Does general movements quality in term infants predict cerebral palsy and milder forms of limited mobility at 6 years?

AIM: To evaluate in term infants associations between quality of general movements and developmental outcome in term infants at 6 years with either cerebral palsy (CP) or limited mobility without CP. METHOD: Participants of this prospective study were 145 term infants (86 male, 59 female). Their general movements quality was assessed at 'writhing' and 'fidgety' general movements age (3wks and 13wks post term). The assessment at 6 years consisted of a neurological examination, including assessment of minor neurological dysfunction (MND), evaluation of mobility with the Movement Assessment Battery for Children, and of behaviour and learning problems with questionnaires. RESULTS: Definitely abnormal general movements at writhing age were not associated with CP, whereas definitely abnormal general movements at fidgety age were (sensitivity 60%; specificity 91%; positive predictive value 19%, negative predictive value 98%). In children without CP, general movements quality was not associated with limited mobility, but it was associated to a minor extent with MND. INTERPRETATION: In term infants, definitely abnormal general movements at fidgety age do predict CP, but with lower accuracy than in preterm infants. General movements quality does not predict limited mobility in children without CP. The study supports suggestions that predictive value of general movements assessment in term infants is lower than that in preterm infants.

Chromothripsis as a mechanism driving complex de novo structural rearrangements in the germline.

A variety of mutational mechanisms shape the dynamic architecture of human genomes and occasionally result in congenital defects and disease. Here, we used genome-wide long mate-pair sequencing to systematically screen for inherited and de novo structural variation in a trio including a child with severe congenital abnormalities. We identified 4321 inherited structural variants and 17 de novo rearrangements. We characterized the de novo structural changes to the base-pair level revealing a complex series of balanced inter- and intra-chromosomal rearrangements consisting of 12 breakpoints involving chromosomes 1, 4 and 10. Detailed inspection of breakpoint regions indicated that a series of simultaneous double-stranded DNA breaks caused local shattering of chromosomes. Fusion of the resulting chromosomal fragments involved non-homologous end joining, since junction points displayed limited or no homology and small insertions and deletions. The pattern of random joining of chromosomal fragments that we observe here strongly resembles the somatic rearrangement patterns--termed chromothripsis--that have recently been described in deranged cancer cells. We conclude that a similar mechanism may also drive the formation of de novo structural variation in the germline.

Antenatal allopurinol for reduction of birth asphyxia induced brain damage (ALLO-Trial); a randomized double blind placebo controlled multicenter study.

BACKGROUND: Hypoxic-ischaemic encephalopathy is associated with development of cerebral palsy and cognitive disability later in life and is therefore one of the fundamental problems in perinatal medicine. The xanthine-oxidase inhibitor allopurinol reduces the formation of free radicals, thereby limiting the amount of hypoxia-reperfusion damage. In case of suspected intra-uterine hypoxia, both animal and human studies suggest that maternal administration of allopurinol immediately prior to delivery reduces hypoxic-ischaemic encephalopathy. METHODS/DESIGN: The proposed trial is a randomized double blind placebo controlled multicenter study in pregnant women at term in whom the foetus is suspected of intra-uterine hypoxia.Allopurinol 500 mg IV or placebo will be administered antenatally to the pregnant woman when foetal hypoxia is suspected. Foetal distress is being diagnosed by the clinician as an abnormal or non-reassuring foetal heart rate trace, preferably accompanied by either significant ST-wave abnormalities (as detected by the STAN-monitor) or an abnormal foetal blood scalp sampling (pH < 7.20).Primary outcome measures are the amount of S100B (a marker for brain tissue damage) and the severity of oxidative stress (measured by isoprostane, neuroprostane, non protein bound iron and hypoxanthine), both measured in umbilical cord blood. Secondary outcome measures are neonatal mortality, serious composite neonatal morbidity and long-term neurological outcome. Furthermore pharmacokinetics and pharmacodynamics will be investigated.We expect an inclusion of 220 patients (110 per group) to be feasible in an inclusion period of two years. Given a suspected mean value of S100B of 1.05 ug/L (SD 0.37 ug/L) in the placebo group this trial has a power of 90% (alpha 0.05) to detect a mean value of S100B of 0.89 ug/L (SD 0.37 ug/L) in the 'allopurinol-treated' group (z-test2-sided). Analysis will be by intention to treat and it allows for one interim analysis. DISCUSSION: In this trial we aim to answer the question whether antenatal allopurinol administration reduces hypoxic-ischaemic encephalopathy in neonates exposed to foetal hypoxia. TRIAL REGISTRATION NUMBER: Clinical Trials, protocol registration system: NCT00189007.

