[The toxicity of bilirubin to the central nervous system]. / La toxicité de la bilirubine sur le système nerveux central.

Whatever the causes of its accumulation, excessive production and/or insufficient elimination, unconjugated bilirubin when it reaches a certain concentration threshold, is responsible for neurones and astrocytes death. In this paper the mechanisms involved in this process of cellular death, from hemolysis to oxydation in neurons and neuroglial cells, are reviewed.

Intracellular generation of free radicals and modifications of detoxifying enzymes in cultured neurons from the developing rat forebrain in response to transient hypoxia.

To address the influence of oxidative stress and defense capacities in the effects of transient hypoxia in the immature brain, the time course of reactive oxygen species generation was monitored by flow cytometry using dihydrorhodamine 123 and 2',7'-dichlorofluorescein-diacetate in cultured neurons issued from the fetal rat forebrain and subjected to hypoxia/reoxygenation (6 h/96 h). Parallel transcriptional and activity changes of superoxide dismutases, glutathione peroxidase and catalase were analyzed, in line with cell outcome. The study confirmed hypoxia-induced delayed apoptotic death, and depicted increased mitochondrial and cytosolic productions of free radicals (+30%) occurring over the 48-h period after the restoration of oxygen supply, with sequential stimulations of superoxide dismutases. Whereas catalase mRNA levels and activity were augmented by cell reoxygenation, glutathione peroxidase activity was transiently repressed (-24%), along with reduced glutathione reductase activity (-27%) and intracellular glutathione depletion (-19%). Coupled with the neuroprotective effects of the glutathione precursor N-acetyl-cysteine (50 microM), these data suggest that hypoxia/reoxygenation-induced production of reactive oxygen species can overwhelm glutathione-dependent antioxidant capacity, and thus may contribute to the resulting neuronal apoptosis.

Transcutaneous bilirubin measurement: a multicenter evaluation of a new device.

OBJECTIVES: The early discharge of neonates from hospitals makes transcutaneous measurement of total bilirubin concentration a useful tool to monitor neonatal jaundice. The objectives of this study were to determine whether 1) transcutaneous bilirubin (TcB) measurement, as performed using BiliCheck (BC), correlates with total serum bilirubin (TSB) levels, measured with standard laboratory methods and with high-pressure liquid chromatography (HPLC-B); 2) infant race, gestational age, postnatal age, or body weight interferes with the measurement of TcB levels in newborn infants; 3) the variability of the TcB measurement is comparable to the variability of TSB measurements; and 4) TcB measurements obtained from the forehead (BCF) and sternum (BCS) generate comparable results. STUDY DESIGN: Newborn infants who were <28 days and >30 weeks' gestational age and who underwent tests for TSB as part of their normal care in 6 different European hospitals were studied. A total of 210 infants were enrolled in the study, 35 at each site. Near simultaneous (within +/- 30 minutes) blood collection for TSB and BCF and BCS measurements were performed. TSB levels were determined by the serum bilirubin method in use at each site, and all HPLC-B determinations were made at the same, independent laboratory. RESULTS: The study group consisted of 140 white, 31 Asian, 14 Hispanic, 9 African, and another 16 newborns of different races. The correlation coefficient (r) between BCF and HPLC-B was 0.890 (95% confidence interval = 0.858-0.915). BCF and BCS generated similar results (r value = 0.890 for BCF and 0.881 for BCS), even if BCS slightly overestimated (mean error = -0.04 mg/dL) and BCF slightly underestimated (mean error = 0.96 mg/dL) in comparison with HPLC-B. Analysis of covariance demonstrated that BC accuracy was independent of race, birth weight, gestational age, and postnatal age of the newborn. Receiver operating characteristic curves were evaluated for BCF and TSB, each compared with HPLC-B. With the use of a cutoff point for HPLC-B of 13 mg/dL (222 micromol/L) and a cutoff of 11 mg/dL on the BCF and TSB, similar sensitivity/specificity (93%/73% for BCF, 95%/76% for TSB) were observed. The use of a cutoff point for HPLC-B of 17 mg/dL (290 micromol/L) and 14 mg/dL (240 micromol/L) for BCF and TSB also produced similar sensitivity/specificity (90%/87% for the BC and 87%/83% for TSB). CONCLUSIONS: Because the correlation coefficient for HPLC-B and BCF is very similar to that found for HPLC-B and laboratory TSB, BC could be used not only as a screening device but also as a reliable substitute of TSB determination. At higher levels of TSB, in which phototherapy and/or exchange transfusion might be considered, BC performed slightly better than the laboratory. The accuracy and precision of the TcB measurement in this study was observed to be comparable to the standard of care laboratory test.

