Spatially localized magnetic resonance spectroscopy of the brains of normal and asphyxiated newborns.

Phase-modulated rotating frame imaging is a modification of magnetic resonance spectroscopy, which uses a linear radiofrequency field gradient to obtain spatially localized biochemical information. Phase-modulated rotating frame imaging was used to study regional cerebral energy metabolism in the brains of 9 normal newborns and 25 newborns after birth asphyxia. Relative concentrations of phosphorus-containing metabolites and intracellular pH were determined for brain tissue at three specified depths below the brain surface for all neonates. Wide variations in metabolite ratios were seen among normal neonates, and considerable metabolic heterogeneity was demonstrated in individual neonates by depth-resolved spectroscopy. Asphyxiated neonates with severe hypoxic-ischemic encephalopathy and a poor neurodevelopmental outcome showed the expected rise in inorganic orthophosphate and fall in phosphocreatine concentrations in both global and spatially localized spectra. Phase-modulated rotating frame imaging showed that metabolic derangement was less in superficial than in deeper brain tissue. The inorganic orthophosphate-adenosine triphosphate ratio from 1 to 2 cm below the brain surface was more accurate than any global metabolite ratio for the identification of neonates with a poor short-term outcome. These data are consistent with the known vulnerability of subcortical brain tissue to hypoxic-ischemic injury in the full-term neonate.

Educational and behavioural problems in babies of 32-35 weeks gestation.

AIM: To identify incidence of school and behaviour problems at age 7 years in children born between 32 and 35 weeks gestation, and investigate perinatal risk factors. METHOD: The study population consisted of all children born at 32-35 weeks gestation to mothers resident in Oxfordshire in 1990. General practitioners, parents, and teachers were asked about health, behaviour, and education by postal questionnaire. Teachers rated children on level of function in six areas using a five point scale. They also completed the Strengths and Difficulties behaviour questionnaire. Perinatal risk factors were identified for children with poor school performance using a univariate and multivariate analysis. RESULTS: Teacher responses were obtained for 117 (66%) of the 176 children in the cohort. Twenty nine (25%) required support from a non-teaching assistant, five (4%) had required a statement of special educational needs, and three (3%) were at special school. Poor outcome was reported for 32% in writing, 31% in fine motor skills, 29% in mathematics, 19% in speaking, 21% in reading, and 12% in physical education. On the behaviour questionnaire, 19% of the cohort achieved an abnormal hyperactivity score (population norm 10%). Multivariate analysis showed perinatal variables that remained significant, independent of other variables; they were discharge from the special care baby unit > 36 weeks postconceptional age (odds ratio 4.15; 95% confidence interval 1.43 to 12.05) and male sex (odds ratio 3.88; 95% confidence interval 1.42 to 10.6). CONCLUSION: Up to a third of children born between 32 and 35 weeks gestation may have school problems. As there are larger numbers in this gestational category compared with smaller babies, this finding has implications for educational services.

Ultrasound findings and clinical antecedents of cerebral palsy in very preterm infants.

OBJECTIVE: To investigate the incidence and timing of neonatal ultrasound lesions, and clinical details about pregnancy and the perinatal period, in a total population of extremely premature children with cerebral palsy, born to mothers who were resident in Oxfordshire. METHODS: Eighteen children born at less than 32 completed weeks of gestation were identified from a regional cerebral palsy register. Eighteen controls were matched for gestation, time, and place of birth. Perinatal records and ultrasound reports were systematically reviewed. Sequential neonatal ultrasound images stored on videotape were reanalysed, blind to the outcome of the infants. RESULTS: Sixteen (89%) of the cerebral palsy cases and one (6%) control had parenchymal cysts on neonatal brain scans. Of the cerebral palsy cases, none had cysts detectable on the first day. Six developed cysts within the first 10 days of life, and two of these had periventricular echodensities when first scanned postnatally. Antenatal complications were recorded in 16 cases and nine controls. The early postnatal appearance of cysts in a few babies with a history of severe antenatal complications suggested that antenatal factors may have contributed to the cerebral pathology. CONCLUSIONS: Intrauterine factors may have contributed to adverse neurological outcome, but 16/18 of the preterm cerebral palsy cases had an associated cerebral lesion which developed in the perinatal period.

