Inge L. van Kamp

Long-term neurodevelopmental outcome after intrauterine transfusion for hemolytic disease of the fetus/newborn: the LOTUS study

OBJECTIVE To determine the incidence and risk factors for neurodevelopmental impairment (NDI) in children with hemolytic disease of the fetus/newborn treated with intrauterine transfusion (IUT). STUDY DESIGN Neurodevelopmental outcome in children at least 2 years of age was assessed using standardized tests, including the Bayley Scales of Infant Development, the Wechsler Preschool and Primary Scale of Intelligence, and the Wechsler Intelligence Scale for Children, according to the childrens age. Primary outcome was the incidence of neurodevelopmental impairment defined as at least one of the following: cerebral palsy, severe developmental delay, bilateral deafness, and/or blindness. RESULTS A total of 291 children were evaluated at a median age of 8.2 years (range, 2-17 years). Cerebral palsy was detected in 6 (2.1%) children, severe developmental delay in 9 (3.1%) children, and bilateral deafness in 3 (1.0%) children. The overall incidence of neurodevelopmental impairment was 4.8% (14/291). In a multivariate regression analysis including only preoperative risk factors, severe hydrops was independently associated with neurodevelopmental impairment (odds ratio, 11.2; 95% confidence interval, 1.7-92.7). CONCLUSION Incidence of neurodevelopmental impairment in children treated with intrauterine transfusion for fetal alloimmune anemia is low (4.8%). Prevention of fetal hydrops, the strongest preoperative predictor for impaired neurodevelopment, by timely detection, referral and treatment may improve long-term outcome.

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.

Ultrasonographic fetal spleen measurements in red blood cell-alloimmunized pregnancies

OBJECTIVES This study was performed to evaluate the possible relationship between fetal spleen size and fetal hemoglobin levels and to assess the predictive value of ultrasonographically measured fetal spleen size as an estimate of the severity of fetal hemolytic anemia. STUDY DESIGN Before 85 consecutive fetal blood samples in 28 red blood cell-alloimmunized pregnancies ultrasonographic fetal spleen measurements were performed. Results were compared with our own longitudinally derived reference ranges and were correlated with fetal hemoglobin deficit. RESULTS A significant positive correlation was found between spleen perimeter and fetal hemoglobin deficit. The ultrasonographic finding of splenomegaly correctly predicted severe fetal anemia (hemoglobin deficit > 5 SD from normal mean) in 44 of 47 cases, a positive predictive value of 94%. At first transfusion all fetuses showing splenomegaly were severely anemic. CONCLUSION Fetal spleen measurements may be a useful adjunct to ultrasonographic evaluation in the management of severe red blood cell-alloimmunized pregnancies.

Pediatric outcome in Rhesus hemolytic disease treated with and without intrauterine transfusion

OBJECTIVE To study the short-term morbidity in Rhesus hemolytic disease of infants treated either with or without intrauterine transfusions (IUT). STUDY DESIGN All term and near term infants (gestational age > or = 36 weeks) with neonatal Rhesus hemolytic disease admitted to our center between January 2000-March 2005 were retrospectively included in the study. We recorded the duration of phototherapy, the need of exchange transfusions, and the need of top-up red blood cell transfusions until 6 months of age. RESULTS A total of 89 infants were included, of whom 52 received at least one IUT. Duration of phototherapy in the IUT and no-IUT group was 3.8 and 5.1 days, respectively (P = .01). The percentage of infants requiring an exchange transfusion in the IUT group was 71% compared to 65% in the no-IUT group (P = .64). The percentage of infants requiring a top-up transfusion in the IUT and no-IUT group was 77% and 26.5%, respectively (P < .01). CONCLUSION Infants with Rhesus hemolytic disease treated with IUT required less days of phototherapy and more top-up red blood cell transfusions than neonates without IUT. However, the need for exchange transfusion was similar in both groups.

Fetal, neonatal and developmental outcomes of lithium-exposed pregnancies.

INTRODUCTION Many women with a bipolar disorder are of reproductive age and will need to continue lithium treatment during pregnancy. The teratogenic and perinatal effects of lithium are known, but not the long-term effects of lithium on neurodevelopment of the children. This study investigates growth, neurological, cognitive and behavioral development of children exposed to lithium in utero. METHOD In an observational retrospective cohort study 15 children who were exposed to lithium in utero were investigated at 3-15 years of age. Neurological development was tested using the Hempel or Touwen examination. Cognitive development was assessed with the Bayley Scales of Infant Development III, Wechsler Preschool and Primary Scale of Intelligence or the Wechsler Intelligence Scale for Children. Parents completed the Child Behavior Checklist to assess behavioral development and a standard questionnaire about general development of the child since birth. RESULTS One child had signs of a minor neurological dysfunction, but without further clinical implications. The results of the cognitive tests were within normal limits, although most children had lower scores on the performance IQ subtest. Growth, behavior and general development were within the normal range. CONCLUSIONS Continuing lithium therapy during pregnancy did not cause adverse effects on growth, neurological, cognitive and behavioral development of exposed children.

