Schizophrenia Bulletin vol. 40 no. 6 pp. 1518–1525, 2014 doi:10.1093/schbul/sbt195 Advance Access publication December 23, 2013

Hospital Admission With Infection During Childhood and Risk for Psychotic Illness—A Population-based Cohort Study

Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden; 2Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden; 3Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; 4Department of Epidemiology and Biostatistics, Drexel University School of Public Health, Philadelphia

1

*To whom correspondence should be addressed; Department of Public Health Sciences, Karolinska Institutet, Widerströmska Huset, Tomtebodavägen 18A, Stockholm 171 76, Sweden; tel: 468-524-801-27, e-mail: [email protected]

A growing body of literature suggests that exposure to infections, particularly maternal infections, during pregnancy confers risk for later development of psychotic disorder. Though brain development proceeds throughout childhood and adolescence, the influence of infections during these ages on subsequent psychosis risk is insufficiently examined. The aim of this study was to investigate the potential association between infections during childhood and nonaffective psychoses in a large population-based birth cohort with follow up long enough to include peak incidence of nonaffective psychosis. We included all individuals born in Sweden between 1973 and 1985, (N = 1 172 879), with follow up on first time inpatient care with nonaffective psychosis from age 14 years until 2006, (N = 4638). Following adjustment for differences in sex, socioeconomic status, family history of psychosis, and hospital admissions involving noninfectious, nonpsychiatric care, we observed a small but statistically significant association between hospital admissions for infections, in general, throughout childhood (0–13 years) and a later diagnosis of nonaffective psychosis, hazard ratio (HR) = 1.10 (95% CI 1.03–1.18), and this association seemed to be driven by bacterial infection, HR = 1.23 (95% CI 1.08–1.40). Bacterial infections and central nervous system infections during preadolescence (10–13 years) conferred the strongest risk, HR 1.57 (95% CI 1.21–2.05) and HR 1.96 (95% CI 1.05–3.62), respectively. Although preadolescence appeared to be a vulnerable age period, and bacterial infection the most severe in relation to psychosis development, the present findings can also indicate an increased susceptibility to hospital admission for infections among children who will later develop nonaffective psychosis due to social or familial/genetic factors. Key words: psychosis/prenatal/schizophrenia/ epidemiology/cohort study

Introduction While the etiology of schizophrenia and other nonaffective psychoses remain elusive, they are currently believed to be caused by a genetic predisposition/vulnerability interacting with environmental exposures to interfere with brain development.1 While no major risk alleles for these disorders have been identified, genetic risk has been consistently reported in the major histocompatibility complex (MHC) region on chromosome 62 enriched in genes involved in immune functions. Among various environmental factors, exposures to prenatal infections have been identified as risk factors, reviewed by Brown & Derkits.3 Although fetal life is a crucial period of brain development, the brain development does proceed throughout childhood and adolescence,4 and thus, the critical period for different exposures can potentially span a wider window than the fetal period alone. Accordingly, disturbances in brain maturation during childhood have also been proposed to contribute to the etiology of schizophrenia.5 However, few studies have examined the risks associated with infections during childhood for developing psychotic illness, reviewed by Khandaker et al,6 and hence important knowledge gaps remain. To date, we and others have concentrated only on infections in the central nervous system (CNS). It is therefore not known if CNS infections contribute to the development of psychosis later in life or if individuals who develop psychosis are more likely to have been diagnosed with such infections due to differences in susceptibility and vulnerability to infections.7 Indeed, infections can potentially directly be involved in the later development of psychosis through mechanisms that are common to all, or certain groups of pathogens (such as viruses or bacteria), or unique to a specific pathogen. In fact, altered systemic levels of cytokines, immune modulating molecules,

© The Author 2013. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: [email protected]

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Åsa Blomström*,1, Håkan Karlsson2, Anna Svensson1, Thomas Frisell3, Brian K Lee4, Henrik Dal1, Cecilia Magnusson1, and Christina Dalman1

