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This chapter should be cited as follows: This chapter was last updated:
Moise, Jr, K, Glob. libr. women's med., June 2011
(ISSN: 1756-2228) 2011; DOI 10.3843/GLOWM.10213

Direct Fetal Transfusion


Kenneth J. Moise, Jr, MD
Professor, Obstetrics and Gynecology and Interim Director, Division of Maternal-Fetal Medicine, Baylor College of Medicine, Houston, Texas, USA

INTRODUCTION
HISTORY
HOW MUCH TO TRANSFUSE?
DYNAMICS OF TRANSFUSED RED BLOOD CELLS IN FETAL CIRCULATION
USE OF MATERNAL BLOOD
ULTRASOUND TO PREDICT FETAL HEMATOCRIT
FETAL PARALYSIS
MONITORING WITH COLOR FLOW DOPPLER
PRACTICAL CONSIDERATIONS
TIMING OF DELIVERY
FETAL PHYSIOLOGIC EFFECTS
COMPLICATIONS
OUTCOME
NEED FOR NEONATAL TOP-UP TRANSFUSION
FETOMATERNAL HEMORRHAGE
PARVOVIRUS INFECTION
PLATELET ALLOIMMUNIZATION
THE FUTURE OF INTRAUTERINE TRANSFUSION
CONCLUSIONS
REFERENCES

INTRODUCTION

Present-day guidelines for the administration of Rhesus (Rh) immune globulin (RhIG) to every Rho(D)-negative women at 28
weeks' gestation and postpartum have greatly reduced the incidence of red blood cell alloimmunization.1 Before the use of
RhIG, nearly 1% of all Rho(D)-negative pregnant women were sensitized.2 Nonetheless, in 1986 the Centers for Disease Control
reported an incidence of Rh hemolytic disease of 10.6 per 10,000 total births in the United States.3 For every 100 affected
patients, nine fetuses require intrauterine transfusion (IUT).4, 5, 6

IUT was the first effort at in utero treatment of the human fetus. During the last 30 years, it has become the treatment of choice
for patients alloimmunized to red blood cell antigens in whom severe fetal anemia develops remote from term.4, 5, 6 In these
cases, IUT generally is indicated if the fetal hemoglobin concentration is less than the 5th percentile for gestational age7 or if
the fetal hematocrit is less than 30%.4, 5, 6

We refer the reader elsewhere for a description of the complete diagnostic evaluation of the pregnancy affected by Rh hemolytic
disease.2, 4, 5, 6, 7, 8, 9 (See also GLOWM Chapter Alloimmune hemolytic disease of the fetus and newborn (erythroblastosis
fetalis): diagnosis, management, and prevention) Instead, this chapter stresses the technical aspects of IUT, including the use
of ultrasound, the physiologic effects of IUT on the fetus, complications, neonatal top-up transfusions, and pregnancy
outcome. The use of IUT in the treatment of fetomaternal hemorrhage, fetal parvovirus infection, and platelet
alloimmunization is described and the future of IUT briefly evaluated.

HISTORY

In 1963, Liley10, 11, 12, 13 initiated the in utero therapy of Rh hemolytic disease by developing the technique of fetal

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intraperitoneal transfusion (IPT). During an amniocentesis, Liley inadvertently placed his needle into the fetal abdomen. After
returning from Africa, one of Liley's research associates described how IPT was commonly used there to transfuse children with
sickle cell anemia. Liley concluded that this could be a feasible route for IUT if the fetal peritoneal cavity could be entered
intentionally.14, 15 After instilling radiopaque dye into the amniotic cavity by amniocentesis, Liley made use of the fetal ability
to concentrate this contrast material in its lower gastrointestinal tract, thereby providing a radiographic target for needle
placement. He then employed paper clips fastened with adhesive tape to mark the maternal skin surface. During the next step
of the procedure, Liley inserted a 16-gauge Tuohy needle into the fetal peritoneal cavity and advanced an epidural catheter
through it to aspirate 200 mL of fetal ascitic fluid and replace it with 100 mL of packed red blood cells. After three fetal deaths,
Liley reported his first success in September 1963.12 Virtually simultaneous, though more aggressive attempts to access the
fetal circulation directly included hysterotomy-facilitated catheter placement into chorionic plate vessels or into the fetal
femoral artery, saphenous vein, or internal jugular vein.16, 17, 18, 19

Before real-time ultrasound was available, IPT involved blindly injecting radiopaque dye into the amniotic cavity. The fetus
would then swallow this contrast material, allowing for identification of its peritoneal cavity at fluoroscopy. Often a chicken-
wire grid molded to the contour of the maternal abdomen was used to ensure accurate needle placement under fluoroscopic
visualization.20, 21 This technique was later modified to include the direct injection of radiopaque dye into the fetal abdomen.22
The use of static gray-scale ultrasound imaging for placement of the transfusion needle was first reported in 1975, significantly
reducing fetal radiation exposure by eliminating the need for pretransfusion amniography.23, 24 Real-time ultrasonography to
guide the transfusion needle during IPT was first described in 1977.25, 26, 27 Only a short time later, fluoroscopy was no longer
used. Saline, which produces small bubbles on real-time ultrasound when briskly shaken and injected under pressure, was used
instead to observe the transfusion needle successfully entering the fetal abdominal cavity.25, 26 Bowman and associates28
stressed that the diameter of the epidural catheter is important to the success of the IPT. To avoid side holes with small
diameters causing hemolysis during red blood cell infusion, they recommended that the end of the epidural catheter be
removed before being used for IPT. They estimated the appropriate transfusion volume for IPT using the following calculation:

IPT remained the only technique for in utero transfusion therapy until 1981, when Rodeck and co-workers29 performed the first
direct fetal intravascular transfusion (IVT) by placing a needle into chorionic plate vessels under fetoscopic visualization. One
year later, Bang and colleagues30 successfully transfused a fetus by inserting a needle into the umbilical vein under ultrasound
guidance. Seven different techniques for IUT have been reported since then (Table 1). The use of fetoscopy in guiding the IUT
needle is described in several studies. This method failed to achieve great popularity.31, 32, 33, 34 Both the direct fetal
intravascular approach and fetal intravascular exchange transfusion were evaluated by investigators in the United States during
the following 4 years.35, 36, 37, 38 Proponents of exchange transfusion postulated that with this technique the fetus was less likely
to become volume-overloaded while more fetal cells were removed from circulation. Advocates of direct IVT believed that the
procedure time was shorter in comparison with fetal-exchange IVT. They also asserted that the placental vascular bed would
absorb the increased circulatory volume without negatively affecting the fetus. The direct intravascular technique became more
widely adopted as experience with both techniques grew. Ultrasound imaging resolution continues to improve, and simple
direct IVT has become the procedure of choice at most centers in the United States; IPT alone is performed rarely unless direct
access to the umbilical cord is not technically feasible. Transfusion of red blood cells directly into the fetal circulation seems
especially important in the treatment of the hydropic fetus whose peritoneal absorption of red blood cells is not inhibited, but it
is thought to require several weeks.39, 40, 41 Comparing neonatal outcome after IVT to that after IPT using historic controls,
Harman and co-workers42 clearly demonstrated that IVT significantly improves the chance for survival in the hydropic fetus.