Bilirubin exerts additional toxic effects in hypoxic cultured neurons from the developing rat brain by the recruitment of glutamate neurotoxicity.

Both hypoxia and bilirubin are common risk factors in newborns, which may act synergistically to produce anatomical and functional disturbances of the CNS. Using primary cultures of neurons from the fetal rat brain, it was recently reported that neuronal apoptosis accounts for the deleterious consequences of these two insults. To investigate the influence of hypoxia, bilirubin, or their combination on the outcome of neuronal cells of the immature brain, and delineate cellular mechanisms involved, 6-d-old cultured neurons were submitted to either hypoxia (6 h), unconjugated bilirubin (0.5 microM), or to combined conditions. Within 96 h, cell viability was reduced by 22.7% and 24.5% by hypoxia and bilirubin, respectively, whereas combined treatments decreased vital score by 34%. Nuclear morphology revealed 13.4% of apoptotic cells after hypoxia, 16.2% after bilirubin, and 22.6% after both treatments. Bilirubin action was specifically blocked by the glutamate receptor antagonist MK-801, which was without effect on the consequences of hypoxia. Temporal changes in [(3)H]leucine incorporation rates as well as beneficial effects of cycloheximide reflected a programmed phenomenon dependent upon synthesis of selective proteins. The presence of bilirubin reduced hypoxia-induced alterations of cell energy metabolism, as reflected by 2-D-[(3)H]deoxyglucose incorporation, raising the question of free radical scavenging. Measurements of intracellular radical generation, however, failed to confirm the antioxidant role of bilirubin. Taken together, our data suggest that low levels of bilirubin may enhance hypoxia effects in immature neurons by facilitating glutamate-mediated apoptosis through the activation of N:-methyl-D-aspartate receptors.

[Combined neuronal toxicity of bilirubin and hypoxia. Study of cultured rat neurons]. / Toxicité neuronale combinée de la bilirubine et de l'hypoxie. Etude sur des neurones de rat en culture.

UNLABELLED: Clinical observations suggest that bilirubin encephalopathy is often seen in newborn infants presenting not only with hyperbilirubinemia but also with alterations in oxygen transport like in severe anaemia. Since bilirubin and hypoxia have been shown to be detrimental to the central nervous system, the present study was designed to test the additional effects of the two insults on the outcome of cultured neurons from the forebrain of 14 day-old embryos. After 6 days in vitro, neurons were exposed either to bilirubin (0.5 microM) or to bilirubin and hypoxia for 6 hours. Thereafter, cells were reoxygenated for 96 hours in standard conditions. Control cells were kept in normoxia. Cell viability was assessed by the methyltetrazolium method. Cell death (apoptosis or necrosis) was characterized by fluorescent nuclear staining with DAPI. Rates of protein synthesis and energy metabolism in neurons were measured by [3H]leucine and [3H]2-deoxyglucose incorporation, respectively. Data are reported as percentages of change as compared to controls. Each experiment involved 5 to 10 dishes per time point and was repeated 2 to 4 times. RESULTS: Bilirubin reduced cell viability by 24.5% vs controls (p < 0.001) at 96 h while 16% of the neurons exhibited morphological features of apoptosis (p < 0.001). The combination of hypoxia with bilirubin induced a 34% decrease in cell viability (p < 0.001) and the percentage of apoptotic cells was higher than after the exposure to hypoxia or to bilirubin alone. The rate of protein synthesis increased significantly in all experimental conditions as early as 1 h after the onset of the insult and at 48 h post reoxygenation. It increased again at 72 h in the cells exposed to bilirubin or to bilirubin and hypoxia. These sequential changes in synthesis of specific proteins seem to be involved in delayed neuronal death. Bilirubin decreased significantly [3H]2-deoxyglucose incorporation at 24 h while it increased when the neurons were exposed to both bilirubin and hypoxia (+60%, p < 0.001) and decreased thereafter. These data confirm the deleterious effects of bilirubin on neuronal viability, on protein synthesis and metabolic rates. The combination of bilirubin with hypoxia resulted in stronger detrimental effects on neurons than bilirubin alone.

