The Relationship of Prenatal and Perinatal
Complications to Cognitive Functioning at Age 7 in
the New England Cohorts of the National
Collaborative Perinatal Project
by Larry J. Seidman, Stephen L. Buka, Jill M. Qoldstein, Nicholas J. Horton,
Ronald O. Rieder, and Ming T. Tsuang
Abstract
Previous literature shows that children who later
develop schizophrenia have elevated rates of prenatal
and perinatal complications (PPCs) and neuropsycho-
logical deficits in childhood. However, little is known
about the relationship of these risk factors to each
other. We evaluated the relationship between PPCs
and neuropsychological functioning at age 7 in a large
epidemiological study of pregnancy, birth, and devel-
opment: the National Collaborative Perinatal Project
(NCPP). Thirteen standardized measures of cognitive
abilities were acquired on 11,889 children at approxi-
mately age 7. Principal components analysis was used
to create three neuropsychological measures: academic
achievement skills, verbal-conceptual abilities, and
perceptual-motor abilities. We measured the relation-
ship between these factors and three measures of
PPCs: low birth weight (LBW), probable hypoxic-
ischemic complications, and chronic hypoxia. All three
measures of PPCs were significantly associated with
lower neuropsychological performance, after control-
ling for various confounders. LBW had the strongest
association with neuropsychological performance, fol-
lowed by an index of presumed hypoxic insults. The
effect sizes between PPCs and cognitive factors at age
7 were consistently largest with perceptual-motor abil-
ities, followed by academic achievement skills and ver-
bal-conceptual abilities. Future studies will evaluate
the effects of specific PPCs and genetic risk factors for
psychosis on cognitive functioning in childhood.
Keywords: Obstetric complications, cognition,
hypoxia, low birth weight
Schizophrenia Bulletin, 26(2):309-321,2000.
Progress in understanding the etiology of schizophrenia
has been slow, but one fruitful strategy has been to exam-
ine the developmental precursors and risk factors of the ill-
ness (Buka et al. 1999). Some of the most established risk
309
Downloaded from https://academic.oup.com/schizophreniabulletin/article/26/2/309/1849323 by guest on 08 February 2022
factors include family history of illness (Tsuang and
Faraone 1996); PPCs or OCs (Geddes and Lawrie 1995);
poor childhood social or school adjustment (Watt 1978;
Marcus et al. 1987); and cognitive and neuromotor capaci-
ties in childhood, particularly attentional dysregulation
(Cornblatt and Keilp 1994) and motor incoordination (Fish
et al. 1992). Each of these factors has been found to be
associated with subsequent illness. However, little is
known about the relationship of these risk factors to each
other and whether these reflect common or distinct etio-
logic pathways (Tsuang and Faraone 1995).
A consistent body of literature shows that offspring of
parents with schizophrenia ("high-risk" study design) have a
syndrome of neuropsychological abnormalities and social
impairments that is predictive of subsequent psychosis (Fish
et al. 1992). A number of these studies report attentional dys-
function in offspring of parents with schizophrenia compared
to offspring from unaffected families (Nuechterlein 1983;
Erienmeyer-Kimling and Comblatt 1992). Deficits have been
reported in tests of concept formation and object sorting and
on the similarities subtest of the Wechsler Intelligence Scale
for Children (Wechsler 1949), suggesting disturbances in
abstract reasoning. Low childhood intelligence quotient (IQ)
and other measures of general intellectual ability (such as IQ
decline) were also predictors of psychosis (Kremen et al.
1998) and schizophrenia, in high-risk and followup studies
(Lane and Albee 1964; Rieder et al. 1977; Aylward et al.
1984; Jones et al. 1994; Crow et al. 1995; Russell et al.
1997). Neuromotor deficits and soft neurologic signs have
been found consistently in children at high risk for schizo-
phrenia (Orvaschel et al. 1979; Lifshitz et al. 1985; Marcus
et al. 1987; Auerbach et al. 1993). However, these childhood
neuropsychological abnormalities have yet to be linked to
PPCs because existing studies typically have not evaluated
both types of precursors to schizophrenia.
Epidemiological studies have identified a number of
Reprint requests should be sent to Prof. LJ. Seidman, Massachusetts
Mental Health Center, Neuropsychology Laboratory, 74 Fenwood RA,
Boston, MA 02115; e-mail: larry_seidman@hmsJiarvard.edu.
Schizophrenia Bulletin, Vol. 26, No. 2, 2000
biological-environmental factors associated with increased
risk of schizophrenia. These factors are mainly associated
with the pregnancy period or the birth process itself and are
usually called OCs (McNeil 1991). In fact, schizophrenia is
considered to have the strongest association with OCs of all
adult onset psychiatric disorders (Jablensky 1995). The
obstetric risk factors most consistently observed in the pre-
histories of people who later develop schizophrenia are
labor and delivery abnormalities (Verdoux et al. 1997), win-
ter birth (Torrey et al. 1997), prematurity (Hultman et al.
1997), and conditions associated with hypoxia (McNeil
1991; Buka et al. 1993; Dalman et al. 1999). Famine during
pregnancy, implicating nutritional factors, has recently been
reported (Susser et al. 1996). Schizophrenia has also been
linked to exposure to infectious agents during the perinatal
period and in early infancy (Mednick et al. 1994; Yolken
and Torrey 1995). These data suggest that adverse events of
pregnancy, birth, and the early infancy period may alter
brain development, resulting in a vulnerable brain that is
more likely to develop schizophrenia in adolescence or
adulthood. This vulnerability is hypothesized to be
increased in persons who are genetically susceptible to the
illness, which is inferred from the presence of a family his-
tory of illness in first-degree relatives (Tsuang and Faraone
19%).
As noted by Zornberg et al. (2000), the inconsistency
in reports about whether there is an association between
PPCs and schizophrenia may be due to various method-
ological differences. One possible problem is that most
definitions of PPCs reflect only indirect measures of
insults to the brain. Moreover, PPCs are heterogeneous in
their etiology. While they may represent a "family" of
abnormalities, the specific nature of different PPCs may
be of considerable relevance to the onset of diseases like
schizophrenia (Zornberg et al. 2000). This suggests that it
may be valuable to evaluate the independent and simulta-
neous effect of a number of PPCs corresponding to differ-
ent events or conditions of pregnancy.
A number of PPCs are candidates for study in rela-
tionship to schizophrenia or to precursors of schizophre-
nia, such as cognitive and neuromotor deficits in child-
hood. Given the range of possible PPCs, the selection of
particular variables should be based on a number of char-
acteristics that would make them biologically plausible
and methodologically feasible to investigate as risk fac-
tors for schizophrenia. Among the general requirements
are whether the PPCs occur frequently enough, whether
they can be measured adequately, and whether they have a
plausible etiological impact on the brain abnormalities
commonly found in schizophrenia. LBW clearly meets
the first two criteria, and fetal hypoxia is relevant to the
latter criterion. For example, events of pregnancy or birth
and delivery that cause hypoxia are considered biologi-
310
L J. Seidman et al.
cally relevant variables because hypoxia or more acute
instances of anoxia have a particularly pernicious effect
on the hippocampus (Hedner 1978) and basal ganglia
(Lou 1996), two of the brain structures considered to be
abnormal in schizophrenia (Shenton et al. 1997). Thus,
conditions that adversely affect the fetal blood supply of
oxygen—either of prolonged duration (chronic fetal
hypoxia) or severe acute episodes—constitute subsets of
PPCs that may be of particular developmental importance
Downloaded from https://academic.oup.com/schizophreniabulletin/article/26/2/309/1849323 by guest on 08 February 2022
to schizophrenia (Buka et al. 1993). In this study we
investigate three measures of PPCs in relation to cognitive
functioning at age 7: LBW, probable hypoxic-ischemic
complications, and chronic hypoxia.
PPCs and Childhood
Neuropsychological Deficits
LBW. LBW is considered to be a marker for newboms at
high risk for later neurological, psychiatric, and neuropsy-
chological problems because it is a likely indicator of
fetal growth problems and has been associated with pre-
natal risk factors, intrapartum complications, and neonatal
disease (Breslau 1995). LBW is a particularly attractive
marker because, compared with other neonatal measures
such as gestational age, it has the advantage of routine
and accurate measurement. LBW has been suggested to
be associated with a variety of cognitive difficulties and
psychiatric outcomes in children (Buka et al. 1992),
including the diagnosis of schizophrenia in adults (Rifkin
et al. 1994), although the results are not consistent for this
association (cf. McNeil 1995).
There is a substantial literature on IQ and LBW (cf.
Breslau 1995), much of it focusing on very low birth
weight. In all 10 studies reviewed by Breslau (1995),
LBW children between the ages of 6 and 14, compared
with normal birth weight children, had lower mean IQ
scores, after controlling for social class and demographic
indexes (e.g., age, sex, race, mother's education, socioe-
conomic class). These samples ranged from small (n = 28)
to moderately large (n = 591). Among a number of perina-
tal factors studied in relationship to IQ at age 7 in a large
subsample (n = 6,582) of the Boston cohort of the NCPP,
Rieder et al. (1977) reported that the strongest correlation
was with LBW (r = 0.12). Rifkin et al. (1994) showed that
LBW was associated with cognitive dysfunction in
patients with schizophrenia.
The question of whether LBW is associated with gen-
eralized or specific cognitive deficits is not completely
resolved. However, increasing research indicates that
LBW is associated with roughly equal effect sizes on both
verbal and performance IQ (Klein et al. 1989; Breslau et
Prenatal/Perinatal Complications and Cognitive Functioning
al. 1994; cf. Breslau 1995). Breslau et al. (19%) demon-
strated that LBW children scored lower on tests measur-
ing various aspects of language (syntax, semantics,
phonology) and spatial, fine motor, tactile, and attention
abilities. Moreover, a linear trend (a gradient relationship)
between birth weight and cognitive functioning has been
observed, with IQ (Breslau et al. 1994; Hack et al. 1994)
and other neuropsychological measures (Breslau et al.
1996). While the current literature is not conclusive,
results seem to favor the proposition that there is a
roughly uniform association between LBW and a range of
cognitive abilities.
Hypoxic Conditions. A number of investigators have
