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 Department of Obstetrics and Gynecology, University Hospitals Leuven, Belgium. Department of Neonatology, University Hospitals Leuven, Belgium. 3 Department of Hematology, University Hospitals Leuven, Belgium and Blood transfusion center, Red Cross Flanders, Leuven, Belgium. 1 2
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 Intrauterine transfusion (IUT) was introduced in 1963 by Liley, who used an intraperitoneal approach (Liley, 1963). Almost 20 years later, the procedure was improved to a transfusion into the umbilical vein under constant ultrasonographic guidance (Berkowitz and Hobbins, 1981; Clewell et al., 1981). The intravascular approach compared to the intraperitoneal route turned out to be especially advantageous to the hydropic fetus because the absorption of red blood cells is less effective from a peritoneal cavity filled with ascites.
Indications for IUT are fetal anemia and thrombocytopenia, although the latter has become an increasingly rare indication since the introduction of immunoglobulins for fetal and neonatal alloimmune thrombocytopenia (Bussel et al., 1988; Van Den Akker et al., 2007). The majority of IUTs used to be performed for fetal anemia caused by Rhesus-D antibodies. Nowadays, despite a large decrease because of prophylactic administration of anti-D immune globulins in Rhesus negative patients, maternal red blood cell (RBC)alloimmunization remains an important cause of fetal anemia (Moise, 2008). However, indications
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have shifted to a diversity of other antibodies than those against the Rhesus-D antigen. Timely referral is now ensured since irregular antibodies are routinely checked for in maternal blood in the first trimester and repeated later in gestation for Rhesus negative mothers. This has led to a lower number of hydrops in fetuses requiring IUT. Risk factors for severe fetal anemia included: relevant obstetric history, presence of maternal red blood cell antibodies, ultrasound markers as cardio-, hepato- and splenomegaly and signs of hydrops and diminished fetal movements. Timing of transfusion used to require amniocentesis for determining delta OD450 indicating levels of bilirubin and thus hemolysis (Pasman et al., 2008). This has changed since the introduction of MCA PSV (middle cerebral artery peak systolic velocity) Doppler measurement to predict severe fetal anemia in 2000 (Mari et al., 2000). Because of the accuracy and non-invasiveness of MCA PSV measurement this new technique quickly became the standard (Oepkes et al., 2006). It can be used weekly or more frequently when required and is a reliable diagnostic tool between 16 and 36 weeks gestation in experienced hands. Furthermore, Doppler measurements can be used for timing of subsequent IUTs (Scheier et al., 2006) instead of planning the subsequent IUTs by a standard schedule. Therefore, although the technique of IUT has not significantly changed, the management of these pregnancies has evolved significantly in the last 14 years. Few studies have reported on the safety of IUT in large cohorts (Van Kamp et al., 2005; Somerset et al., 2006; Tiblad et al., 2011). We will report on the pregnancy and neonatal outcome of all IUTs performed from 2000 till 2014 for fetal alloimmune anemia in the University Hospital of Leuven and identify risk factors for adverse events. Materials and Methods Study subjects All reports of IUTs, performed between January 2000 and January 2014 were collected from the electronic prenatal (Astraia software gmbh Munich, Germany) and obstetrical (Java-KWS, UZ Leuven, Belgium) databases. To ensure full patient inclusion, a cross-check with the hospitals financial records regarding the billing of IUT procedures and with the distribution of blood products from the blood transfusion center was performed. Intrapartum and postpartum data of the children born in referring hospitals, were collected by contacting the referring obstetrician or neonatologist. Prenatal, peripartal and neonatal data were analyzed retrospectively. 130
pasman-.indd 130
In this study, only IUTs for RBC-alloimmuniza tion were included. Hydrops was defined as mild when there was a distinct rim of ascites, with or without pericardial effusion, and as severe when there was an abundant amount of fluid collection, usually ascites, with skin edema (Van Kamp et al., 2001). Prior to 2002, only amniocentesis was used to predict fetal anemia. From 2002 onwards, anemia was predicted by assessment of the MCA PSV, which was converted to multiple of the median (MoM) (Mari et al., 2000). An MCA PSV above 1.5 MoM was considered an indication for IUT. Sonographic features related to fetal hydrops were also indication for fetal blood sampling. A fetus with a hemoglobin value of at least two standard deviations (SD) below the mean for gestational age at fetal blood sampling was regarded as anemic (Nicolaides et al., 1988). Intrauterine transfusion technique During the study period, three operators performed the IUTs. Antenatal corticosteroids were given to women carrying fetuses with at least 26 weeks of gestation age before IUT to anticipate the need for an emergency cesarean section. For the same reason, IUT after 28 weeks of gestation were performed under combined spinal epidural analgesia (CSE). Fetal pain relief and immobilization was achieved by either intravenous or intramuscular injection of a curare derivative (pancuronium or cisatracurium) in combination with atropine and fentanyl. A 20 or 22G spinal needle was used for the IUT. The volume of packed cells to be given (V) was calculated using the formula (Moise et al., 1997): FPV (Ht target – Ht first sample) V = ----------------------------------------------------------------------- Ht donor blood With FPV (fetoplacental blood volume) = 1.046 + (0.14x ultrasound estimated fetal weight (g)) The target hematocrit (Ht) was usually 40%. The hematocrit of the fetal blood sample was assessed through a Sysmex pocH-100i (Sysmex NV Belgium). The donor blood was O Rhesus D-negative or compatible with the antibody of the mother. It was leucodepleted and obtained from CMV negative donors, collected within 72 hours before the procedure. The blood was concentrated to a hematocrit between 75 and 80% and underwent gamma irradiation less than six hours before administration.