Infection During Childhood and Risk for Psychotic Illness

Methods Registers This study is based on linkages to several registers held by Statistics Sweden and the National Board of Health and Welfare. The National Patient Register (NPR) includes virtually all inpatient care in Sweden since 19739 and was used to follow up the study population regarding hospitalization with infection and nonaffective psychoses. Data on perinatal variables were retrieved from the Medical Birth Register (MBR). MBR was initiated in 1973 and includes data from the prenatal, delivery, and neonatal periods from about all deliveries in Sweden (0.5%–3% missing data).10 The Population and Housing Census (PHC) was administered every 5 years and included, by law, all individuals registered and living in Sweden with information on demographic data.11 For the current study, we obtained data on socioeconomic status (SES) from the PHC of 1985, and 1990. The Total Population Register was initiated in 1968.11 This basic register includes the entire Swedish population and its distribution and was used for data on year of migration. Study Population All children born in Sweden between 1973 and 1985 who were alive on their 14th birthday were identified in the NPR. Adopted individuals and individuals who emigrated before 14 years of age were excluded. Assessment of Exposure All diagnoses that arose from infection were identified in ICD-8, -9, and -10 (supplementary table 1). We omitted

all codes “sequel” and “post.” Somatic inpatient care with a primary diagnose of infection was identified and arranged according to age of exposure: first year of life, 1–4 years, 5–9 years, and 10–13 years. The age categories were chosen according to the timing and bulk of neurobiological processes in the brain.4 Psychotic Disorder Data on subsequent inpatients care with a diagnosis of nonaffective psychoses (ICD-10 F20-29 and ICD-9 295, 297 and 298 except 298A and B) from 14  years of age were extracted from the Patient Register. Assessment of Confounders Considered covariates are presented in figure  1; male sex,12 season at time of birth (December-May),13 urban birth (born in municipality with ≥200 000 inhabitants 1980),14 advanced parental age (≥35  years at time of birth, separately for mother and father),15 migration status (parent born outside Sweden, separately for mother and father),16 low SES (one parent unemployed, and household receiving social welfare benefits),17 parental psychiatric history (ICD-8 290–315, ICD-9 280–319, and ICD-10 F 00-99, separately for mother and father),18 hospitalization with other diagnoses (other than of infectious, or psychiatric origin), and maternal hospitalization with infection during pregnancy19 (pregnancy was defined as first day of last menstruation before pregnancy up until day of delivery). The association between these covariates and both the exposure and the outcome were examined (table 1). To decrease the bias due to confounding, but not to lose precision in the estimates, only covariates with an effect of hazard ratio/odds ratio (HR/OR) ≥1.2 on exposure and outcome, and with a prevalence ≥5%, were adjusted for in the analyses. Statistical Methods Several analyses were conducted: The main association investigated was the relationship between a registered diagnosis of infection during childhood, and diagnosis of nonaffective psychosis in adult life. In addition, we explored the effect of exposure at 4 different age periods and, moreover, subdivided the infection diagnoses into bacterial, viral, and other infection (“other infection” included all nonbacterial and nonviral infections, and unknown or not specified infection), and into CNS and non-CNS infection, to explore if the risk is specific. Next, we investigated whether the risk of nonaffective diagnosis increased with number of admissions with infection during childhood. To avoid double registration because of multiple visits with the same infection, we required >21 days between admissions for the same type of infection for it to be considered as a new episode. 1519

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induced by a wide range of infections, are often reported in patients with schizophrenia.8 In addition, the shared components as part of the immune response could implicate a dose-response effect by successive infections. Moreover, specific ontogenetic events occur at different ages throughout childhood, implying various consequences depending on the timing of the insult.4 However, to the best of our knowledge, exposure to infection during specific age periods has not been investigated so far. Hence, in light of the increasing indices of associations between various infections, and immunologic processes during brain development, and psychotic illness, we investigate the effect of any severe infection during childhood on the risk of developing psychotic disorder later in life. We further assess whether the association is general or specific for bacterial, or viral infection, or for CNS, or non-CNS infection. To identify potential windows of vulnerability, we explore exposure to severe infections during 5 age periods and risk for adult psychotic illness. In addition, we investigate a possible dose-response relationship between multiple episodes of infection and psychotic illness.

