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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: Altered palatal morphology has been observed among some preterm children, with possible consequences on chewing, speaking and esthetics, but determinants remain unknown., Aim: To explore the role of neonatal characteristics and neuromotor dysfunction in alteration of palatal morphology at 5 years of age in very preterm children., Study Design: Prospective population-based cohort study., Subjects: 1711 children born between 22 and 32 weeks of gestation in 1997 or born between 22 and 26 weeks of gestation in 1998 were included in the study. They all had a medical examination at 5 years of age., Outcome Measures: Alteration of palatal morphology., Results: The prevalence of altered palatal morphology was 3.7% in the overall sample, 5.1% among boys and 2.2% among girls (adj OR: 2.52; 95%CI: 1.44-4.42). The risk for altered palatal morphology was higher for lower gestational age (adj OR: 0.85; 95%CI: 0.74-0.97 per week), small-for-gestational age children (adj OR: 2.11; 95%CI: 1.20-3.72) or children intubated for more than 28 days (adj OR: 3.16; 95%CI: 1.11-8.98). Altered palatal morphology was more common in case of cerebral palsy or moderate neuromotor dysfunction assessed at 5 years. Results were basically the same when neuromotor dysfunction was taken into account, except for intubation., Conclusion: Male sex, low gestational age, small-for-gestational age and long intubation have been identified as probable neonatal risk factors for alteration of palatal morphology at 5 years of age in very preterm children. Further studies are needed to confirm these results., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

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.

Background: The increasing survival rates of children who are born very preterm raise issues about the risks of neurological disabilities and cognitive dysfunction. We aimed to investigate neurodevelopmental outcome and use of special health care at 5 years of age in a population-based cohort of very preterm children., Methods: We included all 2901 livebirths between 22 and 32 completed weeks of gestation from nine regions in France in Jan 1-Dec 31, 1997, and a reference group of 667 children from the same regions born at 39-40 weeks of gestation. At 5 years of age, children had a medical examination and a cognitive assessment with the Kaufman assessment battery for children (K-ABC), with scores on the mental processing composite (MPC) scale recorded. Data for health-care use were collected from parents. Severe disability was defined as non-ambulatory cerebral palsy, MPC score less than 55, or severe visual or hearing deficiency; moderate deficiency as cerebral palsy walking with aid or MPC score of 55-69; and minor disability as cerebral palsy walking without aid, MPC score of 70-84, or visual deficit (<3/10 for one eye)., Findings: In total, 1817 (77%) of the 2357 surviving children born very preterm had a medical assessment at 5 years and 396 (60%) of 664 in the reference group. Cerebral palsy was diagnosed in 159 (9%) of children born very preterm. Scores for MPC were available for 1534 children born very preterm: 503 (32%) had an MPC score less than 85 and 182 (12%) had an MPC score less than 70. Of the 320 children in the reference group, the corresponding values were 37 (12%) and 11 (3%), respectively. In the very preterm group, 83 (5%) had severe disability, 155 (9%) moderate disability, and 398 (25%) minor disability. Disability was highest in children born at 24-28 completed weeks of gestation (195 children [49%]), but the absolute number of children with disabilities was higher for children born at 29-32 weeks (441 children [36%]). Special health-care resources were used by 188 (42%) of children born at 24-28 weeks and 424 (31%) born at 29-32 weeks, compared with only 63 (16%) of those born at 39-40 weeks., Interpretation: In children who are born very preterm, cognitive and neuromotor impairments at 5 years of age increase with decreasing gestational age. Many of these children need a high level of specialised care. Prevention of the learning disabilities associated with cognitive deficiencies in this group is an important goal for modern perinatal care for children who are born very preterm and for their families.

