ANNOTATIONS

Are Complications of Pregnancy and Birth Causes of Sc h i zo p h re n i a?

THERE has recently been increased psychiatric interest in the hypothesis that complications of pregnancy and birth cause schizophrenia'-6. This issue is relevant to practitioners of developmental medicine for four reasons. First, informed parents may soon be asking awkward questions after difficult deliveries. Second, paediatricans and obstetricians are in a position to make a unique contribution to this aspect of schizophrenia research. Third, potentially there could be important implications for prevention. Finally, in the current medico-legal climate, paediatricians and obstetricians may yet be sued for alleged negligence, supposedly resulting in schizophrenia decades later.

Schizophrenia With a lifetime prevalence of roughly 1 per cent', schizophrenia is one of the most common causes of severe chronic handicap in adulthood. Diagnostic criteria, which used to vary markedly within and between countries, are now much more uniform, with operational definitions being widely used in research studies.

Although children as young as seven occasionally are affected, the onset is most commonly in adolescence or early adult life. The 'positive' symptoms of bizarre hallucinations and delusions tend to occur in episodes, separated by full or partial remissions. Though not affecting all schizophrenics, the 'negative' symp- toms of apathy, emotional blunting, social withdrawal, and poverty of speech are often especially handicapping in the long term, particularly since these symptoms typically are continuous rather than episodic. Treatment with neuroleptic drugs generally is more effective for positive than negative symptoms. Acute exacerbations of positive symptoms may be precipitated by major life events, or by a critical and intrusive family environ- ment. Institutional understimulation can accentuate negative symptoms.

Aetiological theories Family, twin and adoption studies have provided compelling evidence for the importance of genetic factors in schizo- phrenia*. Genetic predisposition cannot be the whole story, however. Given a schizophrenic proband, only about 10 per cent of first-degree relatives and fewer than 50 per cent of monozygotic twins develop schizophrenia, suggesting an important r81e for nongenetic factors. Several environmental factors have been implicated, including acquired brain- damage. Individuals with congenitally or postnatally acquired lesions of the temporal lobes or diencephalon are at

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particularly high risk of schizophrenia’. lo,

though the onset of psychosis may not occur until the brain lesion has been present for decades. Although cases with a recognised ‘organic’ cause only account for a small proportion of schizophrenia, these would be only the tip of the iceberg if schizophrenia were commonly caused by early brain-damage due to pregnancy and birth complications (PBCS).

Before considering the link with PBCS, it is worth noting that there are three bodies of evidence that lend credence to the notion that schizophrenia is, at least in some instances, a neurodevelopmental disorder6. 12. First, in the temperate regions of the northern and southern hemispheres, a modest but statistically significant excess of schizophrenics are born in the winter months13. This winter excess is most plausibly attributed to infective or dietary factors that damage the fetus or infant. Second, schizophrenia in adult life commonly may be preceded by eccentricity, isolation and attentional problems in ~hildhood’~. 15, and similar social and attentional impairments have been found in ‘high-risk’ studies of the children of schizophrenic parents16. These findings suggest that schizophrenia may be a lifelong disorder with mani- festations that vary according to the individual’s development stage. Finally, some neuropathological studies of schizophrenia have suggested a neuro- developmental rather than a neuro- degenerative origin. CytdFrchitectural abnormalities”. in neuronal orientation and distribution have been found that could be explained plausibly by early brain-damage (and/or genetic abnorm- alities). In addition, neuronal loss has been found in the absence of glio~is’~, ’O,

again pointing to brain abnormalities arising early in development.

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The link with pregnancy and birth complications Many different definitions of PBCS have been used, generally involving a checklist of well-recognised obstetric complications, such as pre-eclampsia or premature labour, which are associated with in- creased perinatal mortality. Neonatal complications have sometimes been included as well. Fortunately, the exact 392

definition seems relatively unimportant, since the same conclusion emerges whatever definition is used. A large number of studies have demonstrated that schizophrenics are more likely than matched controls to have experienced PBCS. In the early studies, which are well reviewed by MCNEIL and KAIJ’, mothers’ retrospective accounts were the main source of information on PBCS. Although contemporary birth records were used to provide objective con- firmation in some cases, primary reliance on retrospective recall is an important methodological limitation. Did schizo- phrenics really experience an excess of PBCS, or were their mothers simply more likely to remember any PBCS that did occur?

Three recent Scandinavian studies’”, based entirely on contemporary birth- records, have shown that the link between schizophrenia and PBCS is real and not just a product of biased recall. In Denmark virtually all births are attended by a midwife, who completes a standard- ized form detailing prenatal and perinatal complications. Comparisons of Danish schizophrenics with matched controls2* demonstrated that, on average, the schizo- phrenics had experienced more PBCS in terms of both frequency and severity of complications. This excess has been found among adopted and non-adopted schizophrenics2, and among those with and without a family history of the disorder2* ’. A link between PBCS and schizophrenia also emerged from a Swedish study’ based on hospital birth-records.

