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European Journal of Obstetrics & Gynecology and Reproductive Biology 201 (2016) 8588

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European Journal of Obstetrics & Gynecology and


Reproductive Biology
journal homepage: www.elsevier.com/locate/ejogrb

In utero treatment of severe fetal anemia resulting from fetomaternal


red blood cell incompatibility: a comparison of simple transfusion
and exchange transfusion
Lucie Guilbaud a,*, Charles Garabedian b, Anne Cortey a, Thameur Rakza b,
Bruno Carbonne a,c, Veronique Houfin-Debarge b,d
a
Unite dobstetrique et unite clinique du Centre National de Reference en Hemobiologie Perinatale (CNRHP), Pole Perinatalite Hopital Trousseau, Paris, France
b
Clinique dobstetrique, Pole Femme-Mere-Nouveau-ne, CHRU Lille, France
c
Universite Pierre et Marie Curie, Paris 6, France
d
Universite Lille Nord, France

A R T I C L E I N F O A B S T R A C T

Article history: Objective: To compare in utero exchange transfusions (IUET) and in utero simple transfusions (IUST) for
Received 29 October 2015 the treatment of fetal anemia resulting from red blood cell fetomaternal incompatibility.
Received in revised form 13 February 2016 Study design: Retrospective comparative study from January 2006 through December 2011. The two
Accepted 24 March 2016
techniques were compared for effectiveness, complications, and neonatal outcomes.
Results: 36 patients had 87 IUETs and 85 patients 241 IUSTs. Gestational age at the rst transfusion was
Keywords: similar in both groups (IUET: 27  3.8 weeks; IUST: 27  4.7 weeks; NS) as was the initial fetal hemoglobin
Red-blood cell alloimmunization
level (IUET: 6.4  2.8 g/dL; IUST: 6.0  2.5 g/dL; NS). No signicant differences were noted for postprocedure
Fetomaternal red blood cell incompatibility
Fetal anemia
complications or efcacy. The daily drop in hemoglobin level was similar in both groups (IUET: 0.41  0.23 g/dL/
Intrauterine transfusion day; IUST: 0.44  0.17 g/dL/day; NS) as were the time intervals between two procedures. Gestational age at birth
Intrauterine exchange transfusion was earlier in the IUET group (34.4  1.3 weeks vs 35.5  1.8 weeks; p < 0.001), but the postnatal transfusions or
Rhesus hemolytic disease exchange transfusions rates and the duration of intensive phototherapy did not differ. No signicant differences
were noted for the overall survival rates (IUET: 100%; IUST: 96.4%; p > 0.99).
Conclusion: IUET does not appear to provide any benets compared with IUST, neither to be associated
with a higher complication rate. The choice of the technique depends on availability of packed blood cells
with high hematocrit (7080%).
2016 Elsevier Ireland Ltd. All rights reserved.

Introduction transfusion (IUET). The theoretical advantages of IUET over IUST


are thought to be, on one hand, avoiding hypervolemia associated
Maternal alloimmunization against fetal red cell antigens is the with large transfused volumes in cases of severe anemia, and on
most frequent cause of fetal anemia, mainly due to anti-D (RH1) the other hand, the possibility to remove incompatible fetal red
antibodies [1,2]. The development of prenatal transfusion has blood cells and antibodies to improve the efcacy of transfusion by
substantially improved the management of this disease and thus limiting ongoing hemolysis. On the basis of these pathophysiologic
the prognosis of these children. The management of fetal anemia hypotheses, Jacquetin et al. [7] and Grannum et al. [8] developed
includes intraperitoneal fetal transfusion, intravascular fetal the technique of IUET. However, the red-blood cell exchanges
transfusion, and early delivery when moderate prematurity is at required for IUET are supposed to make the transfusion procedure
less risk of impact on childs adaptation [36]. longer and therefore possibly more risky.
The procedure of fetal transfusion can be a simple transfusion To date, no study has compared IUST and IUET. Our objective
(IUST) or, as similar to postnatal treatment, in utero exchange was therefore to assess and compare the effectiveness and
complications associated with these two techniques.

