Child Health And Development Studies Research Articles

Contributions of maternal prenatal infection and antibiotic exposure to offspring infection and risk for allergic respiratory conditions through age 5

ObjectivesTo determine if maternal prenatal infection increases risk of offspring postnatal infections through age 5 or diagnosis of respiratory allergy at age 5, independent of prenatal/postnatal antibiotic exposure. To evaluate if frequency of offspring infections mediates an association between prenatal infection and respiratory allergy at age 5. Study designSecondary data analyses were performed from the Child Health and Development Studies (CHDS), a prospective, longitudinal birth cohort that enrolled pregnant women from 1959 to 1966 (N = 19,044 live births). The sample included a subset of mother-offspring dyads (n = 2062) with abstracted medical record data from the prenatal period through age 5 that included information on antibiotic use, infection, and offspring respiratory allergy. ResultsSecond trimester maternal infection was associated with an increased risk of offspring infection (IRR = 1.23; 95% CI = 1.09–1.39; p = 0.001). No significant direct associations were detected between prenatal infection and diagnosis of offspring respiratory allergy. Offspring infection (OR = 1.17; 95% CI = 1.13–1.20; p < 0.001) and antibiotic exposure (OR = 1.28; 95% CI = 1.22–1.33; p < 0.001) were significantly associated with a diagnosis of offspring respiratory allergy. Respiratory allergy diagnosis risk was greater with increasing offspring infection exposure and antibiotics. There was a significant indirect effect of second trimester maternal infection on offspring respiratory allergy, due to infections and not antibiotic use, via offspring infection, indicating a partially mediated effect. ConclusionPrenatal maternal infection may contribute to increase risk for early childhood infections, which in turn, may increase risk for allergic conditions.

Prenatal maternal Inflammation, childhood cognition and adolescent depressive symptoms

BackgroundAccumulating evidence indicates that higher prenatal maternal inflammation is associated with increased depression risk in adolescent and adult-aged offspring. Prenatal maternal inflammation (PNMI) may increase the likelihood for offspring to have lower cognitive performance, which, in turn, may heighten risk for depression onset. Therefore, this study explored the potential mediating role of childhood cognitive performance in the relationship between PNMI and adolescent depressive symptoms in offspring. MethodsParticipants included 696 mother-offspring dyads from the Child Health and Development Studies (CHDS) cohort. Biomarkers of maternal inflammation [interleukin (IL)-6, IL-8, IL-1 receptor antagonist (IL-1RA) and soluble TNF receptor-II (sTNF-RII)] were assayed from first (T1) and second trimester (T2) sera. Childhood (ages 9–11) cognitive performance was assessed via standardized Peabody Picture Vocabulary Test (PPVT), a measure of receptive vocabulary correlated with general intelligence. Adolescent (ages 15–17) depressive symptoms were assessed via self-report. ResultsThere were no significant associations between T1 biomarkers and childhood PPVT or adolescent depressive symptoms. Higher T2 IL1-RA was directly associated with lower childhood PPVT (b = -0.21, SE = 0.08, t = -2.55, p = 0.01), but not with adolescent depressive symptoms. T2 IL-6 was not directly associated with childhood PPVT, but higher T2 IL-6 was directly associated at borderline significance with greater depressive symptoms in adolescence (b = 0.05, SE = 0.03, t = 1.96, p = 0.05). Lower childhood PPVT predicted significantly higher adolescent depressive symptoms (b = -0.07, SE = 0.02, t = -2.99, p < 0.01). There was a significant indirect effect of T2 IL-1RA on adolescent depressive symptoms via childhood PPVT (b = 0.03, 95 % CI = 0.002–0.03) indicating a partially mediated effect. No significant associations were found with T2 sTNF-RII nor IL-8. ConclusionsLower childhood cognitive performance, such as that indicated by a lower PPVT score, represents a potential mechanism through which prenatal maternal inflammation contributes to adolescent depression risk in offspring.

