Predicting Intrauterine Transfusion Interval and Perinatal Outcomes in Alloimmunized Pregnancies: Time-to-Event Survival Analysis.

BACKGROUND: The risk factors determining the frequency of intrauterine transfusions (IUTs) for severely affected red blood cell alloimmunized singleton pregnancies are not well known. OBJECTIVE: To assess factors associated with IUT frequency and adverse pregnancy outcomes in transfused pregnancies. METHODS: Retrospective cohort analysis of 246 consecutive cases between 1991 and 2014. Time-to-event survival analysis for repeated events was used to evaluate risk of subsequent IUT. Multivariable logistic regression assessed odds of a composite adverse pregnancy outcome (intrauterine fetal death, termination of pregnancy, neonatal death, preterm birth <34 weeks' gestation). RESULTS: Full information was available on232 cases (94.3%) and 716 IUTs. Fetal hydrops was associated with increased frequency (hazard ratio [HR] 1.29 [95% CIs 1.15-1.47, p < 0.001]) while higher fetal hemoglobin (Hb) pre-IUT (HR) 0.99 (95% CI 0.99-1.00, p = 0.021) and post-IUT (HR 0.99 [95% CI 0.99-1.00] p = 0.042), and higher transfused blood volume (HR 0.98 [95% CI 0.97-0.99] p < 0.001) were associated with reduced IUT frequency. Adverse pregnancy outcomes were more likely with lower gestational age (GA) at initial IUT. Antibody type was not associated with IUT frequency or adverse pregnancy outcomes. CONCLUSIONS: Hydrops is associated with increased IUT frequency while lower GA at initial IUT is associated with higher adverse pregnancy outcomes in alloimmunized pregnancies.Higher transfused blood volumes, pre- and post-IUT Hb are associated with lower IUT frequency.

A descriptive single-centre experience of the management and outcome of maternal alloantibodies in pregnancy.

BACKGROUND: Haemolytic disease of the fetus and newborn (HDFN) occurs when maternal IgG alloantibodies to fetal red blood cell antigens cross the placenta, causing haemolysis in the fetus and/or neonate. After delivery, the main concern is hyperbilirubinaemia, which can cause neurological damage. OBJECTIVES: To summarise our current management and outcome data to inform health-care professionals counselling women whose pregnancies are at risk of HDFN and to compare these data with relevant studies. METHODS: This is a retrospective descriptive study of all high-risk pregnancies at risk of HDFN at Guy's and St. Thomas' NHS Foundation Trust (GSTFT) Maternity Unit over a 7-year period. We defined high-risk pregnancies as those in whom anti-D, anti-c, anti-K or high (>32 or doubling strength) titres of all other antibodies were identified. RESULTS: A total of 130 pregnancies in 112 women were followed up. A single alloantibody was found in 93 pregnancies (71.5%) and multiple alloantibodies in 37 pregnancies (28.5%). Anti-D was most commonly encountered (n = 48, 36.9%), followed by anti-c (n = 31, 23.8%) and anti-E (n = 15, 11.5%). In 65 of 130 pregnancies (50%), antibody concentrations triggered scans to screen for fetal anaemia. Of 130 pregnancies, 6 (4.6%) required intrauterine transfusions, and 31 of 130 (26%) neonates required post-natal intervention. Overall, morbidity was 0.1% and mortality 0.002%. CONCLUSIONS: This study demonstrates that morbidity and mortality caused by HDFN is minimal. These results are reassuring for women at risk of HDFN as even severely affected cases are successfully managed in most instances. Further studies are needed to identify predictors of disease severity.

Complications of intrauterine intravascular blood transfusion: lessons learned after 1678 procedures.