* Corresponding author at: Unite dObstetrique & Unite clinique du Centre


Materials and methods
National de reference en Hemobiologie, Perinatale, Pole Perinatalite, Hopital
Armand Trousseau, 26, avenue du Dr Arnold Netter, 75012 Paris, France.
Tel.: +33 01 44 73 53 42. This retrospective study analyzed a continuous series of all pa-
E-mail address: lucie.guilbaud@gmail.com (L. Guilbaud). tients managed for severe fetomaternal red blood cell incompatibility

http://dx.doi.org/10.1016/j.ejogrb.2016.03.037
0301-2115/ 2016 Elsevier Ireland Ltd. All rights reserved.
86 L. Guilbaud et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 201 (2016) 8588

in two reference maternity hospitals: Jeanne de Flandre Hospital suggested moderate to severe anemia (22/36 patients: 61%) [13]. In
(Lille, France) and Armand Trousseau Hospital (Paris, France). It Paris (IUST group), IUST were performed up to 35 weeks and
included all fetuses that underwent at least one IUET or IUST for fetal antenatal corticosteroid therapy was administered up to 37 weeks
anemia resulting from red-blood cell alloimmunization from January in case of planned cesarean before labor. No delayed cord clamping
2006 through December 2011. IUETs were all performed in the Lille was applied in this center. In both centers, the decision for the time
center and IUSTs were all performed in the Paris center. This study of delivery was discussed in multidisciplinary perinatology
was approved by the French Ethics Committee for Research in meetings after the last transfusion was done and according to
Obstetrics and Gynecology (CEROG 2012-02-04). MCA PSV measurement and estimated hemoglobin level.
For each pregnancy, we collected the obstetric history, the All neonates of the two groups were examined by a pediatrician
womans characteristics, and the specicity of alloimmunization. at birth and received early intensive phototherapy during at least
For each IUET/IUST, we noted gestational age at the transfusion, 72 h. Bilirubin levels were monitored every 12 h from the birth to
technical conditions, volume of transfused blood, incidents occur- at least three days of life. In the IUET group, criteria for postnatal
ring during the procedure (fetal bradycardia, fetal or maternal exchange-transfusion (ET) were bilirubin level at birth above
hemorrhage), and subsequent complications (emergency cesarean, 59.5 mmol/L or bilirubin levels above threshold despite photo-
premature rupture of membranes dened as a rupture before 37 therapy [14]. In the IUST group, criteria for ET were matching the
weeks of gestation, threatened preterm delivery, or in utero death). American Academy of Pediatrics guidelines, except at birth
Then, we assessed prenatal and postnatal effectiveness criteria. (bilirubinemia above 150 mmol/L or bilirubin levels increased
We compared the daily hemoglobin decrease between two above 10 mmol/L/h despite phototherapy) [15]. In both groups,
procedures, the number of procedures per patient, and the interval top-up transfusions were performed at birth in case of hemoglobin
between them. For each newborn, we recorded gestational age, level under 8.5 g/dL or under 11 g/dL with clinical signs of anemia.
weight and hemoglobin at birth, the need for transfer to intensive No recombinant erythropoietin was used in both centers.
care, and the need for intensive phototherapy, postnatal transfu-
sion or exchange transfusion during the two rst weeks of life. The Statistics
survival rate was calculated according to the number of children
alive at discharge from neonatology unit. Infants were categorized into two groups: the IUET group,
The protocols for treatment, monitoring, and follow-up were composed of the fetuses managed in Lille, treated by in utero
similar in both centers [9]. After identication of the responsible exchange transfusions, and the IUST group, of the fetuses managed
antibody, the level of immunization was assessed and its evolution in Paris, by direct in utero transfusion.
