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Background: Accumulating evidence from laboratory animal and human studies suggests that air pollution exposure during pregnancy affects cognitive and psychomotor development in childhood., Methods: We analyzed data from 6 European population-based birth cohorts-GENERATION R (The Netherlands), DUISBURG (Germany), EDEN (France), GASPII (Italy), RHEA (Greece), and INMA (Spain)-that recruited mother-infant pairs from 1997 to 2008. Air pollution levels-nitrogen oxides (NO2, NOx) in all regions and particulate matter (PM) with diameters of <2.5, <10, and 2.5-10 μm (PM2.5, PM10, and PMcoarse, respectively) and PM2.5 absorbance in a subgroup-at birth addresses were estimated by land-use regression models, based on monitoring campaigns performed primarily between 2008 and 2011. Levels were back-extrapolated to exact pregnancy periods using background monitoring sites. Cognitive and psychomotor development was assessed between 1 and 6 years of age. Adjusted region-specific effect estimates were combined using random-effects meta-analysis., Results: A total of 9482 children were included. Air pollution exposure during pregnancy, particularly NO2, was associated with reduced psychomotor development (global psychomotor development score decreased by 0.68 points [95% confidence interval = -1.25 to -0.11] per increase of 10 μg/m in NO2). Similar trends were observed in most regions. No associations were found between any air pollutant and cognitive development., Conclusions: Air pollution exposure during pregnancy, particularly NO2 (for which motorized traffic is a major source), was associated with delayed psychomotor development during childhood. Due to the widespread nature of air pollution exposure, the public health impact of the small changes observed at an individual level could be considerable.

Background: Sedative drug administration is a challenging aspect of the management of mechanically ventilated patients in the out-of-hospital critical care medicine. We hypothesised that the bispectral index of the EEG (BIS) could be a helpful tool in evaluating the depth of sedation in this difficult environment. The main objective of the present study was to assess the agreement of BIS with the clinical scales in the out-of-hospital setting., Methods: This prospective study included mechanically ventilated patients. BIS values were blindly recorded continuously. A Ramsay score was performed every 5 min. The main judgement criterion was the correlation between BIS values and the Ramsay score., Results: 72 patients were included, mostly presenting with toxic coma (36%) or neurological coma (21%). The median (IQR) BIS value was 85 (84-86) when the Ramsay score was 3, 80 (76-84) when the Ramsay score was 4, 61 (55-80) when the Ramsay score was 5 and 45 (38-60) when the Ramsay score was 6. According to Receiver operating characteristic (ROC) curves, BIS was categorised into three classes (BIS<54 corresponding to Ramsay score 6, 54≤BIS<72 for Ramsay score 5 and BIS≥73 for Ramsay score ≤4). Based on these categories, the proportion of appropriate BIS values was 67% (217/323). The concordance correlation coefficient for repeated measurements was 0.54 (0.43-0.64). The agreement between BIS and the Ramsay score is moderate., Conclusions: Prehospital measured BIS values appear poorly correlated with clinical assessment of the depth of sedation. For this reason, the use of BIS to guide prehospital sedation cannot be recommended., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Introduction: Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1), may underestimate activity and does not predict survival in patients with hepatocellular carcinoma (HCC) treated with sorafenib. This study assessed the value of alternative radiological criteria to evaluate response in HCC patients treated with sorafenib., Patients and Methods: A retrospective blinded central analysis was performed of computed tomography (CT) scans from baseline and the first tumor evaluation in consecutive patients treated with sorafenib over a 2-year period in a single institution. Four different evaluation criteria were used: Choi, European Association for the Study of the Liver (EASL), modified RECIST (mRECIST), and RECIST 1.1., Results: Among 82 HCC patients, 64 with Barcelona Clinic Liver Cancer stage B-C were evaluable with a median follow-up of 22 months. Median duration of sorafenib treatment was 5.7 months, and median overall survival was 12.8 months. At the time of the first CT scan, performed after a median of 2.1 months, Choi, EASL, mRECIST, and RECIST 1.1 identified 51%, 28%, 28%, and 3% objective responses, respectively. Responders by all criteria showed consistent overall survival >20 months. Among patients with stable disease according to RECIST 1.1, those identified as responders by Choi had significantly better overall survival than Choi nonresponders (22.4 vs. 10.6 months; hazard ratio: 0.43, 95% confidence interval: 0.15-0.86, p = .0097)., Conclusion: Choi, EASL, and mRECIST criteria appear more appropriate than RECIST 1.1 to identify responders with long survival among advanced HCC patients benefiting from sorafenib.

Context: Asymptomatic sporadic nonfunctioning, well-differentiated pancreatic neuroendocrine tumors (NF-PNETs) are increasingly diagnosed, and their management is controversial because of their overall good but heterogeneous prognosis., Objective: The objective of the study was to assess the natural history of asymptomatic sporadic NF-PNETs smaller than 2 cm in size and the risk-benefit balance of nonoperative management., Experimental Design: From January 2000 to June 2011, 46 patients with proven asymptomatic sporadic NF-PNETs smaller than 2 cm in size were followed up for at least 18 months with serial imaging in tertiary referral centers., Results: Patients were mainly female (65%), with a median age of 60 years. Tumors were mainly located in the pancreatic head (52%), with a median lesion size of 13 mm (range 9-15). After a median follow-up of 34 months (range 24-52) and an average of four (range 3-6) serial imaging sessions, distant or nodal metastases appeared on the imaging in none of the patients. In six patients (13%), a 20% or greater increase in size was observed. Overall median tumor growth was 0.12 mm per year, and neither patients nor tumor characteristics were found to be significant predictors of tumor growth. Overall, eight patients (17%) underwent surgery after a median time from initial evaluation of 41 months (range 27-58); all resected lesions were European Neuroendocrine Tumor Society T stage 1 (n = 7) or 2 (n = 1), grade 1, node negative, with neither vascular nor peripancreatic fat invasion., Conclusions: In selected patients, nonoperative management of asymptomatic sporadic NF-PNETs smaller than 2 cm in size is safe. Larger and prospective multicentric studies with long-term follow-up are now needed to validate this wait-and-see policy.

