A.E.
BENNETT RESEARCH AWARD
Prenatal Rubella, Premorbid Abnormalities, and
Adult Schizophrenia
Alan S. Brown, Patricia Cohen, Jill Harkavy-Friedman, Vicki Babulas,
Dolores Malaspina, Jack M. Gorman, and Ezra S. Susser
Background: Premorbid neurocognitive, neuromotor,
and behavioral function tends to be disturbed in schizo-
phrenia. We previously demonstrated that a birth cohort
clinically and serologically documented with prenatal
rubella evidenced a marked increase in risk of nonaffec-
tive psychosis. In our study, we examined whether rubella-
exposed subjects destined to develop schizophrenia and
other schizophrenia spectrum disorders (SSD), compared
with exposed control subjects, had greater impairment in
several premorbid functions.
Methods: Subjects were interviewed using a direct, com-
prehensive research assessment and diagnosed by consen-
sus. We compared the degree of IQ decline, as well as
premorbid neuromotor and behavioral dysfunction, be-
tween rubella-exposed subjects who developed schizo-
phrenia spectrum psychosis (SSP) and exposed control
subjects from the cohort. We also compared the gesta-
tional timing of rubella infection between the cases and
control subjects.
Results: This rubella-exposed birth cohort evidenced a
markedly increased risk of SSD (20.4% or 11/53). Rubel-
la-exposed SSP cases, compared with rubella-exposed
control subjects, demonstrated a decline in IQ from
childhood to adolescence, and increased premorbid neu-
romotor and behavioral abnormalities. Moreover, it ap-
pears that early gestational rubella exposure may repre-
sent a period of increased vulnerability for SSD.
Conclusions: These findings link a known prenatal expo-
sure, a deviant neurodevelopmental trajectory in childhood
and adolescence, and SSP in adulthood within the same
individuals. Biol Psychiatry 2001;49:473– 486 © 2001 So-
ciety of Biological Psychiatry
Key Words: prenatal, rubella, German measles, premor-
bid, schizophrenia, neurodevelopmental
From the Department of Psychiatry, Columbia University, College of Physicians
and Surgeons, New York State Psychiatric Institute (ASB, PC, JH-F, VB, DM,
JMG, ESS), and Joseph L. Mailman School of Public Health of Columbia
University (ESS), New York, New York.
Address reprint requests to Alan S. Brown, M.D., New York State Psychiatric
Institute, 1051 Riverside Drive, Unit #2, New York, NY 10032.
Received May 16, 2000; revised December 1, 2000; accepted December 20, 2000.
© 2001 Society of Biological Psychiatry
Introduction
A fter more than 100 years of research on schizophre-
nia, its origins have remained elusive. One of the
most intractable barriers toward unraveling the etiologies
of this devastating disorder has been the lack of a clear
model of etiopathogenesis. Within the past 10 years,
however, a compelling hypothesis with the potential to
revolutionize our theoretical approach to this illness has
gained considerable favor. Termed the neurodevelopmen-
tal hypothesis of schizophrenia, it posits that a disruption
in development of the brain creates a vulnerability to the
emergence of the disorder later in life (Waddington et al
1999).
One implication of the neurodevelopmental hypothesis
is that prenatal environmental exposures, including viral
infections, that disturb development of the fetal brain
might be important risk factors for schizophrenia (Brown
and Susser 1996; Susser et al 1999). In this article, we
employ a novel strategy to examine whether prenatal
exposure to a viral infection, the rubella virus, and
associated premorbid functional abnormalities are related
to the risk of adult schizophrenia and other schizophrenia
spectrum disorders (SSD). Important strengths of this
strategy include clinical and serologic documentation of in
utero rubella exposure, longitudinal follow-up data on
neurocognitive and other premorbid functions, and well-
diagnosed cases of schizophrenia and other SSD.
The Neurodevelopmental Hypothesis of
Schizophrenia
Evidence from several diverse areas of research has
converged to support the neurodevelopmental hypothesis
of schizophrenia. One of the strongest pieces of evidence
in support of this hypothesis derives from studies that
examined childhood neurocognition, neuromotor function,
and behavior in individuals destined to develop schizo-
phrenia. With regard to premorbid neurocognitive func-
tion, Jones et al (1994) demonstrated lower IQ, diminished
educational test scores, and increased speech problems
during childhood and adolescence among subjects who
later developed schizophrenia. David et al (1997) showed
that lower IQ scores at the time of military conscription
0006-3223/01/$20.00
PII S0006-3223(01)01068-X
474 BIOL PSYCHIATRY
2001;49:473– 486
(age 19 –20) predicted an increased risk of schizophrenia
later in adulthood. Erlenmeyer-Kimling et al (1991, 1993)
demonstrated that individuals at high genetic risk for
schizophrenia evidenced a tendency for impairment in
attention during childhood.
With respect to neuromotor function, Walker et al
(1994) found an increase in several neuromotor anomalies
during childhood, including abnormal hand posture, cho-
reoathetoid movements, hypertonicity, and hypotonicity in
preschizophrenic subjects compared with control subjects.
Jones et al (1994) found subtle delays in milestones of
motor development among subjects who were later diag-
nosed with schizophrenia.
With regard to deviant behaviors, Done et al (1994)
found greater social maladaptation, including anxiety,
hostility, and social withdrawal, at ages 7 and 11 among
individuals who later developed schizophrenia. Jones
et al (1994) also found increased anxiety in preschizo-
phrenic patients, as well as less social confidence during
adolescence and a preference for solitary play during
childhood.
Other pieces of evidence provide further support for the
neurodevelopmental hypothesis of schizophrenia. Patients
with schizophrenia appear to have an increase in the
number and severity of minor physical anomalies, subtle
malformations reflective of embryonic disturbances in
early gestation (Green et al 1989; Waddington 1993a,
1993b). Neuroimaging studies have documented several
brain abnormalities, including ventriculomegaly and di-
minished volume of the hippocampus and other medial
temporal lobe structures, among patients in their first
episode of schizophrenia (Bogerts et al 1990; DeGreef et
al 1992; Nopoulos et al 1995), suggesting that these
anomalies were present before illness onset. Cavum sep-
tum pellucidum, a brain anomaly that likely reflects in
utero disruption, also occurs at an increased rate among
patients with schizophrenia (Nopoulos et al 1997).
Although the neurodevelopmental model of schizophre-
nia cannot explain all aspects of this illness, it does
provide an important conceptual framework from which to
generate testable hypotheses on potential causal factors.
Schizophrenia certainly has a strong genetic basis, but
there has been increasing suspicion that environmental
risk factors may also play important etiopathogenic roles.
The strongest evidence for this notion is that the discor-
dance rate for schizophrenia among monozygotic co-twins
is approximately 50% (McGuffin et al 1995). Because
these twins are genetically identical, any phenotypic dif-
ferences should reflect an environmental component. The
affected members of these monozygotic twin pairs also
have greater structural and functional brain anomalies
(Suddath et al 1990; Berman et al 1992).
