If the mother is alloimmunized against an antibody known to cause HDFN. and paternal antigen testing determines that the fetus may inherit the corresponding antigen (i.e., the fetus is “at risk”), antibody titers must be drawn at four-week intervals until 28 weeks, then every two weeks until they reach a critical titer (1:16 or 16 in most institutions, 1:4 or 4 for Kell). The critical titer reflects the threshold at which the antibody is capable of causing anemia requiring intervention in-utero. Important caveats include:
- – A Kell alloimmunized pregnancy has the potential to result in severe fetal and neonatal outcomes even below critical titers. This is because anti-Kell has the potential to lyse developing cells in the fetal bone marrow in addition to mature red cells. Proceed with noninvasive testing beginning at a titer of 4 at 18 weeks of gestation5, or earlier in the case of high titers or a previous history of severe HDFN.
- – A woman with a previously affected fetus or newborn is at significant risk of recurrence with increasing severity regardless of titer due to an anamnestic maternal antibody response that may occur as the result of feto-maternal hemorrhage at the time of the previous delivery. For this reason, MCA-PSV should be used to monitor the fetus instead of titers alone. Obtaining titer is not necessary more than once in early pregnancy to determine if the patient is a candidate for immunomodulation with IVIG and/or plasmapheresis. This patient should begin MCA-PSV Doppler ultrasounds at 16 to 18 weeks of gestation15. While rare, severe anemia requiring IUT has been reported as early as 15 weeks in subsequent pregnancies. MCA-PSV determinations are possible and reference values are available as early as 12 weeks gestation7.
- – An extremely high titer found in early pregnancy or previous fetal loss as a result of HDFN may be an indication for intravenous immune globulin (IVIG) treatment and/or plasmapheresis. Though studies examining efficacy of these interventions are limited due the rarity of HDFN and therefore small sample size, results point to a delayed interval to first intrauterine transfusion and higher fetal survival rate 5, 6, 34. Consider referral to a maternal fetal medicine program with experience offering this treatment. For additional articles relating to IVIG and plasmapheresis, see our additional reading by topic page.
Once a critical titer is reached, titer concentration is no longer indicative of severity of HDFN. Noninvasive testing with MCA-PSV scan should be initiated should be initiated at 16 to 18 weeks gestation 15 and repeated weekly (or more frequently if the MoM is rising or approaching 1.5 multiples of the median (MoM). If needed, indexes exist for MCA-PSV scans as early as 12 weeks 7. The ideal MCA-PSV scan is performed by trained personnel during a state of fetal rest, in the absence of fetal breathing, and with no or minimal angle correction. Multiple readings should be obtained despite fetal activity level. Correct technique is critical in determination of the MCA-PSV value. The highest MCA-PSV value of at least three assessments should be recorded and used for clinical decision making. Read more about MCA technique here.
Note that the objective of the MCA-PSV scan is to screen for fetal anemia in order to initiate intervention before progression to fetal hydrops. In the early second trimester (less than 24 weeks gestation), fetal hydrops may not be present despite the finding of an elevated MCA-PSV. These fetuses are still profoundly anemic 97. An MCA-PSV at or above 1.5 MoM for gestational age (calculator available here), indicates possible severe anemia requiring intervention. Some types of steroid administration including oral8, vaginal8, or IM administration9, 35, 36 can affect the fetal blood flow – resulting in undetected fetal anemia. Expert opinion holds that steroid administration has been shown to falsely lower MoM values. Planned delivery or intrauterine transfusion should not be modified based on MoM values observed after administration of steroids. Steroids should only be administered after the decision to transfuse or deliver has been made.
In addition to false lows, MCA scans have a false positive rate of 12%11. Potential causes for falsely elevated MoM scores (scan indicates anemia when no anemia is present) include: fetal activity10, fetal breathing11, and maternal meals12. For this reason, an MCA-PSV closely approaching 1.5 MoM should be reassessed in 2-3 days5, 15.
Some institutions initiate weekly antenatal testing (non-stress tests and biophysical profiles) at 32 weeks gestation for any at risk pregnancies regardless of titer and MoM 14, and this is suggested in recent UpToDate guidance 5.
Considerations for Subsequent Pregnancies
Though cost is generally a prohibitive factor, options exist to prevent alloimmunization entirely in subsequent pregnancies. This includes:
- In-vitro fertilization (IVF) with preimplantation genetic testing (PDG) in the case of a heterozygous paternal genotype for the offending red cell antigen32
- Gestational carrier using an embryo conceived via IVF
- Donor sperm used in intrauterine insemination (IUI) from a donor who does not carry the offending red cell antigen.
To see additional information on alternatives to natural conception visit our Alternatives to Natural Conception page.
If a woman intends to become pregnant again, pregnancy monitoring and potential interventions can be pre-planned with a supportive provider. This may include IVIG and plasmapheresis beginning in the first trimester and assessment for eligibility for inclusion in new clinical trials such as that for nipocalimab. To see additional clinical trials relating to alloimmunization and HDFN, visit our Current Research and Clinical Trials page. For women with previously affected pregnancies requiring IUTs, referral to a specialist with extensive experience in IUTs, IVIG and plasmapheresis may be considered and pre-pregnancy consultation should be initiated.