Neonatal outcome after pregnancy complicated by abnormal velocity waveforms in the umbilical artery.

The neonatal outcome of 61 infants born after pregnancies complicated by absent or reversed end diastolic flow velocities (AREDFV) in the fetal umbilical artery was compared with that of 61 controls matched for gestational age born after high risk pregnancies with documented forward end diastolic flow velocities (EDFV). The AREDFV group was significantly more growth retarded, had lower platelet counts at birth, and were more likely to become significantly thrombocytopenic in the first week after birth. Owing to concerns about the possible increased risk of necrotising enterocolitis in newborn infants after AREDFV, this group was started on enteral feeds later and was more likely to receive parenteral nutrition than the EDFV group. Seven infants with AREDFV and one control infant developed necrotising enterocolitis.

Outcome at school age following antenatal detection of absent or reversed end diastolic flow velocity in the umbilical artery.

AIM: To determine whether fetal compromise, manifested by abnormalities of Doppler recordings of umbilical artery velocity waveforms in utero, is associated with neurodevelopmental or educational abnormalities at school age. METHODS: A cohort of neonates born following high risk pregnancies had been previously identified for a study of the perinatal sequelae of absent (AEDFV) and reversed (REDFV) end diastolic flow velocities. Seventy six children were assessed at 5-12 years of age by a developmental paediatrician who was blinded to perinatal course and Doppler assessments. Forty children born following pregnancies with forward end diastolic flow velocities (FEDFV), were compared with 27 with AEDFV and nine with REDFV. Tests of cognitive, neurological, and sensory function were performed, and reports of behavioural and educational progress were obtained from parents and teachers. RESULTS: There were no significant differences between FEDFV and AEDFV groups, but on tests of mental ability and neuromotor function the REDFV group had worse scores than either FEDFV or AEDFV. Comparing REDFV and FEDFV groups, the British Ability Scales general conceptual ability mean scores were 87.7 versus 101, and the Quick Neurological Screening Test mean scores were 32.8 versus 21.5. CONCLUSIONS: Absence of EDFV is well recognised as a marker of fetal compromise which is associated with acute perinatal sequelae. This study suggests it is not associated with adverse neurodevelopmental outcome. However, we found reversal of EDFV on antenatal assessment to be associated with a wide range of problems at school age, suggesting that REDFV represents intrauterine decompensation which may have adverse effects on the developing brain.

Clinical associations and time of onset of cerebral white matter damage in very preterm babies.

Neuropathological examinations were carried out at necropsy on 83 very pre-term babies who died during their first hospital admission. Forty seven (57%) babies had evidence of cerebral damage-39 with ischaemic white matter damage. The time of onset of ischaemic lesions was thought to be prenatal in 12 cases (31%) and postnatal in a further 12 (31%). The exact timing of damage could not be determined in 15 (38%) cases. Maternal and neonatal case notes were reviewed to ascertain clinical associations of ischaemic white matter damage. There were no clear associations between adverse clinical factors and prenatal ischaemic white matter damage. In contrast, pre-eclampsia, intrauterine growth retardation, and delivery without labour were associated with postnatal damage as were neonatal sepsis, necrotising enterocolitis, and seizures. The absence of a clear association between the timing of adverse clinical factors and the timing of ischaemic cerebral damage suggests that cerebral damage in very preterm babies may result from a sequence of events rather than one specific insult.

Timing and antecedents of periventricular haemorrhage and of cerebral atrophy in very preterm infants.

The brains of 95 consecutively admitted infants born at less than 33 weeks gestation were scanned with ultrasound. Thirty-six (38%) had periventricular haemorrhage (PVH). Eight (8%) had cerebral atrophy (together with PVH in 5). Twelve (40%) of the 30 infants in whom satisfactory timing of PVH was possible bled on the first day of life, but the median age when PVH was first detected was during the second day. The median age when PVH reached its maximum extent was the fourth day. The most significant antecedents of PVH were very short gestation and the presence of severe respiratory illness, particularly hyaline membrane disease, necessitating mechanical ventilation. Analysis of variance showed that pneumothorax arising during ventilation was the single most significant antecedent of PVH. Other significant antecedents, notably prolonged coagulation times, were found almost exclusively in infants with severe respiratory illness. Cerebral atrophy appeared usually to be attributable either to severe asphyxia during delivery or later, or to the formation of cysts at the site of previous haemorrhage into brain tissue.

