D alloimmunization in pregnancy: Management

INTRODUCTION — Hemolytic disease of the fetus and newborn (HDFN) due to maternal D alloimmunization continues to occur worldwide, despite the development and implementation of anti-D immune globulin prophylaxis. Ideally, pregnancies complicated by alloimmunization should be managed by a maternal-fetal medicine specialist proficient in performing the invasive diagnostic and therapeutic procedures that may be needed. In pregnancies with HDFN, appropriate pregnancy monitoring and intervention can markedly reduce adverse fetal and neonatal outcomes.

This topic provides our approach to management of pregnant patients with D alloimmunization. Related issues are discussed separately:

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

●(See "Management of non-RhD red blood cell alloantibodies during pregnancy".)

●(See "Fetal transfusion of red blood cells".)

●(See "RhD alloimmunization: Prevention in pregnant and postpartum patients".)

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

FIRST ALLOIMMUNIZED PREGNANCY — A patient's first pregnancy complicated by D alloimmunization is managed differently from subsequent affected pregnancies because their anti-D titer is usually low at the beginning of the first affected pregnancy and severe fetal anemia may not develop or develops in the late second trimester or the third trimester. In subsequent affected pregnancies, fetal anemia usually is more severe and develops earlier in gestation. (See 'Subsequent pregnancies' below.)

Our approach to managing the first pregnancy complicated by red blood cell alloimmunization is shown in the algorithm (algorithm 1) and described in the following sections [1].

Determine if the fetus is D-positive

Rationale/approach — A D-negative fetus is not at risk for complications from maternal anti-D antibodies since its red blood cells do not carry the target antigen; therefore, one of the initial steps in antenatal management is to determine the fetal RHD type. Paternal RHD type can inform this determination (algorithm 2):

●If the biologic father of the fetus is D-negative – The fetus must also be D-negative. Maternal alloimmunization occurred as a result of a previous pregnancy with a D-positive partner or from some other source of D-positive red blood cells (eg, incompatible blood transfusion, needle sharing). Obviously, the certainty of paternity is imperative, and nonpaternity is more common than one might assume [2]. The clinician should consider documenting the discussion regarding assured paternity in the medical record.

●If the biologic father of fetus is not D-negative – It is useful, but not essential, to know if he is homozygous or heterozygous for RHD (ie, the gene that encodes the D protein). Approximately 60 percent of D-positive White individuals are homozygous and 40 percent are heterozygous.

If he is homozygous for RHD, all of his offspring will be D-positive so further testing for fetal RHD type is unnecessary. As discussed above, the certainty of paternity is imperative.

If he is heterozygous for RHD, unavailable for testing, or paternity is uncertain, then further evaluation is required to determine fetal RHD type. We suggest performing cell-free DNA (cfDNA) testing of maternal plasma to detect fetal RHD inherited from the father. (See 'Cell-free DNA testing' below.)

Laboratory techniques

Cell-free DNA testing — The fetal RHD genotype is determined by testing cfDNA in a sample of maternal plasma after 10 weeks of gestation. This test is widely available in the United Kingdom and Europe. It is also available in the United States from at least one commercial laboratory, but some laboratories only offer panels that include additional testing (eg, common fetal aneuploidies). If cfDNA has been previously collected, RHD testing in laboratories that include/combine with additional testing (common fetal aneuploidies) may not be covered by the insurance carrier. Detailed information on cfDNA is available separately. (See "Prenatal screening for common aneuploidies using cell-free DNA", section on 'Cell-free DNA'.)

●Methodology — In the majority of assays, fetal RHD status is determined by evaluating cfDNA sequences in maternal plasma using a reverse transcriptase polymerase chain reaction (PCR). A meta-analysis of studies of cfDNA for RHD determination reported sensitivity of 99.3 percent (95% CI 98.2-99.7) and specificity of 98.4 percent (95% CI 96.4-99.3) in the first and second trimesters; real-time quantitative PCR sensitivity was higher than conventional PCR [3].

