherapies technical manual recommends that, if the calculated dose of anti-D immune globulin is a fractional unit ≥0.5, then the dose should be rounded up to the next higher whole number and at least one additional vial of anti-D immune globulin should be administered over the calculated amount of 300 micrograms per 15 mL fetal RBCs [74].

In the proficiency testing study discussed above, providing one additional dose of anti-D immune globulin would have prevented underdosing in all cases [75]. As an example of this calculation, a patient with a Kleihauer-Betke result of 1.5 percent fetal cells would be assumed to have had 85 mL fetomaternal hemorrhage. The 85 mL total fetomaternal hemorrhage volume is divided by 30 mL (the amount of fetomaternal bleeding covered by one vial of 300 micrograms of anti-D immune globulin) yielding a need for 2.8 vials of anti-D immune globulin. The 2.8 vials is rounded up to 3 vials and then an extra vial is added; thus, the recommended dose in this case would be a total of 4 vials (1200 micrograms).

No more than five 300 microgram doses should be administered intramuscularly in a 24-hour period. However, large doses, if indicated, can be given using an intravenous preparation (WinRho SDF, Rhophylac). In these cases, no more than 600 micrograms should be given every eight hours intravenously until the total calculated dose is achieved.

Twenty-four hours after the total dose has been administered, we recommend performing an indirect Coombs test to assess for anti-D immune globulin. If none is detected, then additional anti-D immune globulin should be administered and the assay repeated until a positive result is obtained.

Documentation — Although the majority of doses of anti-D immune globulin are issued from hospital blood banks, these preparations can be purchased by private clinicians for use in their offices. Lot numbers of products administered should be documented in the patient's medical chart as well as a logbook so that patients can be contacted if a problem becomes known (eg, manufacturer recall or advisory) or reassured as to the product they received.

MANAGEMENT OF SELECTED CLINICAL SCENARIOS

Should prophylaxis be repeated after 40 weeks of gestation? — The author does not repeat anti-D immune globulin after 40 weeks of gestation. Some authorities have suggested administering a second dose of anti-D immune globulin to patients who have not delivered within 12+3 weeks of the previous dose (ie, at 40+3 weeks of gestation for patients receiving antepartum prophylaxis at 28+0 weeks) because of rare case reports of maternal alloimmunization that were possibly due to waning levels of antibody [10,76,77].

There is no consensus regarding administration of a repeat antepartum dose of anti-D immune globulin at or after the estimated date of delivery [25]. In clinical practice in the United States, a repeat dose at this time is rarely given and waning antibody levels is not considered a medical indication for induction of labor.

Positive titer at delivery — Some patients who receive anti-D immune globulin at 28 weeks will still have a low antibody titer at term (≤4). Anti-D immune globulin should be given to these patients if they deliver a D-positive infant unless alloimmunization is proven as indicated by an anti-D titer >1:4.

Mother is D-positive at delivery — A large fetomaternal hemorrhage at delivery may cause a mixed field agglutination reaction and make a D-negative patient appear to be weakly D-positive. Prior D antigen typing aids in the interpretation of such a result.

Consultation with the transfusion service is recommended in these cases to quantify the volume of the fetomaternal bleeding using the Kleihauer-Betke stain or flow cytometry and to determine the appropriate dose of anti-D immune globulin [78]. (See 'Dosing for large fetomaternal hemorrhages' above.)

Anti-D immune globulin is inadvertently omitted — If anti-D immune globulin is inadvertently omitted after delivery or a potentially sensitizing event, it should be given as soon as possible after recognition of the omission. Partial protection is afforded with administration within 13 days of the birth or a potentially sensitizing event [79], and some experts recommend giving it as late as 28 days [10,27,80].

Antepartum anti-D immune globulin administered shortly before delivery — Patients who deliver less than three weeks from the administration of anti-D immune globulin for the usual indications (eg, routine 28 weeks prophylaxis, third-trimester bleeding) do not require a postpartum dose, unless a large fetomaternal hemorrhage is detected in the immediate postpartum period.

Patients undergoing postpartum permanent contraception procedures — Whether anti-D immune globulin should be administered to patients undergoing a postpartum procedure for permanent contraception (sterilization) is controversial. Some of these patients will subsequently become pregnant as a result of a failed procedure, reanastomosis of the fallopian tubes, or in vitro fertilization. Even if the patient does not become pregnant, if alloimmunization occurs, it will limit the availability of compatible RBC units if they require an emergency blood transfusion later in life.

