ORIGINAL ARTICLE

Obstetric Complications and the Risk

of Schizophrenia
A Longitudinal Study of a National Birth Cohort
Christina Dalman, MD; Peter Allebeck, MD, PhD; Johan Cullberg, MD; Charlotta Grunewald, MD, PhD; Max Köster

Background: Numerous epidemiological studies found
an increased risk of schizophrenia among persons ex-
posed to various obstetric complications. The underly-
ing mechansims are unknown.
Objective: To study specific risk factors, as well as sets
of risk factors, representing 3 different etiologic mecha-
nisms: (1) malnutrition during fetal life; (2) extreme pre-
maturity; and (3) hypoxia or ischemia.
Methods: In this longitudinal cohort study, informa-
tion in the National Birth Register was linked to the Na-
tional Inpatient Register. We followed up 507 516 chil-
dren born between 1973 and 1977 with regard to a
diagnosis of schizophrenia between 1987 and 1995 (238
cases). By record linkage, we also had access to data on
psychiatric illness in the mother. Occurrence of schizo-
phrenia was measured by the Mantel-Haenszel test and
logistic regression.
Results: A number of specific risk factors were associ-
ated with an increased risk of schizophrenia. The rela-
tive risk (95% confidence interval) for preeclampsia was
2.5 (1.4-4.5); vacuum extraction, 1.7 (1.1-2.6); and mal-
formations, 2.4 (1.2-5.1). In logistic regression models,
we found that indicators of all 3 etiologic mechanisms
were associated with increased point estimates of schizo-
phrenia, although at lower risk levels. Preeclampsia, an
indicator of fetal malnutrition, was the only risk factor
with statistically significant increased risk after control
for all potentially confounding factors.
Conclusion: This study supports the theory of an asso-
ciation between obstetric complications and schizophre-
nia. Although preeclampsia was the strongest indi-
vidual risk factor, there was evidence of increased risk
associated with all 3 etiologic mechanisms.
Arch Gen Psychiatry. 1999;56:234-240

From the Stockholm County
Child and Adolescent Public
Health Unit (Dr Dalman) and
the Department of Obstetrics
and Gynecology
(Dr Grunewald), Huddinge
University Hospital; the Center
for Psychosis Research, South
Stockholm Health Authority
(Dr Cullberg); and the Center
for Epidemiology, National
Board of Health and Welfare
(Mr Köster), Stockholm,
Sweden; and the Department of
Social Medicine, Vasa Hospital,
University of Gothenburg
(Dr Allebeck), Gothenburg,
Sweden.
T
HE ORIGIN of schizophre-
nia is largely unknown. A
vulnerability originating
from disturbances in the
central nervous system
(CNS) during the embryonal, fetal, or
neonatal period may possibly explain
some of the reason for the occurrence of
schizophrenia.1
Numerous epidemiological studies
have been published on the association be-
tween obstetric complications and schizo-
phrenia. In a meta-analysis2 of 18 stud-
ies, an overall odds ratio of 2.03 (95%
confidence interval [CI], 1.6-2.4) was
found for schizophrenia following obstet-
ric complications of any kind. Interest-
ingly, the only 2 historical cohort stud-
ies 3,4 in that analysis failed to find a
significant association. However, the num-
ber of schizophrenic or psychotic pa-
tients was small in those studies.
Many studies have used the sum-
mary scale of obstetric complications by
Lewis et al,5 which is unspecific and thus
gives little clue to the underlying cause. Mc-
Neil et al6 showed that the kind of scale used
has consequences for the results obtained,
with higher risk estimates if a weighted scale
is used.7
Several studies found 1 or 2 (rarely
3) significant risk factors that are seldom
confirmed in other studies. Suggested risk
factors are preeclampsia,8-10 small head cir-
cumference,11,12 low birth weight,13-17 Rh
incompatibility,18 fetal distress,19 body
weight heavy for length (weight/length, $1
SD),20 and abnormal presentations.21-23
Most of these studies are relatively small,
including fewer than 100 patients, and,
thus, the results are not precise regard-
ing risk estimates. In some studies,13,24 ma-
ternal recall has been used instead of case
records, which implies an information
bias risk.
Other types of evidence for prenatal
risk factors for schizophrenia are the in-
creased occurrence of minor physical
anomalies (for example, epicanthal fold
and syndactylia) in individuals with