Å. Blomström et al

Based on the theoretical causation model illustrated in figure 1, and the covariates’ association with both the exposure and the outcome (table 1) male sex, urban birth, parental history of psychiatric disorder, parental migration, and admission with other diagnoses were the potential confounders finally included in the adjusted models. In addition, we included admission with any infection during previous time periods in the model to take preceding infections into account. Survival time was calculated in years, and the analyses included a single endpoint defined as the following: 1520

starting from 14 years of age until what came first of nonaffective psychosis, death, emigration, or the December 31, 2006. Hazard ratios and 95% CI were calculated by Cox regression. OR and 95% CI were calculated by logistic regression. All statistical analyses were made by IBM SPSS statistics 21.lnk. Approval The study was approved by the Regional Ethics Committee of Stockholm, EPN. Dnr 2010/1185-31/5.

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Fig. 1.  Covariates associated with infection and nonaffective psychosis (arrows indicate direction of a theoretic causal influence between 2 variables).

Infection During Childhood and Risk for Psychotic Illness

Table 1.  Prevalences of Potential Confounders and Their Association With Nonaffective Psychoses, and Childhood Infection

Male sex Born December–May Urban birth Parental migration Parental age ≥35

Childhood Infection OR (95% CI)

Prevalence (%)

1.4 (1.3–1.4) 1.1 (1.0–1.1) 1.4 (1.3–1.5) 2.0 (1.8–2.1) 1.4 (1.3–1.5) 1.4 (1.3–1.5) 3.1 (2.9–3.4) 2.6 (2.4–2.8) 2.4 (2.2–2.7) 1.5 (1.4–1.6)

1.3 (1.3–1.3) 1.0 (0.9–1.0) 1.2 (1.2–1.3) 1.2 (1.2–1.2) 1.0 (1.0–1.0) 1.0 (1.0–1.0) 1.5 (1.5–1.5) 1.3 (1.2–1.3) 1.3 (1.3–1.4) 1.1 (1.1–1.1)

51 52 14 9 8 18 8 9 3 35

1.3 (1.2–1.4) 1.6 (1.2–2.0)

2.1 (2.1–2.1) 1.8 (1.7–1.9)

34 0.9

Note: CI, confidence interval; HR, hazard ratio; OR, odds ratio. Hospital admission with all diagnoses except a diagnosis of infection or a psychiatric diagnosis.

a

Results A total of 1  172  879 children were followed up in the registers. Altogether, 4638 (0.4%) of the children were subsequently diagnosed with nonaffective psychoses. As expected, children who later developed nonaffective psychosis tended to be male, have older parents, immigrated parents, and parents with diagnoses of mental disorder (table 2). They were more often born in urban environment, brought up in a family with low socioeconomic status, and were more often admitted to hospital with diagnoses other than those involving infections or psychoses (table 2) Of the potential confounders included in the final model, individual-analyses (not shown) identified the strongest confounding effects by hospital admission during childhood with other diagnoses, and by parental psychiatric history on the association between childhood infection and psychosis risk. Adjusting for parental history of more narrow psychiatric diagnoses such as schizophrenia, nonaffective psychosis, or affective psychosis, did not have any substantial influence on the results. Neither did adjustments for maternal infection during pregnancy. There was a statistically significantly increased risk of 10% (fully adjusted) of developing nonaffective psychoses among children who had suffered any severe infection during childhood (table 3) The risk did not differ by age at time of infection, (table 3). The association was strongest between hospital admission with bacterial infection, HR 1.23 (95% CI 1.08–1.40), and the later development of nonaffective psychoses. Exposure to bacterial infection during preadolescence (10–13 years) was associated with the highest risk increase, HR 1.57 (95% CI 1.21–2.05) compared with viral or other infections.

