SFM Fetal Therapy Practice Guidelines: Intrauterine Blood Transfusion

Abstract

Despite routine antenatal anti-D prophylaxis with immunoglobulin, Rh alloimmunization and hemolytic disease of the fetus and newborn continue to occur due to a myriad of reasons. Intrauterine intravascular transfusion (IUT) or fetal blood transfusion is a therapeutic prenatal procedure in which specifically prepared and treated unit of donor red blood cells is injected intravascularly into the umbilical vein under ultrasound guidance. Originally introduced in the year 1963, it continues to be the standard treatment for severe fetal anemia. The objective of this guideline is to provide an evidence-based update of IUT for the perinatal healthcare providers.

Keywords

ICT - intrauterine transfusion - MCA PSV - Rh D alloimmunization

Introduction

Intrauterine intravascular transfusion (IUT) or fetal blood transfusion is a therapeutic prenatal procedure in which a specifically prepared and treated donor red blood cells (RBC) are injected intravascularly into the umbilical vein under ultrasound guidance.[1] Originally introduced in the year 1963, it continues to be the standard treatment for severe fetal anemia.[2] With a better understanding of the immune and nonimmune mechanisms of fetal anemia and the advent of high-resolution ultrasound, there has been a profound change in the technique and protocol of IUT.

Despite routine antenatal anti-D prophylaxis with immunoglobulin, Rh alloimmunization and hemolytic disease of the fetus and newborn (HDFN) continue to occur due to a myriad of reasons outlined below.

The objective of this guideline is to provide an evidence-based update of IUT for perinatal healthcare providers.

Indication

IUT is the standard therapeutic procedure for the treatment of fetal anemia.[2] The various clinical definitions of fetal anemia are outlined below.[3]

Definitions of fetal anemia

Type	Severity
A. Hematological
1. Hb deviation from GA mean	Mild	Moderate	Severe
	< 2 g/dL	2–7 g/dL	> 7 g/dL
2. Hb values expressed as MoM	0.86–0.65	0.64–0.55	≤ 0.54
3. Hematocrit	< 30 %
B. Ultrasound
MCA PSV	1.3–< 1.5 MoM	≥ 1.5 MoM
	Mild anemia	Moderate-to-severe anemia

Measurement of MCA PSV

Sonographically, moderate-to-severe fetal anemia is present when the fetal middle cerebral artery (MCA) peak systolic velocity (PSV) exceeds 1.5 multiples of the median (MoM) between 18 and 35 gestational weeks.[4] [5] The MCA PSV has a sensitivity of 86% and a specificity of 71% for the diagnosis of fetal anemia. The fetal hemoglobin (Hb) is typically less than 10 g/dL or the hematocrit is less than 30% at this level of the MCA PSV. Fetal hydrops usually set in as the Hb concentration falls below 6 to 7 g/dL below the mean for the gestational age.[6]

[Fig. 1] outlines the ultrasound technique for the measurement of MCA PSV.

Fig. 1 Spectral Doppler of MCA in a fetus with severe HDFN. This image demonstrates the technique for measuring the MCA PSV. For the objective of assessing fetal anemia, MCA PSV is assessed between 18 and 35 weeks of gestation. The axial image of fetal brain is insonated with color Doppler and the circle of Willis is demonstrated. A pulsed Doppler gate of width 2 mm is placed at the proximal 2 cm of the MCA from its origin. The chief prerequisites to be observed are maternal and fetal quiescence, avoiding undue pressure with transducer and maintaining an insonation angle of 0 degree ideally (always < 20 degree). Three measurements under ideal condition are documented. HDFN, hemolytic disease of newborn; MCA, middle cerebral artery; PSV, peak systolic velocity.

• Fetal anemia may be caused by:

1. A. Immune mechanisms

The most common indication for performing IUT is HDFN. This occurs when the mother lacks specific RBC antigen (s) and therefore mounts an antibody response against such antigens of the fetal RBC when it enters her blood circulation. The maternal red cell immunoglobulin G antibodies cross the placenta causing extravascular hemolysis of the fetal RBCs. More than 50 red cell antigens have been associated with HDFN. The most prevalent red cell antibodies are Rhesus (Rh) D, Kell, and Rh c.[7] Other antibodies associated with severe HDFN are anti-Rh-e/E (Rhesus), Fy(a)/Fy(b) (Duffy blood group), Kidd (Jka), and anti-M (MNS system).

