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With improving neonatal survival for very premature babies, the challenge for neonatalogists is to ameliorate outcome of surviving babies. Several pharmacological molecules have been shown to have protective effects in different types of in vitro or in vivo animal models of acquired cerebral brain damages. However translational research and conduction of therapeutic trials in human remain difficult due to failure to recognize start of deleterious cascade leading to cerebral damage and additional toxic effect of potential protective molecules. This review concentrates on best evidence emerging in recent years on prevention on brain damage by early drug administration. It has been shown in two randomised trials that prenatal low-dose of magnesium sulphate does not increase paediatric mortality in very-preterm infants and has non significant neuroprotective effects on occurrence of motor dysfunction (with a 0.62 odds ratio in the French trial Premag and 0.71 relative risk in the Australian trial ACTOMgSO4), justifying that magnesium sulphate should be discussed as a stand-alone treatment or as part of a combination treatment, at least in the context of clinical trials. Antenatal corticosteroid therapy increases the survival of very-preterm infants, including the most immature. Moreover in an observational recent study of the Epipage cohort, it has been observed a significant decrease in white matter injury in the 28-32 weeks' gestation group but no effect on long term outcome and behaviour. Conversely in the most immature of the 24-27 weeks' gestation group, no effect has been detected either in white matter injury incidence or in long term outcome rates. Caffeine has a protective effect since a decrease in cerebral palsy has been noted in the caffeine group in a randomised trial studying caffeine versus placebo. For what concern other widely used potential protective molecules during the perinatal period, there is no evidence of cerebral protection with indometacine, nitric oxide, eythropoietin, phenobarbital, and etamsylate. Due to their specific properties, a careful evaluation of aspirin, anaesthetic drugs and tocolytics should be done in the next months.

Objective: To evaluate whether magnesium sulphate (MgSO(4)) given to women at risk of very-preterm birth would be neuroprotective in preterm newborns., Patients and Methods: In 18 French centres, women with fetuses of gestational age less than 33 weeks whose birth was expected within 24 hours were randomised from 1993 to 2003 with follow-up of infants until two years of age after discharge. They received a single injection of 0.1 mg/l de MgSO(4) (4g) or isotonic 0.9% saline over 30 minutes. This study is registered as an International Standard Randomised Controlled Trial, number 00120588. Analyses were based on intention to treat., Results: Data from 688 infants were analysed of which 606 were followed up and 10 were lost to follow-up. Comparing infants who received MgSO(4) or placebo, respectively, has shown a decrease of all primary endpoints (total mortality, severe white matter injury and their combined outcome) and of all secondary endpoints (motor dysfunction, cerebral palsy, cognitive dysfunction and their combined outcomes at two years of age) in the MgSO(4) group. The decrease was nearly significant or significant for gross motor dysfunction (OR: 0.65 [0.41-1.02]) and combined criteria: death and cerebral palsy (OR: 0.65 [0.42-1.03]); death and gross motor dysfunction (OR: 0.62 [0.41-0.93]); death, cerebral palsy and cognitive dysfunction (OR: 0.68 [0.47-1.00]). No major maternal adverse effects were observed in the MgSO(4) group., Discussion and Conclusion: Given its beneficial effects and safety, the use of prenatal low-dose MgSO(4) for preventing neurodisabilities of very-preterm infants should be discussed either as a stand-alone treatment or as part of a combination treatment, at least in the context of clinical trials.

Objective: To assess the impact of antenatal corticosteroids (ACS) on neonatal mortality, cerebral lesions and 5-year neurodevelopmental outcome of infants born at 24-27 and 28-32 weeks of gestational age (GA)., Design: Observational population-based study including all births at GAs between 22 and 32 weeks in 1997 in nine regions of France. Survivors were assessed at the age of 5 years., Sample and Methods: The population enrolled in the follow up comprised 2323 infants; there were 23 deaths before age 5 years and outcome at 5 years was available for up to 1781 subjects. Two GA subgroups (24-27 and 28-32 weeks of GA) were analysed separately. Propensity scores were used to reduce bias in the estimation of the association between ACS treatment and outcomes., Main Outcome Measures: Neonatal death, neonatal white matter injury, cerebral palsy, mental processing composite (MPC) of the Kaufman Assessment Battery for Children test and behavioural difficulties at 5 years., Results: In the 28- to 32-week GA subgroup, there was a significant association between ACS and a decreased risk of both neonatal death (OR = 0.61 [0.41-0.91]) and white matter injury (OR = 0.60 [0.46-0.79]) but only a nonsignificant trend for improved 5-year outcome (cerebral palsy, MPC < 70). In the 24- to 27-week GA subgroup, ACS was associated with a significant decrease risk of neonatal death (OR = 0.43 [0.27-0.68]) but there was only a trend for a lower risk of white matter injury and no beneficial impact on outcome at 5 years. Limiting the analysis to only those who received complete courses of ACS did not modify the results., Conclusion: The study shows that ACS therapy greatly increases the survival of very preterm infants, including the most immature, but there is little evidence that ACS affects long-term neurodevelopmental and behavioural outcome in 28- to 32-week survivors, and none in <28-week survivors.

Whooping-cough is one of the rare diseases for which vaccine prevention has been available for many years. However, in spite of good vaccine coverage in the infant, the pertussis infection remains a frequent disease in the teenagers and adults partially immunized. The missing diagnosis of the infection, added to its often clinical banal expression, contributes to support the circulation of Bordetella pertussis and explains the contamination of the young infants in whom the disease remains a true danger as the few declared deaths show it every year. Control of the disease must go through reinforcement of vaccination as a practitioner of booster vaccine in preadolescents, teenagers and adults. Instituted since 1998 in the French vaccine calendar, the 2nd booster in preadolescence between 11-13 years olds or 5th dose of vaccine is not enough carried out and must be encouraged like the installation of another additional vaccine dose for adults and certain professional categories. The protection of infants too young to have received the 3 doses goes through the vaccination of their entourage, family and socio-professional alike. The new recommendations thus preach to begin vaccination in children from the age of 2 months, a reinforcement of the vaccine boosters in preadolescents, in adults likely to become parents and in the medical and paramedical personnel in contact with very young infants.

