Official reprint from UpToDate

www.uptodate.com 2014 UpToDate

Intrauterine fetal transfusion of red blood cells

Author Section Editor Deputy Editor

Kenneth J Moise Jr, MD Charles J Lockwood, MD Vanessa A Barss, MD

Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2014. | This topic last updated: Sep 30, 2013.

INTRODUCTION The infusion of red blood cells (RBCs) into the fetus is one of the most successful means of
in utero therapy. Although never studied in randomized trials, there is no doubt that this technique has
contributed to survival of the severely anemic fetus. Universal use of Rh(D) immune globulin has dramatically
reduced the need for intrauterine transfusion; however, the procedure continues to be an essential modality for
treatment of severe fetal anemia from a variety of causes.

HISTORY Sir William Liley first introduced the concept of intrauterine transfusion (IUT). While working in New
Zealand, he learned from a visiting fellow that RBCs infused into the peritoneal cavity of African children with
sickle cell disease appeared to migrate into the intravascular space and correct their anemia [ 1]. Liley
postulated that peritoneal infusion (IPT) of RBCs could also be used to transfuse the severely anemic fetus.
Since ultrasonography was not yet available, these early procedures were 'guided' by radiographs or
fluoroscopy. Fetal position was determined by a variety of techniques, such as using radiopaque dyes to
delineate fetal bowel, placing metal markers on the maternal abdomen to indicate fetal position, and inserting
needles to immobilize the fetus.

Static gray scale ultrasonography was first used in conjunction with IUT in 1975, and replaced by real-time
ultrasonography in 1977. The next major advance was in 1981 when an intravascular transfusion (IVT) was
performed by inserting the transfusion needle directly into a fetal vessel on the placental plate [ 2]. Currently, the
standard method of fetal transfusion uses an umbilical vessel or the intrahepatic portion of the umbilical vein for
direct access to the fetal vasculature.

PATIENT SELECTION

General approach Intrauterine transfusion of RBCs is indicated to prevent fetal death from severe anemia.
The procedure is generally limited to fetuses between 18 and 35 weeks of gestation because of technical
limitations before 18 weeks and excessive fetal risk compared with delivery and postnatal transfusion after 35
weeks (see 'Gestational age at first transfusion' below).

Normal fetal hemoglobin concentration increases linearly during pregnancy, from about 10 to 11 g/dL at 17
weeks to about 14 to 15 g/dL at term, one standard deviation is approximately 1 g/dL (table 1) [3-5]. Severe fetal
anemia has been defined in a variety of ways:

Hemoglobin level >7 g/dL below the normal mean for gestational age [ 3]

Hemoglobin level <5.8 to 7.4 g/dL, depending on gestational age. In this study, 12 of 31 fetuses with
severe anemia were hydropic and all 12 had hemoglobin values less than 5 g/dL [4].

Hemoglobin level two standard deviations below the mean value for gestational age

We initiate transfusion when the fetal hemoglobin falls two standard deviations below the mean value for
gestational age. At this level of anemia, intervention is better tolerated and with improved rates of survival than
when attempted in more severely anemic hydropic fetuses.
Causes of severe fetal anemia The most common causes of severe fetal anemia are red cell
alloimmunization, parvovirus infection, chronic fetomaternal hemorrhage, inherited red cell disorders, and
complications of treatment for twin-twin transfusion.

Red cell alloimmunization More than 50 antibodies against red cell antigens have been associated
with hemolytic disease of the fetus/newborn. Among fetuses with erythroblastosis fetalis requiring IUTs, the
most common antibodies are anti-D, anti-K1 (Kell), and antic. (See "Overview of Rhesus (Rh) alloimmunization
in pregnancy" and "Significance of minor red blood cell antibodies during pregnancy".)

Parvovirus infection Fetal anemia related to parvovirus infection is due to arrest of maturation of bone
marrow precursors. Hydrops in these fetuses can be due to heart failure secondary to the resulting high output
state and/or to myocarditis. The utility of fetal transfusion for this indication is supported by pooled data showing
that 188 of 230 (82 percent) of transfused fetuses had a normal outcome as compared to 239 of 435 (55
percent) of those treated conservatively [6]. (See "Parvovirus B19 infection during pregnancy".)

Chronic fetomaternal hemorrhage Chronic fetomaternal hemorrhage (FMH) can lead to fetal anemia.
When severe, these pregnancies present clinically because of decreased or absent fetal movement. The fetal
heart rate may be sinusoidal and ultrasound examination often reveals hydrops. A Kleihauer-Betke test, or other
technique for detection of fetal blood in the maternal circulation, is needed to confirm the diagnosis. In
pregnancies remote from term, data from case reports and small series suggest that IUT can improve fetal
survival. (See "Diagnosis and management of massive fetomaternal hemorrhage".)

Inherited RBC disorders IUT has also been used to treat severe fetal anemia due to alpha thalassemia
[7-10] and congenital dyserythropoietic anemia [11]. Long-term survival in such cases depends upon neonatal
red cell transfusions and subsequent bone marrow transplantation. A single case of fetal xerocytosis has been
reported with resolution of hydrops fetalis and a normal neonatal course [12]. (See "Anemia in children due to
decreased red blood cell production".)

