Intrauterine Fetal Transfusion: Indications and Procedure

Intrauterine treatment of severe fetal anemia was introduced in the early 1960s, by Sir William Liley from New Zealand (1). In those days, Rh-D alloimmunization was a major cause of fetal and neonatal morbidity and mortality. In this pre-ultrasound era, imaging of the fetus was possible by X-ray examination, which could identify fetal hydrops. Liley was inspired by the successful treatment of children with anemia in Africa, where they injected donor blood into the abdominal cavity, making use of the accompanying ascites. Under X-ray guidance, Liley inserted a needle into the abdomen of fetuses thought to be anemic due to Rh-D alloantibodies in the mother, bilirubin-stained amniotic fluid and the suspicion of hydrops fetalis. The actual fetal hemoglobin concentration could not yet be measured.

Several centers around the world adopted this technique, including our department of obstetrics in Leiden (1965). Survival rates were low, in the order of 25% in the early years, increasing with experience and advances in imaging, such as fluoroscopy, in which both a water-soluble and a lipid-soluble radiopaque solution were injected in the amniotic fluid, allowing visualization of the bowel and the skin of the fetus, respectively.

A major improvement of the technique became available in the early 1980s after pioneer work of Jens Bang in Denmark (2) and Ferdinand Daffos (3) in Paris, who used ultrasound to direct a needle into the umbilical vein for direct access to the fetal circulation and intravascular injection of the donor blood. The same procedure, named cordocentesis or fetal blood sampling (FBS), or, mainly in the United States, percutaneous umbilical blood sampling (PUBS), could be used to take a blood sample for hemoglobin/hematocrit measurement. Following a visit to Daffos, our center adopted this technique in 1986, and we still use this method for almost four decades and over 2500 fetal transfusions later. In this chapter, we will list the current indications for intrauterine transfusions (IUT), followed by a detailed description of the techniques that we are currently using.

P55 Haemolytic disease of fetus and newborn

P55.0 Rh isoimmunization of fetus and newborn

P50.3 Hemorrhage into co-twin

P50.4 Hemorrhage into maternal circulation

P56 Hydrops fetalis due to hemolytic disease

P56.0 Hydrops fetalis due to isoimmunization

P35.9 Congenital viral disease, unspecified

Many fetal diseases can be associated with fetal anemia. Mild or even moderate anemia may be well tolerated by the fetus, even for a prolonged period. Expectant management may be safer than an invasive prenatal treatment in these cases. Severe anemia, defined as a hemoglobin concentration below 4 or 5 standard deviation (SD) below the mean for gestational age, may cause heart failure, hydrops and death, if not treated urgently. It is now well established that severe fetal anemia can be reliably diagnosed using middle cerebral artery (MCA) Doppler measurements (4, 5), in which a peak systolic velocity (PSV) > 1.55 multiples of the median (MoM) (PSV-MCA) shows a strong correlation with severe anemia (Figure 1).

In all invasive fetal procedures however, it is important to consider the alternative, which is delivering the baby and treating the anemia after birth. This is almost always easier and safer, but depending on gestational age, there is a downside of iatrogenic prematurity, not only due to immaturity of the fetal lungs but also to the enhanced vulnerability of the fetal blood-brain barrier to bilirubin in the immature fetus. .

Not all severely anemic fetuses are good candidates for IUT. Before offering an IUT to the pregnant person, a thorough diagnostic work-up is needed. In a significant number of cases, the anemia is not the only problem the fetus has. IUT may at least temporarily solve the anemia, but the long-term prognosis may depend on the underlying cause. If the anemia is caused by certain infections or genetic syndromes, IUT may result in fetal survival but not in curing the actual disease. It is essential, in cases of likely poor long-term outcome, to consider the option of withholding the IUT. Examples will be discussed below.

