Edinburgh University Department of Psychiatry, Royal Edinburgh Hospital, Edinburgh
Information and Statistics Division, National Health Service in Scotland, Edinburgh
Correspondence: Dr R. E. Kendell, 3 West Castle Road, Edinburgh EHI0 5AT
Declaration of interest Funded by the Scottish Office Department of Health.
See pp.523-530, this
issue.
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ABSTRACT |
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Aims To determine which obstetric complications are more common in probands with schizophrenia than matched controls.
Method Two hundred and ninety-six probands with an in-patient diagnosis of schizophrenia who had been born in Scotland in 1971-74, and a further 156 born in 1975-78, were closely matched with controls and the incidence of obstetric complications in the two compared using obstetric data recorded in a set format shortly after birth.
Results Not a single complication of pregnancy or delivery was significantly more common in the probands with schizophrenia than the controls in the 1971-74 birth cohort and only emergency Caesarean section and labour lasting over 12 hours were significantly more common in the schizophrenia probands in the 1975-78 cohort.
Conclusion The evidence that schizophrenia is associated with a raised incidence of obstetric complications is weaker than has recently been assumed.
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INTRODUCTION |
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The two case-control studies reported here were designed as an extension of our 1996 study. That had been based on 115 schizophrenic-control pairs derived from all hospital deliveries in Scotland in 1971-74 and was then the largest published study based on obstetric data recorded at the time of birth. By re-examining the original 1971-74 birth cohort 4 years later, by which time many more would have developed schizophrenic illnesses, and conducting an analogous case-control comparison on the subsequent 1975-78 birth cohort, we hoped to obtain a sufficiently large number of matched schizophrenic-control pairs to be able to compare the incidence of individual obstetric complications in the two, and thereby determine whether the complications which were more common in the schizophrenia probands than the controls were indeed those likely to result in foetal anoxia.
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METHOD |
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Obstetric data
SMR2 data consist of fairly extensive demographic and medical information
about the mother and salient features of the current pregnancy, birth and
puerperium. The clinical information was originally recorded on a structured
antenatal record sheet (by the relevant obstetrician) and on a similarly
structured delivery record (by the midwife or obstetrician responsible for the
delivery). This information was then transcribed onto the ISD's SMR2 form (by
a medical records clerk or the obstetrician) when the mother left hospital and
subsequently transferred to magnetic tape. In addition to the mandatory
ratings there was provision on the form for recording other less common
complications of pregnancy, delivery or the puerperium using four digit ICD-8
code numbers. Because the content and layout of the SMR2 form was changed on 1
January 1975, and also because our original study had been based on
individuals born in 1971-74, 1971-74 and 1975-78 births were analysed
separately. As before, the SMR2 records of the probands with schizophrenia
were individually matched with controls who had never been admitted to a
Scottish psychiatric unit with a discharge diagnosis of either schizophrenia
or an affective psychosis on six different variables - the obstetric unit of
birth, gender, date of birth (± 2 months), maternal age (± 2
years), maternal parity (first baby v. second or subsequent baby) and
father's occupation (manual v. non-manual). Twins and singletons were
also matched separately. A composite variable birth weight less than 2500 g
and gestational age less than 37 weeks was added to the SMR2 variables
originally chosen for analysis because of the recent finding by Jones et
al (1998) that this
combination, indicating normal intra-uterine growth but premature delivery,
was a risk factor for schizophrenia. Small for gestational age (below the 5th
percentile) was also added.
SMR2 records were found for 505 (56%) of the 902 people with schizophrenia born in 1971-78 originally identified from the SMR4 file. The main reasons for failure to identify an SMR2 record were birth outside Scotland or home delivery (in 1971 24% of births were either home births or in small obstetric units not supplying SMR2 returns, but this had fallen to 2% by 1978). Changes of surname on adoption, coding errors and failure of the psychiatric hospital to record the original maiden name of married women are other possibilities, but the fact that the male: female ratio was not significantly higher in the 505 probands than in the 397 potential probands for whom no SMR2 record could be found suggests that change of surname on marriage was not an important cause of failure.
Demographic data
Vital demographic information (mainly the father's occupation) was missing
from 34 obstetric records, which reduced the total available for matching from
505 to 471, but because so many potential controls were available (there were
nearly 500 000 hospital deliveries in Scotland in 1971-78) it was possible to
match all but 19 of these on all the six variables described above. We
therefore ended up with 452 matched pairs -296 born in 1971-74 and 156 born in
1975-78.
At the time the SMR4 data were originally extracted from file (October 1997) the age of the 1971-74 probands ranged from 22 to 26 years and 78.7% were male. The age of the 1975-78 probands ranged from 18 to 22 years and 75.6% were male. The high percentage of males is a consequence of the earlier age of onset and hospital admission in male than female patients with schizophrenia.
