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Maternal Infections and Subsequent Psychosis Among Offspring
Stephen L. Buka, ScD;
Ming T. Tsuang, MD, PhD;
E. Fuller Torrey, MD;
Mark A. Klebanoff, MD;
David Bernstein, MD;
Robert H. Yolken, MD
Arch Gen Psychiatry. 2001;58:1032-1037.
ABSTRACT
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Background We tested the hypothesis that maternal infections during pregnancy are
associated with the subsequent development of schizophrenia and other psychoses
in adulthood.
Methods We conducted a nested case-control study of 27 adults with schizophrenia
and other psychotic illnesses and 54 matched unaffected control subjects (matched
for sex, ethnicity, and date of birth) from the Providence, RI, cohort of
the Collaborative Perinatal Project. We retrieved stored blood samples that
had been obtained from these mothers at the end of pregnancy. These samples
were analyzed for total class-specific immunoglobulins and for specific antibodies
directed at recognized perinatal pathogens capable of affecting brain development.
Results Maternal levels of IgG and IgM class immunoglobulins before the mothers
were delivered of their neonates were significantly elevated among the case
series (t = 3.06, P = .003; t = 2.93, P = .004, respectively,
for IgG and IgM immunoglobulin-albumin ratios). Secondary analyses indicated
a significant association between maternal antibodies to herpes simplex virus
type 2 glycoprotein gG2 and subsequent psychotic illness (matched t test = 2.43, P = .02). We did not find significant
differences between case and control mothers in the serum levels of IgA class
immunoglobulins, or in specific IgG antibodies to herpes simplex virus type
1, cytomegalovirus, Toxoplasma gondii, rubella virus,
human parvovirus B19, Chlamydia trachomatis, or human
papillomavirus type 16.
Conclusions The offspring of mothers with elevated levels of total IgG and IgM immunoglobulins
and antibodies to herpes simplex virus type 2 are at increased risk for the
development of schizophrenia and other psychotic illnesses in adulthood.
INTRODUCTION
SCHIZOPHRENIA AND related psychotic illnesses are a class of pervasive
neuropsychiatric disorders of uncertain origin. Family, twin, and adoption
studies have identified a genetic component to schizophrenia and other psychotic
illnesses. However, specific genes have not as yet been identified.1, 2, 3, 4, 5
Epidemiological studies have identified several environmental factors associated
with these illnesses, many related to events that occur during pregnancy or
during the birth process. These include winter and spring birth, birth in
an urban area, prematurity, complications during labor and delivery, and extreme
famine during pregnancy.6, 7, 8, 9, 10
Studies have also suggested an association between exposure to infectious
agents during pregnancy and the subsequent development of schizophrenia,11, 12, 13 although findings
in this area are equivocal14, 15
and with the occurrence of infections in early infancy.16, 17
This body of research suggests that prenatal and perinatal infections and
other environmental insults that adversely affect infant brain development
may result in schizophrenia in later life, most likely in genetically susceptible
individuals.4, 18, 19, 20
The Collaborative Perinatal Project (CPP) was a prospective cohort study
directed at the identification of perinatal factors with adverse effects on
infant and child development. This study monitored more than 55 000 pregnancies
in 12 study sites in the United States between 1959 and 1966. Cohort mothers
were intensively studied during pregnancy and their infants were evaluated
for physical and intellectual development during the first 7 years of life.21, 22 In addition to detailed clinical
evaluations, blood samples were obtained from the mothers and stored in a
repository for further analyses.23 Data generated
by the CPP study have led to the increased understanding of the effect of
infections, nutrition, and other perinatal factors on childhood neurologic,
cognitive, and physical development.24, 25, 26, 27, 28, 29
This article is a report of the findings from a follow-up study in adulthood
of offspring who had been enrolled in the CPP cohort, to test the hypothesis
that maternal infections during pregnancy are associated with the development
of schizophrenia and other psychoses in adult life.
SUBJECTS AND METHODS
The study sample was drawn from the Providence, RI, cohort of the CPP.
Pregnant women were enrolled during clinical visits and selected to be representative
of patients receiving prenatal care at each of the 12 study sites. The Providence
cohort includes 3804 surviving offspring of a sample of 3078 pregnant women.30 Data from examinations and interviews were recorded
by trained staff beginning at the time of registration for prenatal care,
using standardized protocols. Maternal blood samples were collected at registration,
approximately every 2 months after registration, and when the mother was delivered
of the neonate. The samples were stored at National Institutes of Health repositories
at -20°C.
