Noninvasive preventative measures
Plasmapheresis + IVIG
Plasmapheresis or therapeutic plasma exchange (TPE) and intravenous immunoglobulin (IVIG) has been used for over 40 years to lower antibody titers and prevent/reduce fetal hemolysis in cases of extremely high titers or previous pregnancy loss as a result of HDFN. These interventions are most effective when initiated during the first trimester of pregnancy, typically around ten to twelve weeks of gestation. These usually are not effective in reducing fetal anemia once it is present, but these measures have been shown in small studies to reduce the time to initiation of IUT.
The mechanism of action of IVIG is not well-known in this application, though positive results have been demonstrated in small series and one prospective study23, 24, 34. This treatment usually initiates at 1g/kg maternal weight every week.
Plasmapheresis (removal of maternal plasma through an apheresis machine) may enhance the efficacy of IVIG, and though IVIG is sometimes instituted alone, plasmapheresis is not often instituted alone25, 26. The combination of plasmapheresis and IVIG is typically reserved for the most high-risk cases. A case series of 9 pregnancies using this technique reported reduced antibody titers, IUT initiation at a later gestation, and no fetal and neonatal fatalities 26. A common treatment plan for a patient receiving plasmapheresis and IVIG involves initiating several serial plasmapheresis treatments followed by IVIG at ten to twelve weeks’ gestation and continuing with weekly IVIG 26, though this treatment should be considered on a case-by-case basis.
For additional articles relating to IVIG and plasmapheresis, see our additional reading by topic page.
Nipocalimab
A clinical trial is currently ongoing for nipocalimab administered via weekly IV infusion in women who have previously had severely affected pregnancies before 24 weeks gestation and who have anti-D or anti-K antibodies. Visit the official site to assess the patient’s eligibility for this trial. Other trials relating to alloimmunization and HDFN can be found here.
Invasive measures
Intrauterine Transfusion (IUT)
After an MCA-PSV at or above 1.5 MoM, the following interventions should be scheduled within 2-3 days 6, 10 and conducted during the same operative session 6:
- Fetal cordocentesis to determine fetal hemoglobin level (considering MCA-PSV has a false positive rate of 12%)6, 14, 16
- If cordocentesis confirms severe anemia represented by hematocrit lower than 30%, or fetal hemoglobin is more than two standard deviations below the mean value for gestational age, initiate intrauterine transfusion in a skilled facility (See UTD Intrauterine Fetal Transfusion of Red Cells 6 for more detailed information). Availability of cross-matched antigen negative blood should be ensured in advance of the session. Phenotypically matching additional clinically significant antigens (such as Duffy, Kidd, MNS) to the mother is recommended and performed at some centers to prevent the formation of new red cell alloantibodies that can result from exposure to donor blood at the time of intrauterine transfusion 17. Women with one alloantibody are significantly more likely to develop additional antibodies upon exposure 17. The presence of these new antibodies can further contribute to the development of fetal anemia.
- If cordocentesis identifies hemoglobin is above 30%, obtain another blood sample in one to two weeks depending on the value’s closeness to the threshold 6.
The use of maternal premedication for IUT varies by center and may include use of local anesthetics, indomethacin/pethidine/promethazine, or spinal epidural analgesia. The prophylactic use of antibiotics or corticosteroids are sometimes used but their necessity is not well-established 18, 19. Direct injection of fetal medication including atracurium or vecuronium 6, 21 for fetal paralysis is necessary to fetal movement in most cases and has been associated with increased success of the procedure. Some practitioners recommend fentanyl for fetal pain 20 though it is not universally used 22. Click here for more detailed information about medications during IUTs.
Intrauterine transfusion should be guided by continuous ultrasound and staffed, at minimum, by an experienced maternal fetal medicine (MFM) specialist/perinatologist, seasoned ultrasonographer and one or more operating nurses. A recent article found that training under the supervision of an experienced operator requires 30 – 50 procedures for a physician to gain the skills to perform this procedure. An annual volume of 10 procedures has been proposed to maintain proficiency 98.