Red cell alloimmunization

This is the best-known cause of fetal anemia and the most common indication for IUT. In the past, this condition was known to have a very poor prognosis before the invention of IUT, while now survival exceeds 90% with excellent long-term outcomes (6-8). It is important to realize that in red cell alloimmunization, the fetus is essentially completely healthy, only temporarily threatened by the maternal antibodies crossing the placenta, destroying its erythrocytes. These antibodies exclusively attack erythrocytes and timely treatment of the resulting anemia prevents hypoxia and irreversible damage. After birth, the hostile intrauterine environment subsides and although in the first weeks the neonate may still need some form of treatment, the long-term outlook for the child is excellent. This makes the treatment of fetal anemia due to alloantibodies a rewarding endeavor. Although fetal hydrops is in most series the number one predictor of adverse outcome in red cell alloimmunized pregnancies, it is still worthwhile to transfuse severely hydropic fetuses, as the majority will recover. It remains striking how even extremely low hemoglobin concentrations rarely result in irreversible tissue damage (9).

Parvovirus B19 infection

This common viral infection in young children may occasionally occur in pregnant people, typically in those exposed to many young children such as day care workers and teachers. In young children, the infection is often recognized by the characteristic ‘slapped cheeks’ redness in the face, and pregnant people may be advised to avoid close contact with these children. At least 50% of pregnant people have antibodies against the virus, but this is not screened for on a routine basis. The infection in adults may go unnoticed or with non-specific symptoms. The virus may, however, be transferred across the placenta in pregnant people and infect the fetus. The virus preferentially replicates in the bone marrow, in the hematopoietic cells that are very active in the growing fetus. Unlike in alloimmunization, where red cell destruction is the main cause of anemia, the problem in fetal parvovirus infection is decreased red cell production. Since the infection is self-limiting, only lasting a few weeks, the essence of fetal treatment is to restore red cell levels, giving the fetus the time to start producing its own red blood cells again. This explains why in this disease, only one IUT is commonly sufficient.

The diagnosis of fetal anemia due to parvovirus is often made after the ultrasound finding of hydrops, in pregnant people reporting reduced fetal movements. Typically, the fetus has a lot of ascites, a large heart and a thick placenta (Videos 1 and 2). This pattern, found in a pregnant patient working in daycare or who had a history of contact with a young child that had a rash may allow preforming an IUT without waiting for the virology lab results. Anemia due to parvovirus infection may occur throughout the whole pregnancy, and successful IUT treatment has been reported from 13 weeks’ gestation onwards (10). Although some hydropic parvo-survivors may have brain damage, the majority, like in red cell alloimmunization, do remarkably well despite the extremely low hemoglobin levels (11).

Some pregnant people are diagnosed with parvovirus infection before fetal symptoms occur, commonly by testing after exposure to an affected child. We recommend following these women with weekly MCA Doppler till at least 10 weeks after exposure and perform an IUT as soon as the PSV-MCA suggests severe anemia (>1.55 MoM).

Twin Anemia Polycythemia Sequence (TAPS)

This complication of monochorionic twins is now increasingly diagnosed, both the spontaneously occurring form as well as post-laser TAPS. The best treatment however is still unclear (12). One of the options is to transfuse the anemic fetus, best combined with diluting the blood of the co-twin by a partial exchange transfusion (PET). Depending on the gestational age, this can be a challenging procedure, which requires skill, experience and patience. The IUT-PET may need to be repeated every 1-2 weeks until a reasonable gestational age (i.e., 32-34 weeks) is reached and the fetuses can be delivered.

Fetomaternal hemorrhage

Bleeding from the fetus to the pregnant person may occur spontaneously and chronically, or after abdominal trauma. The diagnosis is made by an increased MCA Doppler flow velocity in combination with a significant volume of fetal red cells in the maternal blood by Kleihauer-Betke testing or other techniques (13). A sinusoidal cardiotocogram may raise the suspicion but is not always present. It is often unclear when a next IUT is needed, since in chronic cases the amount of fetal blood loss is impossible to predict by laboratory tests. Close monitoring is essential, and delivering the fetus is a valid alternative in case of rapid recurrence of anemia (13).