The American College of Obstetricians and Gynecologists (ACOG) considers patients undergoing postpartum procedures for permanent contraception candidates for anti-D immune globulin [25], although this is unlikely to be cost-effective.

Patients undergoing intraoperative cell salvage — Clinicians should inform the blood bank if intraoperative cell salvage has been used to ensure that the correct dose of anti-D immune globulin is issued. Intraoperative cell salvage during cesarean birth may contain fetal cells. If the newborn is confirmed as D-positive (or unknown), anti-D immune globulin should be administered to the mother following the reinfusion of salvaged red blood cells (RBCs). A maternal blood sample should be obtained 30 to 45 minutes after reinfusion to estimate the volume of fetal RBCs in the maternal circulation in case more anti-D immune globulin is indicated [81].

False-positive anti-D antibody screen — A change of a single amino acid in the extramembranous portion of both the D and C antigen proteins results in the expression of the G phenotype [82]. The majority of patients who are D- and/or C-positive are also G-positive; if both D and C antigens are absent, the G antigen is also absent. Patients who lack all three antigens can become alloimmunized to the C and G antigen while not developing antibodies to the D antigen. Pregnant individuals who develop anti-C and anti-G antibodies but no anti-D antibodies are candidates for anti-D immune globulin.

In a typical D-alloimmunized patient, the anti-D antibody titer exceeds that of anti-C antibody (if present). If the anti-C titer equals or exceeds the anti-D titer, the clinician should consider the possibility that the anti-D antibody is actually anti-G antibody. Consultation with a blood bank pathologist is indicated for specialized testing for anti-D antibody. If specialized testing only detects anti-C and anti-G antibodies, the patient is at risk for D alloimmunization and standard indications for the administration of anti-D immune globulin should be followed.

False-negative anti-D antibody screen — Rarely, an individual has a low level of alloimmunization that is not detected by the antibody screen early in pregnancy, although a primary immune response has occurred and the individual has the capacity of producing IgG anti-D antibody later in pregnancy. This secondary immune response upon re-exposure to the D antigen cannot be prevented by maternal administration of anti-D immune globulin [83,84]. When alloimmunization is detected, these pregnancies are managed according to standard protocols. (See "RhD alloimmunization in pregnancy: Management".)

Weak D or discordant D typing — When D typing detects a weak D type or Rh testing has been discordant between serial samples, the patient should be treated as D-negative and antenatal and postpartum anti-D immune globulin administered [25].

Patients typed as serologic weak D phenotype (formerly Du), may either exhibit fewer D antigenic sites on their RBCs (weak D type) or they may be missing portions of the intact antigens (partial D phenotype). Weak D testing is routinely undertaken for blood donors, but is not recommended for prenatal testing, which can result in discordancy: A patient may be told that they are "Rh positive" after donating blood and then be told in pregnancy that their blood type is "Rh negative."

Routine molecular genotyping for weak D type has been recommended by a College of American Pathologists Transfusion Medicine Resource Committee Work Group [85]. They recommended that, if type 1, 2, or 3, the patient can be considered D-positive, therefore anti-D immune globulin is not indicated. If not type 1,2, or 3, then the RBCs express too few intact D antigens to be managed as D-positive, and standard anti-D immune globulin is indicated [86]. ACOG, however, does not endorse this recommendation until further economic and scientific studies are completed. In addition, there is some controversy as to whether patients with types 4.0 and 4.1 should be managed as D-positive or negative [87-91]. (See "RhD alloimmunization in pregnancy: Overview", section on 'D variants'.)

Many patients with the partial D phenotype are typed as serologic weak D phenotype or D-negative and receive anti-D immune globulin for the same standard indications as conventional D-negative patients [86]. However, some have sufficient D antigen epitopes to be typed as D-positive, thus they would not be identified as candidates for anti-D immune globulin and may develop antibodies to the missing portions of their D antigen if exposed to normal D-positive RBCs.

