FACTS VIEWS VIS OBGYN, 2015, 7 (2): 129-136 Original paper Intrauterine transfusion for fetal anemia due to red blood cell alloimmunization: 14 years experience in Leuven S.A. PasMAN1, L. ClaES1, L. LEWI1, D. VAN SCHOUBROECK1, A. DEBEER2, M. EMONds3, E. GEUTEN1, L. DE CATTE1, R. DEVLIEGER1 1Department of Obstetrics and Gynecology, University Hospitals Leuven, Belgium. 2Department of Neonatology, University Hospitals Leuven, Belgium. 3Department of Hematology, University Hospitals Leuven, Belgium and Blood transfusion center, Red Cross Flanders, Leuven, Belgium. Correspondence at: Prof. Dr. R. Devlieger, Fetal Medicine Unit, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. E-mail: [email protected] Abstract Objective: The purpose of this study is to report on the pregnancy and neonatal outcome of intrauterine transfusion (IUT) for red blood cell (RBC-)alloimmunization. Material and Methods: Retrospective cohort study of all IUT for RBC-alloimmunization in the University Hospital of Leuven, between January 2000 and January 2014. The influence of hydrops, gestational age and technique of transfusion on procedure related adverse events were examined. Results: 135 IUTs were performed in 56 fetuses. In none of the cases fetal or neonatal death occurred. Mild adverse events were noted in 10% of IUTs, whereas severe adverse events occurred in 1.5%. Hydrops and transfusion in a free loop were associated with an increased risk of adverse events whereas gestational age (GA) at transfusion after 34 weeks was not. Median GA at birth was 35.6 weeks and 9% was born before 34 weeks. Besides phototherapy 65.4% required additional neonatal treatment for alloimmune anemia. Non-hematologic complications occurred in 23.6% and were mainly related to preterm birth. Conclusion: In experienced hands, IUT for RBC-alloimmunization is a safe procedure in this era. Patients should be referred to specialist centers prior to the development of hydrops. IUT in a free loop of cord and unnecessary preterm birth are best avoided. Key words: Intrauterine blood transfusion, fetal therapy, perinatal survival, procedure related complications, fetal anemia, red blood cell alloimmunization. Introduction Indications for IUT are fetal anemia and thrombocytopenia, although the latter has become Intrauterine transfusion (IUT) was introduced in an increasingly rare indication since the introduction 1963 by Liley, who used an intraperitoneal approach of immunoglobulins for fetal and neonatal (Liley, 1963). Almost 20 years later, the procedure alloimmune thrombocytopenia (Bussel et al., 1988; was improved to a transfusion into the umbilical Van Den Akker et al., 2007). The majority of IUTs vein under constant ultrasonographic guidance used to be performed for fetal anemia caused by (Berkowitz and Hobbins, 1981; Clewell et al., Rhesus-D antibodies. Nowadays, despite a large 1981). The intravascular approach compared to the decrease because of prophylactic administration of intraperitoneal route turned out to be especially anti-D immune globulins in Rhesus negative advantageous to the hydropic fetus because the patients, maternal red blood cell (RBC)- absorption of red blood cells is less effective from a alloimmunization remains an important cause of peritoneal cavity filled with ascites. fetal anemia (Moise, 2008). However, indications 129 pasman-.indd 129 30/06/15 10:34 have shifted to a diversity of other antibodies than In this study, only IUTs for RBC-alloimmuniza- those against the Rhesus-D antigen. Timely referral tion were included. Hydrops was defined as mild is now ensured since irregular antibodies are when there was a distinct rim of ascites, with or routinely checked for in maternal blood in the first without pericardial effusion, and as severe when trimester and repeated later in gestation for Rhesus there was an abundant amount of fluid collection, negative mothers. This has led to a lower number of usually ascites, with skin edema (Van Kamp et al., hydrops in fetuses requiring IUT. 2001). Prior to 2002, only amniocentesis was used Risk factors for severe fetal anemia included: to predict fetal anemia. From 2002 onwards, anemia relevant obstetric history, presence of maternal red was predicted by assessment of the MCA PSV, blood cell antibodies, ultrasound markers as cardio-, which was converted to multiple of the median hepato- and splenomegaly and signs of hydrops and (MoM) (Mari et al., 2000). An MCA PSV above 1.5 diminished fetal movements. Timing of transfusion MoM was considered an indication for IUT. used to require amniocentesis for determining delta Sonographic features related to fetal hydrops were OD450 indicating levels of bilirubin and thus also indication for fetal blood sampling. A fetus hemolysis (Pasman et al., 2008). This has changed with a hemoglobin value of at least two standard since the introduction of MCA PSV (middle cerebral deviations (SD) below the mean for gestational age artery peak systolic velocity) Doppler measurement at fetal blood sampling was regarded as anemic to predict severe fetal anemia in 2000 (Mari et al., (Nicolaides et al., 1988). 