Department of Psychological Medicine, University of Wales College of Medicine, Cardiff
Community Medicine, Unit for Psychosis Research, Stockholm, Sweden
Institute of Psychiatry and GKT School of Medicine, London
Sachsska Children's Hospital, Stockholm, Sweden
University of Wales College of Medicine, Cardiff
Department of Social Medicine, University of Göteborg, Sweden
Correspondence: Dr H. V. Thomas, Psychological Medicine Academic Unit, 2nd Floor Monmouth House, Heath Park, Cardiff CF14 4XN, UK. Tel: 029 2074 3229; fax: 029 2074 6595; e-mail: thomashv{at}cardiff.ac.uk
Declaration of interest No conflict of interest. Support from the Swedish Medical Research Council, the Stanley Foundation, the SöderbergKönigska Foundation and the Torsten and Ragnar Söderberg Foundation.
See invited commentaries, pp.
415416, this issue.
See pp. 403408, this
issue
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ABSTRACT |
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Aims To test the hypotheses that individual obstetric complications are most strongly associated with an increased risk of schizophrenia in males, in patients with an early age at first diagnosis and in subjects with a maternal history of psychosis.
Method Cases of schizophrenia diagnosed between January 1971 and June 1994 were identified in the Stockholm County In-Patient Register. Controls were matched on age, gender, hospital of birth and parish of birth. Obstetric data were recorded blind to casecontrol status for 524 cases and 1043 controls.
Results This study did not find any large or consistent effect of gender, age at diagnosis or maternal history of psychosis on the risk of schizophrenia associated with individual complications.
Conclusions Future studies should examine these effects using a much larger sample that includes patients with schizophrenia and control subjects whose genetic risk of schizophrenia has been assessed accurately.
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INTRODUCTION |
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METHOD |
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Of the identified cases, 51 had died, 32 were no longer living in Stockholm County, obstetric notes could not be retrieved for 37 cases (6.5%) and 4 were excluded that lacked controls owing to a low number of births in that parish. Obstetric notes could not be retrieved for 89 (7.9%) of the eligible controls. The present analyses include 524 cases of schizophrenia and 1043 matched controls for whom obstetric records were retrieved from the archives.
Data collection
The birth records were copied in the archives and given code numbers to
conceal case/control status, randomly assembled and given in batches to a
midwife who extracted obstetric data according to a protocol devised by the
research group. Signs of asphyxia at birth were defined as Apgar score <7
at 1, 5 or 10 min (Sykes et al,
1982; Silverman et
al, 1985). For full information on definition of obstetric
complications, see previous paper (Dalman
et al, 2001, this issue).
The National In-Patient Register provided information on mothers who were admitted with a psychotic illness during 1971-1996 (coded 295-299 ICD-8 or 295-298 ICD-9, i.e. all non-organic psychoses; World Health Organization, 1967, 1978).
Statistical analyses
The frequency distribution of age at diagnosis was split approximately into
thirds (<23, 23-27 and 27+ years). Odds ratios for schizophrenia in
relation to individual obstetric complications were calculated for matched
casecontrol sets using conditional logistic regression stratified by
gender and stratified separately by the three categories of age at diagnosis.
It was impossible to calculate odds ratios stratified by maternal history of
psychosis while maintaining the matching, because maternal history was not a
matching criterion. Instead, indicator variables that combined
presence/absence of maternal history and presence/absence of each obstetric
complication were created, with subjects with no maternal history and no
record of each complication acting as the baseline in the odds ratio analyses.
Tests for interaction between two variables were based on the likelihood ratio
statistic. Exact P values for tests of interaction are quoted in the
text for signs of asphyxia at birth because this variable was demonstrated to
be the only independent risk factor for schizophrenia in this data-set
(Dalman et al, 2001,
this issue).
Ninety-five per cent confidence intervals (95% CI) and two-sided P values are quoted. Statistical tests were considered significant at P<0.05. All analyses were performed using Stata Version 5 (Stata Corporation, College Station, TX, USA).
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RESULTS |
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Odds ratios for schizophrenia stratified by gender
The increase in risk of schizophrenia associated with asphyxia at birth,
pre-eclampsia, head circumference less than 32 cm and being small for
gestational age was greater in males than in females
(Table 1). However, the 95% CI
around each odds ratio was wide and did not support any statistically
significant difference in risk. None of the tests for interaction between
gender and individual obstetric complications was statistically significant
(test for interaction between gender and signs of asphyxia at birth,
P=0.84).
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Odds ratio for schizophrenia stratified by age at diagnosis
The estimate of schizophrenia risk associated with an instrumental
delivery, an abnormal foetal heart rate and a gestation of less than 37 weeks
was increased in those subjects diagnosed before 23 years of age
(Table 2). However, the 95% CI
around each odds ratio was wide and did not support any statistically
significant difference in risk. The only significant interaction was that
between age at onset and a labour lasting more than 12 h
(2=7.2, d.f.=2, P=0.03; test for interaction between
age at onset and signs of asphyxia at birth, P=0.57).