Very preterm infants have high rates of neurological impairments and disabilities. These rates have not diminished as the survival rates have improved. Basic science research suggests that magnesium sulphate before birth can be neuroprotective for the preterm fetus. Some, but not all, observational studies in humans also suggest a protective effect of antenatal magnesium sulphate on cerebral palsy. Four randomised controlled trials of antenatal magnesium sulphate have reported long-term neurological effects in surviving infants, but only one of these was designed specifically to evaluate the long-term effects of treatment. These studies found that, overall, antenatal magnesium sulphate therapy had no significant effect on paediatric mortality or neurological outcomes in the first few years of life, including cerebral palsy, but it was found to lower the rate of motor problems at 2 years of age in one study. The role for antenatal magnesium sulphate therapy as a neuroprotective agent for the preterm fetus is not yet established.

Background: Epidemiological and basic science evidence suggests that magnesium sulphate before birth may be neuroprotective for the fetus., Objectives: To assess the effectiveness and safety of magnesium sulphate as a neuroprotective agent when given to women considered at risk of preterm birth., Search Strategy: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (October 2006), CENTRAL (The Cochrane Library 2006, Issue 3), MEDLINE (1966 to October 2006), EMBASE (1980 to October 2006), Current Contents (1992 to October 2006), references of retrieved articles, and abstracts submitted to the Society for Pediatric Research (1996 to 2006)., Selection Criteria: Randomised controlled trials of antenatal magnesium sulphate therapy given to women threatening or likely to give birth at less than 37 weeks' gestational age., Data Collection and Analysis: We independently extracted data regarding clinical outcomes including paediatric mortality, neurologic outcome of survivors (including blindness, deafness, cerebral palsy and major neurosensory disability), and maternal complications and side-effects. At least two authors assessed trial eligibility and quality, and extracted data., Main Results: Four trials (3701 babies) were eligible for this review. No statistically significant effect of antenatal magnesium sulphate therapy was detected on any major paediatric outcome, including mortality (e.g., paediatric mortality relative risk (RR) 0.97; 95% confidence interval (CI) 0.74 to 1.28; four trials; 3701 infants), and neurological outcomes in the first few years of life, including cerebral palsy (RR 0.77; 95% CI 0.56 to 1.06; four trials; 3701 infants), neurological impairments or disabilities. There were also no significant effects of antenatal magnesium therapy on combined rates of mortality with neurologic outcomes. There was a significant reduction in the rate of substantial gross motor dysfunction (RR 0.56; 95% CI 0.33 to 0.97; two trials; 2848 infants). There were higher rates of minor maternal side-effects in the magnesium groups, but no significant effects on major maternal complications., Authors' Conclusions: The role for antenatal magnesium sulphate therapy as a neuroprotective agent for the preterm fetus is not yet established. Given the possible beneficial effects of magnesium sulphate on gross motor function in early childhood, outcomes later in childhood should be evaluated to determine the presence or absence of later potentially important neurologic effects, particularly on motor or cognitive function. Further information will be available from one of the studies where outcomes are being evaluated again at eight to nine years of age, and from another trial currently in progress.

Objective: The present study evaluated the usefulness of a real-time polymerase chain reaction (rtPCR) assay for the detection of Neisseria meningitidis (Nm) and genogrouping on skin lesion biopsies in patients with purpura fulminans (PF)., Design: Retrospective single-centre study., Setting: Adult and paediatric intensive care units at the University Hospital of Rouen., Patients: All patients admitted between January 2000 and January 2006, with a final diagnosis of PF and for which a skin biopsy and blood cultures were performed, were included., Interventions: Skin biopsy and blood cultures were used for culture and rtPCR., Measurements and Main Results: Thirty-four patients fulfilled the criteria (27 children and 7 adults). Nm rtPCR performed on skin biopsy was positive in 100% (34/34) of cases, compared with only 14.7% (5/34) for skin culture (p=0.0001). rtPCR genogrouping on skin biopsy was positive in 58.8% (20/34) of the cases compared with 14.7% (5/34) for skin culture (p=0.0013). For patients (n=17) in whom rtPCR was performed both on blood and skin biopsy, skin biopsy gave a significantly higher rate of Nm detection [100% (17/17) vs. 58.8% (10/17); p=0.023] and genogroup characterisation [76.5% (13/17) vs. 35.3% (6/17); p=0.045] than blood. We encountered no specimen with culture-positive and rtPCR-negative results (negative predictive value of rtPCR 100%)., Conclusion: In suspected PF cases, skin biopsy is more reliable to identify Nm and its genogroup than blood or, probably, CSF, especially when PCR methods are used. This could help the implementation of public health interventions, especially concerning a vaccination policy.

We studied hypoxic preconditioning (HxP) in the murine developing brain, focusing on the role for vascular endothelial growth factor (VEGF). Newborn mice were used as follows: (1) HxP (or normoxia) then intracerebral (i.c.) NMDA or AMPA-kainate agonist; (2) HxP then intraperitoneal (i.p.) anti-VEGFR2/Flk1 or anti-VEGFR1/Flt1 monoclonal blocking antibody (mAb) then i.c. NMDA/AMPA-kainate agonist; (3) i.p. VEGF then i.c. NMDA/AMPA-kainate agonist; and (4) in mutants lacking the hypoxia-responsive element (HRE) of the VEGF-A gene (VEGF( partial differential/ partial differential)) and their wild-type littermates (VEGF(+/+)), HxP followed by i.c. NMDA agonist. HxP reduced the size of NMDA-related cortical and AMPA-kainate-related cortical and white matter excitotoxic lesions. Anti-VEGFR2/Flk1 mAb prevented HxP-induced neuroprotection. VEGF produced dose-dependent reduction in cortical lesions. HxP did not prevent, but instead exacerbated, brain lesions in VEGF( partial differential/ partial differential) mutants. Thus, exogenous as well as endogenous VEGF reduces excitotoxic brain lesions in the developing mouse. The VEGF/VEGFR2/Flk1 pathway is involved in the neuroprotective response to HxP.