Investigation of cerebral energy metabolism in newborn infants by phosphorus nuclear magnetic resonance spectroscopy.

31P NMR spectroscopy can be safely and successfully used to study cerebral energy metabolism in sick newborn infants, provided a suitable life support and monitoring system is available. Studies of normal infants have shown characteristic spectral peaks assigned to adenosine triphosphate, phosphocreatine, phosphodiesters plus phospholipids, inorganic orthophosphate, and a large peak at the phosphomonoester resonance frequency that is attributable mainly to phosphoethanolamine, a precursor of membrane phospholipids. Both the PCr/Pi and PCr/ATP ratios were lower in normal newborn infants than reported in studies using invasive techniques in adult animals. Tissue hypoxia-ischemia was associated with a fall in PCr levels and a rise in Pi. The PCr/Pi ratio, which is an index of cerebral energy status, was normal during the first day of life in infants who had suffered severe birth asphyxia, but subsequently fell to levels well below the normal range. The presence of this latent period raises the possibility of effective early treatment following birth asphyxia, before irreversible impairment of cellular energy metabolism occurs. Low PCr/Pi ratios have also been demonstrated in infants with idiopathic cerebral infarction, periventricular leukomalacia and inborn errors of metabolism. Preliminary experience suggests that ratios below 0.8 are associated with irrecoverable failure of energy metabolism and cellular necrosis. 31P NMRS and other spectroscopic NMR techniques utilizing, for instance, 1H and 13C nuclei, have exciting potential for exploring the mechanisms and methods of prevention of various forms of cerebral damage in the newborn period.

Magnetic resonance spectroscopy.

MRS is a noninvasive technique that does not use ionizing radiation and can be used to measure relative metabolite concentrations in human tissues and organs in vivo. Phosphorus MRS can be used to study energy metabolites and intracellular pH. The first neonatal applications were described in 1983 in a study of cerebral metabolism. Since then, the value of cerebral MRS as research tool and an investigative technique has been confirmed, and its prognostic power in asphyxiated infants has been established. Techniques of spatial localization and quantitation have been developed, but studies of other organs and the use of other nuclei remain at a very preliminary stage. Considering the huge potential of MRS and the proliferation of high field magnets primarily designed for imaging, there has been a disappointing lack of progress in the development of clinical and research applications of spectroscopy. The logistic differences of studying sick infants in strong magnetic fields make MRS a time-consuming and labor-intensive investigation, which will inevitably limit its widespread routine use. Research studies are hampered by the diversity of spectroscopic and signal processing techniques, which make comparisons of data from different groups impossible. Some techniques for the assessment of cerebral hemodynamics such as doppler ultrasound and near infrared spectroscopy have the advantage of being available at the cotside, but MRS is unique in providing quantitative information about a wide range of intracellular metabolites. The altricial development of MRS as a clinical investigative tool in neonatology can be ascribed partly to practical difficulties, but these should not detract from the exciting possibilities opened up by a technique that gives a noninvasive insight into intracellular chemistry. The metabolic information from MRS is an invaluable addition to the information provided by other techniques and will certainly play an important role in unraveling the sequence of events between an hypoxic-ischemic insult and cell death. A better understanding of these mechanisms is a prerequisite to the development of rational therapeutic maneuvers following asphyxial insults.

Cerebral monitoring in newborn infants by magnetic resonance and near infrared spectroscopy.