hypothesized that a set of perinatal conditions indicating
prolonged or acute oxygen deprivation (hypoxia) to the
fetus would be a significant risk factor for adult psychosis
(cf. Buka et al. 1993) or other neuropsychological or neu-
ropsychiatric disturbances (Naeye and Peters 1987; Msall
et al. 1998). It is important to emphasize that no single
measure (e.g., Apgar scores) is sufficient to diagnose
hypoxia. Pediatricians have demonstrated that a variety of
prenatal and perinatal events can cause hypoxic-ischemic
damage to the neonate (Msall et al. 1998). The outcomes
of these conditions can range from absence of abnormal
neurological features or evidence of brain injury to signif-
icant neurological disease such as cerebral palsy or severe
mental retardation, or death (Robertson and Finer 1993).
Hypoxic-ischemic damage to the neonate can result
in germinal matrix hemorrhage, a complication of prema-
turity that is periventricular in location and, when severe,
can extend into the lateral ventricle. The relevance to
schizophrenia is twofold. First, children with these abnor-
malities show persistent ventricular enlargement, behav-
ioral deviations, and neuropsychological deficits, as well
as soft neurological signs—common characteristics of
children at risk for schizophrenia or features identified in
adults with schizophrenia (Murray and Harvey 1989).
Second, Murray and Harvey (1989) report that three
regions of the brain are especially linked to perinatal dam-
age (i.e., the basal ganglia, the hippocampus, and the lat-
eral ventricles), and these three regions are frequently
shown to be different in samples of patients with schizo-
phrenia than in controls in neuroimaging and autopsy
studies (Shenton et al. 1997).
Naeye and Peters (1987) analyzed prospectively col-
lected pregnancy and perinatal data, as well as cognitive
data collected at age 7, from 19,117 children participating
in the NCPP to determine if fetal, intrapartum, and neona-
tal hypoxia were associated with low IQ values.
Consistent with other studies, they found that socioeco-
nomic status (SES) strongly correlated with IQ. When
controlling for SES and other demographic factors, there
311
Schizophrenia Bulletin, Vol. 26, No. 2, 2000
were no significant associations of IQ with labor, delivery,
or neonatal variables, or with early pregnancy events that
can produce acute fetal hypoxia. On the other hand, they
found that antenatal disorders and conditions that can pro-
duce subacute or chronic fetal hypoxia correlated with
low IQ scores. These conditions and disorders included
maternal gestational anemia, hypotension, hypertension,
multiple births, and fetal growth retardation.
Zornberg et al. (2000) have argued that PPCs associ-
Downloaded from https://academic.oup.com/schizophreniabulletin/article/26/2/309/1849323 by guest on 08 February 2022
ated with fetal hypoxia are heterogeneous in etiology, and
some are only indirectly related to fetal brain develop-
ment, such as maternal hypertension (Buka et al. 1993).
They suggest that measures of fetal and neonatal compli-
cations linked more explicitly to neurological abnormali-
ties of mild to moderate severity, and which have been
associated clinically with hypoxic-ischemic encephalopa-
thy in full-term infants, may represent a more homoge-
neous set of conditions of particular relevance to the etiol-
ogy of schizophrenia. They tested this hypothesis by
examining the strength of association of various indexes
of fetal and neonatal complications with adult psychoses
in a sample of 693 subjects from the Providence cohort of
the NCPP. Schizophrenia and other nonaffective psy-
choses were most strongly associated with a theoretically
derived measure of probable hypoxic-ischemic complica-
tions, defined later (Zornberg et al. 2000).
In sum, there is evidence that LBW, both subacute or
chronic hypoxia, and complications associated with prob-
able hypoxic-ischemic encephalopathy can have signifi-
cant consequences for childhood behavior and cognitive
problems, including the later development of schizophre-
nia. In this study, we evaluated the relationship of two risk
factors for schizophrenia—PPCs and cognitive function-
ing at age 7—derived from the NCPP, a large epidemio-
logical study of pregnancy, birth, and development. We
assessed three measures of PPCs in relation to cognitive
functioning at age 7: LBW, presumed hypoxic insults, and
conditions reflecting possible chronic hypoxia. In addi-
tion, to determine whether the consequences on cognition
were relatively selective or widespread, rather than focus-
ing solely on IQ we studied a wide range of 13 measures.
This investigation was designed as a prelude to analyses
of the relationship between PPCs and family history of
psychosis and cognitive functioning at age 7.
Methods
Study Design and Baseline Data Collection. The NCPP
was initiated 40 years ago to investigate prospectively the
prenatal and familial antecedents of pediatric, neurological,
and psychological disorders of childhood. Twelve univer-
Schizophrenia Bulletin, Vol. 26, No. 2, 2000
sity-affiliated medical centers participated in this national
study, including two in New England (Harvard Medical
School and Brown University). The NCPP entailed a single-
study design involving the systematic collection of data
through the prospective observation and examination of
over 50,000 pregnancies through the first 7 years of life.
Obstetrical intake occurred between January 2, 1959, and
December 31, 1965. Cases were selected on the basis of a
sampling frame defined for each study center (Broman et al.
1985). Women in the study were representative of the
patients receiving prenatal care in each participating center.
At the conclusion of the study, a total of 55,908 births had
been recorded nationally, approximately 17,000 of which
occurred in Boston and Providence (the New England
cohorts). In the total population, followup rates for survivors
were 88 percent at 1 year of age, 75 percent at 4 years, and
79 percent at 7 years. Major findings from the NCPP have
been summarized by Niswander and Gordon (1972),
Broman et al. (1975), Nichols and Chen (1981), and
Broman etal. (1985).
Trained staff at each site recorded data from exami-
nations and interviews beginning at the time of registra-
tion for prenatal care, using standardized protocols, forms,
manuals, and codes. At the time of the first prenatal visit,
a complete reproductive and gynecological history, a
recent and past medical history, a socioeconomic inter-
view, and a family history were recorded. An SES index,
adapted from the Bureau of the Census and derived from
the education and occupation of the head of household
along with household income (Myrianthopolous and
French 1968), was assigned to each pregnancy. Prenatal
clinic visits were scheduled every month during the first 7
months of pregnancy, every 2 weeks during the 8th
month, and every week thereafter. An interval prenatal
history was recorded at each prenatal visit, along with
results of pertinent laboratory tests and physical exams.
After the mother's admission for delivery, trained
observers recorded the events of labor and delivery, and
the obstetrician in charge completed a summary of labor
and delivery protocols. The neonate was observed in the
delivery room and examined by a pediatrician at 24-hour
intervals in the newborn nursery. A neurological examina-
tion was performed at 2 days of age. Nurses' observations
and laboratory test results were recorded, and a study
physician completed a diagnostic summary of the nursery
period.
After the neonatal stage, the child was scheduled for
at least five subsequent assessments at ages 4 months, 8
months, 12 months, 4 years, and 7 years. Psychological
examinations were conducted at 8 months, 4 years, and 7
years of age. In this article, we are addressing neuropsy-
chological data collected at the final standardized data
point, at age 7. Family and social history information was
312
L.J. Seidman et al.
obtained from the mother at intake and the 7th year. Study
physicians prepared diagnostic summaries following the
1st and 7th year.
In the New England cohort, standardized measures of
cognitive abilities were acquired on 11,889 children at
approximately age 7. Of those assessed, 98.1 percent were
tested between 6.75 and 8 years of age. A few children
were tested when they were as young as age 6 or as old as
11. In many cases, the sample included multiple children
Downloaded from https://academic.oup.com/schizophreniabulletin/article/26/2/309/1849323 by guest on 08 February 2022
from the same family: 2 siblings, n = 1,740; 3 siblings, n
- 455; 4 siblings, n = 83; 5 or 6 siblings, n = 10. The sex
of the children was approximately equal (51.1% males,
48.9% females).
Cognitive and Academic Achievement Measures at
Age 7. The 7-year assessment included a battery of 13
psychological tasks relevant to the study of cognition
(table 1). Those included in our analyses are seven sub-
tests of the Wechsler Intelligence Scale for Children
(WISC; Wechsler 1949); three tests from the Wide Range
Achievement Test (WRAT; Jastak and Jastak 1965); the
Bender Gestalt Test for Young Children (Koppitz 1964);
the auditory-vocal association test from the Illinois Test of
Psycholinguistic Abilities (ITPA; Kirk et al. 1968); and
the tactile finger recognition test (TFRT; Reitan 1964)
from the Reitan-Indiana Neuropsychological Battery. All
variables had adequate ranges and approximately normal
distributions, with the exception of the TFRT. All vari-
ables were scored in the same direction (higher is better)
with the exception of the Bender Gestalt, where a higher
score meant more errors. As throughout the NCPP, data
quality for these measures was enhanced through system-
atic training, monitoring, and data-checking procedures.
We have conducted analyses demonstrating the psy-
chometric properties of the cognitive measures used at
age 7. We compared published normative data with the
results for the Boston and Providence cohorts. The sample
has somewhat lower mean scores for the WISC (mean
full-scale IQ - 95.3, standard deviation [SD] = 14.1) and
the WRAT (mean reading standard score = 99.0, SD =
15.6, range 45—165) than the normative sample, but val-
ues are consistent with expectations because of the ethnic
composition and lower SES of the sampling frame. The
intercorrelations between the WISC verbal and perfor-
mance scales are essentially identical to those from the
sample on which the measure was developed (Wechsler
1949), as are the intercorrelations among the WRAT sub-
tests (Jastak and Jastak 1965). Finally, 3-month test and
retest results for full-scale IQ with the Providence cohort
are identical to published data for a separate community
sample of youth ages 5-14 (Pearson correlation coeffi-
cient = 0.82) and superior for the stability of WRAT read-
ing and spelling (0.91 and 0.84, respectively) (Brown et
Prenatal/Perinatal Complications and Cognitive Functioning Schizophrenia Bulletin, Vol. 26, No. 2, 2000