Complications after treatment of twin-twin transfusion Fetoscopic laser ablation for treatment of
twin-twin transfusion may be complicated by acute death of one twin and severe anemia in the other twin. In one
series, IUT of the anemic fetus resulted in a healthy survivor in 11 of 19 cases (58 percent) [13]. Chronic twin
anemia-polycythemia syndrome after laser therapy has also been successfully treated with serial IUTs [14].
(See "Management of twin-twin transfusion syndrome".)

BLOOD FOR TRANSFUSION

Preparation RBCs used for IUT must undergo the same testing that occurs for any red cell donor unit. (See
"Laboratory testing of donated blood".)

Additional requirements specific to IUT include:

Type O Rh(D) negative RBCs are transfused.

Donor units are screened for antibody to cytomegalovirus (CMV); the units must be negative.

The donation should be relatively fresh to enhance the level of 2-3-diphosphoglycerate (DPG). In the
United Kingdom, this means that red cells used for IUT should not have been stored more than five days.

British Blood Transfusion Task Force [15] and AABB (formerly the American Association of Blood
Banks) [16] standards require that red cell units for IUT undergo irradiation with 25 Gy of gamma radiation
to the central portion of the donor bag to prevent a graft-versus-host reaction.

Leukodepletion is a requirement in the United Kingdom, but not routinely done in the United States.
However, it is often used to reduce CMV risk and will likely be universally accepted in the United States
in the near future.

Units are washed and tightly packed to a final hematocrit of 75 to 85 percent to reduce the volume
administered to the fetus at the time of IUT. (By comparison, the hematocrit of a unit of RBCs used for
transfusion of adults is approximately 65 percent).
Studies of women undergoing IUT have observed that about 25 percent produce additional RBC antibodies due
to exposure to antigens on donor blood and paternal antigens on fetal blood that are foreign to the mother [17-
19]. The risk is highest when the IUT necessitates passing a needle through the placenta. Matching donor and
recipient units for D, C, c, E, e, and K antigens does not reduce the risk of new antibody formation, as
differences in other minor antigens still exist [18].

Autologous donation by the pregnant patient can be considered as a source of red cells for IUT, as use of
maternal RBCs for IUT eliminates the mother's risk of becoming sensitized to donor RBC antigens. However, all
of the prerequisites for autologous donation must be met and the requirement for a predonation hemoglobin
above 12.5 g/dL will exclude many pregnant patients as potential donors. (See "Surgical blood conservation:
preoperative autologous blood donation".)

A potential fetal advantage of maternal donation is that the RBCs may have a longer half-life, which would
decrease the total number of IUTs necessary for treatment. A study comparing 76 IUTs in which maternal blood
was used to 213 IUTs in which donor red cells were used reported the rate of decline of the fetal hematocrit
between IUT procedures was significantly slower in fetuses that received maternal blood, although this difference
was not evident until after 33 weeks of gestation [20]. In addition, neonates that received maternal blood required
fewer transfusions than neonates whose transfusion came from other donors. The authors hypothesized that the
lower transfusion requirements were related to use of blood with a high proportion of young cells (with a longer
half life) as a result of increased maternal reticulocytosis after repeated maternal donations.

The risk of transmission of blood-borne viral infections may be lower if maternal blood is used for transfusion, but
this has not been studied.

Pregnant women who donate blood should consume a daily prenatal vitamin, as well as supplemental iron (325
mg ferrous sulfate twice daily) and folic acid (1 mg daily). The donated unit can be separated into two smaller
aliquots and refrigerated for up to 42 days; however, this compromises freshness. If the blood is not used by this
date, it can be frozen for use up to 10 years later.

Additional considerations related to pregnancy include positioning the women in the left lateral recumbent
position during the donation, replacing the donated volume with isotonic intravenous fluids, and additional
processing (blood is washed several times to remove the offending antibody). Fetal monitoring during the
procedure is unnecessary. A standard volume of 450 +/- 45 mLs is taken, as subsequent washing and packing
will markedly reduce the final volume available for IUT.

Since the mother and fetus share HLA antigens at many loci, the possibility of graft-versus-host disease
(GVHD) is higher than with use of an unrelated donor unit where HLA mismatch enables the recipient's immune
system to destroy the donor lymphocytes. To avoid transfusion-associated GVHD, the unit should be
leukoreduced using specialized filters, in addition to the standard irradiation protocol.

The use of maternal blood in the CMV seropositive mother is controversial since dormant CMV virus can reside
in polymorphonuclear leukocytes. Both leukoreduction and washing are effective mechanisms for preventing the
transmission of CMV. For this reason, the risks and benefits of use of CMV seropositive maternal blood should
be discussed with the patient in consultation with the blood bank service.

CHOICE OF ACCESS SITE The various methods and points of access for IUT have not been compared in
randomized trials [21]. For this reason, many centers have developed their own preference for a specific
methodology.