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 MATERIALS AND METHODS
BIRTH RECORDS
By using the National Birth Register,41,42 we obtained data
on obstetric complications in all Swedish children born be-
tween 1973 and 1977 (507 516 children). The National Birth
Register has been in operation since 1973 and contains in-
formation on all children born in Sweden, around 100 000
every year. Data are based on forms completed by mid-
wives and the pediatricians in charge and sent to the Na-
tional Board of Health and Welfare with information on risk
factors in pregnancy, events during delivery, anthropomet-
ric data on the child, and conditions present in the neona-
tal period. Diagnoses were given according to Interna-
tional Classification of Diseases, Eighth Revision (ICD-8).43
The proportion of missing data is around 1%.
Anthropometric data and malformations are classified
in the register. Small for gestational age and large for gesta-
tional age are classified according to a method used by the
National Board of Health and Welfare based on birth weight
in relation to gestational age (based on information regard-
ing the last menstruation). Cutoff points for these and other
anthropometric measures are defined according to Maršál
et al44 (standard curves ± 2 SDs based on mean measure-
ments of 759 ultrasonic estimates of Scandinavian chil-
dren). Malformations are classified into types 1 and 2 in the
register. Type 1 includes all registered malformations ex-
cept preauricular appendix, retractile testis, hydrocele tes-
tis, hip-joint luxation, and nevus. Type 2 includes malfor-
mations that are known to be more accurately and completely
recorded than those in type 1. These are malformations in
the CNS, lungs, and intestinal canal, serious malformations
of the heart, ears, or eyes, choanal atresia, facial clefts, esoph-
ageal atresia, intersexuality, and hypospadias.
PSYCHIATRIC RECORDS
Psychiatric Illness in Offspring
By means of the unique personal identity number, the co-
hort was followed up in the National Inpatient Register that
covers between 97% and 98% of all episodes of inpatient
care. They were given clinical diagnoses according to the
Nordic version of International Classification of Diseases,
schizophrenia25,26 and findings from the Dutch Famine
Study by Susser et al,27 in which malnutrition was found
to be related to neurodevelopmental disturbances in-
cluding schizophrenia.
Men have an earlier onset of illness, lower premor-
bid functional level, and poorer outcome than wom-
en.28,29 Thus, an interesting question is whether there is
a sex difference in the risk of schizophrenia following ob-
stetric complications; the results of previous studies are
inconsistent in this respect.11,30-33 Another question that
has been raised is whether obstetric complications are
more common in cases with an early age of onset.8,22,30
Central nervous system disturbances can arise through
several mechanisms. In this study, we considered the fol-
lowing 3 possible etiologic mechanisms that might ex-
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Ninth Revision (ICD-9)45 during 1987 to 1996. We re-
corded all admissions with a diagnosis of schizophrenia
(ICD-9 code 295) between 1987 and 1995, which in-
cluded 238 persons (99 women and 139 men).
Psychiatric Illness in Mothers
Data on the mother in the birth records enabled us to search
for data on psychiatric care in the National Inpatient Reg-
ister from 1973 onward. We collected data on psychotic
illness (codes 295-299 according to ICD-8 until 1986; codes
295-298 according to ICD-9 from 1987) in the mothers for
the period from 1973 to 1995.
CLASSIFICATION OF ETIOLOGIC MECHANISMS
Variables reflecting the 3 types of etiologic mechanisms de-
scribed herein were grouped to identify states reflecting the
following:
1. Fetal malnutrition: preeclampsia during preg-
nancy (ICD-8 code 637.03-637.99), small for gestational
age, ponderal index less than 0.2, which is a measurement
of leanness (weight/length3).
2. Extreme prematurity: delivery before the onset of
week 33 (based on information about last menstruation).
3. Hypoxia or ischemia around birth: cesarean sec-
tion and vacuum extraction in combination with a diag-
nosis of threatening fetal distress or intrauterine anoxia
(ICD-8 codes 776.30-776.40), breech delivery (ICD-8 codes
650.6-662.6), placental abruption (ICD-8 code 651.4), an
Apgar score of 0 to 6 at 1 and 5 minutes, respectively, ac-
cording to a definition of neonatal distress.46
DATA ANALYSIS
We calculated relative risk (RR) estimates with the Mantel-
Haenszel test and 95% CIs.47 Logistic regression analysis
was used to take into account other obstetric complica-
tions as confounders for each other. By logistic regression
analyses, we estimated odds ratios (ORs) for particular vari-
ables, controlling for the other variables included in each
hypothesized etiologic mechanism. We also used logistic
regression analysis to study the impact of each mecha-
nism while controlling for the other 2 hypothesized mecha-
nisms. Finally, we constructed a logistic regression model
with the most important variables from all 3 mechanisms.
plain the association between obstetric complications and
schizophrenia. In particular, we wanted to distinguish these
mechanisms since they require different preventive ap-
proaches and also correlate, with an overlap, to different
types of neuropathologic characteristics.34
1. Reduction in the supply of nutrients, such as oxy-
gen, iodine, glucose, and iron, to the fetus may lead to