There was no major difference in risk increase between CNS and non-CNS infection with one exception, again, during preadolescence as the risk associated with CNS infection increased to HR 1.96 (95% CI 1.05–3.62). Multiple admissions with infection during childhood increased the risk of nonaffective psychoses to HR 1.37 (95% CI 1.06–1.78) for ≥4 infections (table 4). To test the proportional hazard assumption, we included an interaction term between exposure to infection age 0–13 and follow-up time in the model. The interaction term was not significant (P = .474). Discussion In the present study, we observed a small but significant association between hospital admission for infections during childhood and the later development of nonaffective psychoses. This association was strongest for bacterial infections, particularly during preadolescence. Although “other infections” is a large group of unknown origin, the results suggest that the risk increase is not mediated by factors common to all infections but rather by factors specific for bacterial infections. However, to explore the specific role of different pathogens, further analyses of register data in combination with serological and experimental studies are needed. In this first study to investigate non-CNS infections as well as infections in the CNS during childhood, we found that these infections were equally associated with the later development of nonaffective psychosis with the exception of exposure during the preadolescence period. As mentioned earlier, previous studies on the association between childhood infections and psychoses, have with few exceptions only investigated CNS infections. Out of these, only 2 fulfill basic methodological requirements as found by Khandaker et  al, our previous study,20 and 1521

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Maternal Paternal Parental psychiatric illness Maternal Paternal Socioeconomic status Parent unemployed Household receiving social welfare benefits Inpatient care with other diagnosesa Maternal infection during pregnancy

Nonaffective Psychosis HR (95% CI)

Å. Blomström et al

Table 2.  Characteristics of the Study Population All Children Born in Sweden 1973–1985 (N = 1 172 879)

Maternal Paternal Parental psychiatric Maternal illnessc Paternal Parental immigrationd Maternal Paternal Socioeconomic status Parent unemployed Household receiving social welfare benefits Hospital admission First year with infectione 1–4 y 5–9 y 10–13 y 0–13 y Inpatient care with other diagnosesf Percent with ≥4 hospital admissions with infectione during childhood, 0–13 y

Diagnose of nonaffective psychosisa (n = 4638, 0.4%)

n (%)

n

%

599 673 (51.3) 162 793 (13.9) 609 938 (52.2) 94 928 (8.1) 213 553 (18.3) 90 278 (7.7) 102 304 (8.8) 108 559 (9.3) 114 204 (9.8) 38 080 (3.2) 407 759 (34.9)

2 728 835 2 495 466 1 031 972 928 761 801 358 2 138

58.8 18.0 53.8 10.0 22.2 21.0 20.0 16.4 17.3 7.7 46.1

66 955 (5.7) 133 282 (11.4) 57 130 (4.9) 33 395 (2.8) 246 510 (21.1) 399 014 (34.2) 0.75

304 603 297 163 1 140 1 785 1.27

6.6 13.0 6.4 3.5 24.6 38.5

ICD-10 F20-29. >200 000 habitants 1980. c ICD-10 F00-99. d Born outside Sweden. e Diagnoses (supplementary table 1). f Hospital admission with all diagnoses except a diagnosis of infection or a psychiatric diagnosis. a

b

the study by Koponen et al.21 Both these studies reported associations with viral CNS infection. Notably, our previous study had only 23 cases exposed to CNS infection, 19 to viral, and 4 to bacterial, whereas the Finnish study had 6 cases exposed to CNS infection, 4 to viral, and 2 to bacterial infection. Thus, the somewhat contradicting results with the present study may be due to insufficient numbers in the previous studies. Preadolescence seems to be a vulnerable age period in the present study; CNS infections and bacterial infections in general were more strongly associated with future psychosis risk during this period compared with other age periods. This finding is in line with a recent meta-analysis, suggesting that Neisseria Meningitidis, a common cause of bacterial meningitis, is more prevalent among adolescents than among younger children or older individuals.22 Long-term sequelae of bacterial meningitis relating to both cognitive and behavioral problems are being increasingly recognized,23 suggesting a causal relation between certain infections during adolescence and the later diagnosis of psychosis. We here verify the doseresponse relation between consecutive infections and nonaffective psychosis in boys aged 0–3 recently reported by Liang & Chikritzhs and extend it to include also girls and ages 0–13.24 1522