Statistical analysis
A standard case-control analysis of matched case-control sets was carried
out using SPSS for Windows and STATA
(Breslow & Day, 1980; Stata, 1997). Odds ratios, 95%
confidence intervals (CIs) and P values were calculated using
conditional logistic regression. Probands and controls were also compared
using the paired t-test for the normally distributed continuous
variables birthweight, antenatal haemoglobin and gestational age and the
Wilcoxon signed ranks test for the non-normally distributed variable duration
of labour.
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RESULTS |
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1975-78 births
The redesigned SMR2 form introduced on 1 January 1975 provided less
information about the mother's health during pregnancy than the original 1971
form, but more about the delivery and the newborn child. In particular, it
distinguished between elective and emergency Caesarean sections and recorded
the Apgar score 5 minutes after birth. The results of the proband-control
comparisons are shown in Table
2. Again, the two are very similar, though this time there are two
variables which are significantly more common in those with schizophrenia -
emergency Caesarean section (P=0.05) and a duration of labour of over
12 hours (P=0.04). The mean duration of labour is also longer in the
probands than in the controls (P=0.05).
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As before, all of the complications recorded by their ICD-8 code numbers were compared individually as well as corporately. There were significant differences for only two. Delivery complicated by mal-presentation of the foetus was more common in the probands (6 v. 0; P < 0.05) and laceration of the perineum was more common in the controls (9 v. 2; P < 0.05). Again, separate proband-control comparisons were carried out for males and females. None of the differences described above was statistically significant in either of these single gender comparisons, nor did any new significant proband-control differences emerge.
Reappraisal
The results described above are completely different from those obtained in
our previous study of the 1971-74 birth cohort
(Kendell et al, 1996).
Indeed, they are so different they are incompatible. The 1996 study, which was
based on the 115 probands who had developed a schizophrenic illness by the end
of 1992, had produced a strikingly higher incidence of complications both of
pregnancy and delivery in the probands than in the controls (P <
0.001 in each case). Four years later, by which time more than twice as many
members of the birth cohort had developed schizophrenic illnesses, those
proband-control differences had entirely disappeared. Although there is
evidence that a raised incidence of obstetric complications is more common in
people developing a schizophrenic illness before the age of 22 than in those
with a later age of onset (Verdoux et
al, 1997) this could hardly account for a change of such
magnitude. Moreover, there were few significant proband-control differences in
the 1975-78 birth cohort, who were the same age in 1996 as the original
1971-74 cohort had been in 1992.
A comparison of the incidence of obstetric complications in both the probands and the controls of the 1971-74 birth cohort in the original 1996 study and the present one showed that the incidence of complications in the probands with schizophrenia was similar in both. The discrepancy was in the controls, who had a much lower incidence of complications, both of pregnancy and delivery, in the 1996 comparison than in the present one. We therefore compared the frequency of selected complications in four populations: the controls from our original 1996 study of the 1971-74 birth cohort; the controls from our present studies of both the 1971-74 and 1975-78 birth cohorts; and in all 500 000 hospital deliveries in 1971-78 after excluding multiple births, neonatal deaths and the probands with schizophrenia and affective disorders in our present studies. The results are shown in Table 3, and it is apparent that the original 1971-74 controls are anomalous with substantially fewer complications of pregnancy, delivery and the puerperium than the other three populations.
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Initially, this seemed inexplicable because in all three studies (the original study of the 1971-74 birth cohort and the present studies of the 1971-74 and 1975-78 birth cohorts) not only had probands and controls been closely matched on the same six variables, but an almost identical computer program had been used to generate the controls. In a bid to identify the cause of the discrepancy an attempt was made to repeat the original (1996) study of the 1971-74 birth cohort. All the original 115 cases were re-identified and each stage of the original analysis repeated. It eventually became clear that, because the original matching program took the first subject in the SMR2 master file who matched each successive proband on the requisite six variables as that proband's control rather than the closest matching subject, the order in which individual births appeared in the SMR2 file was critical. If the order was left as it stood in the SMR2 master file, which reflected the order in which returns had been made by individual obstetric units to the ISD in Edinburgh, the incidence of complications in the controls was low (Column 4 in Table 4) and almost identical to the results reported in 1996 (Column 2 in Table 4).
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If, on the other hand, the SMR2 file was re-sorted so that, for each obstetric unit, all subjects appeared in sequence according to the date of delivery (Column 6 in Table 4) before matching on the six variables was carried out, the incidence of complications in the controls was far higher and all the significant proband-control differences disappeared. Indeed, in the case of complications of delivery they were reversed.