Peritoneal cavity IPT provides indirect access to the fetal circulation. It utilizes the principle that fluid and
cells in the peritoneal cavity are absorbed through the diaphragmatic lymphatics. In the hydropic fetus, however,
a functional blockage of the lymphatic system probably exists and prevents good absorption of RBCs after IPT.
Thus, the procedure is least effective in those fetuses who are most severely anemic and in need of treatment.
This was best illustrated in a study of hydropic and nonhydropic fetuses matched for severity of disease,
placental location, and gestational age at the first transfusion that compared outcomes with IPT and IVT [22].
Compared to IPT, IVT improved survival almost two-fold in hydropic fetuses and by 13 percent in nonhydropic
fetuses. No randomized trials comparing these techniques have been performed.
Given the higher rate of survival with IVT, it is the preferred method for transfusing the anemic fetus. However,
IPT remains a viable option when fetal vascular access is difficult because of early gestational age or fetal
position [23].

Direct vascular access Intravascular transfusion (IVT) is generally preferred to intraperitoneal transfusion
(IPT) because IVT is significantly more effective in hydropic fetuses and the effects of transfusion are more rapid
[22,24-26]. For direct intravascular access, North American centers typically target the umbilical vein at the
placental end of the cord insertion, while many European centers utilize the intrahepatic portion of the umbilical
vein.

Direct cardiac puncture is another approach; however, it has been associated with a higher rate of fetal death (8
percent versus <3 percent per procedure with use of the umbilical vein) [27]. This technique should probably be
reserved for rare cases when access to the umbilical cord insertion or intrahepatic portion of the umbilical vein is
not possible.

Umbilical cord The optimal site for umbilical cord puncture is into the umbilical vein in the portion of cord
near its insertion into the placenta. Puncture of the umbilical artery, a free-floating middle segment of cord, or
the cord insertion proximate to the fetal umbilicus is less desirable because manipulation of these sites is
associated with a higher rate of fetal bradycardia than the placental insertion site [28,29]. The higher incidence
of bradycardia with umbilical artery puncture (21 versus 3 percent) is probably due to spasm of the muscularis
[28,29]. The cord proximate to the fetal umbilicus appears to have vagal innervation [30], which might account
for the increased the risk of fetal bradycardia. Free-floating midsegments of the umbilical cord have the
additional problem of readily floating away from the needle when cord penetration is attempted.

Intrahepatic umbilical vein Puncture of the intrahepatic portion of the umbilical vein has several
advantages. There is a low incidence of fetal bradycardia, probably due to absence of inadvertent umbilical
artery puncture at this anatomical level [31]. Additionally, blood loss from the cord puncture site is
compensated, at least in part, by its subsequent absorption from the peritoneal cavity. A disadvantage is that
IVT using the intrahepatic umbilical vein may result in a greater degree of fetal pain. The fetal stress hormones
noradrenaline, cortisol, and beta-endorphin have been reported to increase with intrahepatic puncture, a
response not seen with procedures at the placental insertion site [32]. There is also concern that fetal
movement during intrahepatic umbilical vein transfusion places the fetus at higher risk of organ trauma from a
dislodged needle than when transfusion is performed at other sites. For this reason, some clinicians suggest
administering a drug to induce fetal paralysis [29], and others leave the needle unheld [33].

In cases of poor visualization of a cord insertion due to posterior placentation, the use of the intrahepatic portion
of the umbilical vein is a reasonable option when the fetus is properly positioned: the fetal spine must be
towards the maternal back to allow access to the liver. The procedure-related fetal loss rate appears to be
similar to or less than that with puncture of the umbilical vein (1.4 percent) (see 'Complications' below) [29,31].
There are no data from randomized trials.

Combined approach A combined approach (IVT followed by IPT) appears to provide a more stable fetal
hematocrit between procedures, presumably due to slow absorption of RBCs from the intraperitoneal reservoir.
This allows a longer interval between procedures, so fewer IUTs are needed [34,35]. One study using a
combined approach administered packed RBCs by IVT to achieve a final fetal hematocrit of 35 to 40 percent,
immediately followed by a standard IPT [34]. The decline in fetal hematocrit between procedures was markedly
reduced with this approach when compared to IVT alone (0.1 versus 1 percent decline per day).

Special circumstances Several circumstances deserve special mention:

Gestational age less than 22 weeks If IUTs must be initiated early in the second trimester (<22
weeks), particularly if the maternal habitus makes visualization of the cord insertion difficult, an IPT is often the
best approach. In a cohort of six women with a history of high perinatal loss (66 percent mortality) due to severe
fetal anemia prior to 20 weeks of gestation in previous pregnancies, the use of serial IPTs between 16 and 21
weeks in the subsequent pregnancy followed by IVT when technically feasible was associated with improved
survival (6/7 survived to 20 weeks and all six of these fetuses survived to delivery) [23].

Fetal ascites If fetal ascites is present, blood placed by IPT will not be absorbed. In these cases, IVT by
targeting the umbilical cord, intrahepatic portion of the umbilical vein, or in extreme cases, the fetal heart, is
warranted.

Multiple gestation (See 'Transfusion of multiple gestations' below.)