CASE SERIES
Members of this cohort with psychotic illness were identified through
a 2-stage diagnostic assessment procedure. In stage 1 subjects with possible
psychotic illness were identified through (1) personal interviews and/or (2)
record linkage with psychiatric treatment facilities. In a first interview
study, as described previously,30 928 subjects
were selected for follow-up and 693 interviewed (75%) using the Diagnostic Interview Schedule Version III.31
In a second study,32 we selected an additional
775 subjects for follow-up and interviewed 574 (74%). A total of 1267 follow-up
interviews were completed; 29 of these subjects reported clinically relevant
psychotic symptoms. Record linkage efforts identified an additional 14 subjects
with a history of psychiatric treatment for a psychotic illness. For the second
stage, subjects were contacted again and interviewed by a trained diagnostic
interviewer using the Structured Clinical Interview for
DSM-IV.33 Trained diagnosticians (2
clinical psychologists, 2 adult psychiatrists) then completed best-estimate
consensus diagnoses according to the DSM-IV criteria,
based on interview data and medical record review. Diagnostic interviews were
completed for 34 subjects; medical records alone were available for the remaining
9 subjects.
Of the 43 potential subjects with psychosis, 16 were evaluated as being
nonpsychotic, with diagnoses including mild mental retardation, major depressive
disorder (without psychosis), posttraumatic stress disorder, substance abuse,
and obsessive-compulsive disorder. The remaining 27 subjects were determined
to have a major psychotic disorder, including schizophrenia (n = 13), schizophreniform
disorder (n = 1), bipolar disorder with psychotic features (n = 2), brief
psychosis (n = 3), and psychosis not otherwise specified (n = 8). These diagnostic
procedures were completed prior to and independent of the analysis of maternal
serum samples.
CONTROL SERIES
For each of the 27 subjects with psychosis, 2 healthy matched controls
were selected, matched for sex, ethnicity, and date of birth. Controls were
selected from an unaffected subset of 137 of the 693 subjects assessed in
the first interview study, who received no Axis I psychiatric diagnoses. Cases
and controls were stratified into 4 sex and ethnic groups (white or African
American), and within strata sorted by month of birth. The 2 closest controls
within each stratum were selected. In 4 instances there were no remaining
control subjects available within the stratum, resulting in 1 instance in
which a female control was selected for a male case, and 3 instances in which
white controls were selected for African American cases. Month of birth for
controls was within 2 months of the matched case for 76% of the controls (n
= 41) and within 3 months for 89% of the controls (n = 48). Human subjects
approval was granted by human studies review groups at Harvard University,
Boston, Mass, the National Institute of Child Health and Human Development,
Rockville, Md, and local psychiatric facilities. Written consent was obtained
from all interviewed study participants.
PROCESSING OF SERUM SAMPLES AND IMMUNOGLOBULIN MEASUREMENTS
For each study participant, a maternal blood sample was obtained from
the National Institutes of Health repository for the last collection obtained
during pregnancy (usually when the mother was delivered of the neonate). Levels
of total IgG, IgM, IgA, and albumin were measured by laser rate nephelometry.34 For each sample, the level of immunoglobulin was
analyzed in terms of absolute concentrations (measured in milligrams per deciliter)
as well as a ratio of the concentration of immunoglobulin to the concentration
of albumin (immunoglobulin-albumin ratio) to control for individual differences
related to hemodilution that can occur during pregnancy35
or differential evaporation that might occur during sample storage.
