Neonatal origins of schizophrenia
- Department of Psychological Medicine
- Institute of Psychiatry
- De Crespigny Park
- Denmark Hill
- London SE5 8AF
Schizophrenia is not an illness which impinges much upon the daily practice of paediatricians or, indeed, child psychiatrists, as only a tiny proportion of diagnosed cases (< 5%) arise before the age of 16 years.1 Schizophrenia is one of the few chronic diseases which arise principally during late adolescence and early adulthood, normally the healthiest period of life. There is increasing evidence, however, that neurodevelopmental factors, acting in utero and in early childhood, are important in determining the risk for later schizophrenia.2 3
Most schizophrenics have subtle brain abnormalities of developmental origin, and many show impairments of motor, cognitive, and social function in childhood, decades before the onset of frank psychosis. These findings have led to the conclusion that schizophrenia is a neurodevelopmental disorder
The strongest risk factor for schizophrenia is having an affected relative. Prenatal and perinatal risk factors, in particular prenatal viral exposure and fetal hypoxia, also appear to be important
An important clinical implication of the existence of prenatal and neonatal risk factors is that some forms of schizophrenia may be preventable
There is no doubt that genetic factors are involved in the aetiology of schizophrenia.4 First degree relatives of patients have a morbid risk of developing schizophrenia which is eight to 10 times higher than the risk in the general population; this risk rises to approximately 50% in the identical twins of schizophrenics. Now that a neurodevelopmental aetiological model is considered most likely, genes that control early development have come under particular suspicion. Unfortunately, in spite of an intensive effort to locate and identify susceptibility genes for schizophrenia, none has yet been found.5
The fact that the monozygotic concordance rate for schizophrenia is only 50% indicates that environmental factors must also be involved, and simple additive models suggest that between 20–30% of the variance in liability to schizophrenia may be attributable to non-genetic factors. What are these environmental factors and how might they operate?
Schizophrenic patients, as a group, experience a greater number of birth complications than controls.6 7 Inspection of the particular complications associated with schizophrenia suggests that hypoxic-ischaemic brain damage may be the common mechanism.8 Schizophrenics who have suffered perinatal complications are especially likely to show lateral ventricular damage and decreased volume of the hippocampus.9 Recent findings from a 28 year follow up of a Finnish birth cohort have shown that children with perinatal brain damage (defined as neonatal convulsions, low Apgar scores, asphyxia, intraventricular haemorrhage, or abnormal neurological signs in the newborn period) were seven times more likely to develop schizophrenia in adulthood than the remainder of the cohort.10 These results indicate that almost 7% of schizophrenia in the general population might be attributable to this factor. Labour and delivery complications are relatively common in the general population, however, and only rarely are associated with schizophrenia. Therefore, for schizophrenia to result, either a particular neuronal system must be damaged or the individual must carry genetic vulnerability.
A number of studies have shown that schizophrenics are more likely to have had low birth weight and decreased head circumference at birth.11 Minor physical abnormalities and dermatoglyphic abnormalities, which are thought to represent “fossilised” evidence of early developmental deviance, also occur to excess in schizophrenia,12 as do cortical cytoarchitectural changes which are consistent with disturbances of development during gestation.13 These indicators of fetal maldevelopment may indicate environmental insult to the fetus. A study of monozygotic twins discordant for schizophrenia has shown that the affected cotwin had more markers of prenatal developmental disruption than the unaffected twin,14 and a comparison of familial and non-familial schizophrenics showed that minor physical anomalies were more likely to occur in the latter.15 Complications of pregnancy which have been associated with schizophrenia include prenatal exposure to influenza,16 prenatal nutritional deprivation,17 and rhesus incompatibility.18The mechanism of action of these effects is not yet elucidated and effect sizes are small. The association with influenza may reflect a neurotoxic effect of influenza on the fetal brain, or an effect related to maternal immunological responses to infection. The association with rhesus incompatibility may be mediated through fetal hypoxia resulting from haemolysis.