Fetal tumours

Large fetal tumours such as sacrococcygeal and cervical teratomas, and chorioangiomas of the placenta may be associated with a hyperdynamic circulation which results in high PSV-MCA values. The increased fetoplacental blood volume and possible arteriovenous shunts in the tumor may contribute to this, and when fetal blood sampling is done, these pathologies are often found to be associated with only moderate anemia. Cardiac performance may be used in the decision to perform an IUT and when vascular occlusion techniques are applied, the procedure may be combined with an IUT to help the fetus recover or support it when bleeding occurs during or after the procedure (14).  

Homozygous alpha-Thalassemia

Until recently, homozygous alpha-Thalassemia was considered a lethal disease. This inherited genetic disorder cannot be cured with fetal blood transfusions, and survivors may need either stem cell therapy, which carries a considerable risk of demise with life-long immunosuppression or blood transfusions combined with chelation therapy to deal with the iron overload. The major life-long burden in survivors makes IUT controversial, and we would recommend to only offer this in a research setting, or at least after very extensive multidisciplinary counseling in a center that has experience with postnatal treatment of this disease, making sure the parents understand what the disease means for their child (15, 16). The responsibility of the fetal therapy team for the quality of life of survivors of their interventions is an ethically complex debate (17). Anemia due to homozygous alpha-Thalassemia is not so easily detected by ultrasound, as PSV-MCA is not markedly increased, due to the fact that the red cells are present in normal amounts, but the oxygen delivery is hampered. Hydrops, ascites, growth restriction and cardiomegaly are often the only indicators.

Single fetal death in monochorionic twins

In monochorionic twins, one fetus may die without warning, which results in acute blood loss from the healthy co-twin to the demised twin through large vascular anastomoses. In this case, evaluation of the co-twin may reveal a high PSV-MCA, indicating severe anemia. This can be treated with IUT; however, the high risk of brain damage, occurring at the time of the demise, may not be preventable, and the benefit of IUT in this particular complication remains questionable (18).

Fetal anemia of unknown origin

Some fetuses are found to have anemia with or without hydrops, without a clear cause at time of diagnosis. Apart from the above-mentioned example of likely parvovirus infection, we would recommend awaiting the diagnostic work-up, which obviously needs to be done as fast as possible. This should include extensive virology and genetic testing, including whole exome sequencing, fetal liver function tests and blood smears. Examples are Blackfan-Diamond anemia, hemangioendothelioma, elliptocytosis, and neonatal hemochromatosis (19). Although some of these may have a favorable outcome, in line with our view on performing IUT for alpha-Thalassemia, we are reluctant to transfuse anemic fetuses with an unknown cause. This may at least temporarily be life-saving but includes the risk of trading mortality for severe, irreversible and long-term morbidity.

All surgical procedures can be performed in a variety of ways, with preferences of surgeons which are often related to who trained them. Techniques develop over time, and advances in e.g., instruments and imaging may improve results, although proper comparative studies are often lacking. The techniques for IUT described here are a reflection of 37 years of experience with >2500 procedures performed in our Fetal Therapy center Leiden, the Netherlands. We acknowledge that there are certainly other ways to carry out the procedure and we do not claim our way is the best, but the data of this cohort can be used as an illustration of survival and complications rates (8).

Teamwork

Fetal therapy requires a dedicated, well trained and experienced team, with sufficient volume to maintain a high quality. For IUT, this includes a blood bank interested in providing, sometimes urgently, safe blood specifically suited for fetal transfusion, and an experienced neonatology team to take care of this special group of neonates. Overall results of a fetal transfusion center heavily depend on timely diagnosis of fetal anemia, preferably before hydrops occurs. This means a tight organization of the outpatient fetal medicine unit, with well-trained, dedicated sonographers and fetal medicine specialists available 24/7. In addition, timely referrals are essential, so the collaboration with all referring centers must be well organized.