Bilirubin induces apoptosis via activation of NMDA receptors in developing rat brain neurons.

Increased amounts of bilirubin, the end product of heme degradation, are known to be detrimental to the central nervous system, especially in preterm newborns. In an attempt to delineate the cellular mechanisms by which unconjugated bilirubin exerts its toxic effects on neuronal cells in the developing brain, bilirubin (0.25-5 microM) was added to the extracellular medium of 6-day-old primary cultured neurons from the embryonic rat forebrain, and cell alterations were studied over the ensuing 96 h. Bilirubin decreased cell viability dose dependently with an ED(50) around 1 microM. At the dose of 0.5 microM, it triggered delayed cell death that affected 24% of the neurons. Nuclear incorporation of the fluorescent dye DAPI (4,6-diamidino-2-phenylindole) depicted the presence of apoptosis (16%). Apoptosis features were confirmed by DNA fragmentation reflected by a progressive loss of [(3)H]thymidine and sequential changes in macromolecular synthesis, as shown by the time course of [(3)H]leucine incorporation, as well as by the beneficial effects of cycloheximide and caspase inhibitors. In parallel, treatments with glutamate receptor antagonists showed that MK-801, but not NBQX, protected neurons against bilirubin neurotoxicity, suggesting a role for NMDA receptors in bilirubin effects. Coupled with previous work about glutamate toxicity in the same culture model, these data support the hypothesis that low levels of free bilirubin may promote programmed neuronal death corresponding to an apoptotic process which involves caspase activation and requires the participation of NMDA receptors, along with bilirubin-induced inhibition of protein kinase C activity.

[Efficacy and limits of rescue high-frequency oscillatory ventilation in the treatment of hyaline membrane disease in preterm newborns]. / Efficacité et limites de la ventilation par oscillations à haute fréquence après échec de la ventilation conventionnelle chez des prématurés atteints de maladie des membranes hyalines sévère.

UNLABELLED: Conflicting reports of high-frequency oscillatory ventilation (HFOV) use as an alternative to conventional mechanical ventilation have been published. This retrospective study has evaluated the efficacy and safety of rescue HFOV in preterm infants with severe hyaline membrane disease (HMD) after the failure of conventional mechanical ventilation (CMV). POPULATION AND METHODS: All newborns hospitalized in our neonatal intensive care unit (NICU) from 10.1.1993 to 15.4.1995 with CMV failure, defined as the need for more than 55% FiO2 without any improvement for at least six hours, have been retrospectively studied. The infants were shared according to the absence (Gr I) or the presence (Gr II) of persistent pulmonary hypertension of neonate (PPHN) in addition to HMD before HFOV. RESULTS: Gestational age (GA) was 29.2 +/- 3.7 weeks (mean +/- SD) in Gr I and 30.3 +/- 2.8 in Gr II. Birth weight was 1379 +/- 750 g and 1471 +/- 612 g, respectively. As soon as three hours after the onset of HFOV in both groups, a dramatic improvement was observed with a FiO2 drop from 82 +/- 20% to 64.8 +/- 25.5% (P < 0.01). Among the infants, 62% survived without any major disability and 28% died (46% in Gr II vs 12% in Gr I, P < 0.01). A trend towards a worsening of pre-existing brain lesions has been noticed. An increased risk of mortality was observed when a secondary worsening in O2 requirements occurred 24 hours after the onset of HFOV, despite an initial significant improvement. SGA was also associated with a poor prognosis (46% of the deaths vs 29% for AGA infants, P < 0.05). CONCLUSION: HFOV has been successfully used in premature infants with severe respiratory disease and failure of CMV. Criteria of poor prognosis were PPHN and SGA, or a secondary worsening in oxygen requirements after initial improvement. A trend towards aggravation of pre-existing brain lesions has been noticed after HFOV. This aggravation is more frequent when PPHN is associated with HMD. This observation suggests caution for HFOV use when these conditions are present in premature infants.