TRANSFUSION VOLUME AND TARGET HEMATOCRIT

Intravascular transfusion

After 24 weeks of gestation The volume of blood for IVT depends upon the initial fetal hematocrit, size of
the fetus, the hematocrit of the transfused RBCs, and the target hematocrit. After 24 weeks of gestation, we aim
for a target hematocrit of 40 to 50 percent (the normal fetal hematocrit is 37 +/- 4 percent at 17 weeks rising to
43 +/- 7 percent at term [5]). We avoid transfusing the fetus to supraphysiologic hematocrit values (50 to 65
percent), as is done in some centers, as a fetal hematocrit greater than 50 percent is associated with a marked
rise in whole blood viscosity [36], and can lead to complications [37,38].

The simplest method of calculating the volume of packed RBCs to be infused assumes a hematocrit of
approximately 75 percent for the donor unit and uses a series of coefficients for increasing the initial fetal
hematocrit by specific increments (table 2) [39]. As an example, to increase the hematocrit of a 1000
gram fetus from 20 to 40 percent, one multiplies 0.04 (coefficient for raising the hematocrit by 20) and
1000 (the estimated fetal weight in grams) to yield 40 mL (the volume that needs to be transfused).

Another formula for calculating the amount of blood to be transfused is [40]:

Volume transfused (mL) = Volume of fetoplacental unit (mL) X (final - initial hematocrit) divided by the hematocrit
of the transfused blood

The fetoplacental volume (mL) is calculated from the ultrasound estimate of the fetal weight according to the
formula (1.046 + fetal weight in grams X 0.14).

Before 24 weeks of gestation The acute correction of fetal anemia is associated with profound
hemodynamic changes. Cardiac output is markedly depressed due to increased afterload secondary to higher
blood viscosity [41]. Severely anemic fetuses at 18 to 24 weeks of gestation are at highest risk, with 33 percent
fetal mortality after IVT. Therefore, the final post-transfusion hematocrit at these early gestations should not
exceed 25 percent or a four-fold increase from the pre-transfusion value [42]. A second IVT is performed within
48 hours to bring the fetal hematocrit into the normal range; the third procedure is scheduled in 7 to 10 days.

Intraperitoneal transfusion The formula for the volume of intraperitoneal transfusion was determined many
years ago to allow for the maximum infusion of red cells without compromising umbilical venous blood flow due
to excessive intraabdominal pressure. The calculation involves subtracting 20 from the gestational age in weeks
and multiplying by a factor of 10 [43]. Thus, a 30-week fetus would receive 100 mL of blood. Blood in the
peritoneal reservoir can be expected to be absorbed over a 7- to 10-day period.

ANTENATAL CORTICOSTEROIDS We usually administer a course of antenatal corticosteroids to women

26 weeks of gestation before their first IUT in case an emergency delivery is needed. (See "Antenatal
corticosteroid therapy for reduction of neonatal morbidity and mortality from preterm delivery".)

PROCEDURE FOR UMBILICAL VEIN TRANSFUSION

Gestational age at first transfusion IVTs are rarely successful prior to 18 weeks of gestation due to limited
visualization and small size of the relevant anatomic structures [44]. After 35 weeks of gestation, a fetal
transfusion is generally considered riskier than delivery for neonatal treatment of severe anemia [45].

For the rare patient who has very early, severe alloimmunization, medical therapy may maintain the fetal
hematocrit above life-threatening levels long enough to achieve a gestational age when IUT is technically
feasible. A small case series described successful outcome using maternal single volume plasmapheresis
(three procedures after the 12th week of gestation) followed by weekly administration of intravenous immune
globulin (1 g/kg) until 20 weeks of gestation [46]. All nine fetuses subsequently required IUTs.

IPT is also an option for early onset disease in fetuses under 18 to 20 weeks [47].
Technique IUT in previable fetuses can be performed in the ultrasound suite; however, if the fetus has
attained a viable gestational age, many centers perform IUTs in an operating room on the Labor and Delivery unit
because a serious complication (eg, prolonged bradycardia) may necessitate an emergency cesarean delivery.
Patients are usually instructed to avoid oral intake for six to eight hours before the procedure and a heparin lock
is placed for intravenous access.

The uterus is displaced to the left to reduce the risk of maternal hypotension and the abdomen is prepared and
draped as for a surgical procedure. Some clinicians administer prophylactic antibiotics that are effective against
skin flora; no data are available on the value of antibiotic prophylaxis in this setting. Maternal sedation (eg,
midazolam 1 to 2 mg or fentanyl 25 to 50 mcg intravenously) may be administered if needed to reduce maternal
anxiety.

One operator supplies ultrasound guidance using a transducer covered with a sterile sleeve. The cord insertion
site is identified, the skin infiltrated with a local anesthetic, then a 20-gauge six-inch needle is directed into the
umbilical vein under continuous real-time ultrasound visualization. A 22-gauge needle is preferred for gestations
of less than 22 weeks.

An initial sample of blood is withdrawn for complete blood count and reticulocyte count. Although a spun
capillary hematocrit is adequate, we have found the use of a portable automated hemocytometer (eg, Coulter
counter) to be more useful. The automated method is fast and mean corpuscular red cell volume (MCV) can be
determined and used during the first few transfusions as a method of affirming that fetal, as opposed to
maternal, blood has been obtained (MCV greater than 100 mL suggests fetal RBCs). Injection of saline with
visualization of turbulence within the umbilical vein is another method of confirming proper needle position.