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Odds ratios for schizophrenia stratified by maternal history of
psychotic illness
Maternal history of psychotic illness was strongly associated with risk of
schizophrenia (odds ratio=5.9, 95% CI=3.3-10.3). The increase in schizophrenia
risk associated with an instrumental delivery was greater among those subjects
with a maternal history of psychosis (Table
3). However, the 95% CIs did not support any statistically
significant difference in risk. None of the tests for interaction between
maternal psychotic history and individual complications was statistically
significant (test for interaction between maternal history and signs of
asphyxia at birth, P=0.42).
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DISCUSSION |
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Several studies previously have compared the proportion of male and female patients with schizophrenia who have a history of obstetric complications, or the proportion of patients with early and late disease onset who have a history of complications (Kirov et al, 1996; Verdoux et al, 1997; Smith et al, 1998). However, by simply comparing frequencies of complications between subgroups of patients with schizophrenia, these studies could not examine whether gender or age at onset actually modified the effect of any individual complication on schizophrenia risk.
Using a more appropriate analysis, three studies have reported the risk of early-onset schizophrenia associated with individual obstetric complications stratified by gender. Hultman et al (1999) reported that the risk associated with being small for gestational age was increased in males compared with females; the test for interaction between this variable and gender was statistically significant (P<0.05). Dalman et al (1999) demonstrated that the risk of schizophrenia associated with pre-eclampsia, bleeding during pregnancy, a prolonged labour, uterine inertia, vacuum extraction, being small for gestational age and head circumference less than 32 cm was greater in males than in females. However, the 95% CIs did not support any statistically significant difference in risk and no statistical tests for interaction were carried out. Finally, Byrne et al (2000) reported a significant association between a history of a definite complication and an increased risk of schizophrenia among males presenting before the age of 30 years, whereas a history of definite complication was not associated significantly with schizophrenia in females at any age of presentation. In conclusion, no individual complication has been shown to be associated significantly with an increase in schizophrenia risk in both males and females, with the increase in risk among males being significantly greater than that among females.
Our study also aimed to examine the relative aetiological importance of genetic and early environmental risk factors within the neurodevelopmental model of schizophrenia. The results did not demonstrate any evidence to support a modification of the schizophrenia risk associated with obstetric complications by maternal history of psychotic illness.
The manner in which genetic factors and obstetric complications are associated with risk of schizophrenia could be explained by three possible mechanisms. First, obstetric complications might be aetiologically important only in those individuals who already carry some genetic predisposition (Mednick et al, 1987). Alternatively, obstetric complications alone might be sufficient to increase schizophrenia risk in at least some individuals (Murray et al, 1985). It has been suggested also that environmental and genetic risk factors are not completely independent of each other; instead, the obstetric complications might actually be the consequence of some genetic predisposition (Owen et al, 1988).
Marcelis et al (1998) used familial morbid risk of schizophrenia as an indicator of genetic liability to examine whether obstetric complications were associated positively with genetic predisposition in both psychosis and control probands. The authors found no significant associations between the complications and a family history of psychosis or schizophrenia, and concluded that it was unlikely that obstetric complications are purely the expression of genes predisposing to schizophrenia. This suggests that genetic risk and early environmental insults are more likely to be independent risk factors for schizophrenia. The results of our study did not provide any evidence to support an interaction between these two risk factors.
Strengths and limitations of the study
This study benefits from using obstetric data from birth records coded by a
midwife blind to the case/control status of each subject, rather than relying
on maternal recall. The unique personal identification numbers allowed careful
matching of cases and control subjects and verified that the control subjects
were still residents of Stockholm County at the time of inclusion into the
study, thus minimising selection bias.
Although our case-control study benefited from a large sample size, after stratifying by gender, age at diagnosis or maternal history of psychosis only very small numbers of subjects remained in each category who had also experienced any of the obstetric complications. Hence, we had little statistical power to examine the relationships very accurately. The tests for interaction were particularly prone to a lack of statistical power and their results should not be heavily relied upon. It is still possible that gender, age at diagnosis or genetic risk might alter the association between signs of asphyxia at birth and schizophrenia risk that we have reported (Dalman et al, 2001, this issue), but very large studies would be needed to detect this.
Unfortunately our only measurement of genetic risk of schizophrenia was a recorded maternal history of psychosis; data on paternal history would have improved the measurement. It is likely that the transmission of predisposing genes to schizophrenia does not necessarily result in the overt manifestation of the disorder (Gottesman & Bertelsen, 1989; Cannon et al, 1994), so even having full knowledge of maternal and paternal history of overt psychosis would not be an ideal measurement of genetic risk. The ideal measurement would require the identification of the genetic factors necessary for schizophrenia development, or at least markers that are very closely linked to them.
In conclusion, this study did not find any large or consistent effect of gender, age at diagnosis or maternal history of psychotic illness on the risk of schizophrenia associated with individual obstetric complications and indicators of foetal growth. Future studies should aim to examine these effects using a much larger study sample that includes patients with schizophrenia and control subjects whose genetic risk of schizophrenia has been assessed accurately.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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REFERENCES |
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Received for publication August 10, 2000. Accepted for publication August 21, 2000.
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