Community Medicine, Unit for Psychosis Research, Stockholm, Sweden
University of Wales College of Medicine, Cardiff
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, Göteborg University, Sweden
Correspondence: Christina Dalman, MD, Community Medicine, Unit for Psychosis Research, PO Box 175 33, S-118 91 Stockholm, Sweden. E-mail: christina.dalman{at}smd.sll.se
Declaration of interest No conflict of interest. The study was supported by the Stanley Foundation, the Swedish Medical Research Council and the Söderberg-Königska Foundation.
See invited commentaries, pp.
415416, this issue.
See pp. 409414, this
issue.
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ABSTRACT |
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Aims To assess the role of different complications, and in particular to distinguish between disordered foetal development and hypoxia at birth.
Method From the Stockholm County In-Patient Register and community registers, we identified 524 cases of schizophrenia and 1043 controls, matched for age, gender, hospital and parish of birth. Data on obstetric complications were obtained from birth records.
Results There was a strong association between signs of asphyxia at birth and schizophrenia (OR 4.4; 95% C11.9-10.3) after adjustment for other obstetric complications, maternal history of psychotic illness and social class.
Conclusions Signs of asphyxia at birth are associated with an increased risk of schizophrenia in adults.
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INTRODUCTION |
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METHOD |
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Controls
We selected, from the parish register, as controls, the next two births in
time, of the same gender and born in the same hospital as the case. We used
the personal identity number to check at the central taxation office that the
person was still alive and resident in Stockholm County at the time of the
selection of the cases. Eighty-nine birth records (7.9%) could not be
retrieved. For another four cases we could not get controls, owing to the
small number of births in the parish, and these four were excluded, leaving
524 cases and 1043 controls.
Birth records
The 1567 birth records were copied from the archives and given code numbers
to conceal case or control status. The first author (C.D.) selected and
retrieved the birth records. The records were randomly assembled and given in
batches to a midwife, who extracted data according to a protocol devised by
the research group. Gestational age was based on date of mother's last
menstruation
(Tunón
et al, 1996) or ultrasound when available. Small for
gestational age (SGA) was defined as a foetal weight two standard deviations
below Marál
et al's (1996)
standard curves, based on 759 ultrasonic estimates of Scandinavian
foetuses.
Signs of asphyxia were defined as an Apgar score of less than 7 at 1, 5 or
10 minutes (Sykes et al,
1982; Silverman et
al, 1985). The Apgar score was introduced in the 1960s, hence
only 20.5% of the records in this study had an Apgar score. All records with
an Apgar score of 7 (six records) and below 7 (10 records) were examined by an
experienced paediatrician (J.G.) to check the accuracy of the rating. Ten of
these were judged to fulfil the criterion of an Apgar score below 7. All
records that lacked an Apgar scoring were assessed by the midwife according to
a protocol in which the five Apgar items (heart rate, breathing, colour, tone
and excitability of the infant) were defined. The records where the Apgar
score was judged to be below 7 (44 records) were delivered to J.G. for further
scrutiny. The reliability of the midwife's screening was tested in two ways:
(a) a random sample of 300 birth records for infants classified as having no
signs of asphyxia was re-examined by the first author, and none was classified
as false negative; (b) a second midwife scrutinised blindly the records of all
the 44 cases that were originally classified as having signs of asphyxia and a
random sample of 120 classified as unaffected (in total, 164 birth records).
The inter-record agreement was excellent ( 0.95). J.G., blind to
case/control status, estimated the expected Apgar score from the information
in the 44 birth records and classified them into seven groups: Apgar >6
(n=2), Apgar 4-6 at 1 min (n=25), Apgar 0-3 at 1 min
(n=5), Apgar 4-6 at 5 min (n=9), Apgar 0-3 at 5 min
(n=0), Apgar 0-6 at 10-min (n=1), unknown (n=2).
Altogether, 40 subjects were judged to have had an estimated Apgar score below
7. To test the reliability, another paediatrician assessed the 44 records.
There was excellent agreement between the physicians in the classification
into the seven groups above (
0.83). When deciding whether the infants
showed signs of asphyxia or not (i.e. Apgar score <7, or
7), they
disagreed in their assessment of only one subject.
As a result of these procedures, 50 subjects out of 1567 (3.1%) were classified as having an Apgar score below 7. The proportion was the same among those whose Apgar ratings had been recorded (3.1%) as among those who were assessed retrospectively (3.2%). They were divided into slight (Apgar 4-6 at 1 min, n= 32) and moderate/severe asphyxia (Apgar score 0-3 at 1 min and 0-6 at 5 and/or 10 min, n=18).
Pre-eclampsia in the mother was defined as the presence of both proteinuria
(more than traces on a single test, or repeated traces) and hypertension
(140/90 or
150/100 mmHg on admission for delivery).
Classification of obstetric complications
The following a priori classification was used:
We also noted other potentially important risk factors such as bilirubin measurements and any record of jaundice, as well as extreme prematurity (gestational age <33 weeks).