Inadvertent administration of anti-D immune globulin to a D-positive individual — Inadvertent administration of anti-D immune globulin to a D-positive individual is not harmful. Although a positive direct Coombs may result, RBC hemolysis has not been reported. Much higher doses of anti-D immune globulin (50 micrograms/kg) are sometimes used to treat immune thrombocytopenia in nonpregnant D-positive patients and can cause a fall in hemoglobin.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rh disease in pregnancy".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Pregnancy in Rh-negative people (The Basics)")

SUMMARY AND RECOMMENDATIONS

Screening for RBC antibodies – Screening all D-negative pregnant people for red blood cell (RBC) antibodies at the first prenatal visit is good medical practice. If the initial screen is negative, a repeat screen at 28 weeks of gestation is performed prior to the administration of anti-D immune globulin. (See 'General approach when the fetus is, or may be, D antigen positive' above and 'Standard prophylaxis at 28 or 28 plus 34 weeks of gestation' above.)

In a typical D-alloimmunized patient, the D antibody titer exceeds that of C. If the anti-C titer equals or exceeds the anti-D titer, the clinician should consider the possibility that the anti-D antibody is actually anti-G antibody. Consultation with a blood bank pathologist is indicated for specialized testing for anti-D antibody. If specialized testing only detects anti-C and anti-G, the patient is at risk for D alloimmunization and standard indications for the administration of anti-D immune globulin should be followed. (See 'False-positive anti-D antibody screen' above.)

Efficacy of prophylaxis – Routine administration of antepartum and postpartum anti-D immune globulin has reduced the prevalence of D alloimmunization to 0.1 to 0.3 percent of D-negative pregnant people. Reasons for continued occurrence of alloimmunized pregnancies include both failure to administer anti-D immune globulin in accordance with published guidelines and sensitization early in gestation before administration of routine third-trimester antenatal anti-D prophylaxis. (See 'Efficacy' above.)

Fetal RHD genotyping – Noninvasive fetal RHD genotyping using cell-free DNA is the standard approach in some countries. In the United States, it may be an option when a patient has concerns about receiving unnecessary anti-D immune globulin. We believe a cord sample should still be obtained in these cases to confirm that the fetus is D-negative. (See 'Fetal D-negative status known based on evaluation of cell-free DNA' above.)

Indications/timing for prophylaxis – The following recommendations apply to women who are D-negative and whose fetus is, or may be, D-positive:

Third trimester – We recommend routine administration of anti-D immune globulin early in the third trimester (Grade 1A). The optimum dose regimen in the United States is 300 micrograms at 28 weeks of gestation; other countries use 100 to 120 micrograms at 28 and 34 weeks. This practice reduces the incidence of antenatal alloimmunization from 1 to 2 percent to 0.1 to 0.3 percent. (See 'Standard prophylaxis at 28 or 28 plus 34 weeks of gestation' above.)

Conditions that increase the risk of antepartum fetomaternal bleeding – We recommend administration of antenatal anti-D immune globulin when there is an increased risk of fetomaternal bleeding (Grade 1B). Some examples include miscarriage or pregnancy termination (particularly at or beyond the late first trimester), ectopic pregnancy, multifetal reduction, amniocentesis, chorionic villus sampling, blunt abdominal trauma, external cephalic version, antepartum bleeding, and fetal death. We administer 300 micrograms as soon as possible within 72 hours of the event, but a 50 microgram dose can be used for first-trimester events. (See 'Selective prophylaxis for pregnancy complications associated with fetomaternal bleeding' above.)

Given the small fetal blood volume before 20 weeks of gestation, testing for fetomaternal bleeding to confirm appropriate dosing after a potentially sensitizing event is unnecessary before this gestational age. (See 'Administration of anti-D immune globulin' above.)

Repeat dosing for situations where there may be an ongoing risk for fetomaternal bleeding (such as chronic placental abruption or placenta previa with intermittent vaginal bleeding) can be managed with serial determinations of the maternal indirect Coombs every three weeks with repeat dosing if it is found to be negative. (See 'Monitoring and repeat dosing in patients with ongoing bleeding' above.)

Postpartum – We recommend administration of anti-D immune globulin within 72 hours of delivery of a D-positive infant (Grade 1A). We administer 300 micrograms and also test for excessive fetomaternal bleeding in case additional doses are needed. (See 'Prophylaxis after delivery' above.)

Inadvertent omission of prophylaxis – If anti-D immune globulin is inadvertently omitted after delivery or a potentially sensitizing event, it should be given as soon as possible after recognition of the omission. After delivery, partial protection is afforded with administration within 13 days of the birth, and there may be an effect as late as 28 days after delivery. (See 'Anti-D immune globulin is inadvertently omitted' above.)

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Topic 6773 Version 85.0

References

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