Sex-Specific Pathways From Prenatal Maternal Inflammation to Adolescent Depressive Symptoms

Prenatal maternal inflammation has been associated with major depressive disorder in offspring in adulthood as well as with internalizing and externalizing symptoms in childhood; however, the association between prenatal inflammation and offspring depression in adolescence has yet to be examined. To determine whether maternal levels of inflammatory biomarkers during pregnancy are associated with depressive symptomatology in adolescent-aged offspring and to examine how gestational timing, offspring sex, and childhood psychiatric symptoms impact these associations. This was an observational study of a population-based birth cohort from the Child Health and Development Studies (CHDS), which recruited almost all mothers receiving obstetric care from the Kaiser Foundation Health Plan (KFHP) in Alameda County, California, between June 1959 and September 1966. Pregnancy data and blood sera were collected from mothers, and offspring psychiatric symptom data were collected in childhood (ages 9-11 years) and adolescence (ages 15-17 years). Mother-offspring dyads with available maternal prenatal inflammatory biomarkers during first and/or second trimesters and offspring depressive symptom data at adolescent follow-up were included. Data analyses took place between March 2020 and June 2023. Levels of inflammatory biomarkers (interleukin 6 [IL-6], IL-8, IL-1 receptor antagonist [IL-1RA], and soluble tumor necrosis factor receptor-II) assayed from maternal sera in the first and second trimesters of pregnancy. Self-reported depressive symptoms at adolescent follow-up. A total of 674 mothers (mean [SD] age, 28.1 [5.9] years) and their offspring (350 male and 325 female) were included in this study. Higher second trimester IL-6 was significantly associated with greater depressive symptoms in offspring during adolescence (b, 0.57; SE, 0.26); P = .03). Moderated mediation analyses showed that childhood externalizing symptoms significantly mediated the association between first trimester IL-6 and adolescent depressive symptoms in male offspring (b, 0.18; 95% CI, 0.02-0.47), while childhood internalizing symptoms mediated the association between second trimester IL-1RA and adolescent depressive symptoms in female offspring (b, 0.80; 95% CI, 0.19-1.75). In this study, prenatal maternal inflammation was associated with depressive symptoms in adolescent-aged offspring. The findings of the study suggest that pathways to adolescent depressive symptomatology from prenatal risk factors may differ based on both the timing of exposure to prenatal inflammation and offspring sex.

Infection and higher cortisol during pregnancy and risk for depressive symptoms in adolescent offspring

Prenatal infection, particularly at mid-gestation, has been associated with various psychopathological outcomes in offspring; however, findings linking prenatal infection to offspring depression outcomes have been mixed. Previous research indicates that it may be the co-occurrence of prenatal adversities (e.g., infection and stress) that are associated with depression outcomes in offspring. Nevertheless, no study to date has investigated whether higher levels of biomarkers linked to prenatal stress (e.g., cortisol) in the presence of infection may account for these outcomes. Participants were drawn from the Child Health and Development Studies (CHDS), a prospective, longitudinal study of pregnant women and their offspring. The present study included mother-offspring dyads from the Adolescent Study, a subsample of the CHDS cohort, whose offspring were assessed in adolescence and whose mothers also provided sera to be assayed for cortisol (n = 695). Hierarchical multivariable regressions were conducted to examine whether maternal cortisol during the first and second trimesters of pregnancy interacted with maternal infection to predict increased risk for symptoms of depression in adolescent offspring. There was a significant interaction of second trimester infection and higher cortisol on offspring depression scores during adolescence, controlling for maternal education (p = 0.04). Findings suggest that higher maternal cortisol may sensitize mothers and their offspring to the disruptive influences of infection during mid-pregnancy, conferring greater risk of depressive symptomatology in offspring.