Equipment

This ultrasound-guided procedure, like, in our opinion, all ultrasound-guided procedures that carry a risk of severe complications, deserves the highest quality machine available. We have a second high-definition monitor on a swing arm to provide the best possible view of the ultrasound image to the operator. In addition, if the procedure is done in a dual operator setting, both the doctor steering the needle and the assisting sonographer should be suitably experienced, preferably working together often. Excellent communication between the two is vital for the team performance.

The assisting fellow or nurse needs to have sufficient understanding of the procedure and the operators’ demands in various circumstances to make the team perform well. This is true for the other team members in the room as well. We highly recommend having a machine in the operating room which can provide a hemoglobin and hematocrit value within one minute, enabling the operator to keep the needle in the cord and proceed with the transfusion immediately after the anemia is confirmed. The person operating this machine should also quickly calculate the required blood volume to reach the desired post-transfusion hemoglobin/hematocrit. Our donor blood typically has a hematocrit of 85%. Our formula to calculate this volume is derived from work by the pioneer Charles Rodeck, using estimated fetoplacental volume and pre-transfusion hematocrit (20).

Other useful equipment is a blood warmer, set at 38 degrees Celsius, through which several loops of the tube running from the bag of blood to the needle are placed. For this procedure, we do not use intravenous access to the pregnant patient, no antibiotics are given, and anesthesiology is not involved. The only medication we routinely give to the patient is 50mg indomethacin per rectum to reduce uterine contractions.

Setting

In our center, we have a relatively large dedicated fetal operating room, not used for anything else so always available. It has storage of all possible equipment with back-up for everything. There is never a need to send someone elsewhere to get something while the patient is on the operating table. The room is not a full formal OR, but we maintain the highest possible standards for sterility. The patient is brought in on a hospital bed, which we keep close to the room for the rare event of an emergency transfer for a cesarean delivery or other emergencies. The partner or another supporting person sits near the head of the pregnant patient. Both are asked to wear a cap and a facemask. Like any OR there is the option to provide oxygen, and various monitoring equipment is within reach. Only in special high-risk circumstances we inform anesthesiology and the OR managers of our procedure. Our room is located on the labor floor, and therefore there is always the option to arrange an emergency cesarean delivery. Since the rate of emergency cesarean delivery is extremely low (less than once per 5 years), we feel no need to inform our labor team weekly.

Preparation

The donor blood needs to be as fresh as possible, and in our centre is specifically prepared by the national blood bank Sanquin for use in a fetus. Before starting the procedure, we double-check that the bag (commonly around 140 ml) is indeed meant for this patient, is O negative, and has a hematocrit between 80 and 90%, leucocyte-depleted and irradiated. In the past, we used cytomegalovirus-negative blood, but the usefulness of this requirement can be debated. Centers should discuss such details with their blood bank (21). The hemoglobin/hematocrit counter is cleaned and tested, as it is vital that this machine provides a result within 30-60 seconds after fetal blood sampling. A detailed ultrasound is performed, including confirmation of the high PSV-MCA level, measurement of the estimated fetal weight and the position of the umbilical cord with the identification of various potential access sites. The required needle length has to be determined. Sometimes it is decided to turn the table 180 degrees for an easier position of the operator and the sonographer.

Then the operator, an assisting nurse and the sonographer scrub and wear sterile clothing identical to a formal operating room setting. The sterile table is prepared and syringes are marked with a permanent marker pen (citrate, sample, atracurium, saline). The bag of blood is attached to an intravenous-system with a three-way stopcock, enabling aspirating 10 ml and injecting it into the fetus without the need to remove and attach syringes. The tube is led through the blood warmer. Needles are flushed with citrate.