Objective: To evaluate whether magnesium sulphate (MgSO(4)) given to women at risk of very-preterm birth would be neuroprotective in preterm newborns and would prevent neonatal mortality and severe white-matter injury (WMI)., Design: A randomised study., Setting: Eighteen French tertiary hospitals. Population Women with fetuses of gestational age < 33 weeks whose birth was planned or expected within 24 hours were enrolled from July 1997 to July 2003 with follow up of infants until hospital discharge. METHODS Five hundred and seventy-three mothers were randomly assigned to receive a single 40-ml infusion of 0.1 g/ml of MgSO(4) (4 g) solution or isotonic 0.9% saline (placebo) over 30 minutes. This study is registered as an International Standard Randomised Controlled Trial, number 00120588., Main Outcome Measures: The primary endpoints were rates of severe WMI or total mortality before hospital discharge, and their combined outcome. Analyses were based on intention to treat., Results: After 6 years of enrolment, the trial was stopped. Data from 688 infants were analysed. Comparing infants who received MgSO(4) or placebo, respectively, total mortality (9.4 versus 10.4%; OR: 0.79, 95% CI 0.44-1.44), severe WMI (10.0 versus 11.7%; OR: 0.78, 95% CI 0.47-1.31) and their combined outcomes (16.5 versus 17.9%; OR: 0.86, 95% CI 0.55-1.34) were less frequent for the former, but these differences were not statistically significant. No major maternal adverse effects were observed in the MgSO(4) group., Conclusion: Although our results are inconclusive, improvements of neonatal outcome obtained with MgSO(4) are of potential clinical significance. More research is needed to assess the protective effect of MgSO(4) alone or in combination with other neuroprotective molecules.

In France, screening for cytomegalovirus infection (CMV) during pregnancy is not recommended in routine. The transmission of CMV through breastmilk from mothers to preterm infants is frequent (15-20%). The frequency of neuro-sensorial handicap related to congenital CMV infection in very preterm infants is not well documented. We report the case of a female infant born at 30 weeks of gestation. At 15 days, she developed cholestatic jaundice. Urine cultures were positive for CMV. Diagnostic procedure showed no other cause for jaundice. At 40 days, the infant presented with hepato-splenomegaly, purpura and abnormal skin color related to a symptomatic, secondary CMV infection, probably transmitted through breastmilk. Ganciclovir was begun for 21 days. At 12 months, she presents with normal development. This observation raises questions about breastfeeding in very preterm infants. Unexplained prematurity could reflect recent infection or reactivation in the mother. Thus, because of the well-known risks of prematurity on one hand, and CMV infection on the other, we suggest that detection of CMV seropositive mothers should be considered before allowing breastfeeding. If the mother has serologic evidence of recent infection or reactivation, freezing breastmilk at -20 degrees C for 3 days may be an option in order to reduce virolactia, especially during early lactation. This may reduce the risk of postnatal vertical virus transmission with minimal logistical difficulties and without interrupting breastfeeding.

Objectives: Our goal was to compare the prevalence of behavioral problems between very preterm children and term children at 3 years of age and examine the factors associated with behavioral problems in very preterm children., Methods: We conducted a prospective population-based cohort study: the EPIPAGE (Etude Epidémiologique sur les Petits Ages Gestationnels) study. All infants born between 22 and 32 weeks of gestation in 9 regions of France in 1997 were included and compared with a control group of infants born at term. Sociodemographic status, obstetric, and neonatal data were collected at birth and in the neonatal units. At 3 years of age, the behavioral problems of 1228 very preterm singleton children without major neurodisabilities, and 447 term children were studied using the Strengths and Difficulties Questionnaire completed by the parents., Results: Very preterm children were more likely than controls to have behavioral difficulties. Among very preterm children, several medical conditions were associated with a high total difficulty score: major neonatal cerebral lesions diagnosed by cranial ultrasonographic studies, hospitalization within the last year, poor health, and psychomotor delay. A high birth order and sociodemographic factors such as young maternal age and low educational level of the mother were also identified as risk factors for behavioral difficulties. The differences between very preterm children and controls remained significant after adjustment for sociodemographic characteristics, neonatal complications, and neurodevelopmental status, for a high total difficulties score, hyperactivity, conduct problems, and for peer problems. For emotional problems, the difference was at the limit of significance., Conclusions: Very preterm children have a higher risk of behavioral problems at 3 years of age compared with term-born children. Health and neurodevelopmental status of the child were significantly associated with behavioral difficulties.

Objective: To estimate the prevalence of cerebral palsy at 2 years of age among children born very preterm, according to gestational age, infant gender, plurality, and neonatal cranial ultrasound abnormalities., Methods: All infants born between 22 and 32 weeks of gestation in 9 regions of France in 1997 were included in this prospective, population-based, cohort study. The main outcome measure was cerebral palsy prevalence at 2 years. Of the 2364 survivors eligible for follow-up evaluation, 1954 (83%) were assessed at 2 years of age., Results: Among the 1954 children assessed at 2 years, 8.2% had cerebral palsy. Bilateral spastic cerebral palsy, hemiplegia, and monoplegia accounted for 72%, 9%, and 10% of cases, respectively. Fifty percent of the children with cerebral palsy walked independently at the age of 2, 31% were unable to walk but could sit independently, and 19% could not sit (unable to maintain head and trunk control). The prevalence of cerebral palsy was 20% at 24 to 26 weeks of gestation, compared with 4% at 32 weeks. On the basis of ultrasound findings in the neonatal period, we found that 17% of children with isolated grade III intraventricular hemorrhage and 25% of children with white matter damage (ie, ventricular dilation, persistent echodensities, or cystic periventricular leukomalacia) had cerebral palsy, compared with 4% of children with normal ultrasound scans., Conclusions: Despite recent improvements in survival rates, cerebral palsy remains highly prevalent among very preterm children. Severe cranial ultrasound abnormalities predict motor disability strongly, but one third of infants with cerebral palsy had no ultrasound abnormalities.

An ileal perforation occurred shortly after birth in 4 very premature newborns. Diagnosis was made on an abdominal distension with a pneumoperitoneum on X-ray. There were no biological, radiological nor histological signs of necrotizing enterocolitis. There were no digestive short- or long-term complications. According to the few authors who described this syndrome, there are some risk factors, but they were not clearly involved in our cases. Ileal perforation in the absence of signs of necrotizing enterocolitis is rarely reported but should be well known because of its good prognosis.

