Alan S. Brown

Prenatal rubella, premorbid abnormalities, and adult schizophrenia

Abstract Background: Premorbid neurocognitive, neuromotor, and behavioral function tends to be disturbed in schizophrenia. We previously demonstrated that a birth cohort clinically and serologically documented with prenatal rubella evidenced a marked increase in risk of nonaffective psychosis. In our study, we examined whether rubella-exposed subjects destined to develop schizophrenia and other schizophrenia spectrum disorders (SSD), compared with exposed control subjects, had greater impairment in several premorbid functions. Methods: Subjects were interviewed using a direct, comprehensive research assessment and diagnosed by consensus. We compared the degree of IQ decline, as well as premorbid neuromotor and behavioral dysfunction, between rubella-exposed subjects who developed schizophrenia spectrum psychosis (SSP) and exposed control subjects from the cohort. We also compared the gestational timing of rubella infection between the cases and control subjects. Results: This rubella-exposed birth cohort evidenced a markedly increased risk of SSD (20.4% or 11/53). Rubella-exposed SSP cases, compared with rubella-exposed control subjects, demonstrated a decline in IQ from childhood to adolescence, and increased premorbid neuromotor and behavioral abnormalities. Moreover, it appears that early gestational rubella exposure may represent a period of increased vulnerability for SSD. Conclusions: These findings link a known prenatal exposure, a deviant neurodevelopmental trajectory in childhood and adolescence, and SSP in adulthood within the same individuals.

Gestational Influenza and Bipolar Disorder in Adult Offspring

IMPORTANCEnGestational influenza has been associated previously with schizophrenia in offspring, but the relationship between this exposure and bipolar disorder (BD) is unclear. The identification of gestational influenza as a risk factor for BD may have potential for preventive approaches.nnnOBJECTIVEnTo test the hypothesis that maternal influenza during pregnancy is related to BD among offspring.nnnDESIGNnNested case-control study of a population-based birth cohort from the Child Health and Development Study (CHDS). From January 1, 1959, through December 31, 1966, the CHDS recruited nearly all pregnant women receiving obstetric care from the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC). Data on treated maternal influenza from the CHDS were used. Potential cases with BD from the cohort were identified by database linkages of identifiers among the CHDS, Kaiser Permanente database, and a large county health care database; by a mailed questionnaire to the CHDS cohort with subsequent interviews; and from an earlier psychiatric follow-up study on this birth cohort.nnnSETTINGnThe CHDS, Kaiser Permanente, and county health care databases.nnnPARTICIPANTSnCases of BD (nu2009=u200992) confirmed by structured research interviews and consensus diagnosis among the 214 subjects (48% of those ascertained) who participated and control subjects (nu2009=u2009722) matched on date of birth, sex, and membership in KPNC or residence in Alameda County.nnnEXPOSURESnInfluenza.nnnMAIN OUTCOME AND MEASURESnBipolar I or II disorder, BD not otherwise specified, or BD with psychotic features.nnnRESULTSnWe found a significant, nearly 4-fold increase in the risk of BD (odds ratio, 3.82 [95% CI, 1.58-9.24; Pu2009=u2009.003]) after exposure to maternal influenza at any time during pregnancy. The findings were not confounded by maternal age, race, educational level, gestational age at birth, and maternal psychiatric disorders.nnnCONCLUSIONS AND RELEVANCEnMaternal influenza may be a risk factor for BD. Although replication is required, the findings suggest that prevention of maternal influenza during pregnancy may reduce the risk of BD.