A.S. Brown et al
Potential Role of Prenatal Viral Infection
Thus, environmental factors operating during the prenatal
period have emerged as plausible risk factors for neuro-
developmental schizophrenia. Among the environmental
agents examined, much attention has focused on prenatal
viral infection, largely because viral insults are among the
best known and most common causes of developmental
brain disorders (Brown and Susser 1999). The vast major-
ity of these studies have attempted to test whether prenatal
exposure to influenza is associated with an increased risk
of schizophrenia. In the most common type of research
design, the risk of schizophrenia was compared between
individuals who were in utero during known influenza
epidemics and those who were unexposed. In the first of
these studies, conducted in Finland, Mednick et al (1988)
demonstrated that subjects who were in the second trimes-
ter of gestation during the 1957 influenza epidemic had a
significantly increased risk of schizophrenia. Several sub-
sequent studies modeled on that study replicated the
second trimester association (Adams et al 1993; Kunugi et
al 1995; McGrath et al 1994; O’Callaghan et al 1991),
although other investigations have not replicated these
findings (Erlenmeyer-Kimling et al 1994; Susser et al
1994; Torrey et al 1991). An additional research design
utilizes data on maternal influenza infection in individuals;
these studies did not show an association with schizophre-
nia in the offspring (Crow et al 1991; Cannon et al 1996).
These discrepant findings may be due to two limitations
(Brown and Susser 1999). First, most studies defined the
exposure using ecologic data (i.e., it was known that an
individual was in utero at the time of an influenza
epidemic but not whether influenza occurred during the
pregnancy), rather than confirming the infection in indi-
vidual pregnancies. In the studies that attempted to docu-
ment influenza infection during pregnancy, cited above,
exposure status was determined by midwife interviews of
the mother after birth (Crow et al 1991; Cannon et al
1996), instead of clinically documenting maternal influ-
enza at the time of its occurrence. This may have resulted
in nondifferential misclassification of exposure status.
Second, the diagnosis of schizophrenia in previous studies
was ascertained from case registers or clinical records,
rather than from research assessments. Although based on
contemporary data, the lack of a standardized assessment
may tend to result in diagnostic misclassification of the
outcome. Nondifferential misclassification of exposure
and outcome status may have acted to bias the findings
toward the null in some studies.
A further critique of the influenza studies is that this
virus was generally selected for study based on its rela-
tively high frequency in the population, rather than on its
biological plausibility as a risk factor for schizophrenia.
Studies on the teratogenicity of prenatal exposure to
Rubella, Premorbid Anomalies, and Schizophrenia
influenza are mixed; for instance, some have demonstrated
associations with neural tube defects (Coffey and Jessop
1955; Hakosalo and Saxen 1971), whereas others have
shown no such relation (Abramowitz 1958; Leck 1963). It
is nonetheless conceivable that more subtle teratogenic
effects of prenatal influenza, which may be potentially
relevant to schizophrenia, have not been investigated. In
addition, the putative increased risk of schizophrenia
following maternal influenza could result from indirect
mechanisms, rather than from direct infection of the fetal
brain, as occurs in many teratogenic infections. For in-
stance, an autoantibody response to maternal influenza has
been postulated to occur in schizophrenia (Wright et al
1999).
Previous Study on Prenatal Rubella and
Nonaffective Psychosis
One of the first infections to be documented as a cause of
congenital central nervous system congenital anomalies is
rubella. In 1941, Sir Norman Gregg reported a strong
association between congenital cataracts and a rubella
epidemic that shortly preceded these births (Gregg 1941).
Over the subsequent years, the congenital rubella syn-
drome was broadened to include deafness, mental retarda-
tion, and many other developmental outcomes (South and
Sever 1985). Dr. Stella Chess theorized that the conse-
quences of this central nervous system (CNS) viral terat-
ogen might also encompass psychiatric disorders (Chess et
al 1971). To test this hypothesis, Chess and colleagues
conducted psychiatric and psychologic assessments in the
Rubella Birth Defects Evaluation Project (RBDEP), a
cohort of children prenatally exposed to the 1964 rubella
epidemic in New York City. The authors reported an
increased risk of autism, separation anxiety disorder, and
impaired social relations among these rubella-exposed
children compared with population estimates (Chess et al
1971).
This cohort received further follow-up studies in ado-
lescence and young adulthood, during which extensive
psychiatric and psychological testing was performed. At
the young adult follow-up, administered at age 21 to 23,
the cohort received a structured psychiatric interview, the
Diagnostic Interview Schedule for Children (DISC;
Costello et al 1984), which permitted diagnoses of psy-
chotic and other major psychiatric disorders in accord with
DSM-III-R criteria. This provided a unique opportunity to
test the prenatal viral hypothesis of schizophrenia. First,
unlike other infections examined in relation to schizophre-
nia, all of the cohort members of the RBDEP were
clinically documented as having been exposed in utero to
rubella, and a large proportion of both mothers and
offspring were serologically tested and confirmed as
BIOL PSYCHIATRY 475
2001;49:473– 486
positive for the virus. Second, as discussed above, rubella
is a plausible viral risk factor for schizophrenia because it
is a known CNS teratogen. Third, in contrast to previous
studies on prenatal viral infection and schizophrenia, we
had access to diagnoses generated from a standardized,
research-based psychiatric instrument.
We therefore assessed the frequency of psychiatric
disorders in this rubella-exposed cohort (Brown et al
2000). Because the psychiatric assessment was considered
to be a lay interview, our hypothesized diagnostic outcome
was nonaffective psychosis because the correspondence
between lay and clinical interview diagnoses was better
for this broader outcome than for schizophrenia. For
comparison, we assessed the risk of nonaffective psycho-
sis in two age-matched, demographically comparable sam-
ples: a cohort in Albany and Saratoga counties in New
York State (Cohen and Cohen 1996) and the Epidemio-
logic Catchment Area (ECA) sample (Robins and Regier
1991); both comparison samples received psychiatric as-
sessments similar to that of the rubella-exposed cohort,
except the interview was administered on computer for the
rubella-exposed subjects and orally for the comparison
samples. It can be safely assumed that the comparison
samples were unexposed to rubella, which had a preva-
lence in pregnant women of approximately 0.1% during
the time period of birth for the subjects in these samples.
In that study, we found a markedly and significantly
increased risk of nonaffective psychosis in the rubella-
exposed subjects, compared with both the Albany and
Saratoga unexposed and the ECA unexposed (Brown et al
2000). The relative risks of nonaffective psychosis in the
rubella-exposed subjects were greater than fivefold in
comparison with the Albany and Saratoga unexposed
subjects and greater than 16-fold in comparison with the
ECA unexposed subjects. We showed that these results
could not be accounted for by the high proportion of
deafness in the rubella-exposed because the rates of
nonaffective psychosis were similar between hearing-
impaired and nonhearing-impaired individuals.
