Elise Roze

Prenatal Exposure to Organohalogens, Including Brominated Flame Retardants, Influences Motor, Cognitive, and Behavioral Performance at School Age

Background Organohalogen compounds (OHCs) are known to have neurotoxic effects on the developing brain. Objective We investigated the influence of prenatal exposure to OHCs, including brominated flame retardants, on motor, cognitive, and behavioral outcome in healthy children of school age. Methods This study was part of the prospective Groningen infant COMPARE (Comparison of Exposure-Effect Pathways to Improve the Assessment of Human Health Risks of Complex Environmental Mixtures of Organohalogens) study. It included 62 children in whose mothers the following compounds had been determined in the 35th week of pregnancy: 2,2′-bis-(4 chlorophenyl)-1,1′-dichloroethene, pentachlorophenol (PCP), polychlorinated biphenyl congener 153 (PCB-153), 4-hydroxy-2,3,3′,4′,5-pentachlorobiphenyl (4OH-CB-107), 4OH-CB-146, 4OH-CB-187, 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), BDE-99, BDE-100, BDE-153, BDE-154, and hexabromocyclododecane. Thyroid hormones were determined in umbilical cord blood. When the children were 5–6 years of age, we assessed their neuropsychological functioning: motor performance (coordination, fine motor skills), cognition (intelligence, visual perception, visuomotor integration, inhibitory control, verbal memory, and attention), and behavior. Results Brominated flame retardants correlated with worse fine manipulative abilities, worse attention, better coordination, better visual perception, and better behavior. Chlorinated OHCs correlated with less choreiform dyskinesia. Hydroxylated polychlorinated biphenyls correlated with worse fine manipulative abilities, better attention, and better visual perception. The wood protective agent (PCP) correlated with worse coordination, less sensory integrity, worse attention, and worse visuomotor integration. Conclusions Our results demonstrate for the first time that transplacental transfer of polybrominated flame retardants is associated with the development of children at school age. Because of the widespread use of these compounds, especially in the United States, where concentrations in the environment are four times higher than in Europe, these results cause serious concern.

Long-term neuroprotective effects of allopurinol after moderate perinatal asphyxia: follow-up of two randomised controlled trials

Objective Free-radical-induced reperfusion injury has been recognised as an important cause of brain tissue damage after birth asphyxia. Allopurinol reduces the formation of free radicals, thereby potentially limiting the amount of hypoxia–reperfusion damage. In this study the long-term outcome of neonatal allopurinol treatment after birth asphyxia was examined. Design Follow-up of 4 to 8 years of two earlier performed randomised controlled trials. Setting Leiden University Medical Center, University Medical Center Groningen and University Medical Center Utrecht, The Netherlands. Patients Fifty-four term infants were included when suffering from moderate-to-severe birth asphyxia in two previously performed trials. Intervention Infants either received 40 mg/kg allopurinol (with an interval of 12 h) starting within 4 h after birth or served as controls. Main outcome measures Children, who survived, were assessed with the Wechsler Preschool and Primary Scales of Intelligence test or Wechsler Intelligence Scale for Children and underwent a neurological examination. The effect of allopurinol on severe adverse outcome (defined as mortality or severe disability at the age of 4–8 years) was examined in the total group of asphyxiated infants and in a predefined subgroup of moderately asphyxiated infants (based on the amplitude integrated electroencephalogram). Results The mean age during follow-up (n=23) was 5 years and 5 months (SD 1 year and 2 months). There were no differences in long-term outcome between the allopurinol-treated infants and controls. However, subgroup analysis of the moderately asphyxiated group showed significantly less severe adverse outcome in the allopurinol-treated infants compared with controls (25% vs 65%; RR 0.40, 95%CI 0.17 to 0.94). Conclusions The reported data may suggest a (neuro)protective effect of neonatal allopurinol treatment in moderately asphyxiated infants.

Tractography of the corticospinal tracts in infants with focal perinatal injury: comparison with normal controls and to motor development.