The link between PBCS and schizo- phrenia appears to be nonspecific, in the sense that schizophrenia is associated with an increased incidence of a broad range of PBCS’. Although individual studies found that pre-eclampsia’, long labour’, and malpresentation’ were particularly over- represented, these findings have varied from study to study, and may have been due to chance.

Two possible explanations for a noncausal link between PBCS and schizophrenia will be considered at this point, primarily to dismiss them from further consideration. If a genetic pre- disposition to schizophrenia in the

mother, whether manifested or not, increased her chance of having an abnormal pregnancy and delivery, then her offspring would have both a higher rate of PBCS and a greater genetic risk of schizophrenia. This explanation for the link between schizophrenia and PBCS probably can be dismissed. There have been numerous studies of the repro- ductive perormance of schizophrenic women’, and these have not demon- strated a consistent excess of PBCS, either in comparison with pregnancies in which the father was schizophrenic, or in comparison with pregnancies in which neither parent was schizophrenic.

Alternatively, could a raised incidence of PBCS act as a marker for psychosocial disadvantage, and some postnatal component of this disadvantage actually be responsible for the greater liability to schizophrenia? This is unlikely for three reasons. First, there is no evidence that schizophrenia rates are related to parental class2’. Second, even when schizophrenics and controls are carefully matched for parental class and neighbourhood, the former still have an excess of objectively ascertained PBCS’. Most telling of all, the same is true of early adoptees who later become schizophrenic, but not of matched adoptees who did not become schizophrenic’.

Ventricular enlargement, schizophrenia and PBCs Brain-imaging techniques have demon- strated abnormalities in roughly a third of schizophrenics”. In most instances these abnormalities are quantitative rather than qualitative, involving unusually large lateral and third ventricles, sometimes accompanied by widening of the cortical sulci. This cerebral atrophy probably reflects longstanding nonprogressive brain abnormalities that predate the onset of schizophrenia, possibly dating back to early childhood or fetal life6,

In individuals who are not schizo- phrenic, ventricular size reflects both genetic and environmental factors4, 6 , 23.

The same appears to be true in schizophrenia: ventricular enlargement has been linked both to a positive family history of s~hizophrenia~~’ 25 and to en- vironmental insults, including PBCS’.

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Contrary to earlier suggestions4, ven- tricular enlargement is not a distinctive marker for a nongenetic subtype of schizophrenia caused by early brain insults. Thus both ventricular enlarge- ment26 and an excess of P B C S ~ also occur in schizophrenics with a positive family history. Purely genetic and purely acquired cases of schizophrenia may represent the opposite ends of a con- tinuum, with many intermediate cases resulting from the additive or multi- plicative effects of early brain-damage and genetic predisposition. It has been postulated, for example, that schizo- phrenia results from the combination of early brain-damage and a genetic predisposition to schizotypal personality disorder3* 26.

PBCs are weak predictors Although many studies have shown a statistically significant excess of PBCS among schizophrenics, they have not examined whether PBCS are good predictors of later schizophrenia. In some instances, however, it is possible to re- analyse the results to obtain a rough estimate of predictive power. Thus in a study of Danish adoptees2, the prevalence of schizophrenia was 0 .6 per cent over-all, rising to about 1 * 5 per cent in the decile who had experienced the worst obstetric disadvantage, as judged by severity or frequency of PBCs. Although a risk ratio of 2.5 is impressive from one perspective, an increase in absolute risk of less than 1 per cent is fairly trivial from the perspective of most parents and clinicians, particularly when set against the much greater predictive power of a positive family history. Anxious parents can be reassured that in the absence of a positive family history of schizophrenia, survivors of moderately severe PBCS are very unlikely to develop schizophrenia. It is not known whether PBCS are more powerful predictors of schizophrenia if the complications were very severe or if the individual also has a positive family history for schizophrenia.

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Are PBCs causes or effects? Since, on average, schizophrenics have experienced an excess of P B c s , it is tempting to conclude that PBCS cause 393

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schizophrenia. This temptation is all the greater because PBCS potentially could account for the type and distribution of the neuropathological changes found in schizophrenia”. Nevertheless, the temp- tation probably should be resisted. Two lines of evidence suggest that the conventionally recognised PBCS are most unlikely to be important causes of schizophrenia, except perhaps in a small minority of cases. First, as already noted, PBCS are poor predictors of schizophrenia. Second, the prevalence of schizophrenia does not reflect the marked discrepancies that exist between the rates of PBCS in different nations and classes. Perinatal mortality is much higher in developing than developed nations, yet the incidence of strictly defined schizophrenia appears to be remarkably uniform throughout the world”. Similarly, differences in socio- economic status have long been associated with major differences in perinatal mortality, yet there is no evidence for an association between schizophrenia rate and parental class‘’.