Levels of specific IgG class antibodies to cytomegalovirus, rubella
virus, Toxoplasma gondii, human parvovirus B19, herpes
simplex virus type 1, herpes simplex virus type 2 (HSV-2) virion antigen (HSV-1)
and Chlamydia trachomatis were measured by solid-phase
enzyme immunoassay.36 A typical protocol is
as follows: wells of microtiter plates coated with target antigens (obtained
from KMI Diagnostics Inc, Minneapolis, Minn) were reacted with test serum
diluted 1:100 in phosphate-buffered saline solution at pH 7.4 containing 0.1%
polysorbate (Tween) 20. Following incubation for 2 hours at 37°C, the
plates were washed 5 times with phosphate-buffered saline solution containing
0.1% polysorbate 20, and incubated with peroxidase-labeled anti–human
IgG. Following incubation for 1 hour at 37°C, the plates were washed 5
times and incubated with 2-2'-azino-bis[3-ethylbenzthiazoline-6-sulfonic
acid]–hydrogen peroxide peroxidase substrate. Followingreaction for
30 minutes, the amount of color generated by reaction between the antigen-bound
enzyme and the soluble substrate was quantitated by means of a microplate
colorimeter at a wavelength of 450 nm. Assays for the same analyte performed
using different microtiter plates were standardized by the use of standard
curves generated from standard samples run on each assay plate. Solid-phase
enzyme immunoassays were performed for the measurement of IgG antibodies to
HSV-2 type-specific glycoprotein gG236 and
converted to log values to generate a scale equivalent to that of the optical
density results.37 Immunoassays were performed
for the measurement of antibodies to human papillomavirus type 16 using solid-phase
viral-like particles cloned and expressed in baculovirus.38
All samples were analyzed under code, with the laboratory performing the studies
being unaware of the clinical status of the study individuals.
STATISTICAL ANALYSIS
Demographic, familial, and perinatal characteristics of the case and
control groups were compared using the  2 and t tests (2-tailed). To test our primary study hypothesis, we conducted
analyses that considered the matching of 2 controls per case to test for differences
in maternal immunoglobulin levels between the case and control groups. For
each triplet, we calculated the difference between the case value and the
average for the 2 controls and computed a single sample t test on these differences. Similar analyses were conducted to test
secondary hypotheses regarding IgG antibodies to specific pathogens. As noted
earlier, 4 cases and controls were imperfectly matched. Two sets of analyses
were conducted, including and excluding these control subjects.39
We conducted a series of restricted analyses to further address potential
confounding by maternal mental illness, family socioeconomic status (SES),
and other factors.
RESULTS
There are no significant differences between the 27 subjects with psychosis
(cases) and 54 matched controls for any of the sample characteristics examined
(Table 1). Compared with the entire
surviving cohort of 3804 subjects from which the current sample was drawn,
the case series includes a higher proportion of males (77.8%), with a comparable
proportion among controls, as a result of matching. Rates of all other demographic,
family, and perinatal variables for the case and control series were comparable
to the larger cohort from which they were sampled.
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Table 1. Demographic and Clinical Characteristics of Case and Control Subjects*
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We considered several potential risk factors that might occur more commonly
among the pregnancies and births of case subjects and might confound any noted
association between signs of prenatal infection and psychosis. There were
no significant differences between the case and control groups relating to
season of birth, late prenatal care, or maternal age or education. Family
SES (a composite index of maternal and paternal income, educational level,
and occupation at birth)40 and maternal smoking
during pregnancy were lower and weight gain during pregnancy greater among
the case sample but these differences were not statistically significant.
These differences remained nonsignificant when subjected to the matched-set
analyses described earlier.
Levels of total maternal IgG and IgM, but not IgA, class immunoglobulins
were significantly elevated among the case series (Table 2). Differences in the IgG-albumin and IgM-albumin ratios
were particularly pronounced, with differences at the P = .002 level for both ratios. The groups did not differ in terms of
IgA-albumin ratios.
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Table 2. Total Class-Specific Immunoglobulins and Albumin Measured
in the Serum Samples of Case and Control Mothers When Delivered of the Neonates*
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To explore the potential source of these elevated levels of total maternal
IgG class immunoglobulins, we conducted assays for IgG antibodies to infectious
agents of known neuropathologic potential. As summarized in Table 3, we did not observe a significant association between psychosis
and IgG antibodies to T gondii, rubella, cytomegalovirus,
or HSV-1. However, as given in Table 3 and shown in Figure 1, there was
a significant and graded association between maternal antibodies to HSV-2
and adult psychosis. Subjects whose maternal antibodies to HSV-2 exceeded
the 75th percentile of the control sample had an odds ratio of 3.4 for psychosis;
those whose maternal antibodies exceeded the 90th percentile had an odds ratio
of 4.4. Since antibodies to the virion-derived antigens used in standard solid-phase
immunoassays can bind to cross-reactive herpesvirus epitopes,41
we confirmed the specificity of this association by the measurement of antibodies
to HSV-2 type-specific glycoproteins gG1 and gG2.42
The positive finding for HSV-2 antibodies was confirmed using this more precise
measure (t = 2.43, P = .02).
All of the analyses noted earlier were recalculated dropping the 4 imperfectly
matched controls; the results were unchanged.