Severe side effects and drug plasma concentrations in preterm infants treated with doxapram.

A high-performance liquid chromatography method has been developed for simultaneous determination of doxapram and its metabolites including ketodoxapram, the main and only active metabolite. The aim of the study was to evaluate this microtechnique and to report the cases involving severe adverse effects to determine toxic plasma levels in neonates. The method was found to be selective, and showed a good baseline separation of doxapram and metabolites. Recovery, linearity, intraday/interday precision, and limit of detection determined in aqueous solutions and in spiked plasma were satisfactory. The assay is simple, rapid, and plasma-sparing, which represents a true advantage in managing neonates. Case analysis was performed in two consecutive periods: 124 preterm infants in the first period and 173 in the second period. Severe toxic effects were observed in 4 cases in the first period, with doxapram plus keto-doxapram levels 9 mg/L. In the second period, only one case was observed. High-range plasma concentrations were significantly less frequent in the second period than in the first one. The authors conclude that measuring doxapram plus keto-doxapram in plasma may be of interest to avoid severe toxic effects in preterm neonates treated with doxapram.

[Physiopathology of neonatal hyperbilirubinemia]. / Physiopathologie de l'hyperbilirubinémie néonatale.

The most important steps of bilirubin metabolism involved in the pathophysiology of neonatal hyperbilirubinemia are: 1) hemoglobin degradation by heme oxygenase; 2) bilirubin binding to serum albumin; 3) bilirubin conjugation to acid glucoronic by glucoronyl transferase. Progress in the knowledge of these metabolic steps allows to understanding of why massive hemolysis, infections, hypoxia and prematurity increase the risk of kernicterus and therefore justify adapted preventive and therapeutic measures.

Cerebral metabolic consequences of neonatal pathologies in the immature rat.

The cerebral metabolic consequences of hypoxia, seizures and hyperbilirubinemia were explored in immature rates between the postnatal age of 10 (P10) and 21 days (P21) by the quantitative autoradiographic [14C]2-deoxyglucose technique. The effects of a previous bilirubin exposure on cerebral regional permeability to bilirubin were measured by autoradiography. Hypoxia was induced by breathing a 7% N2/93% O2 gas mixture and seizures were initiated by injections of pentylenetetrazol. Hyperbilirubinemia was induced by the perfusion of a bilirubin/albumin solution. Hypoxia and seizures induced a general increase in cerebral metabolic rates to glucose (LCMRglc) in P10 rats, except in hippocampus during seizures. At P14, LCMRglc remained increased during seizures, except in the hippocampus. During hypoxia LCMRglc were unchanged in the genu of the corpus callosum and the anterior commissure and decreased in the cerebellar white matter. At P21, LCMRglc decreased in all white matter regions during hypoxia and in the hippocampus during seizures, while they were unchanged in the amygdala and increased in the nucleus of the solitary tract. During hyperbilirubinemia, LMCRglc decreased at all ages with very marked changes in the nucleus of the auditory nerve at P10 and in the inferior colliculus at P21 (72-86%). Twofold decreases were also recorded in the hippocampus. The basic regional cerebral permeability to the anion was higher at P10 than P21 and the marked increases in regional permeability to bilirubin after a previous exposure to the anion were located in the nucleus of the auditory nerve and the hippocampus.

[Influence of the transfer mode on short-term outcome in neonates with high perinatal risk]. / Influence du mode de transfert sur le devenir à court terme des enfants à haut risque périnatal.