Intrauterine Blood Transfusion: Current Indications and Associated Risks

Fetal anemia is a serious complication in pregnancy and associated with perinatal mortality and morbidity. During 25 years of worldwide experience with intravascular intrauterine blood transfusion, a variety of indications have been described. Intrauterine transfusion (IUT) treatment is considered most successful for fetal anemia due to red cell alloimmunization. Moreover, the use of this procedure has also been reported in pregnancies with parvovirus B19 infection, fetomaternal hemorrhage and placental chorioangiomas, for example. This review focuses on the current indications of intrauterine blood transfusions. In addition, we describe the potential complications of IUT treatment.

Intrauterine transfusion for parvovirus B19 infection: long-term neurodevelopmental outcome

OBJECTIVE To evaluate long-term neurodevelopmental outcome of children treated with intrauterine transfusions for fetal anemia because of parvovirus B19 infection. STUDY DESIGN Children treated with intrauterine transfusions for fetal anemia because of parvovirus B19 infection underwent standardized age-appropriate neurodevelopmental testing. Main outcome was the incidence of neurodevelopmental impairment. RESULTS Twenty-eight children were evaluated at a median age of 5 years (range, 1.5-13 years). Neurodevelopmental impairment was diagnosed in 3 of 28 (11%) children, including 1 child with combined cerebral palsy and severe developmental delay and 2 children with isolated severe developmental delay. CONCLUSION Neurodevelopmental impairment in children treated with intrauterine transfusion for parvovirus B19 infection is increased compared with the general population. Large long-term follow-up studies are required to determine potential risk factors.

Long-Term follow up after intra-Uterine transfusionS; the LOTUS study

BackgroundThe Leiden University Medical Center (LUMC) is the Dutch national referral centre for pregnancies complicated by haemolytic disease of the fetus and newborn (HDFN) caused by maternal alloimmunization. Yearly, 20-25 affected fetuses with severe anaemia are transfused with intra-uterine blood transfusions (IUT). Mothers of whom their fetus has undergone IUT for HDFN are considered high responders with regard to red blood cell (RBC) antibody formation. Most study groups report high perinatal survival, resulting in a shift in attention towards short- and long-term outcome in surviving children.Methods/DesignWe set up a large long-term observational follow-up study (LOTUS study), in cooperation with the Sanquin Blood Supply Foundation and the LUMC departments of Obstetrics, Neonatology and ImmunoHematology & Bloodtransfusion.The first part of this study addresses several putative mechanisms associated with blood group alloimmunization in these mothers. The second part of this study determines the incidence of long-term neurodevelopment impairment (NDI) and associated risk factors in children treated with IUT. All women and their life offspring who have been treated with IUT for HDFN in the LUMC from 1987-2008 are invited to participate and after consent, blood or saliva samples are taken. RBC and HLA antigen profile and antibodies are determined by serologic or molecular techniques. Microchimerism populations are tested by real time polymerase chain reaction (RT PCR).All children are tested for their neurological, cognitive and psychosocial development using standardised tests and questionnaires. The primary outcome is neurodevelopmental impairment (NDI), a composite outcome defined as any of the following: cerebral palsy, cognitive or psychomotor development < 2 standard deviation, bilateral blindness and/or bilateral deafness.DiscussionThe LOTUS study includes the largest cohort of IUT patients ever studied and is the first to investigate post-IUT long-term effects in both mother and child. The results may lead to a change in transfusion policy, in particular future avoidance of certain incompatibilities. Additionally the LOTUS study will provide clinicians and parents better insights in the long-term neurodevelopmental outcome in children with HDFN treated with IUTs, and may improve the quality of antenatal counselling and long-term guidance.

Long-term neurodevelopmental and cardiovascular outcome after intrauterine transfusions for fetal anaemia: a review.

Perinatal survival rates after intrauterine transfusions (IUT) for red cell alloimmunisation now exceed 90%, which demonstrates the safety and efficacy of one of the most successful procedures in fetal therapy. However, improved perinatal survival could lead to an increased number of children with long‐term disabilities. The importance of long‐term follow‐up studies in fetal therapy lies in both the necessity of evaluation of antenatal management as well as in evidence‐based preconceptional and prenatal counselling. This review describes the possible long‐term cardiovascular and neurodevelopmental sequelae after IUT treatment for different indications including red cell alloimmunisation, parvovirus B19 infection, fetomaternal haemorrhage and twin anaemia‐polycythaemia sequence.

Implementation of routine screening for Kell antibodies: does it improve perinatal survival?

BACKGROUND: In 1998 a national program for first‐trimester screening for red cell (RBC) antibodies in all pregnant women was implemented. The aim of our study was to assess the impact on perinatal mortality caused by Kell alloimmunization