Objective: To evaluate the relationship between preterm premature rupture of membranes (PPROM) and cognitive impairment in 5-year-old children born very preterm., Study Design: The Etude Epidémiologique sur les Petits Ages Gestationnels Study is a population-based cohort of children followed up from birth to age 5 years recruited in 9 French regions in 1997. We analyzed data from singletons born between 24 and 32 weeks gestation categorized into 4 groups according to etiology of prematurity: infants born after PPROM, after idiopathic preterm labor, in a vascular context (Vasc), and to women with other complications (Other). Cognitive development at age 5 years was assessed using the Mental Processing Composite score of the Kaufman-Assessment Battery for Children., Results: Among the 1051 children followed up to age 5 years, the mean Mental Processing Composite score was 93.6 ± 19.7, and 13.3% of the children (140 of 1051) had cognitive impairment. After adjustment for potential confounders, the risk of cognitive impairment among infants in the PPROM group was not significantly different than that in the idiopathic preterm labor group (OR, 1.09; 95% CI, 0.62-1.92) and the Other group (OR, 1.36; 95% CI, 0.75-2.47), but was lower than that in the Vasc group (OR, 1.86; 95% CI, 1.16-2.97). In the PPROM group, the risk of cognitive impairment was greater when the latency period (ie, time from rupture to delivery) was <3 days (OR, 2.32; 95% CI, 1.07-5.02)., Conclusion: Preterm infants born after PPROM are not at increased risk for cognitive impairment in childhood, but the time between PPROM and birth may influence that risk., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Objective: To determine whether neonatal infections are associated with a higher risk of adverse neurodevelopment at 5 years of age in a population-based cohort of very preterm children., Methods: We included all live births between 22 and 32 weeks of gestation, from 9 regions in France, in 1997 (EPIPAGE study). Of the 2665 live births, 2277 were eligible for a follow-up evaluation at 5 years of age: 1769 had a medical examination and 1495 underwent cognitive assessment. Cerebral palsy and cognitive impairment were studied as a function of early-onset sepsis (EOS) and late-onset sepsis (LOS), after adjustment for potential confounding factors, in multivariate logistic regression models., Results: A total of 139 (5%) of the 2665 live births included in the study presented with EOS alone (without associated LOS), 752 (28%) had LOS alone (without associated EOS), and 64 (2%) displayed both EOS and LOS. At 5 years of age, the frequency of cerebral palsy was 9% (157 of 1769) and that of cognitive impairment was 12% (177 of 1495). The frequency of cerebral palsy was higher in infants with isolated EOS (odds ratio [OR]: 1.70 [95% confidence interval (CI): 0.84-3.45]) or isolated LOS (OR: 1.71 [95% CI: 1.14-2.56]) than in uninfected infants, and this risk was even higher in cases of combined EOS and LOS (OR: 2.33 [95% CI: 1.02-5.33]). There was no association between neonatal infection and cognitive impairment., Conclusions: Neonatal infections in these very preterm infants were associated with a higher risk of cerebral palsy at the age of 5 years, particularly in infants presenting with both EOS and LOS.

Background: As new treatment modalities develop for the management of vestibular schwannomas (VS) in patients with neurofibromatosis type 2, it remains crucial to ascertain the natural history of the disease., Objective: To determine the relationship between hearing and tumor growth in patients undergoing conservative VS management., Methods: Patients harboring bilateral VS with at least 1 year of radiological follow-up were selected. Conservative management was proposed based on the small tumor size and/or serviceable hearing at presentation. Tumor size was calculated by using the 2-component box model and reported as mean tumor diameter. Hearing was evaluated by using pure-tone average and the American Academy of Otololaryngologists and Head and Neck Surgery classification., Results: Forty-six patients harboring 92 VS were included. The mean clinical and radiological follow-up times were 6.0 and 4.2 years, respectively. The mean tumor diameter was 13 mm at presentation and 20 mm at the end of follow-up. Mean tumor growth rate was 1.8 mm/year. During follow-up, 17 patients (37%) underwent surgery for VS. Surgery-free rate for VS was 88% at 5 years. The number of patients with at least 1 serviceable ear was 39 (85%) at presentation and 34 (74%) at the end of follow-up, including 22 (66%) with binaural serviceable hearing maintained. There was no statistical correlation between tumor growth rate and preservation of serviceable hearing. Tumor growth rates and age at presentation were inversely correlated., Conclusion: This study illustrates the high variability among neurofibromatosis type 2 patients regarding hearing status and VS growth rate and justifies the choice of initial conservative management in selected cases., Abbreviations: : AAO-HNS, American Academy of Otololaryngologists and Head and Neck Surgery classificationMTD, mean tumor diameterNF2, neurofibromatosis type 2PTA, pure-tone averageSDS, speech discrimination scoreVS, vestibular schwannomas.

Objective: To investigate the association of motor and cognitive/learning deficiencies and overall disabilities in very preterm (VPT) children and their relations to gestational age (GA) and brain lesions., Design Setting and Participants: EPIPAGE is a longitudinal population-based cohort study of children born before 33 weeks' gestation (WG) in 9 French regions in 1997-1998. Cumulating data from all follow up stages, neurodevelopmental outcomes were available for 90% of the 2480 VPT survivors at 8 years. Main outcomes were association of motor and cognitive deficiencies and existence of at least one deficiency (motor, cognitive, behavioral/psychiatric, epileptic, visual, and/or hearing deficiencies) in three GA groups (24-26, 27-28, and 29-32WG) and four groups of brain lesions (none, minor, moderate, or severe)., Results: VPT had high rates of motor (14%) and cognitive (31%) deficiencies. Only 6% had an isolated motor deficiency, 23% an isolated cognitive one and 8% both types. This rate reached 20% among extremely preterm. Psychiatric disorders and epilepsy were observed in 6% and 2% of children, respectively. The risks of at least one severe or moderate deficiency were 11 and 29%. These risks increased as GA decreased; only 36% of children born extremely preterm had no reported deficiency. Among children with major white matter injury (WMI), deficiency rates reached 71% at 24-26WG, 88% at 27-28WG, and 80% at 29-32WG; more than 40% had associated motor and cognitive deficiencies. By contrast, isolated cognitive deficiency was the most frequent problem among children without major lesions., Conclusions: In VPT, the lower the GA, the higher the neurodisability rate. Cerebral palsy is common. Impaired cognitive development is more frequent. Its occurrence in case without WMI or early motor disorders makes long-term follow up necessary. The strong association between motor impairments, when they exist, and later cognitive dysfunction supports the hypothesis of a common origin of these difficulties.

Our objective was to understand the functional link between the composition of faecal microbiota and the clinical characteristics of adults with short bowel syndrome (SBS). Sixteen patients suffering from type II SBS were included in the study. They displayed a total oral intake of 2661±1005 Kcal/day with superior sugar absorption (83±12%) than protein (42±13%) or fat (39±26%). These patients displayed a marked dysbiosis in faecal microbiota, with a predominance of Lactobacillus/Leuconostoc group, while Clostridium and Bacteroides were under-represented. Each patient exhibited a diverse lactic acid bacteria composition (L. delbrueckii subsp. bulgaricus, L. crispatus, L. gasseri, L. johnsonii, L. reuteri, L. mucosae), displaying specific D and L-lactate production profiles in vitro. Of 16 patients, 9/16 (56%) accumulated lactates in their faecal samples, from 2 to 110 mM of D-lactate and from 2 to 80 mM of L-lactate. The presence of lactates in faeces (56% patients) was used to define the Lactate-accumulator group (LA), while absence of faecal lactates (44% patients) defines the Non lactate-accumulator group (NLA). The LA group had a lower plasma HCO3(-) concentration (17.1±2.8 mM) than the NLA group (22.8±4.6 mM), indicating that LA and NLA groups are clinically relevant sub-types. Two patients, belonging to the LA group and who particularly accumulated faecal D-lactate, were at risk of D-encephalopathic reactions. Furthermore, all patients of the NLA group and those accumulating preferentially L isoform in the LA group had never developed D-acidosis. The D/L faecal lactate ratio seems to be the most relevant index for a higher D-encephalopathy risk, rather than D- and L-lactate faecal concentrations per se. Testing criteria that take into account HCO3(-) value, total faecal lactate and the faecal D/L lactate ratio may become useful tools for identifying SBS patients at risk for D-encephalopathy.