If conventionally recognised PBcs are unlikely to be major causes of schizo- phrenia, what else could account for the link between PBCS and schizophrenia? One possibility is that the PBCS are effects rather than causes of a schizophrenic liability. The old concept of schizophrenia as a disorder restricted to adult life has given way, at least in part, to the concept of schizophrenia as a neurodevelopmental disorder with different manifestations at different life stages6* ‘I* ‘’9 16-with psy- chotic symptoms predominating in adult- hood, and with social and attentional impairments predominating during child- hood. Extrapolating backward in time, the same underlying neurodevelopmental disorder may also affect the fetus. NELSON and ELL EN BERG^' have shown that pre-existing fetal abnormalities can increase the incidence of various birth complications, including malpresentation and birth asphyxia. Thus if schizophrenia arises from a lifelong disorder of neuronal organisation, it is plausible that fetal manifestations of this disorder could increase the incidence of PBCS.

If prenatal insults do contribute to the underlying neurodevelopmental disorder, one can infer that these insults largely go 394

unrecognised at the time, and that they are probably fairly homogenously distributed across space and class (but not season). Silent prenatal infections with common world-wide viruses, such as influenza virusesz9, may play some part.

Conclusions Although a link exists between recognised PBCS and later schizophrenia, the link is weak, nonspecific and possibly non- causal-with PBCS arguably being con- sequences rather than causes of a liability to schizophrenia. There is no compelling reason at present to conclude either that inadequate perinatal care causes schizo- phrenia or that improved perinatal care could prevent it.

Two research implications are worth noting. First, follow-up studies of survivors of severe perinatal adversity ideally should be continued well into adult life in order to examine the relationship between early brain-insults and adult psychiatric disorder. Second, prenatal and neonatal ultrasound studies of ventricular size could be informative: for example, do the unborn or newborn children of schizophrenic parents have larger ventricles than matched controls? And if so, do the fetuses with the largest ventricles tend to have more birth complications?

ROBERT GOODMAN Department of Child Psychiatry, The Hospital for Sick Children, Great Ormond Street, London WCIN 3JH.

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13. Kendell, R. E., Kemp, I. W. (1987) ‘Winter- born vs. summer-born schizophrenics.’ British Journal of Psychiatry, 151, 499-505.

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15. Rutter, M. (1985) ‘Psychopathology and development: links between childhood and adult life.’ In Rutter, M., Hersov, L. (Eds.) Child and Adolescent Psychiatry: Modern Approaches. Oxford: Blackwell.

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18. Jakob, H., Beckmann, H. (1986) ‘Prenatal developmental disturbances in the limbic allocortex in schizophrenics.’ Journal of Neural Transmission, 65, 303-326.

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Murray, R. M. (1982) ‘Cerebral ventricular size in twins discordant for schizophrenia.’ Lancet, 1, 540-541.

24. Nasrallah, H. A., Kuperman, S., Hamra , B. J., McCalley-Whitters, M. (1983) ‘Clinical differences between schizophrenic patients with and without large cerebral ventricles.’ Journal of Clinical Psychiatry, 44, 407-409.

25. DeLisi, L. E., Goldin, L. R., Hamovit, J. R., Maxwell, E., Kurtz, D., Gershon, E. S. (1986) ‘A family study of the association of increased ventricular size with schizophrenia.’ Archives of General Psychiatry, 43, 148-153.

26. Schulsinger, F., Parnas, J., Peterson, E. T., Schulsinger, H., Teasdale, T. W., Mednick, S. A., Msller, L., Silverton, L. (1984) ‘Cerebral ventricular size in the offspring of schizophrenic mothers: a preliminary study.’ Archives of General Psychiatry, 41, 602-606.

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28. Nelson, K. B., Ellenberg, J. H. (1986) ‘Antecedents of cerebral palsy: multivariate analysis of risk.’ New England Journal of Medicine, 315, 81-86.

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Selective Dorsal Rhizotomy for Spastic Cerebral Palsy

INTEREST in selective dorsal rhizotomy for the spastic element in cerebral palsy has been raised by DR. WARWICK PEACOCK’, a neurosurgeon working initially in Cape Town and more recently in Los Angeles. Earlier this century FOERSTER reported that spasticity was relieved by division of the lumbar and sacral dorsal roots; he also suggested the use of partial root section’. In 1967 GROS and colleagues introduced the technique of partial posterior rhizotomy3. In 1979 FASANO and colleagues published the technique of selectively stimulating the posterior rootlets to discover which were making the more major contribution to the feedback mechanism producing spasticity4. They discovered that stimu- 395