Boys and girls differ in symptoms and neurodevelopmental outcome after perinatal metabolic acidosis, a population-based study.

AIM: To evaluate sex differences in infants born at term with metabolic acidosis with regard to perinatal health and symptomatology, and developmental outcome. METHODS: From a population-based cohort of infants born at term (n = 14 687), 78 were prospectively identified as having metabolic acidosis at birth. Two matched controls per case were selected. Sex differences in perinatal characteristics and in neurodevelopmental outcome at 6.5 years of age were analysed. Subgroup analysis was made based on need of neonatal care and planned follow-up. RESULTS: Acidotic boys who appeared healthy, that is with no need of specialised neonatal care respectively only followed at ordinary health care service, have worse perinatal symptoms and less favourable neurodevelopmental outcome compared to girls. The male disadvantage concerning neurodevelopmental outcome was also indicated in children without acidosis. Outcome at 6.5 years was associated with Apgar at 10 minutes (p = 0.03), need of neonatal care (p = 0.04) and sex (p = 0.02) but not acidosis per se (p = 0.54). CONCLUSION: Sex affected immediate symptomatology in term acidotic infants and neurodevelopmental outcome at the age of 6.5 years. The findings were seen in those who appeared healthy in the neonatal period. The results suggest that sex should be considered in assessment of acidotic children.

Delayed cortical impairment following lipopolysaccharide exposure in preterm fetal sheep.

OBJECTIVE: Preterm infants exhibit chronic deficits in white matter (WM) and cortical maturation. Although fetal infection/inflammation may contribute to WM pathology, the factors contributing to cortical changes are largely unknown. We examined the effect of fetal lipopolysaccharide (LPS) exposure on WM and cortical development as assessed by magnetic resonance imaging (MRI), electroencephalography (EEG), and histopathology in fetal sheep at preterm human equivalent age. METHODS: LPS was administered to fetal sheep at 102.5 ± 0.5 days of gestation. Continuous biophysical recordings were analyzed for 10 days after LPS. At postmortem, measurement of cerebral WM and cortical tissue volumes was achieved by stereological techniques. Specific effects of LPS on MRI-assessed T(1)-weighted and T(2)-weighted images, and immunohistochemical expression of oligodendrocytes, proliferating cells, cortical NeuN-positive and Nurr1-positive neurons (subplate marker), and cell death mechanisms were examined. RESULTS: We observed reductions in WM (~21%; LPS, 1.19 ± 0.04 vs control, 1.51 ± 0.07 cm(3); p < 0.001) and cortical (~18%; LPS, 2.34 ± 0.10 vs control, 2.85 ± 0.07 cm(3); p < 0.001) volumes, associated with overt and diffuse WM injury, T(1)-/T(2) -weighted signal alterations, and reduced numbers of WM oligodendrocytes (LPS, 485 ± 31 vs control, 699 ± 69 cells/mm(2); p = 0.0189) and NeuN-positive (LPS, 421 ± 71 vs control 718 ± 92 cells/mm(2); p = 0.04) and Nurr1-positive (control, 2.5 ± 0.6 vs LPS, 0.6 ± 0.1 cells/mm(2); p = 0.007) cortical neurons after LPS. Moreover, there was loss of the normal maturational increase in cortical EEG amplitude, which correlated with reduced cortical volumes. INTERPRETATION: Fetal exposure to LPS prior to myelination onset can impair both white matter and cortical development in a preclinical large animal model, supporting a role for maternal/fetal infection in the pathogenesis of preterm brain injury.

High-field diffusion tensor imaging characterization of cerebral white matter injury in lipopolysaccharide-exposed fetal sheep.