impaired development of the CNS35 as well as intrauter-
ine growth restriction. In these cases, the lack of me-
tabolites and states of hypoxia are repeated over time and
the basal ganglia is at particular risk of being dam-
aged.34 A more narrow definition of this state would be
chronic fetal hypoxia.4
2. Prematurity increases the risk for intracranial
hemorrhages,36 periventricular leukomalacia,34 and also
 Table 1. Relative Risk (RR) for Schizophrenia in Relation to Selected Risk Factors*
No. of
Variable Exposed Cases
Male 139
Birth hospital category
Regional (highly specialized) 56
County (main hospital) 122
Others 60
Psychotic illness of mother 19
Mother’s marital status
Unmarried 85
Unknown 19
Mother’s age, y
#18 14
19-39 220
$40 4 2.0 (0.8-5.3)
*Ellipses indicate not applicable.
for interstitial respiratory distress syndrome and infec-
tions,37 which may also cause brain damage.
3. Hypoxia or ischemia due to complications dur-
ing delivery could result in brain damage, especially in
the regions of the hippocampus and cortex.34
Although all these etiologic mechanisms are plau-
sible, there is also an association between a psychotic dis-
order in the mother and an increased risk of obstetric com-
plications (shown by Sacker et al38 and also in our data).
Therefore, the occurrence of psychotic disorders in moth-
ers should be taken into account.
The possibility of linking the Swedish National
Birth Register with the National Inpatient Register39,40
enabled us to address several of the issues mentioned
herein. Data on obstetric complications were available
for all Swedish children born between 1973 and 1977
(507 516 children). The children were observed with
regard to diagnosis of schizophrenia to a maximum
age of 22 years. Furthermore, the birth records could
be linked to data on psychiatric illness in the mother,
which enabled us to control for maternal psychotic
illness in the analyses. We wanted to study specific
risk factors as well as sets of risk factors that were
indicators of the 3 etiologic mechanisms mentioned
herein.
RESULTS
The RRs associated with the major risk factors are pre-
sented in Table 1. These factors are controlled for in
the analyses presented below. There was an 8-fold in-
creased risk of schizophrenia among offspring to moth-
ers who had had a psychotic disorder (including schizo-
phrenia) during their adult life. The risk of obstetric
complications, defined as any of the complications in-
cluded as indicators of the 3 mechanisms, was also in-
creased (RR, 1.3 [95% CI, 1.2-1.3]) in this group of moth-
ers. Children born to mothers younger than 19 or older
than 39 years had an increased risk of schizophrenia, al-
though this risk was not statistically significant, except
for males born to mothers older than 39 years (RR, 3.5
[95% CI, 1.4-8.9]) and females born to young mothers
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RR (95% Confidence Interval)
All Female Male
1.3 (1.0-1.7) ... ...
1.1 (0.8-1.6) 1.0 (0.5-1.8) 1.2 (0.8-2.0)
1.0 (0.7-1.4) 1.3 (0.8-2.0) 0.9 (0.6-1.4)
... ... ...
7.8 (5.2-11.6) 4.8 (2.1-10.9) 9.9 (6.3-15.6)
1.3 (1.0-1.8) 1.2 (0.7-1.9) 1.4 (1.0-2.1)
2.2 (1.2-3.8) 2.8 (1.1-6.8) 1.8 (0.9-3.7)
1.4 (0.8-2.5) 2.1 (1.0-4.5) 1.0 (0.4-2.2)
0 (0) 3.5 (1.4-8.9)
(RR, 2.3 [95% CI, 1.1-4.7]). The risk was also in-
creased, although it was not statistically significant, if the
mother was unmarried or if her marital status was un-
known at the time of delivery.
Table 2 shows the RRs of schizophrenia among chil-
dren born with various obstetric complications. We found
that several risk factors during pregnancy, as well as dur-
ing the time around delivery, significantly increased the
risk of schizophrenia: preeclampsia, gestational age
younger than 33 weeks, inertia of labor, vacuum extrac-
tion, a ponderal index less than 20, respiratory illness,
and type 2 malformations. Adjustments for the vari-
ables presented in Table 1 did not dramatically alter the
results. There was a clear difference between the sexes.
Being the fourth child and small for gestational age were
associated with a significantly increased risk of schizo-
phrenia in males, while a birth weight of less than 1500
g significantly increased the risk of schizophrenia among
females.
In Table 3, we analyzed by logistic regression the
impact of the variables included in each etiologic group.
Among the hypoxia or ischemia variables, low Apgar
scores at 5 minutes and vacuum extraction or cesarean
section on indication of fetal distress were associated with
the highest risks, although these risks were not statisti-
cally significant. Among the indicators of malnutrition,
preeclampsia and low ponderal index (leanness) were the
strongest risk factors. The third group consisted only of
1 factor, extreme prematurity, which was associated with
a significantly increased risk. The separate ORs for each
mechanism, without adjustments for the 2 other mecha-
nisms, are also shown in Table 3.
In the next set of regression models, we studied the
impact of each etiologic mechanism adjusted for the other
2 mechanisms. The results are shown at the bottom line
of the specific mechanisms in Table 3. There is an in-
creased risk, although the risk was not statistically sig-
nificant, among those who had been exposed to indica-
tors of fetal malnutrition (a total of 24 individuals with
schizophrenia) and a gestational age younger than 33
weeks (5 individuals). In the hypoxia or ischemia group,
the risk estimate was lower.
 Table 2. Relative Risk (RR) for Schizophrenia Associated With Specific Risk Factors*