Extended-spectrum β-lactamase-producing Enterobacteriaceae isolates (ESBLE) are emerging pathogens that confer resistance to antimicrobial drugs. We conducted a 10-year study in France (January 2001-April 2010) to investigate the incidence of and risk factors for ESBLE infections after liver transplant. Of 710 transplant patients screened preoperatively for ESBLE fecal carriage, 5.5% had ESBLE infection develop within 4 months after surgery; patients with pretransplant ESBLE fecal carriage were more likely to have infection develop than were noncarriers. Typing showed extensive genetic diversity, with a large predominance of CTX-M enzymes. Independent predictors of ESBLE infection were pretransplant fecal carriage, Model for End Stage Liver Disease score >25, and return to surgery. Our results indicate that the influx of preoperatively acquired ESBLE isolates into the hospital outweighs cross-transmission in the epidemiology of ESBLE infections after liver transplant. Transplant candidates should be systematically screened for carriage, and posttransplant infection in carriers should be treated with carbapenems.

Context: Untreated hypothyroidism is known to impair fecundity. Patients treated early for congenital hypothyroidism (CH) have yet to be evaluated in adulthood, because screening programs have been running for only the last 30 years in most industrialized countries., Objective: Our objective was to assess the fecundity of young adults treated early for CH and its determinants., Design, Setting, and Participants: Of the 1748 subjects diagnosed with CH in the first 10 yr after the introduction of neonatal screening in France, 1158 completed a questionnaire on fecundity at a mean age of 25.3 yr. This self-administered questionnaire focused on first attempts to have a child and time to pregnancy. The control group was that used in an analogous study on subjects born between 1971 and 1985., Main Outcome Measures: Fecundability hazard ratios (HR) were estimated with Cox regression models and adjusted for known fecundity confounders (age, smoking, and reproductive history)., Results: Fecundability was similar for the CH and control groups: HR = 1.14 (0.89-1.47) for women, and HR = 0.98 (0.58-1.66) for men. In women, the most severe initial forms of the disease, athyreosis, absence of bone maturation at the knee epiphyseal ossification centers, and a low serum free T(4) concentration at diagnosis (<5 pmol/liter), were associated with lower fecundity: HR = 0.68 (0.50-0.98) (P = 0.02); HR = 0.65 (0.45-0.94) (p = 0.02) and HR = 0.70 (0.50-0.97) (P = 0.03), respectively. However, fecundability was not associated with age at the start of treatment, initial levothyroxine dose, or the adequacy of hypothyroidism control., Conclusion: There is no evidence that fecundity is generally lower in young adults treated early than in the general population. However, fecundity was lower in women suffering from the most severe form of the disease.

The objectives of the study were (1) to assess prevalence of social withdrawal behaviour in infants aged 12 months included in the French Perinatal Risk Factor Study Eden; (2) To study the correlation between relational withdrawal and several perinatal and parental factors assessed in the EDEN study. A longitudinal study using the ADBB scale was conducted within the Eden Cohort in the year 2008. 1,586 infants were included in the study. Fourteen percent of the children who had an ADBB assessment had a score at 5 and over on the ADBB, a scale designed to assess social withdrawal behaviour at age 0-24 months. Social withdrawal at 12 months was associated with low birth weight, low gestational age and with intra uterine growth retardation. Social withdrawal was independently associated with several maternal and paternal risk factors. The level of social withdrawal behaviour increased with a score of maternal difficulties. This study on a large longitudinally followed volunteer sample demonstrate a clear association of social withdrawal behaviour at age one with low birth weight and preterm birth, possibly mediated by parental vulnerabilities. Social withdrawal behaviour seems to be an important alarm signal to detect early on particularly in premature and small for date babies., (© Springer-Verlag 2012)

Background: Global dissemination of Escherichia coli producing CTX-M extended-spectrum β-lactamases (ESBL) is a public health concern. The aim of the study was to determine factors associated with CTX-M- producing E. coli infections among patients hospitalised in the Assistance Publique-Hôpitaux de Paris, the largest hospital system in France (23 000 beds), through a prospective case-control-control study., Methods/principal Findings: From November 2008 to June 2009, 152 inpatients with a clinical sample positive for CTX-M-producing E. coli (cases), 152 inpatients with a clinical sample positive for non ESBL-producing E. coli on the day or within the three days following case detection (controls C1), and 152 inpatients with culture-negative clinical samples since the beginning of hospitalisation and until three days after case detection (controls C2) were included in ten hospitals of the Paris area. Factors studied were related to patient's origin, lifestyle and medical history as well as care during hospitalisation. Those independently associated with CTX-M-producing E. coli were determined. Three independent factors were common to the two case-control comparisons: birth outside of Europe (cases vs C1: OR(1) = 2.4; 95%CI = [1.3-4.5] and cases vs C2: OR(2) = 3.1; 95%CI = [1.4-7.0]), chronic infections (OR(1) = 2.9; 95%CI = [1.3-6.9] and OR(2) = 8.7; 95%CI = [2.0-39.7]), and antibiotic treatment between hospital admission and inclusion (OR(1) = 2.0; 95%CI = [1.0-3.8] and OR(2) = 3.3; 95%CI = [1.5-7.2]). Cases were also more likely to be (i) functionally dependent before hospitalisation than C2 (OR(2) = 7.0; 95%CI = [2.1-23.5]) and (ii) living in collective housing before hospitalisation than C2 (OR(2) = 15.2; 95%CI = [1.8-130.7]) when CTX-M-producing E. coli was present at admission., Conclusion: For the first time, patient's origin and lifestyle were demonstrated to be independently associated with isolation of CTX-M-producing E. coli, in addition to health care-related factors.