Table 1. Neuropsychologlcal battery of tests given at age 7

Teal Description
WISC verbal tests
Vocabulary A measure of fund of knowledge as reflected in word definitions (scale score)
Information A sample of acquired knowledge gained through education (scale score)
Comprehension A measure of verbal knowledge of social mores, judgment, and reasoning
(scale score)

Downloaded from https://academic.oup.com/schizophreniabulletin/article/26/2/309/1849323 by guest on 08 February 2022

Digit span A measure of short-term verbal memory, including working memory (scale
score)
WISC performance tests
Picture arrangement A measure of the ability to interpret and reorder out-of-sequence cartoons
(scale score)
Block design A measure of visual-constructional ability (scale score)
Digit symbol/coding A measure of psychomotor processing (scale score)

WRAT tests
Reading A measure of single word 6ral reading (raw score)
Spelling A measure of written spelling (raw score)
Arithmetic A measure of written calculations and number knowledge (raw score)
ITPA auditory-vocal association test A measure of analogical reasoning using an oral sentence completion tech-
nique (raw score)
Bender Gestalt Test for Young A measure of visual-motor integration, copying figures with a pencil, using the
Children Koppitz scoring system (total score: distortions, rotations, integrations, per-
severations)
Tactile finger recognition test1 A measure of tactile perception (total number of fingers recognized)
Note.—ITPA - Illinois Test of Psycholinguists Abilities; WISC . Wechsler Intelligence Scale for Children; WRAT - Wide Range
Achievement Test
1
From the Reitan-lndiana Neuropsychological Battery.

al. 1989). These analyses indicate that the administration
and results of cognitive assessments in the New England
NCPP cohorts are consistent with, and as reliable and
valid as, other published normative samples.
PPCs. We used three variables as measures of PPCs:
LBW (weight less than 2,500 grams at birth), probable
hypoxic-ischemic complication (HI-P; see below), and
chronic hypoxia (see below).
We classified participants as demonstrating HI-P
according to signs of abnormal fetal and neonatal devel-
opment obtained during a neonatal neurological examina-
tion and/or based on the presence of a pattern of condi-
tions suggesting compromise to intrauterine growth and
development. Participants were coded as evidencing HI-P
if they were bom at 37 weeks or more of gestation and
met at least one of the following four criteria, which can
be grouped under two categories, A and B:
2. Postterm birth with preeclampsia.
B. Neonatal neurological abnormalities in full-term baby
without seizures.
3. Hyperactivity (suspected or definite).
4. Hypotonia (suspected or definite).
The following operational definitions were used:
• SGA: lowest 10th percentile of birth weight for each
week of gestational age.
• Postterm birth: 42 or more weeks of gestational age.
•Preeclampsia: clinical rating of mild to severe
preeclampsia, based on blood pressure readings, protein-
uria, and edema.
• Meconium staining and uterine bleeding (during any
trimester): clinical rating based on obstetrician report
• Hyperactivity and hypotonia: clinical rating based on
pediatric neurological examination at birth.