RR (95% Confidence Interval)

No. of Exposed
Variable Cases All (Crude Data) All† Female‡ Male‡
Born between January and April 95 1.2 (0.9-1.5) 1.2 (0.8-1.4) 1.2 (0.8-1.7) 1.2 (0.8-1.7)
Born in a town with fewer than 43 1.3 (0.9-1.9) 1.3 (0.9-1.8) 1.4 (0.9-2.4) 1.2 (0.7-1.9)
250 000 inhabitants
Pregnancy
Maternal history of prior stillbirth 9 1.7 (0.9-3.3) 1.6 (0.8-3.2) 2.8 (1.3-6.2) 0.9 (. . .)
or death of child during first
week of life
Parity
1 121 1.3 (1.0-1.8) 1.3 (1.0-1.6) 1.1 (0.7-1.7) 1.4 (1.0-2.0)
2-3 100 ... ... ... ...
$4 17 1.7 (1.0-2.8) 1.5 (0.9-2.6) 0.5 (0.1-1.9) 2.2 (1.2-4.1)
Twin birth 5 1.3 (0.5-3.2) 1.3 (0.5-3.1) 0.6 (0.1-4.3) 1.8 (0.7-4.8)
Preeclampsia 11 2.5 (1.3-4.5) 2.5 (1.4-4.5) 1.1 (0.3-4.6) 3.5 (1.8-6.6)
Bleeding during pregnancy 7 1.8 (0.9-3.9) 2.0 (1.0-4.2) 1.4 (0.3-5.7) 2.4 (1.0-5.7)
Threatening premature delivery 6 2.0 (0.9-4.4) 2.3 (1.0-5.0) 2.8 (0.9-8.6) 1.8 (0.6-5.7)
Urinary tract infection 3 0.9 (0.3-2.8) 0.8 (0.3-2.5) 2.2 (0.7-6.6) 0 (0)
Gestational age, wk (based on
information on last
menstruation)
23-32 5 3.4 (1.4-8.2) 2.7 (1.0-7.0) 3.3 (0.8-12.7) 2.2 (0.6-8.8)
33-36 11 1.2 (0.6-2.2) 1.1 (0.6-2.0) 0.5 (0.1-2.1) 1.5 (0.7-2.9)
37-42 215 ... ... ... ...
$43 3 0.4 (0.1-1.3) 0.4 (0.1-1.2) 0.3 (0.0-1.9) 0.5 (0.1-1.8)
Delivery
Other than vertex 21 0.8 (0.5-1.2) 0.8 (0.5-1.2) 0.8 (0.4-1.5) 0.7 (0.4-1.3)
Breech 5 0.8 (0.3-1.9) 0.8 (0.3-1.8) 0.6 (0.2-2.5) 0.9 (0.3-2.7)
Prolonged 20 1.5 (1.0-2.4) 1.6 (1.0-2.5) 1.4 (0.6-3.1) 1.7 (1.0-2.9)
Uterine inertia 17 2.3 (1.4-3.7) 2.4 (1.5-3.9) 1.6 (0.6-4.5) 2.8 (1.6-4.9)
Cesarean section 15 0.8 (0.5-1.4) 0.8 (0.5-1.4) 0.9 (0.4-2.0) 0.8 (0.4-1.6)
