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.
Parvovirus B19 (B19V) is a small single-stranded DNA virus most commonly known as the causative agent for erythema infectiosum, or the fifth disease. Infection with B19V during pregnancy is mostly asymptomatic to the mother and causes no harm to the fetus. However, in 30-50% of cases, vertical transmission takes place and leads in 1-2% to infection of the fetus that may cause serious fetal morbidity and mortality caused by red blood cell destruction and a concurrent decrease of hematopoiesis. The pathogenesis of B19V infection is related to the tropism of B19V for erythroid progenitor cells. Infection and lysis of these cells make B19V a potent inhibitor of hematopoiesis. Elimination of the erythroid lineage can cause fetal anemia, hydrops, and fetal death. The mainstay for the treatment of fetal anemia is intrauterine transfusion (IUT). Perinatal survival rates in fetal anemia because of red cell alloimmunization treated with IUT nowadays exceed 90%. In B19V infection, perinatal survival after treatment with IUT is lower and ranges from 67% to 85%.
As perinatal survival is improving with IUT, attention is now shifting toward short-term and long-term outcome in surviving children. Several studies have focused on the long-term neurodevelopmental follow-up after IUT for fetal alloimmune anemia and report a favorable outcome in the vast majority of children. In the subgroup of fetuses with B19V infection, only 3 small studies have reported on the long-term outcome after IUT.
The objective of this study was to evaluate the long-term neuromotor and cognitive development in a relative large cohort of children treated with IUT for severe anemia induced by intrauterine B19V infection.
Materials and Methods
All live-born children who received 1 or more IUTs between September 1997 and June 2009 for fetal anemia because of intrauterine parvovirus B19 infection were asked to participate in this observational cohort study. The institutional review board of our hospital approved the study. Informed consent was obtained from all participating families. Children underwent a physical and standardized neurologic examination and an assessment of neuromotor and cognitive development. All families were asked to visit our outpatient clinic for this follow-up examination. Families who were unable to travel to the Leiden University Medical Center (LUMC), were visited at home. Children with severe congenital anomalies and syndromal disorders were excluded.
The LUMC is the national referral center for invasive fetal therapy since 1965. IUTs were performed when signs of fetal anemia (increased middle cerebral artery peak systolic flow velocity) were detected on Doppler ultrasound examinations. Technical aspects of intrauterine transfusion were previously described.
Perinatal clinical data were obtained from our IUT-database and referral hospitals. Data recorded are gestational age at IUT, hemoglobin level before and after IUT, presence of hydrops at the start of intrauterine treatment, number of IUTs, gestational age at birth, gender, birthweight, neonatal morbidity (respiratory distress syndrome, necrotizing enterocolitis, and sepsis). Presence of postnatal brain injury on neonatal cerebral imaging (cranial ultrasound, computed tomography scan [CT] or magnetic resonance imaging [MRI]) was recorded if available.
Neuromotor development was assessed by performing a neurologic examination according to Touwen. Presence of cerebral palsy (CP) was assessed according to the criteria of the European CP Network and classified as diplegia, hemiplegia, quadriplegia, dyskinetic, or mixed.
Cognitive development in children up to 3 years of age was tested with the second edition of the Bayley Scales of Infant and Toddler Development (BSID-II). BSID-II scores provide mental development indexes (MDI) and psychomotor development indexes (PDI). Cognitive development in children between 3 and 7 years of age was tested with the third edition of the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III) and in children between 7 and 16 years of age with the third edition of the Wechsler Intelligence Scale for Children (WISC-III). Both the WPPSI-III and the WISC-III provide a Full-Scale Intellectual Quotient (IQ) score and subsection scores for Verbal IQ and Performance IQ. The normative population mean is 100 and the standard deviation (SD) is 15 for all scores. A score of 70-84 indicated mild delay (ie, <−1 SD) and a score <70 indicated severe delay (ie, <−2 SD). A trained psychologist, blinded to the antenatal course and neonatal outcome, performed the tests in all children.
Primary outcome was a composite outcome termed neurodevelopmental impairment (NDI) defined as at least 1 of the following; CP, severe developmental delay (<−2 SD), bilateral deafness requiring hearing amplification, and/or bilateral blindness.
Secondary outcome was presence of minor neurologic dysfunction (MND). This was defined as a moderate abnormality of tone, posture, and movement leading to only minor functional impairment and/or mild developmental delay (defined as a cognitive developmental delay <−1 and >−2 SD).
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