Context: Screening programs resulting in the early treatment of patients with congenital hypothyroidism (CH) have successfully improved neurodevelopmental outcome, but little is known about long-term health., Objectives: The aim of the study was to assess health status, and socioeconomic attainment, for a population-based registry of young adult patients., Design, Setting, and Participants: All 1748 eligible patients diagnosed during the first decade after the introduction of neonatal screening in France were invited to participate in this study at a median age of 23.4 yr. Completed questionnaires were obtained from 1202 of the selected patients. The comparison group included 5817 subjects from the last French Decennial Health Survey., Main Outcome Measures: Health indicators including medical conditions, hearing and visual status, sociodemographic characteristics, and quality of life were measured., Results: Patients with CH were significantly more likely than their peers to report associated chronic diseases (5.7 vs. 2.9%), hearing impairment (9.5 vs. 2.5%), visual problems (55.4 vs. 47.9%), and being overweight with a body mass index of at least 25 kg/m(2) (22.8 vs. 15.7%) (P < 0.0001). Furthermore, fewer patients attained the highest socioeconomic category (14.6 vs. 23.1%) and were in full-time employment (39.9 vs. 44.8%) (P < 0.0001). They were more likely to still be living with their parents and had a lower health-related quality of life than their healthy peers, particularly for mental dimensions, with a mean difference for the mental summary component of 0.35 SD score (P < 0.0001). CH severity at diagnosis, treatment adequacy, and the presence of other chronic health conditions were the main determinants of educational achievement and health-related quality of life scores., Conclusion: These findings highlight the need for careful monitoring of neurosensory functioning, weight, and long-term treatment adequacy throughout childhood and adulthood.

Background: The aim was to evaluate the value of magnetic resonance imaging (MRI) findings in Crohn's disease (CD) in correlation with pathological inflammatory score using surgical pathology analysis as a reference method., Methods: CD patients who were to undergo bowel resection surgery underwent MR enterography before surgery. The CD pathological inflammatory score of the surgical specimens was classified into three grades: mild or nonactive CD, moderately active CD, and severely active CD; fibrosis was also classified into three grades: mild, moderate, and severe. Mural and extramural MRI findings were correlated with pathological inflammatory and fibrosis grades., Results: Fifty-three consecutive patients were included retrospectively. The mean delay between MRI and surgery was 24 days (range 1-90, median 14). The CD pathological inflammatory score was graded as follows: grade 0 (11 patients, 21%), grade 1 (15 patients, 28%), and grade 2 (27 patients, 51%). MRI findings significantly associated with pathological inflammatory grading were wall thickness (P < 0.0001), degree of wall enhancement on delayed phase (P < 0.0001), pattern of enhancement on both parenchymatous (P = 0.02), and delayed phase, (P = 0.008), T2 relative hypersignal wall (P < 0.0001), blurred wall enhancement (P = 0.018), comb sign (P = 0.004), fistula (P < 0.0001), and abscess (P = 0.049). The inflammation score correlated with the fibrosis score (r = 0.63, P = 0.0001)., Conclusions: Our study identified MRI findings significantly associated with surgical pathological inflammation. These lesions are considered potentially reversible and may be efficiently treated medically. We also showed that fibrosis was closely and positively related to inflammation., (Copyright © 2010 Crohn's & Colitis Foundation of America, Inc.)

Aim: To assess cerebral lesions and other medical as well as social characteristics as predictors of risk of mild and severe cognitive deficiencies in very preterm infants., Methods: As part of the EPIPAGE population-based prospective cohort study, perinatal data and cognitive outcome at 5 years of age were recorded for 1503 infants born before 33 weeks of gestation in nine regions of France in 1997. Mild cognitive deficiency was defined as a Mental Processing Composite score on the Kaufman Assessment Battery for Children test of between 70 and 84, and severe cognitive deficiency as a score of <70., Results: After controlling for cerebral lesions and other medical as well as social factors, low parental socio-economic status and lack of breastfeeding were significant predictors of mild and severe cognitive deficiencies, whereas presence of cerebral lesions, being small for gestational age and having a large number of siblings were predictors of severe cognitive deficiency., Conclusion: Predictors of poor cognitive outcome in very preterm infants are low social status, lack of breastfeeding, presence of cerebral lesions on ultrasound scan, being born small for gestational age and having a high number of siblings. Social factors predicted both mild and severe cognitive deficiencies, whereas medical factors predicted mostly severe cognitive deficiencies., (© 2011 The Author(s)/Acta Paediatrica © 2011 Foundation Acta Paediatrica.)

Objectives: To investigate school difficulties, special care and behavioral problems in 8 year-old very preterm (VPT) children., Patient and Methods: Longitudinal population-based cohort in nine regions of France of VPT children and a reference group born at 39-40 weeks of gestation (WG). The main outcome measures were information about school, special care and behavioral problems using Strengths and Difficulties Questionnaire from a questionnaire to parents., Results: Among the 1439 VPT children, 5% (75/1439) were in a specialised school or class, 18% (259/1439) had repeated a grade in a mainstream class and 77% (1105/1439) were in the appropriate grade-level in mainstream class; these figures were 1% (3/327) , 5% (16/327) and 94% (308/327) , respectively, for the reference group. Also, 15% (221/1435) of VPT children in a mainstream class received support at school versus 5% (16/326) of reference group. More VPT children between the ages of five and eight years received special care (55% (794/1436)) than children born at term (38% (124/325)); more VPT children (21% (292/1387)) had behavioral difficulties than the reference group (11% (35/319)). School difficulties, support at school, special care and behavioral difficulties in VPT children without neuromotor or sensory deficits varied with gestational age, socioeconomic status, and cognitive score at the age of five., Conclusions: Most 8-year-old VPT children are in mainstream schools. However, they have a high risk of difficulty in school, with more than half requiring additional support at school and/or special care. Referral to special services has increased between the ages of 5 and 8 years, but remained insufficient for those with borderline cognitive scores.

Aim: The aim of this study was to assess the independent role of cerebral lesions on ultrasound scan, and several other neonatal and obstetric factors, as potential predictors of cerebral palsy (CP) in a large population-based cohort of very preterm infants., Method: As part of EPIPAGE, a population-based prospective cohort study, perinatal data and outcome at 5 years of age were recorded for 1812 infants born before 33 weeks of gestation in nine regions of France in 1997., Results: The study group comprised 942 males (52%) and 870 females with a mean gestational age of 30 weeks (SD 2 wks; range 24-32 wks) and a mean birthweight of 1367 g (SD 393 g; range 450-2645 g). CP was diagnosed at 5 years of age in 159 infants (prevalence 9%; 95% confidence interval [CI] 7-10%), 97 males and 62 females, with a mean gestational age of 29 weeks (SD 2 wks; range 24-32 wks) and a mean birthweight of 1305 g (SD 386 g; range 500-2480 g). Among this group, 67% walked without aid, 14% walked with aid, and 19% were unable to walk. Spastic, ataxic, and dyskinetic CP accounted for 89%, 7%, and 4% of cases respectively. The prevalence of CP was 61% among infants with cystic periventricular leukomalacia, 50% in infants with intraparenchymal haemorrhage, 8% in infants with grade I intraventricular haemorrhage, and 4% in infants without a detectable cerebral lesion. After controlling for cerebral lesions and obstetric and neonatal factors, only male sex (odds ratio [OR] 1.52; 95% CI 1.03-2.25) and preterm premature rupture of membranes or preterm labour (OR 1.72; 95% CI 0.95-3.14) were predictors of the development of CP in very preterm infants., Interpretation: Cerebral lesions were the most important predictor of CP in very preterm infants. In addition, infant sex and preterm premature rupture of membranes or preterm labour were also independent predictors of CP.