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: To assess the frequency of minor neuromotor dysfunctions (MNDs) at age 5 years according to gestational age, to test their association with behavioral and learning difficulties, and to find determining neonatal factors., Design: Prospective population-based cohort study of children born in 1997 and followed up from birth to age 5 years., Setting: All maternity wards in 9 regions of France., Participants: A total of 1662 children born before 33 completed weeks of gestation and 2 control groups including 245 children born at 33 to 34 weeks and 332 children born at 39 to 40 weeks. Main Exposure Birth before 33 weeks. Main Outcome Measure Short version of the Touwen neurological examination classifying children as healthy, having mild MND (MND-1), or having moderate MND (MND-2) depending on the number of abnormal neuromotor signs found., Results: Of children born before 33 weeks, 41.4% had MND-1 and 3.0% had MND-2. These proportions were 30.8% and 0.5%, respectively, for children born at 33 to 34 weeks and 22.0% and 0.7%, respectively, for children born at 39 to 40 weeks. Minor neuromotor dysfunction was independently associated with learning difficulties at age 5 years (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.1-2.2). In very preterm children, factors associated with MND-1 were postnatal corticotherapy (OR, 1.8; 95% CI, 1.3-2.6), multiple births (OR, 0.7; 95% CI, 0.6-0.9), and, in singletons, breastfeeding (OR, 0.8; 95% CI, 0.6-0.99). Being a boy (OR, 3.1; 95% CI, 1.5-6.4), having had acute fetal distress (OR, 2.8; 95% CI, 1.4-5.5) or severe abnormalities on early cranial ultrasonography (OR, 2.7; 95% CI, 1.2-6.2), and having had postnatal corticotherapy (OR, 2.7; 95% CI, 1.2-6.1) increased the risk of MND-2., Conclusions: The high rate of MNDs and their association with an increased risk for learning difficulties justify their screening in case of (even moderate) prematurity.

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.

Aim: To evaluate whether precociously treated subjects with congenital hypothyroidism (CH) are at risk of poor school performance in early adolescence, and to investigate which factors affect their school achievement., Methods: All children treated early for congenital hypothyroidism and born in France during the first 7 y (1979-1985) of the national screening program for congenital hypothyroidism were selected for the study. School performance during childhood, assessed according to age at entry into the first grade of secondary school, was evaluated as normal (usually 11 y of age) vs late entry (> or = 12 y). The national register of children with congenital hypothyroidism enabled a comparison to be made with data from the national population for the same school years., Results: School achievement was similar among the 682 patients with CH and in the national population. After an adjustment for the sex and socioprofessional category of the parents, the severity of CH as assessed by the type (athyreosis. the most severe vs other types), the initial low serum T4 levels (< or = 53 nmol/L vs >53 nmol/L), and the profound bone maturation delay (absence vs presence of the two knee epiphyseal ossification centres at diagnosis), initially low L-thyroxine dosage (below vs > or = 7 microg/kg/day), the absence of near normalization of thyroid hormone levels after 15 d of treatment and poor adequacy of treatment throughout childhood were associated with an increased risk of school delay. School achievement was unaffected by the age at start of treatment (mean age = 22.8 +/- 6.8 d). In a multivariate logistic regression analysis, recurrent episodes of insufficiently suppressed TSH levels (> or = 15 mUi/L at least four times during follow-up from the age of 6 mo onwards) were the most important variable associated with school delay., Conclusion: Careful follow-up of the adequacy of treatment is required throughout childhood, to reduce the risk of school delay.

High levels of alcohol consumption during pregnancy affect the development of the baby's central nervous system. Pregnant women were interviewed about their alcohol consumption during pregnancy, when they first visited the maternity hospital in Roubaix, France. Of the 698 women interviewed, 156 of their children were investigated at the age of 4 1/2 years with a standardised examination to assess the effects of prenatal alcohol exposure on neurological status. Two scores were calculated: a posture score, which measured items while the child was standing; and a minor neurological signs score. The posture score was not related to prenatal alcohol exposure. Consumption of 21 drinks/week (3 drinks/day) or more during pregnancy was significantly associated with a higher number of minor neurological signs, after controlling for relevant covariables. Although prenatal alcohol exposure was related to a lower General Cognitive Index (GCI), minor neurological signs were associated with prenatal alcohol exposure after controlling for GCI.

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.

Objectives: This study investigated the effect of moderate prenatal alcohol exposure on psychomotor development of preschool-age children in a longitudinal study., Methods: Pregnant women were interviewed about their alcohol consumption at their first visit to the maternity hospital in Roubaix, France. Alcohol consumption before pregnancy and during the first trimester was assessed with a structured questionnaire. The psychomotor development of 155 children of these women was assessed with the McCarthy scales of children's abilities when the children were about 4 1/2 years old., Results: Consumption of 1.5 oz of absolute alcohol (approximately three drinks) or more per day during pregnancy was significantly related to a decrease of 7 points in the mean score on the general cognitive index of the McCarthy scales, after gender, birth order, maternal education, score for family stimulation, family status, maternal employment, child's age at examination, and examiner were controlled for., Conclusions: This study showed that moderate to heavy alcohol consumption during pregnancy, at levels well below those associated with fetal alcohol syndrome, has effects on children's psychomotor development.