CHILDHOOD CENTRAL NERVOUS SYSTEM INFECTIONS AND EPILEPSY
Data from the same Finnish cohort as discussed above, showed that individuals who had suffered a viral central nervous system infection during childhood were almost five times more likely to develop schizophrenia than the comparison group.19 The incidence of schizophrenia was particularly high, at 12.5%, among a group of 16 individuals who had contracted neonatal coxsackie B meningitis during an epidemic in one maternity unit. The incidence among the rest of the study population was 0.7%. Patients with schizophrenia in this series were also two to three times more likely to have a history of childhood epilepsy than the rest of the study population.
CHILDHOOD DEVELOPMENTAL ABNORMALITIES
High risk studies
These include: (1) hypoactivity, hypotonia, and poor “cuddliness” during the neonatal period; (2) a disordered pattern of acquisition of milestones in infancy; (3) “soft” neurological signs, in particular poor motor coordination in early childhood; and (4) deficits in attention and information processing in late childhood.
These findings indicate that at least part of the genetic vulnerability to schizophrenia is manifest through abnormal neurodevelopment. Follow up will continue on these high risk samples to determine whether the children who have displayed such neurodevelopmental abnormalities will go on to develop schizophrenia.
General population birth cohort studies
Similar findings have been reported among the 1946 British birth cohort. This cohort of 4746 British children, who were born in one week in March 1946, has been studied on over 20 occasions up to the age of 43 years. The 30 children who went on to develop schizophrenia as adults could be distinguished from their peers in these ways22 :
• Motor developmental milestones, in particular walking, were delayed by an average of 1.2 months
• More speech problems (odds ratio (OR) 2.8)
• Lower educational test scores at ages 8, 11, and 15
• Preference for solitary play at ages 4 and 6 years (OR 2.1).
Home movies’ studies
A unique collection of “home movies” depicting schizophrenic patients during childhood shows that the preschizophrenic children can be distinguished from their siblings, with a high degree of accuracy, by the presence of subtle abnormalities of motor tone and facial expression.23 Retrospective studies have shown that preschizophrenic children have markedly poorer overall social adjustment in childhood than normal controls or children destined to develop affective psychosis.24
Although having an affected relative remains the strongest risk factor for schizophrenia (table 1), there are many prenatal and postnatal risk factors with smaller effect sizes which cannot be ignored. These environmental risk factors may act additively with each other or may indicate the existence of gene environment interactions.25 Birth complications or adverse psychosocial circumstances in childhood may interact with genetic vulnerability to increase the risk of psychosis.26For example, there is a greater risk of schizophrenia among genetically vulnerable children who were placed in poorly functioning adoptive homes compared with those placed in well functioning homes,27 and high risk children reared in a kibbutz had increased rates of schizophrenia compared with those who were reared in family homes.28 In other words, the pathogenic effects of adverse social circumstances appears to increase risk of schizophrenia only in children who have some degree of genetic vulnerability.
An important clinical implication of the prenatal and neonatal risk factors mentioned in this paper is that some forms of schizophrenia may be preventable. Environmental agents can be more easily manipulated than genetic factors. Avoidance of perinatal hypoxia, nutritional supplemention during pregnancy, and prevention of central nervous system infection in childhood, particularly neonatal coxsackie B infection, may help reduce the incidence of schizophrenia. We are still a long way, however, from testing the efficacy of such measures, or indeed from developing an accurate screening test for schizophrenia. Although children destined to develop schizophrenia in adulthood have been shown to differ from their peers in social and intellectual function, these behavioural and cognitive risk factors are non-specific and cannot be applied to the general population. Close observation of children who are genetically vulnerable to schizophrenia, may prove useful in this regard. Measures such as careful supervision of adoptive or foster home placements, social skills training, protection from stressors, and early referral to psychiatric services could help prevent psychotic breakdown among high risk children. Although definitive evidence for such measures is lacking, early treatment of psychosis has been shown to improve prognosis,29 and studies of prevention in schizophrenia are already underway. In conclusion therefore, study of the neonatal and childhood precursors of schizophrenia allow the possibility of prevention and early intervention in at least some cases of the disorder. Although this research is in its early stages, it may not be necessary to wait until the gene or genes for schizophrenia are discovered to begin reorienting our approach to this devastating illness.
Mary Cannon was supported by a Wellcome Trust research training fellowship in clinical epidemiology.