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Table 3. IgG Antibodies to Microbial Pathogens Measured in the Serum
Samples of Case and Control Mothers When Delivered of the Neonates*
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Cumulative percentage of herpes simplex virus type 2 antibody levels
for controls and cases showing the 75th and 90th deciles for the control sample.
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We conducted a series of restricted analyses to address potential residual
confounding by maternal mental illness, weight gain, smoking during pregnancy,
and family SES. We dropped the following: (1) the lowest SES quartile, (2)
the highest weight gain quartile, (3) nonsmokers, (4) heavy smokers (> one-half
pack per day during pregnancy), and (5) offspring of women with any indication
of psychiatric treatment; and reran all of the above analyses. The results
were unchanged; all of the associations reported earlier remained statistically
significant at the P<.05 level. The elevated antibody
values among the psychotic sample do not result from a subset of cases of
lower SES, maternal history of psychiatric treatment, greater weight gain,
or high or low levels of cigarette smoking.
We performed additional analyses to determine if the case and control
mothers differed in terms of exposure to sexually transmitted pathogens other
than HSV-2. We found that the groups did not differ in terms of antibodies
to C trachomatis or to the E6 and E7 proteins of
human papillomavirus type 16.
COMMENT
The study results indicate a significant association between increased
levels of maternal serum IgG and IgM class immunoglobulins at delivery and
the subsequent development of psychosis in offspring. IgG and IgM class antibodies
are both generated in response to infection; IgM immunoglobulins are generally
generated within a few days following systemic infection and are detectable
for several months while IgG immunoglobulins are generated 1 to 3 weeks after
initial infection and are detectable for several years. There were no differences
in maternal levels of serum IgA class antibodies, indicating that the results
were related largely to a systemic, as opposed to a mucosal, immune response.
The differences were apparent when the IgG or IgM levels were expressed as
concentrations per milliliter of serum or as immunoglobulin-albumin ratios.
These findings indicate that the differences were unlikely to be explained
on the basis of differential hemodilution or evaporation of the samples.35 The association of elevated levels of total immunoglobulins
and subsequent psychosis thus provides objective confirmation of previous
studies that have documented a correlation between the history of clinical
signs of infection during pregnancy and the development of schizophrenia in
the offspring.
Further, we observed a statistically significant and graded association
between maternal levels of IgG antibodies to HSV-2 and the subsequent development
of psychosis in the offspring, in both the virion antigen and gG2 HSV-2 assays.
Previous studies have documented a strong association between antibodies to
HSV-2 gG2 glycoprotein and anogenital herpesvirus infections.43, 44, 45
These type-specific assays confirmed the presence of increased levels of antibodies
to HSV-2 in the mothers of offspring who developed psychosis later in life.
Not all of the increased immunoglobulin levels in the case series can be attributed
to HSV-2 infection. Of the 13 cases who had elevated levels of total IgG antibodies
(defined as >1 SD above the mean for the control sample), 5 (38%) also had
elevated HSV-2 antibody levels. The relationship between elevated levels of
immunoglobulins and increased levels of antibodies to HSV-2 should be addressed
in studies of additional populations.
A limitation of this study is the size and heterogeneity of the sample
of 27 psychotic subjects, which include diagnoses of schizophrenia, affective
psychoses, and other psychotic conditions. While this sample is adequate to
detect moderate effect sizes (ie,  0.67) for the continuous measures of
immunoglobulins, power for smaller effects and for categorical exposures is
limited. We found nonsignificant positive associations between adult psychosis
and increased levels of maternal antibodies to rubella and other known perinatal
pathogens that might have reached statistical significance in a larger sample.
We were unable to estimate the relative risk of psychosis for dichotomous
cutoff points of antibody levels indicating maternal infection. Owing to the
limited sample size, we were also unable to determine whether the findings
are specific to schizophrenia, nonaffective psychoses, or other specific classes
of psychosis, all limitations that will be addressed through our ongoing work
with the larger Boston cohort of the CPP.
The 27 psychotic offspring represent 0.71% of the eligible cohort (n
= 3804) and are presumably a subsample of all affected subjects. Case ascertainment
involved both personal screening interviews for approximately half of the
cohort and record linkage with state treatment facilities for the entire sample.