The commonest scenario of red cell alloimmunization is seen in an Rh D negative mother with a Rh D positive partner.[8] Due to prior sensitization with fetal Rh D positive RBCs, an antibody response ensues. The first pregnancy or the sensitizing pregnancy usually escapes from HDFN. However, future pregnancies are at risk of HDFN. In such a woman, the serum anti-Rh D Ig measured via indirect Coombs test (ICT) is usually above the critical level of 1:16.

The surveillance strategy for Rh D incompatible and sensitized pregnancies is outlined below.

• B. Nonimmune mechanisms

Fetal anemia can also occur from nonimmune mechanisms as listed below.

Objectives of Performing Intrauterine Transfusion

• ▪ To treat fetal anemia by improving the oxygen-carrying capacity of the fetal blood by substituting the hemolyzed fetal RBCs with O Rh-negative blood in high concentration thereby preventing hydrops and mortality

• ▪ To suppress fetal erythropoiesis

• ▪ To reverse already developed hydrops

• ▪ To extend the pregnancy to term with the delivery of a healthy nonhydropic neonate

• ▪ To minimize the need for exchange transfusion and prolonged phototherapy

Preparation of the Blood Unit for IUT

The donor blood required for IUT is to be obtained from a transfusion medicine unit with expertise in undertaking such preparation. These units are usually located in tertiary care teaching and research centers, oncology hospitals, and specialized blood banks. These institutions usually have a list of prospective donors of O Rh D negative donors.

• The prerequisites of the blood unit used for IUT are outlined below.

Specific request forms duly filled with the pertinent details of the pregnancy should be dispatched to the laboratory. Verbal communication regarding any specific requirements can be done with the transfusion specialist in charge. Once the blood unit arrives, it should be verified for all the details prior to performing IUT. If there is a delay in performing the IUT, storage should be continued in the cold box provided by the laboratory. The shelf-life of the blood unit is 24 hours after irradiation and hence transfusion must be completed within this time. Otherwise, a new blood unit must be ordered.

• Written and informed consent should be obtained prior to performing the IUT.

Maternal Preparation

The standard protocol for performing any prenatal procedure should be followed.

The procedure setting

A standard procedure room with adequate space and ergonomics is generally used to perform the IUT. A double setting either in the labor room or operation theater may also be used especially for IUTs near term.

The following are the essential requirements of the procedure room:

• The tray for the procedure should have the following contents ([Fig. 2]).

Fig. 2 Contents of the procedure tray prepared for IUT. This image demonstrates the key contents of procedure tray prepared for IUT (image courtesy: Dr. Vivek, AIIMS Kochi). IUT, intrauterine transfusion.

Drugs Used in IUT

The following drugs are used in IUT and should be appropriately constituted-

Choosing an Access

Currently, IUT is performed via the intravascular approach. The umbilical vein at its placental insertion in an anterior placenta and the intrahepatic portion in a posterior placenta is the most preferred approach. Advantages of the intrahepatic approach include avoidance of arterial puncture and secondary vasospasm and cord tamponade, less Fetomaternal haemorrhage (FMH) and success rates in the region of 90%. Intraperitoneal bleeding is rare, and usually self-limiting and functions as an intraperitoneal transfusion ([Fig. 3]).

Fig. 3 Two-dimensional grayscale ultrasound images showing the two common intravascular placements of the needle. This image demonstrates the two sites of intravascular placements of the needle for IUT. (A) Axial image of fetal liver showing the placement of needle inside the umbilical vein. (B) The needle has been guided toward the placental insertion of the umbilical vein. IUT, intrauterine transfusion.

The free loop is usually avoided as it is associated with higher complication rates.

The intraperitoneal approach may be used in selective cases such as an early transfusion (< 22 weeks), in case of failure of the intravascular approach or may be combined with intravascular technique to allow longer interprocedural intervals. Very rarely, direct intracardiac transfusion may be performed as a rescue operation in an actively exsanguinating fetus.

Steps of IUT

Preprocedure checklist—[Annexure I], Consent form—Annexure II.

• Actual steps:

  • Step 1 Set up the transfusion circuit

    • Connect the blood transfusion set to the blood bag.

    • Hang the blood bag on the IV drip stand.

    • Connect the other end of the drip set with the three-way connector.

    • The middle outlet of the three-way is connected to a 10 mL Luer lock syringe and the third end to the Chiba needle.

    • Fill the circuit with blood ensuring no air is present.

    • Take a sample for measuring the donor hematocrit, and enter the value in the calculator.