Limitations in the Activity of Mobility at Age 6 Years After Difficult Birth at Term: Prospective Cohort Study.

BACKGROUND: A difficult birth at term (DBAT) may manifest as fetal acidosis and low Apgar scores and is often referred to as "perinatal asphyxia," especially when infants show signs of neonatal encephalopathy (NE). In contrast to DBAT resulting in moderate-to-severe NE, which is associated with neurodevelopmental disorders, little is known about the prognosis of less severe forms of DBAT, with or without NE. OBJECTIVE: The purpose of this study was to evaluate the International Classification of Functioning, Disability and Health, Children & Youth Version activity "mobility" and other neurodevelopmental sequelae in infants with DBAT at age 6 years. METHODS: The index cohort (n=62; 35 boys, 27 girls) consisted of consecutive term infants with DBAT based on clinical criteria in a Dutch nonacademic hospital from 1999 to 2005. Neonatal encephalopathy was assessed according to the Sarnat grading system and excluded infants with severe NE. The matched reference cohort (n=81; 49 boys, 32 girls) consisted of healthy term infants. The primary outcome at 6 years was limited mobility (Movement Assessment Battery for Children score ≤15th percentile). Secondary outcomes included learning and behavioral problems and the presence of minor neurological dysfunction. RESULTS: Three children developed cerebral palsy and were excluded from analyses. Children with DBAT more often had limited mobility than children without DBAT (risk ratio [RR]=2.44; 95% confidence interval [95% CI]=1.16, 5.14). The risk of limited mobility rose with increasing severity of NE (mild NE: RR=3.38; 95% CI=1.40, 8.16; moderate NE: RR=4.00; 95% CI=1.54, 10.40), and manual abilities especially were affected (RR=4.12; 95% CI=1.40, 12.14). Learning problems, need for physical therapy, and complex minor neurological dysfunction were more common in children with DBAT than in children without DBAT. CONCLUSIONS: Term infants who develop mild or moderate NE following DBAT are at increased risk for limited mobility at age 6 years. Routine monitoring of neuromotor development in these children is warranted.

Maternal allopurinol administration during suspected fetal hypoxia: a novel neuroprotective intervention? A multicentre randomised placebo controlled trial.

