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 children’s 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.
Fetal and neonatal hemolytic disease results from maternal alloimmunization to red cell antigens, for which mother and fetus are incompatible. Maternal immunoglobulin gamma (IgG) antibodies pass the placenta into the fetal circulation and cause destruction of fetal red cells. The resulting progressive fetal anemia leads, when untreated, to fetal hydrops and perinatal death.
Before 1970, hemolytic disease because of antibodies against the Rhesus-D antigen was the most important cause of perinatal death. Several interventions have drastically reduced the incidence and severity of the disease, including postnatal and more recently antenatal anti-D prophylaxis programs, improved diagnostic management and neonatal treatment. One of the major advances was the introduction in 1963 of intrauterine blood transfusions (IUTs), first performed by Liley using the intraperitoneal technique. In the 1980s, this technique was replaced by the intravascular IUT. Nowadays, this treatment is the most successful procedure in fetal therapy, with perinatal survival rates exceeding 95% in experienced centers. However, one of the concerns of the more widespread and successful use of fetal therapy is that a decrease in perinatal mortality may lead to an increase of children with long-term handicaps. Only a few studies with small patient numbers have reported on long-term neurodevelopmental outcome after IUT, with an incidence of adverse outcome ranging from 4.5 to 12%. The aim of our study was to determine the incidence and risk factors for adverse neurodevelopmental outcome after IUT treatment in the largest cohort of children worldwide.
Materials and Methods
In 2008, we designed a large national cohort study to evaluate the long-term neurodevelopmental outcome in children treated with IUT: the LOTUS study (LOng-Term follow-up after intra-Uterine transfusionS). All mothers with red cell alloimmunization treated with IUT between Jan. 1, 1988, and Jan. 1, 2008, at the Leiden University Medical Center and their children were invited to participate in this large follow-up study. For the purpose of this study, we included all children of 2 to 17 years of age who had complete follow-up, including a cognitive development test. Children with severe congenital anomalies and syndromal disorders were excluded. This study was approved by the ethics committee of the Leiden University Medical Center. Informed consent was obtained from all participating families. A limited outcome evaluation in a small part of our study group (11 children treated between 1991 and 1993) was described before. Primary outcome was a composite outcome termed neurodevelopmental impairment (NDI) defined as at least 1 of the following; cerebral palsy (CP), severe cognitive developmental delay (< −2 standard deviation [SD]), bilateral deafness requiring hearing amplification, and/or bilateral blindness.
The Leiden University Medical Center serves as the single national reference center for the management of red cell alloimmunization in pregnancy in the Netherlands. IUTs are performed when signs of fetal anemia are detected on Doppler ultrasound examinations. Details on our management guidelines for alloimmunized pregnancies were previously described. Because the implementation of the IUT program using the ultrasound-guided intravascular transfusion technique at our center in 1987, all relevant perinatal data have prospectively been collected in a computerized database. Data included are as follows: type of alloimmunization, gestational age at IUT, hemoglobin level, presence and severity of hydrops at the start of the intrauterine treatment, number of IUTs, gestational age at birth, sex, birthweight, and neonatal outcome. Neonatal outcome data included: number of exchange transfusions because of severe hyperbilirubinemia, respiratory distress syndrome, necrotizing enterocolitis (classified according to Bell et al ), sepsis (defined as clinical symptoms of infection and a positive bacterial blood culture) and severe cerebral injury detected either on cranial ultrasound, computed tomography scan (CT), or magnetic resonance imaging (MRI). Severe cerebral injury was defined as the presence of intraventricular hemorrhage ≥ grade 3 (classified according to Volpe ), cystic periventricular leukomalacia ≥ grade 2 (classified according to de Vries et al ), and/or ventricular dilatation (defined according to Levene ). Other major cerebral abnormalities associated with adverse neurologic outcome were also recorded and classified as severe cerebral lesions. We recorded the presence of perinatal asphyxia, defined as 3 or more of the following 5 criteria: nonreassuring cardiotocogram patterns, umbilical cord arterial pH <7.10, Apgar score <5 at 5 minutes after birth, failure of spontaneous breathing at 5 minutes after birth, and onset of multiple organ failure.