While our findings suggest that infections can contribute to the development of psychosis, it is possible that these hospital admissions reflect an increased exposure, susceptibility or sensitivity to infections among individuals with other kinds of vulnerability to psychosis. Indeed, our risk estimates were attenuated by adjustment for admission with other diagnoses and parental psychiatric disease, suggesting that social factors related to exposure, as well as familial factors related to psychiatric disease, to some extent, contributed to the present findings. A Danish study recently reported that hospital treatment for infections is more common also among parents of probands in Denmark suggestive of a genetic liability to hospital admission among these individuals.7 Moreover, we recently reported lower levels of several acute phase proteins, involved in the innate, first-line defense against microbes, in neonatal blood from individuals diagnosed with nonaffective psychosis compared with matched control subjects.25 Taken together with an increasing literature consistently reporting genetic risk for psychiatric disorders in the MHC regions,2 these findings suggest that individuals who will later develop nonaffective psychosis might exhibit subtle immune deficiencies that render them more susceptible or vulnerable to early-life infections. The key question is obviously if some of these infections are

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Male Urban birthb Born December–May Parental age ≥35

No diagnose of nonaffective psychosisa (n = 1168 241, 99.6%)

1114

Any infection Bact infection Viral infection Other infection CNS infection Non-CNS infection

1.27 (1.19–1.36) 1.41 (1.24–1.60) 1.14 (1.04–1.26) 1.31 (1.20–1.42) 1.38 (1.03–1.86) 1.27 (1.18–1.36)

Crude HR (95% CI)

1.10 (1.03–1.18) 1.23 (1.08–1.40) 0.99 (0.90–1.10) 1.12 (1.03–1.22) 1.22 (0.91–1.64) 1.10 (1.02–1.18)

Adjusted HR (95% CI) a

299

5

168

108

47

300

Cases N 1.29 (1.15–1.45) 1.17 (0.88–1.56) 1.18 (0.97–1.42) 1.41 (1.21–1.65) 1.06 (0.44–2.56) 1.29 (1.15–1.45)

Crude HR (95% CI)

First Year

1.05 (0.93–1.18) 0.99 (0.74–1.32) 0.98 (0.81–1.19) 1.11 (0.95–1.29) 0.91 (0.38–2.19) 1.06 (0.94–1.19)

Adjusted HR (95% CI) a

576

14

325

236

92

586

Cases N

1–4 y

1.22 (1.12–1.33) 1.51 (1.23–1.86) 1.04 (0.91–1.18) 1.32 (1.18–1.48) 1.27 (0.75–2.14) 1.22 (1.11–1.33)

Crude HR (95% CI) 1.05 (0.96–1.14) 1.30 (1.06–1.60) 0.90 (0.79–1.03) 1.11 (0.99–1.24) 1.08 (0.64–1.83) 1.04 (0.96–1.14)

Adjusted HR (95% CI) b

278

17

140

117

52

290

Cases N

5–9 y

1.31 (1.16–1.47) 1.08 (0.82–1.41) 1.33 (1.10–1.59) 1.41 (1.19–1.67) 1.36 (0.84–2.18) 1.31 (1.16–1.48)

Crude HR (95% CI) 1.17 (1.04–1.32) 0.97 (0.74–1.28) 1.15 (0.96–1.39) 1.28 (1.08–1.51) 1.22 (0.76–1.96) 1.17 (1.04–1.32)

Adjusted HR (95% CI) b

150

10

82

33

56

157

Cases N

10–13 y

1.19 (1.01–1.39) 1.76 (1.35–2.29) 1.17 (0.83–1.65) 1.06 (0.86–1.32) 2.14 (1.15–3.97) 1.17 (0.99–1.37)

Crude HR (95% CI)

1.09 (0.93–1.28) 1.57 (1.21–2.05) 1.01 (0.72–1.43) 1.00 (0.80–1.25) 1.96 (1.05–3.62) 1.07 (0.91–1.26)

Adjustedb HR (95% CI)

1.23 (1.14–1.32)

1.10 (1.02–1.19)

1.27 (1.10–1.47)

1.04 (0.90–1.20)

Adjusteda HR (95% CI)

1.55 (1.21–1.98)

Crude HR (95% CI)

3 (N = 66)

1.20 (0.94–1.53)

Adjusteda HR (95% CI)

1.90 (1.47–2.46)

Crude HR (95% CI)

≥4 (N = 59)

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Note: CI, confidence interval; HR, hazard ratio. a Adjusted for male sex, urban birth, parental migration, parental psychiatric history, and hospital admission with other diagnoses.

