Do Hypertension and Diuretic Treatment in Pregnancy Increase the Risk of Schizophrenia in Offspring?

Eighty-four cohort members developed schizophrenia (1.1%). Table 1 shows the characteristics of the cohort members with schizophrenia and of the cohort comparison subjects. Univariate analysis showed that the two groups differed in the distributions of hypertension, diuretic treatment in the third trimester, and maternal schizophrenia (p<0.10). The distributions of maternal preeclampsia, proteinuria, barbiturate treatment in the second or third trimester, and diuretic treatment in the second trimester were not significantly different between groups.

Table 2 shows the results for the multiple logistic regression analyses. Data in the first column indicate the effects of the variables listed, with the effects of maternal age and social status controlled. Increased risk of schizophrenia was strongly associated with having a mother with schizophrenia and less strongly associated with prenatal exposure to diuretic treatment in the third trimester. When effects of maternal schizophrenia, treatment with diuretics in the third trimester, and maternal hypertension were assessed jointly in the model (second column), all three factors emerged as independent predictors of schizophrenia. We did not find significant associations between prenatal exposure to diuretics and other psychoses besides schizophrenia. Neither prenatal exposure to diuretics nor maternal hypertension was associated with elevated risk of developing reactive psychosis (ICD-8 code 298), other psychosis (ICD-8 code 297), or affective psychosis (ICD-8 code 296).

Diuretics were prescribed in the third trimester to treat hypertension, among other conditions. Presumably, the mothers with more severe cases of hypertension received treatment, while those with milder cases did not. Univariate analysis (Table 3) showed that the distributions of maternal age, social status, and indexes of pregnancy and delivery complications differed significantly between diuretic-treated hypertensive mothers and untreated hypertensive mothers. As shown in Table 4, diuretics were prescribed in the third trimester for conditions other than hypertension. The reference category in this analysis was pregnancies that were unexposed to both diuretics in the third trimester and hypertension. The presence of maternal hypertension combined with the absence of diuretic treatment was not significantly associated with increased risk of schizophrenia. In the absence of maternal hypertension, prenatal exposure to diuretics was not a significant predictor of the outcome. Including the indexes of pregnancy and delivery complications as covariates did not materially alter the trends showed in Table 4. Thus, the combination of hypertension and diuretic treatment in the third trimester remained a significant predictor, with about the same predictive capacity in this analysis as in the model without the covariates of pregnancy and delivery complications. The table shows that the combination of maternal hypertension and third-trimester exposure to diuretics was significantly associated with schizophrenia (odds ratio=4.01 [95% CI=1.41–11.40]). The combination of maternal hypertension and third-trimester exposure to diuretics was not significantly associated with other categories of psychotic disorder (ICD-8 codes 296, 297, and 298). Earlier research demonstrated a 2.5-fold elevated relative risk of schizophrenia in offspring for preeclampsia (10). In this study, however, we did not find a significant association between preeclampsia and increased risk of schizophrenia (Table 1). A restriction of the cohort by excluding all cases (N=304) with classifications of either mild or severe preeclampsia did not substantially dilute the predictive effect of the combination of maternal hypertension and diuretics presented in Table 4.

To address the question of differential effects of various diuretic substances, we analyzed more detailed information on prescribed drugs in pregnancy for a subsample of 1,766 individuals from the Copenhagen Perinatal Cohort (20). In a preliminary analysis with limited statistical power (data not shown), we did not find indications of significant differential effects of various diuretics (e.g., thiazides, loop diuretics, carbon anhydrase inhibitors, or “unknown diuretic cures”) in relation to the outcome.

We found an increase in the risk of schizophrenia in offspring prenatally exposed to diuretics during the third trimester and a statistically significant fourfold increase in the risk of schizophrenia in offspring of hypertensive mothers treated with diuretics in the third trimester. The increase in the risk of schizophrenia was statistically significant when the analysis included additional confounders and other risk factors for schizophrenia.