  • Step 2 Insert a 22G spinal needle and administer the loaded drugs (paralytic agent + anesthetic) into the fetal thigh/deltoid depending on the ease of access

  • Step 3 Insert the Chiba needle

    • Infiltration of local anesthesia if required.

    • Enter the planned intravascular site with the 20 G Chiba needle

    • Draw blood for fetal blood hematocrit and complete hemogram (exclude erythrocyte sedimentation rate), serum bilirubin, blood group, direct Coombs test, reticulocyte count, and fetal karyotype.

  • Step 4 Calculating the transfusion volume

    • The parameters required to calculate the intravascular transfusion volume are

      1. Initial fetal hematocrit

      2. Feto placental blood volume

      3. Donor hematocrit

      4. Target hematocrit 45 to 50%

    • The formula most commonly used is

      Fetoplacental vol x (desired hematocrit – fetal hematocrit)

      Donor hematocrit – desired hematocrit

    • Feto placental volume = Ultrasound EFW x 0.14

    • Fetoplacental blood volume can be calculated based on fetal weight or based on gestational age. The latter is not affected by the presence of fetal hydrops.

    • Online calculators are available at the Perinatology.com Web site ( http://perinatology.com/protocols/rhc.htm ), Fetal Medicine Barcelona ( http://medicinafetalbarcelona.org/calc/ and mobile app) and the Fetal Medicine Foundation UK Web site ( www.fetalmedicine.org/calculators ).

  • Step 5 Transfusing the calculated volume

    • Draw blood from the blood bag into the syringe then close the three-way knob of this side (the side toward the blood bag) and push the blood from the syringe into the needle

    • Hold the syringe vertically to avoid air bubble entry.

    • Ask the circulating nurse to note the amount transfused.

  • Step 6 Monitor the fetal activity during the procedure. Be watchful for fetal bradycardia.

  • Step 7 After the calculated volume has been transfused, inject 2 mL of normal saline via the intravascular needle, wait for a minute, and take a fresh sample of fetal blood for postprocedure hematocrit.

  • Step 8 Post-transfusion monitoring

    • Post-transfusion hematocrit: This is important as it decides as to when and whether a next transfusion may be required.

    • Document the fetal heart rate, MCA PSV, and the Myocardial performance index

    • Weekly MCA PSV

Planning Subsequent Transfusions

Subsequent transfusions are decided based on the expected fall in the hematocrit. Usually, after the first transfusion the fall in Hb is 0.4 g/dL per day. After the second transfusion, the fall in Hb is 0.3 g/dL per day and 0.2 g/dL per day after the third. The figures of 0.4,0.3,0.2 multiplied by 3 will give the hematocrit (in %). Otherwise, a fall of 1% in hematocrit per day can be used for the sake of convenience. The MCA PSV is not very reliable after transfusions because of the different characteristics of the adult blood and the fetal blood. Some authors have proposed a higher cutoff of 1.7 MoMs instead of 1.5. Another empirical regime is transfusing at 10 days, 2 weeks, and 3 weeks for the second, third, and subsequent IUTs.

Complications[9] [10]

The procedure-related fetal loss rate in IUT is 0.9 to 4.9%. There is a higher incidence of loss in fetal hydrops, early gestational age, failure of the use of a fetal paralytic agent, use of a free loop of cord for transfusion, arterial puncture, operator expertise, and the severity of anemia. In anatomically normal fetuses, the loss rate is 1%. In those fetuses with structural anomalies and hydrops, the procedure-related loss is 7 and 25%, respectively.

Avoiding a transplacental transfusion, prior cross-match of donor sample with maternal sample and the potential use of a single donor for all transfusions in a particular fetus can prevent the generation of new antibodies. Cord accidents can be avoided by using fetal paralytic agents (preventing needle dislodgement from fetal movement).

The neurodevelopmental outcome following IUT has been observed to be normal in 95% of children assessed at a median age of 8.2 years. Cerebral palsy, severe developmental delay, and bilateral deafness were detected in 2, 3, and 1% of children, respectively. Factors independently associated with neurodevelopmental impairment included severe hydrops, number of IUTs, and severe neonatal morbidity.

Planning Delivery after IUT

A successful IUT regime will result in term delivery more than or equal to 37 weeks of gestation. Generally, if the last transfusion was performed at 34 to 35 weeks, delivery can be planned after 3 to 4 weeks. Induction of labor can be offered if there are no obstetrical contraindications. Delivery should be done at an institution with the availability of neonatologists and level III facilities.

