Obstetric conditions and risk of first admission with schizophrenia: A Danish national register based study

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Abstract

A range of complications of pregnancy, abnormal fetal growth and development, and complications of delivery have been associated with increased risk of schizophrenia. Few studies have been able to adjust for a broad range of potential confounding factors. A national population nested case-control study based on Danish longitudinal registers was conducted to investigate the risk of schizophrenia associated with exposure to a range of obstetric events. The sample included 1039 first admissions to, or contacts with Danish psychiatric services with an ICD-8 or ICD-10 diagnosis of schizophrenia and 24, 826 individually matched controls. Adjusting for the other obstetric factors, family psychiatric history, and socio-economic and demographic factors, risk of schizophrenia was associated with maternal non-attendance at antenatal appointments (Incidence Rate Ratio (IRR) 2.08, 95% CI: 1.0, 4.4), gestational age of 37 weeks or below (IRR 1.51, 95% CI: 1.0, 2.2), maternal influenza (IRR 8.2, 95% CI: 1.4, 48.8), preeclampsia (IRR 2.72, 95% CI: 1.0, 7.3), threatened premature delivery (IRR 2.39, 95% CI: 1.4, 4.1), haemorrhage during delivery (IRR 2.43, 95% CI: 1.1, 5.6), manual extraction of the baby (IRR 2.15, 95% CI: 1.1, 4.4), and maternal sepsis of childbirth and the puerperium (IRR 2.91, 95% CI: 1.1, 7.9). There was no significant interaction between the obstetric factors and either sex or family psychiatric history. The data suggest a modest association between prematurity, indicators of hypoxia, maternal infections, and maternal behaviours and risk of the later development of schizophrenia after adjusting for a number of possible confounding factors.

Introduction

Obstetric complications (OCs) increase the risk of schizophrenia by about a factor 2.0 (Cannon et al., 2002, Cannon et al., 2002, Geddes and Lawrie, 1995, Geddes et al., 1999, Verdoux et al., 1997). Complications of pregnancy, abnormal fetal growth and development, and complications of delivery have been associated with schizophrenia (Cannon et al., 2002, Cannon et al., 2002). A meta-analysis suggested that risk of schizophrenia associated with OCs might be particularly important for those with a young age at onset (Verdoux et al., 1997). More OCs occur during the pregnancies of and births to mothers with schizophrenia, compared to mothers of controls (Bennedsen et al., 1999, Bennedsen et al., 2001a, Bennedsen et al., 2001b) and there is some evidence that OCs interact with familial predisposition to increase the risk of schizophrenia (Cannon et al., 2002, Cannon et al., 2002). Interpretations of the association between OCs and schizophrenia include that OCs alone might cause schizophrenia (McNeil, 1988), that they are examples of environmental mediators that interact with genetic predisposition to increase risk (Cannon et al., 2002, Cannon et al., 2002), or that the OCs are a product of an etiologic process already in progress at the time of conception, or shortly thereafter (Goodman, 1988). If the latter interpretation were true it would imply that interventions to lower the rate of OCs would not change the rate of schizophrenia, and that little about the etiologic process itself would be learned from the study of OCs.

An important possibility is that the relationship between OCs and risk of schizophrenia can be explained by the confounding or modifying effects of socioeconomic and demographic factors, and family history of psychiatric illness. Our aims were: 1. To replicate the association between OCs and risk of schizophrenia in our unique, national population-based sample using prospectively collected register-based information. 2. To assess whether the association between OCs and schizophrenia could be explained by the confounding or modifying effects of variables such as parental socioeconomic status, urban place of birth, parental age, maternal citizenship, and family history of psychiatric illness. To our knowledge, no prior study has been able to adjust for all of these confounders.

Section snippets

Case population

All persons over age 15 years born in Denmark between 1973 and 1983 and in contact with a Danish psychiatric facility for the first time between 1981 and 1998 with a diagnosis of ICD-8 (World Health Organisation, 1967) (until the end of December, 1993) or ICD-10 (World Health Organisation, 1992) (from January, 1994) schizophrenia, and known maternal identity, comprised the study sample. From 1973–1994 “contacts” included only psychiatric hospital admissions: from January 1994 all psychiatric

Births in the years 1973–1983

Background factors had prevalence's and IRR's as might be expected from the literature (Table 1). Univariate IRRs indicated that higher risk of schizophrenia was associated with family history of schizophrenia and other psychiatric disorders, birth in the city, no reference to a father, mother not a Danish citizen, lower level of education in mothers, lower parental wealth, younger (less than 20 years) and older maternal (40 years and older) age, and raised paternal age (greater than 50 years).

Discussion

The major findings of this study were: 1. A replication of earlier studies that complications occurring during the pregnancy, the delivery, and the puerperium were identified as risk factors for schizophrenia. 2. We documented that the association was not explained by a range of other known risk factors for schizophrenia namely family psychiatric history, parental age, urban place of birth, maternal citizenship and parental socioeconomic factors. 3. Furthermore we found an effect of individual

Role of funding source

Funding for this study was provided by the Danish Research Council (grant number 9600264), by the Stanley Medical Research Institute, and by the NIMH Grant #MH53188; the funding bodies had no further role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Authors contributions

Majella Byrne was involved in the study design and interpretation of the data, conducted the statistical analysis, and wrote the manuscript. Esben Agerbo generated the original dataset, was involved in the study design, and interpretation of data. William Eaton was involved in the study design, interpretation of the data, and in gaining funding. Preben Bo Mortensen was involved in the study design, in the interpretation of data and in gaining funding. All authors contributed significantly to

Conflicts of interest

All other authors declare that they have no conflicts of interest.

Acknowledgements

This study was funded by the Danish Research Council (grant number 9600264), by the Stanley Medical Research Institute and by the NIMH Grant #MH53188.

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