OBJECTIVE: Maternal alloimmunization to fetal red-blood-cell antigens is a major cause of fetal anemia, which can lead to hydrops and perinatal death if untreated. The cornerstone of management during pregnancy is intrauterine intravascular blood transfusion (IUT). Although this procedure is considered relatively safe, complications continue to occur. The aim of this study was to evaluate rates of procedure-related complications and perinatal loss following IUT, and their change over time, in order to identify factors leading to improved outcome. METHODS: This was a retrospective analysis of all IUTs for red-cell alloimmunization performed at the national referral center for fetal therapy in The Netherlands, from 1988 to 2015. Differences in complication rates and their associations with alterations in transfusion technique after 2001 were assessed. RESULTS: Between 1988 and 2015, 1678 IUTs were performed in 589 fetuses. For IUTs performed in 2001 and onwards, there was significant improvement in survival (88.6% vs 97.0%, P < 0.001) and a decline in procedure-related complications per fetus (9.8% vs 3.3%, P = 0.001) and per procedure (3.4% vs 1.2%, P = 0.003) compared with those performed before 2001. Procedure-related perinatal loss declined from 4.7% to 1.8% per fetus (P = 0.053). Beneficial changes in transfusion technique were routine use of fetal paralysis, increased use of intrahepatic transfusion and avoidance of arterial puncture. CONCLUSIONS: IUT has become an increasingly safe procedure in recent years when performed by experienced hands. The chosen technique should be fine-tuned according to the patient's individual situation. The declining complication rates are most likely related to center volume: this rare procedure is best performed in experienced fetal therapy centers. © 2016 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Perinatal survival and procedure-related complications after intrauterine transfusion for red cell alloimmunization.

OBJECTIVES: To study the perinatal survival and procedure-related (PR)complications after intrauterine transfusions in red cell alloimmunization. METHODS: Prospective data of 102 women with Rh-alloimmunized pregnancy undergoing intrauterine intravascular transfusion for fetal anemia, from January 2011 to October 2014 were analyzed. Main outcome measures were perinatal survival and procedure-related (PR) complications. RESULTS: A total of 303 intrauterine transfusions were performed in 102 women. Of 102 fetuses, 22 were hydropic at first transfusion. The mean period of gestation and hematocrit at first transfusion was 26.9 ± 3.3 weeks (range 19.7-33.8 weeks) and 17 ± 7.82 % (range 5.7-30 %), respectively. Average number of transfusions was 2.97 (range 1-7) per patient. Overall survival was 93 % and mean period of gestation at delivery was 34.5 ± 1.94 (range 28.3-37.4) weeks. Mean hematocrit at delivery was 36.9 ± 8.77 % (range 10-66 %). Fetal death occurred in four cases (3PR), neonatal death occurred in three cases (2PR). Emergency cesarean delivery after transfusion was performed in four pregnancies. The total PR complication rate was 2.97 %, resulting in overall PR loss in 1.65 % per procedure. CONCLUSION: Our results compare favorably with other studies published in the literature. Intravascular transfusion is a safe procedure improving perinatal survival in fetuses with anemia due to Rh-alloimmunization.

Diagnosis and treatment of severe hemolytic disease of the fetus and newborn: a 10-year nationwide retrospective study.

OBJECTIVE: Outcome after intrauterine transfusions due to severe hemolytic disease of the fetus and newborn. DESIGN: Nationwide population-based retrospective cohort study. SETTING: All women treated with intrauterine transfusions for hemolytic disease of the fetus and newborn in Finland in 2003-2012. POPULATION: 339 intrauterine transfusions, performed in 104 pregnancies of 84 women. METHODS: Information on antenatal screening of red cell antibodies and red cell units issued for intrauterine transfusion was obtained from the Finnish Red Cross Blood Service database, and obstetric and neonatal data from hospital records. MAIN OUTCOME MEASURES: Procedure-related complications, perinatal mortality, neonatal morbidity. RESULTS: Overall survival was 94.2% (95% confidence interval 89.7-98.7). There were four fetal and two neonatal deaths. Procedure-related fetal loss rate was 1.2% (95% confidence interval 0.04-2.4) per procedure and 3.8% (95% confidence interval 0.1-7.5) per pregnancy. Of the four procedure-related losses, three were due to technically difficult intrauterine transfusions causing infection and preterm birth. Of the live born infants, 19% (95% confidence interval 11.3-26.7) were born before 32 weeks' gestation. The incidence of severe neonatal morbidity (respiratory distress syndrome, severe cerebral injury, sepsis) was 22.2% (95% confidence interval 13.4-30.2). Poor outcome (death, severe neonatal morbidity) was negatively associated with gestational age at first transfusion (p = 0.001) and at birth (p = 0.00006). Follow-up of the infants was too incomplete to assess the neurodevelopmental outcome. CONCLUSIONS: Although overall survival is comparable with previous studies, our concern is procedure-related infections and preterm births. Close collaboration between the university hospitals is needed to ensure timely treatment, operator skills and systematic follow-up of the children.