Study of Premorbid Function and Schizophrenia
The data obtained on this unique cohort provided us with
a further opportunity: to elucidate the relation of premor-
bid dysfunction to later SSD. Although previous studies,
reviewed above, yielded groundbreaking evidence of spe-
cific early antecedents of schizophrenia, they had two
significant limitations. First, suspected early developmen-
tal factors that might explain these premorbid deficits, and
the ensuing schizophrenic illness, could not be meaning-
fully delineated because of insufficient data on potential
prenatal or childhood risk factors. Second, these investi-
gators did not examine the relation between change in
476 BIOL PSYCHIATRY
2001;49:473– 486
premorbid neurocognitive function during childhood and
adolescence and risk of adult schizophrenia. A prediction
of two well-cited models of schizophrenia pathogenesis
(Feinberg 1983; Weinberger 1987) is that adolescent
individuals destined to develop schizophrenia should evi-
dence a decline in neurocognitive performance before
illness onset (see Discussion).
Fortunately, the RBDEP cohort permitted us to address
both of these limitations. Extensive, longitudinal informa-
tion on childhood and adolescent neurocognitive, neuro-
motor, and behavioral function was collected on virtually
all rubella-exposed cohort members. To use these data to
maximal advantage, however, we needed to obtain more
precise diagnoses. In our previous study of nonaffective
psychosis in the RBDEP cohort, the diagnostic assess-
ments, although research-based, were conducted by lay
interviewers and lacked sufficient symptom items to yield
definitive diagnoses of SSD. Moreover, because the cohort
members were aged only 21–23 years at the time of
assessment, they had not passed through a large proportion
of the risk period for the development of schizophrenia.
Hence, we conducted an additional follow-up of the
rubella-exposed birth cohort 10 years after their initial
assessment. This follow-up featured improved diagnostic
precision from a more thorough and clinically based
research diagnostic assessment, the Diagnostic Interview
for Genetic Studies (DIGS; Nurnberger et al 1994). In
addition, the subjects, who are presently in mid-adulthood,
have passed through more of the risk period for the
development of SSD.
These unique design features thus provided the oppor-
tunity to further elucidate the relationship between pre-
morbid function and risk of SSD in subjects with a known
prenatal viral exposure. We hypothesized that rubella-
exposed subjects who later developed SSD would evi-
dence a decline in IQ from childhood to adolescence, as
well as greater neuromotor and behavioral abnormalities,
compared with rubella-exposed control subjects. The re-
fined diagnoses and the available data on the gestational
timing of rubella exposure also facilitated the examination
of whether early gestational exposure to rubella posed a
particularly increased risk of adult SSD, as it does for
other manifestations of congenital rubella (South and
Sever 1985).
Methods and Materials
Assessment of Risk of SSD in the RBDEP Cohort
DESCRIPTION OF BIRTH COHORT. The rubella-exposed
birth cohort was derived from the RBDEP, which was estab-
lished at New York University Medical Center in 1964, the year
of a major rubella pandemic. The purpose of the RBDEP was to
study the clinical manifestations of congenital rubella and de-
A.S. Brown et al
Figure 1. Sample attrition in the Rubella Birth Defects Evalua-
tion Project cohort.
a
207 from original sample ⫹5 additional children with congenital
rubella born 1963–1965
b
208 from original sample ⫹4 additional children from childhood
follow-up
c
Eligibility criteria consisted of I.Q. ⱖ70 and no major physical
handicaps except for deafness
Note: Two rubella exposed subjects in the young adult and present
follow-up assessments were derived from an additional recruitment of
subjects who were diagnosed with congenital rubella from 1963–1965
but were not members of the original RBDEP cohort.
velop appropriate management techniques (Chess et al 1971;
Cooper et al 1969). The great majority of subjects were recruited
by announcements and bulletins, which were disseminated to
physicians throughout New York City, requesting referrals for
pregnancies in which rubella was clinically diagnosed. A small
minority of infants diagnosed with congenital rubella syndrome
were also enrolled in the cohort. The total number of infants
enrolled in the RBDEP was 243. Serologic confirmation of
infection was obtained in the vast majority of mothers and infants
tested.
The RBDEP cohort received follow-up assessments during
childhood, adolescence, and young adulthood. Figure 1 depicts
the numbers of subjects assessed at each follow-up. During each
of these follow-ups, the investigators attempted to locate as many
of the subjects in the original cohort as possible. At the young
adult assessment, subjects meeting eligibility criteria were ad-
ministered the DISC (Costello et al 1984). These criteria, which
were established to enhance validity of the interview, included
IQ ⬎ 70 and no major physical handicaps (with the exception, in
many cases, of deafness). We had previously demonstrated, in
the RBDEP cohort, an increased risk of nonaffective psychosis in
subjects meeting these criteria (see Introduction). In the second
column of Figure 1, we present the numbers of subjects who met
these eligibility criteria and who were followed up during
adolescence, young adulthood, and our present study. Given that
we also sought to administer a diagnostic interview in our study,
we elected to target for follow-up the same subjects previously
assessed with the DISC in young adulthood. As demonstrated in
Figure 1, the subjects assessed for the present study constituted
Rubella, Premorbid Anomalies, and Schizophrenia BIOL PSYCHIATRY 477
2001;49:473– 486

80% (53 of 66) of the eligible sample assessed in young
adulthood.
TRACING AND LOCATION. Contact information, including
addresses and telephone numbers of parents of cohort members,
was abstracted from paper files from the adolescent follow-up of
the RBDEP cohort. Because this information was at least 10
years old, we then instituted a series of increasingly comprehen-
sive searches across electronic media (including national tele-
phone directories CD, Edge, Autotrack Plus; Database Technol-
ogies Online, Boca Raton, FL). until a probable match emerged
with the paper files or there was a sequential trail linking the
individual to previous known addresses, telephone numbers, or
to a social security number.
PARENT MAILING. Parents of cohort members were first
sent a letter with information about the study, including a
postcard on which they could provide contact information on the
cohort members or indicate whether they preferred not to provide
that information. For cohort members whose parents did not
respond to the mailing, we obtained contact information from
electronic searches (see “Tracing and Location”) and from
organizations and schools for the deaf.
CONTACT OF COHORT MEMBERS. For cohort members
who were located, a letter was mailed containing a postcard by
which they could indicate their option to decline participation.
Those subjects who did not decline participation were telephoned
to provide information about the study, to answer questions, and
to invite their participation. Subjects who agreed to participate
were scheduled for the diagnostic assessment.
DIAGNOSTIC ASSESSMENTS. We used the DIGS as the
diagnostic assessment. The DIGS is a polydiagnostic instrument
that has been extensively tested for reliability with good results
(Nurnberger et al 1994). This interview was administered by
trained clinicians with a minimum of a master’s degree in a
mental health field; all interviewers were blind to the study
hypotheses. A certified sign language interpreter was present at
all interviews for subjects who had a history of at least mild
deafness. Subjects were diagnosed by consensus of two psychi-
atric diagnosticians in accord with DSM-IV criteria, following
independent review of all DIGS material including the narrative.
For subjects who could not be located or who declined the
interview, psychiatric diagnostic information was obtained using
the Family Interview for Genetic Studies (FIGS; NIMH Molec-
ular Genetics Initiative 1991), which was administered to cohort
members’ mothers who agreed to participate. Subjects were
diagnosed following review of the information by a psychiatric
diagnostician.
Of the 66 subjects in the targeted sample, 48 received the
DIGS, and an additional 5 subjects received the FIGS. Thus, we
assessed 80.3% (53 of 66) of the targeted cohort members.