Maternal Iron Deficiency and the Risk of Schizophrenia in Offspring

CONTEXTnIron is essential for brain development and functioning. Emerging evidence suggests that iron deficiency in early life leads to long-lasting neural and behavioral deficits in infants and children. Adopting a life course perspective, we examined the effects of early iron deficiency on the risk of schizophrenia in adulthood.nnnOBJECTIVEnTo determine whether maternal iron deficiency, assessed by maternal hemoglobin concentration during pregnancy, increases the susceptibility to schizophrenia spectrum disorders (SSDs) among offspring.nnnDESIGNnData were drawn from a population-based cohort born from 1959 through 1967 and followed up for development of SSD from 1981 through 1997.nnnPARTICIPANTSnOf 6872 offspring for whom maternal hemoglobin concentration was available, 57 had SSDs (0.8%) and 6815 did not (99.2%).nnnMAIN OUTCOME MEASUREnProspectively assayed, the mean value of maternal hemoglobin concentration was the primary exposure. Hemoglobin concentration was analyzed as a continuous and a categorical variable.nnnRESULTSnA mean maternal hemoglobin concentration of 10.0 g/dL or less was associated with a nearly 4-fold statistically significant increased rate of SSDs (adjusted rate ratio, 3.73; 95% confidence interval, 1.41-9.81; P = .008) compared with a mean maternal hemoglobin concentration of 12.0 g/dL or higher, adjusting for maternal education and ethnicity. For every 1-g/dL increase in mean maternal hemoglobin concentration, a 27% decrease in the rate of SSDs was observed (95% confidence interval, 0.55-0.96; P = .02).nnnCONCLUSIONSnThe findings suggest that maternal iron deficiency may be a risk factor for SSDs among offspring. Given that this hypothesis offers the potential for reducing the risk for SSDs, further investigation in independent samples is warranted.

Maternal Smoking During Pregnancy and Bipolar Disorder in Offspring

OBJECTIVEnMaternal smoking during pregnancy is associated with a number of adverse externalizing outcomes for offspring from childhood to adulthood. The relationship between maternal smoking and bipolar disorder in offspring, which includes externalizing symptoms among its many manifestations, has not been investigated in depth. The authors examined whether offspring exposed to maternal smoking in utero would be at increased lifetime risk for bipolar disorder after accounting for other factors related to maternal smoking.nnnMETHODnIndividuals with bipolar disorder (N=79) were ascertained from the birth cohort of the Child Health and Development Study. Case subjects were identified by a combination of clinical, database, and direct mailing sources; all case subjects were directly interviewed and diagnosed using DSM-IV criteria. Comparison subjects (N=654) were matched to case subjects on date of birth (±30 days), sex, membership in the cohort at the time of illness onset, and availability of maternal archived sera.nnnRESULTSnAfter adjusting for potential confounders, offspring exposed to in utero maternal smoking exhibited a twofold greater risk for bipolar disorder (odds ratio=2.014, 95% confidence interval=1.48-2.53, p=0.01). The associations were noted primarily among bipolar offspring without psychotic features.nnnCONCLUSIONSnPrenatal tobacco exposure may be one suspected cause of bipolar disorder. However, it will be necessary to account for other unmeasured familial factors before causal teratogenic effects can be suggested.

Maternal thyroid autoantibody and elevated risk of autism in a national birth cohort

OBJECTIVEnAutoimmune disruption may contribute to risk for autism; however, since previous studies relied upon clinical diagnoses, exposure misclassification and recall bias are limitations. Thyroid peroxidase antibody (TPO-Ab) is an autoantibody involved in autoimmune thyroiditis. We aimed to test the a priori hypothesis that positivity to maternal serum TPO-Ab (TPO-Ab+) (defined as >156 IU/ml) during pregnancy is related to childhood autism.nnnMETHODnThe study was based on a nested case-control design of the Finnish Prenatal Study of Autism (FiPS-A), a national birth cohort that includes prospectively drawn archived maternal serum specimens from virtually the entire pregnant population of Finland beginning in 1983. Cases of childhood autism (ICD-10F84.0) born from 1987 to 2005 were ascertained by performing linkages between national birth and inpatient/outpatient registries. All diagnosed cases in Finland over the birth years, and comparison subjects without ASD or severe/profound intellectual disability were matched 1:1 on date of birth, sex, birthplace, and residence in Finland. Maternal serum specimens were assayed in 967 matched case-control pairs for TPO-Ab by a chemiluminescent microparticle immunoassay blind to case/control status. Data were analyzed by conditional logistic regression for matched sets.nnnRESULTSnThe prevalence of maternal TPO-Ab+ was significantly increased in pregnancies giving rise to autism cases (6.15%) compared to controls (3.54%). The odds of autism were increased by nearly 80% among offspring of mothers who were TPO-Ab+ during pregnancy (OR=1.78, 95% CI=1.16-2.75, p=0.009), compared to mothers negative for this autoantibody. There was also a significant relationship between maternal TPO-Ab defined as a continuous variable and odds of autism (OR=1.09, 95% CI=1.01, 1.17, p=0.02). Measures of maternal thyroid hormones did not differ between groups.nnnCONCLUSIONSnThese findings provide the first biomarker-based evidence that a class of known maternal autoimmune disorders is related to autism in offspring.