IntroductionOur aims were to (1) assess the corticospinal tracts (CSTs) in infants with focal injury and healthy term controls using probabilistic tractography and (2) to correlate the conventional magnetic resonance imaging (MRI) and tractography findings in infants with focal injury with their later motor function.MethodsWe studied 20 infants with focal lesions and 23 controls using MRI and diffusion tensor imaging. Tract volume, fractional anisotropy (FA), apparent diffusion coefficient (ADC) values, axial diffusivity and radial diffusivity (RD) of the CSTs were determined. Asymmetry indices (AIs) were calculated by comparing ipsilateral to contralateral CSTs. Motor outcome was assessed using a standardized neurological examination.ResultsConventional MRI was able to predict normal motor development (n = 9) or hemiplegia (n = 6). In children who developed a mild motor asymmetry (n = 5), conventional MRI predicted a hemiplegia in two and normal motor development in three infants. The AIs for tract volume, FA, ADC and RD showed a significant difference between controls and infants who developed a hemiplegia, and RD also showed a significant difference in AI between controls and infants who developed a mild asymmetry.ConclusionConventional MRI was able to predict subsequent normal motor development or hemiplegia following focal injury in newborn infants. Measures of RD obtained from diffusion tractography may offer additional information for predicting a subsequent asymmetry in motor function.

Development of fine motor skills in preterm infants

Fine motor skills are related to functioning in daily life and at school. We reviewed the status of knowledge, in preterm children, on the development of fine motor skills, the relation with gross motor skills, and risk factors for impaired fine motor skills.

Functional impairments at school age of preterm born children with late-onset sepsis.

BACKGROUND Late-onset sepsis is a relatively common complication particularly of preterm birth that affects approximately a quarter of very low birth weight infants. AIM We aimed to determine the motor, cognitive, and behavioural outcome at school age of preterm children with late-onset sepsis compared to matched controls. STUDY DESIGN AND SUBJECTS A prospective case-control study that included preterm infants (gestational age<32weeks and/or birth weight<1500g) admitted to our Neonatal Intensive Care Unit in 2000-2001 with a culture-proven late-onset sepsis, and controls matched for gestational age. OUTCOME MEASURES At school age we assessed motor skills, intelligence, visual perception, visuomotor integration, verbal memory, attention, executive functioning, and behaviour. RESULTS At 6-9years, 21 of 32 children with late-onset sepsis (68%) had borderline or abnormal motor outcome with most problems in fine motor skills. Their total IQ was 89 compared to 98 in controls. In addition, verbal memory and attention were affected compared to controls (0.61 standard deviations (SD), 95% confidence interval (CI) 0.04-1.17, p=0.033 and 0.94 SD, 95% CI 0.32-1.62, p=0.011, respectively). Multiple episodes of sepsis and gram-negative sepsis were risk factors for worse cognitive outcome. CONCLUSIONS At school age, a majority of preterm children with late-onset sepsis had motor problems. Their IQ was considerably lower than matched controls, and memory and attention were specifically impaired. Outcome at school age of preterm children with late-onset sepsis was worse than previously thought.

Neurodevelopmental outcome in preterm infants

Aim  To determine the distribution of cognitive and motor scores in preterm children, and to establish the influence of brain lesions and decreasing gestational age thereon.

Functional impairments at school age of children with necrotizing enterocolitis or spontaneous intestinal perforation.

We aimed to determine motor, cognitive, and behavioral outcome at school age of children who had either necrotizing enterocolitis (NEC) or spontaneous intestinal perforation (SIP). This case-control study included infants with NEC Bells stage IIA onward, infants with SIP, and matched controls (1996–2002). At school age, we assessed motor skills, intelligence, visual perception, visuomotor integration, verbal memory, attention, behavior, and executive functions. Of 93 infants with NEC or SIP, 28 (30%) died. We included 52 of 65 survivors for follow-up. At mean age of 9 y, we found that 68% of the children had borderline or abnormal scores on the Movement Assessment Battery for Children (versus 45% of controls). Their mean total intelligence quotient (IQ) was 86 ± 14 compared with 97 ± 9 in the controls. In addition, attention and visual perception were affected (p < 0.01 and p = 0.02). In comparison to controls, surgically treated children were at highest risk for adverse outcome. In conclusion, at school age, the motor functions and intelligence of many children with NEC or SIP were borderline or abnormal and, specifically, attention and visual perception were impaired. Children with NEC or SIP form a specific risk group for functional impairments at school age even though the majority does not have overt brain pathology.

Long-term neurodevelopmental impairment in neonates surgically treated for necrotizing enterocolitis: enterostomy associated with a worse outcome.