After withdrawing a blood sample, we give a short acting paralytic agent to minimize fetal movement. Options
include vecuronium (0.1 mg per kg of ultrasound estimated fetal weight) [48] or atracurium besylate (0.4 mg per
kg of estimated fetal weight) [49,50], drugs which are associated with minimal fetal cardiovascular effects.
These agents provide fetal paralysis for up to one to two hours. Fetal paralysis appears to improve the safety of
fetal transfusion, and may prevent 80 percent of procedure-related fetal heart rate changes [29].

If the fetus is anemic (ie, hematocrit less than 30 percent or two standard deviations below the mean for
gestational age), a second operator infuses packed RBCs using a 20 cc syringe attached to a three-way
stopcock connected, via extension tubing, to the blood bag and the procedure needle. In addition, a nonluer lock
stopcock is used to connect the procedure needle and distal end of the extension tubing to facilitate
manipulation of the tubing without disturbing the needle. During the infusion, the primary operator should be able
to visualize the transfused blood streaming away from the needle in the umbilical vein as it mixes with fetal
blood.

The fetal heart rate should be monitored periodically using color flow or pulsed Doppler ultrasound. Swirling at
the tip of the needle (as opposed to streaming inside the vein away from the tip of the needle) indicates a
decrease in fetal cardiac output and the need to check for fetal bradycardia. Bradycardia usually responds to
slowing or stopping the transfusion, needle removal, maternal oxygen administration, and repositioning in the left
lateral decubitus position. If bradycardia occurs, we initially stop the infusion and then restart at a slower rate if
the fetal heart rate promptly recovers. If bradycardia persists for more than 30 seconds, the procedure needle
should be removed and the fetal heart rate continuously monitored by ultrasound. Visualization of opening and
closing of the atrioventricular valves (AV) indicates continued fetal cardiac output. The fetal heart should be
observed continuously; if severe bradycardia persists for more than three minutes, we would perform an
emergency cesarean delivery in pregnancies of a viable gestational age. If the AV valves are not moving (ie,
cardiac arrest), delivery by emergent cesarean delivery is warranted if the fetus is of a viable gestational age.

Posttransfusion monitoring After the infusion has been completed, another fetal blood sample is obtained
for posttransfusion complete blood count. We also perform a Kleihauer-Betke test or fetal cell staining using
flow cytometry to determine the proportion of adult RBCs, which indicates the extent of suppression of fetal
erythropoiesis after the first transfusion.

Fetal heart rate monitoring is continued until resumption of fetal movement and a reactive tracing are
documented. An ultrasound examination is scheduled for the following day, as most cases of fetal loss occur
within the first 24 hours post-procedure.
TIMING TRANSFUSION FREQUENCY IN ALLOIMMUNIZATION

Second and subsequent transfusions After the first IUT, a decline in fetal hematocrit of approximately 1
percent per day can be expected if the fetus is not hydropic (1.88 percent if the fetus is hydropic [51]).
Therefore, a second IUT is planned 10 to 14 days after the first IUT, depending upon the final hematocrit
achieved at the conclusion of that transfusion. Predicting the fetal hematocrit after a transfusion is an inexact
process given fluid shifts from the extravascular to the intravascular compartment, bleeding from the cord
puncture site when the needle is removed, and possibly from decreased survival of adult RBCs in the fetal
circulation [52-54].

After the first two or three transfusions, the interval between subsequent procedures can usually be lengthened
to three to four weeks because of suppression of fetal erythropoiesis, as noted by Kleihauer-Betke stain or fetal
cell staining by flow cytometry and reticulocyte count [52,53,55].

Some centers base the interval between transfusions on the expected decline in fetal hemoglobin of 0.4
g/dL/day, 0.3 g/dL/day, and 0.2 g/dL/day after the first, second, and third transfusion [56] or empirically
transfuse 10 days, two weeks, and three weeks after the first, second, and third transfusion, respectively.

Doppler ultrasound measurement of the peak systolic velocity of the fetal middle cerebral artery has also been
investigated for the timing of the second intrauterine transfusion. In one study, a threshold value of 1.69 MoM's
predicted all cases of severe fetal anemia with a false positive rate of 6 percent [57]. A threshold value of 1.32
MoM's predicted all cases of moderate anemia with a false positive rate of 37 percent. The authors concluded
that higher peak systolic values should be used to detect severe anemia after IUTs have been initiated than
when the fetus has never undergone IUT (threshold 1.50 MoM). After two transfusions, a 1.50 MoM threshold
only detected 64 percent of fetuses with severe anemia (hemoglobin deficit >6 g/dL) [56]. Proposed
explanations for the higher threshold included a change in the rheology of the fetal blood due to the presence of
adult-hemoglobin containing donor red cells, as well as a change in the fetal cerebral circulation due to the
differential oxygen binding capacity of these transfused red cells.

If one uses middle cerebral artery Doppler for determining when to undertake the second transfusion, the
threshold for performing the second transfusion should be 1.32 MoM, which correlates with moderate to severe
anemia in the fetus who has undergone a single intrauterine transfusion [57]. However, there are really no good
data to support the use of middle cerebral artery (MCA) Doppler to decide when to repeat transfusions, and
most experts use the empiric intervals described above for timing the frequency of transfusion.