Cesarean section for fetal distress 2 2.7 (0.6-10.7) 2.7 (0.7-10.3) 3.9 (0.6-24.3) 2.1 (0.3-14.25)
Vacuum extraction 21 1.7 (1.1-2.7) 1.7 (1.1-2.6) 1.2 (0.5-3.1) 1.9 (1.1-3.2)
Vacuum extraction for fetal distress 2 1.7 (0.4-6.8) 1.5 (0.3-7.2) 0 (0) 2.3 (0.5-10.9)
Use of forceps 0 0 (0) 0 (0) 0 (0) 0 (0)
Placental abruption 1 1.3 (0.2-9.4) 1.1 (0.1-9.1) 0 (0) 1.6 (0.2-13.9)
Offspring
Apgar score
At 1 min, 0-6/7-10 12/222 1.2 (0.7-2.2) 1.2 (0.6-2.1) 0.8 (0.3-2.5) 1.4 (0.7-2.7)
At 5 min, 0-6/7-10 6/228 2.2 (1.0-5.0) 1.9 (0.9-4.4) 3.1 (0.9-10.9) 1.4 (0.5-4.2)
Length, cm
,48 41 1.0 (0.7-1.4) 1.0 (0.7-1.4) 0.8 (0.5-1.4) 1.2 (0.7-1.9)
49-54 186 ... ... ... ...
$55 9 1.3 (0.7-2.6) 1.3 (0.6-2.4) 2.1 (0.7-6.3) 1.0 (0.5-2.4)
Birth weight, g
#1499 2 3.0 (0.7-12.0) 2.9 (0.8-11.4) 6.0 (1.7-21.4) 0 (0)
1500-2499 14 1.7 (1.0-3.0) 1.5 (0.9-2.7) 0.8 (0.2-2.5) 2.2 (1.1-4.1)
2500-4499 217 ... ... ... ...
$4500 5 0.8 (0.3-1.9) 0.7 (0.3-1.8) 0.6 (0.1-4.2) 0.8 (0.3-2.2)
Ponderal index ,20 3 3.4 (1.1-10.5) 3.4 (1.1-10.1) 2.5 (0.4-16.9) 4.1 (1.1-15.5)
(weight/length3)
Large for gestational age 5 0.8 (0.4-2.1) 0.8 (0.3-2.1) 0.4 (0.1-3.1) 1.1 (0.4-3.0)
Small for gestational age 13 1.3 (0.7-2.2) 1.2 (0.7-2.1) 0.4 (0.1-1.6) 1.9 (1.1-3.6)
Head circumference, cm
#31 11 1.6 (0.9-2.9) 1.4 (0.8-2.7) 0.8 (0.3-2.5) 2.1 (1.0-4.5)
32-37 215 ... ... ... ...
$38 8 1.4 (0.7-2.8) 1.3 (0.6-2.7) 0.8 (0.1-6.0) 1.4 (0.6-3.1)
Respiratory illness 21 1.7 (1.1-2.6) 1.5 (1.0-2.4) 1.6 (0.7-3.3) 1.5 (0.8-2.7)
Neonatal hyperbilirubinemia 15 1.1 (0.7-1.8) 1.1 (0.6-1.8) 1.3 (0.6-2.9) 1.0 (0.5-1.9)
Malformation
Type 1 8 1.7 (0.9-3.5) 1.7 (0.9-3.4) 1.8 (0.6-5.7) 1.7 (0.7-4.0)
Type 2 7 2.5 (1.2-5.2) 2.4 (1.2-5.1) 2.3 (0.6-9.0) 2.5 (1.1-5.9)