Phosphorus magnetic resonance spectroscopy (MRS) and near infrared spectroscopy (NIRS) have been used to study the brains of normal newborn infants and infants with cerebral disorders admitted to a neonatal intensive care unit. MRS, which involves transporting the infant to the spectrometer, allows measurement of mobile phosphorus compounds such as adenosine triphosphate and phosphocreatine in brain tissue, and has been performed on over 160 babies. NIRS gives cotside information about cerebral oxygenation and haemodynamics and has recently been introduced. These techniques, especially when used together, show promise of providing important information about the mechanisms and prognostic significance of hypoxic-ischaemic damage to the brain--the most important cause of permanent neurodevelopmental disabilities in infants who require intensive care.

Neonatal risk factors for cerebral palsy in very preterm babies: case-control study.

OBJECTIVE: To identify neonatal risk factors for cerebral palsy among very preterm babies and in particular the associations independent of the coexistence of antenatal and intrapartum factors. DESIGN: Case-control study. SETTING: Oxford health region. SUBJECTS: Singleton babies born between 1984 and 1990 at less than 32 weeks' gestation who survived to discharge from hospital: 59 with cerebral palsy and 234 randomly selected controls without cerebral palsy. MAIN OUTCOME MEASURES: Adverse neonatal factors expressed as odds ratios and 95% confidence intervals. RESULTS: Factors associated with an increased risk of cerebral palsy after adjustment for gestational age and the presence of previously identified antenatal and intrapartum risk factors were patent ductus arteriosus (odds ratio 2.3; 95% confidence interval 1.2 to 4.5), hypotension (2.3; 1.3 to 4.7), blood transfusion (4.8; 2.5 to 9.3), prolonged ventilation (4.8; 2.5 to 9.0), pneumothorax (3.5; 1.6 to 7.6), sepsis (3.6; 1.8 to 7.4), hyponatraemia (7.9; 2.1 to 29.6) and total parenteral nutrition (5.5; 2.8 to 10.5). Seizures were associated with an increased risk of cerebral palsy (10.0; 4.1 to 24.7), as were parenchymal damage (32; 12.4 to 84.4) and appreciable ventricular dilatation (5.4; 3.0 to 9.8) detected by cerebral ultrasound. CONCLUSION: A reduction in the rate of cerebral palsy in very preterm babies requires an integrated approach to management throughout the antenatal, intrapartum, and neonatal periods.

Reproducibility of measurement of pulsatility index by Doppler ultrasound of the anterior cerebral artery of preterm infants.

Ten preterm infants were each studied by three observers using a commercial duplex Doppler ultrasound scanner, in order to determine the intra-observer and inter-observer variability in the measurement of pulsatility index (PI) of the anterior cerebral artery. There was considerable difference in estimates of PI, with a mean range of 0.11 between the three observers for each infant. Intra-observer variability exceeded inter-observer variability and had a coefficient of variation of 8.4%. The five observers involved in this study had less than six months experience of duplex scanning. The results suggest that the PI can be measured with acceptable reproducibility by personnel with limited experience.

Neocerebellar hypoplasia in a neonate following intra-uterine exposure to anticonvulsants.

An infant with dysmorphic features was born to an epileptic mother who had taken phenytoin and sodium valproate throughout pregnancy. The infant began to have intractable seizures 10 minutes after delivery, and retrospective reports from the mother suggested they may have occurred in utero. Ultrasound examination of the brain showed a very wide subarachnoid space and CT confirmed cerebral and cerebellar underdevelopment. The infant died at three days of age and autopsy revealed a small brain with neocerebellar hypoplasia. This case might represent an extreme example of anticonvulsant teratogenicity.

Intravenous aminophylline and cerebral blood flow in preterm infants.

The effect of aminophylline on cerebral blood flow (CBF) was studied in 10 preterm infants who were receiving 6.2 mg/kg intravenously over 20 minutes followed by a maintenance infusion. CBF was measured intermittently using near infrared spectroscopy. Heart rate, blood pressure, oxygen saturation, and transcutaneously measured carbon dioxide tension (TcPCO2) were recorded continuously. Aminophylline administration was associated with a fall in CBF from a median of 15.9 ml/100 g/min to 11.2 ml/100 g/min. Median fall in CBF was 4.1 ml/100 g/min (95% confidence interval 1.7 to 6.5). Heart rate rose and TcPCO2 fell in all infants, median fall being 0.66 kPa. The reduction in CBF was greater than would be expected on the basis of the modest fall in TcPCO2.