Nonaffective psychosis

Crude HR (95% CI)

Crude HR (95% CI)

Adjusteda HR (95% CI)

2 (N = 187)

1 (N = 802)

No. of Hospital Admissions During Childhood

1.37 (1.06–1.78)

Adjusteda HR (95% CI)

Table 4.  Adjusted HRa of Nonaffective Psychoses Among Children With Hospital Admission for Infection During Childhood Compared With Children Who Were Not

Note: CI, confidence interval. a Adjusted for male sex, urban birth, parental migration, parental psychiatric history, and hospital admission with other diagnoses. b Adjusted for male sex, urban birth, parental migration, parental psychiatric history, hospital admission with other diagnoses, and infection during previous time periods.

1089

45

633

443

240

Cases N

Type of Infection

0–13 y

Hospital Admission With Infection

Table 3.  Hazard Ratio (HR) of Nonaffective Psychoses Among Individuals Born in Sweden 1973–1985 After Hospital Admission With Various Infectious Agents During Childhood

Infection During Childhood and Risk for Psychotic Illness

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causally involved in the development of psychosis. While this remains to be established, it is interesting to note that infections of neonatal wild-type mice and mice genetically deficient in MHC presentation suggest that immune function is critically involved in determining the long-term outcome of the infection in terms of cognitive abilities and sensorimotor gating in adult mice.26 Limitations

Conclusion We here report a small association between hospital admissions for infections in general throughout childhood and a later diagnosis of nonaffective psychosis. While bacterial infection and CNS infections during preadolescence appeared to confer the strongest risk, we cannot exclude that our present findings indicate an increased susceptibility to hospital admission for infections among children who will later develop nonaffective psychosis. Supplementary Material Supplementary material is available at http://schizophre niabulletin.oxfordjournals.org. Funding The Swedish Research Council (2006-3002); the regional agreement on medical training and clinical research (20090401). Acknowledgment The authors have declared that there are no conflicts of interest in relation to the subject of this study. References 1. Lewis DA, Levitt P. Schizophrenia as a disorder of neurodevelopment. Annu Rev Neurosci. 2002;25:409–432.

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In register-based studies, incomplete reporting and crude exposure information is a limitation. However, registered diagnoses of psychotic disorders, including schizophrenia have proved to be reliable.27,28 The validity of infectious disease diagnoses in the NPR is high. Among diagnoses that include false positive registrations, the majority are anyhow a diagnosis of infection.29 Nevertheless, considering this misclassification risk, the association between specific infections and subsequent psychotic disorder has to be interpreted with caution. The exposure included hospital treated infections, hence, probably only severe infections. The majority of infections do not require hospital care, resulting in misclassification and a plausible underestimation of the association.