Abstract IA11: Timing of environmental contributions to cancer in a multigenerational cohort

Abstract Transdisciplinary studies of environmental risk factors for cancer can discover paths to prevention. Using breast cancer as a case study, we review findings on the relation of a ubiquitous legacy environmental chemical, DDT, to breast cancer in three generations in the Child Health and Development Studies cohort. Although banned in the U.S. and in many places worldwide in the 1970s, the DDT story illustrates the potential role of legacy environmental chemicals in current cancer etiology. We demonstrate the importance of accounting for windows of susceptibility and induction time to cancer and provide evidence for multigenerational and transgenerational effects relevant to breast cancer risk in current generations. Findings provide proof of concept that the current environment may have lasting effects 60 years in the future. Findings support prudent management of current environmental exposures with known biologic toxicity. Waiting 60 years to understand human effects is too late to protect the public health and prevent cancer. The Child Health and Development Studies (CHDS) is a 60-year, prospective follow-up of 20,000 pregnancies that occurred in the 1960s and the resultant generations. The CHDS provides unique and valuable data to characterize how pregnancy and in utero exposures and responses contribute to disease risk in multiple generations. Maternal perinatal blood samples simultaneously provide the opportunity to measure the pregnancy exposome for Generation 1 mothers, the in utero exposome for Generation 2, and the germline exposome for Generation 3. In the CHDS we are also able to study the grandpaternal exposome in relation to granddaughters’ breast cancer risk factors, a design that estimates transgenerational effects via the paternal line. CHDS generations are tracked for place of residence, cancer risk factors, and cancer incidence to provide high quality of evidence avoiding errors of recall and accurate exposure assessment. We review breast cancer findings for Generation 1 (cohort mothers), Generation 2 (cohort daughters), and Generation 3 (cohort granddaughters). We describe perinatal DDT associations with breast cancer in mothers and daughters, with breast density in daughters, and with breast cancer risk factors in granddaughters. We show the results of next steps to uncover mechanisms, including DNA methylation patterns in breast cancer-related genes in the daughters’ generation associated with in utero DDT exposure, and the correlation of the maternal metabolome with DDT in mothers. We also compare the human, observational metabolomics data in maternal perinatal serum with parallel data from controlled experimental studies in mice designed to replicate the DDT dose and perinatal exposure in our human cohort. Along with DDT, we show findings on the relation of in utero exposure to PFASs, a class of chemicals of current concern that were also present in the 1960s. Along with grandmaternal associations, we also show early findings on some grandpaternal variables that are independently correlated with granddaughter breast cancer risk factors. We highlight findings based on high-resolution metabolomics data and exposome analyses in conjunction with epidemiologic data. These metabolomics data serve as important molecular footprints that result from gene and environmental interactions. We employ novel computational and statistical approaches to facilitate the interpretation of these high-dimensional data and integrative analysis, draw insights on the biologic effects of DDT and PFASs compounds, and explore the implication of findings on risk for breast cancer. Citation Format: Barbara A. Cohn. Timing of environmental contributions to cancer in a multigenerational cohort [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr IA11.

A vision for exposome epidemiology: The pregnancy exposome in relation to breast cancer in the Child Health and Development Studies

Etiology of complex diseases, such as breast cancer, involves multiple genetic, behavioral and environmental factors. Gene sequencing enabled detection of genetic risks with relatively small effect size, and high-resolution metabolomics (HRM) to provide omics level data for exposures is poised to do the same for environmental epidemiology. Coupling HRM to the Child Health and Development Studies (CHDS) cohort combines two unique resources to create a prototype for exposome epidemiology, in which omics scale measures of exposure are used for study of distribution and determinants of health and disease. Using this approach, exposures and biologic responses during pregnancy have been linked to breast cancer in the CHDS. With improved chemical coverage and extension to larger populations and other disease processes, development of exposome epidemiology portends discovery of new disease-associated environment factors with small effect size as well as new capabilities to disentangle these from behavioral and other risk factors.

Reprint of “Metabolome Wide Association Study of Serum Poly and Perfluoroalkyl Substances (PFASs) in Pregnancy and Early Postpartum”

High-resolution metabolomics (HRM) profiling of metabolic fingerprints can improve understanding of how poly and perfluoroalkyl substances (PFASs) induce metabolic alterations of in utero environment and impact fetal health. HRM profiling and quantification of PFASs were performed for 397 maternal perinatal serum samples collected from 1959-1967 in the Child Health and Development Studies (CHDS). We used Metabolome-Wide Association Studies (MWAS) and pathway enrichment analysis for metabolic associations with PFOS, its precursor EtFOSAA, and EtFOSAA-to-PFOS ratio. Distinct metabolic profiles were found with EtFOSAA and PFOS. Urea cycle metabolites such as arginine, lysine and creatine had opposite associations with EtFOSAA (negative) and PFOS (positive); whereas, carnitine shuttle metabolites were found to be exclusively and positively associated with PFOS indicating perturbation in fatty acid metabolism. These differential metabolic associations for precursor and end-product represent an important first step in identifying how PFASs alter the in utero environment and potentially leads to disease risk.