Increased perinatal loss after intrauterine transfusion for alloimmune anaemia before 20 weeks of gestation.

OBJECTIVES: To evaluate and compare perinatal outcome after intrauterine transfusions (IUT) performed before and after 20 weeks of gestation. To analyse contributing factors. DESIGN: Retrospective analysis. SETTING: The Dutch referral centre for fetal therapy. POPULATION: IUTs for fetal alloimmune anaemia. METHODS: Fetuses were divided into two groups: fetuses requiring the first IUT before 20 weeks of gestation (Group 1) and those in which the IUTs started after 20 weeks (Group 2). The cause of perinatal loss was classified as procedure-related (PR) or not procedure-related (NPR). The cohort was divided into two periods to describe the change of perinatal loss over time. MAIN OUTCOME MEASURES: Perinatal loss of fetuses requiring the first IUT before 20 weeks of gestation, compared with perinatal loss later in gestation. RESULTS: A total of 1422 IUTs were performed in 491 fetuses. Perinatal loss rate in Group 1 was higher (7/29 24% versus 35/462 8%, P = 0.002). Especially NPR was higher for IUTs performed before 20 weeks (4/37 11% versus 19/1385 1%, P < 0.001). Kell alloimmunisation was overrepresented in Group 1 (7/29 24% versus 52/462 11%, P = 0.04). In a multivariate regression analysis, only hydrops was independently associated with perinatal loss (P = 0.001). In recent years, a decline in total perinatal loss was found (36/224 16% versus 6/267 2%, P < 0.001), but perinatal loss in Group 1 did not decline (4/224 1.8% versus 3/267 1.1%, P = 0.5). CONCLUSIONS: Perinatal loss after IUT performed before 20 weeks of gestation is increased compared with loss after IUT performed later in gestation. In addition, we confirmed earlier observations that hydrops is a major contributor to adverse outcome. Early and timely detection and treatment may prevent hydrops and improve outcome.

Antecedentes históricos de nuestra Revista: la cesárea abdominal y la exanguinotransfusión en la profilaxis de la muerte neonatal por enfermedad hemolítica: contribución casuística / Historical background of our journal: the abdominal cesarean section and exchange transfusion in the prophylaxis of hemolytic disease of the newborn death: Casuistic contribution

We have studied cases of neonatal hemolytic disease. In one, a child born of a cesarean operation, offered a benign clinical aspearance during the first two days, and the exsanguinotransfusion was omitted, the child died from grave hemolytic icterus that started on the third day. The other case, a child born from a normal labour with severe anemia, purpura, and an important hemolytic blood picture and absence of platelets, underwent the exsanguinotransfusion, recovering rapidly.

Antecedentes históricos de nuestra Revista: la cesárea abdominal y la exanguinotransfusión en la profilaxis de la muerte neonatal por enfermedad hemolítica: contribución casuística / Historical background of our journal: the abdominal cesarean section and exchange transfusion in the prophylaxis of hemolytic disease of the newborn death: Casuistic contribution

We have studied cases of neonatal hemolytic disease. In one, a child born of a cesarean operation, offered a benign clinical aspearance during the first two days, and the exsanguinotransfusion was omitted, the child died from grave hemolytic icterus that started on the third day. The other case, a child born from a normal labour with severe anemia, purpura, and an important hemolytic blood picture and absence of platelets, underwent the exsanguinotransfusion, recovering rapidly.(AU)

Complications of intrauterine intravascular transfusion for fetal anemia due to maternal red-cell alloimmunization.

