Schizophrenia in the Offspring of Antenatally Depressed Mothers in the Northern Finland 1966 Birth Cohort: Relationship to Family History of Psychosis

The Northern Finland 1966 birth cohort is an unselected, population-based sample of 12,058 children born alive (13). It covers 96.3% of all live births in the provinces of Oulu and Lapland in Finland with an estimated date of birth between January 1, 1966, and December 31, 1966. This general population birth cohort has been followed for more than 30 years. Data include all subjects alive and living in Finland at age 16 years (N=11,017). Permission to gather data was obtained from the Ministry of Social and Health Affairs, and the study has been approved by the Ethics Committee of the Faculty of Medicine of the University of Oulu.

Data concerning the mother and offspring were gathered antenatally and at birth in 1965–1966. As part of the antenatal data collection, the mothers were asked by the interviewing nurse at the antenatal clinic during midgestation (mainly between the 24th and 28th gestational week) whether they felt that their mood during pregnancy had so far been normal, depressed, or very depressed; 13.9% of the mothers rated themselves as depressed (11.8%) or very depressed (2.1%) during pregnancy (10). In the analyses, these two categories were considered as "depressed." The information regarding the mothers' antenatal mood was available for 10,658 (96.7%) offspring living in Finland at the age of 16 years.

Data on mothers' immediate postnatal mood were not available, but we did have information on later severe, hospital-treated maternal depression, dating from the time when offspring were 6 years of age and onward. Of all the cohort members, mothers appearing on the Finnish Hospital Discharge Register between 1972–1997 for any depression (i.e., ICD-8 codes 2960, 2968, 3004; ICD-9 codes 2961, 2968, 3004; and ICD-10 codes F32-F34) were identified. Diagnoses of depression included both nonpsychotic and psychotic episodes.

All the cohort members' mothers and fathers appearing on the Finnish Hospital Discharge Register between 1972–1997 for any psychosis (i.e., ICD-8 and ICD-9 codes 295–299 and ICD-10 codes F20-33, except nonpsychotic mood disorders) were identified. We grouped cohort members into those with and without a psychotic parent to reflect the familial risk for psychosis.

All cohort members over 16 years appearing on the Finnish Hospital Discharge Register between years 1982–1997 for any mental disorder were identified (14, 15). The Finnish Hospital Discharge Register covers all mental and general hospitals, beds in local health centers, and private hospitals nationwide. We used all available information to provide diagnostic information. All case records were scrutinized, and diagnoses were validated against DSM-III-R criteria, after which the diagnoses were rereviewed by a professional panel. There were 160 subjects with a psychotic episode prior to age of 31 years, of whom 146 were living in Finland in 1999.

Those 146 subjects were asked to participate in a field study during 1999–2001, and 91 subjects agreed to participate. The Structured Clinical Interview for DSM-III-R (SCID-I) (16) and all available anamnestic information of the subjects with hospital case records were used for diagnostic assessment: 61 cases with a diagnosis of schizophrenia and 12 subjects with other psychoses were detected (17). The diagnoses of the subjects who did not participate in the field study were based on validation of hospital notes against DSM-III-R criteria (15, 18).

Through these methods, a total of 111 cases of DSM-III-R schizophrenia and 45 cases of other psychosis were identified; the cumulative incidence of schizophrenia in the members of the Northern Finland 1966 birth cohort was 1.0%. The other psychoses included both affective and nonaffective psychoses, except schizophrenia. Data on maternal depressed mood were missing in four cases of schizophrenia (schizophrenia cases with information on maternal depressed mood: N=107) and in one case of other psychosis (N=44).

Cross-tabulations and chi-square tests (Pearson two-sided and Wald) were used to assess the relationships between maternal depressed mood during pregnancy, parental psychosis, and cumulative incidence of schizophrenia (and other psychoses) in the offspring. Unless otherwise stated, we treated the offspring without parental psychosis and without maternal depression as a reference group. We also conducted additional analyses in the subgroups with a family history of psychosis where offspring with parental psychosis but no maternal antenatal depression were the reference group. Crude and adjusted odds ratios with 95% confidence intervals (95% CI) were calculated for the different groups of offspring. Since there was little difference between crude and adjusted odds ratio and confidence interval data, adjusted results are presented in this article with crude odds ratios and confidence intervals included in a data supplement that accompanies the online version of this article. Estimates were calculated for offspring with hospital-treated schizophrenia, other psychosis and any psychosis, and these were all compared with the category of nonpsychotic offspring (healthy offspring or offspring with nonpsychotic mental disorder). Logistic regression analyses (24) were conducted to examine the association of maternal antenatal mood, parental psychosis, and schizophrenia in the offspring and were adjusted for sex and obstetric complications. Analyses were performed using SPSS 16.0 for Windows statistical software.

The cumulative incidence of schizophrenia was 0.9% among children of nondepressed mothers and 1.3% among offspring of mothers with antenatal depressed mood (Table 1). The prevalence of other psychosis was 0.4% in both groups.