Published data and anecdotal clinical experience do not support the use of middle cerebral artery Doppler
assessment to time serial IUTs beyond the first two transfusions [58]. After two previous intrauterine
transfusions, 66 to 100 percent of the fetus' red cells contain adult hemoglobin. In this setting, where most of
the fetal red cells have been replaced by donor cells, MCA-PSV loses its ability to discriminate moderate-to-
severe fetal anemia from mild anemia. Studies performing both cordocentesis and Doppler velocimetry prior to a
third transfusion have reported that a cut-off MCA-PSV of >1.50 MoM would have missed 20 to 33 percent of
cases of severe anemia [56,59]. MCA-PSV has lower accuracy after multiple transfusions presumably because
adult red cells are smaller, less rigid, and show increased erythrocyte aggregation compared to fetal red cells,
and thus the relationship between blood velocity and hemoglobin concentration is different.

Rapid normalization of MCA occurs after fetal transfusion. As an example, a study of fetuses with mean
hemoglobin of 7.2 3 g/dL determined MCA before and immediately after initial intrauterine transfusion [60].
Mean MCA dropped from an elevated to normal level, 52.8 21.5 to 30.9 6.9 cm/s. This probably indicates an
acute change in the abnormal fetal physiology associated with the anemic state.

Last transfusion Most centers perform fetal transfusions up to 35 weeks of gestation. We suggest maternal
administration of phenobarbital (30 mg orally three times per day for 10 days) after the last transfusion to
enhance fetal hepatic maturity. In a series of 71 patients with hemolytic disease of the fetus/newborn who
underwent intrauterine transfusion, 33 patients received phenobarbital prior to delivery; 38 patients did not,
primarily because many delivered shortly after the last transfusion due to nonreassuring antenatal testing or a
mature fetal lung profile [61]. Patients in the phenobarbital group had significantly fewer neonatal exchange
transfusions (adjusted relative risk 0.23, 95% CI 0.06-0.76). A randomized trial is needed to better define the
efficacy of short-term phenobarbital in reducing the need for neonatal exchange transfusion.

TRANSFUSION OF MULTIPLE GESTATIONS Reports of IUTs in multiple gestations have been limited to
case descriptions in twins. The largest series reported to date included only five pregnancies: four cases of
dichorionic twin gestations and one case of monochorionic twins [62]. In the one case of monochorionic
gestation, the IUT of one fetus was quickly followed by the movement of donor red cells through intraplacental
anastomoses, as illustrated by a positive Kleihauer-Betke stain at the time of fetal blood sampling of the second
twin. In the subsequent IUTs, the transfusion of only one member of the twin pair resulted in adequate levels of
hemoglobin in both twins.

Since intraplacental anastomoses are rare in dichorionic twins, each fetus should undergo sampling and the
amount to be transfused for IUT calculated in a similar fashion as a singleton. There are insufficient data to
guide therapy in monochorionic twins, a situation where intraplacental anastomoses are almost universal. One
suggested approach would be to measure the peak MCA velocity in the non-targeted twin as a baseline. After
the first twin has been transfused to the desired hematocrit, a repeat MCA could be undertaken in the non-
targeted twin while the patient is still in the operative setting. A normalization of the previously elevated MCA
peak systolic velocity would indicate that the suspected anemia in the second twin fetus has been corrected
through inter-twin transfusion.

In multiple gestations in which all fetuses need to undergo IVT, use of the intrahepatic portion of the umbilical
vein for access will allow for correct identification of each fetus.

TIMING OF DELIVERY Induction of labor is undertaken approximately three weeks after the last IUT. Fetal
lung maturity should be determined if delivery is preterm. We suggest using the lamellar body count, as this
test is not affected by blood or bilirubin in the amniotic fluid [63]. (See "Assessment of fetal lung maturity".)

COMPLICATIONS Procedure related complications of IPT were illustrated in a series describing the
outcome of 77 fetal IPTs in 35 pregnancies [64]. Transfusion-related complications occurred in five cases (two
fetal colon infusions, two fetal retroperitoneal infusions, one fetal abdominal wall hematoma), but no fetus died,
required urgent delivery, or suffered long-term sequelae. These procedures were performed under direct
ultrasound guidance and with intensive perinatal management. Series from the pre-ultrasound era reported
higher complication rates, but these procedures were performed without continuous visualization and other
modern enhancements [65,66].

The risks of IVT were best illustrated by a large series reported from a single hospital [29]. This series of 740
IVTs in 254 patients described the following procedure related complication rates:

Perinatal death: 1.6 percent per procedure

Emergency cesarean delivery: 2.0 percent per procedure

Infection: 0.3 percent per procedure

Premature rupture of membranes: 0.1 percent per procedure

Inadvertent arterial puncture: 3 percent

Bradycardia or tachycardia: 5 percent of procedures (but 57 percent of procedures resulting in perinatal

death or emergency delivery)

Bleeding from puncture site: 0 to 17 minutes

The total procedure related complication rate, corrected for procedures with more than one complication, was
3.1 percent.