Table 1. Techniques for intrauterine transfusion

Intraperitoneal
Intravascular by cordocentesis
Exchange transfusion
Simple direct transfusion
Intravascular by intrahepatic venous puncture

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Simple direct transfusion


Intracardiac by fetal cardiocentesis
Simple direct transfusion
Combined approaches
Exchange intravascular transfusion followed by intraperitoneal transfusion
Simple direct intravascular transfusion followed by intraperitoneal transfusion

Because complications unique to IVT had been reported, the need for IVT in the severely anemic but nonhydropic fetus
remained controversial.43, 44, 45 Moreover, with the use of direct IVT alone, fetal hematocrits between procedures varied widely.
The combination of IVT and IPT therefore was tested at Baylor College of Medicine.46 First, packed red blood cells with a
hematocrit of 80% or higher were infused by IVT to increase the fetal hematocrit to approximately 40%. Next, a standard IPT
was performed to create a red blood cell reservoir in the fetus for later absorption between IUTs. This combined approach
resulted in a more stable fetal hematocrit and longer intervals between procedures (Fig. 1).36, 46 As a result of the combined
IVT/IPT approach, the average daily decline of the fetal hematocrit was only 0.01% compared with 1.14% when IVT alone was
used. Other centers have validated these findings and also use the combined IUT technique.47, 48

Fig. 1 . Fetal hematocrit before and after direct intravascular transfusion in patient A
(A) and before and after combined direct intravascular/intraperitoneal transfusion
in patient B (B). (Patient A data from Berkowitz RL, Chitkara U, Wilkins I et al:
Technical aspects of intravascular intrauterine transfusions: Lessons learned from
thirty-three procedures. Am J Obstet Gynecol 157:4, 1987)

As an alternate site for IUT, the intrahepatic umbilical vein has been used when access is impossible at the placental cord
insertion.49, 50, 51 Nicolini and co-workers50, 51 transfused 72 severely anemic fetuses intrahepatically with a 90% success rate.
There were few complications, which consisted mainly of fetal bradycardia and intraperitoneal bleeding. Fetal bradycardia
during IUT often is related to inadvertent umbilical arterial puncture and vasospasm.7, 52 During intrahepatic transfusion, the
incidence of fetal bradycardia was low because of the absence of the umbilical artery at the needle insertion site. Only
occasional fetal intraperitoneal bleeding occurred in this series. The extravasated blood was absorbed from the peritoneal cavity
in all cases, and there were no adverse fetal effects.50, 51

Westgren and co-workers53 described direct fetal intracardiac transfusion (ICT) in patients with severe Rh hemolytic disease.
Six patients with evidence of severe erythroblastosis fetalis underwent the procedure at 1931 weeks' gestation. A total of 25
ICTs were completed, with a complication rate of 20%. According to these authors, ICT offers an alternative if direct IVT into
the umbilical cord is impossible.53 Using ICT, Harman7 described the resuscitation of five fetuses from exsanguinating
hemorrhage after umbilical cord puncture. After the initial ICT was successful, serial IVTs were performed subsequently with
good outcome.

HOW MUCH TO TRANSFUSE?

Target fetal hematocrits at the conclusion of IUT vary among treatment centers.54 A final fetal hematocrit of 5060% is usually
the goal when IVT alone is performed. A rise in fetal whole-blood viscosity during transfusion can be minimized by restricting
the posttransfusion fetal hematocrit to approximately 5055%.55 The final target hematocrit in the combined IVT/IPT
approach is usually approximately 40%. This is more physiologic because the fetal hematocrit normally ranges from 33% at 17

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weeks' to 47% at 40 weeks' gestation.56 To estimate the volume of red blood cells needed for an IVT, the fetoplacental volume is
determined first.57 The fetoplacental volume relative to fetal weight estimated by ultrasound is rather constant throughout the
course of pregnancy.58 This value in milliliters is equal to 1.046 plus the ultrasound-estimated fetal weight in grams multiplied
by 0.14. The volume to be transfused during IVT is then computed:

This calculation is based on a simple dilution formula and can be computerized. Repeated hematocrit determinations during
the IVT can be avoided in this manner.57 Alternatively, a transfusion coefficient can be used to determine the amount of blood
to be transfused (Table 2).59

Table2. Volume of blood (hematocrit 78%*) to be transfused to obtain desired increase in fetal hematocrit

Desired incremental Transfusion coefficient*


increase in initial fetal (multiply by the fetal
hematocrit (%) weight in grams)

10 0.02

15 0.03

20 0.04

25 0.05

30 0.06

Most fetuses undergoing IVT with a normal umbilical venous pressure have a pressure of less than 10 mmHg at the end of the
transfusion.60 Monitoring fetal umbilical venous pressure is still useful for assessing the fetal response to IUT61 because
pressure increases of more than 10 mmHg have predicted fetal death within 24 hours after IVT with a sensitivity of 80%.62
Severely anemic and hydropic fetuses experience particularly high loss rates. Radunovic and co-workers62 therefore
recommended that the posttransfusion fetal hematocrit not exceed 25% or a fourfold increase from the pretransfusion value.
Selbing and associates63 noted that if the fetus is given more than 20 mL of fluid for each kilogram of its ultrasound-estimated
weight, its chance of survival is reduced significantly. These authors strongly suggested an upper transfusion limit of 20 mL/kg,
which corresponds to approximately one fifth of the fetoplacental blood volume.

Timing of subsequent fetal transfusions varies among institutions. At Baylor College of Medicine, anemic fetuses are transfused
every 2 weeks for the first two transfusions; then the interval between procedures is lengthened to 34 weeks. Severely anemic
fetuses diagnosed early in the second trimester are an exception to this guideline. Such fetuses are transfused at first to achieve
a final hematocrit of approximately 25%. In a subsequent IUT approximately 48 hours later, a posttransfusion hematocrit of
35% is the goal. Equations to predict fetal hematocrit at the beginning of subsequent IUTs have been developed, and timing of
repeat transfusions can thus be estimated optimally.7, 64, 65

DYNAMICS OF TRANSFUSED RED BLOOD CELLS IN FETAL CIRCULATION

Initial studies of the effects of IUT focused on the rate of absorption of transfused blood from the peritoneal cavity by the

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fetus.39,66 At first, there was great concern that hydropic fetuses were unable to absorb red blood cells after IPT.39 One case
report showed that 2 hours after a 60-mL IPT, only 18% of circulating red blood cells in the fetus were adult-type cells.67 Using
chromium-labeled packed red blood cells during IPT, it was later demonstrated that, though over several weeks' time, even the
hydropic fetus can absorb them from its peritoneal cavity.40,41