Needle insertion

Over the past two decades, we have increasingly used the intrahepatic portion of the umbilical vein as our preferred target, a method pioneered by Umberto Nicolini already in the late 1980s (22). The only exception is when an anterior placenta and the placental cord insertion appear an easy target. After carefully selecting the ideal entry site, local analgesia is given and a 20 or 22 G needle is inserted.

1. Intrahepatic umbilical vein

In early gestation, up to around 20 weeks, we prefer a 22 G needle to match the small size of the vessel. This needle however is more flexible than the 20 G, and adjustment of the initial route may be difficult (Video 3). Procedures at a very early gestational age require even more careful site selection and route (Videos 4 and 5). We advise to aim for the umbilical vein as most central in the fetus as possible, close to the ductus venosus and portal vein and approach the vessel perpendicular. This approach prevents the fetus from ‘rolling’ and moving away from the needle tip. This part is done with the stylet in the needle. If necessary (in very small veins) we advise to puncture through the vessel and getting intravascular access by slowly retracting the needle in combination with a rotation, after removal of the stylet (since the tip has an oblique edge) with a few amount of citrate and mild negative pressure on the syringe. Too much pulling on the syringe will result in sucking the vessel wall to the needle and blocking the needle, so this is a delicate maneuver. When blood is obtained, the syringe is replaced by a citrated-flushed, empty syringe to sample 1-2 ml blood. Only 0.5 ml is needed for the hemoglobin/hematocrit counter, the rest is used for other lab tests and research. After the blood sample we inject the predetermined amount of paralyzing agent (currently we use atracurium) into the vein, this may also confirm correct placement by visualizing the fluid flowing into the vein and the ductus venosus (Video 6

2. Placental site insertion

In this variant, access to the umbilical vein can be reached with or without the stylet (Videos 7 and 8). The syringe needs to be filled with citrate if inserted without. In case of puncture with stylet the operator should aspirate before injecting fluids, as the needle is filled with air, once the stylet is removed. Again the 22 G needle is used up to around 20 weeks. The high hematocrit donor blood requires quite a bit of pushing power to get through such a thin needle. With the 20 G, it is easier to feel differences in required pushing pressure, warning the operator when the tip is against the vessel wall. With the larger volumes needed in later gestation, a larger diameter needle also leads to a shorter procedure duration. It is important to avoid the arteries, since even touching them may lead to spasm and bradycardia. If accidentally, the needle is inserted in an artery and blood is obtained, it is certainly an option to continue the transfusion into the artery, but injecting into the vessel wall must be avoided even more than with the vein. We also use fetal paralysis in case of an anterior placenta and placental cord insertion, since this was shown to reduce complications.

We rarely use fetal paralysis before inserting the needle in the cord (Video 9). Although this can easily be done with a 22G needle into the thigh of the fetus, it may result in an immobile fetus in an unfavorable position.

Blood transfusion

We infuse fetuses with a rate of about 10-15 ml per minute, or slower in case of hydrops. It is highly recommended to use warm blood for the transfusion. When bradycardia or tachycardia is observed, the injection is halted and we wait for normalization of the heart rate. Obviously, it is useful to understand why the fetus reacts to the transfusion, so needle tip position must be verified. Occasionally, the blood transfusion needs to be interrupted and a careful injection of some saline and subsequent aspiration of blood is used to confirm correct needle tip position.

In case of the intrahepatic vein transfusion, a cross section through the descending aorta is almost always present in the field of view, allowing the operator to see the fetal heart rate continuously without the need for the sonographer to turn on Doppler or observe the heart.

