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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.

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.)

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.

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.

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.

Objective: To identify the main prenatal risk factors for cerebral palsy in very preterm singletons and twins., Methods: The data were from the Epipage study, which included all very preterm children (< 33 weeks) born in 1997 in 9 regions of France. The analysis included 1,954 children for whom a medical questionnaire was completed at the age of 2 years (83% of the surviving children). The risk factors studied were pregnancy complications and specific factors in twins (type of placenta and death of cotwin). Logistic regression analysis was carried out for singletons and generalized estimating equation models used for twins., Results: The proportion of cerebral palsy was 8% in singletons and 9% in twins. For singletons, spontaneous preterm labor (adjusted odds ratio [OR] 3.4, 95% confidence interval [CI] 1.7-6.7), preterm premature rupture of membranes (PPROM) with short latency (adjusted OR 4.9, 95% CI 2.0-11.8), and prolonged PPROM (adjusted OR 2.7, 95% CI 1.4-5.3) were associated with a higher risk of cerebral palsy than was hypertension. No such link was found between these pregnancy complications and cerebral palsy in twins. For twins, a monochorionic placenta (OR 1.9, 95% CI 1.0-3.6) increased the risk of cerebral palsy, but the OR became nonsignificant after adjustment (OR 1.7, 95% CI 0.8-3.4)., Conclusion: In very preterm singletons, spontaneous preterm labor and PPROM increased the risk of cerebral palsy compared with hypertension.

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.