Factors influencing colonisation with gentamicin resistant gram negative organisms in the neonatal unit.

The proportion of babies colonised with gentamicin resistant Gram negative organisms in a nursery over a 30 month period did not correlate with the quantity or duration of aminoglycosides used, but it did correlate with two indicators of workload: the number of baby days and a score based on the level of nursing care required. Spread of resistant organisms may be more likely as workload increases.

Reduced use of surface cultures for suspected neonatal sepsis and surveillance.

Data on infection in a neonatal unit were collected prospectively for seven years. After the first four years, the number of surface cultures obtained from neonates with suspected sepsis and for surveillance was reduced. Rates of systemic infection (sepsis and meningitis) were not significantly different in the four years before and the three years after this change. Reduction in surface culture information made no observable difference to detection of colonisation in neonates with early onset sepsis (within first 48 hours of life) nor to antibiotic choice in late onset sepsis. Decisions concerning the length of antibiotic course in suspected infection were not adversely affected. Reduction in the number of surface cultures led to considerable saving of time, effort, and cost while appearing safe in terms of clinical practice and outcome.

Periventricular intraparenchymal cerebral haemorrhage in preterm infants: the role of venous infarction.

Haemorrhage into cerebral parenchymal tissue supero-lateral to the angles of the lateral ventricles is a major cause of death and disability in preterm infants. It is frequently associated with germinal layer and intraventricular haemorrhage but the mechanism by which parenchymal haemorrhage occurs is uncertain. Recent studies have suggested that it is due to bleeding into tissue previously damaged by ischaemia following cerebral hypoperfusion. We have studied 68 preterm infant brains, of which four contained early intraparenchymal haemorrhage supero-lateral to the angles of the lateral ventricles which were associated with large germinal layer and intraventricular haemorrhages. The anatomical distribution and histological features of these haemorrhages suggested that they resulted from venous infarction and that the venous drainage of the periventricular tissues had been obstructed by the germinal layer haemorrhages. In these four infants, bleeding into parenchymal tissues could be regarded as a complication of germinal layer and intraventricular haemorrhage rather than of cerebral hypoperfusion.

Alpha-1-antitrypsin deficiency presenting as a bleeding diathesis in the newborn.

Three cases of alpha-1-antitrypsin deficiency are reported. Each infant presented in the newborn period with a haemorrhagic tendency which responded to vitamin K. Two of them subsequently developed cirrhosis, and Case 2 is one of the few reported cases in infantile cirrhosis associated with the heterozygous protease inhibitor (Pi) SZ phenotype. On the basis of these 3 patients we feel that the exclusion of alpha-1-antitrypsin deficiency by Pi phenotyping should be considered in any baby presenting with a bleeding diathesis, especially in view of the genetic implications of the homozygous Pi ZZ phenotype.

Precision of ultrasound diagnosis of pathologically verified lesions in the brains of very preterm infants.

Abnormalities detected by a mechanical sector scanner were compared 'blind' with autopsy findings in the brains of 56 infants born at less than 33 weeks gestation. Intraventricular haemorrhage was found in 53 of 112 hemispheres and had been accurately diagnosed by ultrasound (sensitivity 91 per cent; specificity 81 per cent). Isolated germinal layer haemorrhage was less successfully identified (sensitivity 61 per cent; specificity 78 per cent); false-positive diagnoses were partly due to difficulty in distinguishing haemorrhage from the normal choroid plexus in extremely preterm infants. Haemorrhagic parenchymal lesions were correctly identified in nine infants (sensitivity 82 per cent; specificity 97 per cent). Only 11 of 39 hemispheres with histological evidence of hypoxic-ischaemic injury, without marked bleeding, were correctly identified by ultrasound (sensitivity 28 per cent), mainly because of failure to detect small areas of periventricular leucomalacia and diffuse gliosis. 10 hemispheres with periventricular echodensities thought to represent leucomalacia showed no histological evidence of hypoxic-ischaemic injury (specificity 86 per cent). Ventricular dilatation in seven infants was always associated with evidence of hypoxic-ischaemic injury at autopsy.