Of the 91,451 live born subjects, 88,829 (97.2%) were traced; linkage with the Psychiatric Registry identified 637 with schizophrenia-related diagnoses and 676 with other psychiatric disorders. As we previously reported [25
] the cumulative incidence was estimated as 1.0% by age 30 and in a proportional hazards model, variables significantly predicting incidence included paternal age (relative risk (RR) = 1.39 per decade, 95% confidence limits = 1.2–1.6, p < .0001; male sex (1.4, 1.2–1.6, p = .0002); length of the parents' marriage (0.80, 0.73–0.89, p < .0001 per 5 years); and low social class (1.2, 1.0–1.5, p = .0141). Maternal age was less strongly associated with schizophrenia; compared to age < 30, the RRs associated with ages 30–34 and 35+ were 1.2 (0.94–1.5) and 1.5 (1.1–2.1, p = .0066). All the aforementioned estimates were adjusted for each other.
We considered whether there were secular or seasonal trends in incidence that might confound the interpretation of findings for any one year (data not tabulated). We found no evidence for change in incidence over the years; comparing offspring born in 1964–67 and 1968–71 with a reference group based on 1972–76 the RRs for schizophrenia were 1.0 (0.90–1.4) and 1.1 (0.9–1.4) respectively, after adjusting for parents' characteristics. There was no significant variation in schizophrenia estimated for any single year and no meaningful trend with the data reanalyzed with "epidemiologic" years set from April-March, July-June or October-September. Regarding season, while there were some variations in incidence between individual calendar months, these were not obviously seasonal; furthermore, we found no significant trend for schizophrenia by testing season as sine and cosine transformations of time in an annual cycle, together with their first harmonics. We concluded that it was appropriate to compare the cohort born to women who were pregnant in June 1967 with the entire data set, adjusting for calendar month of birth and demographic variables.
Table shows the raw data assessing effects of the war. The left side of the table shows the cohorts defined by calendar month of birth, while the right side of table shows the data re-calculated using standard months of ~30.4 days. The use of standard months shifts few subjects to an earlier or later interval but maintains the general findings. There were 450–500 births per month in 1967 and 1968, except in February 1968 in which there were somewhat fewer, corresponding to a decrease in conceptions in June 1967, i.e. during the war and soon after, or an increased fetal loss. The raw data suggest a two- to three-fold excess of schizophrenia in the cohort born in January 1968, whose mothers would have been in the second month of pregnancy in June 1967. There was a similar excess of other disorders in the cohort born a month earlier, who would have been in the third month of intrauterine life in June 1967. There were somewhat fewer cases of schizophrenia than expected in the cohort born in August 1967 (exposed in the seventh month), and somewhat more of other disorders in the cohort born in June 1967 (exposed in the final month or at birth). There was no unusual incidence of schizophrenia or other conditions among offspring conceived in the three months after the war, or in those born in the three months before it.
Numbers of offspring born (N), cases of schizophrenia (Schiz) and other psychiatric disorders (Other psych) in the months surrounding June 1967, by month of birth and estimated stage of life during the war.
Table shows the RRs of schizophrenia by sex, estimated using proportional hazards methods to control for confounding variables; and table shows the same for other psychiatric conditions. The nine birth cohorts exposed in each month of intrauterine life are compared, simultaneously, with the remainder of the cohort. The incidence of schizophrenia was more than doubled for offspring who were in the second month of gestation in June 1967. The risk for other psychiatric disorders was also increased for those who were in the third month of pregnancy at that time, confirming the findings in table . In both schizophrenia (table ) and other conditions (table ) effects observed after the war were stronger in females than in males.
Numbers of cases, relative risks (RR) and 95% confidence limits (CL) for schizophrenia, by standard month of birth and sex.
Numbers of cases, relative risks (RR) and 95% confidence limits (CL) for other psychiatric conditions, by standard month of birth and sex.