Assays for the RHD exon 4; exons 5 and 7; exons 4, 5, and 7; or exons 4, 5, 7, and 10 have been recommended [4-9]. More than one D region (eg, exons 7 and 10, intron 4) should be examined to ensure that negative results reflect true RHD negativity and not the presence of a D variant (see "RhD alloimmunization in pregnancy: Overview", section on 'D variants').

The one assay available in the United States employs next generation sequencing and quantitative template technology with two amplicons for exon 4 and one for exons 5, 7, and 10. A study of 1061 preclinical samples reported a sensitivity of 100 percent (CI 99-100) and a specificity of 100 percent (CI 99-100) [10].

Interpretation:

•Presence of the RHD exons in maternal plasma indicates fetal cfDNA is present and the fetus carries RHD and thus is D-positive.

•Absence of the RHD exons in maternal plasma indicates the fetus does not carry RHD and thus is D-negative, as long as it can be proven that fetal cfDNA and not maternal cfDNA was tested.

Identification of Y chromosome gene sequences (SRY) in the plasma sample confirms the presence of fetal cfDNA and validates the test results. If the fetus is female, the maternal white blood cells are analyzed for single nucleotide polymorphisms (SNPs) and these results are compared with the SNPs in the cfDNA sample. If a discordance in SNPs is noted, the SNPs that are different from the mother are assumed to be paternal in origin, thus confirming the presence of fetal DNA [11]. The hypermethylated RASSF1A promoter has also been reported as a universal fetal marker to confirm the presence of fetal DNA [12-14]. Such technologies negate the need for drawing a paternal sample.

●False negatives and positives – False-negative results are a serious concern as appropriate monitoring and interventions might be withheld. False negatives can be due to a low level of fetal cfDNA in the maternal sample because it was drawn too early in gestation (<8 to 10 weeks of gestation) or to insensitive laboratory techniques [15].

False positives are rare, and less of a concern. Presumably they would lead to unnecessary fetal and maternal monitoring, but a low chance of unnecessary intervention. Causes of false-positive results are described separately. (See "Prenatal screening for common aneuploidies using cell-free DNA", section on 'False-positive and false-negative results'.)

Other laboratory testing options

●Amniocentesis – Fetal RHD status can be determined by PCR on uncultured amniocytes obtained by amniocentesis after 15 weeks of gestation [16]. Whenever amniotic fluid is obtained for fetal testing and the fetus is RHD-negative, a false-negative result due to maternal cell contamination should be excluded by performing SNP testing on maternal DNA and DNA derived from amniocytes.

Transplacental amniocentesis should be avoided, if possible, as it may worsen alloimmunization (chorionic villus biopsy is avoided for the same reason [17]). The magnitude of this risk is unknown.

Chorionic villus sampling should be strongly discouraged since interruption of the chorion villi may result in fetomaternal hemorrhage and a marked increase in the maternal titer [18].

●Anti-sera to Rh antigens – In the past, laboratories used anti-sera to the Rh antigens (D, C/c, E/e) in paternal blood and gene frequency tables based upon ancestry to estimate paternal zygosity at the RHD locus. Although useful, these estimates are based on population genetics and self-identified ethnicity. Direct genetic testing is more reliable and is commercially available for RHD.

Triage based on fetal D type

●D-positive fetus – These pregnancies need to be monitored for HDFN with serial maternal indirect Coombs titers and, when a critical titer is reached, Doppler evaluation of the fetal middle cerebral artery peak systolic velocity (MCA-PSV). (See 'Serially assess maternal anti-D titer in at risk pregnancies' below.)

Some mothers with D alloimmunization develop antibodies to more than one red blood cell antigen, especially other Rh antigens, including C, c, E, and e. There are no specific guidelines for management of these pregnancies; they are typically managed as described in the following sections of this topic. However, the presence of additional red blood cell antibodies (especially anti-C) appears to be associated with a more aggressive maternal immune response, thus increasing the risk for development of severe fetal anemia and need for fetal transfusion [19-21].