Neonatal hepatic enzyme induction is done prenatally by transplacental therapy: start maternal oral phenobarbital 30 mg three times daily 10 days prior to the planned delivery date. This reduces the need for exchange transfusion by 75%.

Annexure I Preprocedure checklist

Written informed consent

Alert the obstetrician, neonatologist and the anesthetist

Pre-procedure scan and documentation of the EFW, MCA PSV, MPI, cervical length and proposed site of intravascular access

Laboratory staff informed

Minimum three EDTA vials properly labeled (donor, preprocedure and postprocedure fetal samples)

Verification of the blood bag

Procedure tray

Dilution and constituted drugs (pancuronium, fentanyl)

Heparinization of the tubings

Online/offline calculator kept ready to calculate the blood volume

Preprocedure medications: antibiotic, tocolysis, and sedative

Abbreviations: EFW, estimated fetal weight; MCA, fetal middle cerebral artery; MPI, myocardial performance index; PSV, peak systolic velocity.

Annexure II Consent form for IUT

• I………………………………………………………., w/o ………………………………………………….. hailing from ………………………………….. do hereby give my consent for the procedure “Fetal Blood Transfusion”

• I have understood the following information before giving consent, explained to me in my own language by the doctor

1. That the baby inside my womb is affected by severe anemia and continuation of pregnancy without any treatment may result in severe damage or death to the fetus

2. Fetal blood transfusion is the current standard of treatment for fetuses with such conditions

3. The procedure is generally safe for the mother; however, it carries a 1 to 2% chance of procedure-related miscarriage.

4. Depending on the severity of the fetal condition, the survival can be expected to be around 85 to 95% if regular transfusions are undertaken till delivery

5. Post-delivery, the baby may still require transfusion till the baby's blood system is able to compensate adequately

6. That I need to inform immediately to my obstetrician if any symptoms arise such as fever, persistent abdominal cramps, profuse bleeding or leaking fluid per vaginum, or generalized feeling of unwellness following the procedure

• Patient Witness

• Date:

• Counseled by Dr

Conflict of Interest

None declared.

Informed Consent

Informed consent was obtained from all women.

• References

• 1 Liley AW. Intrauterine transfusion of foetus in haemolytic disease. BMJ 1963; 2 (5365): 1107-1109
• 2 Rodeck CH, Nicolaides KH, Warsof SL, Fysh WJ, Gamsu HR, Kemp JR. The management of severe rhesus isoimmunization by fetoscopic intravascular transfusions. Am J Obstet Gynecol 1984; 150 (06) 769-774
• 3 Nicolini U, Nicolaidis P, Fisk NM, Tannirandorn Y, Rodeck CH. Fetal blood sampling from the intrahepatic vein: analysis of safety and clinical experience with 214 procedures. Obstet Gynecol 1990; 76 (01) 47-53
• 4 Mari G, Deter RL, Carpenter RL. et al; Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses. Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. N Engl J Med 2000; 342 (01) 9-14
• 5 Oepkes D, Seaward PG, Vandenbussche FP. et al; DIAMOND Study Group. Doppler ultrasonography versus amniocentesis to predict fetal anemia. N Engl J Med 2006; 355 (02) 156-164
• 6 Moise KJ. Fetal anemia due to non-Rhesus-D red-cell alloimmunization. Semin Fetal Neonatal Med 2008; 13 (04) 207-214
• 7 Lindenburg IT, van Kamp IL, Oepkes D. Intrauterine blood transfusion: current indications and associated risks. Fetal Diagn Ther 2014; 36 (04) 263-271
• 8 Pasman SA, Claes L, Lewi L. et al. Intrauterine transfusion for fetal anemia due to red blood cell alloimmunization: 14 years experience in Leuven. Facts Views Vis ObGyn 2015; 7 (02) 129-136
• 9 Zwiers C, Lindenburg ITM, Klumper FJ, de Haas M, Oepkes D, Van Kamp IL. Complications of intrauterine intravascular blood transfusion: lessons learned after 1678 procedures. Ultrasound Obstet Gynecol 2017; 50 (02) 180-186
• 10 van Kamp IL, Klumper FJ, Meerman RH, Oepkes D, Scherjon SA, Kanhai HH. Treatment of fetal anemia due to red-cell alloimmunization with intrauterine transfusions in the Netherlands, 1988-1999. Acta Obstet Gynecol Scand 2004; 83 (08) 731-737

Publication History

Article published online:
21 March 2024