2000). Because of the accuracy and non-invasiveness of MCA PSV measurement this new technique Intrauterine transfusion technique quickly became the standard (Oepkes et al., 2006). It can be used weekly or more frequently when During the study period, three operators performed required and is a reliable diagnostic tool between 16 the IUTs. Antenatal corticosteroids were given to and 36 weeks gestation in experienced hands. women carrying fetuses with at least 26 weeks of Furthermore, Doppler measurements can be used gestation age before IUT to anticipate the need for for timing of subsequent IUTs (Scheier et al., 2006) an emergency cesarean section. For the same reason, instead of planning the subsequent IUTs by a IUT after 28 weeks of gestation were performed standard schedule. Therefore, although the under combined spinal epidural analgesia (CSE). technique of IUT has not significantly changed, the Fetal pain relief and immobilization was achieved management of these pregnancies has evolved by either intravenous or intramuscular injection of a significantly in the last 14 years. curare derivative (pancuronium or cisatracurium) in Few studies have reported on the safety of IUT in combination with atropine and fentanyl. A 20 or large cohorts (Van Kamp et al., 2005; Somerset et 22G spinal needle was used for the IUT. The volume al., 2006; Tiblad et al., 2011). We will report on the of packed cells to be given (V) was calculated using pregnancy and neonatal outcome of all IUTs the formula (Moise et al., 1997): performed from 2000 till 2014 for fetal alloimmune anemia in the University Hospital of Leuven and FPV (Ht target – Ht first sample) identify risk factors for adverse events. V = ------------------------------------------------------------------------ Ht donor blood Materials and Methods With Study subjects FPV (fetoplacental blood volume) = 1.046 + (0.14x All reports of IUTs, performed between January ultrasound estimated fetal weight (g)) 2000 and January 2014 were collected from the electronic prenatal (Astraia software gmbh Munich, The target hematocrit (Ht) was usually 40%. The Germany) and obstetrical (Java-KWS, UZ Leuven, hematocrit of the fetal blood sample was assessed Belgium) databases. To ensure full patient inclusion, through a Sysmex pocH-100i (Sysmex NV a cross-check with the hospitals financial records Belgium). The donor blood was O Rhesus regarding the billing of IUT procedures and with the D-negative or compatible with the antibody of the distribution of blood products from the blood mother. It was leucodepleted and obtained from transfusion center was performed. Intrapartum and CMV negative donors, collected within 72 hours postpartum data of the children born in referring before the procedure. The blood was concentrated hospitals, were collected by contacting the referring to a hematocrit between 75 and 80% and underwent obstetrician or neonatologist. Prenatal, peripartal gamma irradiation less than six hours before and neonatal data were analyzed retrospectively. administration. 130 FACTS VIEWS VIS OBGYN pasman-.indd 130 30/06/15 10:34 IUT was performed into the umbilical vein either in Table I. The contribution of Rhesus-D at the placental cord root, into its intrahepatic course alloimmunization did not change over time. or into a free loop of cord, by choice of the operator. Hematological values before and after IUT are After completion of the IUT, a second blood sample shown in Table II. The hemoglobin level before was taken to confirm adequate transfusion. In some IUT was found to be between –1.1 and –10.8 SD cases blood was transfused into the peritoneal cavity below the normal mean (Nicolaides et al., 1988). as an addition to the IV transfusion. Usually, the The hemoglobin level was within 2 SD (non anemic) aim was to diminish the direct burden on the in four of 127 procedures, which were all first cardiovascular system, or to prolong the period until transfusions between 29 and 33 weeks. In 5.4%, the the next procedure. Delivery was usually planned 2 achieved Ht was below 35%, mostly because of weeks after the last IUT. Neonatal follow-up was concern for cardiovascular decompensation. In collected until discharge from the hospital in good 6.9% the achieved Ht was above 45%. condition, including ambulant controls during the There were 48 (86%) nonhydropic, five (9%) first 6 weeks of life. mildly hydropic and three (5%) severely