Bloodstream infections (BSIs) are a major cause of mortality in liver transplant recipients. The incidence, microbiology, and outcome of BSIs in the first year after liver transplantation were analyzed in 704 patients who underwent transplantation at a single center between 1997 and 2007. BSIs occurred in 205 (29.1%) of the 704 patients. Overall, 259 episodes were documented, and they resulted in an incidence rate of 36.8%. Of these episodes, 39.4%, 27.8%, 17%, and 15.8% occurred in the very early period (< or = 10 days after liver transplantation), the early period (days 11-30), the intermediate period (days 31-90), and the late period (days 91-365), respectively. The most frequent pathogens were Enterobacteriaceae members (41%), Staphylococcus aureus (19.8%), enterococci (13.1%), Pseudomonas aeruginosa (8.8%), and yeasts (7.1%). The median time of onset ranged from 7 days for methicillin-resistant S. aureus to 25 days for Enterobacteriaceae. Mortality at 15 days after BSIs was 16.2%. Kaplan-Meier survival curves showed that patients with BSIs had a significantly higher 1-year mortality rate than those without BSIs (28.3% versus 16.6%, P < 0.001 with the log-rank test). When the time of BSI onset was considered, 1-year mortality was significantly associated with very early and early episodes (P < 0.001) but not with intermediate and late episodes (P = 0.47). In conclusion, BSIs are frequent and early complications after liver transplantation and are mostly caused by gram-negative bacilli. A BSI in the first posttransplant month is a significant predictor of 1-year survival.

Objective: Low-dose aspirin (LDA) given during pregnancy may alter brain development in very preterm infants. We report the short- and long-term outcomes of very preterm infants according to LDA treatment., Patients and Methods: Data were from the Etude Epidemiologique des Petites Ages Gestationnels (EPIPAGE) cohort study, which included all infants born before 33 weeks of gestation in 9 French regions in 1997. This study was restricted to 656 children who were born to 584 women with an obstetric history of placental vascular disease or with chronic hypertension or renal or autoimmune diseases. The main outcome measures were mortality, cerebral lesions, and outcome at 5 years of age, which were measured by a diagnosis of cerebral palsy; behavioral difficulties, which were assessed with the Strength and Difficulties Questionnaire; and cognitive impairment, which was measured by the mental processing composite scale of the Kaufman Assessment Battery for Children (an IQ-equivalent measure of cognitive ability in 2 dimensions: sequential and simultaneous processing scores)., Results: LDA treatment was administered to 125 of 584 (21%) mothers and was not significantly associated with mortality, cerebral lesions, cerebral palsy, or global cognitive impairment of the children at 5 years of age. The proportion of low simultaneous processing scores (<70) was lower in the group with LDA (7% vs 19% without LDA; P = .04). This association was not significant after adjustment for propensity score, prognostic factors, and social class (adjusted odds ratio [aOR]: 0.59 [95% confidence interval (CI): 0.17-2.06]). LDA treatment was associated with a reduction, at the limit of significance, in total behavioral difficulties (aOR: 0.44 [95% CI: 0.19-1.02]) and hyperactivity (aOR: 0.43 [95% CI: 0.17-1.05])., Conclusions: LDA was not associated with adverse neonatal or long-term outcomes. Moreover, the results suggest that LDA may be associated with a reduction in neurobehavioral difficulties. More research is needed to assess the effects of aspirin alone or combined with other neuroprotective agents.

Unlabelled: The immature brain is highly susceptible to the consequences of very preterm birth with a high rate of long-term neurodisabilities in survivors and high use of specific outpatient services to limit the functional effects of the disabilities. To assess the economic burden for the social and health care system, it is necessary to inventory the community supports and need for special education or rehabilitation used by preterm children. Such studies are few and were done only in extremely low-birthweight or extremely preterm newborns in the United States., Objective: To study the rates of specific outpatient services and special education at 5 years of age and between 5 and 8 years of age in a geographically-defined population of children born very preterm., Design, Setting and Patients: 2901 liveborn children before 33 weeks'gestation (WG) and one control group of 666 liveborn children at 39-40WG were included in nine regions of France in 1997 corresponding to more than one third of all births. At five years, these children had a medical examination and were evaluated by a psychologist at local centres organised for the study in every region. Cognitive function was assessed by the mental processing composite scale (PMC) of the Kauffmann Assessement Battery for Children test, which is considered to be equivalent to intelligence quotient and behavioral difficulties using the Strength and Difficulties questionnaire completed by the parents. Data for dependence or compensatory aids, i.e. occupational therapy or physical therapy, speech therapy, psychologist or psychiatrist visits, orthoptic therapy, wearing glasses, wearing hearing aid, specific equipment to walk (walker, wheelchair...), orthopaedic treatment or anti-epileptic treatment were collected from parents. At eight years, a postal questionnaire was sent to the parents to collect data on specific outpatient services and special treatments at home and school. Stata software was used (version 9.0). Main outcome measures. Parent Questionnaire for identifying children with chronic conditions and specific health care needs at 5 and 8 years and categorization of developmental neurodisabilities based on examination of children and psychometric evaluation at 5 years., Results: At 5 years data were obtained for respectively 1817 and 396 children born before 33WG or at 39-40WG, which represent 80% of the very preterm children and 71% of the at term children. At 8 years we obtained data for 63% of the very preterm children and 59% of the at term children. At 5 years, care in a rehabilitation center and/or specific outpatient services were required for 41% of children born between 24 and 28WG, 32% of children born between 24 and 32WG and 15% of those born at 39-40WG. Between 5 and 8 years, these figures were respectively 61%, 50% and 36%. In the very preterm group, rates of specific outpatient services were higher than 80% if the child had a motor and/or a neurosensory deficit. In case of cognitive deficiencies (PMC < 85), rates of specific outpatient services were low at 37% at 5 years and increases at 63% between 5 and 8 years., Conclusion: Compared to the children born at term, the very preterm children have considerable educational needs, which are inversely related to gestational age at birth and to age of the children at the time of reporting. Despite economic burden, efforts to improve access to services are necessary, in particular in case of cognitive impairment.