*Controlling for confounders listed in Table 1. Ellipses indicate not applicable. See “Materials and Methods” for definition of type 1 and type 2 malformations.
†Adjusted for psychotic illness in mother, mother’s age and marital status, the child’s year of birth, birth hospital, and sex.
‡Adjusted for psychotic illness in mother, mother’s age and marital status, the child’s year of birth, and birth hospital.

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 Table 3. Odds Ratios (ORs) for Schizophrenia: The Impact of Indicators Included in Each Etiologic Mechanism and
the Mechanisms in Relation to Each Other Using Logistic Regression Models*

OR (95% Confidence Interval)

Indicator No. of Exposed Cases All† Female‡ Male

Hypoxia/Ischemia
Placental abruption 1 1.1 (0.2-8.2) ... 1.8 (0.2-13.4)
Cesarean section for fetal distress 2 2.6 (0.6-10.9) 3.8 (0.5-28.9) 1.9 (0.3-14.1)
Vacuum extraction for fetal distress 2 1.6 (0.4-6.6) ... 2.3 (0.6-9.4)
Apgar score
At 1 min, 0-6 12 1.0 (0.5-1.9) 0.5 (0.1-1.9) 1.3 (0.6-2.8)
At 5 min, 0-6 6 2.0 (0.8-5.2) 3.9 (1.0-14.8) 1.3 (0.4-4.7)
Breech delivery 5 0.8 (0.3-1.9) 0.7 (0.2-2.8) 0.9 (0.3-2.7)
Exposed to any of the indicators listed above 22 1.3 (0.8-2.0) 1.1 (0.5-2.3) 1.4 (0.8-2.5)
Adjusted for the 2 other mechanisms 22 (8 female, 14 male) 1.1 (0.7-1.7) 0.9 (0.4-2.0) 1.2 (0.7-2.1)
Malnutrition
Preeclampsia 11 2.3 (1.3-4.3) 1.2 (0.3-4.7) 3.0 (1.5-8.6)
Small for gestational age 13 1.1 (0.6-1.9) 0.4 (0.1-1.6) 1.6 (0.9-3.1)
Ponderal index ,20 (weight/length3) 3 3.0 (0.9-9.7) 3.7 (0.5-27.8) 2.7 (0.6-11.5)
Exposed to any of the indicators listed above 24 1.6 (1.1-2.5) 0.8 (0.3-1.9) 2.3 (1.4-3.8)
Adjusted for the 2 other mechanisms 24 (5 female, 19 male) 1.5 (1.0-2.3) 0.7 (0.3-1.8) 2.1 (1.3-3.4)
Prematurity
Gestational age ,33 wk 5 3.1 (1.3-7.6) 5.0 (1.6-16.0) 2.0 (0.5-8.0)
Adjusted for the 2 other mechanisms 5 (3 female, 2 male) 2.7 (1.0-7.3) 4.3 (1.0-18.1) 1.9 (0.5-8.0)

*Ellipses indicate not applicable.

†Adjusted for psychotic illness in mother, mother’s age and marital status, the child’s year of birth, and birth hospital.
‡Adjusted for psychotic illness in mother, mother’s age and marital status, the child’s year of birth, birth hospital, and sex.