When the calculated volume is infused, we take a 1 ml blood sample to verify the hemoglobin level, after a short period of waiting to allow mixing of the transfused blood. In this time the needle is flushed with about 1 cc of saline, to prevent blood clotting in the needle during the waiting period. Often, it is needed to transfuse a bit more than the formula of Rodeck, especially in fetuses with a large liver and spleen size. It is useful to verify the post-transfusion hemoglobin again after a ‘top-up’, to enable better estimation of the interval to the next IUT. In case of an intrahepatic vein IUT, we now almost always take the opportunity to give extra blood into the intraperitoneal space, a method also already introduced in the 1980s by Nicolini and Rodeck (23). This blood will be taken up slowly in the following days, and does not cause stress to the fetal heart. This combined intravascular-intraperitoneal IUT has not been formally evaluated but we plan to do so soon. The goal is to prolong the interval between transfusions. The technique requires a bit of practice. After the intravascular part, the needle is retracted to just outside of the liver but the tip should remain within the abdominal cavity. This is best done by injecting some saline when the tip exits the liver tissue, to create an artificial space in which the donor blood, anything between 10-30 ml depending on gestational age, can be injected. A clear rim of ‘ascites’ then becomes visible. It is important to avoid injecting the blood into the abdominal muscles and the liver, although this should not cause real harm. When the tip is clearly in a free space the blood can be injected as fast as the thin needle allows.

Complications

A summary of (procedure-related) complications in recent studies is shown in the following table.

Tricks of the trade

1) Bradycardia During the Procedure: Bradycardia during an IUT is not an uncommon complication. Its management depends on the type of access obtained. In the case of intra-peritoneal injection, bradycardia usually results from an increase in intra-abdominal pressure and will resolve after fluid drainage from the peritoneal cavity. In the case of intra-venous access, it usually results from an unintentional and inevitable puncture of the umbilical artery. It is recommended to remove the needle and re-establish the access. The fetal heart rate should be closely monitored. If the bradycardia does not resolve, it is likely due to umbilical artery spasm, and emergency delivery is indicated for viable fetuses.

2) Cord Hematoma: This can be a complication of IUT with intra-venous access. In most cases, it is self-limited and will resolve spontaneously without further complications. However, as it can potentially compress the umbilical vessels, Doppler studies are necessary. In cases with normal Doppler measurements, expectant management and close follow-up are recommended. Closer follow-up and possibly delivery are advised in rare cases with progressive abnormal Doppler findings.

3) Hydrops: As fetal patients with hydrops often suffer from more severe anemia and have very low hemoglobin levels, it is advised that blood transfusion occurs through a combination of intra-venous and intra-peritoneal accesses. Intra-venous transfusion helps to rapidly correct the anemia, and intra-peritoneal transfusion, being absorbed more slowly, maintains a more sustained hemoglobin level. It is crucial not to fully correct the anemia in the first transfusion, as these patients are more likely to have some level of cardiac dysfunction and may not tolerate volume overload. A second session can be scheduled within 2-3 days for full correction.

4) Umbilical Vein Clot: This is a rare complication of IUT with intra-venous access. If it occurs with confirmed obstruction in Doppler studies, emergent delivery is indicated for viable fetuses.

Alternative techniques

We are aware that there are other options for IUT, such as puncturing a free loop of the cord, inserting the needle in the cord root from the amniotic cavity-side in posterior placentas, and even intracardiac transfusions. In rare cases, we have used all these methods, but we regard them as less safe, more as a last resort. Ideally, all centers performing IUTs should monitor their performance and outcomes, both on center level and on operator level, and compare them with published literature from similar centers.

In general, the interval between the first and second IUT is 2-3 weeks, and from the second IUT onwards it can be 4-5 weeks (Figure 2). We see the patients in our outpatient clinic every week, and evaluate PSV-MCA in combination with general fetal well-being. PSV-MCA performance is not as good as before the first IUT but still very useful (29). Occasionally, the subsequent IUT needs to be done a bit earlier than expected. We do not perform IUTs beyond 35+0 weeks’ gestation. We currently aim for delivery between 36 and 37 weeks, but are currently postponing this towards 38 weeks at the request of our neonatologists.

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