Parental education was determined by the level of education of each parent individually. A score of 1 was given if the parent’s education was low, a score of 2 for an average educational level, and a score of 3 for higher levels of education. Education scores of both parents were then added (score range from 2 to 6). Ethnicity was recorded as white or nonwhite. Children were considered to be white when 1 or both parent(s) were of white ethnicity.
Follow-up
All participating families visited our outpatients clinic from August 2008 to November 2010. At this visit, a physical and neurologic examination according to Touwen et al and an assessment of cognitive development using standardized tests were performed. All children were assessed by 1 of the 3 investigators specialized in developmental assessment (I.L., V.S., and E.L.).
Presence of CP was assessed according to the criteria of the European CP Network and classified as diplegia, hemiplegia, quadriplegia, dyskinetic, or mixed. Minor neurologic dysfunction (MND) was defined as a moderate abnormality of tone, posture, and movement leading to only minor functional impairment or minor developmental delay.
Cognitive development in children aged 2 to 3 years was assessed according to the Dutch version of the Bayley Scales of Infant Development, 2nd edition (BSID-II). BSID-II scores provide a mental developmental index (MDI). Children between 3 and 7 years of age were tested with the Dutch version of the Wechsler Preschool and Primary Scale of Intelligence, 3rd edition (WPPSI-III-NL). Cognitive development in children between 7 and 17 years of age was assessed with the Dutch version of the Wechsler Intelligence Scale for Children, 3rd edition (WISC-III-NL). Both the WPPSI and the WISC provide a full scale IQ score. BSID-MDI, WPPSI, and WISC scores follow a normal distribution curve with a mean score of 100. A score of 70-84 indicates mild delay (ie, < −1 SD) and a score <70 indicates severe delay (ie, < −2 SD). A trained psychologist (J.K.), blinded to the antenatal course and neonatal outcome, performed the tests in all children.
Risk factors
Potential risk factors for NDI were investigated including severity of fetal anemia (actual hemoglobin level and Z-hemoglobin), presence, and severity of fetal hydrops (classified according to van Kamp et al ) at start of the intrauterine treatment, number of IUTs, gestational age at birth (divided into 3 groups: neonates born before 32 weeks’ gestation, between 32 and 35 weeks’ gestation, and after 35 weeks’ gestation), severe neonatal morbidity, and perinatal asphyxia. Standardized Z scores of hemoglobin (Z-hemoglobin) were defined as the number of SDs that an actual value deviated from the normal mean for gestational age. Reference values for hemoglobin were derived from the literature. Severe neonatal morbidity was defined as the presence of 1 or more of the following: respiratory distress syndrome, necrotizing enterocolitis ≥ grade 2, sepsis, and/or severe cerebral injury.
Statistical analyses
We used univariate logistic regressions to test the association between NDI and the potential risk factors. We entered the risk factors into a multivariate logistic regression model and included additional potential confounders, including sex, parental education, and ethnicity. Multiple logistic regression analysis was used to measure the independent effect of the potential risk factors for NDI. Results of logistic regression were considered significant at P values < .05. We used the Pearson correlation test to calculate the correlation between hemoglobin at first IUT and IQ score. Analyses were performed using SPSS version 16 (SPSS Inc, Chicago, IL).
Results
During the study period 1284 IUTs were performed in 451 fetuses. Thirty-one fetuses died in utero and 11 in the neonatal period resulting in a perinatal survival rate of 91% (409/451). Two more children died during childhood because of causes unrelated to hemolytic disease of the fetus/newborn (1 accidental infant death occurred because of incorrect construction of the bedframe and 1 infant death was due to acute cardiomyopathy and pulmonary hypertension). Thus, the overall survival rate was 90% (407/451). Three children were diagnosed with congenital anomalies, including Kinsbourne’s syndrome, congenital cerebellar hypoplasia, and Phelan-McDermid syndrome and were excluded from further analysis. A total of 342 children were 2 to 17 years of age and thus eligible for the study. Fifty-one (15%) children were lost-to-follow-up because of declined consent (6%, 21/342) or loss of contact address (9%, 30/342). Complete follow-up data were obtained from 291 children by a visit at our outpatient clinic. A flowchart showing the derivation of our study population is shown in Figure 1 .