Among the remaining 13 subjects, 3 were not interviewed
because their parents did not permit us to contact them; 3 agreed
to be interviewed but could not attend the interview because of
logistical difficulties; 1 did not agree to be interviewed; 1 could
Table 1. Demographic and Hearing Status in Rubella-Exposed
Subjects: SSP Cases and Control Subjects
Control
SSP Subjects
(N ⫽ 8) (N ⫽ 28) p
Age (mean, SD) 33.8 (.75) 34.0 (.58) .38d
Gender (% male) 62.5 46.4 .69c
Ethnicity (% White) 75.0 82.1 .64c
Socioeconomic statusa 2.9 (1.6) 2.6 (1.0) .66d
(mean, SD)
Hearing statusb 3.4 (2.1) 3.0 (2.1) .66d
(mean, SD)
SSP, schizophrenia spectrum psychosis.
a
Based on Hollingshead two-factor index (5 point scale; 1 ⫽ highest, 5 ⫽
lowest).
b
Based on 6-level scale of Mindel and Vernon 1971 (1 ⫽ profound hearing
loss, 6 ⫽ normal hearing).
c
By Fisher’s Exact Test, two tailed.
d
By Student’s t test.
not be located; and 5 could be located but not contacted, and their
parents could not be reached for administration of the FIGS.
DEFINITION OF THE OUTCOME. Our primary outcome
was defined as schizophrenia and other schizophrenia spectrum
disorders (SSD), in accord with a previous definition (Kendler et
al 1995; Kendler and Walsh 1995), based on evidence of familial
aggregation of these disorders. This definition includes the
following DSM-IV diagnoses: schizophrenia, schizoaffective
disorder, psychotic disorder NOS, delusional disorder, schizo-
typal personality disorder, and paranoid personality disorder.
Premorbid Function as a Predictor of Adult
Schizophrenia Spectrum Psychosis (SSP)
DEFINITION OF GROUPS FOR COMPARISON. In a case-
control design nested within the rubella-exposed cohort de-
scribed above (see Methods), we compared premorbid IQ,
neuromotor dysfunction, and deviant behaviors between subjects
diagnosed with SSP and control subjects. Cases with schizophre-
nia spectrum personality disorders were excluded from the main
analysis because these disorders by definition do not have a clear
age of onset, which is required to identify a function as
“premorbid.” The control subjects were rubella-exposed individ-
uals from this birth cohort who were free of both SSD and major
affective disorders. Subjects with major affective disorders were
excluded as control subjects because SSD and affective disorders
may share certain developmental precursors (van Os et al 1997).
As demonstrated in Table 1, the case and control groups were
generally similar with respect to age, ethnicity, and socioeco-
nomic status, although the proportion of male subjects was
somewhat higher in the SSD group (this is discussed further in
Results). The SSD cases and control subjects were also compared
with regard to hearing ability, which was found to be similar
between the two groups.
CHILDHOOD AND ADOLESCENT FOLLOW-UP ASSESS-
MENTS. During childhood (mean age 8) and adolescence
(mean age 13), members of the RBDEP birth cohort were
478 BIOL PSYCHIATRY A.S. Brown et al
2001;49:473– 486

administered intellectual, behavioral, psychosocial, and psychi- graphic variables differed between SSP cases and control sub-
atric assessments. A virtually complete data set containing the jects. Because the groups did not differ on these variables, they
results of these assessments was available for these two follow- were not controlled for in subsequent analyses. To compare the
ups. Using these data, we compared the occurrence of premorbid groups on performance IQ at each time point, a repeated
abnormalities demonstrated in previous studies to be predictive measures analysis of variance (ANOVA) was conducted to test
of SSD between rubella-exposed SSD cases and control subjects. for between group effects (case vs. control subject), time effects
Based on these previous studies, we selected the following (childhood vs. adolescence), and their interaction. To further
domains of premorbid function: IQ, neuromotor dysfunction and address this question, we used Fisher’s Exact Test to compare the
mannerisms, and several deviant behaviors. groups with respect to the proportions evidencing a decline in
performance IQ between childhood and adolescence. Because of
ASSESSMENT INSTRUMENTS. We assessed IQ with the the relative rarity of neuromotor dysfunction, mannerisms, and
Wechsler Intelligence Scale for Children (WISC) during child- deviant behaviors and because of the modest number of subjects,
hood and the Wechsler Intelligence Scale for Children-Revised these categories were collapsed for the statistical analysis. The
(WISC–R) during adolescence. For those subjects with deafness, SSP cases and control subjects were compared with respect to the
a certified sign interpreter assisted. Although the verbal IQ scale presence of any of these premorbid abnormalities using Fisher’s
was administered to the deaf children wherever feasible, it was Exact Test. We also used Fisher’s Exact Test to compare the
considered too unreliable in this predominantly deaf sample. gestational timing of prenatal rubella between cases and control
Therefore, the performance IQ scale and its subtests (picture subjects.
completion, picture arrangement, block design, and object as-
sembly) were used to determine cognitive function. As noted
above, all subjects who were targeted for the psychiatric inter-
Results
view in mid-adulthood had IQ ⬎ 70. Risk of Schizophrenia Spectrum Disorders
Neuromotor status was assessed using a clinical exam adminis-
tered by a neurologist. Subjects were rated in accord with the criteria The numbers and proportions of interviewed subjects with
of Chess and Hassibi (1978). These criteria were operationalized on each DSM-IV diagnosis in the rubella-exposed cohort are
a 5-point scale, as follows: 1 (profound dysfunction), 2 (severe presented in Table 2. We found that 20.4% (11 of 53) of
dysfunction), 3 (moderate dysfunction), 4 (mild dysfunction), and 5 the sample was diagnosed with SSD. For the 48 subjects
(normal). Further details on the definitions for each of these ratings diagnosed after receiving the DIGS, 20.8% (10) received a
are provided in Chess and Hassibi (1978). Data on neuromotor SSD diagnosis. Although we did not assess psychiatric
status were available for only the adolescent follow-up. For our disorders in a cohort unexposed to rubella, this figure is
study, “neuromotor abnormality” was defined as a rating of at least substantially higher than population estimates from previ-
mild neuromotor dysfunction (i.e., a rating ⬍ 5).
Mannerisms were coded by trained raters using a global score.