OBJECTIVE: The purpose of this study was to establish the true procedure-related complication rate of intrauterine transfusion therapy. STUDY DESIGN: A cohort study of 254 fetuses treated with 740 intrauterine blood transfusions for red-cell alloimmunization in a single center in the years 1988 to 2001. Our database was searched for perinatal deaths, emergency deliveries, infections, and preterm rupture of membranes associated with intrauterine blood transfusion. Complications were categorized by two independent obstetricians as procedure-related (PR) or not procedure-related (NPR). Logistic regression analysis was used to identify risk factors for complications. RESULTS: Overall survival was 225/254 (89%). Fetal death occurred in 19 cases (7 PR) and neonatal death in 10 cases (5 PR). There were two cases of intrauterine infection with Escherichia coli (both PR) and two other cases of preterm premature rupture of membranes (1 PR) within a week of a procedure. Emergency delivery after a transfusion was performed in 18 pregnancies (15 PR). The total PR complication rate was 3.1%, resulting in an overall PR loss rate of 1.6% per procedure. Arterial puncture, transamniotic cord puncture, refraining from fetal paralysis, and advancing gestational age were associated with the occurrence of PR complications. CONCLUSION: Our study shows that intrauterine transfusion is a safe procedure, with a relatively low PR perinatal loss rate. Arterial puncture and transamniotic cord needling carry a high risk for serious complications, whereas fetal paralysis improves the safety of the procedure. This information on risks of intrauterine transfusion therapy may help to further improve the safety of intrauterine transfusions. Data on complication rates of intrauterine transfusions are essential in counseling patients.

Treatment of fetal anemia due to red-cell alloimmunization with intrauterine transfusions in the Netherlands, 1988-1999.

OBJECTIVE: To assess pregnancy outcome after intrauterine transfusion (IUT) for fetal anemia due to red-cell alloimmunization in the Netherlands over 11 years, in order to improve care and counseling. METHODS: A retrospective cohort study was conducted from January 1, 1988, to January 1, 1999. Data were collected prospectively on all red-cell alloimmunized pregnancies requiring intrauterine blood transfusions. Primary outcome variables were fetal and neonatal survival in relation to the type of antibody, gestational age and presence or absence of hydrops. In addition, we studied short-term neonatal morbidity and procedure-related complications. RESULTS: A total of 210 fetuses from 208 pregnancies received 593 transfusions. Overall survival rate was 86%. Survival of hydropic fetuses (78%) was significantly different from those without hydrops (92%). Low survival rates were especially found in hydropic fetuses with the first transfusion at gestational ages of 20 weeks or less (55%) or between 28 and 32 weeks (59%). In maternal rhesus D [Rh(D)] immunization 89% of fetuses survived, whereas survival in the case of Kell immunization was 58%. All fetuses with anemia due to Rh(c) immunization survived. The overall fatal procedure-related complication rate was 1.7% per procedure, resulting in a fetal loss rate of 4.8%. CONCLUSIONS: Intrauterine intravascular transfusions are effective in the management of fetal alloimmune anemia. Fetal hydrops, mostly associated with late referral, decreases the chance of survival. To improve the outcome of red-cell alloimmunized pregnancies early diagnosis of fetal anemia and referral to a specialized center are important, enabling the start of treatment before hydrops develops.

Amniotic fluid delta OD 450 values accurately predict severe fetal anemia in D-alloimmunization.

OBJECTIVE: To assess the diagnostic accuracy of amniotic fluid Delta OD 450 values in the second and third trimesters of D-alloimmunized pregnancies. METHODS: We searched our database for singleton D-alloimmunized pregnancies with nonhydropic fetuses, where amniocentesis was performed within 4 days of first fetal blood sampling. Amniotic fluid Delta OD 450 values were plotted on an extrapolated Liley's chart. Sensitivity and specificity were calculated for two commonly used cutoff levels, Liley's zone 3 and the upper third of Liley's zone 2. Severe fetal anemia was defined as a hemoglobin concentration of more than 5 standard deviations below the normal mean for corresponding gestational age. RESULTS: Seventy-nine pregnancies met our inclusion criteria. Overall accuracy of the extrapolated Liley's curve in predicting severe fetal anemia was 75% (95% confidence interval [CI] 64, 84) for zone 3 and 86% (95% CI 77, 93) when the upper third of zone 2 was included. Sensitivity of Delta OD 450 values in Liley's zone 3 or the upper third of Liley's zone 2 was 95% (95% CI 74, 100) before and 98% (95% CI 89, 100) after 27 weeks. CONCLUSION: Liley's extrapolated curve predicts severe fetal anemia with reasonable accuracy and high sensitivity.