Table 4. Odds Ratios (ORs) for Schizophrenia: Comparison Between the Strongest Risk Factors in a Logistic Regression Model

All Female Male

No. of OR* (95% No. of OR† (95% No. of OR† (95%

Factor
Cesarean section or vacuum
extraction for fetal distress
Apgar score at 5 min, 0-6
Preeclampsia
Ponderal index ,20
(weight/length3)
Gestational age ,33 wk
Exposed Cases Confidence Interval) Exposed Cases Confidence Interval)
Hypoxia/Ischemia
4 2.1 (0.8-5.6) 1 1.6 (0.2-11.3)
6 1.5 (0.6-3.6) 3 1.6 (0.4-6.6)
Malnutrition
11 2.1 (1.1-4.1) 2 1.1 (0.3-4.4)
3 2.5 (0.8-8.3) 1 1.8 (0.3-14.8)
Prematurity
5 2.5 (0.9-7.2) 3 3.6 (0.8-16.1)
Exposed Cases Confidence Interval)
3 2.3 (0.7-7.4)
3 1.4 (0.4-4.6)
9 2.8 (1.4-5.8)
2 3.0 (0.7-13.1)
2 1.9 (0.5-8.4)

*Adjusted for psychotic illness in mother, mother’s age and marital status, the child’s year of birth, and birth hospital.
†Adjusted for psychotic illness in mother, mother’s age and marital status, the child’s year of birth, birth hospital, and sex.

By comparing the unadjusted and the adjusted ORs
for each of the 3 mechanisms in Table 3, we were able to
study the effects of confounding between the different
mechanisms. The risk estimate for prematurity was re-
duced, which could be interpreted as if some of the risk
was explained by factors of malnutrition during preg-
nancy and hypoxia or ischemia at birth. The ORs of mal-
nutrition and hypoxia or ischemia were less reduced in
this procedure. Notably, the risks were still increased,
which indicates independent effects.
The risks were unevenly distributed between the
sexes (Table 3). Indicators of malnutrition were associ-
ated with higher risk in males (OR, 2.1 [95% CI, 1.3-
3.4]), while the females had increased risk following pre-
maturity (OR, 4.3 [95% CI, 1.0-18.1]). Proportionally
more males were exposed to the obstetric complications
(Table 3).
In a final model, the strongest risk factors from each
etiologic group in Table 3 were entered in a logistic re-
gression model to assess the separate effects of the most
important risk factors of the 3 etiologic mechanisms
(Table 4). The risk associated with a low Apgar score,
low ponderal index, and prematurity was reduced, es-
pecially among the females, compared with the findings
in Table 3. However, the point estimates were increased
for complications of all 3 mechanisms, although only pre-
eclampsia remained significantly associated with an in-
creased risk of schizophrenia.