We presume that the explanation of this striking and unexpected finding is that the SMR2 forms of straightforward, uncomplicated deliveries are generally completed, returned to the ISD and logged in the master file soon after the delivery, whereas the SMR2 forms of complicated deliveries tend to be returned to the ISD later on, either because the mother and/or baby remain in hospital longer after delivery or for other reasons. As a result, for any given date of birth, uncomplicated deliveries tend to precede complicated deliveries in the master file and, unless the master file is re-sorted first to remove this bias, uncomplicated deliveries tend to be selectively picked as controls. We also have some evidence to support this assumption. We compared the lengths of stay in the obstetric unit of the selected controls in the repeat of the 1996 study (i.e. using the SMR2 master file as it stood - Column 4 in Table 4) with the average length of stay of all other potential controls (i.e. women on the SMR2 master file who also matched the proband on the six variables). Six of the selected controls had the same length of stay as the average of the other potential controls, 26 had a longer stay and 77 (three times as many) had a shorter stay in the obstetric unit. We therefore conclude that the case-control comparisons shown in Tables 1 and 2 are valid and that the results of our original study of the 1971-74 cohort (Kendell et al, 1996) are seriously misleading and should be ignored.
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DISCUSSION |
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Comparison with previous studies
This failure to find substantial differences between patients with
schizophrenia and controls is at variance with most of the existing literature
and, in particular, with the meta-analysis of Geddes & Lawrie
(1995). However, Geddes &
Lawrie were careful to point out that there was a gap in their funnel plot in
the region of small negative studies, and that the association they found
between obstetric complications and schizophrenia might have been inflated by
both selection and publication biases. It is also important to note that
neither of the two cohort studies in their meta-analysis produced a
significant schizophrenia-control difference; and that these and their 16
case-control studies only contained a total of 1000 subjects with
schizophrenia, whereas the two reported here contained nearly half that
number. Moreover, most of those 1000 subjects with schizophrenia were derived
from studies with serious methodological deficiencies. In several obstetric
information had been obtained retrospectively, from mothers or other family
members or even from adult psychiatric case notes, and in others the matching
of patients and controls was imperfect.
Other recent studies
Recently, three substantial and well-designed studies based on obstetric
records have been published. Jones et al
(1998) reported a 28-year
follow-up of a large Finnish birth cohort whose intra-uterine development and
births had been systematically documented in 1966. Seventy-six cases of
well-validated DSM-III-R schizophrenia were identified in this cohort, making
it possible to identify obstetric risk factors for the development of
schizophrenia. Low birth weight and the combination of low birth weight and
short gestation were both significantly associated with subsequent
schizophrenia. So too were placental abruption and an Apgar score of less than
8 at 1 minute. But no association was found with any of the common
complications of pregnancy and delivery and the authors concluded that most of
the relationships they found appeared to be due largely to
characteristics of the child, not the delivery.
The other two studies (Hultman et al, 1999; Dalman et al, 1999) were very similar both to our study and to one another. Both were based on a Swedish national cohort of births in the 1970s, used obstetric information recorded in a standard form at the time the infant left hospital, and identified members of the cohort who subsequently developed schizoprenic illnesses from a national register of admissions to psychiatric hospitals. Hultman et al identified 167 probands with schizophrenia (aged 15-21 years at the time of their first psychiatric admission) in the 1973-79 birth cohort and compared each of them with five controls. They studied a total of 44 variables and found schizophrenia to be significantly associated with multi-parity (odds ratio 2.0) and maternal bleeding during pregnancy (odds ratio 3.5). They also found significant associations in males, but not in females, for birth weight low for gestational age, coming fourth or later in a sibship and maternal bleeding in pregnancy. Dalman et al identified 238 probands with schizophrenia from a more restricted birth cohort (1973-77), presumably because they searched the psychiatric register at a later date when the cohort was somewhat older (up to age 22). They also compared their probands, not with individually matched controls, but with the rest of the birth cohort (over 500 000 individuals) using logistic regression analysis. Despite the fact that Dalman et al (1999) and Hultman et al (1999) were using the same Swedish national data, and that most of their probands with schizophrenia must have been the same people, the results reported by Dalman and her colleagues are surprisingly different. They studied 32 obstetric variables and, after adjusting for psychotic illness in the mothers, found several of these to be associated with an increased risk of schizophrenia. Pre-eclampsia (relative risk 2.5) was the most important risk factor, followed by vacuum extraction (relative risk 1.7) and congenital malformations (relative risk 2.4). Their final conclusion was that foetal malnutrition in utero, hypoxia at the time of delivery and prematurity all contribute independently to the aetiology of schizophrenia, and that malnutrition is relatively more important in males and prematurity more important in females.