Of the offspring with parental psychosis, 3.3% had schizophrenia, compared with 0.9% of those without a psychotic parent (adjusted odds ratio=3.9, 95% CI=2.2–6.8). Fifteen of the 107 schizophrenia patients (14.0%) had a history of psychosis in one or both parents. Ten schizophrenia patients had a history of maternal psychosis and six had a father with psychosis (one had a history of psychosis in both parents).

Of the other psychosis patients, 15.9% (N=7 of 44) had a history of parental psychosis. Five of them had a history of maternal psychosis, and three had a father with psychosis (one had a history of psychosis in both parents). There were 92 (86.0%) schizophrenia cases and 37 (84.1%) other psychosis patients without a known psychotic episode in their parents.

Among offspring of mothers with depressed mood during pregnancy, the risk for schizophrenia was higher where there was a history of psychosis in a parent (adjusted odds ratio=9.4, 95% CI=4.2–20.9; p<0.001) than in those with only a depressed mother but without parental psychosis (adjusted odds ratio=1.0; 95% CI=0.6–1.8) and was also higher than the risk in those without maternal depression and with only a psychotic parent (adjusted odds ratio=2.6; 95% CI=1.2–5.4; p=0.011) (Table 1). The reference group was birth cohort members without maternal antenatal depression and without parental psychosis. The pattern of results for risk of other psychoses in the offspring was very similar to that for risk of schizophrenia in the offspring.

The adjusted odds ratio for schizophrenia was 14.2 (95% CI=4.9–41.2) among offspring of mothers with depressed mood and fathers with psychosis (Table 1). The respective adjusted odds ratio was 8.0 (95% CI=2.8–22.8) among offspring of mother with both antenatal depression and psychosis.

When we restricted our analysis to only the offspring of parents with psychosis, maternal antenatal depressed mood was associated with increased risk for schizophrenia (adjusted odds ratio=3.6, 95% CI=1.3–10.2; Wald χ²=5.7, p=0.017 [Table 2]). Here the reference group is offspring with a family history of psychosis but no maternal antenatal depression. The risk for schizophrenia was statistically significantly higher in the offspring with psychosis in the father and antenatal depression in the mother than in the subjects with paternal psychosis but no maternal depression (adjusted odds ratio=9.0, 95% CI=1.6–51.7; Wald χ²=6.1, p=0.013).

The cumulative incidences of schizophrenia in the offspring by presence of maternal antenatal depression and familial risk for psychosis are presented in Figure 1, which shows the effect of the combination of maternal depressed mood and familial psychosis risk on the age at onset of psychotic symptoms in schizophrenia.

In further logistic regression analyses, we made additional adjustments for maternal smoking in pregnancy. The risks for schizophrenia in the offspring remained at the same level. Among offspring of mothers depressed during pregnancy, the risk of schizophrenia was higher among those with at least one psychotic parent (adjusted odds ratio=8.7, 95% CI=3.7–20.8) than in those with no parental psychosis (odds ratio=1.0, 95% CI=0.5–1.8) or those with only a psychotic parent and no maternal depressed mood (odds ratio=2.3, 95% CI=1.0–5.0).

Maternal antenatal depressed mood was linked to later hospitalization of the mothers due to depression. Of mothers with antenatal depressed mood, 77 (5.2%) had later hospital-treated depression, whereas 261 (2.8%) mothers without depression during pregnancy were later hospitalized due to depression (odds ratio=1.9, 95% CI=1.4–2.4). Of the offspring with schizophrenia, 12 had mothers with hospital-treated depression later on, two with both antenatal depressed mood and later severe depression.

There are some limitations in the study. First, it is notable that maternal depressed mood did not signify a clinical condition but was the mothers' self-reported depressed mood. However, the prevalence of antenatally depressed mood was in the same range as in earlier reports (11, 12). Furthermore, mothers reported their mood to the nurse who had met with them on their earlier visits to the antenatal clinic, i.e., who had known them earlier (10). Another limitation of this study is the absence of information about maternal postnatal mental state. Antenatal depression is a risk factor for postnatal depression. However, information on later hospital-treated maternal depression was available from the offspring's age of 6 years onward. Many subjects with schizophrenia have comorbid depression and may describe their negative symptoms or disorganization as depression—the self-report of depression may represent more active or more significant disease (perhaps both a genetic and environmental risk factor). Data on maternal use of psychiatric medication and on parental psychoses during pregnancy and early childhood were lacking. Information was not available on mothers' nutrition and parents' substance use during pregnancy. The lack of fathers' depression history is a major limitation that makes it difficult to discriminate gene-gene versus gene-environmental hypotheses.

A major strength of the study is that this was a prospective project with a long follow-up time, started antenatally. The subjects were representative, with all cohort members born in the same year and in a geographically defined area. The topic of the study is novel; to the authors' knowledge, this is the first report of schizophrenia in the offspring of antenatally depressed mothers where familial vulnerability was taken into account in a population-based sample.