When the intrauterine exposure to the war was classified by trimesters rather than by months, differences were smaller and not significant. Offspring whose mothers were in the first, second and third trimesters during the war showed adjusted RRs, respectively of 1.33 (0.80–2.12), 0.95 (0.53–1.71) and 0.62 (0.30–1.26). For other psychiatric conditions the corresponding RRs were 1.13 (0.67–1.93), 0.68 (0.33–1.38) and 1.49 (0.94–2.34).
We conducted a post-hoc analysis of schizophrenia comparing the cohort presumed to have been in the second month of gestation at the time of the June 1967 war versus all others (data not tabulated). The excess incidence was observed more in offspring of fathers aged < 30 (RR = 3.7, 1.4–10.0, based on 5 cases in 227 offspring versus 194/39,602) than in offspring of fathers aged 30+ (1.5, 0.5–4.3, based on 4/405 vs 284/47,691); more in association with the two lower social classes (4.3, 1.7–11, 7/210 vs 186/23,687) than in the four higher social classes (0.9, 0.2–3.6, 2/427 vs 298/64,505) and more in those whose mothers had 0–8 years of education (3.2, 1.4–7.5, 7/254 vs 209/29,661) than in those with 9+ years of education (0/331 vs 193/52,504). Residence in census tracts bordering the 1948 border was not a general risk factor for schizophrenia in the whole cohort (RR = 1.1, 0.6–2.0 based on 9 cases in 1,125 offspring); however, this residential area showed an excess risk of schizophrenia in those who were in the second month of intrauterine life during the war (RR = 33, 2.7–400 based on 2 cases in 7 offspring versus a reference group of 7 cases in 1116 offspring).
We did not extend the study to cover the 1973 war because insufficient time had passed for the accrual of cases of schizophrenia. A preliminary analysis, however, suggested consistent findings; there was an increased incidence of schizophrenia in offspring of mothers who had been in the second month of gestation in October 1973 (RR = 1.4, 0.6–3.5) and of other conditions in those who were in the third month (RR = 1.9, 0.9–4.1).
We questioned whether the excess risk of schizophrenia after the June 1967 war might be associated with changes in the distribution of birth weight or gestational age, since maternal stress is believed to contribute to pre-term birth [37
] and low birth weight has been associated with schizophrenia [38
]. In this cohort, there was a weak and non-significant relationship between low birth weight (< 2500 g) and schizophrenia (RR = 1.2, 0.9–1.7) after controlling for confounding variables. In the cohort estimated to have been in the second month of intrauterine life in June 1967 we observed an unusually low proportion of low birth weight offspring (3.2% versus 6.3% expected). Controlling for low birth weight, however, increased the RR for schizophrenia and narrowed its confidence interval. Similarly, controlling for low birth weight led to a small increase in the RR of other psychiatric disorders, for those in the third month of gestation during the war.
To corroborate the findings from the whole cohort, we studied the sub-cohort (N = 11,467) with data on of last menstrual date and/or expected date of delivery. From the 11,040 traced live-born offspring, we excluded 1,421 with uncertain gestational age (day of month set at "0" or "10"), leaving 9,519 available for analysis, with 91 cases of schizophrenia. Figure shows adjusted relative risks of schizophrenia according to estimated gestational age in the war. There were wide confidence limits so that none of the RRs were statistically significant; however, they confirm an increased incidence of schizophrenia and other conditions in offspring whose mothers were stressed in early pregnancy (specifically in the second month) and fewer than expected cases of schizophrenia following stress in later pregnancy. This conclusion was unchanged after controlling for pre-term births (i.e. gestations of less than 37 weeks) or for low birth weight (< 2500 g). The figure also suggests an excess incidence of other conditions in early pregnancy.
Relative risks of schizophrenia and other psychiatric conditions in offspring born to mothers pregnant during war of June 1967. Sub-cohort of 9,519 offspring with information on gestational age.
Conclusions for this study were not altered further adjustment for ethnic groups or by restricting the cohort to singleton births or to Jews.