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 COMMENT
In this population-based cohort study, controlling for psy-
chotic illness in mothers and other known risk factors,
we found that several complications during pregnancy
and delivery were associated with an increased risk of
schizophrenia. A possible explanation of the fact that we
found more obstetric risk factors than those found in pre-
vious studies is that our study included a relatively large
and homogeneous group of patients with an early age at
onset of schizophrenia. Two previous studies8,22 fo-
cused on patients with early age at onset and suggested
that obstetric complications might be a stronger risk fac-
tor in this group. This finding has been supported by other
authors.19,29,31,48
When reviewing previous findings regarding ob-
stetric risk factors, the patterns of causes are difficult to
discern. Attempts have been made to understand the un-
derlying mechanisms. McNeil et al6 found an increased
risk when using a weighted scale7 compared with other
scales.5,23 In a cohort study,4 there was no association with
specific subcategories of exposure (chronic fetal hy-
poxia, prematurity, or other complications), but the num-
ber of patients with psychoses was small.
To understand more about the underlying mecha-
nisms, we grouped possible risk factors based on previ-
ous clinical knowledge and studies of the disease. This re-
sulted in 3 sets of risk factors: malnutrition during fetal
life, extreme prematurity, and hypoxia or ischemia around
birth. The etiologic mechanisms have some features in com-
mon but still seem to be independent of each other. Hy-
poxia is a factor in common for the mechanism of mal-
nutrition during fetal life as well as hypoxia or ischemia
around birth. Nevertheless, we made this classification
based on clinical practice and the knowledge that brain
damage following chronic hypoxia during fetal life dif-
fers from that following an acute episode of hypoxia at birth.
Prematurity is associated with a number of different con-
ditions, such as intraventricular hemorrhages, periven-
tricular leukomalacia, interstitial respiratory distress syn-
drome, infections, as well as hypoxia or ischemia around
birth and fetal malnutrition. Despite this, the results of the
logistic regression analysis favor our hypothesis that all 3
subcategories represent different possible mechanisms al-
though some features are mutual.
We tried to be strict in our selection of the indica-
tors to avoid unnecessary dilution of the results. Never-
theless, the factors are more or less good indicators of
the conditions they are defined as representing. For ex-
ample, breech delivery does not automatically result in
hypoxia or ischemia. The term small for gestational age
used herein as an indicator of malnutrition is only a de-
scription independent of the cause, which could be ge-
netic influence, chromosomal abbreviations, or infec-
tions, although it is often caused by malnutrition.
Preeclampsia was found to be the strongest risk fac-
tor for schizophrenia, which has been described in pre-
vious studies.8-10 Geddes et al49 concluded in their meta-
analysis that an association is found only when using birth
records instead of maternal recall. In our study, data were
based on ICD-8 and ICD-9 codes from the birth records.
A possible cause for increased risk of schizophrenia might
ARCH GEN PSYCHIATRY/ VOL 56, MAR 1999
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be that in preeclampsia there is an abnormal fetal blood
flow, which is associated with reduced supply of nutri-
tion to the fetus.41,50 Interestingly, Ley51 found an in-
creased occurrence of minor neurological dysfunctions
and intellectual impairment at 7 years of age following
abnormal blood flow during fetal life.
The risk of schizophrenia following obstetric com-
plications was higher in males than in females. This is
in accordance with findings by some authors9,27-32 but not
with others.8,11,22,33 The difference between the sexes is
perhaps more pronounced for cases with an early age at
onset of schizophrenia.
Because this longitudinal study included a national
sample of mothers and their offspring, in other words, it
was a population-based study, the risk for selection bias
was reduced. The information is based on case records
that are consecutively collected in the National Birth Reg-
ister. Any misclassification should therefore be ran-
domly distributed in the study. The register has been vali-
dated regarding errors of recording41 and proved to be
of acceptable quality, except for information about meth-
ods of anesthesia during delivery and metabolic testing
of the newborn.
Concerning potential confounders, we were able to
adjust for mother’s psychotic illness during her adult life
(1973-1995) by linkage with the National Inpatient Reg-
ister. To our knowledge, this has not been possible in other
studies. The size of the hospital and age of the mother
were controlled for, and they were also proxy factors for
being a citizen of a large town at birth and parity, respec-
tively, which is why we were able to omit these sus-
pected confounders from the analysis. We did not have
specific information on social class, which is a possible
confounder in studies on obstetric complications. For ex-
ample, are low birth weight and young gestational age
more common in lower social classes?52 We collected data
on marital status, which, in previous studies of the Na-
tional Birth Register, proved to be a good indicator of so-
cial position.42
Our conclusion from the findings of this national
cohort study including cases of schizophrenia with an
early age at onset supports the theory that some of the
occurrence of schizophrenia could be associated with a
vulnerability originating from obstetric complications. Al-
though preeclampsia, which is a cause of fetal malnutri-
tion, was the strongest individual risk factor, there was
evidence of increased risk associated with the other 2
mechanisms that were studied: extreme prematurity and
hypoxia or ischemia at birth. The increased risks asso-
ciated with the different etiologic mechanisms re-
mained, although at lower risk levels, in the logistic mod-
els, which indicates independent effects. Thus, it seems
as if these etiologic mechanisms are acting in different
ways but may result in the same future vulnerability for
schizophrenia. One explanation could be that the differ-
ent pathways result in the same kind of damage. Schizo-
phrenia could result from many different disturbances
that may cause an altered balance in the CNS of a rather
unspecific nature. Nevertheless, knowledge of specific risk
factors for schizophrenia is a public health interest, since
at least some of the obstetric risk factors we confirmed
can potentially be prevented.
 Accepted for publication December 8, 1998.
The study was supported by grants from the Swedish
Medical Research Council and the Söderberg-Königska Foun-
dation, Stockholm, Sweden.
We thank Johan Gentz, MD, PhD, for pediatric advice
and Anthony David, FRCPsych, and Glyn Lewis, FRCPsych,
for fruitful discussions and for commenting on this article.
We also thank Bengt Haglund, PhD, for statistical advice.
Corresponding author: Christina Dalman, MD, Sö-
dra Stockholms Sjukvårdsområde, Department of Psychia-
try, Unit for Psychosis Research, PO Box 4402, S-102 68
Stockholm, Sweden (e-mail: christina.dalman@smd.sll.se).
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