Unlabelled: The prevention of mother-to-child transmission is important in the control of HIV. Despite preventive measures, the objective of a zero transmission rate from mother to child has not yet been reached even in Northern countries., Observation: A retrospective study covering a 14-year period (January 1988 through December 2001) examined records of 80 children born to HIV-positive mothers at Rouen University Hospital Center. Four children were contaminated. We report several particularities of these four children, contaminated despite the preventive measures taken., Conclusion: Prevention of mother-to-child transmission involves not only administration of antiretrovirals during pregnancy, but also better follow-up of pregnancy and delivery and more effective management of risk factors such as drug addiction and poverty. Multidisciplinary follow-up is needed for these children in view of our current lack of knowledge of the long-range side effects of these antiretrovirals.

Holt-Oram syndrome, the major "heart-hand" syndrome is defined by the association of radial defects or triphalangeal thumbs and septal heart defects. The transmission is autosomal dominant and the causative gene has been shown to be TBX5, located on 12q24.1, which encodes a transcription factor. Genetic heterogeneity has been suggested by several reports. We identified a 14(q23.3 approximately 24.2q31.1) deletion in a boy presenting severe bilateral asymmetrical radial aplasia, congenital heart defects, and developmental delay. This deletion, whose size could be estimated to be 9.6-13.7 Mb, was shown to be inherited via his mother's interchromosomal insertion. This is the second report of a chromosome 14 interstitial deletion associated with clinical features of Holt-Oram syndrome. These observations suggest the existence of a new "heart-hand" locus on chromosome 14q., (2005 Wiley-Liss, Inc.)

Tobacco during pregnancy remains a health priority. It is associated with an increased risk of preterm birth and intra-uterine growth retardation which are well-known risk factors of diplegia or cognitive sequellae. Several studies support the existence of an association between smoking in pregnancy and a less optimal cognitive development. However this point has not been confirmed in a few recent studies, in particular when confounding factors are taken into account. Behavioral disorders are significantly associated with smoking during pregnancy. Nicotine was the best studied component of tobacco in animal studies. It was show that it interferes directly by stimulation of neurotransmitters or indirectly by inducing brain hypoxia.

Does neonatal and postnatal management of a new-born exposed in utero to tobacco smoking differ from a non-exposed neonate? Which are the biomarkers for perinatal exposition? In order to address these two questions a Medline and Embase search was carried out. For the first question, the review of the literature suggests that tobacco is one of main factors increasing the rates of preterm birth to a significant degree and primarily early prematurity, and intrauterine growth restriction. Moreover, maternal smoking during pregnancy increases perinatal mortality. Management tends to reduce perinatal morbidity and mortality of these new-born, but there is in fact no published research which proposes precise recommendations for an accurate management distinct from the non-exposed child. Among the biomarkers used for the routine diagnosis of in utero tobacco smoke exposure, the umbilical cord cotinine level is probably the most reliable and noninvasive for the new-born. However, the maternal curve can be studied and measurement of the exhaled carbon monoxide in late pregnancy is a valid reflection of neonatal impregnation.

Alcohol exposition during pregnancy has irreversible effects on the fetus brain. In hamsters, intrapallial injection of the glutamate receptor agonist ibotenic acid (100ng) on the day of birth (P0) induced neuronal migration disorders. In utero alcohol (7%) exposure from day 5 of gestation to P5, enhanced lesions size measured in pups' brain at P5. The administration for the same period of the taurine derivative acamprosate together with alcohol or in water to pregnant females reduced the rate of occurrence of nodular heterotopia, sub-pial ectopia and microgyria in non-alcohol-exposed pups. In addition acamprosate diminished lesion size in alcohol-exposed and non-exposed pups. A significant dose-related effect of acamprosate was observed. In addition, acamprosate rescued 27% of the pups injected with 10 microg ibotenic acid, a lethal dose in alcohol-exposed animals.

Alcohol is one of the most common noxious substance to which fetuses are exposed. The aim of the study was to determine the effects of in utero alcohol exposure on excitotoxin-induced neuronal migration disorders. Female hamsters received alcohol (7%) for 3-5 mo or for the last 9-12 d of gestation. Alcohol diet was continued for 5 d during lactation in both groups. Drinking behavior was monitored. Peak plasma alcohol levels were 104+/-12 mg/dL and 225+/-6 mg/dL after 30 min for hamsters receiving an intragastric dose of 3 mL or 5 mL alcohol, respectively. At birth, pups received intrapallial injections ibotenic acid (1 ng, 100 ng, or 10 microg). Histology and N-methyl-D-aspartic acid (NMDA) receptor labeling by 3H-MK-801 in the pups cortices were studied. Short-term-alcohol-exposed pups had normal body and brain weights at birth, but their body growth was retarded postnatally. Ibotenic acid induced similar neuronal migration impairments in control and alcohol-exposed pups (nodular heterotopia in the white matter and/or deep cortical layers, subpial ectopia, and micro- or polymicrogyria). The size of lesions induced by 100 ng ibotenic acid was increased in alcohol-exposed pups; the 10 microg dose was lethal. The density of 3H-MK-801 binding sites was similar in the three groups, indicating that exacerbated ibotenic acid excitotoxicity in alcohol-exposed pups did not result from increased NMDA receptor density. This study shows that alcohol exposure at levels that do not induce neuron migration disorders is sufficient to enhance the effects of the hypoxia-ischemia mimicking effects of ibotenic acid.