BACKGROUND Necrotizing enterocolitis (NEC) patients often have neurodevelopmental impairment, but the long-term follow-up data is limited. We determined whether surgical factors were of prognostic value for long-term neurodevelopment in children surviving surgery for NEC (SNEC). PATIENTS AND METHODS SNEC patients born between 1996 and 2002 were tested for verbal (VIQ), performance (PIQ) and total (TIQ) intelligence using Wechslers Intelligence Scale for Children, Third Edition, Dutch Version, and motor skills using the Movement Assessment Battery for Children (M-ABC). Neonatal and surgical data were obtained retrospectively to assess prognostic factors. RESULTS 19 patients (12 boys), median age 9.9 years (range 6.2-13.1), gestational age 31.0 weeks (range 25.2-40), birth weight 1 250 g (range 780-3 175) were evaluated. Infants with an enterostomy (n=14) scored lower on intelligence than children with a primary anastomosis (n=5): VIQ 85 ± 12 vs. 101 ± 15, p=0.04; PIQ 79 ± 13 vs. 92 ± 11, p=0.06; TIQ 82 ± 11 vs. 97 ± 13, p=0.04. Motor skills were either suspect or clinically impaired in 74%. Clinical classification of results suggest more children in the enterostomy group had a performance rated as clinically impaired compared to the primary anastomosis group, although no statistical difference in M-ABC score was found. There were no differences between primary anastomosis and enterostomy patients with regard to gestational age, birth weight, comorbidities, preoperative Bell stage, residual small and large bowel lengths, inotropic medication, duration of ventilatory support, NICU and hospital stay, and physical exam data on follow-up. However, a selection bias could not be ruled out. CONCLUSIONS The results suggest that an enterostomy in SNEC patients could be associated with worse neurodevelopmental outcomes by the age of 6-13 years compared to a primary anastomosis, although the severity of illness was comparable between both groups. Further studies are needed to prevent selection bias and to elucidate the impact of abdominal surgical factors on neurodevelopmental outcome and the underlying pathophysiology.

Neonatal DTI early after birth predicts motor outcome in preterm infants with periventricular hemorrhagic infarction

Background:To determine the association between early neonatal diffusion tensor imaging (DTI) and the development of unilateral spastic cerebral palsy (USCP) in preterm infants with periventricular hemorrhagic infarction (PVHI).Methods:Preterm infants with PVHI were assessed with early (≤4 wk after birth) and term-equivalent age MRI-DTI. Involvement of corticospinal tracts was assessed by visual assessment of the posterior limb of the internal capsule (PLIC) on DTI (classified asymmetrical, equivocal, or symmetrical) and by an atlas-based approach calculating fractional anisotropy asymmetry index in the PLIC. Motor outcome was assessed at ≥15 mo corrected age.Results:Seven out of 23 infants with PVHI developed USCP. Their PLIC was visually scored as asymmetrical in 6 and equivocal in 1 on the early DTI. Thirteen out of 16 infants with a symmetrical motor development had a symmetrical PLIC on early DTI, the remaining 3 were equivocal. All infants with USCP had a fractional anisotropy asymmetry index of >0.05 (optimal cut-off value) on early DTI. In infants with a symmetrical motor development (n = 16), 14 had an asymmetry index ≤0.05 while 2 had an index >0.05.Conclusion:DTI in preterm infants with PVHI within a few weeks after birth is associated with later motor development.

Long-term neurological outcome of term-born children treated with two or more anti-epileptic drugs during the neonatal period.

BACKGROUND Neonatal seizures may persist despite treatment with multiple anti-epileptic drugs (AEDs). OBJECTIVE To determine in term-born infants with seizures that required two or more AEDs, whether treatment efficacy and/or the underlying disorder were related to neurological outcome. DESIGN/METHODS We included 82 children (born 1998-2006) treated for neonatal seizures. We recorded mortality, aetiology of seizures, the number of AEDs required, achievement of seizure control, and amplitude-integrated-EEG (aEEG) background patterns. Follow-up consisted of an age-adequate neurological examination. Surviving children were classified as normal, having mild neurological abnormalities, or cerebral palsy (CP). RESULTS Forty-seven infants (57%) had status epilepticus. The number of AEDs was not related to neurological outcome. Treatment with three or four AEDs as opposed to two showed a trend towards an increased risk of a poor outcome, i.e., death or CP, odds ratio (OR) 2.74; 95% confidence interval (CI) 0.98-7.69; P=.055. Failure to achieve seizure control increased the risk of poor outcome, OR 6.77; 95%-CI 1.42-32.82, P=.016. Persistently severely abnormal aEEG background patterns also increased this risk, OR 3.19; 95%-CI 1.90-5.36; P<.001. In a multivariate model including abnormal aEEG background patterns, failure to achieve seizure control nearly reached significance towards an increased risk of poor outcome, OR 5.72, 95%-CI 0.99-32.97, P=.051. We found no association between seizure aetiology and outcome. CONCLUSIONS In term-born infants with seizures that required two or more AEDs outcome was poorer if seizure control failed. The number of AEDs required to reach seizure control and seizure aetiology had limited prognostic value.