●D-negative fetus – The D-negative fetus is not at risk for HDFN if the mother has no other red blood cell antibodies. Maternal or fetal monitoring for HDFN and intervention are unnecessary.

If the mother has other red blood cell antibodies, then it is possible that a D-negative fetus is at risk for HDFN from these antibodies. The evaluation and management of these pregnancies is described separately. (See "Management of non-RhD red blood cell alloantibodies during pregnancy".)

Serially assess maternal anti-D titer in at risk pregnancies

Indirect Coombs — In the first alloimmunized pregnancy with a D-positive fetus, the maternal indirect Coombs titer (ie, indirect antiglobulin test) is monitored monthly until 24 weeks and then every two weeks, as long as it remains stable. Rising titers should be repeated weekly until the titer reaches the "critical" level (see 'Critical titer' below). Maternal administration of anti-D immune globulin after the primary immune response to the D antigen has occurred will not prevent a rise in titer; anti-D immune globulin should not be administered to sensitized patients [22,23].

Serial titers should be determined by the same laboratory since variation in titers among laboratories is common. As a quality control measure, the laboratory should consider repeating the titer from the prior sample each time it performs a titer on a newly submitted sample. Intralaboratory variation occurs, but a truly stable titer should not vary by more than one dilution when repeated in a given laboratory. As an example, a titer of 2 that increases to 4 may not represent a true increase in the amount of antibody in the maternal circulation, but a rise to 8 is likely real.

Gel microcolumn assay (GMA) — The GMA card is gaining widespread acceptance by blood banks to replace the traditional tube agglutination tests (indirect Coombs titer) for determining anti-D antibody titers. Advantages of GMA over tube tests include: it is less susceptible to interlaboratory and intralaboratory sources of variability, yields clear objective results that are stable, takes less time, and is compatible with automation [24]. However, GMA may yield higher titer values than tube tests. In several studies, the increase was usually only one or two dilutions, which is not clinically significant (a fourfold difference is clinically significant) [24,25], but some studies reported greater discordance [26,27]. More data are needed to establish the correlation between GMA titer and severity of fetal anemia (ie, the threshold for a "critical titer") before this assay can be used to manage alloimmunization in pregnancy. For this reason, standard tube titers should still be used for clinical management of the alloimmunized pregnancy.

Critical titer

●Definition and level – The critical titer is the titer at which the fetus is at risk for developing severe anemia; it is established by the laboratory based on validation in its patient population and can vary among laboratories. Below this titer, the fetus is at risk for developing mild to moderate, but not severe, anemia. Most laboratories lack enough alloimmunized patients to establish a critical titer with validation in their population and therefore consider an anti-D titer of 16 as a critical value. In Europe and the United Kingdom, a threshold value of 15 international units/mL is the critical value, based upon comparison with an international standard [28].

●Incidence – In one series of 570 patients with D-alloimmunization and first alloimmunized pregnancy, approximately 70 percent (392 patients) developed a critical titer of >16 [29]. The average gestational age for developing a critical titer in pregnancies that developed HDFN was 26+3 weeks of gestation versus 28+5 weeks in pregnancies without HDFN.

●Prognosis – In the series described above, patients who reached a critical titer gave birth to offspring with HDFN in approximately 45 percent of cases [29]. The critical titer was associated with severe HDFN (fetal demise, hydrops fetalis, or need for fetal transfusion) in 23 percent of cases, moderate HDFN (need for neonatal exchange transfusions) in 6 percent of cases, and mild HDFN (neonatal phototherapy/simple blood transfusion) in 17 percent of cases.