Facts Views Vis Obgyn
30/06/15 10:34
IUT was performed into the umbilical vein either at the placental cord root, into its intrahepatic course or into a free loop of cord, by choice of the operator. After completion of the IUT, a second blood sample was taken to confirm adequate transfusion. In some cases blood was transfused into the peritoneal cavity as an addition to the IV transfusion. Usually, the aim was to diminish the direct burden on the cardiovascular system, or to prolong the period until the next procedure. Delivery was usually planned 2 weeks after the last IUT. Neonatal follow-up was collected until discharge from the hospital in good condition, including ambulant controls during the first 6 weeks of life. Mild procedure related adverse events were considered e.g. transient contractions requiring tocolysis and transient bleeding from the puncture site. Severe adverse events were defined as (1) rupture of membranes or preterm birth within seven days after transfusion, (2) intrauterine infection, (3) emergency cesarean section for fetal distress within 24 hours after procedure, (4) fetal death and (5) neonatal death (Van Kamp et al., 2005). Statistical analysis Data were stored and analyzed using an Excel database (Microsoft Corp) and analyzed by SPSS for Windows version 20.0.0. Univariate analysis was performed with procedure related adverse events as the independent factor and hydrops, severity of anemia, gestational age prior to 20 weeks or after 34 weeks and puncture technique as dependent factors. Continuous variables were analyzed using parametric independent samples t-test and categorical variables were analyzed using Chi-square test as appropriate. For the multivariate logistic regression analysis, only variables that were significant on univariate analysis were included in the model. A value of P
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 Department of Obstetrics and Gynecology, University Hospitals Leuven, Belgium. Department of Neonatology, University Hospitals Leuven, Belgium. 3 Department of Hematology, University Hospitals Leuven, Belgium and Blood transfusion center, Red Cross Flanders, Leuven, Belgium. 1 2
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 Intrauterine transfusion (IUT) was introduced in 1963 by Liley, who used an intraperitoneal approach (Liley, 1963). Almost 20 years later, the procedure was improved to a transfusion into the umbilical vein under constant ultrasonographic guidance (Berkowitz and Hobbins, 1981; Clewell et al., 1981). The intravascular approach compared to the intraperitoneal route turned out to be especially advantageous to the hydropic fetus because the absorption of red blood cells is less effective from a peritoneal cavity filled with ascites.
Indications for IUT are fetal anemia and thrombocytopenia, although the latter has become an increasingly rare indication since the introduction of immunoglobulins for fetal and neonatal alloimmune thrombocytopenia (Bussel et al., 1988; Van Den Akker et al., 2007). The majority of IUTs used to be performed for fetal anemia caused by Rhesus-D antibodies. Nowadays, despite a large decrease because of prophylactic administration of anti-D immune globulins in Rhesus negative patients, maternal red blood cell (RBC)alloimmunization remains an important cause of fetal anemia (Moise, 2008). However, indications
pasman-.indd 129
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have shifted to a diversity of other antibodies than those against the Rhesus-D antigen. Timely referral is now ensured since irregular antibodies are routinely checked for in maternal blood in the first trimester and repeated later in gestation for Rhesus negative mothers. This has led to a lower number of hydrops in fetuses requiring IUT. Risk factors for severe fetal anemia included: relevant obstetric history, presence of maternal red blood cell antibodies, ultrasound markers as cardio-, hepato- and splenomegaly and signs of hydrops and diminished fetal movements. Timing of transfusion used to require amniocentesis for determining delta OD450 indicating levels of bilirubin and thus hemolysis (Pasman et al., 2008). This has changed since the introduction of MCA PSV (middle cerebral artery peak systolic velocity) Doppler measurement to predict severe fetal anemia in 2000 (Mari et al., 2000). Because of the accuracy and non-invasiveness of MCA PSV measurement this new technique quickly became the standard (Oepkes et al., 2006). It can be used weekly or more frequently when required and is a reliable diagnostic tool between 16 and 36 weeks gestation in experienced hands. Furthermore, Doppler measurements can be used for timing of subsequent IUTs (Scheier et al., 2006) instead of planning the subsequent IUTs by a standard schedule. Therefore, although the technique of IUT has not significantly changed, the management of these pregnancies has evolved significantly in the last 14 years. Few studies have reported on the safety of IUT in large cohorts (Van Kamp et al., 2005; Somerset et al., 