The psychiatric diagnoses in the present study were clinical ICD-8 diagnoses. However, in Denmark, the ICD-8 diagnosis of schizophrenia was used conservatively, and previous studies have shown that almost all patients with a diagnosis of schizophrenia meet the DSM-III-R criteria for schizophrenia (21). The rather narrow concept of schizophrenia according to ICD-8 is likely to have led to diagnostic caution rather than overinclusiveness. Had we extended the period of follow-up beyond 1994, some late-onset cases of schizophrenia might have been identified, and it is also possible that some cases of paranoid psychoses or reactive psychosis may have been reclassified as cases of schizophrenia after 1994. Prenatal exposure to diuretics or maternal hypertension was, however, not associated with any of these diagnostic categories.

From a methodological viewpoint, our prospective study is well suited to examining putative associations between prenatal exposure to medication and adverse outcomes many years later (17, 18). The taxonomy and definitions used to diagnose hypertensive disease in pregnancy have evolved during the last 40 years, and it is possible that the term “hypertension” in our data set might refer to conditions that would now be labeled differently (i.e., gestational hypertension or chronic hypertension). It is also possible that the threshold for the diagnosis of preeclampsia may have been higher 40 years ago, and the study lacked statistical power to examine the predictive capacity of this variable. Exposure to drug treatment during pregnancy was recorded a few days after birth, and we do not consider misclassification of exposure to diuretics or other drugs a major problem. Prenatal exposure to diuretics in the second trimester was more rare than exposure in the third trimester, and it is possible that the present study was not large enough to detect an effect of second-trimester exposure in relation to adult outcome.

A methodological advantage was that data on many variables were collected during pregnancy or immediately after the birth, thus minimizing the risk of recall bias. Another advantage was that we were able to control the confounding effect of the social status of the family breadwinner in our analysis. Social status was slightly higher in diuretic-treated hypertensive women than in women without these two factors, and, moreover, lower social status correlated with increased risk of schizophrenia. A minor limitation was that cases of late-onset schizophrenia (after age 34–35 years) were not captured, as follow-up was limited to the period up to 1994.

To establish a drug-associated risk of a specific adult outcome in a nonexperimental setting requires comparability of the exposed group and the nonexposed group. Although we sought to control for relevant confounders, the decision to prescribe diuretics might have been influenced by factors that were not captured by the variables in the database. The indexes of pregnancy and delivery complications may be related to the severity of hypertension, but they are not direct measures of the severity of hypertensive disease in pregnancy. Differences in the severity of maternal hypertension might explain the apparent effects of diuretics if the mothers with the most severe hypertension were systematically more likely to be prescribed diuretics in the third trimester than those with less severe hypertension. Since we cannot rule out that such a prescription pattern may have existed, and since the study was not large enough to establish a specific drug-associated risk, we believe that the current findings should be interpreted with caution.

Received Feb. 25, 2002; revision received Sept. 9, 2002; accepted Sept. 13, 2002. From the Danish Epidemiology Science Center, Institute of Preventive Medicine, Copenhagen University Hospital, Copenhagen, Denmark; the Department of Health Psychology, Institute of Public Health, University of Copenhagen; the Kinsey Institute for Research in Sex, Gender, and Reproduction, Indiana University, Bloomington, Ind.; and the Social Science Institute and Department of Psychology, University of Southern California, Los Angeles. Address reprint requests to Dr. Sørensen, Department of Health Psychology, Institute of Public Health, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark; [email protected] (e-mail). Supported by a Sygekassernes Helsefond (Health Insurance Foundation) grant to Dr. Sørensen, grants HD-17655 and HD-20263 from the National Institute of Child Health and Human Development to Dr. Reinisch, grant DA-05056 from the National Institute on Drug Abuse to Dr. Reinisch, grant 9700093 from the Danish Research Council to Dr. Mortensen, and grant 1400/2-4-1997 from the Danish National Board of Health to Dr. Mortensen. The authors thank Vibeke Munk, B.A., for comments on the manuscript.