Transfusion volume can be calculated using a simplified formula by Giannina et al29 to attain a final fetal hematocrit of 45% 30, 31. For IVT, transfusion volume = 0.02 × target increase in fetal Ht per 10% × g of estimated fetal weight, assuming that donor blood hematocrit is approximately 75%. 16 Fetal hemoglobin/hematocrit testing through cordocentesis at the time of intravascular transfusion allows for a precise calculation of transfusion quantity. It is important to note that transfusing too large of a volume of blood can result in fetal loss due to an acute change in blood viscosity and subsequent cardiac failure. This is especially true in the early second trimester fetus (<24 weeks gestation). Fetal hematocrit should never be raised higher than 3x the initial value. A repeat procedure to normalize the fetal hematocrit can be undertaken 48 hours later.
In some centers, an intravascular transfusion is supplemented by an intraperitoneal procedure (IPT) at the same setting. This allows for the slow absorption of blood between procedures in an effort to maintain a more stable hematocrit. The formula for determining the IPT volume is (# weeks gestation – 20) X 10 = volume to be transfused in cc. Blood in the peritoneal reservoir will be absorbed over 7-10 days. IPTs have also been used to successfully correct fetal anemia in severe cases of HDFN that present prior to 20 weeks gestation. In this situation, attempts to gain access to the fetal umbilical cord to perform an intravascular transfusion are associated with as high as a 20% perinatal loss 97.
The goal of an intrauterine transfusion is to maintain the fetal hematocrit above 25% . To this end, some experts will typically transfuse 10 days after the first transfusion, 2 weeks after the second transfusion, and 3 weeks after the third transfusion. Beyond the third transfusion, additional transfusions typically take place at 3-4 week intervals due to suppression of fetal erythropoiesis and the high percentage of donor RBCs which are safe from hemolysis. A second approach to the timing of intrauterine transfusions is to expect a decline in hemoglobin of 0.4 g/dL/day after the first transfusion, 0.3 g/dL/day after the second transfusion, and 0.2 g/dL/day after the third transfusion. This approach requires caution due to a potentially inaccurate fetal hemoglobin immediately after the procedure as a result of fetal fluid shifts, and bleeding from the puncture site6. Information regarding the accuracy of MCA-PSV for determining the timing of additional transfusions is mixed, and providers must familiarize themselves with the various data available61, 62, 63, 64, 65.
Fetal survival has increased in recent years following the incorporation of continuous ultrasound and clinical implementation and discussion of published research techniques. Even so, a large cohort study examining the outcomes of intrauterine transfusion found that 1.8% of fetuses died from the procedure even under the care of an experienced practitioner 16. Van den Alker et al found that 23% of severely hydropic fetuses had severe thrombocytopenia 81. Fetal thrombocytopenia increases fetal mortality, especially for severely hydropic fetuses 81. A copy of Table 1 from Zwiers et al.16 shows a representative summary of fetal survival after intrauterine transfusion. 
Additional IUT-related complications include bleeding from the puncture site, cord occlusion, brady- or tachycardia, chorioamnionitis, and preterm premature rupture of the membranes (PPROM) which may require emergency caesarian or lead to maternal and fetal morbidity or mortality 31, 39. For this reason IUTs performed at or after viability are usually performed in or proximate to an operating suite where delivery may be carried out immediately. Normal neurologic outcome occurs in 94-95.2% of cases after IUTs. Severe hydrops may be associated with a higher risk of impairment 71, 72. The incorporation of IUT into a provider’s clinical practice should be weighed heavily against experience and available resources. Please contact the Allo Hope Foundation for referral recommendations to an experienced facility if patient need requires.
Additional information regarding IUT technique is available here.
After the last IUT, phenobarbital is considered in many institutions to enhance the fetus’ liver function and therefore accelerate the breakdown of bilirubin in neonatal circulation. In one study, mothers took 30mg phenobarbital three times daily after their last IUT until delivery. The incidence of exchange transfusion was significantly lower in neonates whose mothers took phenobarbital in advance of delivery 27. Due to the time required for phenobarbital to work, this intervention was not shown to be efficacious when administered to the neonate after delivery in a randomized controlled trial 28.