The survival of transfused red blood cells in the fetal circulation also has been investigated. Maternal donor lymphocytes were
shown to persist for more than 2 years in the peripheral blood of four infants transfused in utero.68 A case report by Jones and
co-workers69 suggested that the half-life of the donor adult erythrocyte is only 30 days in a second-trimester fetus, compared
with approximately 60 days if transfused into an adult. Pattison and Roberts,70 however, studied 27 anemic fetuses and found
that adult erythrocyte survival in the fetus was similar to that in the adult circulation. These authors also noted that red blood
cell survival was independent of the route of transfusion, gestational age, or presence of hydrops. The fraction of transfused red
blood cells surviving at 29 days after IVT was approximately 65%, compared with 8% in the above-cited case report.69

USE OF MATERNAL BLOOD

There has been considerable change in the source of donor red blood cells for IUT. Virtually all centers use fresh, O-negative
cells for IUT; several centers use maternal blood as an alternate source. This source of fresh red blood cells is readily available,
the risk of maternal alloimmunization to new red blood cell antigens due to any fetomaternal hemorrhage is theoretically
reduced, and transmission of viral infections to the fetus is likely to be decreased. However, Vietor and colleagues71 studied 91
women treated with IUT for severe red blood cell alloimmunization and tested them for the development of additional
alloantibodies. These investigators detected new alloantibodies against red blood cell antigens in 24 women (26%). These were
usually directed against fetal rather than donor antigens. The use of maternal red blood cells during IUT in these cases would
not have prevented further alloantibody formation. Finally, the use of maternal red blood cells for IUT has a psychologic benefit
in that any guilt over fetal rejection would be alleviated by providing mothers with a practical way to help their fetuses.

Up to 6 U of maternal blood can be safely harvested for fetal transfusion during a gestation.72 Regular intake of prenatal
vitamins, folate, and ferrous sulfate prevents significant maternal donor anemia. All mothers are screened routinely for
syphilis, West Nile virus, HIV1 and 2, human T-cell lymphotropic virus type 1 (HTLV-1), and all known forms of hepatitis
before donating for their fetuses. Donated red blood cells are washed to remove the offending antibodies and packed to achieve
a hematocrit of approximately 80%. Units then are processed through a leukocyte-poor filter and irradiated with approximately
2500 rad (25 Gy) to prevent any graft-versus-host reaction. Great care must be taken to ensure timely processing of fresh blood
to avoid transfusion of blood with high plasma potassium levels, which could cause fetal arrhythmias after IUT.73, 74 Mothers
with antibodies to cytomegalovirus may still donate because this virus resides in white blood cells removed during the filtration
process. If initial cordocentesis reveals an ABO incompatibility between mother and fetus, maternal red blood cells should be
used only with great caution because of the risk of fetal sensitization. At Baylor College of Medicine, maternal blood was utilized
in two such cases with no adverse effects observed in the fetus or neonate.

ULTRASOUND TO PREDICT FETAL HEMATOCRIT

Ultrasound has played an important role in improving the outcome in pregnancies affected by Rh hemolytic disease. It is used
to establish the correct gestational age on which parameters such as normal fetal hematocrit and amniotic bilirubin levels are
based. Ultrasound provides invaluable needle guidance during amniocentesis, cordocentesis, and IUT. Unfortunately, its use in
the diagnosis of fetal anemia is limited until overt hydrops fetalis is present. Although some investigators have advocated serial
ultrasound examinations to detect signs of impending hydrops fetalis, Nicolaides and co-workers75 were unable to correlate
fetal hematocrit with increased placental thickness or increased umbilical vein diameter. Because the liver and spleen are
sources of extramedullary hematopoiesis in response to fetal anemia, these organs have been studied separately to predict fetal
anemia. Two studies76, 77 have proposed that an increase in fetal liver dimensions is a good predictor of anemia. Oepkes and co-
workers78 measured the fetal splenic perimeter with ultrasound and noted that splenomegaly was present in all nonhydropic,
anemic fetuses. Splenomegaly predicted a hemoglobin deficit in excess of five standard deviations from the normal range for a
given gestational age, with a sensitivity of 93%. Some hydropic fetuses still had no splenomegaly.

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The cardiac output of the anemic fetus has been demonstrated to be increased over controls.79 This would lead to enhanced
velocity of blood in various fetal vessels. For this reason, Doppler ultrasound has been studied to see whether it could serve as a
valuable adjunct in the evaluation of the status of the fetus requiring IUT.80 Pulsed Doppler wave forms from the fetal
descending aorta have been used to predict hematocrit before IVT.81, 82 Copel and co-workers83 have proposed the following
formula to predict fetal hematocrit:

When they applied this formula to 16 fetuses, they achieved a sensitivity of 90% and a specificity of 69%. Copel and co-
workers83, 84 further concluded that their Doppler technique was useful in predicting fetal hematocrit and the need for an initial
IUT, but the timing of subsequent IUTs was not improved. Pulsed Doppler flow-velocity indices in the umbilical artery do not
correlate with fetal blood gas values in red blood cell-alloimmunized pregnancies, nor do they predict fetal hematocrit except in
very severely affected fetuses clearly requiring IUT.85, 86 Study of fetal cerebral vessels, such as the common carotid and middle
cerebral arteries, has not proved Doppler findings in these vessels to be any more useful in the prediction of fetal anemia.87, 88

Investigations to evaluate the clinical usefulness of pulsed Doppler flow-velocity indices in the management of severe red blood
cell alloimmunization confirmed the hyperdynamic circulation produced by the fetal anemia in both arterial and venous
vessels.89 An association with the degree of fetal anemia was again found only for the flow-velocity wave forms in the fetal
aorta. Steiner and associates90 showed that the clinical usefulness of the peak aortic velocity is hampered by its low predictive
value. Bahado-Singh and co-workers91 demonstrated that the splenic artery resistance index increases in fetuses with severe
anemia. These authors postulated that this occurs as a reflection of vascular congestion from red blood cells trapped in the
splenic circulation.

Doppler flow velocity assessment is now the standard of care for the diagnosis of fetal anemia.92, 9, 93 Chapter Alloimmune hemolytic
disease of the fetus and newborn (erythroblastosis fetalis): diagnosis, management, and prevention

FETAL PARALYSIS

The operator has been plagued by fetal movement during IUT since the first description of the procedure by Liley.12 Fetal
immobilization was first described by Liggins,94 who performed IPT by an impaling technique using multiple needle punctures
of the fetus. Since then, IUT has been made easier by the widespread use of fetal paralytic agents. Fetal paralysis was first
introduced in 1985 in Australia.49 In the United States, D-tubocurarine initially was injected into the fetal thigh under
ultrasound guidance.95 The intravascular use of pancuronium bromide through cordocentesis was reported subsequently.96, 97
The absorption of red blood cells from the fetal peritoneal cavity was found to be markedly reduced after injection of
pancuronium bromide in a sheep model.98 Therefore, short-acting agents such as atracurium besylate and vecuronium bromide
are currently in use.99, 100, 101 These two paralytic agents also do not cause the fetal tachycardia and loss of short-term fetal
heart rate variability frequently demonstrated with the use of pancuronium bromide.102 A vecuronium or pancuronium
bromide dose of 0.1 mg/kg of ultrasound-estimated fetal weight results in almost immediate cessation of fetal movement when
injected intravascularly at the beginning of an IUT. This fetal paralytic effect lasts for up to 2 hours, and no untoward effects in
neonates have been reported.