Strengths and weaknesses of this study
This present investigation has the same strengths and weaknesses as most
other studies based on routinely recorded clinical data. The obstetric (SMR2)
data were fairly comprehensive and recorded in a set numerical format within a
few days of delivery. They therefore could not have been influenced by
subsequent events or our expectations. Their existence also enabled us to
obtain larger numbers of matched pairs than any previous case-control
comparison. On the other hand, information about their accuracy and
reliability is limited. Some information about the latter is available from a
study of 1991 SMR2 data by the staff of the ISD in which a random sample of
651 SMR2 returns were compared with the patients' hospital records. Incomplete
demographic information was a common problem (the woman's maiden name, for
example, was not recorded in 9% of returns) but inaccurate recording of
obstetric information was uncommon (mode of delivery, birthweight and Apgar
score were incorrectly recorded in only 0.9%, 0.5% and 0.6% of records, though
duration of labour was incorrect in 3.7%). No similar study has yet been
carried out on the psychiatric (SMR4) data. Discharge diagnoses are more
likely to be reliable and valid than admission diagnoses, but these were
purely clinical diagnoses and not based on operational criteria. Low
reliability will, of course, tend to diminish proband-control differences. It
could hardly, though, obscure those differences completely unless they were in
reality very modest. The availability of the obstetric records of over 500 000
hospital births for the 8-year period 1971-78 meant that the probands could be
closely matched with controls on all relevant variables without any
significant loss (only 19 of 471 probands remained unmatched, a 4% loss). The
fact that births were ranked by date of birth before the controls were
identified, and that the program employed picked the closest match for each
proband rather than the first, also ensured that the matching process was not
subject to the serious bias which, with hindsight, distorted the results of
our original 1996 study.
Implications
Despite their methodological strengths and substantial numbers of probands
it is difficult to reconcile the four most recent investigations of the role
of obstetric complications in the genesis of schizophrenia
(Jones et al, 1998;
Hultman et al, 1999;
Dalman et al, 1999 and
this present study) with one another. Taken as a whole they suggest that the
incidence of obstetric complications is raised in people with schizophrenia,
but that the magnitude of this increase is much less than the 2:1 excess
indicated by the earlier literature summarised by Geddes & Lawrie
(1995). Nor is there any
agreement on which individual obstetric variables are the most important risk
factors, and therefore no clear leads to the pathogenic mechanisms potentially
involved. It should also be noted that our study, which found fewer
differences between probands and controls than any previous comparison, had a
larger number of probands with schizophrenia than any of its predecessors.
At this stage, therefore, there are only two safe conclusions. First, the relationship between obstetric complications and schizophrenia is less firmly established than has recently been assumed. Second, a further meta-analysis is needed, restricted to investigations based on a clearly defined birth cohort and obstetric data recorded at the time of delivery.
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Clinical Implications and Limitations |
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LIMITATIONS
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REFERENCES |
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Breslow, N. E. & Day, N. E. (1980) The analysis of case-control studies. Statistical Methods in Cancer Research, Vol. 1. IARC Scientific Publications, No. 32. Lyon: International Agency for Research on Cancer.
Dalman, C., Allebeck, P., Cullberg, J., et al
(1999) Obstetric complications and the risk of schizophrenia:
a longitudinal study of a national birth cohort. Archives of
General Psychiatry, 56,
234-240.
Geddes, J. R. & Lawrie, S. M. (1995) Obstetric complications and schizophrenia: a meta-analysis. British Journal of Psychiatry, 167, 786-793.[Abstract]
Hultman, C. M., Sparén, P.,
Takei, N., et al (1999) Prenatal and perinatal risk
factors for schizophrenia, affective psychosis, and reactive psychosis of
early onset: case-control study. British Medical
Journal, 318,
421-426.
Jones, P. B., Rantakallio, P., Hartikainen, A., et al
(1998) Schizophrenia as a long-term outcome of pregnancy,
delivery and perinatal complications: a 28-year follow-up of the 1966 North
Finland general population birth cohort. American Journal of
Psychiatry, 155,
355-364.
Kendell, R. E., Juszczak, E. & Cole, S. K. (1996) Obstetric complications and schizophrenia: a case control study based on standardised obstetric records. British Journal of Psychiatry, 168, 556-561.[Abstract]
Kendrick, S. & Clarke, J. (1993) The Scottish record linkage system. Health Bulletin, 51, 72-79.[Medline]
Stata (1997) Stata Statistical Software: release 5.0. College Station, TX.
Verdoux, H., Geddes, J. R., Takei, N., et al (1997) Obstetric complications and age at onset in schizophrenia: an international collaborative meta-analysis of individual patient data. American Journal of Psychiatry, 154, 1220-1227.[Abstract]
World Health Organization (1978) Mental Disorders: Glossary and Guide to their Classification in Accordance with the Ninth Revision of the International Classification of Diseases. Geneva: WHO.
World Health Organization (1992) The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. Geneva: WHO.
Received for publication January 12, 1999. Revision received October 25, 1999. Accepted for publication October 26, 1999.
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