2. Stefansson H, Ophoff RA, Steinberg S; Genetic Risk and Outcome in Psychosis (GROUP). Common variants conferring risk of schizophrenia. Nature. 2009;460:744–747. 3. Brown AS, Derkits EJ. Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry. 2010;167:261–280. 4. de Graaf-Peters VB, Hadders-Algra M. Ontogeny of the human central nervous system: what is happening when? Early Hum Dev. 2006;82:257–266. 5. Luna B, Sweeney JA. Studies of brain and cognitive maturation through childhood and adolescence: a strategy for testing neurodevelopmental hypotheses. Schizophr Bull. 2001;27:443–455. 6. Khandaker GM, Zimbron J, Dalman C, Lewis G, Jones PB. Childhood infection and adult schizophrenia: a metaanalysis of population-based studies. Schizophr Res. 2012;139:161–168. 7. Nielsen PR, Laursen TM, Mortensen PB. Association between parental hospital-treated infection and the risk of schizophrenia in adolescence and early adulthood. Schizophr Bull. 2013;39:230–237. 8. Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, Kouassi E. Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry. 2008;63:801–808. 9. Kvalitet och innehåll i patientregistret. www.socialstyrelsen.se. Accessed July 10, 2013. 10. TheNational Board of Health and Welfare. The medical birth register. 2011. http://www.socialstyrelsen.se/register/halsodataregister/medicinskafodelseregistret. Accessed June 8, 2013. 11. SCB-data för forskning 2011. In: SCBr, ed. Innehållsbeskrivning av olika register. Örebro, Sweden: SCB, registerenhet; 2011. 12. Mitford E, McCabe K, Reay R, Turkington D. Inclusion criteria in epidemiological psychosis research: the importance of reporting outpatient data, gender and affective psychoses. Acta Psychiatr Scand. 2011;124:412–3. 13. Davies G, Welham J, Chant D, Torrey EF, McGrath J. A systematic review and meta-analysis of Northern Hemisphere season of birth studies in schizophrenia. Schizophr Bull. 2003;29:587–593. 14. Harrison G, Fouskakis D, Rasmussen F, Tynelius P, Sipos A, Gunnell D. Association between psychotic disorder and urban place of birth is not mediated by obstetric complications or childhood socio-economic position: a cohort study. Psychol Med. 2003;33:723–731. 15. Byrne M, Agerbo E, Ewald H, Eaton WW, Mortensen PB. Parental age and risk of schizophrenia: a case-control study. Arch Gen Psychiatry. 2003;60:673–678. 16. Cantor-Graae E, Selten JP. Schizophrenia and migration: a meta-analysis and review. Am J Psychiatry. 2005;162:12–24. 17. Wicks S, Hjern A, Dalman C. Social risk or genetic liability for psychosis? A study of children born in Sweden and reared by adoptive parents. Am J Psychiatry. 2010;167:1240–1246. 18. Dean K, Stevens H, Mortensen PB, Murray RM, Walsh E, Pedersen CB. Full spectrum of psychiatric outcomes among offspring with parental history of mental disorder. Arch Gen Psychiatry. 2010;67:822–829. 19. Khandaker GM, Zimbron J, Lewis G, Jones PB. Prenatal maternal infection, neurodevelopment and adult schizophrenia: a systematic review of population-based studies. Psychol Med. 2013;43:239–257. 20. Dalman C, Allebeck P, Gunnell D, Infections in the CNS during childhood and the risk of subsequent psychotic illness: a cohort study of more than one million Swedish subjects. Am J Psychiatry. 2008;165:59–65.

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26. Asp L, Holtze M, Powell SB, Karlsson H, Erhardt S. Neonatal infection with neurotropic influenza A virus induces the kynurenine pathway in early life and disrupts sensorimotor gating in adult Tap1-/- mice. Int J Neuropsychopharmacol. 2010;13:475–485. 27. Dalman Ch, Broms J, Cullberg J, Allebeck P. Young cases of schizophrenia identified in a national inpatient register– are the diagnoses valid? Soc Psychiatry Psychiatr Epidemiol. 2002;37:527–531. 28. Ekholm B, Ekholm A, Adolfsson R, Evaluation of diagnostic procedures in Swedish patients with schizophrenia and related psychoses. Nord J Psychiatry. 2005;59:457–464. 29. Ludvigsson JF, Andersson E, Ekbom A, External review and validation of the Swedish national inpatient register. BMC Public Health. 2011;11:450.

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21. Koponen H, Rantakallio P, Veijola J, Jones P, Jokelainen J, Isohanni M. Childhood central nervous system infections and risk for schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2004;254:9–13. 22. Christensen H, May M, Bowen L, Hickman M, Trotter CL. Meningococcal carriage by age: a systematic review and meta-analysis. Lancet Infect Dis. 2010;10:853–861. 23. Pace D, Pollard AJ. Meningococcal disease: clinical presentation and sequelae. Vaccine. 2012;30(suppl 2):B3–B9. 24. Liang W, Chikritzhs T. Early childhood infections and risk of schizophrenia. Psychiatry Res. 2012;200:214–217. 25. Gardner RM, Dalman C, Wicks S, Lee BK, Karlsson H. Neonatal levels of acute phase proteins and later risk of nonaffective psychosis. Transl Psychiatry. 2013;3:e228.

Hospital admission with infection during childhood and risk for psychotic illness--a population-based cohort study.

A growing body of literature suggests that exposure to infections, particularly maternal infections, during pregnancy confers risk for later developme...
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