White matter (WM) lesions in preterm newborns may lead to cerebral palsy. To study WM lesions in a mouse model, we used intrapallial stereotactic injections of ibotenic acid, an N-methyl-D-aspartate receptor agonist. Previous studies support a contribution of tissue-type plasminogen activator (t-PA) to the brain lesions seen in various adult excitotoxic models. Therefore, we studied both 5-day-old (P5) wild-type mice and t-PA knock-out (t-PA-/-) mice. The ibotenic acid doses required to induce WM cysts were lower in the wild-type mice (EC50 < 0.01 microg/animal) than in the t-PA-/- mice (EC50 = 2.5 microg/animal) (p < 0.01), indicating the existence of t-PA-dependent and t-PA-independent mechanisms. Dose-dependent prolonged cyst growth occurred in the wild-type mice only. Early microglial activation and astrogliosis were similar in the wild-type and t-PA-/- mice. In adult mice (P45), demyelination occurred at the injection site in both groups but the astroglial scar was denser in the wild-type than in the t-PA-/- mice. These data support involvement of t-PA at several stages of WM lesion formation. Inactivation of t-PA might confer protection by prolonged hemostasis. The role of t-PA in cyst expansion suggests a new approach to the development of neuroprotective strategies in infants with developing WM lesions.

Objective: To evaluate the prevalence of cranial ultrasound abnormalities in very preterm infants as a function of gestational age, plurality, intrauterine growth restriction, and death before discharge., Study Design: A prospective, population-based cohort of 2667 infants born between 22 and 32 weeks of gestation in 1997 in nine regions of France, transferred to a neonatal intensive care unit, for whom at least one cranial ultrasound scan was available., Results: The frequencies of white matter damage (WMD), major WMD, cystic periventricular leukomalacia (PVL), periventricular parenchymal hemorrhagic involvement, and intraventricular hemorrhage with ventricular dilatation were 21%, 8%, 5%, 3%, and 3%, respectively. The risk of WMD increased with decreasing gestational age. Mean age at diagnosis of cystic PVL was older for the most premature infants. Intraventricular hemorrhage with ventricular dilatation was associated with a higher risk of cystic PVL. Intrauterine growth restriction was not associated with a lower prevalence of cystic PVL., Conclusion: The frequency of WMD is high in very preterm babies and is strongly related to gestational age. The incidence of cystic PVL did not differ between babies with intrauterine growth restriction and babies who were appropriate for gestational age.

Meconium peritonitis is an inflammatory peritonitis induced by meconium extruding into the peritoneal cavity through a perforation of the fetal intestine. Antenatal diagnosis is possible. Prognosis depends on the pathology having caused perforation. This is often unknown. The objectives of this article are to analyze the contribution of antenatal investigations to estimating neonatal prognosis of meconium peritonitis, and to define optimal management. We describe a case of meconium peritonitis diagnosed in utero with particularly severe ultrasound presentation suggesting a potentially lethal course for the neonate. An eutrophic infant was delivered vaginally after preliminary aspiration of the meconium ascites. The neonate presented with a very distended abdomen and responded well to neonatal resuscitation. Laparotomy exploration confirmed the diagnosis of meconium peritonitis. No cause was identified. No obvious perforation was found. The postsurgery period was uneventful. At later follow-up the infant was doing well, free of further problems notably of any digestive disorder. Antenatal ultrasound features suggestive of severe meconium peritonitis are distended fetal bowel loops, huge cystic masses, major meconium ascites, and polyhydramnios. These neonates have a high risk of obstruction and intestinal perforation. Intestinal resection is frequently required. Cardiopulmonary resuscitation is necessary more often in these neonates with a higher risk of fatal outcome due to respiratory distress syndrome or surgery complications. Prognosis remains good after antenatal diagnosis for neonates free of cystic fibrosis, providing delivery takes place in a center with adequate technical facilities.

The term "periventricular leukomalacia" (PVL) usually covers necrotic and/or gliotic lesions from perinatal origin occurring in the periventricular ring of telencephalic white matter. However focal white matter necrosis is often associated to a diffuse white matter disease and to brainstem and grey matter lesions, making up the basis of a true encephalopathy. PVLs are diagnosed in 4% to 10% of infants born before 33 weeks of gestation. The proportion of PVLs from prenatal origin is estimated around one third of cases. Recent progresses in neuroepidemiology, developmental neurobiology and imaging methods permitted to revisit the pathophysiology of PVLs on a multifactorial basis. The end result of these multiple factors seems to be calcium influx due to glutamatergic overactivation triggered by cytokines, free radicals, and deficits in neurotrophic factors. Periventricular topography can be explained by properties of the brain at this specific step of brain development. Carrying motor and neuropsychological consequences, PVLs could be the most severe danger for very premature brains. Positive rolandic sharp waves recorded on EEG and precocious abnormally echogenous periventricular images on ultrasound suggest prospective periventricular cysts. Cystic periventricular cavitations certify the diagnosis of PVL. More subtle lesions of PVL do not reach the cystic grade and their diagnosis is confirmed by MRI. Treatment of infections is already available and potentially a tool for prevention. When the overwhelming glutamatergic signal has been triggered, neuroprotective agents turning off the excitotoxic cascade, including calcium blockers, growth factors and others, are promising therapeutic tools.

Background and Aims: This study investigated the effects of enterally supplied glutamine on mesenteric blood flow in premature neonate., Methods: Twenty-five neonates, aged at least 14 days and free of acute illness participated in a prospective, randomised, double-blind study. All were fed with total enteral nutrition enriched with glutamine (0.7 g kg(-1)day(-1), group 1) or isonitrogenous control (group 2). Blood flow velocities in the superior mesenteric artery were analysed by pulsed Doppler US before and after 21 days of supplemented feeding. Peak systolic velocity (PSV), end-diastolic velocity (EDV) and time-averaged mean velocity (TAV) were measured and resistance index (RI) and flow (Q) were calculated., Results: Both groups were well matched clinically at inclusion. At inclusion, the velocimetry parameters were (mean +/- SD) : PSV:114.9 +/- -38 cms(-1), EDV:17.5 +/- 7.5 cm x s(-1), TAV:44.8 +/- 18.2 cms(-1), RI : 0.8 +/- 0.1, Q : 2.4 +/- 1.2 mls(-1). Mesenteric blood flow parameters remained stable between day 0 and day 21 with same values in both groups., Conclusions: Superior mesenteric blood flow remained stable in neonates after 14 days of life and did not appear to be influenced by enteral glutamine at that stage., (Copyright 2003 Elsevier Science Ltd.)

Maternal smoking is associated with an increased risk of intra-uterine growth retardation and conduct disorder in their children, and is a major risk factor for sudden infant death syndrome. Among the numerous compounds present in cigarette smoke, carbon monoxide and nicotine have been largely studied. They can both affect the fetal brain by inducing intra-uterine hypoxia or by acting directly on the developing brain.