Objectives: We compared the frequency of behavioral problems in very preterm and term children at 5 years of age. We hypothesized that behavioral problems would be associated with cognitive impairment and environmental factors and that differences between the 2 groups would be reduced but persist after adjusting for cognitive performance and environmental factors., Patients and Methods: The Etude Epidémiologique sur les Petits Ages Gestationnels (EPIPAGE) study was a prospective population-based cohort study that included all births occurring between 22 and 32 weeks' gestation and a control group of infants born at 39 to 40 weeks' gestation in 1997 in 9 French regions. Neonatal and obstetrics data were collected at birth. At 5 years of age, sociodemographic status and neurodevelopmental and cognitive development of the children, as well as maternal mental well-being, were assessed. The behavioral problems of 1102 very preterm and 375 term singletons without major impairments were studied by using the parent-completed Strengths and Difficulties Questionnaire., Results: Parents of very preterm children reported significantly more behavioral problems, with a twofold higher prevalence compared with term children for hyperactivity/inattention, emotional symptoms, and peer problems. Behavioral problems were associated with low cognitive performance, developmental delay, hospitalizations of the child, young maternal age, and poor maternal mental well-being. Very preterm children were still at higher risk of behavioral problems compared with term children after adjustment for cognitive performance and all others factors., Conclusions: Behavioral problems were strongly related to cognitive impairment, but very preterm children were still at higher risk even after adjusting for cognitive performance. Early screening for behavioral problems should be encouraged for all very preterm children, and maternal well-being should also be the focus of special attention.

The aim of this study was to follow-up infants who were assessed in early infancy, at approximately 6 months of age, to determine the developmental impact of social withdrawal at approximately 30 months of age. Infants were administered the Bayley Scales of Infant Development-Third Edition, and the mothers complete the Behavior Assessment System for Children (BASC), Second Edition-Parent Rating Scale-Preschool form. Significant negative correlations were found between infant social withdrawal and Cognitive and Language scales of the Bayley Scales, and the Social and Communication scales of the BASC. Significant positive correlations were found between the infant social withdrawal and later higher scores on Atypicality and Attention scales. These results provide support for the use of the Alarm Distress Baby Scale as a measure of infant social withdrawal, and its association with later development and behavior.

Background: Systemic chemotherapies are associated with limited response rates and significant toxicity in patients with malignant digestive endocrine tumors (DET). Preliminary studies have reported interesting results with temozolomide in patients with DET., Aim: It was the aim of this study to assess the efficacy and safety of temozolomide in patients with malignant DET., Patients and Methods: Twenty-one patients, median age 61 years (range 56-77), with metastatic well-differentiated DET were retrospectively studied. All patients except 1 had received prior treatment (hepatic resection, chemotherapy). All patients had progressive disease in the 3 months prior to entry into the study. Temozolomide was administered at doses of 200 mg/m(2) daily for 5 days, every 28 days. Treatment was assessed for safety, progression-free and overall survival., Results: The median number of temozolomide cycles was 5 (range 2-15). Grade 3 hematological toxicity occurred in 5 patients. There were no toxic deaths. According to the Response Evaluation Criteria in Solid Tumors criteria, partial response and stabilization were obtained in 1 (5%) and 17 patients (81%), respectively. The median time to progression was 9 months (range 3-26). The 1-year progression-free survival and overall survival were 42 and 77%, respectively., Conclusion: Temozolomide is a well-tolerated oral chemotherapy in patients with malignant DET, including those who have already received treatment. In patients with progressive disease, temozolomide controls tumor progression in 86% of cases., (2009 S. Karger AG, Basel.)

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.

Objectives: The objectives of this study were (1) to evaluate the prevalence of relational withdrawal behaviour in infants aged 14-18 months attending a public health centre in Paris, (2) to check some identified risk factors for relational withdrawal behaviour in this population., Methods: A cross-sectional study was conducted in infants aged 14-18 months attending a child health screening centre during the year 2005., Results: A total of 640 children were included in the study. Thirteen percent of the 640 infants (n=83, 95% CI [10.4%; 15.6%]) had an ADBB score at 5 and over 5 on the ADBB. There was a clear relationship between withdrawal behavior and having psychological difficulties as reported by parents, and between withdrawal and developmental delay. Withdrawal was also significantly associated with being a boy, with living in risk conditions (e.g. child being in joint custody, or with living in a foster family), with being adopted, or with being a twin. More withdrawn infants were taken care of at home., Conclusion: Sustained relational withdrawal behaviour was linked with developmental disorders and psychopathology and not with SES, ethnical origin or rank of birth. The scale could be used in screening early psychopathology in infants aged 2-24 months of age.

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.

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.

Objectives: To evaluate the risk of very preterm birth (22-32 weeks of gestation) associated with previous induced abortion according to the complications leading to very preterm delivery in singletons., Design: Multicentre, case-control study (the French EPIPAGE study)., Setting: Regionally defined population of births in France., Sample: The sample consisted of 1943 very preterm live-born singletons (< 33 weeks of gestation), 276 moderate preterm live-born singletons (33-34 weeks) and 618 unmatched full-term controls (39-40 weeks)., Methods: Data from the EPIPAGE study were analysed using polytomous logistic regression models to control for social and demographic characteristics, lifestyle habits during pregnancy and obstetric history. The main mechanisms of preterm delivery were classified as gestational hypertension, antepartum haemorrhage, fetal growth restriction, premature rupture of membranes, idiopathic preterm labor and other causes., Main Outcome Measures: Odds ratios for very preterm birth by gestational age and by pregnancy complications leading to preterm delivery associated with a history of induced abortion., Results: Women with a history of induced abortion were at higher risk of very preterm delivery than those with no such history (OR + 1.5, 95% CI 1.1-2.0); the risk was even higher for extremely preterm deliveries (< 28 weeks). The association between previous induced abortion and very preterm delivery varied according to the main complications leading to very preterm delivery. A history of induced abortion was associated with an increased risk of premature rupture of the membranes, antepartum haemorrhage (not in association with hypertension) and idiopathic spontaneous preterm labour that occur at very small gestational ages (< 28 weeks). Conversely, no association was found between induced abortion and very preterm delivery due to hypertension., Conclusion: Previous induced abortion was associated with an increased risk of very preterm delivery. The strength of the association increased with decreasing gestational age.

The objective was to determine whether the temperament of very preterm singleton infants born before 29 weeks' gestation differs from their full-term counterparts at 9 months and to examine the influence of neurological sequelae on temperament in very preterm infants. The parents of very preterm infants from nine French regions and a group of full-term infants were sent the Infant Characteristics Questionnaire when the infants were 9 months old. The analysis included 266 singleton very preterm infants from the same regions born before 29 weeks' gestation and 546 full-term singleton infants. There were no significant differences for the Difficult, Unadaptable, and Unpredictable scales between very premature and term infants. Very preterm infants had a slightly higher Dull scale score than term infants. After taking into account mother's age, duration of hospitalization, and cerebral lesions found on neonatal ultrasound scans, this difference was no longer significant. Among very premature infants, those with cerebral lesions as diagnosed by neonatal ultrasound scan were rated higher on the Dull and Unadaptable scales. Delays in development at 9 months were also related to higher Dull and Unpredictable scales. These data suggest that prematurity does not affect temperament ratings at 9 months as assessed by the mother. However, very preterm infants with neurological insults, documented by the neonatal cerebral ultrasound or by a delay in development, are rated higher by their mothers on the Dull, Unadaptable, and Unpredictable scales.

