Type A Studies.
provides an overview. For the purpose of this meta-analysis, we retrieved data to enable us to extract or calculate the RR of schizophrenia for those exposed (1) at any time during pregnancy, (2) in a particular trimester of pregnancy, and (3) in a particular month of pregnancy. In all studies, births were assumed to be full-term (9-month) deliveries. Where possible, the results were considered separately for men and women. Two of the authors (J.-P.S. and A.F.) independently extracted the data and calculated the RRs. Discrepancies were resolved by discussion.
Eight Ecological Studies from Europe, America, and Australia (Type A Studies) of Schizophrenia Risk for Subjects In Utero in the First, Second, or Third Trimester of Prenatal Life During the 1957 Pandemic of A2 Influenza
We used the natural logarithm of the RR. The variance V of a RR is given by the formula: V = 1/a − 1/b + 1/c − 1/d, where a is the number of preschizophrenic births in the index period, b is the number of live births in the index period, c is the number of pre-schizophrenic births in the control period, and d is the number of live births in the control period. Although 3 studies did not mention the numbers of live births,2,14,15
we estimated these numbers (see below). Because an estimation is always imperfect, we also calculated the variance of each RR using another formula, V = 1/a + 1/c, where a is the number of cases in the index period and c is the number of cases in the control period. This method of variance estimation is not influenced by the size of denominators.24
All analyses were carried out using the fixed-effects model with MetaWin 2.0 statistical software.25
A homogeneity statistic, Q
, was calculated to test whether the studies could be considered to share a common population effect size. A significant Q
statistic indicates heterogeneity of the individual study effect sizes, which means that a certain amount of variance cannot be attributed to sampling error. If the value of Q
was statistically significant, we repeated the analysis using the random-effects model, which is more conservative and takes the extra variance into account.24,26
The arrival of A2 influenza and the peak of the epidemic differed by country. Most studies considered infants born in the first month after the peak as being exposed during the ninth month of pregnancy and classified the other months accordingly. Two studies departed from this rule and considered those born during the peak month of the epidemic as being exposed during the ninth month of pregnancy.14,17
In order to apply the same method to all studies, we reclassified exposure in these 2 studies using the approach used in the other studies. Morgan et al,18
in their study of Western Australia, increased the power of their study to find a second-trimester effect by considering those born in the period from November 1957 until March 1958 as being exposed during this trimester. This was possible because the epidemic in Western Australia lasted from July to September 1957. For the purpose of the present meta-analysis, however, we reanalyzed data from this study as for the other studies. Because the peak occurred in September 1957, people born during the periods October to December 1957, January to March 1958, and April to June 1958 were considered as being exposed during the third, second, and first trimesters, respectively.
While the extraction of RRs was straightforward in some studies, the methods used for 5 studies require further clarification. First, the study from Finland examined hospital admissions of people born in Uusimaa County, a region including Greater Helsinki.1
The authors compared the proportion of schizophrenia diagnoses among psychiatric patients born in the index period with that of schizophrenia diagnoses among patients born in the control periods. Among patients born from February 15 to May 14, 1958 (ie, exposed to the pandemic during the second trimester of fetal life), 34.6% were diagnosed with schizophrenia compared with 20.8% among patients born in the corresponding period in the previous 6 years. The authors controlled for differences between the index and the control groups in the risk period for psychiatric admission by excluding those subjects from the control group who had their first hospital admission at an older age than the maximum age at first admission for patients in the index group (ie, 26 years and 56 days). The authors reported an excess of schizophrenic births among people born in Uusimaa County who were exposed during the second trimester of pregnancy. However, the proportion of schizophrenia diagnoses among hospitalized patients is not a good outcome variable for statistical analysis because it remains unclear whether an increase in the proportion is due to an increase in schizophrenia or a decrease in other diagnoses. A more direct approach involves the calculation of the risk of hospitalization for schizophrenia among subjects born in Uusimaa County. In order to calculate population-based RRs, we obtained information from the Finnish Bureau of Statistics on the number of live births in Uusimaa County for each month during 1951–1958. Because the 3-month periods of fetal exposure began on the 15th day of a given month (eg, February 15, 1958, to May 14, 1958), the number of live births for the research periods was estimated by interpolation. Monthly figures by gender were not available but could be estimated using the proportion of male and female live births in Finland during the period 1950–1960 (51.2% and 48.8%, respectively). The calculation of population-based RRs yielded striking findings (see ). To begin with, the risk of hospital admission for schizophrenia was very high (1.9%–2.7%) among people born in Uusimaa County and was higher than the recently estimated lifetime risk among the Finnish population (0.87%).27
Moreover, the RR for people exposed during the second trimester was decreased rather than increased (RR = 0.85, 95% CI: 0.68–1.07). Although the statistical analysis of the Finnish study has been criticized,15
the decreased population-based RR is a novel finding. The recalculated schizophrenia risk among the Uusimaa population and the decreased population-based RR for exposure in the second trimester question the validity of the 1988 publication. For the purpose of the present meta-analysis, we used the population-based RRs given in .
