TABLE 1.
Ecologic and Maternal Report Studies of Prenatal Exposure to Influenza and Development of Schizophrenia
| Authors, Year (Reference) | Epidemic and Region | Numbers of Cases | Numbers of Noncases | Description of Associationa | Commentsb | ||
|---|---|---|---|---|---|---|---|
| Strengths | Limitations | Other | |||||
| Mednick et al., 1988 (3) | 1957 A2 epidemic in Uusimaa County, Finland | 216 exposed cases, 1,565 unexposed cases | Not reported | 2nd trimester | Exposed and unexposed cases matched by birth month | Data collected only to age 26 | Data reported as proportion of cases with schizophrenia among all hospitalized cases with psychiatric disorders |
| Kendell and Kemp, 1989 (4) | 1918–1919 and 1957 influenza A epidemics in Edinburgh, Scotland | Edinburgh Case Register: 122 exposed cases, 210 unexposed cases; Scottish national data: 227 exposed cases, 525 unexposed cases | Not reported | 1957 epidemic in Edinburgh: 6th month; no associations for Scottish national data | Increased incidence of Parkinson’s disease in those exposed to 1918–1919 pandemic | ||
| Barr et al., 1990 (5) | Epidemics between 1911 and 1950 in Denmark | 7,239 cases; exposure status of individual cases not reported | Not reported | 6th month | Large national sample; data adjusted for seasonality | Relatively low schizophrenia birthrate (2.4 per 1,000); this may be due to strict diagnostic criteria | |
| O’Callaghan et al., 1991 (6) | 1957 A2 epidemic in England and Wales | 339 exposed cases, 1,331 unexposed cases | Live births during exposure years: 126,959; average live births during unexposed years: 126,327; number of noncases not reported | 5 months after peak of epidemic, births of individuals who developed schizophrenia were 88% higher than average in the corresponding previous and subsequent 2 years, females only | Several years of discharge records were missing from data | ||
| Sham et al., 1992 (7) | Outbreaks from 1939 to 1960 in England and Wales | 14,830 cases; exposure status of individual cases not reported | Not reported | 3rd–7th month; 1.4% increase in number of schizophrenia births for every 1,000 deaths attributed to influenza | Examined temporal trends between influenza prevalence and schizophrenia births | ||
| Adams et al., 1993 (8) | Outbreaks from 1911 to 1960 in Scotland, England, and Denmark | Scotland: 16,960 cases (broad criteria), 8,229 cases (narrow criteria); England: 22,021 cases; Denmark: 18,723 cases (broad criteria), 14,260 (narrow criteria); exposure status of individual cases not reported | Not reported | 1957 A2 epidemic in Scotland and England: 4th month; England, general outbreaks: 6th–7th month; 1957 A2 epidemic in Denmark: 4th– 6th month; 1918–1919 pandemic in Denmark: no association; associations were strongest in females | Large national samples | Data sets were limited to cases still under psychiatric care after January 1963 (Scotland) or April 1969 (Denmark) | Scottish and Danish cases were determined using both broad (any diagnosis of schizophrenia) and narrow (discharge diagnosis of schizophrenia on at least two occasions) diagnostic criteria |
| Takei et al., 1993 (9) | Outbreaks from 1938 to 1965 in England and Wales | 6,982 cases; exposure status of individual cases not reported | Not reported | 5th month, females only | Inverse relationship between female schizophrenia births and affective psychosis births | ||
| Erlenmeyer-Kimling et al., 1994 (10) | 1957 A2 influenza epidemic in Croatia | 348 exposed cases, 3,761 unexposed cases | Live births during exposure period: 77,662; average live births during unexposed years: 81,559.5 | None | National sample | ||
| McGrath and Castle, 1995 (11) | Outbreaks in 1954, 1957, and 1959 in Queensland, Australia | 1954 outbreak: 234 exposed cases, 1,985 unexposed cases; 1957 outbreak: 220 exposed cases, 1,938 unexposed cases; 1959 outbreak: 193 cases from index year, 1,921 cases from comparison year | 33,688 exposed noncases, 336,475 unexposed noncases | 4th month, 1954 epidemic, males only; 5th month, 1957 epidemic, females only; no association, 1959 epidemic | Southern Hemisphere study | ||
| Mednick et al., 1994 (12) | 1957 A2 epidemic in Helsinki | 25 cases total; 2nd trimester: 15 exposed cases, 13 with “definite influenza infection”; 1st and 3rd trimester: 10 exposed cases, 2 with “definite influenza infection”; no unexposed cases | Not reported | 2nd trimester | Small number of cases; of 50 cases, only 25 had records; no unexposed group or comparison group | ||
| Selten and Slaets, 1994 (13) | 1957 A2 epidemic in the Netherlands | 873 exposed cases, 3,761 unexposed cases | 77,680 exposed noncases; average number of live births during unexposed years: 79,468 | None | Large national sample | ||
| Susser et al., 1994 (14) | 1957 A2 influenza epidemic in the Netherlands | 183 exposed cases, 808 unexposed cases | 99,205 exposed noncases, 400,708 unexposed noncases | None | Large national sample | ||
| Takei et al., 1994 (15) | Outbreaks from 1938 to 1965 in England and Wales | 138 exposed cases; average of unexposed cases born during four comparison years: 148.5 | Not reported | 5 months after epidemics, females only (relative risk=1.07, 95% CI=1.02–1.13) | Poisson regression used to determine correlation between influenza prevalence and schizophrenia births; replication of 1993 study, but eliminated subjects born during 1958 Asian flu pandemic, responsible for significant effect in the previous study | ||
| Kunugi et al., 1995 (16) | 1957 A/B mixed and A2 epidemic in Japan | 133 exposed cases; average of unexposed cases per year during comparison years: 116.5 | Not reported | 5 months after A/B type epidemic, females only | Excluded patients who were in remission at time of the study | ||