BACKGROUND: Transferring in utero children with high perinatal risk has been widely recommended in France over the last few years. The purpose of this study is to describe the different transfer modes for children less than 32 weeks GA or less than 1,500 g birthweight and analyse their impact on death and severe neurological lesion. POPULATION AND METHODS: This retrospective study concerned live births in a definite geographic area (Lorraine, France). Four hundred and twenty-seven children born alive between 1989 and 1992 and hospitalized in eight neonatology units were recruited. Multivariate analysis (logistic regressions) were performed to assess the influence of transfer mode on death or severe neurological lesion. RESULTS: Sixty-two percent of the children were born in the level 3 maternity, 19% in a level 1 maternity and 19% in a level 2 maternity. One hundred and twenty-one children (28%) were transferred in utero and 116 (27%) were transferred extra muros. Thirty children died during the hospital stay. Multivariate analysis does show that neonatal extra muros transfer plays a significative role on neonatal death after adjustment for other risks factors (OR = 3.3 (1.1-9.91). Thirty-one children presented a severe neurological lesion. In comparison with neonates born in the level 3 maternity without transfer, extra muros transfer appears to be a very significant risk factor (P = 0.0008): OR for transfer from level 2 and level 1 maternity is 15.8 (3.8-66.5), and 5.6 (1.3-24) respectively. There is no significant increased risk for children born after maternal transfer or born in a level 2 maternity without transfer. CONCLUSION: These data are consistent with data from the literature and confirm the risk related to extra muros transfer in premature babies less than 32 weeks GA or less than 1,500 g birthweight.

Influence of post-hypoxia reoxygenation conditions on energy metabolism and superoxide production in cultured neurons from the rat forebrain.

Brain reperfusion and/or reoxygenation may be of particular importance in the etiology of neuronal damage after hypoxic-ischemic insult in neonates, especially with reference to the generation of free radicals. To investigate this issue, the influence of either standard reoxygenation or transient hyperoxia was studied on the consequences of severe hypoxia in a model of cultured neurons isolated from the fetal rat brain. Culture dishes were exposed for 6 h to hypoxia (95% N2/5% CO2). They were then placed under normoxia (95% air/5% CO2) or hyperoxia (95% O2/5% CO2) for 3 h, and finally returned to normoxia. Control cultures were kept under normoxic conditions. Cell morphology, protein concentrations, lactate dehydrogenase leakage, energy metabolism, as reflected by specific transport and incorporation of 2-D-[3H]deoxyglucose, as well as superoxide radical formation were analyzed as a function of time. Po2 values in the cell incubating medium were decreased by 78% by hypoxia and increased by 221% by hyperoxia. No morphologic alteration could be noticed before 72 h posthypoxia, when cell degeneration became apparent, with a concomitant reduction in protein contents. Hypoxia-reoxygenation induced a transient cellular hypermetabolism, as shown by a 36% increase in 2-D-[3H]deoxyglucose uptake 24 h after hypoxia, and then a 23% decrease below control values at 72 h. It also led to a sharp increase in the formation of superoxide radicals (+108%). Transient hyperoxia during reoxygenation did not exacerbate these events, and thus would not enhance their deterimental effects on cell integrity.

Effects of fentanyl administration on general and cerebral haemodynamics in sick newborn infants.

Despite the wide use of fentanyl for analgesia in newborns, concerns have been raised about potential haemodynamic side-effects. Since sick newborns may lose their cerebral blood flow autoregulation, a drug-induced haemodynamic instability could lead to brain injury. We assessed the effects of a 15-min infusion of fentanyl (3 micrograms/kg) on the general and cerebral haemodynamics in 15 newborns (median gestational age 29 weeks, 25th-75th percentile, range 28-31 weeks; birthweight 1170 g, range 955-1790 g). The heart rate and mean arterial blood pressure were continuously recorded. Mean cerebral blood flow velocity and pulsatility index were measured using pulsed Doppler ultrasound before, during and up to 60 min after the onset fentanyl administration. No significant modification of general or cerebral haemodynamics was observed. In conclusion, the infusion of 3 micrograms/kg of fentanyl did not lead to any deleterious effect on the general or cerebral haemodynamics in sick normovolaemic newborns.

Autoradiographic mapping of local cerebral permeability to bilirubin in immature rats: effects of hyperbilirubinemia.