In utero DDT exposure and breast density before age 50

Prior studies in the Child Health and Development Studies (CHDS) found in utero exposure to the pesticide, dichlorodiphenyltrichloroethane (DDT), increased breast cancer risk by age 52. Mammographic density is considered a primary risk factor for breast cancer. We conducted a study of 309 daughters from the CHDS to examine in utero DDT exposure and mammographic density in midlife. Among daughters with high (>75th percentile) exposure to p,p’-Dichlorodiphenyldichloroethylene (DDE), p,p’-DDT was significantly correlated with increased dense area and percent density regardless of her body mass in midlife. In the subset of women with lower (<75th percentile) p,p-DDE, p,p’-DDT was associated with increased non-dense breast area. This was explained by adjustment for midlife BMI suggesting that p,p’-DDT may be obesogenic. In aggregate our findings indicate that early life p,p’-DDT exposure impacts breast density in a complex way that depends on the hosts biological ability to sequester and process DDT and levels of exposure.

Human prenatal exposure to polychlorinated biphenyls (PCBs) and risk behaviors in adolescence

Polychlorinated biphenyls (PCBs) are chemicals used in a variety of products before they were widely banned due to toxic effects in humans and wildlife. Because of continued persistence and ubiquity of these contaminants, risk of exposure to people living in industrialized countries is still high. Experimental research show that developmental exposure to PCB may alter function of brain pleasure centers and potentially influence disinhibitory behaviors, including tobacco and alcohol use. Yet, the potential effects of developmental PCB exposure on adolescent substance use have not been studied in humans. We used the Child Health and Development Studies (CHDS), a prospective birth cohort study in the Oakland and East Bay areas of California, to investigate associations between prenatal exposure to PCB congeners (66, 74, 99, 118, 138, 153, 170, 180, 187, and 203) and later disinhibitory behaviors in adolescents, specifically alcohol consumption and smoking, in a randomly selected sample (n = 554). Total prenatal PCB exposure was not associated with disinhibitory behaviors, among adolescents. However, the adjusted odds ratio (aOR) for being a current smoker, was higher in subjects within the third quartile of maternal PCB 66 exposure compared to those below the median (aOR = 1.93; 95% CI 1.05, 3.55). The aOR for drinking >2 alcoholic beverages per week, were also higher for adolescents within the third (aOR = 1.46; 95% CI 0.86, 2.47) and fourth quartile of PCB 66 exposure (aOR = 1.39; 95% CI 0.83, 2.35), but the differences did not reach statistical significance. These results suggest that this specific PCB congener may play a role inducing neurodevelopmental alterations that could potentially increase the risk of becoming a long-term user of tobacco and possibly alcohol. There were no notable differences between magnitude or direction of effect between boys and girls. Future replicate analyses with larger longitudinal samples and animal experimental studies of potential underlying mechanisms are warranted.

Metabolome Wide Association Study of Serum Poly and Perfluoroalkyl Substances (PFASs) in Pregnancy and Early Postpartum

High-resolution metabolomics (HRM) profiling of metabolic fingerprints can improve understanding of how poly and perfluoroalkyl substances (PFASs) induce metabolic alterations of in utero environment and impact fetal health. HRM profiling and quantification of PFASs were performed for 397 maternal perinatal serum samples collected from 1959-1967 in the Child Health and Development Studies (CHDS). We used Metabolome-Wide Association Studies (MWAS) and pathway enrichment analysis for metabolic associations with PFOS, its precursor EtFOSAA, and EtFOSAA-to-PFOS ratio. Distinct metabolic profiles were found with EtFOSAA and PFOS. Urea cycle metabolites such as arginine, lysine and creatine had opposite associations with EtFOSAA (negative) and PFOS (positive); whereas, carnitine shuttle metabolites were found to be exclusively and positively associated with PFOS indicating perturbation in fatty acid metabolism. These differential metabolic associations for precursor and end-product represent an important first step in identifying how PFASs alter the in utero environment and potentially leads to disease risk.