OBJECTIVE: To determine whether maternal allopurinol treatment during suspected fetal hypoxia would reduce the release of biomarkers associated with neonatal brain damage. DESIGN: A randomised double-blind placebo controlled multicentre trial. PATIENTS: We studied women in labour at term with clinical indices of fetal hypoxia, prompting immediate delivery. SETTING: Delivery rooms of 11 Dutch hospitals. INTERVENTION: When immediate delivery was foreseen based on suspected fetal hypoxia, women were allocated to receive allopurinol 500 mg intravenous (ALLO) or placebo intravenous (CONT). MAIN OUTCOME MEASURES: Primary endpoint was the difference in cord S100ß, a tissue-specific biomarker for brain damage. RESULTS: 222 women were randomised to receive allopurinol (ALLO, n=111) or placebo (CONT, n=111). Cord S100ß was not significantly different between the two groups: 44.5 pg/mL (IQR 20.2-71.4) in the ALLO group versus 54.9 pg/mL (IQR 26.8-94.7) in the CONT group (difference in median -7.69 (95% CI -24.9 to 9.52)). Post hoc subgroup analysis showed a potential treatment effect of allopurinol on the proportion of infants with a cord S100ß value above the 75th percentile in girls (ALLO n=5 (12%) vs CONT n=10 (31%); risk ratio (RR) 0.37 (95% CI 0.14 to 0.99)) but not in boys (ALLO n=18 (32%) vs CONT n=15 (25%); RR 1.4 (95% CI 0.84 to 2.3)). Also, cord neuroketal levels were significantly lower in girls treated with allopurinol as compared with placebo treated girls: 18.0 pg/mL (95% CI 12.1 to 26.9) in the ALLO group versus 32.2 pg/mL (95% CI 22.7 to 45.7) in the CONT group (geometric mean difference -16.4 (95% CI -24.6 to -1.64)). CONCLUSIONS: Maternal treatment with allopurinol during fetal hypoxia did not significantly lower neuronal damage markers in cord blood. Post hoc analysis revealed a potential beneficial treatment effect in girls. TRIAL REGISTRATION NUMBER: NCT00189007, Dutch Trial Register NTR1383.

Does perinatal asphyxia contribute to neurological dysfunction in preterm infants?

BACKGROUND: Children born preterm are known to be at risk for neurodevelopmental disorders. The role of perinatal asphyxia in this increased risk is still a matter of debate. AIM: To analyze the contribution of perinatal asphyxia in a population of preterm infants admitted to a secondary paediatric setting to neurological dysfunction in the first months after birth and to the development of cerebral palsy. METHODS: 17 preterm infants with perinatal asphyxia born before 35 weeks postmenstrual age (PMA) and 34 carefully matched preterm controls without asphyxia were studied. Neuromotor outcome was examined by means of three assessments of the quality of general movements (GM) at "preterm" (around 34 weeks PMA), "writhing" (around term age) and "fidgety" GM age (around 3 months post term). Follow-up until at least 18 months corrected age focused on the presence of cerebral palsy (CP). RESULTS: GM-quality of infants with asphyxia and of those without did not differ. Multivariate analysis revealed that abnormal GMs at "preterm" age were associated with respiratory problems, those at "writhing" age with none of the assessed risk factors, and those at "fidgety" age with the severity of periventricular leukomalacia (PVL) on neonatal ultrasound scan. Perinatal asphyxia was not associated with the development of CP. CP was associated with PVL and the presence of abnormal GMs at "fidgety" age. CONCLUSION: Perinatal asphyxia in preterm infants is not associated with an increased risk for neurodevelopmental problems including CP. Respiratory problems during the neonatal period are associated with PVL and adverse neurological outcome.

Quality of general movements in term infants with asphyxia.

BACKGROUND: Perinatal asphyxia may result in a developmental disorder. A recently developed non-invasive tool to investigate brain function at an early age is the assessment of general movements (GMs). AIM: To evaluate relationships between perinatal risk factors and the quality of GMs in the neonatal period and at 3 months in term newborns with asphyxia in a secondary paediatric setting. METHODS: 64 term (>36 weeks postmenstrual age (PMA)) infants with perinatal asphyxia were studied. GMs were assessed at 'writhing' GM age (38-47 weeks PMA) and at 'fidgety' GM age (48-56 weeks PMA). Pre- and perinatal factors were collected in a standardized way. RESULTS: Multivariate analysis revealed that DA GMs at 'writhing' age mainly correlated with asphyxia related illness. DA GMs at 'fidgety' age correlated in particular with abnormalities on the neonatal ultrasound scan of the brain. CONCLUSION: In secondary paediatric settings GM-assessment especially around 3 months is a valuable tool for the assessment of the integrity of the nervous system in term infants with asphyxia.