Parental characteristics
We recorded maternal age (in 5-year bands), parity (1, 2-3, 4+), attendance
at antenatal care (regular, none or irregular), civil status (married,
unmarried or divorced). Socio-economic index (SEI)
(Ericson et al,
1993a) was based on the highest SEI in the family: group
I (SEI 54-87)=upper-level executives, self-employed, professionals; group II
(SEI 33-47)=assistant non-manual employees; group III (SEI 11-22)=unskilled
and skilled employees in goods and service production. Through a linkage with
the National Inpatient Register we were able to identify mothers who had been
admitted to hospital with a psychotic illness (295-299 ICD-8, 295-298 ICD-9)
between 1971 and 1996.
Statistical analysis
Odds ratios (ORs) and 95% confidence intervals (CIs) for schizophrenia in
relation to individual obstetric complications were calculated for matched
casecontrol sets using conditional logistic regression. Odds ratios
were adjusted for possible confounding variables, both one by one and
simultaneously. A similar method was used to study the continuous variables,
in quintile groups, but we also examined the statistical significance of
quadratic functions using likelihood ratio tests.
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RESULTS |
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Associations between individual obstetric complications
Subjects with one complication were more likely to have another
complication. For example, 20.0% of subjects who had shown signs of asphyxia
at birth, and 21.3% of subjects who were breech presentations during labour,
also had a birth weight below 2500 g.
Odds ratios for schizophrenia in relation to indicators of foetal
growth impairment and short gestational age
Those who were SGA (OR 1.5; 95% CI 0.9-2.4), showed delay in gaining weight
after birth (OR 1.9; 95% CI 1.0-3.4) or whose mothers had had pre-eclampsia
(OR 1.6; 95% CI 0.7-3.5) all showed trends towards greater risk of
schizophrenia, although this was not statistically significant
(Table 1). The odds ratio for
schizophrenia in subjects whose birth weight was less than 2500 g was 1.8 (95%
CI 1.0-3.1). Adjusting for length of gestation barely affected the odds ratios
in relation to birth weight, birth length, ponderal index and head
circumference. The odds ratio for schizophrenia in those who had extremely
short gestational age (<33 weeks) was 2.7 (95% CI 0.7-9.7)
(Table 1).
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Odds ratios were also calculated for the continuous variables (birth
weight, birth length, ponderal index, head circumference, gestation length),
using the distribution among the controls divided into fifths. None of these
variables, when analysed in this manner, was demonstrated to be associated
with risk of schizophrenia. A quadratic model did not significantly improve
the fit of the data. For example, the odds ratio for birth weight in quintile
groups was 1.0 (95% CI 1.0-1.1). There was no statistically significant
relationship with birth weight when a quadratic term was included
(2=1.05, d.f.=2, P=0.59).
Odds ratios for schizophrenia in relation to indicators of hypoxia at
birth
There was an increased risk of schizophrenia in subjects who had signs of
asphyxia at birth (OR 2.7; 95% CI 1.5-4.8)
(Table 2). The odds ratios were
about the same when divided into slight (OR 2.6; 95% CI 1.3-5.3) or moderate
to severe asphyxia (OR 2.8; 95% CI 1.0-7.4). Children who had to remain in
hospital were also at increased risk for schizophrenia. There were too few
cases of emergency Caesarean sections, placental abruption and cord prolapse
to perform meaningful analysis for these factors. Foetal heart rate <100 or
>160 b.p.m. was not associated with increased risk, nor were the weaker
indicators (breech and foot presentation, labour lasting more than 12 hours
and instrumental delivery).
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Odds ratios for schizophrenia in relation to other obstetric risk
factors
The obstetric records also provided data on jaundice at birth, although the
number of subjects for whom bilirubin measurements were thought necessary was
small (n=140). A bilirubin measurement of 15 mg% or more, in
comparison to having no record of jaundice, was demonstrated to be associated
with an increased risk of schizophrenia (OR 2.1; 95% CI 1.1-3.7). After
adjustments for confounders and other birth and pregnancy variables (as in the
last column of Table 3) this
point estimate was unchanged (OR 2.0; 95% CI 0.8-5.4), although no longer
statistically significant.
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Adjusted odds ratios for schizophrenia
Table 3 presents the
adjusted odds ratios for those complications which were demonstrated to have
an odds ratio for schizophrenia >1.5 or <0.7 from Tables
1 and
2. Adjusting either separately
or simultaneously for maternal history of psychotic illness, maternal age,
parity, socio-economic classification, civil status and attendance at
antenatal care did not substantially alter the odds ratios for most of the
obstetric complications listed. However, after adjusting for these possible
confounding variables, the odds ratio for schizophrenia in relation to signs
of asphyxia at birth was increased to 4.5 (95% CI 2.2-9.5).
Since several of the complications are associated with each other, the odds ratio for schizophrenia in relation to any one obstetric complication was also further adjusted separately for every other complication. The adjustments reported in Table 3 simultaneously take into account each of the remaining six complications listed. The odds ratio for schizophrenia in relation to any signs of asphyxia was 4.4 (95% CI 1.9-10.3) after adjusting for other complications. If the relationship with asphyxia was causal, the population-attributable fraction would be 7.7% (Rothman, 1986). The strengths of associations between schizophrenia and all other complications were reduced and no longer statistically significant after these adjustments.