BACKGROUND: In gyrencephalic species such as sheep, precise anatomical and microstructural characterization of the consequences of fetal inflammation remains scarce. The goal of this study was to characterize changes in white matter (WM) structure using advanced magnetic resonance imaging (MRI) following lipopolysaccharide (LPS) exposure in the preterm-equivalent fetal sheep. METHODS: Preterm (0.7 gestation) fetal sheep received vehicle (Sham group) or LPS (LPS group), and fetal brains were collected 10 d later for subsequent ex vivo MRI. T1-weighted (T(1)W), T2-weighted (T(2)W), and diffusion tensor imaging (DTI) data were collected. RESULTS: Fetuses exposed to LPS exhibited reductions in WM volume and corpus callosum thickness at 10 d recovery. Characteristic patterns of diffuse and focal WM lesions (necrosis or cysts) could be identified by various T1, T2, and DTI signal changes. CONCLUSION: Fetal LPS exposure induces a pattern of injury characterized by diffuse and focal WM injury that closely reproduces that observed clinically in preterm infants. This work provides anatomical and microstructural MRI assessment, as well as histopathological correlates, of the consequences of LPS exposure in an animal model with a WM structure similar to that of the human brain. This work will help to further our understanding of MRI changes in preterm infants.

Swedish randomized controlled trial of cardiotocography only versus cardiotocography plus ST analysis of fetal electrocardiogram revisited: analysis of data according to standard versus modified intention-to-treat principle.

OBJECTIVE: To undertake a renewed analysis of data from the previously published Swedish randomized controlled trial on intrapartum fetal monitoring with cardiotocography (CTG-only) vs. CTG plus ST analysis of fetal electrocardiogram (CTG+ST), using current standards of intention-to-treat (ITT) analysis and to compare the results with those of the modified ITT (mITT) and per protocol analyses. METHODS: Renewed extraction of data from the original database including all cases randomized according to primary case allocation (n=5 049). MAIN OUTCOME MEASURE: Metabolic acidosis in umbilical artery at birth (pH <7.05, base deficit in extracellular fluid >12.0 mmol/l) including samples of umbilical vein blood or neonatal blood if umbilical artery blood was missing. RESULTS: The metabolic acidosis rates were 0.66% (17 of 2 565) and 1.33% (33 of 2 484) in the CTG+ST and CTG-only groups, respectively [relative risk (RR) 0.50; 95% confidence interval (CI) 0.28-0.88; p=0.019]. The original mITT gave RR 0.47, 95%CI 0.25-0.86 (p=0.015), mITT with correction for 10 previously misclassified cases RR 0.48, 95%CI 0.24-0.96 (p=0.038) and per protocol analysis RR 0.40, 95%CI 0.20-0.80 (p=0.009). The level of significance of the difference in metabolic acidosis rates between the two groups remained unchanged in all analyses. CONCLUSION: Re-analysis of data according to the ITT principle showed that regardless of the method of analysis, the Swedish randomized controlled trial maintained its ability to demonstrate a significant reduction in metabolic acidosis rate when using CTG+ST analysis for fetal surveillance in labor.

Atresia of the submandibular duct orifices: an unusual cause of feeding problems and failure to thrive in an infant.

UNLABELLED: Atresia of the submandibular duct orifice is a rare developmental anomaly, which causes swelling of the duct by accumulation of saliva. The cystic mass in the floor of the mouth can cause feeding problems, which can be treated by surgical opening of the duct. We report the first Swedish case in a male infant, who had severe difficulties to feed because of bilateral swellings of the submandibular ducts caused by orifice atresia. CONCLUSION: This is the first case that has described failure to thrive because of this condition and catch up after treatment. It is important to remember that evaluation of feeding problem in an infant must include inspection of the oral cavity.

EEG and spectral edge frequency: analysis in posthypoxic newborn piglets.

OBJECTIVE: To evaluate the frequency content of the electroencephalogram (EEG) during recovery after a severe hypoxic insult in newborn piglets. METHODS: EEG was continuously monitored in nine newborn piglets exposed to a severe hypoxic period. Power spectra in five frequency bands were calculated using Fourier transformation. Spectral edge frequency 90 (SEF90) was defined as the frequency below which 90% of the power in the EEG was located. The piglets were divided into two groups; Group 1 represented piglets with some EEG recovery and Group 2 represented piglets without any EEG recovery. RESULTS: The recovery of the EEG in Group 1 had the same time course in all frequency bands. SEF90 indicates recovery earlier than the value of total power. But SEF90 also signals activity in the EEGs that were almost completely suppressed. When SEF90 was calculated during periods of periodic EEG activity during the very early phase of recovery, the values fell within the same range as during the control period. CONCLUSION: Spectral analysis of continuous EEG in newborn piglets exposed to very severe hypoxia showed that no specific frequency band of the EEG preceded the other ones during recovery. The results of the SEF90 measure, demonstrates the need for critical analysis of the raw EEG before any reliable estimation of cerebral function can be made.