Cases of Schizophrenia That Were or Were Not Exposed in Prenatal Life to the 1957 A2 Influenza Pandemic in Uusimaa County, Finland
Second, the study from 10 health regions of England and Wales compared the number of patients born in a particular index month with the mean number of patients born in the corresponding month in the 2 previous and 2 subsequent years.2
The authors assumed that there were no major fluctuations in the number of births in the general population. We estimated RRs by using the numbers of patients born in the index and control periods. For example, the RR for those born 5 months after the peak of the epidemic was 48 divided by 25.5 (ie, the mean for the 4 control periods) = 1.88. We used data from another publication to estimate the denominator needed (ie, number of live births) to calculate the variance of the RR. According to a follow-up study of all children born in Great Britain in the week of March 3–9, 1958, the risk of developing schizophrenia was 0.0035.22
Because the data source (hospital admissions recorded by the Mental Health Inquiry) and length of follow-up were similar for both studies, we assumed that the risk was similar among the subjects from the 10 health regions and estimated the numbers of live births and the variance of the RRs.
A third study, the study of the national registry of Scotland, compared the number of preschizophrenic births in an index month with the mean number of such births in the same month in the 2 previous years.15
The authors failed to adjust for the somewhat longer period of risk for subjects born in the control years. However, because data were collected up to 1988, most subjects had passed the period of maximum risk. The number of live births was estimated using data from another publication with the same data set in which the authors reported that the risk of hospitalization for schizophrenia and entry into the national registry was 0.00158 for people born in 1958.28
The fourth and largest study, conducted in the United States, used information from 10 states on the month and year of birth of all individuals diagnosed with schizophrenia who were receiving mental health services.14
The number of patients born from 1950 to 1959 was 43
778, with approximately 3368 patients being born in the 9-month period after the pandemic. Using the monthly numbers of live births in these states, the authors calculated monthly birth rates of future schizophrenic patients during the period 1950–1959, not stratified by gender. Because this study is larger than the other studies combined, and to prevent it from dominating the meta-analysis, we compared the birth rate in an index month with the average birth rate in the same calendar month of only 1 previous year and 1 subsequent year. For instance, the birth rate in November 1957 was 0.00444. Because the mean birth rate of schizophrenic patients in November 1956 and November 1958 was 0.00390, the RR was estimated at 44.4/39.0 = 1.138. The authors provided sufficient information to allow an estimation of denominators.
Lastly, with regard to the Dutch study,13
we obtained information about the number of live births per month from Statistics Netherlands and calculated population-based RRs. The epidemic in the Netherlands peaked between mid-September and mid-October 1957. Subjects born in October 1957 were regarded as being exposed during the ninth month of pregnancy, and subjects born in June 1958 were considered to have been exposed during the first month of pregnancy. The risk of subjects born in index periods was compared with that of subjects born in the corresponding periods in the 2 previous and 2 subsequent years.
Type B Studies.
Japanese researchers, inspired by the findings in England and Wales,2
tested the hypothesis that the risk of schizophrenia would be increased in subjects born 5 months after the epidemic, ie, in November or December 1957 or April or May 1958. Kunugi et al19
compared the number of patients, by gender, who had been born in the 4 above-mentioned index months with the mean number of patients born during the corresponding months of the 2 previous and 2 subsequent years (ie, 16 calendar months). Mino et al21
used a similar method. The only study to provide information on the number of live births was that of Izumoto et al.20
In order to apply the same method to all Japanese studies, we summed the numbers of patients born in these particular index and control months (see ). We then compared the number of patients born in the 4 index months with the mean number of patients born in the 16 control months and estimated RRs. The risk of schizophrenia among Japanese men and women born in the control months of the Izumoto et al study was 0.008209 and 0.006298, respectively. Assuming the same risk in the 2 other Japanese studies, we estimated the numbers of births in the control months for the 3 studies combined, by gender. Given the estimated RRs for males and females, the denominators for the index groups could be estimated, by gender.
Three Ecological Studies From Japan (Type B Studies) Showing Cases of Schizophrenia That Were or Were Not Exposed in the Fifth Month of Prenatal Life to the 1957 A2 Influenza Pandemic