MONITORING WITH COLOR FLOW DOPPLER

The use of color flow Doppler ultrasound also has improved the technique of IUT.103 Color flow Doppler has an advantage over
gray-scale ultrasound in that it allows for accurate localization of fetal vessels in difficult cases, such as early gestational age,
oligohydramnios, or poor fetal positioning over the umbilical cord insertion site. When targeting the fetal hepatic vein for IUT,
color flow Doppler helps to identify the vessel. During the actual injection of blood, intravascular turbulence at the tip of the
transfusion needle is visible on color flow Doppler imaging.103 In addition, the fetal heart rate can be monitored by observation
of the umbilical artery pulsations. Thus, the operator's view of the transfusion needle is not interrupted by the need to observe

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the fetal heart rate directly on the ultrasound monitor. Finally, during IPT the color flow Doppler can be used to monitor the
free flow of fluid into the peritoneal space, thereby confirming proper placement of the transfusion needle.

PRACTICAL CONSIDERATIONS

At Baylor College of Medicine, the following IUT procedure is used.103 The IUT is performed in close proximity to the labor and
delivery suite. With the patient under mild sedation and the abdomen prepped and draped in the usual sterile fashion, a 20-
gauge needle, 6 inches in length, is directed under local anesthesia and real-time ultrasound guidance into the placental
umbilical cord insertion. An initial fetal blood sample is sent for spun hematocrit, complete blood and reticulocyte counts,
Kleihauer-Betke stain, and total and direct bilirubin. Next, the fetus is paralyzed with a pancuronium dose of 0.1 mg/kg of
ultrasound-estimated fetal weight; fetal analgesia is provided by the use of fentanyl (10 g/kg of estimated fetal weight). These
medications can be mixed in the same syringe and injected directly into the umbilical vessel. Red blood cells then are
transfused at a rate of approximately 510 mL/min. A final sample of fetal blood is obtained for a hematocrit and a Kleihauer-
Betke stain. After the IVT is completed, a standard IPT is undertaken in the combined IVT plus IPT approach performed at our
center; we accomplish this simply by redirecting the IVT needle. After the procedure, the fetal heart rate is monitored
continuously for at least 2 hours, after which the patient is discharged home. A follow-up ultrasound is performed the next
morning.

TIMING OF DELIVERY

The timing of delivery in fetuses undergoing serial IUTs has undergone considerable change. During the era of IPT, fetuses
affected by hemolytic disease were delivered routinely at 32 weeks' gestation. Hyaline membrane disease and
hyperbilirubinemia necessitating neonatal exchange transfusion were frequent complications. The widespread use of IVT
during the past decade has led many centers to perform the final procedure at approximately 35 weeks' gestation with delivery
planned approximately 3 weeks later. This change in management has virtually eliminated hyaline membrane disease and the
need for neonatal exchange transfusions for elevated bilirubin. The addition of at least 10 days of maternal phenobarbital (30
mg three times daily) at our center has resulted in a 75% reduction in the need for neonatal exchange tranfusions.104 Once fetal
viability is reached, IUTs should be undertaken close to the labor and delivery suite so that an immediate cesarean section can
be performed in cases of fetal distress.

FETAL PHYSIOLOGIC EFFECTS

IVT leads to extensive fetal cardiovascular changes. The procedure greatly stresses the developing fetus with acute changes in
intravascular volume and viscosity. Umbilical venous pressure increases between 1.7 and 4.6 mmHg.60,105,106 Fetal cardiac
output decreases by as much as 25%,105 begins to return to pretransfusion levels within 2 hours,107 and returns to normal by
approximately 24 hours after the procedure.79 To explain fully the fetal hemodynamic response to IVT, it has been suggested
that the procedure leads to increased fetal cardiac afterload secondary to an increase in fetal blood viscosity. The fetus responds
to this rise in afterload by a decrease in stroke volume, leading to a decrease in cardiac output and fetal heart rate and an
increase in right atrial and umbilical venous pressures.7,105 Pulsed Doppler assessment of umbilical and fetal femoral, renal, and
cerebral vessels has demonstrated generalized fetal vasodilatation in response to this increase in afterload.108,109 Results of
investigations using pulsatility index as an indicator of fetal anemia and its correction by IVT also are indicative of a decrease in
fetal vascular impedance immediately after IVT.105,108,109,110

An increase in fetal vasodilator prostaglandins, which allows the human fetus to tolerate large increases in intravascular
volume, has been reported after IVT.111,112 An increase in atrial natriuretic peptide, a vasodilator, also contributes to the
apparent acute decrease in vascular tone observed in the human fetus immediately after IVT.113,114,115 Interestingly, a paradoxic
increase in fetal plasma arginine vasopressin has been observed in association with IVT.116 This finding remains unexplained.

IVT also leads to significant alterations in fetal metabolism. Nicolini and co-workers117 found that the umbilical venous pH and

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base excess decrease while the PCO2 acutely increases after IVT. In this study, the transfused blood had a mean pH of 6.76.
These investigators believed that the fetoplacental circulation was effective in correcting this exogenous source of acidosis. The
oxygen dissociation curve of fetal hemoglobin favors the uptake of oxygen in the placenta. Therefore, replacing fetal red blood
cells with adult cells could seriously affect oxygen delivery to fetal tissues. Soothill and colleagues118 compared blood gas values
of fetuses transfused with adult hemoglobin-containing red blood cells to those of controls. Transfused fetuses had a lower
umbilical arterial pH and greater base deficit, while umbilical venous PO2 was higher. These authors postulated that an
increase in uteroplacental blood flow is the compensatory mechanism for fetal tissue hypoxia caused by transfused red blood
cells carrying only adult hemoglobin.