The paediatrician--past, present and future--a conversation with Nils Rosén von Rosenstein.

UNLABELLED: An imagined conversation takes place with the author of the first textbook of Paediatrics, Nils Rosén von Rosenstein. Enormous progress in the prevention and treatment of diseases of children is demonstrated. But a different spectrum of diseases has replaced the old one. And in spite of unprecedented material well-being a substantial minority of our children cannot make full use of their capabilities. CONCLUSION: We must resume the full responsibility for our children and act as their advocates in society.

ST analysis of the fetal electrocardiogram - Comments on recent experimental data.

In their paper, Andriessen at al present a validation of fetal ECG analysis and the clinical STAN device in midgestation fetal lambs exposed to 25 minutes of umbilical cord occlusion. The study presents results that contrast remarkably from previously published experimental data which raises a number of questions and comments. The most striking finding of Andriessen et al is the recording of an extremely high number of alarms from the STAN equipment during control conditions when no alarms at all are expected. These patterns have never been seen, neither in the clinical situation nor in our own fetal sheep studies. The reason for this becomes apparent when their way of recording the FECG is scrutinized. In their assessment of STAN, Andriessen at al use an assumed negative aVF lead with the assumption that it will reflect the FECG in the same way as the unipolar scalp lead used clinically. The signal used for disqualification of STAN is itself not qualified to properly represent the fetal scalp lead signal that STAN is designed for. To question a proven technology is fully accepted but those attempting would be asked to argue along fully validated data and related analysis including questioning of their own data.

Neurochemical markers of brain damage in cerebrospinal fluid during induction treatment of acute lymphoblastic leukemia in children.

BACKGROUND: Central nervous system (CNS) irradiation has been replaced by systemic high-dose methotrexate (MTX) and intrathecal MTX in acute lymphoblastic leukemia treatment due to the risk of late effects. However, treatment without CNS irradiation might also cause brain damage. PROCEDURE: Cerebrospinal fluid (CSF) was analyzed in 121 patients in an attempt to detect CNS injury. Seventy-three samples were analyzed for neuron-specific enolase (NSE), 108 for glial fibrillary acidic protein (GFAp), 110 for neurofilament protein light chain (NFp), and 70 for ascorbyl radical (AsR). Samples were taken at day 0, 8, 15, and 29 during induction treatment, including intrathecal MTX. Levels at days 8, 15, and 29 were compared with the levels before treatment. RESULTS: NSE levels were 9.0 (+/-3.5) microg/L (mean (+/-SD)) at day 0, 15.0 (+/-5.3) at day 8 (P < 0.001), 13.6 (+/-4.7) at day 15 (P < 0.001) and 11.1 (+/-4.3) at day 29 (P < 0.001). GFAp were 177 (+/-98) ng/L at day 0, 206 (+/-101) at day 8 (P < 0.001), 200 (+/-106) at day 15 (n.s.) and 228 (+/-137) at day 29 (P < 0.001). NFp were below the detection limit 125 ng/L at day 0 in all 110 CSF samples analyzed, and increased significantly above the detection limit in 6/77 samples at day 8, in 11/84 at day 15 and in 22/91 at day 29. The AsR content did not change significantly. CONCLUSIONS: Levels of NSE, GFAp, and NFp increased in CSF, which can be interpreted as early signs of brain damage. AsR levels do not show any convincing signs of oxidative stress.

Sex differences in electrocortical activity in human neonates.