A. Patterns of disordered growth and development dur-
ing a pregnancy with complications.
1. Small for gestational age (SGA), with preeclampsia,
meconium staining of the amniotic fluid, or uterine
bleeding.
This classification approach is a minor modification of
recent work by our group (Zomberg et al. 2000).
Possible chronic hypoxia was defined as it was in
previous analyses from the NCPP (Naeye and Peters
1987) and our previous work (Buka et al. 1993, 1998).

313
Schizophrenia Bulletin, Vol. 26, No. 2, 2000
Subjects were coded as positive for presumed chronic
fetal hypoxia if prenatal records indicated one or more of
the following: (1) mild to severe preeclampsia (see
above), (2) maternal hypertension (i.e., diastolic blood
pressure during pregnancy of 95 mm Hg or greater), (3)
maternal hypotension (i.e., diastolic blood pressure during
pregnancy of less than 60 mm Hg), or (4) gestational dia-
betes (based on insulin therapy, insulin reaction, or blood
sugar 200 mg or greater during pregnancy).
Data Analysis. We performed principal component analy-
sis with varimax rotation in SAS PROC FACTOR (SAS
Institute 1997) using the 13 cognitive variables to create
our age 7 outcome variables. The scree plot and eigenval-
ues very close to or above 1 were used to determine the
final factor solution. We also report the relationship of
PPCs to me 13 test scores that compose the factor analysis.
In evaluating the relationship of PPCs to the cognitive fac-
tors, we controlled for possible confounders of the rela-
tionship between PPCs and cognitive measures, including
SES, race (Caucasian vs. non-Caucasian), mother's age at
birth, age of child at assessment, and NCPP site
(Providence vs. Boston). These variables were selected
because they have been found to be associated with cogni-
tive measures in other studies and frequently used as
covariates in analyses of PPCs in relationship to cognitive
outcome measures. The relationship of PPCs and age 7
cognitive measures was assessed using the general linear
mixed model (Cnaan et al. 1997). We performed a series of
linear regression models using SAS PROC MIXED (SAS
Institute 1997) adjusting for the correlation of observations
from siblings nested within a family. We specified a com-
pound symmetry (exchangeable) covariance structure,
which assumes that measurements on any two siblings
within a given family have the same covariance (i.e., are
interchangeable). All pairwise interactions between the
potential confounders and main effects for PPCs were
included in all of these regression models.
We performed separate analyses for each of the
derived factors. For each factor, we fit five models: one
with no PPC, one with just LBW, one with just HI-P, one
with just chronic hypoxia, and one with all three main
effect terms for PPCs. We also calculated approximate
measures of how much variance is accounted for by the
model (pseudo-^? squared, ignoring the correlation
between the siblings) to qualitatively assess how much
additional information is accounted for by each measure
of PPC independently and together. To assess the sensitiv-
ity of our results to certain influential subjects, the regres-
sion models were refit having excluded 12 subjects with
large residuals and/or high influence (measured using
Cook's distance). The results remained very similar, so all
subjects were included in the final models.
314
L J. Seidman et al.
Results
Principal Components Analysis of Cognitive Variables.
We determined that a three-factor solution wiui a varimax
rotation provided considerable variable reduction with a
reasonable conceptual interpretation, although we also
applied our regression model to all 13 individual mea-
sures. One of the subtests (WISC block design) loaded
very similarly on factors 2 (verbal-conceptual abilities)
Downloaded from https://academic.oup.com/schizophreniabulletin/article/26/2/309/1849323 by guest on 08 February 2022
and 3 (perceptual-motor abilities). We chose to include
that subtest as a variable in factor 3 because it appeared to
be conceptually closer to other variables on that factor.
Table 2 provides the factor loadings, along with our labels
for these factors. We repeated the factor analysis, partial-
ing out age at assessment, as well as excluding subjects
with full-scale IQ less than 70, but the resulting factor
structure was very similar.
New cognitive variables were constructed by sum-
ming each of the z-scored (normalized) individual mea-
sures with factor loadings that exceeded 0.45 in absolute
magnitude with weight equal to 1. For the Bender Gestalt
test, the negative of the score was used. These new factors
were normalized so that they had a mean of 0 and a vari-
ance of 1. The new cognitive factors showed a moderately
high degree of intercorrelation: factor 1 (academic
achievement skills) and factor 2 (verbal-conceptual abili-
ties), r = 0.648; factor 1 and factor 3 (perceptual-motor
abilities), r = 0.571; factor 2 and factor 3, r = 0.545. As
expected, the correlations between observations on sib-
lings within a given family were moderate (r = 0.34 for
factor 1; r = 0.42 for factor 2; r = 0.27 for factor 3). For
the TFRT, we also fit regression models where the out-
come was dichotomized, so that a score of 9 or higher was
considered to be normal, and a score of 8 or less was
abnormal. These results were consistent with those where
the outcome was continuous. The results from the contin-
uous outcome are reported.
PPCs. The relationship of PPCs to each other was tested
to determine their agreement in the full study sample. We
calculated the co-occurrence (kappa coefficient) of the
three indicators of PPCs. We found that the co-occurrence
was relatively low: HI-P and chronic hypoxia, 0.13; HI-P
and LBW, 0.12; chronic hypoxia and LBW, 0.01. The
prevalence of the PPCs in the sample was HI-P, 10.2 per-
cent; chronic hypoxia, 12.7 percent; and LBW, 8.2 percent
Relationship Between PPCs and Cognition. All three
measures of PPCs are significantly associated with
lower cognitive performance for each of the three fac-
tors, after controlling for the various confounders. The
results were similar in the Providence and Boston sites.
Table 3 displays the results for the models for the fac-
PrenataiyPerinatal Complications and Cognitive Functioning Schizophrenia Bulletin, Vol. 26, No. 2, 2000

tors, with one PPC in the model and when all PPCs
were controlled simultaneously. Table 4 displays the
results for the 13 individual test scores when all PPCs
were controlled simultaneously. Because the PPCs were
dichotomous and because the outcomes were standard-
ized to have a mean of 0 and variance of 1, the beta
coefficients in tables 3 and 4 can be interpreted as the
estimated effect in standard units resulting from one
PPC while holding the other PPCs and confounders
Discussion
In this study, we evaluated the relationship between two
classes of risk factors for schizophrenia—PPCs and neu-
ropsychological functioning at age 7—in a large, prospec-
tive, longitudinal study of pregnancy, birth and develop-
ment, and neuropsychological outcome. A principal
components analysis of 13 test variables led to three fac-