Objective: To determine the effects of fluorinated glucocorticoids on the occurrence and extent of ischaemic-like excitotoxic grey and white matter cerebral injuries in an animal model., Design: A study of the influence of single or repeated doses of glucocorticoids when creating excitotoxic lesions in mice pups, mimicking some aspects of periventricular leucomalacia and cortical-subcortical stroke as observed in human neonates., Sample: Four hundred and sixty-seven mouse pups out of more than 30 litters., Methods: An excitotoxic lesion was created by intracerebral injection of ibotenate, a glutamatergic agonist, in day five postnatal mice pups. A single dose of betamethasone or dexamethasone was administered, in a dose of 0.006-6 and 0.001-1 mg/kg, respectively, 24 hours before or 15 minutes after each ibotenate injection. Repeated doses of dexamethasone (0.01 mg/kg per day) or betamethasone (0.006 mg/kg) were given for five days before or after ibotenate injections. The measurement of white matter and grey matter lesions and the occurrence of cysts were assessed under light microscope on cresyl violet-stained brain sections., Main Outcome Measures: Size of white matter cystic lesions., Results: A single injection of betamethasone or dexamethasone had a significant neuroprotective effect when administered after the excitotoxin. Betamethasone injected once prior to ibotenate also had a protective effect. Repeated administration of each steroid before or after excitotoxin injection provided more protection than a single injection., Conclusion: Fluorinated glucocorticoids reduced neonatal brain lesions observed in a mouse model treated by excitotoxin injection.

X-linked lissencephaly with absent corpus callosum and ambiguous genitalia is a newly recognized syndrome responsible for a severe neurological disorder of neonatal onset in boys. Based on the observations of 3 new cases, we confirm the phenotype in affected boys, describe additional MRI findings, report the neuropathological data, and show that carrier females may exhibit neurological and magnetic resonance imaging abnormalities. In affected boys, consistent clinical features of X-linked lissencephaly with absent corpus callosum and ambiguous genitalia are intractable epilepsy of neonatal onset, severe hypotonia, poor responsiveness, genital abnormalities, and early death. On magnetic resonance imaging, a gyration defect consisting of anterior pachygyria and posterior agyria with a moderately thickened brain cortex, dysplastic basal ganglia and complete agenesis of the corpus callosum are consistently found. Neuropathological examination of the brain shows a trilayered cortex containing exclusively pyramidal neurons, a neuronal migration defect, a disorganization of the basal ganglia, and gliotic and spongy white matter. Finally, females related to affected boys may have mental retardation and epilepsy, and they often display agenesis of the corpus callosum. These findings expand the phenotype of X-linked lissencephaly with absent corpus callosum and ambiguous genitalia, may help in the detection of carrier females in affected families, and give arguments for a semidominant X-linked mode of inheritance.

Complex choristomas are very rare ocular tumors. We report a case of a 3-month-old infant who was referred to us because of a left congenital conjunctivo-corneal protruding mass. Total excision removing 2/3 of the limbus was performed and replaced simultaneously by a limbal autograft. Histopathological examination of the excised choristoma revealed many pilosebaceous follicules in the conjunctival tissue, keratinized epithelium, lacrimal glands, and differentiated cartilage.

Based on clinical, epidemiologic, and experimental studies, the aetiology of white matter damage, specifically periventricular leukomalacia (PVL), is multifactorial and involves pre- and perinatal factors possibly including genetic factors, hypoxic-ischaemic insults, infection, excess cytokines, free radical production, increased excitatory amino acid release, and trophic factor deficiencies. The article summarizes research findings about the aetiology of white matter damage and cerebral palsy in preterm infants. The information is organized according to specific antecedents, for which we present epidemiological and neurobiological data. The most important prenatal factor appears to be intrauterine infection. We discuss the evidence supporting the hypothesis that the foetal inflammatory response contributes to neonatal brain injury and later developmental disability. We recently established an animal model of excitotoxic lesions in the developing mouse brain. Brain damage was induced by intra-cortical injections of ibotenate, a glutamatergic agonist. When administered on post-natal day 5 ibotenate induced the formation of white matter cysts. Our animal model could be used to further explore the mechanisms involved in the formation of PVL. Potentially preventive strategies will be discussed., (Copyright 2001 Harcourt Publishers Ltd.)

Foetal and neonatal brain is under the influence of environmental factors from maternal and extra-maternal origin. Based on the available data, these environmental factors can be classified into three arbitrary groups: (i) factors and maternal status with a demonstrated deleterious effect on the foetal brain (i.e. ethanol, cocaine, some drugs including anticonvulsants, some viral infections, maternal diabetes, untreated maternal phenylketonuria); (ii) factors highly suspected to interfere with foetal brain development (i.e. lead and other heavy metals, some drugs like benzodiazepines, nicotine); (iii) factors which have been shown to be safe for the developing brain in the available studies (i.e. low to moderate doses of caffeine, methadone). However, most of these studies do not address the potential risk of environmental factors on minimal to moderate cognitive and behavioural disturbances. Finally, the impact of the neonatal environment on brain development in very pre-term infants is probably underestimated., (Copyright 2000 Harcourt Publishers Ltd.)

Clinical evidence suggests that control mechanisms for local and global attention are lateralized in the temporal-parietal cortex. However, in the human occipital (visual) cortex, the evidence for lateralized local/global attention is controversial. To clarify this matter, we used functional MRI to map activity in the human occipital cortex, during local and global attention, with sustained visual fixation. Data were analyzed in a flattened cortical format, relative to maps of retinotopy and spatial frequency peak tuning. Neither local nor global attention was lateralized in the occipital cortex. Instead, local attention and global attention appear to be special cases of visual spatial attention, which are mapped consistently with the maps of retinotopy and spatial frequency tuning, in multiple visual cortical areas.