Loss to follow-up in the interview component was marginally elevated for males
and subjects of lower SES. However, owing to changes in maiden names and our
focus on publicly funded psychiatric hospitals, males and lower SES subjects
are somewhat overrepresented in the linkage sample. The net effect, as reflected
by the sociodemographic characteristics of the psychotic sample compared with
the entire cohort (ie, slightly lower SES, greater proportion of males), indicates
that the case series reflects a reasonably representative subset of the psychotic
subjects among this cohort, supporting the generalizability of the study results.
There are several possible pathophysiological mechanisms by which maternal
infection with viruses such as HSV-2 might lead to the subsequent development
of psychosis in their offspring. It is possible that some of the infants were
directly infected with HSV-2 as a result of maternal viral shedding during
pregnancy or delivery. Since viral cultures were not collected, the rate and
timing of viral shedding cannot be precisely determined.46, 47
However, the potential relationship between HSV-2 infection and subsequent
psychosis is plausible in light of the tropism of HSV-2 for the infant central
nervous system48, 49 and of case
reports of the onset of psychosis following documented cases of HSV encephalitis.50, 51 It is also possible that some of
the HSV-2 seropositive mothers infected their children after birth; however,
this possibility is rendered unlikely in light of the low incidence of postnatal
infection of HSV-2 that occurs during childhood.52
The possibility that the presence of antibodies to HSV-2 is a marker for increased
sexual exposure or another sexually transmitted disease that could adversely
affect the fetus is rendered unlikely by the lack of association with antibodies
to other sexually transmitted pathogens such as C trachomatis or human papillomavirus.53 However,
direct studies of HSV-2 infection and other sexually transmitted pathogens
will be required to define the relationship between HSV-2 infection and the
development of psychosis. In addition, the possible effects of changing levels
of HSV-2 prevalence on the epidemiology of psychosis should be the subject
of future studies.
None of the infants who developed psychosis as adults had evidence of
encephalitis or other major neurologic abnormalities apparent at birth. This
finding is consistent with that of Brown et al,47
who found no cases of clinically apparent HSV-2 infection in infants of mothers
who acquired antibodies to HSV-2 prior to the onset of labor. However, HSV-2–infected
infants who are asymptomatic at birth have not been systematically studied
in follow-up for extensive periods. The long-term follow-up of infants with
documented perinatal exposure to HSV-2 will be required to completely define
the potential effects of maternal HSV-2 infection on the developing central
nervous system and to define the relationship between perinatal HSV-2 infection
and adult neurologic or psychiatric diseases.
AUTHOR INFORMATION
Accepted for publication May 2, 2001.
This study was funded by the Stanley Foundation, Bethesda, Md, with
additional support provided by the National Institute of Mental Health.
We thank Inna A. Ruslanova, MS, Stanley Neurovirology Laboratory, The
Johns Hopkins School of Medicine, Baltimore, Md, for the performance of the
immunoassays and Richard L. Wagner, MD, Rhode Island Psychiatric Research
and Training Center, Brown University, Providence, for the initial identification
of subjects in the study samples. We also thank Raphael Viscidi, MD, for providing
the papillomavirus proteins; Therese Datiles, MS, for coordinating the immunoglobulin
measurements; Lisa Denny, MD, JoAnn Donatelli, MA, and Christiana Provencal,
MA, for the collection of patient data; Ann Cusic and Caitlin Thomas for data
entry and manuscript preparation. We are grateful to Jill Goldstein, PhD,
and Larry Seidman, PhD, for their suggestions and Richard Whitley, MD, Larry
Corey, MD, Ann Arvin, MD, and Jonathan Zenilman, MD, for their reading of
the manuscript. We thank the CPP study members for their continued participation.
From the Harvard School of Public Health (Drs Buka and Tsuang), Harvard
Medical School (Drs Buka and Tsuang), and Harvard Institute of Psychiatric
Epidemiology and Genetics (Drs Buka and Tsuang), Boston, Mass; Stanley Research
Laboratory (Dr Torrey), and Division of Epidemiology, Statistics and Prevention
Research, National Institute of Child Health and Human Development (Dr Klebanoff),
Bethesda, Md; Children's Hospital Medical Center, Cincinnati, Ohio (Dr Bernstein);
and the Stanley Division of Developmental Neurovirology, The Johns Hopkins
School of Medicine, Baltimore, Md (Dr Yolken).
Reprints: Stephen L. Buka, ScD, Harvard School of Public Health,
677 Huntington Ave, Boston, MA 02115.
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