2006; Tiblad et al., 2011). We will report on the pregnancy and neonatal outcome of all IUTs performed from 2000 till 2014 for fetal alloimmune anemia in the University Hospital of Leuven and identify risk factors for adverse events. Materials and Methods Study subjects All reports of IUTs, performed between January 2000 and January 2014 were collected from the electronic prenatal (Astraia software gmbh Munich, Germany) and obstetrical (Java-KWS, UZ Leuven, Belgium) databases. To ensure full patient inclusion, a cross-check with the hospitals financial records regarding the billing of IUT procedures and with the distribution of blood products from the blood transfusion center was performed. Intrapartum and postpartum data of the children born in referring hospitals, were collected by contacting the referring obstetrician or neonatologist. Prenatal, peripartal and neonatal data were analyzed retrospectively. 130
pasman-.indd 130
In this study, only IUTs for RBC-alloimmuniza tion were included. Hydrops was defined as mild when there was a distinct rim of ascites, with or without pericardial effusion, and as severe when there was an abundant amount of fluid collection, usually ascites, with skin edema (Van Kamp et al., 2001). Prior to 2002, only amniocentesis was used to predict fetal anemia. From 2002 onwards, anemia was predicted by assessment of the MCA PSV, which was converted to multiple of the median (MoM) (Mari et al., 2000). An MCA PSV above 1.5 MoM was considered an indication for IUT. Sonographic features related to fetal hydrops were also indication for fetal blood sampling. A fetus with a hemoglobin value of at least two standard deviations (SD) below the mean for gestational age at fetal blood sampling was regarded as anemic (Nicolaides et al., 1988). Intrauterine transfusion technique During the study period, three operators performed the IUTs. Antenatal corticosteroids were given to women carrying fetuses with at least 26 weeks of gestation age before IUT to anticipate the need for an emergency cesarean section. For the same reason, IUT after 28 weeks of gestation were performed under combined spinal epidural analgesia (CSE). Fetal pain relief and immobilization was achieved by either intravenous or intramuscular injection of a curare derivative (pancuronium or cisatracurium) in combination with atropine and fentanyl. A 20 or 22G spinal needle was used for the IUT. The volume of packed cells to be given (V) was calculated using the formula (Moise et al., 1997): FPV (Ht target – Ht first sample) V = ----------------------------------------------------------------------- Ht donor blood With FPV (fetoplacental blood volume) = 1.046 + (0.14x ultrasound estimated fetal weight (g)) The target hematocrit (Ht) was usually 40%. The hematocrit of the fetal blood sample was assessed through a Sysmex pocH-100i (Sysmex NV Belgium). The donor blood was O Rhesus D-negative or compatible with the antibody of the mother. It was leucodepleted and obtained from CMV negative donors, collected within 72 hours before the procedure. The blood was concentrated to a hematocrit between 75 and 80% and underwent gamma irradiation less than six hours before administration.
Facts Views Vis Obgyn
30/06/15 10:34
IUT was performed into the umbilical vein either at the placental cord root, into its intrahepatic course or into a free loop of cord, by choice of the operator. After completion of the IUT, a second blood sample was taken to confirm adequate transfusion. In some cases blood was transfused into the peritoneal cavity as an addition to the IV transfusion. Usually, the aim was to diminish the direct burden on the cardiovascular system, or to prolong the period until the next procedure. Delivery was usually planned 2 weeks after the last IUT. Neonatal follow-up was collected until discharge from the hospital in good condition, including ambulant controls during the first 6 weeks of life. Mild procedure related adverse events were considered e.g. transient contractions requiring tocolysis and transient bleeding from the puncture site. Severe adverse events were defined as (1) rupture of membranes or preterm birth within seven days after transfusion, (2) intrauterine infection, (3) emergency cesarean section for fetal distress within 24 hours after procedure, (4) fetal death and (5) neonatal death (Van Kamp et al., 2005). Statistical analysis Data were stored and analyzed using an Excel database (Microsoft Corp) and analyzed by SPSS for Windows version 20.0.0. Univariate analysis was performed with procedure related adverse events as the independent factor and hydrops, severity of anemia, gestational age prior to 20 weeks or after 34 weeks and puncture technique as dependent factors. Continuous variables were analyzed using parametric independent samples t-test and categorical variables were analyzed using Chi-square test as appropriate. For the multivariate logistic regression analysis, only variables that were significant on univariate analysis were included in the model. A value of P