All ratings were done by consensus of two raters. The scale was
Table 2. Diagnostic Breakdown (DSM-IV) of Rubella-
defined as 1 (extremely prominent), 2 (severe), 3 (moderate), 4 Exposed Subjects in the RBDEP Cohort (Primary Axis I
(mild), and 5 (insignificant or none). For the present study, Diagnoses Only), N ⫽ 53
“mannerisms” were considered to be present if there was a rating
of at least mild mannerisms (i.e., a rating ⬍ 5). Data were Diagnosis N %
available from both the childhood and adolescent follow-ups. Schizophrenia Spectrum Disorders 11 20.8
A semistructured interview regarding a battery of deviant Schizophrenia 3 5.7
childhood behaviors was administered to the parents and teachers Schizoaffective disorder 1 1.9
of each subject. The results of these interviews were reviewed by Psychotic disorder NOS 4 7.5
trained chart abstracters, and the presence or absence of deviant Schizotypal personality disorder 2 3.8
behaviors were coded based on operationalized criteria. For our Paranoid personality disorder 1 1.9
study, we focused on five deviant behaviors suggested in Affective Disorders 14 26.4
Bipolar affective disorder 0 0
previous studies, reviewed above, to be disturbed in children
Major depressive disorder, unipolar 13 24.5
destined to develop schizophrenia or that represent prominent Mood disorder NOS 1 1.9
clinical features of patients with schizophrenia (Wing 1995). Anxiety Disorders
These were aggressiveness, temper tantrums, short attention span Social phobia 1 1.9
and distractibility, emotional immaturity, and suspiciousness. Alcohol/Substance Abuse/Dependence
Data were available from both the childhood and adolescent Cannabis dependence 1 1.9
follow-up assessment, and from interviews of the parent and the Childhood Disorders 2 3.8
teacher for both childhood and adolescence. Conduct disorder 1 1.9
Disorder of infancy/childhood/adolescence NOS 1 1.9
Other 2 3.8
Data Analysis Uncomplicated bereavement 1 1.9
Learning disorder 1 1.9
We first examined the frequency distributions and parameters of
No Psychiatric Diagnosis 22 41.5
the variables. We then examined whether several relevant demo-
Rubella, Premorbid Anomalies, and Schizophrenia BIOL PSYCHIATRY 479
2001;49:473– 486

Table 3. Premorbid Performance IQa in Rubella-Exposed Table 5. Premorbid Neuromotor Dysfunction, Mannerisms,
Subjects: Comparison between SSP Cases and Control and Deviant Behaviors in Rubella-Exposed Subjects:
Subjects Assessed during Childhood and Adolescenceb Comparisons between SSP Cases (N ⫽8) and Control Subjects
(N ⫽ 28)
Childhood Adolescence
N (%)
N Mean SD Mean SD
Neuromotor dysfunctiona
SSP 8 100.3 19.2 89.5 14.8
SSP 2 25
Controls 28c 107.4 13.6 104.7 15.2
Control subjects 2 7.1
SSP, schizophrenia spectrum psychosis. Mannerismsb
a
Performance IQ only. SSP 4 50.0
b
Effect of group (F ⫽ 3.73, p ⫽ .06), time (F ⫽ 14.6, p ⫽ .001), and group ⫻ Control subjects 8 28.6
time interaction (F ⫽ 5.46, p ⫽ .03; repeated measures analysis of variance).
c
One control missing for childhood assessment. Deviant behaviorsc
SSP 8 100.0
Control subjects 17 60.7
ous studies (Eaton 1985; Kendler et al 1996). The age of At least one of the above
premorbid abnormalitiesd
onset of SSD was at least 18 in all cases; thus, the last of SSP 8 100.0
the premorbid assessments was conducted at least 5 years Control subjects 18 64.3
before the onset of psychosis.
SSP, schizophrenia spectrum psychosis.
a
Mild dysfunction or greater.
b
Mild or greater.
Premorbid Abnormalities in Relation to Adult SSD c
Includes at least one of the following: aggressiveness, temper tantrums, short
attention span, emotional immaturity, suspiciousness.
PREMORBID PERFORMANCE IQ. The mean (SD) d
p ⫽ .08, Fisher’s Exact Test.
performance IQ scores for the SSP group and the control
group during childhood and adolescence, respectively, are
presented in Table 3. As demonstrated, the mean child- cases demonstrating an IQ decline of at least 3 points
hood IQ in the SSP cases is less than in control subjects, between the childhood and adolescent assessments was
but this difference widens substantially during adoles- 87.5%, compared with 33% in the control group (p ⫽ .02,
cence. This is due to an approximately 11-point decline in Fisher’s Exact Test).
IQ from childhood to adolescence in the SSP cases, In an additional analysis, we examined whether the
compared with a less than 3-point decline in the control findings persisted when all cases of SSD (i.e., the inclu-
subjects. Repeated measures ANOVA revealed a signifi- sion of schizophrenia spectrum personality disorders)
cant group (SSP cases vs. control subjects) by time were examined for IQ decline. We found that 73% (8 of
(childhood vs. adolescence) interaction (F ⫽ 5.46, p ⫽ 11) of subjects with SSD had an IQ decline from child-
.03), indicating that the slopes generated by the respective hood to adolescence, compared with 37% (10 of 27) of
changes in IQ from childhood to adolescence differed control subjects (Fisher p ⫽ .046).
significantly between the SSP group and the control Finally, given that the proportion of male subjects in the
group; this difference was accounted for by a greater IQ SSD group was somewhat higher than the proportion of
decline in the SSP group. female subjects, we evaluated the possibility that the
To examine whether the decline in mean IQ in the SSP finding on IQ decline was confounded by gender by
cases was accounted for by a small number of outliers, we comparing the proportions of subjects with IQ decline
compared the respective proportions of subjects with an between male and female subjects in the assessed sample.
IQ decline between the SSP group and the control group The respective proportions of subjects with an IQ decline
(Table 4). This was not the case: the proportion of SSP were 65% (15/23) for male subjects and 61% (17/28) for
female subjects, arguing against the possibility of con-
Table 4. Proportions of Rubella-Exposed Subjects with founding by gender.
Decline in IQa from Childhood to Adolescence: Comparison
of SSP Cases and Control Subjects Other Premorbid Abnormalities
N with IQ % with IQ The proportions of subjects with neuromotor dysfunction,
N decline decline p
mannerisms, and deviant behaviors in the SSP group and
SSP 8 7 87.5 the control groups are presented in Table 5. As demon-
.02b
Control subjects 27c 10 37.0 strated in the table, the SSP group, compared with the
SSP, schizophrenia spectrum psychosis. control group, had more subjects diagnosed with each of
a
Decline of at least 3 performance IQ points.
b
Statistically significant; Fisher’s Exact Test, two tailed.
these premorbid abnormalities. Because of the relatively
c
One control missing childhood IQ score. small numbers of subjects with these abnormalities, we
480 BIOL PSYCHIATRY A.S. Brown et al
2001;49:473– 486

Table 6. Gestational Timing of Maternal Rubella Infection:
Comparison of SSD Cases and Control Subjects
Control Subjects
SSD (N ⫽ 9)a (N ⫽ 22)b
Gestational
month N % N %
1 1 11.1 1 4.5
2 4 44.4 5 22.7
3 3 33.3 9 32.1
4 0 0 3 13.6
5 0 0 4 18.2
6 1 11.1 0 0
⬎6 0 0 0 0
SSP, schizophrenic spectrum psychosis.
a
Data available on 9 of 11 SSD cases.
b
Data available on 22 of 28 control subjects.
collapsed the measures into one category to conduct a
meaningful statistical analysis. This analysis revealed an
increase in the proportion of SSP cases, compared with
controls, with at least one of these premorbid abnormali-
ties, although the finding fell short of statistical signifi-
cance (p ⫽ .08, Fisher’s Exact Test, two tailed).