Objectives: To assess the relation between cigarette smoking during pregnancy and neonatal respiratory distress syndrome (RDS) in very preterm birth, and to analyse the differential effect of antenatal steroids on RDS among smokers and non-smokers., Design: A population based cohort study (the French Epipage study)., Setting: Regionally defined births in France., Methods: A total of 858 very preterm liveborn singletons (27-32 completed weeks of gestation) of the French Epipage study were included in this analysis. The odds ratio for RDS in relation to smoking in pregnancy was estimated using a logistic regression to control for gestational age. The odds ratio for RDS in relation to antenatal steroids was estimated taking into account an interaction between antenatal steroids and cigarette smoking, using multiple logistic regression to control for gestational age, birthweight ratio, main causes of preterm birth, mode of delivery, and sex., Results: The odds ratio for RDS in relation to smoking in pregnancy adjusted for gestational age (aOR) was 0.59 (95% confidence interval (CI) 0.44 to 0.79). The aOR for RDS in relation to antenatal steroids was 0.31 (95% CI 0.19 to 0.49) in babies born to non-smokers and 0.63 (95% CI 0.38 to 1.05) in those born to smokers; the difference was significant (p = 0.04)., Conclusions: Cigarette smoking during pregnancy is associated with a decrease in the risk of RDS in very preterm babies. Although antenatal steroids reduce the risk of RDS in babies born to both smokers and non-smokers, the reduction is smaller in those born to smokers.

Advances in perinatal care have lead to the survival of an increasing number of children born very premature. The purpose of this review is to discuss findings in the literature regarding long term developmental outcome of infants born prematurely especially for studies with children at least 5 years old, born in the 80's or after, in a context of care with increased use of antenatal corticoids, in utero transfer, and surfactant therapy. Developmental sequelae, which are seen in children older than those presenting severe deficiencies, concerns a greater number of very premature children. They have poorer outcomes than term children or normal birth weight controls for cognitive-neuropsychological skills, school performances and behavior. Long term follow up of these children shows that consequences are still present for adolescents or young adults. There is a gradient of developmental sequelae in children that is inversely related to decreasing gestational age or birth weight. Developmental sequelae are related to neonatal medical complications and social risks factors. Research should be conducted in order to better understand etiology and neuropathological basis of sequelae, and the long term developmental implication of being born very premature and the type of care or intervention which could improve their development. An early and regular follow up by a team specialized in child development should be proposed in order to detect developmental sequelae and propose early intervention.

Objective: This study was undertaken to explore the association between fetal sex, mode of onset of labor, and principal cause of very preterm birth. Study design The analysis uses data on 2624 very preterm singleton births less than 33 weeks' gestation from a prospective study of all very preterm births in 9 French regions in 1997., Results: Fifty-seven percent of the spontaneous births were male versus 50.8% of births after medical decision (P=.005). This pattern was explained by sex differences in causes of preterm birth. Male infants had a greater incidence of very preterm birth after spontaneous labor (relative risk [RR]=1.42 [1.21-1.66]), but one third less risk of indicated preterm birth associated with hypertension both with and without growth restriction (RR=0.73 [0.55-0.97] and 0.77 [0.60-0.97])., Conclusion: These results support previous reports of greater male susceptibility to preterm labor. The finding that pregnancies carrying female infants have a greater predisposition to indicated very preterm birth associated with hypertension has not been reported previously and merits further study.

Objective: To evaluate the outcome for all infants born before 33 weeks gestation until discharge from hospital., Design: A prospective observational population based study., Setting: Nine regions of France in 1997., Patients: All births or late terminations of pregnancy for fetal or maternal reasons between 22 and 32 weeks gestation., Main Outcome Measure: Life status: stillbirth, live birth, death in delivery room, death in intensive care, decision to limit intensive care, survival to discharge., Results: A total of 722 late terminations, 772 stillbirths, and 2901 live births were recorded. The incidence of very preterm births was 1.3 per 100 live births and stillbirths. The survival rate for births between 22 and 32 weeks was 67% of all births (including stillbirths), 85% of live births, and 89% of infants admitted to neonatal intensive care units. Survival increased with gestational age: 31% of all infants born alive at 24 weeks survived to discharge, 78% at 28 weeks, and 97% at 32 weeks. Survival among live births was lower for small for gestational age infants, multiple births, and boys. Overall, 50% of deaths after birth followed decisions to withhold or withdraw intensive care: 66% of deaths in the delivery room, decreasing with increasing gestational age; 44% of deaths in the neonatal intensive care unit, with little variation with gestational age., Conclusion: Among very preterm babies, chances of survival varies greatly according to the length of gestation. At all gestational ages, a large proportion of deaths are associated with a decision to limit intensive care.

Objectives: To compare the use of health and social services between children born before 33 weeks (very preterm), children born at 33 or 34 weeks (moderately preterm) and children born at 39 or 40 weeks (full term)., Population and Methods: All very preterm children born in 1997 in nine French regions and a representative sample of the two other groups were followed up since birth. Data on the use of services between discharge from initial neonatal hospitalisation and the 9 months after birth were obtained by mail questionnaire filled in by parents., Results: 38.2% of very preterm children, 24.3% of moderately preterm children and 10.3% of full term children were admitted to hospital at least once. Respiratory tract disorder was the main reason for rehospitalisation of very preterm children. The total number of visits, visits to specialists, and chest therapy were more frequent among very preterm children than among the two other groups., Conclusion: Medical care of very preterm children is intensive after discharge from initial neonatal hospitalisation. Need of services are also substantial for moderately preterm children.

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.

Newborns with severe congenital hypothyroidism (often defined by the absence of knee epiphyses at diagnosis) are still at risk of loss of intellectual potential despite early treatment. Although there is no significant sexual dimorphism in the age at appearance and size of the knee epiphyses in normal newborns, it was our clinical impression that these epiphyses were more often absent in hypothyroid newborn males than in affected females. Using the large French database of congenital hypothyroidism, we studied the presence or absence of knee epiphyses at diagnosis, as well as the length of gestation and the birth weight of 1827 term newborns with athyreosis or ectopic thyroid. Boys were twice as likely as girls to have absent epiphyses [odds ratio, 2.1 (95% confidence interval, 1.6-2.7), P < 0.001, after adjustment for etiology, plasma free T(4) concentration, and presence or absence of clinical signs at diagnosis, gestational age and birth weight]. Compared with the general population of French newborns, those with congenital hypothyroidism were more often born after a prolonged gestation (> or =42 wk) and with a high birth weight (9% were above the 95th centile, as opposed to the expected 5%), regardless of sex. We conclude that the impact of congenital hypothyroidism on fetal skeletal maturation is sexually dimorphic. This may result from less efficient conversion of T(4) to T(3) by growth plate chondrocytes in males.