●Management if the critical titer is reached or exceeded – These pregnancies require fetal assessment with Doppler ultrasound to determine whether the fetus is likely to be severely anemic. The critical titer is a crude screening test, not diagnostic of severe anemia. The threshold is chosen to maximize sensitivity at 100 percent, but specificity is low (50 to 60 percent [29,30]) and less than that of MCA Doppler (>85 to 90 percent [31-34]). In fact, maternal indirect Coombs titers can rise even though the fetus is D-negative; the reason is unclear.

If fetal RHD has not yet been determined by cfDNA testing or certain RHD homozygous paternity, then we recommend fetal RHD evaluation at this point to avoid potentially unnecessary serial Doppler ultrasound monitoring and fetal blood sampling.

Begin Doppler velocimetry when critical titer reached

Determine MCA-PSV to evaluate severity of fetal anemia — When the critical titer is reached or exceeded and the fetus is RHD-positive, Doppler velocimetry for MCA-PSV is performed to distinguish fetuses that are likely to be moderately or severely anemic from those who are not. There is no value in continuing to measure maternal titers after the critical titer has been reached.

Doppler assessment of the fetal MCA-PSV is based on the principle that the fetal hemoglobin level determines blood flow in the MCA: MCA-PSV increases as fetal hemoglobin level falls [35].

●A 2009 meta-analysis including nine observational studies (675 fetuses) provided compelling evidence that Doppler interrogation of the MCA-PSV performs well as a screening tool for severe fetal anemia of any etiology [31]. When severe anemia was defined as fetal hemoglobin <0.55 multiples of the median (MoM) for gestational age, sensitivity and specificity of peak systolic MCA Doppler interrogation were 75.5 and 90.8 percent, respectively.

In the seminal study included in this review, both hemoglobin level in blood obtained by cordocentesis and MCA-PSV were measured in 111 fetuses at risk for anemia due to maternal red cell alloimmunization and compared with values in 265 normal fetuses [32]. The sensitivity of increased MCA-PSV (above 1.5 MoM) for the prediction of moderate or severe anemia was 100 percent (95% CI 86-100), either in the presence or absence of hydrops, with a false-positive rate of 12 percent.

The same authors conducted a follow-up prospective study of 125 fetuses at risk for alloimmune anemia and reported the overall performance of MCA-PSV for moderate to severe anemia (hemoglobin level below 0.65 MoM) was sensitivity 88 percent, specificity 87 percent, positive predictive value 53 percent, and negative predictive value 98 percent [33]. One of nine fetuses with severe anemia was missed, possibly due to a screening interval longer than two weeks.

●A subsequent meta-analysis of 12 studies (696 fetuses) published from 2008 to 2018 found that MCA-PSV ≥1.5 MoM had sensitivity and specificity of 86 percent (95% CI 75-93) and 71 percent (95% CI 49-87), respectively, for prediction of moderate to severe anemia in nontransfused fetuses [34]. Sensitivity progressively fell with an increasing number of transfusions. (See "Fetal transfusion of red blood cells", section on 'Scheduling subsequent transfusions'.)

Doppler technique — Proper technique for measuring MCA-PSV is important and is described elsewhere [36,37]. Ideally, the measurement is obtained when the fetus is in a quiet behavioral state since results can be inaccurate when the fetus is active [38,39].

Because MCA-PSV increases across gestation (figure 1), results should be adjusted for gestational age. Conversion calculators, such as the one found at perinatology.com or fetalmedicinebarcelona.org/calc-en, can be used to convert the actual MCA-PSV in cm/second to MoM to correct for gestational age.

Frequency of Doppler evaluation — The optimal interval between Doppler examinations has not been determined. Experts suggest one- to two-week intervals based on clinical experience and what is known about progression of fetal anemia in this setting [32]. The author of this topic performs weekly measurements for three weeks initially, and then every other week if the trend is not concerning (ie, it appears to be following the typical increase associated with advancing gestational age). However, a value of 1.4 or 1.5 MoM would prompt increasing the frequency to one or two times per week.