Gestational Timing of Rubella Infection in Relation
to Adult SSD
The frequency distributions of maternal rubella by gesta-
tional month were compared between rubella-exposed
subjects diagnosed with SSD and rubella-exposed control
subjects. As demonstrated in Table 6, for the 1st and 2nd
months of gestation, the respective proportions of SSD
cases, compared with controls, were increased. Moreover,
only 11.1% (1 of 9) of the SSD cases was exposed to
rubella after the first trimester, compared with 31.8% (7 of
22) of the controls. This difference was not statistically
significant, however (Fisher p ⫽ .38), perhaps owing to
the small sample sizes.
Discussion
We have demonstrated that premorbid abnormalities, in-
cluding IQ decline between childhood and adolescence,
predict adult SSP in a birth cohort with a known prenatal
viral exposure. These results provide the first evidence
linking a specific prenatal exposure to premorbid abnor-
malities predictive of later SSP and to the SSP outcome
within the same individuals. Because the last of the
premorbid assessments was conducted at least 5 years
before the onset of psychosis, it is unlikely that prodromal
signs of SSP could explain the findings.
These data extend the results of previous studies on
premorbid abnormalities in schizophrenia in an important
way (David et al 1997; Erlenmeyer-Kimling et al 1991;
Jones et al 1994; Walker et al 1994). In those studies, the
etiology of the premorbid abnormalities was not known,
and premorbid IQ and other neurocognitive functions at
more than one point in time were not available on
sufficient numbers of cases to permit a meaningful anal-
ysis. In contrast, the precise documentation of exposure,
and complete data on premorbid function in our cohort,
provides evidence that a prenatally induced brain lesion
can play a role in such premorbid abnormalities. More-
over, a decline in premorbid intellect from childhood to
adolescence, revealed by the longitudinal data on IQ,
suggests a dynamic pathogenic process that antedates the
illness and that ultimately becomes expressed in adulthood
as SSP. Although the findings on premorbid neuromotor
and behavioral abnormalities fell short of statistical sig-
nificance, they appear to warrant further study.
BIOLOGICAL PLAUSIBILITY AND CAUSAL MECHA-
NISMS. The biological plausibility of prenatal rubella as
a risk factor for schizophrenia is substantive (see Brown
and Susser 1999 for review). Rubella virus in pregnancy
leads to placental infection, resulting in fetal invasion
(Whitley and Stagno 1991). The virus has numerous
teratogenic effects, many of which involve disruption in
development of the CNS. Neurodevelopmental disorders
strongly associated with rubella include sensorineural
deafness, mental retardation, learning disabilities, and
cerebral palsy (South and Sever 1985). Each of these
disorders, or their associated manifestations, have been
reported to occur, to varying degrees, in schizophrenia
(David et al 1995; Griffith et al 1994; Reid 1989; Walker
et al 1994). With regard to potential causal mechanisms by
which rubella may lead to schizophrenia, gross neuro-
pathologic abnormalities in congenital rubella syndrome
provide some important clues. In a magnetic resonance
imaging (MRI) study, Lim et al (1995) demonstrated that
congenital rubella patients with schizophrenia-like symp-
toms had ventriculomegaly, significantly diminished cor-
tical gray matter volume, and a similar pattern of gray
matter volume deficit; all of these abnormalities were also
found in a comparison group of unexposed patients with
schizophrenia. These findings suggest a concordance with
respect to several relevant aspects of brain pathology between
congenital rubella and schizophrenia, which may be relevant
to some or all of the premorbid deficits observed.
Neuropathologic findings gleaned from ultrastructural
investigations suggest several different mechanisms by
which rubella may induce developmental damage. First,
rubella acts to inhibit mitosis, resulting in hypocellularity
and diminished brain growth, leading in turn to micro-
cephaly in some cases (Boue and Boue 1969; Rorke 1973;
South and Sever 1985). This process also causes retarda-
tion of myelination because of reduced replication of
oligodendrocytes (Kemper et al 1973). Some neuropatho-
Rubella, Premorbid Anomalies, and Schizophrenia
logic studies of schizophrenia have revealed abnormalities
in the anterior cingulate, frontopolar cortex, entorhinal
cortex, and hippocampus that may be viewed as consistent
with neuronal loss (Beasley and Reynolds 1997; Benes et
al 1991; Falkai and Bogerts 1986). There have, however,
been several notable nonreplications of these findings, and
there is mounting evidence that in some brain regions,
neuronal density is actually increased in schizophrenia
(Selemon and Goldman-Rakic 1999).
In a second putative mechanism, gestational rubella
induces a proinflammatory immune response, leading to
cerebrovascular damage in the fetal circulation, including
endothelial destruction and pericapillary collections of
granular material (Rorke et al 1968; Townsend 1994). This
process results in ischemic damage, with the necrotic foci
following the damaged blood vessels or their terminal
supply fields. Rubella also induces an autoimmune re-
sponse against several endocrine organs (Clarke et al
1984) and thus conceivably could damage the brain
through such a mechanism.
The pathogenic mechanisms may not necessarily be
specific to prenatal rubella but could extend to other
viruses as well. Maternal fever, or other consequences of
maternal viral infection, may also mediate the observed
association.
GESTATIONAL TIMING. As presented above, the 1st
and 2nd gestational months may represent a period of
especially increased vulnerability to the development of
SSD. This suggests that a rubella-induced disturbance in
embryogenesis may be relevant to the pathogenesis of
SSD, consistent with the well-documented increased vul-
nerability to the anomalies comprising congenital rubella
syndrome following early gestational exposure (South and
Sever 1985). This developmental period consists of the
early embryonic stages, including cleavage and implanta-
tion; formation of the major divisions of the brain and
subsequently the early cerebral hemispheres; creation and
closure of the neural tube; extensive development of the
hippocampus, amygdaloid, hypothalamic, and thalamic
regions, and formation of the cortical plate (O’Rahilly and
Muller 1999). Given the relatively undifferentiated nature
of the brain during this developmental period and the
diversity of regional brain abnormalities implicated in
schizophrenia, it is difficult to attribute the pathogenesis of
schizophrenia following prenatal rubella to any particular
developmental stage or brain area. It should also be noted
that a disruption in embryogenesis may have downstream
effects on later developmental stages. Moreover, active ru-
bella infection has been shown to persist in the infant as late
as 18 months following birth (South and Sever 1985),
suggesting that viral effects on brain development during the
postnatal period may also play important contributory roles.
BIOL PSYCHIATRY 481
2001;49:473– 486
Models of Pathogenesis
Two prominent models of pathogenesis of schizophrenia,
mentioned briefly in the Introduction, appear most rele-
vant to our findings and thereby provide us with a point of
departure toward delineating the relationships observed
between prenatal rubella, premorbid dysfunction, and
adult schizophrenia. Reciprocally, our findings may have
implications for validating and further elaborating these
models.