An important compensatory response to anemia in the adult is an increase in the 2,3-diphosphoglycerate level, which reduces
the oxygen affinity of adult hemoglobin and facilitates oxygen delivery to the tissues. Soothill and co-workers119 demonstrated
that when adult red blood cells were transfused into the fetal circulation of 34 anemic fetuses, the 2,3-diphosphoglycerate
concentration increased in direct correlation with the degree of anemia, allowing for improved fetal tissue oxygenation. Socol
and associates120 reported that IVT decreases hemolysis and reduces circulating levels of fetal plasma glutathione. Glutathione,
liberated from hemolyzed fetal red blood cells, causes the inhibition of insulin activity in anemic fetuses, leading to a
compensatory fetal hyperinsulinemic response.121 IVT therefore may prevent the hyperinsulinemia frequently associated with
red blood cell alloimmunization.120

Nasrat and associates122 demonstrated that there is a potential risk for iron overload in Rh-alloimmunized fetuses undergoing
IUT. These authors described plasma ferritin levels indicative of iron overload in several fetuses. Severe fetal hemolytic anemia
leads to elevated iron stores, which further increase in direct correlation with the volume of red blood cells transfused. Neonatal
cholestasis and hepatitis due to severe intrahepatic iron deposition after IUT have been reported recently.123 Therefore iron
supplementation should be withheld in newborns with hemolytic disease until serum ferritin levels return to the normal range.

COMPLICATIONS

Before paralytic agents were in use to immobilize the fetus during IUT, fetal movement had the potential to result in visceral
injury or umbilical cord trauma during the procedure. One case report even describes an IPT with subsequent fetal omental
herniation through the fetal abdominal needle puncture site.124 Anterior placental location increases the risk of damage to a
major fetoplacental vessel with subsequent fetal exsanguination.125 Perinatal infectious complications, such as viral hepatitis,
also have been reported in the early experience with IPT.126, 127

Several reports have described sinusoidal fetal heart rate patterns immediately after IPT.128, 129 A transient sinusoidal fetal
heart rate after IPT is not necessarily an ominous sign; however, if persistent, it may herald fetal cardiac decompensation. This
likely is caused by an increase in intra-abdominal pressure adversely affecting fetal heart rate control as a result of increased
vagal stimulation.130 Animal experiments have revealed that IPT causes increased fetal intraperitoneal pressure, which can lead
to fetal hypoxia from umbilical vein compression.130 The need for intraperitoneal pressure monitoring during IPT has since
been supported by human data as well.106, 131

IVT has led to complications not previously described with IPT, even though IVT generally is safe with a procedure-related
pregnancy loss rate of approximately 13%.8, 52, 132 Entering umbilical vessels during IVT can cause an umbilical cord
hematoma with resulting fetal compromise.44 Some authorities have proposed that transient fetal bradycardia results from a
perivascular blood collection leading to umbilical arterial vasospasm, with the extravasated fetal blood acting as an irritative
focus. If umbilical vein thrombosis occurs in addition to the hematoma, fetal death may be the consequence.45 Thus, visible
echogenic turbulence is a sine qua non feature of the successful IVT. Disappearance of this marker signifies loss of proper
needle location.133 Furthermore, Moise and colleagues134 noted that increased bilirubin levels due to hemolysis in the fetus of
an alloimmunized pregnancy resulted in icteric serum in spun capillary hematocrit tubes. This finding is useful in confirming
fetal vascular access in cases of anterior placentation, where visualization of the needle tip with ultrasound may be problematic.

Fetal bradycardia secondary to umbilical arterial vasospasm transiently occurs in approximately 4% of IVTs, especially as the
target transfusion volume is being approached.7, 52 When the umbilical artery is entered, the incidence of fetal bradycardia

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approaches 30%.132 Therefore, the umbilical vein should be targeted routinely for IVT. On occasion, however, the umbilical
artery is inadvertently punctured; in these cases, infused red blood cells will stream back toward the placenta during ultrasound
visualization. Although immediate removal of the transfusion needle frequently is recommended, at our center we proceed with
caution and frequently monitor the fetal heart rate using color flow Doppler. Slowing or stopping the transfusion and maternal
oxygen administration usually leads to complete resolution of the fetal bradycardia. If these maneuvers do not reverse the
bradycardia, the needle should be removed. Maternal repositioning in the left lateral position is undertaken. If the fetus is
viable, we observe the bradycardia for up to 10 minutes before proceeding with an emergency cesarean section. Normal
function of the atrioventricular valve leaflets in the fetal heart is a good indication that cardiac output is being maintained
despite the slow heart rate. Cessation of movement of these valve leaflets on ultrasound examination warrants delivery.

Congenital viral infections can occur when donor blood is used for IVT. An unfortunate case of fatal congenital cytomegalovirus
infection acquired through IUT was described previously.135 Rare, but especially concerning, are cases of severe fetal brain
injury after IVT.136, 137 Dildy and co-workers43 documented an unexplained fetal porencephalic cyst after IVT. An increase in
blood viscosity and fetal bradycardia during the IVT may have contributed to this complication by leading to fetal cerebral
hypoperfusion. Fortunately, the infant later was discharged home with a normal neurologic status.

Fetomaternal hemorrhage can accelerate fetal hemolytic disease in the pregnant patient previously sensitized to red blood cell
antigens. Moise and co-workers138 described a case of poor fetal outcome after first-trimester transcervical chorionic villi
sampling in a previously alloimmunized patient. The patient's antibody titers became elevated, resulting in the demise of a
hydropic fetus early in the second trimester. These authors proposed that red blood cell alloimmunization is an absolute
contraindication for chorionic villi sampling. Similarly, the placenta should be avoided during placement of the IUT needle.
Nicolini and associates139 described fetomaternal hemorrhages with an average volume of 2.4 mL in 21 of 32 patients
undergoing IVT with an anterior placenta. Maternal alloantibody titers became elevated when the estimated volume of
fetomaternal hemorrhage exceeded 1 mL. Hence, any significant fetomaternal hemorrhage may lead to more severe fetal
hemolytic disease during a patient's subsequent pregnancies.

OUTCOME

Survival of the fetus after IUT varies with the operator's experience, the institution, and the technique used. Results of studies
on the outcome after IPT alone are presented in Table 3.135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153,
154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164 Of 2483 reported fetuses who underwent IPT between 1963 and 1988, 39% survived.

Only 17% of hydropic fetuses survived after IPT alone. Table 4 summarizes the reported experience with both IVT and IVT/IPT.
Of 411 fetuses who underwent the procedure, 84% did well165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178; 94% of
nonhydropic fetuses and 74% of hydropic fetuses survived. An overall fetal survival rate of approximately 80% was reported by
Baylor College of Medicine IUT using the combined IVT/IPT approach.4, 5, 6

Table 3. Summary of studies using fetal intraperitoneal transfusion (IPT)

Technique No. of Total No. of Survivors with Survivors


Author Year for IPT Patients Survivors Hydrops without Hydrops

Watts et al141 1988 IPT/ultrasound 35 30 4 26

Bowman and 1983 IPT/ultrasound 24 22 6 16


Manning28

Berkowitz and 1981 IPT/ultrasound 17 12 4 8


Hobbins142

Clewell et al143 1981 IPT/ultrasound 16 11 NA NA

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Acker et al144 1980 IPT/ultrasound 35 18 5 13