Cerebral cortical activity in healthy, full-term human neonates (10 boys and 10 girls) was evaluated using spectral estimation of electroencephalogram frequency content with new equipment and analysis technique allowing the assessment of the lowest frequencies (i.e. infraslow waves). The activity was analysed under quiet sleep and active wakefulness taking sex into consideration. During sleep, the mean amount of infraslow activity was 27% larger in boys, whereas during wakefulness the average amount of higher frequencies was 17% larger in girls. Both these differences indicate an earlier maturation of cortical function in girls than in boys.

Pathophysiology of foetal oxygenation and cell damage during labour.

A foetus exposed to oxygenation compromise is capable of several adaptive responses, which can be categorised into those affecting metabolism and those affecting oxygen transport. However, both the extent and duration of the impairment in oxygenation will have a bearing on these adaptive responses. Although intrapartum events may account for no more than one-third of cases with an adverse neurological outcome, they are important because they can be influenced successfully. This review describes the mechanisms underlying foetal hypoxia during labour, acid-base balance and gas exchange, and the current scientific understanding of the role of intrauterine asphyxia in the pathophysiology of neonatal encephalopathy and cerebral palsy. Although the mechanisms involved include similar initiating events, principally ischaemia and excitotoxicity, and similar final common pathways to cell death, there are certain unique maturational factors that influence the type and pattern of cellular injury.

Spectroscopy study of the dynamics of the transencephalic electrical impedance in the perinatal brain during hypoxia.

Hypoxia/ischaemia is the most common cause of brain damage in neonates. Thousands of newborn children suffer from perinatal asphyxia every year. The cells go through a response mechanism during hypoxia/ischaemia, to maintain the cellular viability and, as a response to the hypoxic/ischaemic insult, the composition and the structure of the cellular environment are altered. The alterations in the ionic concentration of the intra- and extracellular and the consequent cytotoxic oedema, cell swelling, modify the electrical properties of the constituted tissue. The changes produced can be easily measured using electrical impedance instrumentation. In this paper, we report the results from an impedance spectroscopy study on the effects of the hypoxia on the perinatal brain. The transencephalic impedance, both resistance and reactance, was measured in newborn piglets using the four-electrode method in the frequency range from 20 kHz to 750 kHz and the experimental results were compared with numerical results from a simulation of a suspension of cells during cell swelling. The experimental results make clear the frequency dependence of the bioelectrical impedance, confirm that the variation of resistance is more sensitive at low than at high frequencies and show that the reactance changes substantially during hypoxia. The resemblance between the experimental and numerical results proves the validity of modelling tissue as a suspension of cells and confirms the importance of the cellular oedema process in the alterations of the electrical properties of biological tissue. The study of the effects of hypoxia/ischaemia in the bioelectrical properties of tissue may lead to the development of useful clinical tools based on the application of bioelectrical impedance technology.

A simple and rapid method for the determination of "free" iron in biological fluids.

We present a convenient method for determining "free" or non-protein-bound iron in biological fluids. The new method is based on the bathophenantroline method for determination of total serum iron, and comprises binding of iron by a chromogenic chelator (bathophenantroline-disulphonate, BPS), which is specific for ferrous iron. The ferrous complex of BPS absorbs strongly at 535 nm, and the detection limit is less than 1 microM in a sample size of 50 microliters. The chelator does not liberate iron from either haemoglobin or transferrin. Interference from copper or zinc in concentrations up to 50 microM does not significantly disturb measurements. The main problem when measuring in blood plasma, the high and fluctuating background in the region around 535 nm, has been overcome through filtering techniques. Data from measurements of ferrous iron in microdialysate, cerebrospinal fluid, and blood plasma in different animal models and clinical conditions are presented as illustrative examples of the usefulness of the method. The method allows the determination of ferric, as well as ferrous, iron in the same sample.

Visual evoked potentials in disproportionately growth-retarded human neonates.

