Neurobehavioural teratology

Neurobehavioural teratology investigates abnormal development of the nervous system and of cognition and complex behaviour that results from prenatal environmental insults. Neurobehavioural research addresses the prevalence of cognitive-behavioural disorders in exposed individuals and the consequences of the brain insult on other developing brain systems, to identify risks for functional or behavioural deficits. Investigators focus on cognitive-behavioural deficits and their underlying anatomy and embryology. Assessment emphasizes not only IQ but also neuropsychological profiles, because learning disability or difficulty in visuomotor integration may be evident in children who function in the low to average range of general mental ability.

The natural history of intrauterine drug exposure on motor, cognitive, emotional, and social behaviour is an area of growing concern. Multiple drug exposures during pregnancy is common among substance-abusing mothers. Of syndromes associated with intrauterine substance abuse, alcohol abuse has been studied the most extensively. Subsequently, retinoids, anticonvulsants (lithium, tegretol, and valproic acid), and the selective serotonin-reuptake inhibitors have also been studied. Other teratogens do not lead to major malformations of the nervous systems but they do compromise its integrity (for example, lead, heroin, methadone), and are associated with neurotoxic damage or effects on neurochemical systems.

The greatest period of vulnerability to drugs in a human pregnancy is during the period of embryogenesis (days 14 to 60). During embryogenesis, many neurobehavioural teratogens (for instance, retinoids and ethanol) produce syndromes with abnormalities that involve craniofacial, neural, and major organ systems. Behavioural abnormalities without detectable physical abnormality occur when the insult occurs during the fetal period. The extent of malformation is stage specific and dose dependent, with outcomes ranging from death with malformation, malformation and survival, effects on growth, and cognitive-neuropsychological or behaviour disorder. The same exposure to alcohol needed to produce cognitive-behavioural change in the fetal period would generally cause malformation if it occurred during embryogenesis. The term 'developmental toxicology' is sometimes used if the insult occurs in the postnatal period.

There may be a genetic vulnerability that influences the extent of expression of response to environmental toxins in an individual. A common family of regulatory genes are involved in the formation of structures of the face, head, hindbrain, parts of the heart, and thymus gland, all of which share a common origin from neural crest cells (anterior neural tube). These regulatory genes, known as HOX genes, provide rules for assembling various structures and for determining particular anatomical segments. Transgenic mice who lack certain of these HOX genes show syndromic craniofacial, hindbrain, heart, and thymus abnormalities. Because the retinoid family is involved in controlling these HOX genes, a similar pattern is produced by excessive retinoid administration, as in hypervitaminosis of vitamin A. Thus, both genetic and teratogenetic agents may produce similar developmental abnormalities. Understanding these mechanisms helps to understand how an abnormal facial appearance may suggest an abnormal brain.

retardation, and a characteristic facial appearance. (21 The extent of the abnormality depends on the time of maximal exposure to alcohol and the dose. Approximately half of those affected have co-ordination problems, are hypotonic, and have attention deficits. Between 20 and 50 per cent have other birth defects, including eye and ear anomalies and cardiac anomalies. Those children who do not show growth retardation or congenital anomalies may show more subtle changes, such as attention problems, reduced speed of information processing, motor clumsiness, speech disorders, fine motor impairment, and learning problems, especially in mathematics. These findings have been documented in a prospective longitudinal study of the effects of prenatal alcohol exposure on a birth cohort of 500 offspring who were selected from 1529 consecutive pregnant women in prenatal care in community hospitals.(22) Dose-dependent effects are most clear from the neurobehavioural status of subjects with regular neurodevelopmental evaluations from birth to age 14 years. The more subtle abnormalities are referred to as 'fetal alcohol effects', or alcohol-related neurodevelopmental disorder. Subjects with average to above-average IQ may demonstrate neuropsychological deficits in complex attention, verbal learning, and executive functioning.(2 2,4> Both attention-deficit disorder and autistic-like behaviour have been described (25,26) in children with fetal alcohol syndrome and fetal alcohol effects disorder who test in the moderate to severe range of mental retardation.

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