followed by quantication of antibody. Weekly Doppler assess- The qualitative variables were expressed as frequencies and
ment of middle cerebral artery peak systolic velocity (MCA PSV) percentages, and the quantitative variables as means and standard
was performed when quantication of antibodies indicated a risk deviations. The groups were compared with the Chi-square test or
of fetal anemia (RH1 dosage >1 mg/mL, KEL1 titer >1/32). Fishers exact test, as appropriate, for the qualitative indicators,
Indication of IUET/IUST was determined when MCA PSV increased and Students t test, for the quantitative variables. A p-value less
above 1.501.55 MoM, suggesting fetal anemia, which was than 0.05 was considered signicant. Data were analyzed with SAS
conrmed by fetal blood sampling at the beginning of transfusion software (SAS Institute Inc., Cary, NC, 25513).
procedure. The transfusion techniques used for IUET/IUST were
identical to those previously described [4,10,11]. They were
performed in an operating room with at least two obstetricians Results
and one pediatrician. In both techniques, a 20-ga needle was
inserted in the umbilical vein, proximal to the placento-umbilical The 36 patients in the IUET group underwent 87 procedures,
junction, under ultrasound guidance. The severity of anemia was and the 85 patients in the IUST group, 241. Table 1 summarizes the
assessed using a point-of-care hemoglobin measurement (Hemo- womens characteristics. The groups did not differ signicantly for
cue1 in Paris and Stat Prole1 pHOx1 in Lille). A short-acting age, parity, specicity of alloimmunization, or severity of fetal
paralytic agent was injected intra-venously in order to limit anemia. All specicities of fetomaternal red blood cell incompati-
complications related to fetal movements. In case of IUET, an initial bility were represented and a majority of RH1 antibodies (IUET:
volume based on fetal weight and gestational age was transfused 80.5%, IUST: 70.6%) and KEL1 antibodies (IUET: 16.6%, IUST: 22.3%)
before starting exchange and blood component statuses were were recorded.
evaluated during IUET. In case of IUST, the target hemoglobin level
was dened using the curves of Forestier [12], and successive
transfusions (35 mL) were performed until this level was reached. Table 1
Patient characteristics.
Packed red blood cells (PRBC) used were of group O, fresh,
leukocyte depleted, irradiated and a pre-transfusion compatibili- IUET IUST p
zation with the maternal blood was always obtained. The IUET n = 36 n = 85
center used PRBC stored in SAG Manitol with hematocrit certied Number of procedures 87 241
equal or greater than 50%, and the IUST center used reduced Age 32.4  6.1 31.9  4.4 0.61
volume PRBC (hematocrit of 70 to 80%). Ultrasound monitoring of Parity 3.2  1.8 3.2  1.3 0.92
Antibodies
the fetus was performed continuously throughout the procedure, RH1 29 (80.5%) 60 (70.6%) 0.43
and fetal heart rate monitoring was performed before and after the KEL1 6 (16.6%) 19 (22.3%) 0.62
procedure when gestational age was 26 weeks or more. In the two Othera 1 (2.9%) 6 (7.1%) 0.11
centers, decision to repeat transfusions was based on anticipated Antenataly referred women 24 (64%) 57 (67%) 0.90
GA at rst transfusion 27  3.8 weeks 27  4.7 weeks 0.95
hemoglobin drop associated with MCA PSV measurement.
Initial Hb (g/dL) 6.4  2.8 6.0  2.5 0.49
The peripatum management was slightly different in the two Initial PSV-MCA (MoM) 1.86  0.28 1.88  0.29 0.96
centers. In Lille (IUET group), IUET were performed up to 34 weeks; Fetal hydrops 3 (8.3%) 7 (8.2%) 0.87
and birth was scheduled according to the ultrasound data after GA: gestational age; Hb: hemoglobin; PSV MCA: peak systolic velocity of the middle
prenatal corticosteroid therapy. In 2009, this hospital also began cerebral artery.
delayed cord clamping at birth for infants whose ultrasound data a
RH3, RH4, MNS1, JRA.
L. Guilbaud et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 201 (2016) 8588 87