Metabolome Wide Association Study of serum DDT and DDE in Pregnancy and Early Postpartum

The advancement of high-resolution metabolomics (HRM) and metabolome-wide-association study (MWAS) enables the readout of environmental effects in human specimens. We used HRM to understand DDT-induced alterations of in utero environment and potential health effects. Endogenous metabolites were measured in 397 maternal perinatal serum samples collected during 1959-1967 in the Child Health and Development Studies (CHDS) and in 16 maternal postnatal serum samples of mice treated with or without DDT. MWAS was performed to assess associations between metabolites and p,p’-DDT, o,p’-DDT and p,p’-DDE levels, followed by pathway analysis. Distinct metabolic profiles were found with p,p’-DDT and p,p’-DDE. Amino acids such arginine had a strong association with p,p’-DDT and o,p’-DDT in both women and mice, whereas lipids and acyl-carnitine intermediates were found exclusively associated with p,p’-DDE in CHDS women indicating mitochondrial impairment. It suggests that the role of serine and fatty acid metabolism on the causal disease pathway should be examined.

Maternal infection and stress during pregnancy and depressive symptoms in adolescent offspring

Maternal infection during pregnancy has been linked to increased risk of offspring depression. Additionally, maternal stress during pregnancy has been consistently linked with adverse offspring outcomes associated with depression. Relatedly, stress has been associated with increased risk of infection; however no study has investigated stress-infection interactions during pregnancy and risk for offspring depression. Participants were drawn from the Child Health and Development Studies (CHDS), a prospective, longitudinal study that enrolled pregnant women from 1959 to 1966. Maternal health and birth outcome information were collected, as well as open-ended interviews about worrisome events during pregnancy. The present study included participants from a subsample of women whose offspring (n = 1711) completed self-reports of depressive symptoms during adolescence. Results indicated that maternal infection during only the second trimester was associated with higher scores on adolescent offspring depressive symptoms, while controlling for maternal education at birth, adolescent age, and maternal depressive symptoms at adolescence. Maternal experiences of daily stress during pregnancy moderated this association, such that mothers diagnosed with second trimester infection and who experienced daily stress had offspring with significantly higher depression scores than mothers of adolescents diagnosed with an infection alone. Findings have potential implications for prevention and intervention strategies.

Toward earlier identification and preventative intervention in schizophrenia: evidence from the London Child Health and Development Study

The London Child Health and Development Study (CHADS) is a prospective, longitudinal investigation of children, sampled from the general community aged 9–11 years and assessed biennially, who present premorbid risk markers for schizophrenia. The study aims to characterise developmental trajectories of psychological, cognitive, and biological functioning in at-risk children and identify potential targets for early preventative intervention. This review summarises CHADS findings, discusses these in the context of recent theory regarding aetiology and prevention of schizophrenia, and highlights challenges to be addressed with future research. We review (1) epidemiological information on the prevalence and correlates of developmental antecedents of schizophrenia in the general child population, (2) evidence of psychosocial, cognitive, and biological dysfunctions in at-risk children presenting multiple antecedents of schizophrenia and at-risk children with a family history of schizophrenia, and (3) related findings from an associated sample of help-seeking children receiving intervention. Community-based screening of 9–11-year olds identified ~9 % with a triad of antecedents of schizophrenia [including psychotic-like experiences (PLEs)] who are putatively at-risk of psychosis; these children reported greater exposure and responsivity to stressors, impairments in general intelligence and specific cognitive functions, brain structure and function abnormalities, and neuromotor dysfunction. Preliminary evidence suggests distressing PLEs are a viable target for cognitive-behavioural intervention in at-risk children. Intervention in early, premorbid phases of illness might alleviate current difficulties and avert future schizophrenia using benign treatments. The CHADS programme has identified several markers that may index early pathophysiology and constitute potential targets for preventative intervention.

