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      Neurocognitive Development in Children Experiencing Intrauterine Growth Retardation and Born Small for Gestational Age: Pathological, Constitutional and Therapeutic Pathways

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          Interest in the neurocognitive and psychosocial outcomes in children who are born small for gestational age (SGA) has increased since the recent approval of growth hormone (GH) therapy in this indication. The objective of GH treatment in SGA children is to provide a symptomatic treatment for growth retardation. From a patient perspective, the ultimate goals of GH therapy are the reduction in the present or future risk of neurocognitive, psychological, social or occupational impairment, not the accompanying improvements in growth velocity and final height per se. Therefore, from a scientific perspective, neurocognitive and psychosocial endpoints become relevant domains of assessment to determine the final treatment benefit experienced by the patient born SGA. This article reviews recent available studies on developmental risks in SGA, and then transforms the empirical findings into an integrated conceptual framework on the sources and mediators of neurocognitive and psychosocial outcomes in intrauterine growth retardation and SGA. This framework depicts two distinct therapeutic pathways by which GH therapy may improve neurocognitive and behavioural outcomes. The first (‘traditional’) pathway is the prevention of exposure to short-stature-related stressors via an improvement in growth velocity and final height. The second pathway refers to potential metabolic, and thus neurotropic and psychotropic, effects of GH binding at receptors in the central nervous system, thus changing neuronal activity. To date, the existence and potential mechanisms of such physiologically and not psychologically mediated effects of GH on neurocognitive functioning in SGA patients remain hypothetical.

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          Most cited references 12

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          International Small for Gestational Age Advisory Board consensus development conference statement: management of short children born small for gestational age, April 24-October 1, 2001.

          To provide pediatric endocrinologists, general pediatricians, neonatologists, and primary care physicians with recommendations for the management of short children born small for gestational age (SGA). A 13-member independent panel of pediatric endocrinologists was convened to discuss relevant issues with respect to definition, diagnosis, and clinical management of short children born SGA. Panel members convened over a series of 3 meetings to thoroughly review, discuss, and come to consensus on the identification and treatment of short children who are born SGA. SGA is defined as birth weight and/or length at least 2 standard deviations (SDs) below the mean for gestational age ( 2 SD below the mean; this catch-up process is usually completed by the time they are 2 years of age. A child who is SGA and older than 3 years and has persistent short stature (ie, remaining at least 2 SD below the mean for chronologic age) is not likely to catch up and should be referred to a pediatrician who has expertise in endocrinology. Bone age is not a reliable predictor of height potential in children who are SGA. Nevertheless, a standard evaluation for short stature should be performed. A diagnosis of SGA does not exclude growth hormone (GH) deficiency, and GH assessment should be performed if there is clinical suspicion or biochemical evidence of GH deficiency. At baseline, insulin-like growth factor-I, insulin-like growth factor binding protein-3, fasting insulin, glucose, and lipid levels as well as blood pressure should be measured, and all aspects of SGA-not just stature-should be addressed with parents. The objectives of GH therapy in short children who are SGA are catch-up growth in early childhood, maintenance of normal growth in childhood, and achievement of normal adult height. GH therapy is effective and safe in short children who are born SGA and should be considered in those older than 2 to 3 years. There is long-term experience of improved growth using a dosage range from 0.24 to 0.48 mg/kg/wk. Higher GH doses (0.48 mg/kg/wk [0.2 IU/kg/d]) are more effective for the short term. Whether the higher GH dose is more efficacious than the lower dose in terms of adult height results is not yet known. Only adult height results of randomized dose-response studies will give a definite answer. Monitoring is necessary to ensure safety of medication. Children should be monitored for changes in glucose homeostasis, lipids, and blood pressure during therapy. The frequency and intensity of monitoring will vary depending on risk factors such as family history, obesity, and puberty.
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            Birth weight, childhood socioeconomic environment, and cognitive development in the 1958 British birth cohort study.

            To examine the combined effect of social class and weight at birth on cognitive trajectories during school age and the associations between birth weight and educational outcomes through to 33 years. Longitudinal, population based, birth cohort study. 10 845 males and females born during 3-9 March 1958 with information on birth weight, social class, and cognitive tests. Reading, maths, draw a man, copying designs, verbal and non-verbal ability tests at ages 7, 11, and 16, highest qualifications achieved by 33, and trajectories of maths standardised scores at 7-16 years. The outcome of all childhood cognitive tests and educational achievements improved significantly with increasing birth weight. Analysis of maths scores at 7 and of highest qualifications achieved by 33 showed that the relations were robust to adjustment for potential confounding factors. For each kilogram increase in birth weight, maths z score increased by 0.17 (adjusted estimate 0.15, 95% confidence interval 0.10 to 0.21) for males and 0.21 (0.20, 0.14 to 0.25) for females. Trajectories of maths z scores between 7 and 16 years diverged for different social class groups: participants from classes I and II increased their relative position on the score with increasing age, whereas classes IV and V showed a relative decline with increasing age. Birth weight explained much less of the variation in cognition than did social class (range 0.5-1.5% v 2.9-12.5%). The postnatal environment has an overwhelming influence on cognitive function through to early adulthood, but these strong effects do not explain the weaker but independent association with birth weight.
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              School difficulties in 20-year-olds who were born small for gestational age at term in a regional cohort study.

              To investigate the relation between school difficulties and being born small for gestational age (SGA) at full term in adolescents and young adults. 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). 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. 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.

                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                February 2006
                27 January 2006
                : 64
                : Suppl 3
                : 83-88
                Department of Pediatrics, University of Bonn, Bonn, Germany
                89322 Horm Res 2005;64:83–88
                © 2005 S. Karger AG, Basel

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                Page count
                Figures: 2, Tables: 2, References: 18, Pages: 6


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