Other methods for assessing fetal anemia

●Fetal blood sampling – Fetal blood can be sampled to precisely determine the severity of fetal anemia, but this procedure carries a 1 to 2 percent risk of fetal loss, with the highest risk at lower gestational ages and in hydropic fetuses. We reserve fetal blood sampling for pregnancies in which MCA-PSV >1.5 MoM suggests moderate to severe anemia (See "Fetal blood sampling".)

●Amniotic fluid bilirubin level – Amniocentesis to determine amniotic fluid bilirubin levels (delta OD₄₅₀) was historically used to indirectly estimate the severity of fetal anemia. Bilirubin in amniotic fluid derived from fetal pulmonary and tracheal effluents correlates with the degree of fetal hemolysis [40,41]. However, Doppler velocimetry is as, or more, sensitive and specific for detection of severe fetal anemia and has the advantage of being noninvasive [42]. For these reasons, delta OD₄₅₀ assay is no longer readily available at most commercial laboratories.

MCA-PSV-based management

MCA-PSV ≤1.5 MoM for gestational age

Fetal surveillance — An MCA-PSV ≤1.5 MoM for gestational age is consistent with absence of moderate to severe anemia. As long as MCA-PSV remains at this level, we perform weekly antenatal testing beginning at 32 weeks of gestation. Historically, alloimmunization has been considered an indication for antepartum fetal surveillance, although no well-designed studies have evaluated the utility, type, or frequency of testing [43]. (See "Overview of antepartum fetal assessment".)

Delivery timing — If no fetal transfusion is performed and the MCA-PSV remains ≤1.5 MoM for gestational age, we schedule delivery at 37+0 to 38+6 weeks of gestation, consistent with the Society for Maternal-Fetal Medicine and American College of Obstetricians and Gynecologists guidelines [36,44]. This is a prudent approach because the sensitivity of MCA-PSV for detecting severe fetal anemia decreases after 35 weeks, thus the benefits of delivery, newborn evaluation, and treatment (if needed) in this setting likely exceed the small risk of mild neonatal immaturity from an early term birth.

MCA-PSV >1.5 MoM for gestational age

Fetal blood sampling and criteria for transfusion — For pregnancies with MCA-PSV >1.5 MoM for gestational age, we obtain fetal blood by cordocentesis or from the hepatic vein for hemoglobin determination and have blood readily available for fetal transfusion, but only perform the transfusion if the fetal hemoglobin level is less than the level that is two standard deviations below the mean value for gestational age; reference values have been established (table 1). A hematocrit less than 30 percent can also be used as the threshold for fetal transfusion [45]. If the hemoglobin is above this threshold, we obtain another fetal blood sample in one to two weeks, depending on the value.

Fetal hemoglobin level should be checked before transfusion because a high MCA-PSV is not definitive proof of clinically significant fetal anemia; false positives occur [32,33]. The procedure for fetal transfusion carries risk, which can be avoided by avoiding unnecessary transfusions for high MCA-PSVs not associated with clinically significant fetal anemia.

Transfusion at a moderately reduced hemoglobin level results in a better fetal outcome than waiting until development of severe anemia (hemoglobin deficit >7 g/dL below the normal mean for gestational age [46]) or hydrops (typically hemoglobin is less than 5 g/dL) [32]. Selection of patients for transfusion is reviewed in more detail separately. (See "Fetal transfusion of red blood cells", section on 'Selection of patients and procedures'.)

Intravascular fetal transfusion is generally limited to pregnancies between 18 and 35 weeks of gestation because before 18 weeks, the small size of the relevant anatomic structures poses technical challenges, and after 35 weeks, fetal transfusion is considered riskier than delivery followed by postnatal transfusion therapy [47]. Thus, at ≥35 weeks of gestation, we would deliver a fetus with MCA-PSV >1.5 MoM for gestational age without fetal blood sampling to check the fetal hemoglobin.

Transfusion — The procedure for fetal transfusion, timing of subsequent transfusions, and posttransfusion fetal surveillance are reviewed separately (See "Fetal transfusion of red blood cells", section on 'Procedure'.)