Toward earlier identification and preventative intervention in schizophrenia: evidence from the London Child Health and Development Study.

PurposeThe London Child Health and Development Study (CHADS) is a prospective, longitudinal investigation of children, sampled from the general community aged 9–11 years and assessed biennially, who present premorbid risk markers for schizophrenia. The study aims to characterise developmental trajectories of psychological, cognitive, and biological functioning in at-risk children and identify potential targets for early preventative intervention. This review summarises CHADS findings, discusses these in the context of recent theory regarding aetiology and prevention of schizophrenia, and highlights challenges to be addressed with future research.MethodsWe review (1) epidemiological information on the prevalence and correlates of developmental antecedents of schizophrenia in the general child population, (2) evidence of psychosocial, cognitive, and biological dysfunctions in at-risk children presenting multiple antecedents of schizophrenia and at-risk children with a family history of schizophrenia, and (3) related findings from an associated sample of help-seeking children receiving intervention.ResultsCommunity-based screening of 9–11-year olds identified ~9 % with a triad of antecedents of schizophrenia [including psychotic-like experiences (PLEs)] who are putatively at-risk of psychosis; these children reported greater exposure and responsivity to stressors, impairments in general intelligence and specific cognitive functions, brain structure and function abnormalities, and neuromotor dysfunction. Preliminary evidence suggests distressing PLEs are a viable target for cognitive-behavioural intervention in at-risk children.ConclusionsIntervention in early, premorbid phases of illness might alleviate current difficulties and avert future schizophrenia using benign treatments. The CHADS programme has identified several markers that may index early pathophysiology and constitute potential targets for preventative intervention.

Perinatal oxytocin increases the risk of offspring bipolar disorder and childhood cognitive impairment

BackgroundWe tested the hypothesis that perinatal oxytocin, given to pregnant women to induce labor, is related to offspring bipolar disorder (BP) and worse childhood cognitive performance among offspring. We also tested the association between childhood cognition and later BP. MethodsA population-based birth cohort derived from the Child Health and Development Study (CHDS) which included nearly all pregnant women receiving obstetric care from the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC) between 1959 and 1966. Prospectively obtained medical and offspring cognitive performance were used. Potential cases with BP from the cohort were identified by database linkages. This protocol identified 94 cases who were matched 1:8 to controls. ResultsPerinatal oxytocin was associated with a 2.4 times increased odds of later BP. Oxytocin was also associated with decreased performance on the Raven Matrices, but not on the Peabody Picture Vocabulary Test (PPVT). Childhood cognition was not associated with later BP. LimitationsLoss to follow-up must be considered in all birth cohort studies. In addition, the childhood cognitive battery did not include tests related to multiple domains of cognition which have been associated with later BP. A third limitation is the modest sample size of those exposed to oxytocin. ConclusionsThis study provides evidence for a potentially important perinatal risk factor for BP and cognitive impairment in childhood. While the association between perinatal oxytocin and offspring BP must be viewed cautiously until further studies can attempt to replicate the result, it lends support to the broader view that neurodevelopmental factors contribute to BP.

DDT Exposure and Its Associations with Pregnancy Complications in the Child Health and Development Studies Cohort

The Child Health and Development Studies (CHDS), a prospective pregnancy cohort, investigated whether DDT exposure plays a role in cardiovascular disease (CVD) early in the disease process. Previou...

Gestational Influenza and Bipolar Disorder in Adult Offspring

Gestational 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. To test the hypothesis that maternal influenza during pregnancy is related to BD among offspring. Nested 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. The CHDS, Kaiser Permanente, and county health care databases. Cases of BD (n = 92) confirmed by structured research interviews and consensus diagnosis among the 214 subjects (48% of those ascertained) who participated and control subjects (n = 722) matched on date of birth, sex, and membership in KPNC or residence in Alameda County. Influenza. Bipolar I or II disorder, BD not otherwise specified, or BD with psychotic features. We found a significant, nearly 4-fold increase in the risk of BD (odds ratio, 3.82 [95% CI, 1.58-9.24; P = .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. Maternal 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.