Focal arterial infarction in the full-term newborn is an important cause of acquired cerebral lesions in the perinatal period. Clinical motor seizures, most often unifocal, are the nearly constant disclosing symptom confirmed by focal EEG abnormalities. A multifactorial physiopathology is usual, including genetic and perinatal environmental factors. In the past decade, various acquired or genetic thrombophilias have been discussed as risk factors. For several of the involved mechanisms, the excitotoxic cascade could represent a common final pathway leading to neuronal cell death. Early magnetic resonance imaging studies and EEG help to identify the newborns with strokes who are likely to develop hemiplegia and disabilities at school. Protection of the human fetal brain remains difficult, since the triggering factor initiating the excitotoxic cascade is rarely observed. Treatment of seizures is nevertheless necessary, because it seems that they accelerate anoxia-induced neuronal death in animal models of focal hypoxic ischemia., (Copyright 2001 S. Karger AG, Basel)

Periventricular leukomalacia (PVL) is the main cause of neurologic handicap in pre-term infants. The understanding of cellular and molecular mechanisms leading to white matter damage is critical for development of innovative therapeutic strategies for PVL. The pathogenesis of PVL remains unclear but possibly involves glutamate excitotoxicity as an important molecular pathway. We previously described a neonatal mouse model of excitotoxic white matter lesion mimicking human PVL. In the present study, we used this experimental tool to investigate the cellular populations and the glutamate receptor subtypes involved in excitotoxic white matter lesions. Combined immunohistochemical, electron microscopic, and cell death detection data revealed that microglial activation and astrocytic death were the primary responses of white matter to excitotoxic insult. In vitro experiments suggested that microglia activated by ibotenate released soluble factors that kill astrocytes. The use of selective agonists and antagonists of glutamate receptors revealed that N-methyl-D-aspartate (NMDA) receptor activation was essential and sufficient to produce cystic white matter lesions. NMDA receptor immunohistochemistry labeled microglial cells in the neonatal periventricular white matter. The developing white matter displayed a window of sensitivity to excitotoxic damage that was paralleled by the transient presence of NMDA receptor-expressing white matter cells. Assuming that similar pathophysiologic mechanisms are present in human pre- term infants, microglia and NMDA receptors could represent key targets for treatment of PVL.

Intracerebral administration of ibotenate produces, through activation of N-methyl-D-aspartate (NMDA) receptors, neuronal heterotopias in the newborn hamster neocortex: high doses of ibotenate induce periventricular and subcortical neuronal heterotopias, while low doses of ibotenate produce intracortical heterotopias and molecular layer ectopias. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are closely related peptides with neurotrophic properties. They share common VPAC1 and VPAC2 receptors, which use cAMP as a second messenger. Previous studies have shown that VIP prevents excitotoxic neuronal death and exacerbates glutamate-induced c-fos neuronal expression. In order to gain new insight into the molecular control of neuronal migration, the present study examined the effects of VIP and PACAP on ibotenate-induced heterotopias in the newborn hamster. Co-treatment with VIP and a high dose of ibotenate produced a pattern of neuronal heterotopias similar to the one observed in animals treated with low doses of ibotenate alone. Pups co-injected with a low dose of ibotenate and a VIP antagonist displayed cortical dysgeneses similar to those observed in animals treated with high doses of ibotenate alone. The modulating effects of VIP on excitotoxin-induced heterotopias were mimicked by forskolin, PACAP, and by a specific VPAC2 receptor agonist but not by a VPAC1 agonist, and were blocked by a protein kinase A (PKA) inhibitor. Taken together, these data suggest that VIP and PACAP can attenuate ibotenate-induced heterotopias in newborn hamster and that this effect is mediated by the VPAC2 receptor utilizing the cAMP-PKA pathway.

Disorders of neuronal migration in cerebral cortex are associated with neurological impairments, including mental retardation and epilepsy. Their causes and pathophysiology remain largely unknown, however. In patients with Zellweger disease, a lethal panperoxisomal disorder, and in mice lacking the Pxr1 import receptor for peroxisomal matrix proteins, the absence of peroxisomes leads to abnormal neuronal migration. Analysis of Pxr1-/- mice revealed that the migration defect was caused by altered N-methyl-D-aspartate (NMDA) glutamate receptor-mediated calcium mobilization. This NMDA receptor dysfunction was linked to a deficit in platelet-activating factor, a phenomenon related to peroxisome impairment. These findings confirm NMDA receptor involvement in neuronal migration and suggest a link between peroxisome metabolism and NMDA receptor efficacy.

Increased survival of very preterm infants and extremely preterm infants does not imply an increase in neurodevelopmental sequelae. However, preterm infants remain at high risk of severe cerebral palsy with neuromotor dysfunction and mental retardation. Necrotic or hemorrhagic lesions occurring in the periventricular ring of telencephalic white matter are the most threatening events for the developing brain of these infants. Recent progress in neuroepidemiology, developmental neurobiology and imaging methods has made it possible to revisit the pathophysiology of brain lesions on a multifactorial basis. Treatment and early detection of infections is a priority. Neuroprotective agents capable of arresting neuron cell death (antagonists of the excitotoxic cascade, free-radical antagonists, proinflammatory cytokine antagonists, growth factors) are new strategies for the prevention of cerebral palsy.

Activity-dependent neurotrophic factor (ADNF) is a newly identified compound that prevents in vitro neuronal death when present in fentomolar concentrations. ADNF-14, a 14 amino acid peptide derived from ADNF, has the same effects on growth as the parent molecule. However, the transduction pathways and target cells for these highly potent trophic factors are still unknown. We previously described a mouse model of excitotoxic lesions of the developing neocortex mimicking several hypoxic or hypoxic-like brain lesions observed in human fetuses and neonates. In this model, cotreatment with the excitotoxin ibotenate and ADNF-14 prevented both neuronal death in pups injected on the day of birth and white matter cystic lesions in pups treated 5 d after birth. In the present study, coadministration of ibotenate, ADNF-14, and selective transduction pathway inhibitors showed that activation of protein kinase C (PKC) and mitogen-associated protein kinase kinase was critical for neuroprotection. Immunocytochemistry revealed that ADNF-14 activated PKC and mitogen-associated protein kinase in cortical neurons on the day of birth and in white matter astrocytes on the fifth postnatal day. Taken in concert, these data identify PKC and mitogen-associated protein kinase pathways as critical to ADNF-14-induced neuroprotection of the developing brain against excitotoxic damage.