Frigoletto et al23 1981 IPT/x-ray 330 137 5 132

Ellis145 1980 IPT/x-ray 217 81 NA NA

Hamilton146 1977 IPT/x-ray 82 29 1 28

Bock147 1976 IPT/x-ray 34 19 NA NA

Holt et al148 1973 IPT/x-ray 93 44 NA NA

Whitfield et al149 1972 IPT/x-ray 170 72 NA NA

Bashore et al150 1971 IPT/x-ray 116 34 8 26

Duhring and 1970 IPT/x-ray 25 12 NA NA


Zwirek151

Fong et al152 1970 IPT/x-ray 73 18 2 16

Eyster et al153 1969 IPT/x-ray 7 5 NA NA

Horger and 1969 IPT/x-ray 59 19 NA NA


Hutchinson154

Mandelbaum155 1969 IPT/x-ray 142 36 NA NA

Queenan156 1969 IPT/x-ray 591 203 NA NA

Wade et al157 1969 IPT/x-ray 48 12 NA NA

Bjerre et al158 1968 IPT/x-ray 11 4 NA NA

Stenchever and 1968 IPT/x-ray 8 2 NA NA


Cibils159

Bishop et al160 1967 IPT/x-ray 44 22 NA NA

Cherry and 1967 IPT/x-ray 11 4 NA NA


Rosenfield161

Fairweather et 1967 IPT/x-ray 35 16 NA NA


al162

Friesen et al163 1967 IPT/x-ray 47 15 NA NA

Hutchinson et 1967 IPT/x-ray 28 11 NA NA


al164

McCutcheon and 1967 IPT/x-ray 26 9 NA NA


Little140

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Charles et al165 1966 IPT/x-ray 17 5 NA NA

Karnicki166 1966 IPT/x-ray 68 33 NA NA

Work et al167 1966 IPT/x-ray 13 6 NA NA

Bowes et al168 1965 IPT/x-ray 7 3 NA NA

Green et al169 1965 IPT/x-ray 30 10 NA NA

Liley12 1963 IPT/x-ray 1 1 NA NA

Queenan156 1969 Hysterotomy 23 3 NA NA

Total = 958 (39%) 35 (17%) 265 (53%)


2483
Hydrops =
210
No
Hydrops =
502

NA, not available

Table 4. Summary of studies using direct fetal intravascular transfusion

Technique No. of Total No. of Survivors with Survivors without


Author Year for IVT Patients Survivors Hydrops Hydrops

Moise et al4, 5, 1994 IVT + IPT 20 19 10 9


6

Rodeck et al170 1991 IVT + IPT 18 16 16 0

Weiner et al171 1991 IVT 48 46 11 35

Harman et al42 1990 IVT 44 40 18 22

Lemery et 1989 IVT 15 10 2 8


al172, 173

Nicolini et al47 1989 IVT + IPT 30 25 NA NA

Pattison and 1989 IVT 20 18 1 17


Roberts70

Poissonnier et 1989 IVT + IPT 107 84 29 55


al174

Ronkin et al175 1989 IVT 8 8 2 6

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Barss et al176, 1988 IVT + IPT 13 11 4 7


177

Grannum et 1988 IVT 26 21 16 5


al178

Orsini et al179 1988 IVT 15 10 4 6

Parer136 1988 IVT 5 4 NA NA

Socol et al180 1987 IVT 3 3 3 0

Berkowitz et 1986 IVT 8 6 2 4


al35, 181

Doyle et al182 1986 IVT 8 5 0 5

Nicolaides et 1986 IVT 18 17 10 7


al183

de Crespigny et 1985 IVT 4 3 1 2


al49

Bang et al30 1982 IVT 1 1 1 0

Total = 411 347 (84%) 130 (74%) 188 (94%)


Hydrops =
175
No
Hydrops =
201

IPT, intraperitoneal transfusion; IVT, intravascular transfusion; NA, not available.

Initially it seemed that infants severely affected by red blood cell alloimmunization and transfused in utero had lower birth
weights than matched controls,184, 185 but fetal catch-up growth after IVT has been observed in more recent studies.186, 187 It
has been shown clearly that birth weights of infants transfused in utero are comparable to those of matched controls.

Few long-term outcome studies exist assessing infants transfused in utero.188, 189, 190, 191 Follow-up evaluations of fetuses
treated with IPT have identified increased numbers of inguinal hernias in males and umbilical hernias in females as compared
with matched siblings.192 In assessing overall physical, intellectual, and social maturity in IPT survivors for several years,
Turner193 considered only 50% to be completely normal. Other investigators have evaluated survivors of IPT for up to 11 years
and found no significant developmental or physical abnormalities.192, 194

Follow-up of IVT survivors is limited and must be viewed cautiously considering that the lives of more moribund fetuses have
been saved.188, 191 Doyle and co-workers188 studied 38 infants who had undergone IVT and found 35 to be developing normally.
The three abnormal outcomes were attributed to prematurity.

NEED FOR NEONATAL TOP-UP TRANSFUSION

Lozinska195 demonstrated that IUT suppresses hematopoiesis. Therefore, many infants treated with IUT before birth require

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top-up transfusions during the early months of life. Because their red blood cell population consists mainly of transfused
adult erythrocytes, reticulocytes are virtually absent. Neonatal exchange transfusions, however, rarely are necessary. Typically,
infants with a history of IVT present with symptomatic anemia at 1 month of age and require a simple red blood cell
transfusion. A review of 40 cases at Baylor College of Medicine showed that a top-up transfusion is necessary in approximately
50% of infants at a mean age of 38 days of life.196 Most infants received only one such transfusion although some required as
many as three. A recent retrospective series from the Netherlands found that 76% of the 52 infants in their series that had
received intrauterine transfusions required top-up transfusions.197 Infants requiring late neonatal transfusion are characterized
by a lower reticulocyte count at their final IUT, higher umbilical cord hemoglobin at delivery, and a greater number of adult red
blood cells seen on a cord Kleihauer-Betke smear. The affected infants have exhibited bone marrow erythroid hypoplasia, low
serum erythropoietin, and a decreased number of circulating reticulocytes.198, 199 The mechanism causing the decreased
erythropoietin is poorly understood; however, because passively acquired maternal antibodies remain elevated for at least 6
weeks in these neonates, the reticulocytopenia could be caused by high bone marrow levels of anti-red blood cell antibodies.

Therefore, weekly hematocrit and reticulocyte determinations should be performed for the first 2 months of life in infants with
a history of IUT.200 Infants with a hemoglobin of less than 56 g/dL clearly should be transfused, even if they are symptom-
free. Infants showing signs related to severe anemia, such as failure to thrive and lethargy, also are candidates for transfusion.
Scaradavou and colleagues201 reported the use of erythropoietin to treat late anemia caused by suppression of erythropoiesis
due to IUT for Rh alloimmunization. Subcutaneous injection of 200 U erythropoietin per kilogram of body weight three times
per week, combined with ferrous sulfate and folic acid supplementation, was effective in markedly decreasing the need for
postnatal transfusion.