The first model, exemplified by Weinberger’s hypoth-
esis (Weinberger 1987), argues that a fixed early brain
lesion interacts with later maturational events during
adolescence to produce the psychopathology of schizo-
phrenia in early adulthood. One of the most compelling
pieces of evidence cited in this model is that the dorsolat-
eral prefrontal cortex (DLPFC), a brain region that is
underactivated in schizophrenic patients challenged with
working memory tasks (Weinberger et al 1986), reaches
functional maturity during late adolescence and early
adulthood. This evidence includes studies in monkeys
indicating that a DLPFC lesion has no marked effect on
delayed-response tasks (a measure of DLPFC function)
during infancy or the prepubescent period but has severe
consequences for the performance of these tasks during
adulthood (Goldman and Alexander 1977). Weinberger
(1987) discussed further evidence from previous studies
that dopamine, the neurotransmitter most clearly impli-
cated in the pathophysiology of schizophrenia, plays a key
role in functions subserved by the DLPFC. With regard to
brain development, postnatal changes occur in dopamine
tissue concentrations and synthesis rates in the prefrontal
cortex of rheusus monkeys, with peak values demonstrated
at the onset of puberty (Goldman-Rakic and Brown 1982).
Rosenberg and Lewis (1995) demonstrated in rhesus
monkeys a marked increase in the density of tyrosine
hydroxylase-positive varicosities (predominantly reflect-
ing dopamine axons) in the middle cortical layers, which
reached a peak at the onset of puberty.
An alternative model of schizophrenia pathogenesis was
exemplified by Feinberg’s hypothesis (Feinberg 1983). In
contrast to Weinberger, Feinberg posited a pathogenic
maturational process during adolescence that leads to
schizophrenia through a defect in reorganization of brain
function. According to Feinberg, these changes could be
accounted for in large part by the rather striking decline in
synaptic density, termed programmed synaptic elimina-
tion, shown to occur in humans between late childhood
and early adolescence (Huttenlocher 1979). In this model,
schizophrenia could result from a fault in programmed
synaptic elimination during adolescence, such that “too
many, too few, or the wrong synapses” are eliminated. In
support of this model, Feinberg (1983) cited evidence
from psychophysiologic studies demonstrating profound
482 BIOL PSYCHIATRY
2001;49:473– 486
changes during adolescence in the sleep electroencepha-
logram; alterations in event-related potentials, such as the
P300 wave; and a decline in cortical metabolic rate.
The recent literature has provided further evidence in
support of this model. Findings in schizophrenia are
consistent with an exaggerated loss of synapses in this
disorder. Evidence of increased neuronal density in the
prefrontal cortex (Selemon et al 1995; Selemon and
Goldman-Rakic 1999) suggests a reduction in interneuro-
nal neuropil, which is largely comprised of synapses.
Although consistent with a loss of synapses, they do not,
however, specify the period of life during which this
alteration occurs. Neuroimaging studies that have fol-
lowed childhood-onset schizophrenia cases during adoles-
cence have demonstrated an exaggerated and progressive
decline in volume of cortical gray matter (Rapoport et al
1999), cerebrum and hippocampus, and progressive en-
largement of the lateral ventricles (Giedd et al 1999).
These authors noted that the results might be accounted for
by excessive synaptic pruning in the cases. This finding is
of particular relevance to our study, given that childhood-
onset cases represent a developmental subtype of schizo-
phrenia. Decreases in the ratio of gray to white matter
during normal childhood and adolescence (Thompson et al
1985) and peripubertal reduction in volume of cortical
gray matter (Jernigan and Tallal 1990) also have been
demonstrated, consistent with large-scale synaptic elimi-
nation during this developmental period. Interestingly, in a
study cited above (Lim et al 1995), patients with congen-
ital rubella and schizophrenia had decreased volume of
cortical gray matter, but not white matter. Keshavan et al
(1994) also reported several findings in schizophrenia that
are consistent with a loss of synapses in later development.
Delineation of Pathogenic Mechanisms
These models provide a heuristic framework with which to
delineate pathogenic mechanisms in early and later devel-
opment that may underlie our findings. Although specu-
lative, we wish to suggest two potential interpretations.
The first derives from a model exemplified by Weinberg-
er’s hypothesis (Weinberger 1987). Our subjects experi-
enced an early brain insult, in this case, from prenatal
exposure to rubella, which manifested as a mildly de-
creased IQ in childhood and as neuromotor and behavioral
abnormalities in childhood and adolescence. In accord
with the model, one could argue that between childhood
and adolescence, the deterioration in IQ among certain
individuals was due to an interaction between this early
brain lesion and functional maturation of brain regions
subserving more complex mental functions. Arnsten and
Goldman-Rakic (1985) suggested that the maturation of
dopamine systems in the prefrontal cortex during adoles-
A.S. Brown et al
cence (discussed under Models of Pathogenesis above)
may explain certain cognitive abilities that emerge during
that developmental period. It is therefore conceivable that
a disturbance in this developmental process may have
contributed to the IQ decline observed in our study and
also may have created a vulnerability to adult SSD. It is
worth noting that our findings underscore an implication
of this model that is not explicitly stated: as mesocortical
dopamine afferents mature during puberty, one might
expect to observe the emergence of subtle neurocognitive
deterioration at that time in those with the putative early
brain “lesion” and the tendency to develop adult schizo-
phrenia. This model focuses instead on the onset of
diagnosable schizophrenia, which more typically emerges
from a few to as many as 10 to 15 years after the end of
adolescence.
The application of aspects of a model exemplified by
Feinberg (1983) to our data provides a second, and
perhaps equally compelling, interpretation. Although this
model does not include a prenatal insult, it could nonethe-
less be argued that, in susceptible individuals, a brain
lesion induced by prenatal rubella could initiate a cascade
of events that reverberate throughout development. This
pathogenic process could disrupt programmed synaptic
elimination, resulting in neurocognitive deterioration be-
tween childhood and adolescence and contributing to
increased vulnerability to schizophrenia in adulthood. This
explanation is of particular interest, given that much of the
decline of synaptic density found by Huttenlocher (1979)
occurred between the ages at which our subjects were
assessed during childhood and adolescence. This process
might also explain the decrement in IQ between these two
time periods in our study, because, as argued by Feinberg
(1983), the elimination of redundant synapses may be
responsible in part for more efficient utilization of neuro-
nal networks. This ability may give rise to the complex
problem solving and abstract thought that characteristi-
cally emerges during adolescence. Indeed, subjects with
particular types of mental retardation appear to have either
unusually high or low synaptic densities (Cragg 1975;
Ferrier and Gullotta 1990; Huttenlocher 1979).
Limitations
Limitations of the studies presented herein include the
following.
1. Lack of an unexposed cohort. The absence of a birth
cohort unexposed to rubella, and representative of
the exposed cohort, does not permit us to accurately
estimate the effect size. Nonetheless, we can ap-
proximate this figure by comparing the risk of SSP
in the rubella cohort with population estimates of the
risk of nonaffective psychosis, which are between
Rubella, Premorbid Anomalies, and Schizophrenia
0.5% and 1% (Kendler et al 1996). Therefore, given
the greater-than-15% prevalence of SSP in the
rubella-exposed birth cohort, this would suggest a
relative risk of approximately 15-fold.
2. Psychotic disorder NOS. As noted in Table 1, 4 of
the 11 subjects with SSD were diagnosed with
psychotic disorder NOS. It could therefore be ar-
gued that our findings could be explained to some
degree by the presence of atypical psychotic disor-
ders that bear little phenomenologic resemblance to
schizophrenia. Each of our cases of psychotic dis-
order NOS, however, had clear evidence of psy-
chotic symptoms frequently found in schizophrenia,
including auditory hallucinations, persecutory delu-
sions, and mind reading; for 3 of the 4 cases, these
symptoms were chronic.