To study brain function in the neonatal period, disproportionately growth-retarded (n = 33) and appropriately grown (n = 21) infants were examined using Doppler flow velocities prenatally and visual evoked potentials postnatally. Visual evoked potentials recordings were made at gestation of 40 and 46 weeks. The group of growth-retarded infants had significantly prolonged latencies to both of the two major peaks (designated P and N), most pronounced for the P peak. This result was observed at both ages investigated and corresponds to a developmental delay of 3 weeks. For individuals, the increase in P latency correlated to prenatal flow indices and to neonatal anthropometric parameters indicative of growth retardation. We conclude that in utero growth retardation affects brain development as assessed by visual evoked potentials in the neonatal period. This developmental delay may be produced by intracerebral factors during the process of growth retardation, and these alterations may have a prognostic value.

Remote sessions and frequency analysis for improved insight into cerebral function during pediatric and neonatal intensive care.

A project involving recording and analysing EEG together with cardiovascular signals and temperature has been initiated. The aim of this project is to establish difficulties and possibilities involved with implementing a system for remote sessions and analysing EEG in correlation with other physiological signals. One objective is to find indicators of cerebral function during postasphyxia neonatal intensive care and pediatric cardiopulmonary bypass surgery with hypothermia. Remote sessions for joint interpretation have been carried out between pediatricians and clinical neurophysiologists, and EEG has been analyzed using frequency analyzing tools. One result is the discovery of reversible spectral changes coinciding with blood pressure falls, which may indicate loss of autoregulation function. This finding is one outcome from initial use of a system, developed during the project to facilitate communication about, and analysis of the recorded signals. Thus, already from a limited number of remote sessions and the use of basic signal processing techniques, important results have been achieved and better insight has been gained of how cerebral function is affected by cardiopulmonary bypass surgery. In this paper, we present our experiences from introducing a system for remote consultations, and evaluate the use for such a system in the current applications.

Developmental outcome at 6.5 years after acidosis in term newborns: a population-based study.

OBJECTIVES: Infants who develop encephalopathy after perinatal asphyxia have an increased risk of death and adverse neurologic outcome. Conflicting results exist concerning outcome in healthy infants with metabolic acidosis at birth. The aim of the current study was to evaluate whether metabolic acidosis at birth in term infants who appear healthy is associated with long-term developmental abnormalities. METHODS: From a population-based cohort (14,687 deliveries), 78 infants were prospectively identified as having metabolic acidosis (umbilical artery pH < 7.05 and base deficit in the extracellular fluid >12.0 mmol/L). Two matched controls per case were selected. The child health and school health care records were scrutinized for developmental abnormalities. RESULTS: Outcome measures at 6.5 years of age for 227 of 234 children (97%) were obtained. No differences were found concerning neurologic or behavioral problems in need of referral action or neurodevelopmental diagnosis in comparison of control children with acidotic children who had appeared healthy at birth, ie, had not required special neonatal care or had no signs of encephalopathy. CONCLUSIONS: Infants born with cord metabolic acidosis and who appear well do not have an increased risk for neurologic or behavioral problems in need of referral actions or special teaching approaches at the age of 6.5 years.

Automatic classification of background EEG activity in healthy and sick neonates.

The overall aim of our research is to develop methods for a monitoring system to be used at neonatal intensive care units. When monitoring a baby, a range of different types of background activity needs to be considered. In this work, we have developed a scheme for automatic classification of background EEG activity in newborn babies. EEG from six full-term babies who were displaying a burst suppression pattern while suffering from the after-effects of asphyxia during birth was included along with EEG from 20 full-term healthy newborn babies. The signals from the healthy babies were divided into four behavioural states: active awake, quiet awake, active sleep and quiet sleep. By using a number of features extracted from the EEG together with Fisher's linear discriminant classifier we have managed to achieve 100% correct classification when separating burst suppression EEG from all four healthy EEG types and 93% true positive classification when separating quiet sleep from the other types. The other three sleep stages could not be classified. When the pathological burst suppression pattern was detected, the analysis was taken one step further and the signal was segmented into burst and suppression, allowing clinically relevant parameters such as suppression length and burst suppression ratio to be calculated. The segmentation of the burst suppression EEG works well, with a probability of error around 4%.