TABLE 4.

Other Birth Cohort Studies of Prenatal Infection and Schizophrenia

Authors, Year (Reference)	Study Design	Numbers of Cases	Numbers of Noncases	Description of Associationa	Comments
					Strengths	Limitations	Other
Crow et al., 1991 (41)	Retrospective assessment for influenza in a birth cohort born March 3–9, 1958, exposed to the 1957 A2 epidemic in England, Wales, and Scotland; cases identified via record search; diagnoses established by chart review (Present State Examination criteria)	16,268 total cases; exposed 1st trimester: 231 cases; exposed 2nd trimester: 945 cases; exposed 3rd trimester: 675 cases; number of unexposed cases not reported	Not reported	None	Large national sample; used individual pregnancies to determine exposure	Low statistical power; exposure to influenza determined from retrospective maternal interview
Cannon et al., 1996 (42)	Retrospective assessment for influenza in pregnancies during 1957 A2 influenza epidemic in Ireland and later schizophrenia	2 exposed cases, 2 unexposed cases	236 exposed and 285 unexposed comparison subjects	None	Individual pregnancies	Exposure to influenza determined from retrospective maternal interview; low power due to small number of cases	Diagnoses made by chart review using the Research Diagnostic Criteria
Brown et al., 2000 (43)	Birth cohort study of rubella, based on physician diagnosis and/or rubella antibody titer, followed up for nonaffective psychosisb	11 exposed cases with nonaffective psychosis, 18 unexposed cases	42 exposed noncases, 1,526 unexposed noncases	Prenatal rubella exposure associated with increased risk of nonaffective psychosis (relative risk=5.2, 95% CI=1.9–14.3)	Rubella exposure was determined by either prospective clinical diagnosis or verification in a subsample by antibody titers; diagnoses based on psychiatric interviews	Lack of unexposed cases with verified rubella diagnoses; however, prenatal rubella was rare in the comparison cohorts
Brown et al., 2001 (44)	Birth cohort study of rubella, based on physician diagnosis and/or rubella antibody titer, followed up for schizophrenia spectrum disordersc	11 exposed schizophrenia spectrum disorder cases, no unexposed cases	42 exposed noncases, no unexposed noncases	Prenatal rubella-exposed birth cohort evidenced a markedly high risk of schizophrenia spectrum disorder (11/53, 20.4%)	Diagnoses based on psychiatric interviews	No unexposed cohort to calculate effect size, although relative risk estimated at ~15-fold based on general population estimates of risk of schizophrenia spectrum disorders; small sample size	Cases included schizophrenia, schizoaffective disorder, psychotic disorder not otherwise specified, delusional disorder, schizotypal personality disorder, and paranoid personality disorder
Mortensen et al., 2007 (45)	National cohort-based case-control study of Toxoplasma gondii combining data from national population registers and patient registers and a national neonatal screening biobank of filter paper blood spots in Denmark; subjects born after 1981 and followed up for schizophrenia through 1999	30 exposed cases, 41 unexposed cases	171 exposed and 513 unexposed comparison subjects	Elevated Toxoplasma gondii IgG anti-body (odds ratio=1.79, 95% CI=1.01– 3.15)	Study compared risks for schizophrenia, schizophrenia-like disorders, and affective disorders; effect was specific to schizophrenia	Diagnoses based on psychiatric registry; partial ascertainment of eligible sample due to missing filter paper blood spots	Blood spots taken from infant; diagnoses based on psychiatric registry
Sørensen et al., 2009 (46)	Data from Copenhagen Perinatal Cohort, born 1959–1961 at Rigshospitalet in Copenhagen, linked with the Danish National Psychiatric Register for diagnoses of schizophrenia	32 cases exposed to any bacterial infection, 121 unexposed cases	1,033 noncases exposed to any bacterial infection, 6,755 unexposed noncases	Maternal bacterial infectionsd: 1st trimester, for both ICD-8 (odds ratio=2.53, 95% CI=1.07–5.96) and broadly defined schizophrenia (ICD-8 and/or ICD-10) (odds ratio=2.14, 95% CI=1.06–4.31); 2nd trimester, for ICD-8 (odds ratio=2.31, 95% CI=1.15–4.35) and broadly defined schizophrenia (odds ratio=1.82, 95% CI=1.06–3.14), only in unadjusted analysis		Diagnoses based on psychiatric registry; although exposures were based on clinical diagnoses, bacterial infections may have been misclassified; broad categories of infection (i.e., viral, bacterial); low statistical power
Clarke et al., 2009 (47)	Data from Medical Birth Register linked with Finnish Population Register to identify women in Helsinki treated during pregnancy for upper urinary tract infection between 1947 and 1990; psychiatric out-comes of adult offspring identified through Finnish Hospital Discharge Register	36 cases exposed prenatally to upper urinary tract infection, 35 unexposed; 12 cases with a family history of psychosis, 59 cases with no family history	9,596 noncases exposed prenatally to upper urinary tract infection, 13,808 unexposed noncases; 1,497 noncases with a family history of psychosis, 21,907 noncases with no family history	No statistically significant association with prenatal infection alone, but observed interaction between prenatal exposure to upper urinary tract infection and family history (risk difference=0.51, 95% CI=0.06–0.96); 38%–46% of cases in sample may have developed schizophrenia as a result of the synergistic action of both risk factors	Large sample size; used sibling comparison group; hospital-treated infection provided exact information on time of exposure during pregnancy	Small number of cases; statistical power too low to examine each trimester separately

^aMeasures of effect (relative risk, rate ratio, or odds ratio) are reported here if reported in the original paper; p≤0.05 unless otherwise noted.

^bNonaffective psychosis was defined as 1) at least one psychotic symptom (delusions and/or hallucinations) for a minimum of 6 months; 2) no evidence of a major affective disorder (bipolar or unipolar) by DSM-III-R criteria concurrent with the psychosis; and 3) no evidence that a medical condition or substance use initiated or maintained the psychosis. Diagnoses were established using psychiatric interview (Diagnostic Interview Schedule for Children) and DSM-III-R criteria.

^cSchizophrenia spectrum disorders included schizophrenia, schizoaffective disorder, schizotypal personality disorder, delusional disorder, and “other schizophrenia spectrum psychoses.” Diagnoses were established using both psychiatric interview (Diagnostic Interview for Genetic Studies) and medical chart review

^dMaternal bacterial infections included sinusitis, tonsillitis, pneumonia, cystitis, pyelonephritis, bacterial venereal infection, and any other bacterial infection.