| Takei et al., 1995 (17) | Outbreaks from 1947 to 1969 (except the epidemic year 1958) in the Netherlands | “Typical” schizophrenia patients: 4,726 cases; “less typical”: 5,389 cases; exposure status of individual cases not reported | Not reported | None | Poisson regression used to determine correlation between influenza prevalence and schizophrenia births; cases divided into typical schizophrenia patients (hebephrenic type, catatonic type, paranoid type, residual schizophrenia) and “less typical” schizophrenia (acute schizophrenic episode, latent schizophrenia, schizoaffective type, unspecified schizophrenia); trend was stronger in “typical” patients, but not significant | ||
| Takei et al., 1996 (18) | Outbreaks from 1915 to 1970 in Denmark | 9,462 cases; exposure status of individual cases not reported | Not reported | 6 months after outbreaks (relative risk=1.12, 95% CI=1.01– 1.2); population attributable risk fraction was 1.4% | First hospital admission series; Poisson regression used to determine correlation between influenza prevalence and schizophrenia births; findings stronger for narrow diagnostic criteria (schizophrenia, no affective psychosis) than for broad criteria (including affective psychosis) | ||
| Grech et al., 1997 (19) | Epidemics from 1923 to 1965 in England and Wales | Paranoid schizophrenia: 2,897 cases; non-paranoid schizophrenia: 14,350 cases; exposure status of individual cases not reported | Not reported | None | Data covered 80% of population; examined temporal trends between influenza prevalence and schizophrenia births; groups subdivided into paranoid schizophrenia and non-paranoid schizophrenia (other subtype of schizophrenia or diagnosis with-out reference to diagnostic subtype) | ||
| Morgan et al., 1997 (20) | Six epidemics from 1950 to 1960 in Australia | 342 exposed cases, 134 unexposed cases | Exposed live births: 82,963; unexposed live births: 32,462 | None | Exposed and unexposed matched by trimester; geographically well-defined population with low migration rate | 1st-trimester exposure associated with increased risk of mental retardation | |
| Selten et al., 1998 (21) | 1957 A2 epidemic in Antillean and Surinamese immigrants in the Netherlands | 57 Antillean cases and 16 Surinamese cases; exposure status of individual cases not reported | Live births, 1958: 522; live births, 1956: 489; live births, 1959: 454; exposure status not reported; no data from 1957, 1960 | None | Increase in depression among exposed | ||
| Izumoto et al., 1999 (22) | 1957 A2 influenza epidemic in Kochi, Japan | 188 exposed cases, 22,754 unexposed cases | 753 exposed noncases; 93,297 unexposed noncases | 2nd trimester, females only (relative risk=2.86, 95% CI=1.37–5.26) | Included both inpatient and outpatient schizophrenia cases | Did not control for confounders | |
| Westergaard et al., 1999 (23) | Epidemics from 1950 to 1988 in Denmark | 2,669 cases total; 6th monthc, influenza prevalence; “low”: 2,198 exposed cases; “intermediate”: 225 exposed cases; “high”: 246 exposed cases | Total size of cohort: 1,746,366 | None | Birth order and influenza prevalence used as proxy measures for exposure to prenatal infection; prevalence categorized as low, intermediate, or high for influenza notifications of <5, 5–9, or ≥10 per 1,000 population, respectively; number of siblings and sibling interval used as proxy measures for exposure to childhood infections; large sibship (4 or more siblings) associated with increased risk of schizophrenia | ||
| Mino et al., 2000 (24) | 1957–1958, 1962, and 1965 epidemics in Japan | 1957: 165 exposed cases, 972 unexposed cases; 1962: 191 exposed cases, 653 unexposed cases; 1965: 150 exposed cases, 584 unexposed cases | Not reported | None | Subjects derived from many different randomly selected facilities in Japan; used place of residence in lieu of place of birth | ||
| Limosin et al., 2003 (25) | Epidemics from 1949 to 1981 in France | 974 cases total; 4th month: 49 exposed cases; 5th month: 57 exposed cases; 6th month: 45 exposed cases; 7th month: 37 exposed cases; number of unexposed cases not reported | 974 noncases total; 4th month: 34 exposed noncases; 5th month: 36 exposed noncases; 6th month: 43 exposed noncases; 7th month: 44 exposed noncases; Number of unexposed noncases not reported | 5th month (odds ratio=1.61, 95% CI=1.04–2.49) (case subjects compared to healthy unrelated comparison subjects); (odds ratio=2.24, 95% CI=1.49–3.35) (case subjects compared to siblings) | All subjects were interviewed to confirm diagnosis or comparison group status | Compared influenza prevalence and schizophrenia births; comparison subjects included nonschizophrenic siblings and matched nonsibling comparison subjects; some comparison subjects had DSM-IV diagnoses (anxiety, affective, substance-use, and personality disorders); mothers of case patients were slightly but significantly older than comparison subjects | |
a
Measures of effect (relative risk, rate ratio, or odds ratio) are reported here if reported in the original paper; p≤0.05 unless otherwise noted. “Nth month” indicates gestational month of exposure. Rather than estimating gestational age, some studies reported the number of months after the peak of an epidemic during which schizophrenia births increased. This distinction is noted in the table.
b
Many studies used similar designs. These columns include only notable departures from common features of the studies presented below. All of the studies in the Table share the following limitations (unless otherwise indicated): ecologic data and psychiatric registries to determine exposure and case status, respectively. Calculation of trimester of exposure assumed full-term pregnancy.
c
Data reported here only for 6th month for this study; findings were similar for 4th and 5th months.