ABSTRACT. To investigate the prognostic significance of abnormalities of oxidative phosphorylation, the brains of 61 newborn infants born at 27-42 wk of gestation and suspected of hypoxic-ischemic brain injury were examined by surface-coil phosphorus magnetic resonance spectroscopy. Of these infants, 23 died, and the neurodevelopmental status of the 38 survivors was assessed at 1 y of age. Of the 28 infants whose phosphocreatine/inorganic orthophosphate (PCr/Pi) ratios fell below 95% confidence limits for normal infants, 19 died, and of the nine survivors, seven had serious multiple impairments (sensitivity 74%, specificity 92%, positive predictive value for unfavorable outcome 93%). Of the 12 infants with ATP/total phosphorus ratios below 95% confidence limits 11 died (sensitivity 4774 specificity 97%, positive predictive value 91%). Among the 46 infants with increased cerebral echodensities, PCr/Pi was more likely to be low, and prognosis poor, in infants whose echodensities were diffuse or indicated intraparenchymal hemorrhage than in infants whose echodensities were consistent with periventricular leukomalacia. We conclude that when reduced values for PCr/ Pi indicating severely impaired oxidative phosphorylation are found in the brains of infants suspected of hypoxicischemic injury, the prognosis for survival without serious multiple impairments is very poor, and that when ATP/ total phosphorus is reduced, death is almost inevitable. (Pediatr Res 25445-451, 1989) Abbreviations 31P MRS, phosphorus magnetic resonance spectroscopy PCr, phosphocreatine Pi, inorganic orthophosphate PME, phosphomonoester PDE, phosphodiester total P, total mobile phosphorus pHi, intracellular pH BE, base excess SDS, standard deviation score GQ, Griffiths general quotient PVL, periventricular leukomalacia energy metabolism in the brain tissue of newborn infants (1, 2). pH, can also be estimated.In previous investigations, we found that abnormalities indicating abnormal oxidative phosphorylation were detectable in the brain after birth asphyxia (3) and in the presence of cerebral echodensities detected by ultrasound that are associated with various forms of hypoxic-ischemic brain injury (4). In the latter study, it was shown that evidence of severely abnormal oxidative phosphorylation was related to subsequent loss of brain tissue. The purpose of the present investigation was to explore the prognostic significance of abnormalities of oxidative phosphorylation for survival and for neurodevelopmental status at 1 y of age in a group of infants suspected of hypoxic-ischemic brain injury.

SUMMARY The brains of 158 consecutively admitted very preterm infants were repeatedly examined with real time ultrasound. Abnormalities, most commonly periventricular haemorrhage, were detected in 79 (50 %). The 109 infants who survived were followed up until they were 16-23 months old. Major or minor neurological or developmental sequelae were found in 5 of 62 infants (8 %) with normal ultrasound scans and in an identical proportion, 2 of 25 infants (8 %), with uncomplicated periventricular haemorrhage. By contrast, 15 of 21 infants (71 %) whose ventricles became enlarged (with or without periventricular haemorrhage) had abnormalities at follow up. The proportion with sequelae depended on the cause and extent of the enlargement. Three of 8 infants (38%) with mild (usually transient) ventricular distension had sequelae, compared with 3 of 4 (75 %) with hydrocephalus and 9 of 9 (100%) with cerebral atrophy (2 of whom also had hydrocephalus). Adverse neurodevelopmental sequelae at follow up appeared more often to be attributable to cerebral ischaemia and infarction than to periventricular haemorrhage.

This study addressed the hypothesis that in human infants severe in utero insults induce a significant proportion of brain cells to undergo apoptosis. Morphologic criteria were used to quantify apoptosis and necrosis in the cingulate gyrus of two groups of infants: six infants who died after severe birth asphyxia with hypoxic-ischemic encephalopathy, and six others who suffered unexpected and apparently sudden intrauterine death at or close to term. The fraction of apoptotic cells was much higher than basal levels determined in animal experiments, and within both groups increased in proportion to the severity of injury as determined by total cell death (p < 0.05). The mean fraction of apoptotic cells was similar in asphyxiated infants, 8.3% (95% confidence interval for the population, 3.7-12%), and in stillbirths, 6.7% (0.2-13.6%). In the asphyxiated group, 20.8% (11-30.6%) of cells were necrotic, but significantly less necrosis, 3% (0.4-5.6%), was seen in stillborn infants (p < 0.05). Cell death was apoptotic after birth asphyxia in 26% (1-51%) and 78% (41-100%) in stillborn infants. In situ end labeling studies confirmed the presence of DNA fragmentation in apoptotic cells. These results demonstrate that infants who die after intrauterine insults, both those with evidence of delayed cerebral injury after hypoxia-ischemia and those without, have a significant number of cells in the brain with the morphologic characteristics of apoptosis. They confirm that apoptosis contributes significantly to cerebral damage in the perinatal period.

SUMMARY The eyes of 177 very preterm (<33 weeks' gestation) infants, born between 1979 and 1982 and admitted to a neonatal intensive care unit, were examined as part of an ongoing follow-up study of neurodevelopmental outcome. Ocular pathology was diagnosed in 37 (21%) of the 177 infants: 14 (8%) had retinopathy of prematurity (ROP)-progressive in three-and nine (5%) infants had delayed visual maturation (DVM). The ocular pathology was permanent in 26 (15%) of the 177 infants. Refractive errors were the commonest problem and accounted for permanent sequelae in eight of the 14 infants with ROP and two of the nine with DVM. The presence or absence of ROP was related to a wide range of prospectively coded perinatal variables and to the results of routine neonatal ultrasound brain scans and neurodevelopmental follow-up assessments made in the first 18 months of life. As in previous studies, infants with ROP were of shorter gestation, lower birth weight, and required oxygen therapy for longer than unaffected infants, but the condition was only weakly associated with other indices of respiratory illness. In contrast, ROP was strongly associated with evidence of brain damage, often consistent with hypoxic ischaemic injury. We conclude that an underlying lesion in ROP may be hypoxic ischaemic damage to the retinal circulation.

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.