Benefits and risks of fetal red-cell transfusion after 32 weeks gestation.

OBJECTIVE: To compare the outcome after intrauterine transfusion (IUT) between fetuses treated before and those treated after 32 weeks gestation. SETTING: National referral center for intrauterine treatment of red-cell alloimmunization in The Netherlands. STUDY DESIGN: Retrospective evaluation of an 11 year period, during which 209 fetuses were treated for alloimmune hemolytic disease with 609 red-cell IUTs. We compared fetal and neonatal outcome in three groups: fetuses only treated before 32 weeks gestation (group A, n=46), those treated both before and after 32 weeks (group B, n=117), and those where IUT was started at or after 32 weeks (group C, n=46). RESULTS: Survival rate was 48% in group A, 100% in group B, and 91% in group C. Moreover, fetuses in group A were hydropic significantly more often. Short-term perinatal loss rate after IUT was 3.4% in the 409 procedures performed before 32 weeks and 1.0% in the 200 procedures performed after 32 weeks gestation. CONCLUSION: Perinatal losses were much more common in fetuses only treated before 32 weeks gestation. Two procedure-related perinatal losses in 200 IUT after 32 weeks remain a matter of concern because of the good prospects of alternative extrauterine treatment.

[Blood group immunization: results of treatment of fetal anemia with intra-uterine intravascular blood transfusion in the Netherlands, 1987-1995]. / Bloedgroepimmunisatie: resultaten van behandeling van foetale anemie met intra-uteriene intravasculaire bloedtransfusie in Nederland, 1987-1995.

OBJECTIVE: To evaluate outcome of red cell alloimmunized pregnancies treated with intravascular intrauterine blood transfusions. DESIGN: Retrospective. METHODS: Medical records of all women and neonates treated with intrauterine transfusions in the period March 1987-December 1995, were reviewed. Survival rates of the infants were analysed in relation to both gestational age and the presence or absence of hydrops at the time of the first transfusion. RESULTS: In 153 pregnancies 155 foetuses underwent 462 transfusions (median: 3; range: 1-7). Patients were immunized against RhD in 88%. Kell in 7% and Rhe in 5% of the cases. Overall survival rate was 83%. No difference in survival rate was found between children with the first transfusion early (< or = 26 weeks) or late (> 26 weeks) in pregnancy. Survival rate for foetuses without hydrops was significantly higher than for those with hydrops (90% versus 73%). The mildly hydropic foetuses had a significantly higher survival rate than the severely hydropic foetuses (94% versus 53%). Absence of intrauterine reversal of hydrops was associated with a bad outcome. CONCLUSION: Intravascular transfusion is an effective and safe procedure for correction of foetal anaemia provided it is performed by an experienced multidisciplinary team. In contrast to gestational age at first transfusion severity of hydrops is predictive for successful treatment, so timely institution of treatment is of paramount importance.

Rh disease: intrauterine intravascular fetal blood transfusion by cordocentesis.

A total of 49 cordocenteses, including 40 intrauterine intravascular fetal blood tranasfusions, were performed in 30 pregnancies complicated by red cell isoimmunization. Transfusions were started at 19-33 weeks' gestation and repeated up to five times, at one-to-four week intervals. The volumes of transfused blood were 20-110 ml, hematocrits were 58-82 percent and the rate of transfusions was 1-15 ml/min. The pretransfusion fetal hemoglobins were 3.5-11.6 g/dl and the posttransfusion fetal hemoglobins were 7.5-15.6 g/dl. There were three intrauterine deaths and two neonatal deaths. The overall survival rate was 83.3 percent including all cordocenteses. The survival rate for the intrauterine transfusions was 81 percent.