A Danish National Birth Cohort study of maternal HSV-2 antibodies as a risk factor for schizophrenia in their offspring.

Several studies have implicated early infections, including maternal infection with herpes simplex virus 2 (HSV-2), as an environmental risk factor for schizophrenia. A case-control study nested within the national Danish birth cohort constituted by the PKU Biobank covering all children born in Denmark since 1981. 602 cases of schizophrenia (ICD-10 F20) were ascertained in the Danish Psychiatric Central Register, covering all in- and out-patient contacts in Denmark, and 602 controls were matched individually on gender, exact date of birth and living in Denmark on the date the case became a case. Incidence rate ratio for schizophrenia was estimated using conditional logistic regression. Main exposure was HSV-2 IgG antibody levels. Confounders and potential interacting factors included family history of mental illness, place of birth and gestational age at time of birth. Elevated levels of maternal HSV-2 IgG were associated with schizophrenia risk (IRR 1.56; 95% CI 1.17-2.07, p=0.002). This association was not confounded by a maternal or sibling history of psychiatric illness, place of birth, parental age, gestational age, or immigrant status of the parents. However, adjustment for paternal psychiatric history reduced risk slightly (IRR 1.43; 95% CI 1.06-1.92, p=0.02). The study replicates an association between maternal HSV-2 IgG levels and schizophrenia risk. Since the confounding by familial risk factors is confined to paternal mental illnesses not belonging to the schizophrenia spectrum, we hypothesize that this confounding may be partly due to other risk factors, e.g., other sexually transmitted infections, rather than reflecting variations in genetic liability to develop schizophrenia.

Mortensen PB ，Pedersen CB ，Hougaard DM ，Nørgaard-Petersen B ，Mors O ，Børglum AD ，Yolken RH ... -  《-》

Maternal exposure to sexually transmitted infections and schizophrenia among offspring.

Animal models and epidemiologic studies suggest that prenatal maternal infection, and sexually transmitted infection (STI) in particular, is associated with an increased risk of schizophrenia in the offspring. However, findings from prior research studies on common infections, including herpes simplex virus type 2 (HSV-2) and Chlamydia trachomatis (C. trachomatis) have been inconsistent. To investigate these associations, we conducted a case-control study nested in the population-based Finnish Prenatal Study of Schizophrenia. Using linked national registries, 963 cases with schizophrenia (ICD-10 F20) or schizoaffective disorder (ICD-10 F25), and 963 matched controls were identified from among all persons born between 1983 and 1998 in Finland. HSV-2 IgG antibody levels were quantified in archived maternal serum samples drawn during pregnancy. Mothers of 16.4% of cases versus 12.6% of controls were HSV-2 seropositive. Mean levels of maternal HSV-2 IgG were marginally higher among cases than controls (index values of 0.98 versus 0.86; p=0.06). The unadjusted odds ratio (OR) of maternal HSV-2 IgG seropositivity was 1.33 (95% confidence interval (CI)=1.03-1.72, p=0.03). Following adjustment for covariates, the relationship was attenuated (OR=1.22, CI=0.93-1.60; p=0.14). In an exploratory analysis of another STI, C. trachomatis antibodies were measured in a subsample of 207 case-control pairs drawn from the cohort. The proportions of subjects that were seropositive and the mean levels of C. trachomatis antibodies were similar for cases and controls. This study does not support a strong association of HSV-2 or C. trachomatis IgG antibodies in maternal serum during early to mid-gestation with the development of schizophrenia in the offspring.

Cheslack-Postava K ，Brown AS ，Chudal R ，Suominen A ，Huttunen J ，Surcel HM ，Sourander A ... -  《-》

Maternal exposure to herpes simplex virus and risk of psychosis among adult offspring.

Buka SL ，Cannon TD ，Torrey EF ，Yolken RH ，Collaborative Study Group on the Perinatal Origins of Severe Psychiatric Disorders ... -  《-》

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

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.

Byrne M ，Agerbo E ，Bennedsen B ，Eaton WW ，Mortensen PB ... -  《SCHIZOPHRENIA RESEARCH》

Parental age and risk of schizophrenia: a case-control study.

Advanced paternal age has been suggested as a possible risk factor for schizophrenia. It is not known whether this is explained by known risk factors for schizophrenia, including sibship characteristics, death of a parent before first hospital admission, season and place of birth, and family history of psychiatric illness, or by socioeconomic factors. We investigated the risk of schizophrenia associated with parental age, adjusting for known risk factors for schizophrenia, including family psychiatric history, and controlling for socioeconomic and demographic factors. We performed a national population, nested, case-control study based on Danish longitudinal register data. The sample included 7704 patients with an ICD-8 or ICD-10 diagnosis of schizophrenia admitted to a psychiatric facility between 1981 and 1998 in Denmark, and 192 590 individually time-, age-, and sex-matched population controls, their parents, and siblings. The risk of schizophrenia associated with increasing parental age was investigated using conditional logistic regression and controlling for family socioeconomic and demographic factors and family psychiatric history. Advanced paternal and maternal age was associated with increased risk of schizophrenia in univariate analyses. Controlling for socioeconomic factors and family psychiatric history, increased risk of schizophrenia was identified in those with a paternal age of 50 years or older. Sex-specific analyses revealed that the risk of schizophrenia was increased for males with fathers 55 years or older (incidence rate ratio [IRR], 2.10; 95% confidence interval [CI], 1.35-3.28); for females, the risk associated with paternal age was substantial for fathers aged 50 to 54 years (IRR, 2.22; 95% CI, 1.44-3.44) and 55 years or older (IRR, 3.53; 95% CI, 1.82-6.83). Increased risk of schizophrenia was associated with advanced paternal age, particularly in females, lending support to the theory that de novo mutations, possibly X-linked, associated with increased parental age might be responsible for some cases of schizophrenia.

Byrne M ，Agerbo E ，Ewald H ，Eaton WW ，Mortensen PB ... -  《archives of general psychiatry》