Downloaded from https://academic.oup.com/schizophreniabulletin/article/26/2/309/1849323 by guest on 08 February 2022

fixed.
A review of the effect sizes indicates that LBW had
the strongest association with all three factors, regardless
of whether the regression was run with one or three
PPCs in the model (see table 3). HI-P was also strongly
associated with the three factors, although its relation-
ship to the verbal-conceptual abilities factor was some-
what weaker. Chronic hypoxia also had a significant
effect on all three factors, although it had the smallest
effect sizes. The effect sizes between PPCs and cognitive
factors were consistently largest with factor 3 (percep-
tual-motor abilities) and smallest with factor 2 (verbal-
conceptual abilities). The largest effects on individual
tests (all of which are considered to be small effects)
were noted between LBW and WISC picture arrange-
ment, WRAT arithmetic, WRAT reading, and the Bender
Gestalt test (table 4).
tors: academic achievement skills, verbal-conceptual abil-
ities, and perceptual-motor abilities. We measured the
relationship between these neuropsychological factors and
three measures of PPCs: LBW, HI-P, and chronic hypoxia.
The measures of PPCs were relatively independent of
each other. All three PPC measures were significantly
associated with lower neuropsychological performance,
after controlling for various sociodemographic con-
founders and for each other. The effect sizes were gener-
ally small. LBW had the strongest association with the
neuropsychological functions, followed by HI-P. Maternal
conditions suggesting chronic hypoxia also had a signifi-
cant effect on all factors (though it was the smallest
effect). The effect sizes between PPCs and cognitive fac-
tors were consistently largest with perceptual-motor abili-
ties, intermediate with academic achievement skills, and
smallest with verbal-conceptual abilities.

Table 2. Principal component analysis of 13 cognitive variables at age 7 1

Factor 1 Factor 2 Factor 3
Academic achievement Verbal-conceptual Perceptual-motor
Variables skills abilities abilities
WRAT arithmetic raw score 0.740 0.315 0.278
WRAT reading raw score 0.879 0.243 0.107
WRAT spelling raw score 0.882 0.221 0.157
WISC block design scale score 0.178 0.491 0.461
WISC digit symbol/coding scale score 0.332 -0.132 0.476
WISC comprehension scale score 0.022 0.731 0.042
WISC digit span scale score 0.545 0.313 0.159
WISC information scale score 0.414 0.673 0.047
WISC picture arrangement scale score 0.292 0.542 0.292
WISC vocabulary scale score 0.296 0.770 0.063
ITPA auditory-vocal association raw score 0.435 0.652 0.165
Bender Gestalt Koppitz raw score -0.377 -0.334 -0.501
Tactile finger recognition raw score 0.009 0.149 0.767
Eigenvalue 5.636 1.167 0.946
Variance proportion 0.434 0.090 0.073
Note.—ITPA - Illinois Test of Psycholinguistic Abilities; WISC - Wechsler Intelligence Scale for Children; WRAT = Wide Range
Achievement Test.
1
Boldface denotes variables defining the factor.

315
Schizophrenia Bulletin, Vol. 26, No. 2, 2000 LJ. Seidman et al.

These results are consistent with the literature on

LBW and cognition (Breslau 1995) and with a prior study
from a subsample of the NCPP (Rieder et al. 1977)
CO
demonstrating that LBW is a risk factor for abnormal cog-
O CM
LLT CO CO CO CO CO nitive development, after potential confounders are
o
S2. o q s o O
O.
o
addressed. It is clear that LBW has a significant effect on
neuropsychological function, even after controlling for
**
Irth

'c ** # « j *
SES and other sociodemographic confounders. LBW may

-0.1 79**
-0.225**

-0.185**
-0.176**

-0.154**
m S ~
-0.211"

have the strongest correlation with cognitive factors

Downloaded from https://academic.oup.com/schizophreniabulletin/article/26/2/309/1849323 by guest on 08 February 2022

Low

M because it is more precisely measured than the other fac-

tors. While LBW is undoubtedly associated with some
biological features, it had very little relationship to the
two measures of hypoxia used in this study. The biologi-
cal bases for the observed deficits associated with LBW
might also include other classes of PPCs not evaluated in
this study such as viruses, substance use, or poor nutri-
tion, or with genetic factors, including risk for psychotic
2
I

I
1
1
1

a>
LO
CM
LO
CM
CO
CM
LO
CM
CO
CM
CO
CM
illness.
•a .2 LU O O O O
X q q The results are also consistent with predictions made
O, O, 2 2
£ by Zornberg et al. (2000), who hypothesized that pre-
J *
sumed hypoxic insults^—based on measures of fetal and
:lent

* *
o
-0.1 13*'

-0.0 72*'
-0.0 78*'
-0.0 94*'

u
-0.0 86*

neonatal complications linked more explicitly to neuro-

a

LO
iroi

a Sf8 q logical abnormalities of mild to moderate severity in the

o newborn—would have a larger effect on neuropsychologi-
o cal performance than indirect measures of hypoxia based
CO
on maternal conditions of pregnancy. In this study, HI-P
CS showed consistendy larger effect sizes than measures of
V CB chronic hypoxia on neuropsychological function at age 7.
1 schem
orsaft

The two measures of hypoxia co-occurred infrequently

co" o> CO CO o" and had independent effects on cognition, suggesting that
07 CM CM CM CM CM
8
•g o q q q q they may be tapping different sources of presumed
i J2- 2 2
5 hypoxia. Alternatively, the two measures of hypoxia may
* * ** * be weakly associated because of methodological reasons,
c ** * * *
.1 most likely the indirect indication of potential insult in the
.901

107*

133*
153*

182*

CO S u *
o
*3 LO chronic hypoxia variable. Nevertheless, our results indi-
O
«S E CO
j cating a significant relationship between chronic hypoxia
?
CO
s
a
o
and cognition are consistent with that reported by Naeye
and Peters (1987).
Itiv

c A question raised by Breslau (1995) is whether cer-

CO tain neuropsychological functions, such as visual motor
o
o
JO JO a s °
w .JS o deficits, are more strongly associated with PPCs (such as
: skil
skil

r*-
ies
:ies

g CO V

1
CO
© CD LU y o. LBW) than other neuropsychological functions. While it
CD c c •5 <n E :
CO CD CO
8
is true that there was some ordering of effects, with acade-
E CO
-9 E CO •9 § ^ mic achievement skills and perceptual-motor abilities
ptual-m tor;

"S
ptual-m tors
imic acl eve

imic acl eve

tual

|ery

•S 8 5
2 CD ffi o
^. more strongly associated with LBW and HI-P than were
• ^
a. o "r- CL o 5 o V
o
i mode
r mode

l-conce

o 8 •3. D a verbal-conceptual abilities, all factors had significant rela-

C CO
tionships with PPCs. Thus, while the use of a wide range
redl

en
! 8
Q. 8. 2 8 CO
cu s of tests and resulting factors provides a more differenti-
•§ ated picture than overall IQ, the significant associations
o o o
o
CD
8. 8 i ? CD
CL
I .1
Ion

o CO
between all three measures of PPCs with all three neu-
CD c\i CO cj CO
CO
0>
.Q
S
S
o
CO
O
t5
CO
o
CO
o
CO
CO
CD
C
o
CO
o
T5 T3 ?
O
"1
CO •S
3 O
ropsychological factors suggests relatively generalized
deficits, consistent with the literature (Breslau 1995;
v
Usi