Other risks associated with IVT have been described primarily in case reports and are not quantifiable:

Bleeding from the puncture site can cause a cord hematoma, worsen anemia, or lead to exsanguination.
Most cord hematomas resolve without fetal sequelae, but a large hematoma that compresses the
 umbilical vessels may cause fetal compromise [67].

Fetal brain injury may occur, possibly related to changes in intravascular volume, hemodynamics, and/or
viscosity [37,68].

Risks associated with either IVT or IPT include:

Cord trauma or visceral injury from fetal movement. These risks are minimized with use of paralytic
agents.

Transplacental needle insertion can result in significant fetal bleeding if a large fetoplacental vessel is
lacerated. Fetomaternal hemorrhage can also occur and potentially increase maternal alloantibody titers
as well as severity of hemolytic disease in the index or future pregnancies [69].

Viral or bacterial agents can be transmitted from needle insertion or infused blood [70].

OUTCOME

Survival Overall survival after IUT is about 89 percent, but varies with center, experience, and the presence
of hydrops fetalis [71]. Survival of hydropic fetuses is lower than that of fetuses who are not hydropic at first IUT
(70 versus 92 percent). Results from a single treatment center where 213 fetuses received 599 IUTs were similar
to the multicenter experience: survival with any degree of hydrops was 78 percent as compared to 92 percent for
nonhydropic fetuses [72].

Survival is also lower when severe anemia occurs at less than 20 weeks of gestation. The higher rate of fetal
loss at early gestational ages reflects the technical difficulties of invasive therapy in a very small fetus, as well
as the inability of the very immature fetus to tolerate the hemodynamic changes of severe anemia and the
hemodynamic changes following transfusion [68,73,74].

Neonatal transfusion If the neonatal hematocrit is near normal because of a recent IUT, neonatal exchange
transfusion may not be necessary. With senescence of the transfused red cells, approximately 50 percent of
these infants will require a "top-up" transfusion at one month of age due to suppression of fetal erythropoiesis
from IUT and persistence of maternal antibody not removed by exchange transfusion [75]. In some cases, up to
four top-up transfusions may be necessary before reticulocytosis begins and anti-red cell antibodies disappear
[76]. Management of these infants is discussed separately. (See "Postnatal diagnosis and management of
alloimmune hemolytic disease of the newborn".)

Neurologic outcome

Hemolytic disease of the fetus/newborn One long-term concern of IUT is that advances in treatment
techniques have allowed more moribund and hydropic fetuses to survive and these infants may be at higher risk
of long-term morbidity. Available data are reassuring, but are limited to mostly small series [77-82].

The LOTUS study is the largest study to assess the incidence and risk factors for neurodevelopmental
impairment in children with hemolytic disease of the fetus/newborn treated with IUT [83]. Alloimmunization was
related to Rh(D) in 80 percent of cases, 26 percent of the fetuses were hydropic, the mean gestational age at
first transfusion was 26 weeks, the mean number of transfusion was 3, and all of the pregnancies were delivered
between 35 and 37 weeks of gestation. Major findings at follow-up at median age 8.2 years (range 2 to 17 years)
were:

Isolated severe developmental delay: 5/291 (1.7 percent)

Isolated cerebral palsy: 2/291 (0.7 percent)

Isolated bilateral deafness: 3/291 (1.0 percent)

Cerebral palsy and severe developmental delay: 4/291 (1.4 percent)

Composite neurodevelopmental impairment (cerebral palsy, severe development delay, bilateral deafness,
 or blindness): 14/291 (4.8 percent)

This incidence of severe neurodevelopmental delay (3.1 percent) was similar to that of the normal Dutch
population (2.3 percent). However, the incidence of cerebral palsy (2.1 percent) was higher than expected in a
normal population (0.7 percent with delivery between 32 and 36 weeks and 0.2 percent with delivery at 37 weeks
of gestation or greater).

The major risk factor for neurodevelopmental impairment was hydrops, which was present in 9/14 (64 percent)
children with neurodevelopmental impairment versus 66/277 (24 percent) without; in a multivariate regression
model, severe hydrops but not mild hydrops was a significant independent risk factor.

High neonatal bilirubin levels due to increased red blood cell destruction may cause hearing loss. Phototherapy
and exchange transfusion are the two major modalities used to prevent complications from hyperbilirubinemia,
but hearing loss has been reported rarely despite therapy [78]. (See "Treatment of unconjugated
hyperbilirubinemia in term and late preterm infants" and "Clinical manifestations of unconjugated
hyperbilirubinemia in term and late preterm infants", section on 'Kernicterus'.)

Parvovirus Although data are limited, small series and studies of hydropic fetuses undergoing IUT's for
parvovirus infection suggest that these children are at increased risk of delayed psychomotor development. (See
"Parvovirus B19 infection during pregnancy", section on 'Intrauterine blood transfusion'.)

SUMMARY AND RECOMMENDATIONS

Intrauterine transfusion is indicated for treatment of severe fetal anemia, which may result from red cell
alloimmunization, parvovirus infection, chronic fetomaternal hemorrhage, or inherited red cell disorders.
(See 'Patient selection' above.)

We initiate transfusion when the fetal hematocrit falls below 30 percent or two standard deviations below
the mean hematocrit for gestational age. Intervention at this level of anemia is more likely to be
successful and less likely to result in fetal complications than when attempted on the hydropic fetus.
(See 'Patient selection' above.)