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DISCUSSION |
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Our results are in accordance with previous findings that foetal distress (O'Callaghan et al, 1992), high scores on risk of asphyxia scale (Günther-Genta et al, 1994) and use of resuscitation (Geddes et al, 1999), often related to low Apgar scores, are associated with an increased risk of schizophrenia. In three population-based studies (Jones et al, 1998; Dalman et al, 1999; Hultman et al, 1999) there was a trend towards increased frequency of low Apgar scores among infants who later developed schizophrenia, although the association was not statistically significant. Jones et al (1998) did not adjust for other complications of pregnancy and birth, although the unadjusted results indicated associations with birth factors that are consistent with our data. The two Swedish studies (Dalman et al, 1999; Hultman et al, 1999) did not adjust for socio-economic status, which appeared to increase the association with asphyxia in our study. Another reason for the discrepancy between these two studies and our present one may be that their investigations were restricted to cases with onset before 23 years of age, since aetiological mechanisms might differ between different ages of onset. One further difference was that in our study asphyxia was rated by paediatricians and based on actual birth records, rather than relying upon register data from a large number of sources.
There was no evidence of any independent association between continuous measures of foetal size, including foetal length, head circumference, ponderal index and foetal weight, even after adjustments for gestational age. These measures have been widely interpreted as indicators of foetal development, including foetal brain development, and of a satisfactory intrauterine environment. These indices may be of no relevance in this context or too blunt.
A weak association was also found between jaundice, defined as hyperbilirubinaemia (>15 mg%), and subsequent schizophrenia. This has not been found in the majority of studies, but has previously been described (Hollister et al, 1996; Dalman & Cullberg, 1999). In the present study we did not rely on a diagnosis of jaundice in the birth records but made use of serum bilirubin levels collected at the time, which may explain our finding.
Strengths of the study
The study was large, and identified people with schizophrenia from a
population-based register, hence it was relatively free from selection bias.
The obstetric information was collected at birth and measured without recall
bias in relation to casecontrol status. We were able to ensure that
controls were resident in Stockholm at the time that the cases were
identified, thus further reducing any possibility of selection bias. Finally,
we were able to adjust for a number of confounding factors. By matching for
hospital of birth, we could take account of any hospital variation in coding
the complications. There is also a geographical variation in rates of birth
complications and schizophrenia (Ericson
et al, 1993b;
Mortensen et al,
1999), so we also matched for parish of birth. Finally, we also
adjusted for attendance at antenatal care, social class at birth (SEI
classification and civil status) and maternal psychotic illness, which are
potential confounders.
Limitations of the study
There may be some confounding factors on which we have no data: for
example, maternal substance misuse. We relied upon clinical diagnosis of
schizophrenia, although the validity of diagnosis in Sweden is high, with a
sensitivity of 85% in one study
(Kristjansson et al,
1987). Signs of asphyxia were assessed by clinicians from case
records rather than more directly recorded at time of birth. Nevertheless,
this assessment was blind to casecontrol status and was shown to be
reliable. Any random misclassification should have reduced the association.
The Apgar score itself is an imperfect measure of asphyxia and the resulting
state of hypoxia (Sykes et al,
1982; Silverman et
al, 1985), and for that reason we restricted the
classification to slight and moderate/severe signs of asphyxia. Despite the
large size of the sample, some of the complications we studied were uncommon
and the confidence intervals relatively broad. In particular, our results are
compatible with important associations between schizophrenia and
pre-eclampsia, low birth weight, hyperbilirubinaemia and prematurity.
Possible mechanisms
Our results support a relationship between hypoxia at birth and
schizophrenia, but some of the indicators of foetal disturbances (for example,
pre-eclampsia and prematurity) could not be dismissed as risk factors for
schizophrenia. It is difficult to deduce causal mechanisms from complications
of birth and pregnancy. Disorders of pregnancy, such as pre-eclampsia, could
reduce the supply of nutrients, including glucose and oxygen (intra-uterine
hypoxia), which would interfere with brain development
(Dobbing, 1979). In contrast,
an infant who has developed normally may experience relatively short-term
insult around the time of birth because of hypoxia. Hypoxic brain damage is
particularly seen in the brain-stem nuclei, hippocampus and cortex
(Volpe, 1995) and is thought
to be caused by acidosis and waste products, including amino acids and free
radicals (Kjellmer & Hagberg,
1994; Volpe,
1995). N-methyl-D-aspartate receptors (NMDA receptors)
are considered to play a key role (Volpe,
1995). Reduced volume of the hippocampus has recently been
described in schizophrenia patients with a history of obstetric complications
(Stefanis et al,
1999). Greater understanding of the effect of hypoxia on brain
development and adult brain function will probably help us to understand more
about the pathogenesis of schizophrenia.
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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 June 22, 1999. Revision received January 27, 2000. Accepted for publication January 27, 2000.
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