Parental age and risk of bipolar disorder in offspring

We investigated prospectively documented parental age and bipolar disorder (BD) in a multi-ethnic birth cohort. The study was based on a nested case–control design from the Child Health and Development Study (CHDS) birth cohort from 1959 to 1966. Potential cases with BD were ascertained by database linkages between CHDS, Kaiser Permanente Medical Care Plan (KPNC), and Alameda County Behavioral Health Care Services, and mailed questionnaires. Consensus diagnoses with the SCID for DSM-IV-TR were made. The total number of BD cases was 94. Controls (N=746) were selected from the birth cohort and matched on date of birth, sex, and KPNC membership or residence in Alameda County. For every 10-year increment of paternal age, there was no significant association with BD, adjusting for maternal age. There was also no significant association between maternal age, modeled in 10-year increments, and risk of BD after adjustment for paternal age and maternal race, although there was a suggestion for a protective relationship between increasing maternal age and BD with psychotic features. These findings suggest that if advanced paternal age is a risk factor for BD, the strength of the relationship is small.

Associations between birth weight, preeclampsia and cognitive functions in middle-aged adults.

Both reductions in birth weight and preeclampsia (PE) have been associated with decrements in scores on tests of intelligence in children and adolescents. We examined whether these decrements persist into middle adulthood and expand into other domains of cognitive functioning. Using data from the Early Determinants of Adult Health project and from the ancillary project, Fetal Antecedents of Major Depression and Cardiovascular Disease, we selected term same-sex sibling sets or singletons from these sets, from the New England Family Study (NEFS) and the Child Health and Development Studies (CHDS), discordant on either fetal growth or PE, to test the hypotheses that prenatal exposure to inflammation was associated with decrements in attention, learning and executive function 40 years later. Exposure was defined as a continuous measure of percentile birth weight for gestational age, reduced fetal growth (<20th percentile of birth weight for gestational age) or maternal PE. Given that the sample was comprised, in part, of sibling sets, the analyses were performed using mixed models to account for the inter-sibling correlations. Analyses were performed separately by study site (i.e. NEFS and CHDS). We found few statistically significant associations (suggesting a possible type II error) consistent with previous literature, suggesting that the associations with low birth weight do not persist into midlife. We discuss the possible reasons for the lack of associations, which include the possible mediating effects of the postnatal environment.

Assaying organochlorines in archived serum for a large, long-term cohort: Implications of combining assay results from multiple laboratories over time

Conserving irreplaceable, archived serum samples may sometimes conflict with the objective of minimizing measurement error due to laboratory effects. We sought to determine whether we could successfully combine assay results for DDT-related compounds and polychlorinated biphenyls (PCBs) in serum from the same birth cohort obtained from different laboratories over time. Using the Child Health and Development Studies (CHDS) serum archive, we compared variability for assays of a quality control pool to variability for assays of subject serum. The quality control pool was created from native archived serum samples that were pooled, then aliquoted, blinded and inserted pair-wise into assay batches along with the subject serum for 5 studies using CHDS samples conducted over a 13 year period by three different laboratories. We found that the variability between laboratory and over time within laboratory was small relative to inter-individual variability for p,p′-DDT (1,1,1-trichloro-2,2-bis( p-chlorophenyl)ethane), p,p′-DDE (1,1′-dichloro-2,2′-bis( p-chlorophenyl)ethylene) and o,p′-DDT (1,1,1-trichloro-2-( p-chlorophenyl)-2-( o-chlorophenyl)-ethane). Results were also consistent for most PCB congeners which were detectable in 85% or more of samples. Our results suggest that it is possible to combine assays for DDT and PCB congeners measured at positive levels as they are accumulated for cohort subjects without risking meaningful misclassification due to variation stemming from laboratory or time period. This has significant implications for future study costs, conservation of irreplaceable archived samples and for leveraging past investments for future research. For PCB congeners with very low levels, findings caution against pooling of assays without further exploration.