FETOMATERNAL HEMORRHAGE

Massive fetomaternal hemorrhage is the cause of fetal death in 1 per 1000 births and results in significant fetal morbidity in at
least 1 per 800 deliveries.202 Seven cases of IUT in this situation have been described. Decreased fetal movement was the chief
complaint in four of these cases, and subsequent fetal monitoring revealed a sinusoidal fetal heart rate pattern.203,204,205 In the
remaining three cases, routine ultrasound showed a hydropic fetus.206,207,208 The maternal Kleihauer-Betke smear was positive
in every case, and IUT was performed immediately. A single IUT procedure was needed in three cases, two procedures in
another three cases, and five procedures in the remaining case. With this intervention, pregnancy was prolonged in three cases.
In the first case, an IPT at 21 weeks' gestation was successful in reversing hydrops fetalis with subsequent delivery of a normal
infant at 38 weeks' gestation.206 Thorp and co-workers208 performed two IVTs at 26 and 27 weeks' gestation. Hydrops fetalis
was noted to resolve, and a normal infant was born at 39 weeks' gestation. At Baylor College of Medicine, Montgomery and co-
workers207 transfused an affected fetus five times beginning at 27 weeks' gestation using the combined IVT/IPT approach.
Abdominal delivery of a 1740-g infant at 30 weeks' gestation was required as a result of chorioamnionitis. The infant's initial
hematocrit was 57%, and its neonatal course was uneventful. In all other reported cases, fetal bradycardia or the return of
decreased fetal movement necessitated delivery by cesarean section. Cordocentesis in three of these fetuses revealed a
decreasing hematocrit due to continued fetomaternal hemorrhage. The use of IUT in the treatment of fetomaternal hemorrhage
therefore may prove beneficial only in selected cases.

PARVOVIRUS INFECTION

Human parvovirus B19 causes erythema infectiosum (fifth disease) in children. During outbreaks, household contacts as well as
school teachers frequently are exposed. Approximately 50% of persons lack immunity, and 20% of these will become infected
after exposure.209, 210 One third of infected pregnant women will remain asymptomatic and will not manifest the exanthem
typical of this disease.211 Reported rates of fetal infection range from 2.5% to 38%.212, 213 Parvovirus suppresses the fetal bone
marrow and inhibits fetal erythropoiesis with the subsequent development of aplastic anemia, nonimmune hydrops, and fetal
death.

Maternal parvovirus infection is often confirmed by detection of a specific IgM antibody that appears 34 days after the onset

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of clinical disease and persists for 34 months.214 Fetal infection usually occurs 46 weeks after maternal infection, although
hydrops fetalis has been reported as late as 12 weeks after the maternal illness. If maternal infection has been confirmed, the
fetus should undergo weekly ultrasound examinations for the presence of hydrops fetalis for a total of 12 weeks. If hydrops is
noted, donor red blood cells and platelets should be prepared, and cordocentesis performed. Studies of fetal blood usually show
a negative direct Coombs' test, severe anemia, occasional thrombocytopenia, an inappropriately low reticulocyte count, normal
serum bilirubin, elevated total IgM, and elevated liver enzymes.215 Under the electron microscope, viral particles may be
observed in fetal ascitic fluid or blood.216 Using probes specific for human parvovirus B19, viral DNA also can be identified in
some fetal body fluids.214 Spontaneous resolution of hydrops fetalis secondary to fetal parvovirus infection has been reported
by several authors.217, 218 Thus, if the fetal reticulocyte count is elevated before the first IUT, a second procedure is not
necessary because recovery of the fetal bone marrow is ongoing. Nonimmune hydrops due to in utero parvovirus infection may
require several weeks to resolve after the fetal hematocrit has returned to normal.

In one series of 539 cases of parvovirus-induced hydrops, spontaneous resolution of the hydrops occurred in one third of cases
while an additional 30% of fetuses died without treatment. IVT resulted in an 84% overall survival.219 Therefore, IVT should be
strongly considered as a therapeutic option in cases of fetal parvovirus infection with resultant hydrops fetalis. Although initial
neonatal outcome was thought to be normal in those cases treated with IVT, more recent data call this into question. Nagel et
al.220 followed 16 survivors that had presented with hydrops in utero. Thirty-two percent demonstrated psychomotor delay
mild in three cases and severe in two cases.

PLATELET ALLOIMMUNIZATION

Neonatal alloimmune thrombocytopenia, a disease process analogous to red blood cell alloimmunization, complicates 1 per
10002000 live births.221 In this situation, transplacental passage of maternal antibodies to fetal platelet antigens of paternal
origin results in severe fetal and neonatal thrombocytopenia. In utero intracranial hemorrhage occurs in 10% of cases and has
been documented as early as the second trimester.222, 223 In 75% of affected fetuses, the platelet antigen involved is HPA-1.224
Unlike Rh alloimmunization, the first fetus may already be severely affected; maternal antibody titers are not predictive of the
degree of fetal thrombocytopenia.222, 225 The clinician often becomes aware of the disease only after an affected infant is born to
the patient or her sister. Subsequent pregnancies are commonly complicated by progressively worsening fetal disease.226

The initial evaluation of an affected neonate should include platelet antigen testing of the newborn, mother, and father.
Determining the paternal zygosity with respect to the HPA-1 antigen will assist in the prediction of the fetal antigen status in
the vast majority of instances because only 5% of fathers are heterozygous.227 The likelihood of recurrent HPA-1 fetomaternal
incompatibility is therefore approximately 94%.227 Khouzami and associates228 described the use of amniocentesis to
determine the fetal platelet antigen status employing allele-specific oligonucleotide probes in uncultured amniocytes.
Currently, fetal platelet count and antigen status of any subsequent pregnancy are determined most commonly by
cordocentesis at 20 weeks' gestation. Unfortunately, this approach is not without risk. Several cases of fetal death caused by
hemorrhage have occurred after cordocentesis in the investigation of platelet alloimmunization.229 Therefore, maternal
platelets for immediate transfusion should be available at the time of cordocentesis should excessive streaming of blood occur
from the umbilical vessel puncture site. Alternatively, if the fetal platelet count can be assessed rapidly while the cordocentesis
needle is still in place, platelet transfusion should be performed for counts less than 50,000/mm3. This threshold is based on
neonatal courses complicated by bleeding in infants born to women with autoimmune thrombocytopenia.230 Because
approximately 98% of the population is HPA-1 antigen positive, maternal platelets should be used for fetal transfusion.231 The
platelets are obtained by apheresis 24 hours before their anticipated use, washed to remove any trace of offending antibodies
and resuspended in ABO-compatible plasma.