Physiological and pathological fetal levels of lactic dehydrogenase (LDH), including its five different iso-enzymes are still poorly known. Our objectives were to compare total LDH levels and its five iso-enzymes between a control group of healthy fetuses and a group of fetuses with severe intra-uterine growth restriction (IUGR), and to determine the biochemical associations and the prognostic value of elevated LDH activity in fetuses with IUGR. Total LDH levels, haematologic values and liver enzyme activities were measured in 108 healthy fetuses from 17 to 37 weeks of gestation and in 44 fetuses with severe IUGR. Total fetal LDH in plasma from the healthy fetuses were constant throughout pregnancy (mean (SD)= 305.09 (46.97)). Total LDH values in plasma significantly increased in cases of IUGR (p=0.003), and the degree of increase was significantly correlated with fetal erythroblastosis (n =44, r=0.80, p<0.001). LDH 5 significantly decreased in the IUGR group (p=0.03). Total LDH values strictly above 400 IU/l (a value equal to the mean+2 SD in the healthy fetus group) were found to be significantly associated with thrombocytopenia (p<0.001), erythroblastosis (p=0.008) and an increase in AST value (p=0.03). These results suggest that the fetal LDH value in plasma is a useful biological marker for severe chronic distress.

The prevention of cerebral palsy and neuroprotection of the immature brain continue to be health care priorities. The pathophysiology of perinatal brain lesions associated with cerebral palsy seems to be multifactorial and includes pre- and perinatal factors such as preconceptional events, hormone and growth factors deficiencies, maternal infections with production of cytokines, and hypoxic/ischemic perfusion failures. Excitotoxic cascade could represent a common pathway that leads to neural cell death and subsequent brain damage. Brain injuries induced by ibotenate, a glutamatergic analog, which are essentially mediated through the N-methyl-D-aspartate receptor, mimic some aspects of the white matter cysts and transcortical necrosis observed in human perinatal brain damage. The purpose of the present study was to assess the protective role of several pharmacological agents, administered in conjunction with ibotenate, against induced excitotoxic lesions. We injected ibotenate in the developing mouse brain 5 d postnatally, after the full settlement of neuronal layers. Co-treatment with kynurenic acid, an antagonist of the facilitating glycine site of the N-methyl-D-aspartate receptor, or with N(G)-nitro-L-arginine, an inhibitor of nitric oxide synthesis, induced a dose-dependent neuroprotective effect. Conversely, zinc gluconate, a blocking agent of the channel linked to the N-methyl-D-aspartate receptor, and a free radical scavenger (U74389F), were unable to protect the developing brain against excitotoxic attack. These data help to clarify some molecular mechanisms involved in excitotoxic lesions of the developing mouse brain and permit us to envision new strategies in the prevention of cerebral palsy.

Cortical dysplasias are frequently caused by excitotoxic brain damage due to hypoxia or ischemia during development. Ibotenate, a glutamatergic agonist, was injected in the neopallium of rat pups at day of birth. The resulting cytoarchitectonic pattern includes neuronal depopulation in deep cortical layers, sulcus formation, and molecular ectopias, mimicking human polymicrogyria and disorders of neuronal migration. These cortical dysplasias persist until adulthood, providing a rat model to investigate the long-term functional consequences of cortical malformations.

Intracerebral administration of the excitotoxin ibotenate to newborn mice induces white matter lesions mimicking periventricular leukomalacia, the most frequent brain lesion occurring in premature human babies. In this model, coinjection of vasoactive intestinal peptide prevents white matter lesions. In the present study, coadministration of ibotenate, vasoactive intestinal peptide, and selective transduction inhibitors showed that protein kinase C and mitogen-associated protein kinase pathways were critical for neuroprotection. In vivo and in vitro immunocytochemistry revealed that vasoactive intestinal peptide activated protein kinase C in astrocytes and neurons, and mitogen-associated protein kinase in neurons. In vitro neuronal transduction activation was indirect and required medium conditioned by astrocytes in which protein kinase C had been activated by vasoactive intestinal peptide. Although vasoactive intestinal peptide did not prevent the initial in vivo appearance of white matter lesion, it promoted a secondary repair of this lesion with axonal regrowth. Through protein kinase C activation, vasoactive intestinal peptide also prevented ibotenate-induced white matter astrocyte death. These data support the following hypothetical model: Vasoactive intestinal peptide activates protein kinase C in astrocytes, which promotes astrocytic survival and release of soluble factors; these released factors activate neuronal mitogen-associated protein kinase and protein kinase C, which will permit axonal regrowth.

Background: Focal dermal hypoplasia syndrome is mainly defined by the association of abnormalities of extremities, atrophy and linear hyperpigmentation of the skin, localized deposits of superficial fat, anomalies of the eyes and of the nails. Neonates are often small for their age., Case Reports: Three sporadic cases are reported. Mental delay and omphalocele were observed in the first case. The neurological development was subnormal in the second and an unusual monodactyly was seen in the third., Conclusion: Most cases are sporadic, but in family cases, an X-linked dominant factor is likely. When a first affected offspring is observed, skin examination and X-ray should be carried out in parents to evaluate the risk of recurrence in their children. As the gene site has not yet been determined, antenatal diagnosis should be suspected on echography when fetal growth delay is associated to distal limb and/or ocular anomalies.

The main contribution of EEG during intensive care in infants with hypoxic-ischemic encephalopathy is i) to help determine whether infants with subtle clinical manifestations present with epileptic seizures, ii) to determine whether paralyzed or heavily sedated infants present with convulsive phenomena, iii) to assess the therapeutical response to anticonvulsants, 4) to contribute, in combination with ultrasound scanning, to diagnostic evaluation of the severity of lesions, and to provide valuable prognostic informations via the analysis of the background activity, as normal EEG is highly predictive of normal outcome, whereas various abnormal EEG features are constantly associated with subsequent major neurological abnormalities or death. These EEG features are readily available from a very early stage and may both precede and be prognostically more sensitive than information obtained from ultrasound. Recording of neonatal electroencephalogram requires awareness of the normal development of electroencephalographic features in the newborn, skilled technicians, and experienced readers of EEG tracings.