Delivery timing

●Fetuses who do not undergo transfusion – If no fetal transfusion was performed and the MCA-PSV is >1.5 MoM for gestational age at ≥35+0 weeks of gestation, we proceed with delivery and evaluate/treat the newborn for HDFN rather than initiate these interventions in utero.

●Transfused fetuses – If a fetal transfusion was performed, labor is induced approximately three weeks after the last transfusion, typically at 37+0 or 38+0 weeks of gestation, or a cesarean birth is scheduled if indicated for standard obstetric indications. (See "Fetal transfusion of red blood cells", section on 'Timing delivery'.)

Intrapartum monitoring and care — Intrapartum care is routine. If the fetus is D-positive, we perform continuous fetal heart rate monitoring. A severely anemic fetus may show a sinusoidal pattern. (See "Intrapartum fetal heart rate monitoring: Overview", section on 'Sinusoidal pattern' and "Intrapartum category I, II, and III fetal heart rate tracings: Management", section on 'Management of sinusoidal category III pattern'.)

Given the presence of maternal antibodies and especially when multiple maternal antibodies are present, cross-matching for two units of red blood cells should be considered to enable the Blood Bank to have blood readily available in the event of a maternal hemorrhage. This blood could also be processed quickly for neonatal use, if needed.

We do not consider alloimmunization a contraindication to delayed cord clamping, even in severe HDFN. Limited data on delayed cord clamping in alloimmunized pregnancies suggest a short-term benefit and lack of harm. In the only randomized trial evaluating the outcome of delayed versus early cord clamping in 70 D-positive fetuses of D-alloimmunized pregnancies, delayed clamping improved red blood cell volume at two hours of life without significantly increasing risks for double volume exchange transfusion, partial exchange transfusion, and duration of phototherapy during the hospital stay, or blood transfusion through 14 weeks of life [48]. The pregnancies ranged 28 to 41 weeks of gestation and approximately 50 percent of the neonates in each group had received fetal transfusions (mean three transfusions, range two to five).

SUBSEQUENT PREGNANCIES

Prevention of an affected fetus in future pregnancies — Each subsequent pregnancy after the first affected pregnancy is likely to manifest more severe HDFN, and at an earlier gestational age. HDFN can be prevented by avoiding conception of a D-positive fetus.

A D-positive fetus can be avoided in the following ways:

●In vitro fertilization (IVF) with preimplantation genetic testing – If the potential biologic father is heterozygous for RHD, IVF with preimplantation genetic testing can be used to identify RHD-negative embryos and only these embryos are considered for embryo transfer [49]. An accuracy of 95 percent is widely quoted by laboratories that perform this testing; therefore, we recommend confirmatory fetal testing with cell-free DNA (cfDNA) after 10 weeks of gestation. (See "Preimplantation genetic testing".)

●Use of a gestational carrier – If the potential biologic father is homozygous for RHD, the intended parents can conceive by IVF and their embryo can be carried by a gestational carrier who is not alloimmunized. (See "Gestational carrier pregnancy".)

●Use of donor sperm – Sperm from a D-negative donor can be used for intrauterine insemination of the alloimmunized mother. (See "Donor insemination".)

Prognosis in subsequent alloimmunized pregnancies — Pregnancies after the first alloimmunized pregnancy are characterized by increasingly severe HDFN due to the entry of fetal red blood cells into the maternal circulation at each birth, which causes an anamnestic maternal antibody response. A patient whose prior pregnancy was complicated by the need for fetal transfusion, fetal hydrops, preterm birth because of severe fetal anemia, or neonatal exchange transfusion can expect severe fetal anemia to develop in subsequent pregnancies with a D-positive fetus. The severe anemia typically occurs earlier in gestation than in the prior pregnancy; one case report described severe anemia as early as 15 weeks of gestation [50]. In a study of 69 patients with a prior fetal transfusion, 86 percent had a fetal transfusion in the next pregnancy, and this occurred at a median three weeks earlier than in the prior pregnancy [51]. There was no explanation for the lack of need for intervention in the 10 pregnancies with D-positive fetuses. All 11 neonates (one set of twins) required phototherapy, four required exchange transfusions, and one required a simple transfusion; newborn information was unavailable in one case.