Usi

oc
LL LL LL LL LL LL Breslau et al. 1996). Nevertheless, it must be recognized

316
Table 4. OC predictors of age 7 cognitive functioning tests after adjusting for confounders1
Probable Hypoxlc-lschemic
Complication Chronic Hypoxla Low Birth Weight
Regression effects using all 3 OCS Beta Beta Beta
per model for Individual Herns coefficient (SE) coefficient (SE) coefficient (SE)
Factor 1
WRAT reading -0.090** (0.029) -0.049 (0.026) -0.163**** (0.032)
WRAT spelling -0.125**** (0.029) -0.042 (0.025) -0.145**** (0.032)
WRAT arithmetic -0.126**** (0.029) -0.087*** (0.026) -0.185**" (0.032)
WISC digit span -0.099** (0.031) -0.047 (0.027) -0.123*** (0.034)
Factor 2
WISC vocabulary -0.035 (0.028) -0.039 (0.025) -0.106*** (0.031)
WISC comprehension -0.094** (0.031) -0.111"** (0.027) -0.004 (0.034)
WISC information -0.002 (0.030) • -0.070** (0.026) -0.158**** (0.033)
ITPA auditory-vocal association -0.113**** (0.029) -0.061* (0.026) -0.112*** (0.032)
WISC picture arrangement -0.061* (0.030) -0.025 (0.027) -0.215"** (0.033)
Factor 3
Tactile finger recognition -0.001 (0.031) -0.079** (0.027) -0.121*" (0.034)
Bender Gestalt visual-motor 0.137"** (0.030) 0.085** (0.027) 0 . 1 6 0 " " (0.033)
WISC digit symbol/coding -0.127**" (0.032) 0.011 (0.028) -0.050 (0.035)
WISC block design -0.086** (0.030) -0.076** (0.027) - 0 . 1 4 5 " " (0.033)
Note.—ITPA = Illinois Test of Psycholinguists Abilities; OC <= obstetric complication; SE = standard error; WISC = Wechsler Intelligence Scale for Children; WRAT - Wide Range
Achievement Test.
1
Values are adjusted for socioeconomlc status, race, mother's age at birth, age of child at assessment, and National Collaborative Perinatal Project site.
*p < 0.05; "p < 0.01; '"p < 0.001; ""p < 0.0001

i
CD

£
z
o

Downloaded from https://academic.oup.com/schizophreniabulletin/article/26/2/309/1849323 by guest on 08 February 2022

