Maternal cortisol during pregnancy and offspring schizophrenia: Influence of fetal sex and timing of exposure.

INTRODUCTION: Maternal stress during pregnancy has been repeatedly linked to increased risk for schizophrenia; however, no study has examined maternal cortisol during pregnancy and risk for the disorder. Study aims were to determine whether prenatal cortisol was associated with risk for schizophrenia and risk for an intermediate phenotype-decreased fetal growth-previously linked to prenatal cortisol and schizophrenia. Timing of exposure and fetal sex also were examined given previous findings. METHODS: Participants were 64 cases diagnosed with schizophrenia spectrum disorders (SSD) and 117 controls from a prospective birth cohort study. Maternal cortisol was determined from stored sera from each trimester and psychiatric diagnoses were assessed from offspring using semi-structured interviews and medical records review. RESULTS: Maternal cortisol during pregnancy was not associated with risk for offspring schizophrenia. There was a significant interaction between 3rd trimester cortisol and case status on fetal growth. Specifically, cases exposed to higher 3rd trimester maternal cortisol had significantly decreased fetal growth compared to controls. In addition, these findings were restricted to male offspring. CONCLUSIONS: Our results indicate that higher prenatal cortisol is associated with an intermediate phenotype linked to schizophrenia, fetal growth, but only among male offspring who developed schizophrenia. Findings were consistent with evidence that schizophrenia genes may disrupt placental functioning specifically for male fetuses, as well as findings that males are more vulnerable to maternal cortisol during pregnancy. Finally, results suggest that examining fetal sex and intermediate phenotypes may be important in understanding the mechanisms involved in prenatal contributors to schizophrenia.

Fetal exposure to maternal stress and risk for schizophrenia spectrum disorders among offspring: Differential influences of fetal sex.

Exposure to adverse life events during pregnancy has been linked to increased risk of schizophrenia spectrum disorders (SSD) in offspring. Nevertheless, much of the previous work inferred maternal stress from severe life events rather than directly assessing maternal reports of stress. The present study aimed to examine maternal reports of stress during pregnancy and risk for offspring SSD. Participants were 95 SSD cases and 206 controls who were offspring from a large birth cohort study that followed pregnant women from 1959 to 1966. During pregnancy interviews, women were asked if anything worrisome had occurred recently. Interviews were qualitatively coded for stress-related themes, including reports of daily life stress, by two independent raters. None of the maternal psychosocial stress themes were significantly associated with increased odds of offspring SSD in analyses of the full sample. However, results indicated a significant daily life stress by infant sex interaction. Maternal daily life stress during pregnancy was associated with significantly increased odds of SSD among male offspring. Findings suggest sex-specific fetal sensitivity to maternal reported daily life stress during pregnancy on risk for SSD, with males appearing to be more vulnerable to the influences of maternal stress during pregnancy.

Maternal-fetal blood incompatibility and the risk of schizophrenia in offspring.

OBJECTIVE: Predicated on a maternal immune response to paternally inherited foreign fetal blood antigens, we hypothesized that maternal-fetal blood incompatibility increases susceptibility to schizophrenia in the offspring. The relation between schizophrenia and maternal-fetal blood incompatibility, arising from the D antigen of the Rhesus (Rh) and the ABO blood group antigens, was examined in a cohort of live-births. METHOD: The data were drawn from the Prenatal Determinants of Schizophrenia Study, a cohort of births occurring between 1959 and 1967 to women enrolled in a Kaiser Permanente Plan-Northern California Region (KP). Adult offspring belonging to the KP from 1981 to 1997 were followed for the incidence of schizophrenia spectrum disorder (SSD). Cox proportional hazards regression was the primary analytic technique. RESULTS: Among second and later born offspring, the adjusted incidence rate ratio (RR(adj)) of SSD was 1.80 (95% CI=0.71-4.58) for the Rh incompatible offspring compared with the Rh compatible offspring; with the males exhibiting higher rate ratio (RR(adj)=2.37; 95% CI=0.82-6.86) than the females (RR(adj)=0.93 95% CI=0.12-7.01). Among all offspring, the RR(adj) for ABO incompatibility was lower and the elevated rate ratio was similarly limited to the males (RR(adj)=1.68; 95% CI=0.76-3.70). For Rh and/or ABO incompatibility, the RR(adj) was 1.57 (95% CI=0.87-2.82). A statistically significant result was detected only for the male offspring (RR(adj)=2.22; 95% CI=1.10-4.47). CONCLUSION: Although the results should be interpreted with caution given the few events of SSD, the findings extend the line of evidence that maternal-fetal blood incompatibility is a risk factor for schizophrenia spectrum disorder; with the strongest evidence to date implicating that the susceptibility pertains only to male offspring.

Paternal age and risk of schizophrenia in adult offspring.

OBJECTIVE: The study examined the relation between paternal age at the time of birth and risk of schizophrenia in the adult offspring. METHOD: Data from the birth cohort of the Prenatal Determinants of Schizophrenia study were used in this study. Virtually all members of this birth cohort had prospective information about paternal age at the time of the offspring's birth. Subjects with schizophrenia and other schizophrenia spectrum disorders (N=71) among members of this birth cohort were previously ascertained. In separate analyses, paternal age was modeled as a continuous variable and as a categorical variable, and its relation with the risk of adult schizophrenia and other schizophrenia spectrum disorders and with the risk of schizophrenia separately were examined. RESULTS: There was a marginally significant, monotonic association between advancing paternal age and risk of adult schizophrenia and schizophrenia spectrum disorders. The association held after the analysis controlled for the effects of maternal age and other potential confounders. Similar results were observed when only subjects with schizophrenia were included in the analysis. CONCLUSIONS: Advanced paternal age at the time of birth of the offspring may be a risk factor for adult schizophrenia.