Anemia is an inadequate amount of red blood cells. Anemia is caused when maternal alloantibodies (anti-D, anti-K, anti-E, anti-c, and others), cross into the fetal circulation and attach to the baby’s red blood cells. Once attached, the antibodies destroy the blood cells (hemolysis), causing anemia and Hemolytic Disease of the Fetus and Newborn (HDFN). It is important to remember that not all babies are at risk of developing fetal anemia. Antigen negative fetuses will not be at risk for HDFN. In a first affected pregnancy, women with titers that are below critical (16 for most antibodies, 4 for anti-K) are at extremely low risk for fetal anemia.
During pregnancy, a specialized kind of ultrasound called an MCA-PSV Doppler is used as a screening tool to detect fetal anemia. This scan measures how fast the blood is flowing inside the baby’s brain (the PSV) and will compare it to the average velocity of other fetuses at the same gestational age. This results in a Multiple of the Median (MoM) number. If the MoM is ≥ 1.5, the baby is considered to be moderately anemic. At this point a cordocentesis is performed to determine the baby’s hemoglobin or hematocrit level. If the hematocrit is <30% the fetus is considered to be anemic.
Tests for Fetal Anemia
MCA-PSV Doppler Ultrasounds – Screening for Fetal Anemia
For women who have had a previously affected pregnancy or who have critical titers, 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.
Cordocentesis – Confirmation of Fetal Anemia
Because the MCA-PSV has a false positive rate of 12%, fetal cordocentesis is used to definitively determine if the fetus is anemic 6, 14, 16. In this test, a needle is inserted through the mother’s abdomen into the fetal vein. A small blood sample is drawn and tested to determine the fetal hematocrit or hemoglobin. 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, treatment with intrauterine transfusion is done in a skilled facility (See UTD Intrauterine Fetal Transfusion of Red Cells 6 for more detailed information). If cordocentesis identifies hemoglobin is above 30%, another blood sample is obtained in one to two weeks depending on the value’s closeness to the threshold 6.
Signs of Anemia
Signs of anemia vary by fetus. They can include (but are not limited to):
- An MoM of 1.5 or higher on an MCA-PSV scan. Some fetuses will not have any signs of fetal anemia besides an elevated MoM value.
- Pericardial effusion
- Fetal hydrops
- Abnormal amniotic fluid levels
- Reduced fetal movement
Treatments for Anemia
- 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).
- 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.