Management of subsequent alloimmunized pregnancies — Management of these pregnancies is illustrated in the algorithm (algorithm 3).

●All subsequent pregnancies

•Determine the fetal RHD type early in gestation using cfDNA.

•When the fetus carries RHD, obtain a baseline maternal titer early in gestation. An extremely high titer (≥1028) suggests the need for immunomodulation early in pregnancy (discussed below). Serial maternal titers in subsequent pregnancies are unnecessary. They are less informative than in the first affected pregnancy since they are less predictive of the onset of fetal anemia.

●Further management depends on patient-specific factors

•Prior severe HDFN (fetal demise, hydrops fetalis, or need for fetal transfusion) at <24 weeks of gestation or baseline anti-D titer ≥1028 – If the prior pregnancy was complicated by severe HDFN before 24 weeks or the anti-D titer in the current pregnancy is ≥1028, monitor the middle cerebral artery peak systolic velocity (MCA-PSV) weekly, beginning at 15 weeks of gestation. Absence of ascites/hydrops on ultrasound examination should not be considered indicative of absence of severe anemia. In one series of 30 fetuses with severe anemia before 22 weeks of gestation, 71 percent did not exhibit hydrops [52]. MCA-PSV-based management is similar to that described above for first alloimmunized pregnancies, except measurement of MCA-PSV is performed weekly [36]. (See 'Begin Doppler velocimetry when critical titer reached' above.)

Intravascular fetal transfusion for severe anemia is generally limited to pregnancies ≥18 weeks because the small size of the relevant anatomic structures before 18 weeks poses technical challenges. Fetal death occurred in 6 of 30 fetuses who underwent fetal transfusion 16 to 22 weeks in the aforementioned series [52].

For the rare patient with very severe alloimmunization (anti-D titer ≥1028) and previous perinatal loss or need for intrauterine transfusions before 24 weeks of gestation, administration of intravenous immunoglobulin G (IVIG) with or without plasma exchange starting at 10 to 12 weeks of gestation may maintain the fetal hematocrit above life-threatening levels until the fetus reaches a gestational age when fetal transfusion is technically feasible and less likely to be associated with fetal death. In a multicenter review, initiation of weekly IVIG infusion before 13 weeks of gestation was associated with a delay in the development of severe anemia by 25 days compared with the previous pregnancy [53]. A variety of therapeutic regimens have been described in case reports and small cases series [53,54]. The American Society for Apheresis guidelines on use of therapeutic apheresis describe fetal transfusion as the mainstay of treatment, but state IVIG and/or therapeutic plasma exchange may be indicated if there is a high risk of fetal demise or signs of hydrops prior to 20 weeks [55].

Intraperitoneal fetal transfusion is technically feasible as early as 15 weeks of gestation and has a lower risk of procedure-related complications than intravascular transfusion at this early gestational age. (See "Fetal transfusion of red blood cells", section on 'Choosing a fetal access site'.)

A phase II trial of a monoclonal antibody (nipocalimab) to block the FcRn receptors of the placenta in patients with severe HDFN has been completed and results are pending [56].

•Prior HDFN at ≥24 weeks of gestation, preterm birth because of MCA-PSV >1.5 MoM for gestational age, or neonatal exchange transfusion

-Monitor MCA-PSV weekly, beginning at 16 weeks of gestation.

MCA-PSV-based management is similar to that described above for the first alloimmunized pregnancy, except measurement of MCA-PSV is usually performed more often (ie, weekly) [36]. (See 'Begin Doppler velocimetry when critical titer reached' above.)