Fetal transfusions are rarely successful prior to 18 weeks of gestation due to limited visualization and the
small size of the relevant anatomic structures. In utero transfusions are not performed after 35 weeks of
gestation because procedure related morbidity exceeds morbidity associated with delivery. (See
'Gestational age at first transfusion' above and 'Timing of delivery' above.)

For the hydropic fetus, we recommend intravascular transfusion (IVT) (Grade 1B). IVT results in
significantly higher survival rates than intraperitoneal transfusion (IPT) in this population. For nonhydropic
fetuses, we suggest IVT (Grade 2C). IVT appears to be more effective and its effects are more rapid than
IPT, but both procedures are effective. (See 'Choice of access site' above.)

We suggest using the umbilical vein near the placental insertion site or the intrahepatic vein for
intravenous transfusion. There is an increased risk of complications from transfusion into the umbilical
artery or into a free floating loop of cord. The umbilical artery should always be avoided, and the free
floating cord used only as a last resort. (See 'Choice of access site' above.)

We aim for a target hematocrit of 40 to 50 percent. The volume of blood for intravascular transfusion is
calculated from a formula and depends upon the initial fetal hematocrit, size of the fetus, the hematocrit
of the transfused RBCs, and the target hematocrit. (See 'Transfusion volume and target hematocrit'
above.)

We suggest administering a short-acting paralytic agent to the fetus (Grade 2C). Reduction in fetal
movement reduces the risk of complications. (See 'Technique' above.)

After the first transfusion, a decline in fetal hematocrit of approximately 1 percent per day can be
expected. After the first two transfusions, which are 10 to 14 days apart, the interval between subsequent
procedures usually can be lengthened to three to four weeks because of suppression of fetal
 erythropoiesis. Doppler ultrasound measurement of the peak systolic velocity of the fetal middle cerebral
artery can be used for timing the second intrauterine transfusion, but the utility of using middle cerebral
artery (MCA) Doppler to determine the interval between the second and third transfusions has not been
verified. (See 'Timing transfusion frequency in alloimmunization' above.)

Packed red blood cells used for intrauterine transfusion must undergo the same testing that occurs for
any red cell donor unit. In addition, these units should be fresh, depleted of leukocytes, irradiated, tightly
packed to a final hematocrit of 75 to 85 percent, and type O Rh(D) negative. (See 'Blood for transfusion'
above.)

We give the mother phenobarbital (30 mg orally three times per day) for 10 days after the last transfusion
to enhance fetal hepatic maturity and reduce the need for neonatal exchange transfusion (Grade 2C).
(See 'Last transfusion' above.)

The best estimate of risk of procedure-related fetal loss is 1 to 2 percent and the overall risk of procedure-
related complications is 3 percent. Fetal bleeding, infection, and trauma account for most of the mortality
and morbidity. (See 'Complications' above.)

Overall survival after intrauterine transfusion is about 85 percent, but varies with center, experience, and
the presence of hydrops fetalis. Survival of hydropic fetuses is lower than that of fetuses who are not
hydropic at first transfusion. (See 'Survival' above.)

Normal neurologic outcome can be expected in over 90 percent of surviving infants, even if hydrops fetalis
is noted at the time of the first transfusion. (See 'Neurologic outcome' above.)

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Topic 5385 Version 13.0

GRAPHICS

Normal mean and <2 S.D. values for fetal hemoglobin

Gestational age, Mean hemoglobin, <2 S.D. hemoglobin from the

weeks gm/dL mean, gm/dL

18 11.3 9.3

19 11.5 9.5

20 11.7 9.7

21 11.9 9.9

22 12.1 10.1

23 12.3 10.3

24 12.5 10.5

25 12.7 10.7

26 12.8 10.8

27 13.0 11.0

28 13.2 11.2

29 13.4 11.4

30 13.6 11.6

31 13.8 11.8

32 14.0 12.0

33 14.2 12.2

34 14.4 12.4

SD: standard deviations; gm/L: grams/liter.

Data from: Nicolaides, KH, Soothill, PW, Clewell, WH, Rodeck, CH, et al. Fetal haemoglobin
measurement in the assessent of red cell isoimmunization. Lancet 1988; 8594:1073.

Graphic 53399 Version 1.0

Transfusion coefficient for calculating transfusion volume for fetal
transfusion

Target hematocrit minus beginning hematocrit = Transfusion

Desired increment in hematocrit coefficient

10 0.02

15 0.03

20 0.04

25 0.05

30 0.06

As an example, to increase the hematocrit of a 1000 gram fetus from 20 perc ent to 40
percent, one multiplies 0.04 (coefficient for raising the hematocrit by 20) and 1000 (the
estimated fetal weight in grams) to yield 40 mL (the volume that needs to be transfused).

Data from: Moise, KJ, Whitecar, PW. Antenatal therapy for hemolytic disease. In: Alloimmune
Disorders of Pregnancy. Anemia, thrombocytopenia and neutropenia in the fetus and newborn.
Hadley, A, Soothill, P (Eds), Cambridge University Press, Cambridge, UK 2002. p.182.

Graphic 50073 Version 3.0