A. E. Bennett research awardPrenatal rubella, premorbid abnormalities, and adult schizophrenia
Introduction
After more than 100 years of research on schizophrenia, 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 neurodevelopmental 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.
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 schizophrenia. With regard to premorbid neurocognitive function, 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 (age 19–20) predicted an increased risk of schizophrenia later in adulthood. Erlenmeyer-Kimling et al 1991, Erlenmeyer-Kimling and Cornblatt 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, choreoathetoid 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 diagnosed 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 preschizophrenic 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, Waddington 1993b. Neuroimaging studies have documented several brain abnormalities, including ventriculomegaly and diminished 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 septum 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 schizophrenia 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 discordance rate for schizophrenia among monozygotic co-twins is approximately 50% (McGuffin et al 1995). Because these twins are genetically identical, any phenotypic differences 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.
Thus, environmental factors operating during the prenatal period have emerged as plausible risk factors for neurodevelopmental 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 majority 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 trimester of gestation during the 1957 influenza epidemic had a significantly increased risk of schizophrenia. Several subsequent 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 schizophrenia 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 individual pregnancies. In the studies that attempted to document 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 influenza 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 relatively 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 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 instance, an autoantibody response to maternal influenza has been postulated to occur in schizophrenia (Wright et al 1999).
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 syndrome was broadened to include deafness, mental retardation, and many other developmental outcomes (South and Sever 1985). Dr. Stella Chess theorized that the consequences of this central nervous system (CNS) viral teratogen 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 adolescence 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 psychotic 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 schizophrenia, 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 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 psychosis in two age-matched, demographically comparable samples: a cohort in Albany and Saratoga counties in New York State (Cohen and Cohen 1996) and the Epidemiologic Catchment Area (ECA) sample (Robins and Regier 1991); both comparison samples received psychiatric assessments 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 prevalence 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.
The data obtained on this unique cohort provided us with a further opportunity: to elucidate the relation of premorbid dysfunction to later SSD. Although previous studies, reviewed above, yielded groundbreaking evidence of specific early antecedents of schizophrenia, they had two significant limitations. First, suspected early developmental factors that might explain these premorbid deficits, and the ensuing schizophrenic illness, could not be meaningfully delineated because of insufficient data on potential prenatal or childhood risk factors. Second, these investigators did not examine the relation between change in 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 evidence a decline in neurocognitive performance before illness onset (see Discussion).
Fortunately, the RBDEP cohort permitted us to address both of these limitations. Extensive, longitudinal information on childhood and adolescent neurocognitive, neuromotor, 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 assessments, 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 opportunity to further elucidate the relationship between premorbid function and risk of SSD in subjects with a known prenatal viral exposure. We hypothesized that rubella-exposed subjects who later developed SSD would evidence a decline in IQ from childhood to adolescence, as well as greater neuromotor and behavioral abnormalities, compared with rubella-exposed control subjects. The refined 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).
Section snippets
Description of birth cohort
The rubella-exposed birth cohort was derived from the RBDEP, which was established 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 develop 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
Risk of schizophrenia spectrum disorders
The numbers and proportions of interviewed subjects with each DSM-IV diagnosis in the rubella-exposed cohort are presented in Table 2. We found that 20.4% (11 of 53) of the sample was diagnosed with SSD. For the 48 subjects diagnosed after receiving the DIGS, 20.8% (10) received a SSD diagnosis. Although we did not assess psychiatric disorders in a cohort unexposed to rubella, this figure is substantially higher than population estimates from previous studies Eaton 1985, Kendler et al 1996. The
Discussion
We have demonstrated that premorbid abnormalities, including 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 abnormalities 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
Models of pathogenesis
Two prominent models of pathogenesis of schizophrenia, mentioned briefly in the Introduction, appear most relevant 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 hypothesis (Weinberger 1987), argues that a fixed
Delineation of pathogenic mechanisms
These models provide a heuristic framework with which to delineate pathogenic mechanisms in early and later development that may underlie our findings. Although speculative, we wish to suggest two potential interpretations. The first derives from a model exemplified by Weinberger’s hypothesis (Weinberger 1987). Our subjects experienced an early brain insult, in this case, from prenatal exposure to rubella, which manifested as a mildly decreased IQ in childhood and as neuromotor and behavioral
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 approximate this figure by comparing the risk of SSP in the rubella cohort with population estimates of the risk of nonaffective psychosis, which are between 0.5% and 1% (Kendler et al 1996). Therefore, given the greater-than-15%
Support for causality
Although causality is usually difficult to prove, the data support the three essential properties of a causal relationship (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
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
Acknowledgements
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
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