Studies concerning smoking during pregnancy and cognitive development of the child were reviewed. Some studies tend to support the existence of an association between smoking during pregnancy and a less optimal cognitive development of the child. The meaning of these relationships remains obscure, since it cannot be assumed that they are due to maternal cigarette smoking: they could be due to different characteristics of smokers or non-smokers. In the older studies, potential confounding factors were not adequately taken into account and in some recent studies, the observed difference was no longer significant after taking into account the maternal educational level and the family stimulation of the child. Behavior problems are associated with smoking during pregnancy in nearly all studies but the same problem of confounding factors remains. It is thus difficult to conclude presently from these studies if there is a causal relationship between prenatal exposure to tobacco smoke and cognitive development.

Objective: To study perinatal and neonatal mortality of very preterm infants and to assess the association with birth weight and multiple births., Methods: Infants enrolled in the Epipage study born between 22 and 32 weeks gestational age in 9 French regions in 1997 were included in this study. The main outcome measure was stillbirth and death before discharge from hospital., Results: During the study period, 4397 births and therapeutic abortions meeting the inclusion criteria were recorded (including 16% therapeutic abortions and 18% stillbirths). Survival rate for babies born between 22 and 32 weeks was 67% of all births (stillborn + liveborn) and 85% among livebirths. Survival rose with increasing gestational age: survival (livebirths) was 50% at 25 weeks gestation, 78% at 28 weeks and 97% at 32 weeks. Survival was lower for infants with a birthweight below the 10th percentile and for multiple-pregnancy infants. The different stages of the follow-up planned up to 5 years are presented together with the response rate to the postal follow-up questionnaire., Conclusion: This cohort provides mortality data on very premature infants during pregnancy, at birth, during hospitalization before discharge. Survival of liveborn infants was stratified by gestational age and was consistent with other geographically based studies of very preterm infants born in the 1990s.

Objective: To investigate the relation between school difficulties and being born small for gestational age (SGA) at full term in adolescents and young adults., Methods: A total of 236 full-term singletons who were born SGA (birth weight and/or length below the third percentile) from 1971 through 1978 and 281 full-term singletons who were born appropriate for gestational age (AGA; between the 25th and 75th percentiles) from the maternity registry of Haguenau, France. Participants were evaluated at a mean age of 20.6 (+/-2.1) years. The outcomes measured were late entry into secondary school (normal age: 11 years) and failure to take or pass the baccalaureate examination at the end of secondary school (normal age: 18 years)., Results: Late entry into secondary school was more frequent for the SGA than the AGA children (odds ratio: 2.3) after adjustment for maternal age and educational level, parental socioeconomic status, family size, and gender. A significantly higher proportion of term SGA adolescents failed to take or pass the baccalaureate examination than AGA adolescents (odds ratio: 1.6). SGA participants with a smaller head circumference entered secondary school late more often than SGA participants with a larger head circumference, but the association was not significant after adjustment., Conclusion: Being born SGA at term is associated with poorer school performance at 12 and 18 years. Fetal adaptation to conditions that retard growth during gestation may not be successful in maintaining brain development.

Background: The aim of the study was to assess the validity of the French version of the Infant Characteristics Questionnaire (ICQ), which was developed by Bates in 1979 to investigate the parental perceptions of infant temperament at 6 months of age., Methods: The French version was established after translation/back-translation, and tested on a sample of 794 mothers, who gave birth in 1995 in four French Departments and who returned the questionnaire which was mailed 6 months after the birth., Results: The non-response rate of each item was very low (< 2%). Factor analysis resulted in the same four factors as in the American data: fussy/difficult, unadaptable, unpredictable, dull. However, some of the items did not have similar factor loadings. Thus new factor scores were defined for the French version of the ICQ. Internal consistency, as measured by the Cronbach coefficient, was satisfactory (> 0.7) for the factors fussy/difficult and unadaptable. It was lower, but acceptable (> 0.6) for the two other factors. The infant's temperament was not related to birth parameters. In contrast, some factor scores were significantly associated with parity, mother's education, as well as her health and the infant's health after leaving the maternity ward., Conclusions: The French version of the ICQ is well accepted and has a good validity. This scale provides a useful instrument for research, especially for epidemiological studies on infant health and development, as well as their determinants.

Very high levels of alcohol consumption during pregnancy are harmful for the central nervous system of the child and affect morphogenesis and growth. The aim of this study was to investigate the effects of moderate prenatal alcohol exposure on development at preschool age in a longitudinal study. Pregnant women were interviewed on their alcohol consumption during pregnancy at their first visit to the maternity hospital of Roubaix, France. The development of their 160 children was assessed at the age of 4 1/2. Multiple regression analyses indicated that consumption of 1.5 oz of absolute alcohol (approximately 3 drinks) or more during pregnancy was significantly related to a decrease of 7 points on the general cognitive index of the McCarthy scales, after controlling for confounders. This level of consumption was also related to a higher score on minor neurological anomalies, a lower height of the child, and a higher score on facial features. This level of 1.5 oz of absolute alcohol/day should not be interpreted as a biological threshold, because the study does not allow conclusions to be drawn regarding the effects of lower levels of alcohol consumption. Alcohol consumption during pregnancy can affect the development of the child, at levels well below those associated with fetal alcohol syndrome.

This study was designed to identify the factors affecting folate status in pregnant women and to explore the relationship between folate status and alcohol consumption during pregnancy. For this purpose, 347 French women were recruited during 1985-1986 on their first visit to the antenatal clinic at Roubaix Hospital (northern France). Alcohol consumption was ascertained by a standardized interview. Folate status assessment was available for 246 pregnant women who were not given folate supplementation. Average folate levels during pregnancy were lower among young women and smokers. Serum folate values diminished with the educational level, and red cell folate values increased with high parity. Unexpectedly, high red cell folate values were strongly related with high alcohol consumption after adjustment for the maternal risk factors associated with alcohol consumption and folate status. This was probably because in the Roubaix region where the study was conducted women consume mostly beer, which contains folates. Pregnancy outcome was not related to folate levels; birthweight was negatively associated with alcohol consumption during the first trimester of pregnancy.

In tempered countries, higher sudden infant death rates are observed during winters, which is in favor of an infectious factor in the etiology. According to the geographic regions, the rates of SIDS are showing a downward gradient from the north of France to the south. In an attempt to assess the infectious hypothesis, we carried out a research about space-time clusters of Sudden infant deaths. The Knox's méthode was used with data of the medical causes of death registered in France from 1981-82 to 1985-86, by areas. Clusters were found in several regions, but they are moving from one year to another. The interpretation of these findings remains difficult because of the large number of tests.