Schizophrenia Bulletin, Vol. 26, No. 2, 2000
that this inference is tentative because it is based on a sin-
gle evaluation at age 7. It is possible that patterns of asso-
ciation between these PPCs and neuropsychological func-
tions may change with normal or abnormal development.
For example, as verbal-conceptual abilities become
increasingly essential in adolescence, a previously latent
vulnerability may emerge and be more strongly associated
with PPCs. This type of model has been proposed by
Weinberger (1987) to explain the emergence of frontal
lobe deficits in persons with schizophrenia who had been
previously (relatively) asymptomatic.
We regard the results for the three PPCs investigated
as a work in progress in terms of our conceptualization
and measurement of adverse events during the prenatal
and perinatal periods that may increase the risk for schiz-
ophrenia and premorbid conditions. We and others in the
field are attempting to move from a broad model of PPCs
as any deviations from a normal course of pregnancy to
more narrow definitions of the class, timing, and types of
PPCs that are both biologically plausible and empirically
justified risks for schizophrenia. In so doing, those work-
ing with prospective cohorts are challenged to use obstet-
rical information of 30-40 years past to approximate con-
ditions affecting the fetus that are of contemporary
clinical significance. Furthermore, given the relatively
low prevalence of schizophrenia and other psychoses,
investigation of single, rare OCs is not possible because
of limited statistical power for such analyses.
The choice of the two indexes of hypoxia examined
in this study reflects one of the many potential solutions to
this challenge. By considering conditions associated with
chronic hypoxia (rather than any PPCs), we have
attempted to limit the range of obstetric events under
inquiry. We recognize that many of the OCs included in
our definition of chronic hypoxia represent risks for, but
not necessarily the presence of, prolonged reduced oxy-
gen supply to the fetus, and that this is therefore an imper-
fect measure. Accordingly, the second hypoxia variable
(HI-P) attempts to focus more narrowly on the condition
of the neonate (i.e., size, gestational age, neonatal neuro-
logical symptoms) that might indicate the occurrence of a
hypoxic insult These criteria are also imperfect
Another solution that we find promising is that pro-
posed by Dalman et al. (1999). These authors describe
three potential etiologic mechanisms through which OCs
may affect the development of schizophrenia: (1) reduced
supply of nutrients to the fetus, (2) hypoxic or ischemic
insults during delivery, and (3) prematurity (with associ-
ated risks for intraventricular hemorrhage). In the future
we will continue to work with experts in fetal medicine,
neurology, and psychiatry to define and refine subclassifi-
cations of PPCs to advance identification of conditions
during the prenatal and perinatal periods that may inde-
318
L J. Seidman et al.
pendently or interactively (with genetic vulnerability)
increase the risk of schizophrenia.
This investigation was designed as a prelude to
analyses of the independent and interacting relationship of
PPCs and family history of psychosis on cognitive func-
tioning at age 7. In future analyses we plan to compare the
impact of these three PPCs on the neuropsychological
functions obtained in the factor analysis in interaction
with family history of psychotic illness. We intend to
Downloaded from https://academic.oup.com/schizophreniabulletin/article/26/2/309/1849323 by guest on 08 February 2022
extend analyses examining the relationship of PPCs,
genetic vulnerability (based on family history of schizo-
phrenia and affective psychoses), and full-scale IQ at age
7 (Seidman et al. 1999; Goldstein et al., this issue). It will
also be important to test whether the pattern of conse-
quences of PPCs will be the same in offspring of parents
with schizophrenia or affective psychosis as in healthy
controls. Rieder et al. (1997) found different effects
between PPCs and full-scale IQ in offspring of continuous
schizophrenia subjects than in a large sample of unse-
lected controls from the NCPP. Such an analysis will
enable a test of the specificity of certain PPCs on cogni-
tion in schizophrenia.
References
Auerbach, J.; Hans, S.; and Marcus, J. Neurobehavioral
functioning and social behavior of children at risk for
schizophrenia. Israel Journal of Psychiatry and Related
Science, 30:40-49, 1993.
Aylward, E.; Walker, E.; and Bettes, B. Intelligence in
schizophrenia: Meta-analysis of the research.
Schizophrenia Bulletin, 10:430-459, 1984.
Breslau, N. Psychiatric sequelae of low birth weight.
Epidemiologic Reviews, 17:96-106, 1995.
Breslau, N.; Chilcoat, H.; Delrotto, J.; Andreski, P.; and
Brown, G. Low birth weight and neurocognitive status at six
years of age. Biological Psychiatry, 40:389-397,19%.
Breslau, N.; Delrotto, J.; Brown, G.G.; Kumar, S.;
Ezhuthachan, S.; Hufnagle, K.G.; and Peterson, E.L. A
gradient relationship between low birth weight and IQ at
age 6 years. Archives of Pediatrics and Adolescent
Medicine, 148:377-383, 1994.
Broman, S.; Bien, E.; and Shaughnessy, P. Low Achieving
Children: The First Seven Years. Hillsdake, NJ: Lawrence
Erlbaum Associates, 1985.
Broman, S.H.; Nichols, P.I.; and Kennedy, W.A.
Preschool IQ: Prenatal and Early Developmental
Correlates. New York, NY: Halsted Press, 1975.
Brown, S J.; Rourke, B.P.; and Cicchetti, D. Reliability of
tests and measures used in the neuropsychological assess-
Prenatal/Perinatal Complications and Cognitive Functioning
ment of children. Clinical Neuropsychologist, 3:353-368,
1989.
Buka, S.L.; Goldstein, J.M.; Seidman, L.J.; Zornberg,
G.L.; Denny, L.R.; and Tsuang, M.T. Chronic fetal
hypoxia and other obstetric risk factors for psychotic ill-
ness: A replication study. [Abstract]. Schizophrenia
Research, 29:14,1998.
Buka, S.L.; Goldstein, J.M.; Seidman, L.J.; Zornberg,
G.L.; Donatelli, J.A.; Denny, L.R.; and Tsuang, M.T.
Prenatal complications, genetic vulnerability, and schizo-
phrenia: The New England Longitudinal Studies of
Schizophrenia. Psychiatric Annals, 29:151-156, 1999.
Buka, S i . ; Lipsitt, Li*.; and Tsuang, M.T. Emotional and
behavioral development of low-birthweight infants. In:
Friedman, S.L.; and Sigman, M.D., eds. The Psychological
Development of Low Birthweight Children (Annual
Advances in Applied Developmental Psychology, volume 6).
Norwood, NJ: Ablex Publishing Corporation, 1992. pp.
21-36.
Buka, S.L.; Lipsitt, L.P.; and Tsuang, M.T. Perinatal com-
plications and psychiatric diagnosis. Archives of General
Psychiatry, 50:151-156, 1993.
Cnaan, A.; Laird, N.M.; and Slasor, P. Using the general
linear mixed model to analyze unbalanced repeated mea-
sures and longitudinal data. Statistics in Medicine,
16:2349-2380, 1997.
Comblatt, B.A., and Keilp, J.G. Impaired attention, genet-
ics and the pathophysiology of schizophrenia.
Schizophrenia Bulletin, 20(l):31^6,1994.
Crow, T.J.; Done, DJ.; and Sacker, A. Childhood precur-
sors of psychosis as clues to its evolutionary origins.
European Archives of Psychiatry and Clinical
Neuroscience, 154:61-69, 1995.
Dalman, C ; Allebeck, P.; Cullberg, J.; Grunewald, C ; and
Koster, M. Obstetric complications and the risk of schizo-
phrenia. Archives of General Psychiatry, 56:234-240,
1999.
Erlenmeyer-Kimling, N., and Comblatt, B.A. Summary of
attentional findings in the New York high-risk project.
Journal of Psychiatric Research, 26:405-^26, 1992.
Fish, B.; Marcus, J.; Hans, S.L.; Auerbach, J.G.; and
Perdue, S. Infants at risk for schizophrenia: Sequelae of a
genetic neurointegrative defect: A review and replication
analysis of pandysmaturation in the Jerusalem Infant
Development Study. Archives of General Psychiatry,
49:221-235, 1992.
Geddes, J.R., and Lawrie, S.M. Obstetric complications
and schizophrenia: A meta-analysis. British Journal of
Psychiatry, 67:786-793, 1995.
319
Schizophrenia Bulletin, Vol. 26, No. 2, 2000
Goldstein, J.M.; Seidman, L.J.; Buka, S.L.; Horton, NJ.;
Donatelli, J.A.L.; Rieder, R.O.; and Tsuang, M.T. Impact
of genetic vulnerability and hypoxia on overall intelli-
gence by age 7 in offspring at high risk for schizophrenia
compared with affective psychoses. Schizophrenia
Bulletin, 26(2):323-334, 2000.
Hack, M.; Taylor, H.G.; Klein, N.; Eiben, R.;
Schztschneider, C ; and Mercuri-Minich, N. School-age
Downloaded from https://academic.oup.com/schizophreniabulletin/article/26/2/309/1849323 by guest on 08 February 2022
outcomes in children with birth weights under 750 g. New
England Journal of Medicine, 331:753-759,1994.
Hedner, T.H. Central monoamine metabolism and neona-
tal oxygen deprivation: An experimental study of the rat
brain. Acta Physiologica Scandinavica, 460(Suppl):l-34,
1978.
Hultman, CM.; Ohman, A.; Cnattingius, S.; Wieselgren,
I.M.; and Lidstrom, L.H. Prenatal and neonatal risk fac-
tors for schizophrenia. British Journal of Psychiatry,
170:128-133, 1997.
Jablensky, A. Schizophrenia: Recent epidemiologic
issues. Epidemiologic Reviews, 17:10-20, 1995.
Jastak, J.F., and Jastak, S. The Wide Range Achievement
Test. Wilmington, DE: Jastak Associates, 1965.