•Prior neonatal phototherapy only

-Monitor MCA-PSV beginning at 18 weeks gestation weekly for three weeks initially, and then every other week if the trend is not concerning (ie, it appears to be following the typical increase associated with advancing gestational age). However, a value of 1.4 to 1.5 MoM would prompt increasing the frequency to one or two times per week. (See 'Begin Doppler velocimetry when critical titer reached' above.)

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 5^th to 6^th 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 10^th to 12^th 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

●First affected pregnancy — Severe fetal anemia develops in 16 percent of cases, generally in the late second trimester or the third trimester. The evaluation and management of the first affected pregnancy are shown in the algorithm (algorithm 1). The major considerations are:

•Fetal D status – Predict the likelihood that the fetus is D-positive based on paternal blood type and zygosity (algorithm 2). Confirm fetal RHD, when appropriate, by testing cell-free DNA (cfDNA). (See 'Determine if the fetus is D-positive' above and 'Triage based on fetal D type' above.)

•Maternal anti-D titers – Follow maternal anti-D titers until the critical titer is reached (≥16), then assess for moderate to severe fetal anemia by serial Doppler assessments of the middle cerebral artery peak systolic velocity (MCA-PSV). (See 'Begin Doppler velocimetry when critical titer reached' above.)

•MCA-PSV and blood sampling to evaluate for fetal anemia – For pregnancies with MCA-PSV >1.5 multiples of the median (MoM) for gestational age, determine fetal hemoglobin by percutaneous sampling and transfuse those in whom anemia is confirmed. (See 'MCA-PSV >1.5 MoM for gestational age' above.)

•Transfusion – Transfusion of severe anemia (hemoglobin deficit >7 g/dL below the normal mean for gestational age) is required to prevent hydrops and death. We suggest transfusion for moderate anemia (fetal hemoglobin level less than the level that is two standard deviations below the mean for gestational age). Transfusion at a moderately reduced hemoglobin level results in a better fetal outcome than waiting until development of severe anemia. Reference values for hemoglobin levels two standard deviations below the mean for gestational age have been established (table 1). A hematocrit less than 30 percent can also be used as the threshold for fetal transfusion.

If the hemoglobin is above this threshold, we obtain another fetal blood sample in one to two weeks, depending on the value. (See 'Fetal blood sampling and criteria for transfusion' above and "Fetal transfusion of red blood cells".)

•Timing delivery – If MCA-PSV first becomes >1.5 MoM for gestational age at ≥35+0 weeks of gestation, we suggest delivery rather than fetal blood sampling with transfusion, if indicated (Grade 2C). At this gestational age, fetal blood sampling and transfusion are considered riskier than delivery followed by postnatal evaluation and transfusion. (See 'Delivery timing' above.)

If a fetal transfusion was performed, labor is induced approximately three weeks after the last transfusion, typically at 37+0 or 38+0 weeks of gestation, or a cesarean birth is scheduled if indicated for standard obstetric indications. (See 'Delivery timing' above.)

●Previously affected fetus/infant – A patient whose prior pregnancy was complicated by severe fetal anemia can expect development of severe fetal anemia in subsequent pregnancies with an D-positive fetus and the severe anemia typically occurs earlier in gestation than in the prior pregnancy. Evaluation and management are shown in the algorithm (algorithm 3). (See 'Prognosis in subsequent alloimmunized pregnancies' above.)

For the rare patient with very severe alloimmunization (anti-D titer ≥1028) and previous perinatal loss or need for intrauterine transfusions before 24 weeks of gestation, we suggest administration of intravenous immunoglobulin G (IVIG) with or without plasma exchange (Grade 2C). This intervention should be started at 10 to 12 weeks of gestation and may maintain the fetal hematocrit above life-threatening levels until the fetus reaches a gestational age when fetal transfusion is technically feasible and less likely to be associated with fetal death. (See 'Management of subsequent alloimmunized pregnancies' above.)