Table 2 weeks (1.0 week) in the IUET group and 32.1 weeks (2.0 weeks) in
Volume of transfused blood according to the gestational age at the transfusion
the IUST group (p < 0.001). The time between the last procedure and
procedure.
birth was similar in both groups (IUET: 23.2  9.3 days; IUST: 21.3
Gestational IUET transfused IUST transfused days  9.7; p = 0.27). Gestational age at birth was higher in the IUST
age (weeks) blood volume blood volume (mL)
than the IUET group (35.5  1.8 vs 34.4  1.3 weeks; p < 0.001).
exsanguined blood Mean [minmax]
volume (mL) n = 85
At birth, the mean hemoglobin level was higher in the IUET than
Mean [minmax] in the IUST group (13.3  3.5 g/dL vs 11.1  2.5 g/dL; p < 0.001). On
n = 36 the other hand, there was no difference between the two groups in
<24 24.0 [1076] 23.0 [535] the need for either an exchange or top-up transfusion and duration of
2428 21.9 [079] 46.4 [20100] intensive phototherapy in the rst two weeks of life.
2832 27.0 [0130] 77.0 [25140] No statistical difference was found between the two groups with
>32 72.0 [7164] 123.0 [35220]
regard to survival rate. Two women in the IUST group had a
termination of pregnancy (TOP). The rst case concerned RH1 red
The volumes of PRBC transfused in simple transfusion and blood cell incompatibility, diagnosed at 25 weeks with fetal hydrops
exchange transfusion according to the gestational age at the and PSV-MCA greater than 2.5 MoM. The initial fetal hemoglobin
transfusion procedure are reported in Table 2. Given the small size concentration at the transfusion was 2.3 g/dL. The ultrasound
of each gestational age categories, no statistical calculation was follow-up showed ventricular cerebral dilatation that worsened
performed to compare transfused volume. progressively with signs of cerebral atrophy. The second case
A comparison of the complications associated with these involved anti-KEL1 alloimmunization, with initial hemoglobin at
procedures was performed between the two groups. Bradycardia 1.3 g/dL at the rst transfusion at 21 weeks (delayed referral). At 24
occurred during 1.1% of the IUETs and 0.8% of the IUSTs (p > 0.99). weeks, both the fetal ultrasound and a fetal cerebral MRI evidenced
One case of fetomaternal hemorrhage was reported in the both left hemisphere cerebellar porencephaly [17]. There was one case of
groups (p > 0.99) [16]. One emergency cesarean was performed in neonatal death described previously in the IUST group, and no one in
the IUET group at 31 weeks and 4 days; the child was healthy. In the IUET group. Finally, the survival rate in the IUET group was 100%
the IUST group, three emergency cesareans followed transfusions. (36/36), and 96.4% (82/85), in the IUST group (p > 0.99).
Two of these cesareans were performed because of abnormal fetal
heart rate during the procedure, respectively at 28 weeks and Comments
6 days and 32 weeks and 6 days, with favorable neonatal evolution
despite prematurity. The third cesarean occurred at 32 weeks and 4 Our study is the rst to compare IUST and IUET and demonstrates
days, during a second transfusion procedure, in a rhesus disease no difference in the rate of complications per procedure, number of
referred belatedly at 31 weeks with fetal hydrops and an procedures per patient, need for neonatal treatment of anemia and
hemoglobin level at 4.7 g/dL at rst IUST. After the second IUDT, survival rate between the two procedures.
abnormal fetal heart rate led to an emergency cesarean. The This study illustrates that severe fetomaternal red blood cell
newborn had signs of disseminated intravascular coagulation and incompatibility due to RH1 antibodies still exits in spite of the
died 24 h after birth in multiple organ failure. The placental alloimmunization prevention during pregnancy. Otherwise, it
examination after cesarean showed an umbilical vein thrombosis. reminds us that KEL1 antibodies may be responsible for severe
The postprocedure complications statement did not reveal any fetal anemia requiring antenatal red blood cell transfusion.
preterm labor, chorioamnionitis or fetal death. In the IUST group, The rate of complications associated with these types of
there was one case of premature rupture of the membranes transfusions was relatively low and similar to the literature [18]. In
(PROM) at 31 weeks and 4 days, 4 days after the third and last the largest series (n = 740 IUST), Van Kamp et al. [4] found a
transfusion procedure. No case of PROM was reported in the IUET complication rate of 3.1% associated with the IUST procedure,
group (p > 0.99). No difference was found between the two groups including two women with chorioamnionitis, one with PROM, and
with regard to post procedure complications. 15 emergency cesareans. The complications associated with fetal
In terms of prenatal effectiveness (Table 3), the daily exchange-transfusions are less known. In a previous study of 225
hemoglobin decrease was similar regardless of the transfusion IUET, a complication rate of 7.5% per procedure was noted [11].
technique used, and decreased more slowly as the procedures were Our results about survival in fetuses receiving IUST or IUET are
repeated. The mean gestational age at the last transfusion was 31.1 also similar to the results of other groups: among the 451 fetuses