Autism with Intellectual Disability Related to Dynamics of Head Circumference Growth during Early Infancy

BACKGROUNDnIt is not yet definitively known whether dynamic features of head circumference growth are associated with autism. To address this issue, we carried out a nested matched case-control study using data from national well baby clinics in Finland; autism cases were identified from the Finnish Hospital and Outpatient Discharge Registry.nnnMETHODSnA nonparametric Bayesian method was used to construct growth velocity trajectories between birth and 2 years of age in autism cases and matched control subjects (n = 468 in main analyses, 1:1 matched control subjects). Estimates of odds ratios for autism risk in relation to the growth velocities were obtained using conditional logistic regression.nnnRESULTSnGrowth velocity of head circumference at 3 months of age, adjusting for gestational age at birth and maternal age, is significantly associated with autism (p = .014); the finding was observed in subjects with comorbid intellectual disability (ID) (p = .025) but not in those without ID (p = .15). Height growth velocity among subjects with autism and without ID is significantly associated with autism at 6 months (p = .007), and weight growth velocity at 18 months without ID (p = .02) and 24 months without ID (p = .042) and with ID (p = .037).nnnCONCLUSIONSnAcceleration in head circumference growth is associated with autism with comorbid ID at 3 months but not subsequently. This association is unrelated to acceleration in height and weight, which are not strongly associated with autism until after 6 months.

Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring

OBJECTIVEnMany studies have implicated prenatal infection in the etiology of schizophrenia. Cytokines, a family of soluble polypeptides, are critically important in the immune response to infection and in other inflammatory processes. The goal of this study was to determine whether second-trimester levels of four cytokines-interleukin-8 (IL-8), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha)-are higher in the mothers of offspring who later developed schizophrenia spectrum disorders than in matched comparison subjects.nnnMETHODnThe authors conducted a nested case-control study of maternal serum cytokine levels in a large birth cohort, born 1959-1967. Cases (N=59) were subjects diagnosed with schizophrenia spectrum disorders (mostly schizophrenia and schizoaffective disorder) who had available second-trimester maternal serum samples. Comparison subjects (N=105) were members of the birth cohort, had not been diagnosed with a schizophrenia spectrum disorder or major affective disorder, and were matched to subjects with schizophrenia for date of birth, gender, length of time in the cohort, and availability of maternal sera. Maternal second-trimester serum levels of IL-8, IL-1beta, IL-6, and TNF-alpha were determined by sandwich enzyme-linked immunosorbent assay.nnnRESULTSnThe second-trimester IL-8 levels in mothers of offspring with schizophrenia spectrum disorders were significantly higher than those of the mothers of comparison subjects. There were no differences between subjects with schizophrenia and comparison subjects with respect to maternal levels of IL-1beta, IL-6, or TNF-alpha.nnnCONCLUSIONSnUsing prospectively collected prenatal sera in a large and well-characterized birth cohort, the authors have documented a significant association between maternal IL-8 level during the second trimester and risk of schizophrenia spectrum disorders in the offspring. These findings provide further support for a substantive role of in utero infection or inflammation in the etiology of schizophrenia. Moreover, these results may have important implications for elucidating the mechanisms by which disrupted fetal development raises the risk of this disorder.