Kernicterus is characterized by the accumulation of bilirubin mainly into subcortical brainstem nuclei. Inasmuch as premature infants are more susceptible to kernicterus, we hypothesized that the cerebral permeability to bilirubin could vary by cerebral region and with age. Therefore, in the present study, we measured the blood-to-brain transfer constant (Ki) of [3H]bilirubin in 6-8 rats at postnatal age 10 (P10) or 21 d (P21) in basal conditions and after a bilirubin perfusion to explore age-related and bilirubin-induced changes in the cerebral permeability to the dye. Blood-to-brain transfer of [3H]bilirubin was measured in 39 brain regions by quantitative autoradiography in 15-min experiments. Rats exposed to unlabeled bilirubin received a loading dose of 160 mg/kg over 15 min followed by a 90-min bilirubin perfusion at a speed of 64 mg/kg/h. At P10, cerebral permeability to bilirubin ranged from 0.07 to 0.12 microL/g/min, except in the auditory nerve, dentate nucleus, hypothalamus, and thalamus where it reached 0.41-0.47 microL/g/min. At P21, Ki of bilirubin was significantly lower than at P10 and ranged from 0.03-0.06 microL/g/min in most brain areas. In P10 bilirubin-exposed rats, permeability to bilirubin significantly increased over control levels in all brain regions but three. The largest increases (> 350%) were recorded in the sensory regions, most limbic areas, hypothalamus, and thalamus. At P21, hyperbilirubinemia induced increases in blood-to-brain transfer of bilirubin of 50-200% in 16 brain areas, except in the hippocampus, sensory-motor cortex, and thalamic nuclei where they reached 200-433%. Thus, it appears that the immature rat brain (P10) is very permeable to bilirubin. The increased permeability with preexposure to the dye, especially in brain regions which are affected in infants with kernicterus, could be related either to the large decrease in the value of the albumin:bilirubin ratio between control (15-16) and hyperbilirubinemic conditions (1.7-1.8) and/or to an increased permeability to bilirubin.

Mapping of the consequences of bilirubin exposure in the immature rat: local cerebral metabolic rates for glucose during moderate and severe hyperbilirubinemia.

The regional cerebral metabolic consequences of bilirubin intoxication are not well known. With the quantitative autoradiographic [14C]2-deoxyglucose (2DG), we studied the effect of moderate or severe bilirubin infusion on local cerebral metabolic rates for glucose utilization (LCMRglcs) in 10 (P10) and 21 day-old (P21) rats. After an 80 or 160 mg/kg loading dose of bilirubin administered over 15 min, the speed of bilirubin infusion was reduced to 32 or 64 mg/kg/h for the following 105 min, for moderate or severe intoxication, respectively. This infusion protocol led to plasma bilirubin concentrations of 100-200 nmol/ml (moderate intoxication) or 200-300 nmol/ml (severe intoxication). Cerebral bilirubin concentration was 10 nmol/g at P10 and undetectable at P21 in moderate hyperbilirubinemia while it reached 22-34 nmol/g at both ages during severe hyperbilirubinemia. At P10, bilirubin infusion, moderate or severe, induced significant decreases in LCMRglcs in 17 and 15 brain regions of the 24 studied, respectively. At P21, moderate hyperbilirubinemia induced a decrease in LCMRglcs in only 2 regions, auditory cortex and auditory nerve. Conversely, at that age, severe bilirubin intoxication led to significant decreases in LCMRglcs in all regions studied. These results demonstrate that metabolic changes induced by bilirubin are directly correlated to its entry into the brain which occurs without any alteration in the blood-brain barrier. Indeed, the effects of the dye are quite discrete during moderate hyperbilirubinemia at P21 when no bilirubin is detectable in the brain while they are massive during severe hyperbilirubinemia at P21 and at both levels of intoxication at P10 when bilirubin has entered the brain in measurable amounts.

Regional cerebral metabolic consequences of bilirubin in rat depend upon post-gestational age at the time of hyperbilirubinemia.