Table 3
Comparison of the groups for effectiveness.

IUET IUST p
n = 36 n = 85

Prenatal criteria Hb decrease per day between two procedures (g/dL/day)


Between procedures 1 and 2 0.41  0.23 (n = 24) 0.44  0.17 (n = 66) 0.50
Between procedures 2 and 3 0.34  0.16 (n = 15) 0.34  0.09 (n = 49) >0.99
Between procedures 3 and 4 0.30  0.08 (n = 8) 0.31  0.06 (n = 27) 0.70
Number of procedures per patient (median [minmax]) 2 [16] 3 [17] 0.12
Time between 2 procedures (days) 19.7  8.3 19.8  7.2 0.96
GA at last procedure (weeks) 31.1  1.0 32.1  2.0 <0.001
Time between the last procedure and birth (days) 23.2  9.3 21.3  9.7 0.27

Neonatal criteria GA at birth (weeks) 34.4  1.3 35.5  1.8 <0.001


Hb at birth (g/dL) 13.3  3.5 11.1  2.5 <0.001
Number of postnatal transfusions 16 (44.4%) 31 (36.5%) 0.54
Number of postnatal exchange transfusions 11 (33.0%) 12 (14.2%) 0.06
Duration of intensive phototherapy (days) 3.5  2.4 3.7  2.6 0.70

GA: gestational age; Hb: hemoglobin; weeks: weeks of gestation.


Signicance of italic values: p < 0.05.
88 L. Guilbaud et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 201 (2016) 8588

treated by IUST in the LOTUS study, the survival rate was 91% [19], and the comparison of two different procedures performed in two
and in the IUET study by Poissonnier et al. [10], the survival rate different centers implies to analyze the results with caution and a
was 78.5%. In our series of 328 transfusion procedures in 121 randomization controlled trial would be the ideal method to
fetuses, we observed a survival rate of 96.5% in the IUST group and propose rm conclusions.
100% in the IUET group. These good results are probably related to Despite these limitations, this study was performed in two
the early and regular monitoring of the patients but should be centers with the same protocols for treatment and the same
interpreted in light of the slightly smaller size of our series. Even if population characteristics. IUET does not appear to provide any
we represent two of the largest reference centers in fetal anemia perinatal benets but it is not associated with a higher complica-
treatment in France, it was not possible to enrolled the thousand tion rate. Accordingly, we support that the choice between IUET
transfusions needed to get a statistical power of 90%. and IUST should be based on the availability of reduced volume
These results show no excess of complications or mortality packed red blood cell with hematocrit level above 70% and on the
associated with the IUET procedure although it is theoretically a teams experience.
longer procedure than IUST. Unfortunately, in this retrospective
study, we could not compare the mean duration of the procedures
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