The volume of platelet concentrate to be used can be calculated with the following formula:

where V represents the volume of platelets to be transfused, VFP is the estimated fetoplacental blood volume for the respective

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gestational age,58 C1 is the fetal platelet concentration before transfusion, C2 is the concentration of the donor platelets, and C3
is the fetal platelet concentration desired after transfusion.232 The optimal posttransfusion fetal platelet count to prevent
bleeding complications has yet to be determined. For this reason, most clinicians will transfuse a quantity of platelets
empirically, based on the formula presented here. Although a final fetal platelet count should be obtained at the conclusion of
the procedure, it is not necessary to wait for the result before the transfusion needle is removed.

Initially, fetal platelet transfusions in cases of platelet alloimmunization involved serial infusions of maternal platelets by
cordocentesis. Four cases have been described.232, 233, 234 In two of these cases, the median daily decline in fetal platelet count
was 23,600/mm3. Because of the short platelet half-life of 47 days, weekly transfusions are required to maintain an adequate
fetal platelet count (Fig. 2).233 Bussel and colleagues235 have argued that this approach is associated with undue risk to the fetus
from multiple umbilical cord punctures. Using an alternative approach, Lynch and co-workers236 successfully combined the
maternal administration of steroids and weekly intravenous gamma globulin injections to increase the fetal platelet count at
delivery to greater than 50,000/mm3 in 11 of 18 cases. No case of intracranial hemorrhage occurred in the treatment group,
compared with a 33% incidence in antecedent siblings.236 Therefore, serial in utero platelet transfusions are not a reasonable
primary approach to the management of affected fetuses with alloimmune thrombocytopenia.

Fig. 2 . Fetal platelet count before and after platelet


transfusions in patient A (A) and in patient B (B).
(Nicolini U, Tannirandorn Y, Gonzalez P et al:
Continuing controversy in alloimmune
thrombocytopenia: Fetal hyperimmunoglobulinemia
fails to prevent thrombocytopenia. Am J Obstet
Gynecol 163:1145, 1990)

Daffos and co-workers232 proposed cordocentesis at term in fetuses suspected of having thrombocytopenia due to maternal
platelet alloimmunization. If fetal thrombocytopenia is detected, transfusion with maternal platelets can then be performed.
Subsequent induction of labor with vaginal delivery would be a safe option. Ten cases of fetal transfusion with platelets just
before delivery have been reported.225, 232, 234, 237 Initially, investigators performed the fetal platelet transfusion and then
proceeded with elective cesarean section, with the reasoning that cesarean delivery alone is not completely protective against
intracranial hemorrhage in fetuses affected by alloimmune thrombocytopenia.238 More recently, vaginal delivery was allowed
after fetal platelet transfusion in four of the 10 cases in this series. There were no adverse neonatal sequelae. Sia and
colleagues,238 however, recommended vaginal delivery only with a posttransfusion fetal platelet count greater than
100,000/mm3.

Severe fetal thrombocytopenia has been associated with hydrops fetalis caused by red blood cell alloimmunization and
parvovirus infection.215, 239, 240 In these cases, random-donor platelets also should be available at the time of IUT with red
blood cells. If the fetal platelet count is noted to be less than 50,000/mm3, transfusion with platelets may prevent fetal death
due to prolonged bleeding from the umbilical vessel puncture site.

THE FUTURE OF INTRAUTERINE TRANSFUSION

Unfortunately, IUT only briefly relieves the symptoms of severe fetal anemia or thrombocytopenia caused by red blood cell or
platelet alloimmunization and is intended only to prolong the intrauterine period available to the developing fetus to achieve
maturity. Even though gamma globulin and steroids are promising alternatives to serial fetal platelet transfusion in the
treatment of alloimmune thrombocytopenia,236 efforts to treat Rh hemolytic disease directly by administration of intravenous
gamma globulin, plasmapheresis, oral Rh antigen ingestion, or promethazine have failed to date.241, 242, 243, 244 IVT is well
established at many centers throughout the United States, and improvement of fetal survival beyond the 84% presented here is
unlikely. To achieve better treatment results, a direct approach to the disease is needed.

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The human Rh gene has been cloned, and the exact blood type of the developing embryo can be determined.245, 246, 247, 248
Using in vitro fertilization techniques, preimplantation diagnosis would allow for the exclusive return of Rho(D)-negative
embryos to the uterus.249 Such an approach would lead to an unaffected fetus in all successful implantations.

Using a rabbit model of Rh hemolytic disease developed by Moise and associates,250 immunization to paternal leukocytes has
been demonstrated to offer promise as a method of maternal immunotherapy for the treatment of red blood cell
alloimmunization.251

CONCLUSIONS

Widespread use of RhIG has reduced the incidence of Rh hemolytic disease in the United States to only 1 per 1000 live births.3
Only 9% of affected patients require IUT yielding less than 500 cases in the United States annually.4,5,6 To optimize outcome
with IUT as state-of-the-art therapy for severely anemic fetuses remote from term, regionalization of treatment should be
considered at centers where a minimum of 10 fetal transfusions per year are performed. After diagnostic testing using
ultrasound and amniocentesis performed by local obstetricians has shown a severely affected fetus requiring cordocentesis and
possible IUT, the patient would enter the referral network. Concentrating patients with severe hemolytic disease at such centers
would also provide the opportunity for continued basic and clinical research.

IUT is a safe procedure8,52,132 and has saved the lives of many fetuses, including several infected with human
parvovirus.211,215,252,253 It is the best available therapy until red blood cell alloimmunization can be prevented completely. IUT in
the treatment of fetomaternal hemorrhage may prove beneficial only in selected cases.203,204,205,206,207,208 Fetal platelet
transfusions in cases of severe platelet alloimmunization are of limited therapeutic value because of the short half-life of this
blood component.232,233,234,235

REFERENCES

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3 Chavez GF, Mulinare J, Edmonds LD: Epidemiology of Rh hemolytic disease of the newborn in the United States. JAMA
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4 Moise KJ: Changing trends in the management of red blood cell alloimmunization in pregnancy. Arch Pathol Lab Med
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5 Moise KJ, Milam JD, Carpenter RJ: Changing trends in the diagnosis and treatment of Rh alloimmunization. Texas Med
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6 Moise KJ: Management of red cell alloimmunization in pregnancy. In Sacher RA, Brecher ME (eds): Obstetric
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12 Liley AW: Intrauterine transfusion of foetus in haemolytic disease. Br Med J 2: 1107, 1963

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23 Frigoletto FD, Umansky I, Birnholz J et al: Intrauterine fetal transfusions in 365 fetuses during fifteen years. Am J
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new technique. Am J Obstet Gynecol 131: 273, 1978

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33 Mandelbaum B, Pontarelli DA, Brushenko A: Amnioscopy for prenatal transfusion. Am J Obstet Gynecol 98: 1140, 1966

34 Rodeck CH, Nicolaides KH, Warsof SL et al: The management of severe Rhesus isoimmunization by fetoscopic
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38 Grannum PA, Copel JA, Plaxe SC et al: In utero exchange transfusion by direct intravascular injection in severe
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