While the accumulation of bilirubin in specific brain regions has been well characterized at autopsy in kernicteric infants, data on the regional effects of early cerebral bilirubin intoxication are still missing. Therefore, the quantitative autoradiographic [14C]2-deoxyglucose technique was applied to the measurement of the effects of a bilirubin infusion on local cerebral metabolic rates for glucose (LCMRglc) in immature rats. A loading dose of 80 mg/kg bilirubin was first administered to the animals over 15 min. Thereafter, the velocity of the infusion was reduced to 32 mg/kg/h and the infusion was continued for 105 min. The animals were studied at two ages, postnatal day 10 (P10) and P21. The [14C]2-deoxyglucose was injected to the animals 45 min before the end of the infusion. Bilirubin infusion led to plasma concentrations ranging from 100 to 200 mumol/l at both ages and to brain amounts of 10-16 nmol/g at P10 while bilirubin was not detectable in brain at P21. Hyperbilirubinemia induced widespread decreases in LCMRglcs at P10 and had rather limited consequences on cerebral glucose utilization at P21. At P10, decreases in LCMRglcs were mostly prominent in regions that have been shown to preferentially accumulate bilirubin in kernicteric infants. In conclusion, there appears to be a good correlation between these metabolic data and regional brain permeability to bilirubin.

[Handicaps and the perinatal period. II. Perinatal pathology and severe deficiencies]. / Handicaps et périnatalité. II. Pathologie périnatale et déficiences graves.

BACKGROUND: In the last two decades, the infant mortality rate has dramatically declined. But improved management of newborns may induce an increased prevalence of neurodevelopmental handicaps. The aim of this paper is to estimate the rate of major disabilities and their relationships to perinatal events. POPULATION AND METHODS: Three hundred and sixteen children born in 1984 and registered by the "Commission Départementale de l'Education Spéciale" (CDES) were included in the study. Among these, 97 had either cerebral palsy, blindness, deafness, or mental retardation. These 97 children were compared to 602 school age controls using a multivariate analysis (logistic regression). RESULTS: The rate of major disabilities among the 6-year old children is 3.4/1000. It was 5/1000 in 1972 and 4.3/1000 in 1976. This frequency is higher in the children who were preterm (odds ratio--OR = 4.8), small for gestational age (OR = 3.3) or suffered from perinatal asphyxia (OR = 32.8). These three factors accounted for 37.4% of major disabilities. CONCLUSION: This study emphasizes the relationships between perinatal events and some major handicaps but also shows that antenatal factors may be involved in neurodevelopmental problems.

[Handicaps in the perinatal period. I. Perinatal pathology and difficulties in school]. / Handicaps et périnatalité. I. Pathologie périnatale et difficultés scolaires.

BACKGROUND: Major handicaps are closely related to perinatal events. However, relationship of these events with other moderate disabilities such as school problems are still unclear. POPULATION AND METHODS: A representative sample of 1,408 children at school age and born in Lorraine in 1984 was studied. Two hundred and fifty children with problems were compared with 602 controls without school problems, using a multivariate analysis. RESULTS: The incidence of school difficulties among 6-year old children (in the last year of nursery school) is 17.8%. Children are at higher risk of school problems if their parents are not (odds ratio [OR] = 7.9) or are poor school graduate (OR = 2.7), if they are boys (OR = 2.0), if they are born at the end of the year (OR = 1.1) and also if they are preterm (OR = 2.7) or small for gestational age (OR = 2.5). Preterm delivery and intra-uterine growth retardation accounted for 9.6% of school difficulties. CONCLUSION: The relationship between perinatal events and school difficulties warrants to continue with prevention during pregnancy, especially among groups with multiple risk factors.

Patent foramen ovale with left to right shunt in bronchopulmonary dysplasia: coincidental or associated complication?

Despite the use of exogenous surfactants, the incidence of bronchopulmonary dysplasia (BPD) has not decreased as much as expected. Of 208 newborns involved in trials with Exosurf at our center, 51 had BPD. Among these newborns, 8 were found retrospectively to have secondary worsening of respiratory distress syndrome after initial improvement with surfactant treatment. Oxygen requirements decreased from 89 +/- 15% to 58 +/- 16% (mean +/- SD), respectively, before and 48 h after surfactant, and then reached a plateau of 34 +/- 10% before dramatic deterioration at 22 +/- 9 days of life. The patients had signs of cardiac failure and increased oxygen requirements of up to 76 +/- 19% within 6 h. A patent foramen ovale (PFO) was demonstrated at echocardiography with a left to right shunt at Doppler. No other cause of worsening was found. Five infants had significant improvement when treated with digoxin and furosemide. This retrospective study raises questions about the relationship between PFO and BPD that should be explored in a prospective study.