3. Deafness. It could be argued that deafness may have
played a role in the development of SSD. Our
findings, however, argue otherwise. As demon-
strated in Table 1, hearing ability (measured on a
continuous scale) was similar between the SSD
cases and the control subjects, and the proportion of
subjects with normal hearing or slight hearing loss
was the same in the SSD cases (36% or 4/11),
compared with the control subjects (32% or 9/28).
Second, previous studies that examined the relation-
ship between deafness and psychosis are inconclu-
sive. Altshuler and Sarlin (1969) found a 2.5%
prevalence of schizophrenia in hospitalized deaf
subjects, although selection bias and differences in
diagnostic standards between deaf and hearing pa-
tients may have contributed to a spurious associa-
tion. Severe hearing impairment in military induct-
ees was associated with an increased risk of
schizophrenia (David et al 1995), but hearing dys-
function could have resulted from intrauterine infec-
tions such as rubella.
4. Potential for selection bias. We first consider
whether selection bias may have resulted in a
spuriously increased risk of SSD in our cohort. Our
follow-up rate of more than 80% (53) of the 66
targeted subjects was well above acceptable stan-
dards for prospective cohort studies and thus is
unlikely to lead to appreciable bias. Because these
66 targeted subjects were derived from an eligible
sample of 131 assessed in adolescence, it could be
argued, however, that selection bias may have led to
a spuriously increased risk of SSD; however, a
sensitivity analysis assuming that none of those lost
to follow-up had SSD yielded a prevalence of 8.4%
(11/131), which is still substantially elevated com-
pared with population estimates. Moreover, the 53
eligible, assessed subjects and the 78 eligible, unas-
BIOL PSYCHIATRY 483
2001;49:473– 486
sessed subjects were similar to one another on age
(all subjects were age 33–34 during the time period
of our study), gender (% male: assessed ⫽ 45% [n ⫽
24], unassessed ⫽ 59% [n ⫽ 46]; Fisher’s p ⫽ .15),
and ethnicity (% white: assessed ⫽ 75% [n ⫽ 40],
unassessed: 80% [n ⫽ 62]; ␹2 ⫽ 1.09, p ⫽ .58),
suggesting that the assessed subjects were represen-
tative of the sample from which they were derived.
Furthermore, bias in selecting individuals with more
severe manifestations of rubella was obviated by our
criterion of excluding subjects with mental retarda-
tion and multiple physical handicaps. Second, we
specifically consider whether selection bias may
have given rise to a spurious increase in premorbid
abnormalities in SSD cases compared with control
subjects. This appears to be unlikely for two rea-
sons. First, all of the SSD cases and control subjects
in our study derived from a single birth cohort, and
uniform selection procedures were used at each
follow-up assessment. Second, to address the possi-
bility that differential loss to follow-up may have
produced a spurious association between IQ decline
and SSP, we examined whether the proportions of
subjects with IQ decline differed between the as-
sessed and unassessed subjects, a necessary condi-
tion for this type of bias. These proportions were
similar: 53% (27 of 51 assessed) versus 46% (32 of
70 unassessed) manifested at least a 3-point decline
in IQ (␹2 ⫽ 0.62, p ⫽ .43).
5. Lack of data on family history of psychiatric illness.
It is worth noting that despite the high prevalence of
SSD in the rubella-exposed subjects, the majority
did not develop SSD. Although early gestational
timing of the infection appears to play a role, one
must also consider the potential effect of genetic
predisposition to psychiatric disorders, especially
SSD. To address this question, we shall attempt to
obtain data on family history of psychiatric illness in
future work.
6. Relatively small sample size. The number of rubella-
exposed cases of SSP is relatively small. We be-
lieve, however, that the small sample size is coun-
terbalanced by the high-quality, prospective data
and the biological plausibility and coherence of the
findings presented.
7. Lack of data on social environment and IQ decline.
It is conceivable that a dynamic interaction between
early signs of congenital rubella and the social
environment could have played a role in the IQ
decline observed in our cases. Although we found
no evidence that indicators of the social environ-
ment, such as socioeconomic status, differed be-
tween subjects with clear manifestations of congen-
484 BIOL PSYCHIATRY
2001;49:473– 486
ital rubella and those without such manifestations,
our data were not sufficient to examine the interac-
tion between these two factors.
Support for Causality
Although causality is usually difficult to prove, the data
support the three essential properties of a causal relation-
ship (Hill 1965). These are: 1) Association. A strong
association between prenatal rubella and SSD— greater
than 10-fold the risk in the unexposed population—
provides strong evidence that the association is valid; 2)
Temporal order. The study is designed such that there is
no knowledge of the outcome when the exposure is
assessed because the rubella exposure clearly precedes the
SSD outcome by many years. 3) Direction (lack of
confounding). Three lines of evidence support this prop-
erty. First, as stated in 1 above, the association is strong.
Second, the association persisted when potential con-
founders were controlled. Third, as reviewed above (see
Introduction and Discussion), the relation between prena-
tal rubella and SSD is biologically plausible. Our study
provides two further pieces of evidence that support
causality: verification of the diagnosis of SSD and the
demonstration of a relation between premorbid anteced-
ents and risk of SSP.
Conclusions
In summary, we have provided further validation for a
markedly increased risk of SSD in a birth cohort with
prenatal exposure to rubella. Moreover, rubella-exposed
subjects destined to develop SSD, compared with rubella-
exposed control subjects, had evidence of a deviant
neurodevelopmental trajectory, manifested by increased
premorbid abnormalities characteristic of patients with
schizophrenia and an IQ decline between childhood and
adolescence. These findings provide further support for
prenatal rubella as an etiology of SSD, as well as empirical
support for pathogenic models of this disorder. Future
studies are essential to independently replicate these find-
ings in other cohorts, to examine structural and functional
indicators of brain pathology among rubella-exposed SSD
cases and control subjects, and to investigate potential
interactions between prenatal rubella exposure and vulner-
ability genes.
Rubella has been virtually eliminated in industrialized
countries; however, it remains a threat in many developing
countries. Our findings therefore may have implications
for prevention of SSD. Moreover, these findings may
encourage further work on other prenatal viral agents in
the etiopathogenesis of schizophrenia.
A.S. Brown et al
This work was supported by a grant from the Theodore and Vada Stanley
Foundation (ASB) and by Grant Nos. K08 MH01206 (ASB) and 1P20
MH50727 (JMG) from the National Institute of Mental Health. The
authors thank Stella Chess, M.D.; Louis Cooper, M.D.; Michaeline
Bresnahan, Ph.D.; Will Daniel, MSW; and Barbara Wahl, M.S. for their
contributions to this work. Presented in part at the International Congress
on Schizophrenia Research, April 1999, Santa Fe, New Mexico, and at
the Fifth Stanley Research Symposium on the Neurovirology and
Neuroimmunology of Schizophrenia and Bipolar Disorder, November
1999, Bethesda, MD.
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