Jones, P.; Rodgers, B.; and Murray, R.M. Child develop-
mental risk factors for adult schizophrenia in the British
1946 birth cohort. Lancet, 344:1398-1402,1994.
Kirk, S.A.; McCarthy, JJ.; and Kirk, W.D. Illinois Test of
Psycholinguistic Abilities, Revised. Wood Dale, IL:
Stoelting, 1968.
Klein, N.K.; Hack, M.; and Breslau, N. Children who
were very low birthweight: Development and academic
achievement at nine years of age. Journal of
Developmental and Behavioral Pediatrics, 10:32—37,
1989.
Koppitz, E.M. The Bender Gestalt Test for Young
Children. New York, NY: Grune and Stratton, 1964.
Kremen, W.S.; Buka, S.L; Seidman, LJ.; Goldstein, J.M.;
Koren, D.; and Tsuang, M.T. IQ decline during childhood
and adult psychotic symptoms in a community sample: A
19-year longitudinal study. American Journal of
Psychiatry, 155:672-677,1998.
Lane, E.A., and Albee, G.W. Early childhood intellectual
differences between schizophrenic adults and their sib-
lings. Journal of Abnormal and Social Psychology,
68:193-195, 1964.
Lifshitz, M.; Kugelmass, S.; and Karov, M. Perceptual-
motor and memory performance of high-risk children.
Schizophrenia Bulletin, ll(l):74-84,1985.
Lou, H.C. Etiology and pathogenesis of attention-deficit
hyperactivity disorder (ADHD): Significance of prematu-
Schizophrenia Bulletin, Vol. 26, No. 2, 2000
rity and perinatal hypoxic-haemodynamic encephalopa-
thy. Acta Paediatrica, 85:1266-1271, 1996.
Marcus, J.; Hans, S.L.; Nagler, S.; Auerbach, J.G.; Mirsky,
A.F.; and Aubry, A. Review of the NIMH Israeli Kibbutz-
City Study and the Jerusalem Infant Development Study.
Schizophrenia Bulletin, 13(3):426-438, 1987.
McNeil, T.F. Obstetric complications in schizophrenic
parents. Schizophrenia Research, 5:89-101, 1991.
McNeil, T.F. Perinatal risk factors and schizophrenia:
Selective review and methodological concerns.
Epidemiologic Reviews, 17:107-112, 1995.
Mednick, S.A.; Huttunen, M.O.; and Machon, R.A.
Prenatal influenza infections and adult schizophrenia.
Schizophrenia Bulletin, 20(2):263-267, 1994.
Msall, M.E.; Bier, J.; LaGrasse, L.; Tremont, M.; and
Lester, B. The vulnerable preschool child: The impact of
biomedical and social risks on neurodevelopmental
function. Seminars in Pediatric Neurology, 5:52-61,
1998.
Murray, R.M., and Harvey, I. The congenital origins of
schizophrenia. Psychiatric Annals, 19:525-529,1989.
Myrianthopoulos, N.C., and French, K.S. An application
of the U.S. Bureau of the Census socioeconomic index to
a large, diversified patient population. Social Science in
Medicine, 2:283-299,1968.
Naeye, R.L., and Peters, E.C. Antenatal hypoxia and low
IQ values. American Journal of Diseases of Childhood,
141:50-54, 1987.
Nichols, P.L., and Chen, T.C. Minimal Brain Dysfunction:
A Prospective Study. Hillsdale, NJ: Lawrence Erlbaum
Associates, 1981.
Niswander, K.R., and Gordon, M. The Women and Their
Pregnancies. Washington, DC: U.S. Government Printing
Office, 1972.
Nuechterlein, K.H. Signal detection in vigilance tasks and
behavioral attributes among offspring of schizophrenic
mothers and among hyperactive children. Journal of
Abnormal Psychology, 92:4-28, 1983.
Orvaschel, H.; Mednick, S.; Schulsinger, F ; and Rock, D.
The children of psychiatrically disturbed parents:
Differences as a function of the sex of the sick parent.
Archives of General Psychiatry, 36:691-695, 1979.
Reitan, R.M. Manual of Administration and Scoring the
Reitan-Indiana Neuropsychological Battery for Children
(Aged 5 through 8). Indianapolis, IN: University of
Indiana Medical Center, 1964.
Rieder, R.O.; Broman, S.H.; and Rosenthal, D. The off-
spring of schizophrenics: n . Perinatal factors and IQ.
Archives of General Psychiatry, 34:789-799, 1977.
320
L J. Seidman et al.
Rifkin, L.; Lewis, S.; Jones, P.; Toone, B.; and Murray, R.
Low birth weight and schizophrenia. British Journal of
Psychiatry, 165:357-362, 1994.
Robertson, C.M.T., and Finer, N.N. Long-term follow-up
of term neonates with perinatal asphyxia. Clinical
Perinatology, 20:483-498, 1993.
Russell, A.J.; Munro, J.C.; Jones, P.B.; Hemsley, D.R.;
and Murray, R.M. Schizophrenia and the myth of intellec-
Downloaded from https://academic.oup.com/schizophreniabulletin/article/26/2/309/1849323 by guest on 08 February 2022
tual decline. American Journal of Psychiatry,
154:635-639, 1997.
SAS Institute. SAS/STAT Software: Changes and
Enhancements Through Release 6.12. Cary, NC: SAS
Institute, 1997.
Seidman, LJ.; Goldstein, J.M.; Buka, S I . ; Zornberg, G.L.;
Denny, L.R.; Donatelli, J.; Burbridge, J.; and Tsuang, M.T.
Effects of genetic vulnerability and obstetric complications
on cognitive functioning in offspring at high risk for psy-
chosis. Schizophrenia Research, 36:54,1999.
Shenton, ME.; Wible, C.G.; and McCarley, R.W. A review of
magnetic resonance imaging studies of brain abnormalities in
schizophrenia. In: Krishnan, KJLR., and Doraiswamy, RM,
eds. Brain Imaging in Clinical Psychiatry. New York, NY:
Marcel Dekker, 1997. pp. 297-380.
Susser, E.; Neugebauer, R.; Hoaek, H.W.; Brown, A.S.;
Lin, S.; Labovitz, D.; and Gorman, J. Schizophrenia after
prenatal famine: Further evidence. Archives of General
Psychiatry, 53:25-31, 1996.
Torrey, E.F.; Miller, J.; Rawlings, R.; and Yolken, R.H.
Seasonality of births in schizophrenia and bipolar disor-
der: A review of the literature. Schizophrenia Research,
28:1-38, 1997.
Tsuang, M.T., and Faraone, S.V. The case for heterogene-
ity in the etiology of schizophrenia. Schizophrenia
Research, 17:161-175,1995.
Tsuang, M.T., and Faraone, S.V. Epidemiology and
behavior genetics of schizophrenia. In: Watson, S.J., ed.
Biology of Schizophrenia and Affective Disease. New
York, NY: Raven Press, 1996. pp. 163-195.
Verdoux, H.; Geddes, J.R.; Takei, N.; Lawrie, S.; Bovet,
P.; Eagles, J.M.; Heun, R.; McCreadie, R.G.; McNeil,
T.F; O'Callaghan, E.; Stober, G.; Willinger, M.V.; and
Murray, R.M. Obstetric complications and age at onset in
schizophrenia: An international collaborative meta-analy-
sis of individual patient data. American Journal of
Psychiatry, 154:1220-1227, 1997.
Watt, N.F. Patterns of childhood social development in
adult schizophrenics. Archives of General Psychiatry,
36:160-165, 1978.
Wechsler, D. The Wechsler Intelligence Scale for Children.
New York, NY: The Psychological Corporation, 1949.
Prenatal/Perinatal Complications and Cognitive Functioning
Weinberger, D.R. Implications of normal brain develop-
ment for the pathogenesis of schizophrenia. Archives of
General Psychiatry, 44:660-669,1987.
Yolken, R.H., and Torrey, E.F. Viruses, schizophrenia and
bipolar disorder. Clinical Microbiology Review,
8:131-145, 1995.
Zornberg, G.L.; Buka, S.L.; and Tsuang, M.T. Hypoxic
ischemia-related fetal/neonatal complications and risk of
schizophrenia and other nonaffective psychoses: A 19-
year longitudinal study. American Journal of Psychiatry,
157:196-202,2000.
Acknowledgments
Preparation of this article was supported in part by an
award from the Stanley and National Association for
Research in Schizophrenia and Affective Disorders
Foundations to Dr. Larry J. Seidman, an award from the
Stanley Foundation to Dr. Stephen L. Buka, National
Institute of Mental Health Grants MH 55748 and 56956 to
Dr. Jill M. Goldstein, and National Institute of Mental
Health Grant MH 50647 to Dr. Ming T. Tsuang.
321
Schizophrenia Bulletin, Vol. 26, No. 2, 2000
The Authors
Larry J. Seidman, Ph.D., is Associate Professor of
Psychology, Harvard Medical School, Department of
Psychiatry at Massachusetts Mental Health Center
(MMHC), and Director of Neuropsychology, MMHC,
Boston, MA. Stephen L. Buka, Sc.D., is Associate
Professor, Department of Maternal and Child Health and
Epidemiology, Harvard School of Public Health, Boston,
Downloaded from https://academic.oup.com/schizophreniabulletin/article/26/2/309/1849323 by guest on 08 February 2022
MA. Jill M. Goldstein, Ph.D., is Associate Professor of
Psychiatry, Harvard Medical School, Department of
Psychiatry, MMHC. Nicholas J. Horton, Sc.D., is
Postdoctoral Fellow, Department of Biostatistics, Harvard
School of Public Health. Ronald O. Rieder, M.D., is
Professor of Clinical Psychiatry, Department of
Psychiatry, College of Physicians and Surgeons,
Columbia University, and Vice Chairman for Education,
New York State Psychiatric Institute, New York, NY.
Ming Tsuang, M.D., Ph.D., D . S c , is Stanley Cobb
Professor of Psychiatry, Department of Psychiatry,
Harvard Medical School, MMHC; Professor, Department
of Epidemiology, Harvard School of Public Health; and
Director, Harvard Institute of Psychiatric Epidemiology
and Genetics, Boston, MA.
 Announcement
AEP BOOQ European Psychiatry:
G R O W I N G TOGETHER IN DIVERSITY
The 10th Congress of the Association of European Psychiatrists (AEP) will
convene in Prague, Czech Republic, October 28 through November 1, 2000.

Downloaded from https://academic.oup.com/schizophreniabulletin/article/26/2/309/1849323 by guest on 08 February 2022

The scientific program will include main lectures, plenary sessions, section
symposia, symposia, debates, free communications, poster sessions, work-
shops, and courses.
For further information, contact:
AEP Congrasi Organizers
P.O. Box5OOOB
Tel Aviv 61 5OO, iBnael
Phonei +372-3-514001B/9
E-malli AEP2OOO@kenes.com
Wab: www, kenes .com\aep