Maternal Cytokine Levels during Pregnancy and Adult Psychosis

doi:10.1006/brbi.2001.0644

Brain, Behavior, and Immunity

Volume 15, Issue 4, December 2001, Pages 411-420

https://doi.org/10.1006/brbi.2001.0644 Get rights and content

Abstract

We investigated levels of maternal cytokines in late pregnancy in relation to the subsequent development of adult schizophrenia and other psychoses in their offspring. The sample included the mothers of 27 adults with schizophrenia and other psychotic illnesses and 50 matched unaffected controls from the Providence cohort of the Collaborative Perinatal Project. Serum samples were analyzed for interleukin 1 beta (IL-1-β), interleukin 2 (IL-2), interleukin 6 (IL-6), interleukin 8 (IL-8), and tumor necrosis factor alpha (TNF-α) by enzyme immunoassay. Maternal levels of TNF-α were significantly elevated among the case series (t = 2.22, p = .04), with evidence of increasing odds of psychosis in relation to higher cytokine levels. We did not find significant differences between case and control mothers in the serum levels of IL-1, IL-2, IL-6, or IL-8. These data support previous clinical investigations reporting maternal infections during pregnancy as a potential risk factor for psychotic illness among offspring.

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Women who contract a viral or bacterial infection during pregnancy have an increased risk of giving birth to a child with a neurodevelopmental or psychiatric disorder. The effects of maternal infection are likely mediated by the maternal immune response, as preclinical animal models have confirmed that maternal immune activation (MIA) leads to long lasting changes in offspring brain and behavior development. The present study sought to determine the impact of MIA-exposure during the first or second trimester on neuronal morphology in dorsolateral prefrontal cortex (DLPFC) and hippocampus from brain tissue obtained from MIA-exposed and control male rhesus monkey (Macaca mulatta) during late adolescence. MIA-exposed offspring display increased neuronal dendritic branching in pyramidal cells in DLPFC infra- and supragranular layers relative to controls, with no significant differences observed between offspring exposed to maternal infection in the first and second trimester. In addition, the diameter of apical dendrites in DLPFC infragranular layer is significantly decreased in MIA-exposed offspring relative to controls, irrespective of trimester exposure. In contrast, alterations in hippocampal neuronal morphology of MIA-exposed offspring were not evident. These findings demonstrate that a maternal immune challenge during pregnancy has long-term consequences for primate offspring dendritic structure, selectively in a brain region vital for socioemotional and cognitive development.
Prenatal infection and schizophrenia: A decade of further progress
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Epidemiologic studies have provided evidence that prenatal exposure to maternal infection is associated with an increased risk of developing schizophrenia in the offspring. Research over the past decade has added further to our understanding of the role of prenatal infection in schizophrenia risk. These investigations include several well-powered designs, and like some earlier studies, measured maternal antibodies to specific infectious agents in stored serum samples and large registers to identify clinically diagnosed infections during pregnancy. Convergent findings from antibody studies suggest that prenatal maternal infection with Toxoplasma gondii is associated with increased schizophrenia risk in the offspring, while associations with HSV-2 infection are likely attributable to confounding. Maternal influenza infection remains a viable candidate for schizophrenia, based on an early serological study, though there has been only one attempt to replicate this finding, with a differing methodology. A prior association between maternal serologically confirmed cytomegalovirus infections require further study. Clinically diagnosed maternal infection, particularly bacterial infection, also appears to be associated with increased risk of offspring schizophrenia, and heterogeneity in these findings is likely due to methodological differences between studies. Further clarification may be provided by future studies that address the timing, type, and clinical features of infections. Important insight may be gained by examining the long-term offspring outcomes in emerging epidemics such as Zika virus and COVID-19, and by investigating the interaction between exposure to prenatal infection and other risk or protective factors.
Dual hit mouse model to examine the long-term effects of maternal immune activation and post-weaning social isolation on schizophrenia endophenotypes
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Evidence suggests that early life adversity, such as maternal immune activation (MIA), can alter brain development in the offspring and confer increased risk for psychopathology and psychiatric illness in later life. In this study, the long-term effects of MIA, post-weaning social isolation, and the combination were assessed on behavioural and immunological profiles in adult male and female offspring.
On gestation day 12.5, pregnant mice were weighed and injected with either polyinosinic:polycytidylic acid (5 mg/kg) or saline and cytokines levels were assayed 3 hrs later to confirm immune activation. The behaviour and immunological profiles of male and female offspring were examined in adolescence (P34–36), and adulthood (P55–80).
MIA induced an increase in the pro-inflammatory cytokine IL-6 in pregnant dams three hours after administration (p < 0.001) that correlated with a decrease in body temperature (p < 0.05). The effect of MIA on the immunological phenotype of the offspring was evident in adolescence, but not in adulthood. MIA selectively induced hypoactivity in adolescent males, a phenotype that persisted until adulthood, but had no effect on cognition in males or females. In contrast, social isolation stress from adolescence resulted in impaired sociability (p < 0.05) and increased anxiety (p < 0.05) particularly in adult females. There was no synergistic effect of the dual-hit on immune parameters, sociability, anxiety or cognitive behaviours.
Given the negative impact and sex-dependent effects of SI stress on locomotor and anxiety-like behaviour, future investigations should examine whether the health risks of social isolation, such as that experience during the COVID-19 pandemic, are mediated through increased anxiety.
Primate Models as a Translational Tool for Understanding Prenatal Origins of Neurodevelopmental Disorders Associated With Maternal Infection
2022, Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
Pregnant women represent a uniquely vulnerable population during an infectious disease outbreak, such as the COVID-19 pandemic. Although we are at the early stages of understanding the specific impact of SARS-CoV-2 exposure during pregnancy, mounting epidemiological evidence strongly supports a link between exposure to a variety of maternal infections and an increased risk for offspring neurodevelopmental disorders. Inflammatory biomarkers identified from archived or prospectively collected maternal biospecimens suggest that the maternal immune response is the critical link between infection during pregnancy and altered offspring neurodevelopment. This maternal immune activation (MIA) hypothesis has been tested in animal models by artificially activating the immune system during pregnancy and evaluating the neurodevelopmental consequences in MIA-exposed offspring. Although the vast majority of MIA model research is carried out in rodents, the nonhuman primate model has emerged in recent years as an important translational tool. In this review, we briefly summarize human epidemiological studies that have prompted the development of translationally relevant MIA models. We then highlight notable similarities between humans and nonhuman primates, including placental structure, pregnancy physiology, gestational timelines, and offspring neurodevelopmental stages, that provide an opportunity to explore the MIA hypothesis in species more closely related to humans. Finally, we provide a comprehensive review of neurodevelopmental alterations reported in current nonhuman primate models of maternal infection and discuss future directions for this promising area of research.
Prenatal psychological or metabolic stress increases the risk for psychiatric disorders: the “funnel effect” model
2022, Neuroscience and Biobehavioral Reviews
Adverse stressful experiences in utero can redirect fetal brain development, ultimately leading to increased risk for psychiatric disorders. Obesity during pregnancy can have similar effects as maternal stress, affecting mental health in the offspring. In order to explain how similar outcomes may originate from different prenatal conditions, we propose a “funnel effect” model whereby maternal psychological or metabolic stress triggers the same evolutionarily conserved response pathways, increasing vulnerability for psychopathology. In this context, the placenta, which is the main mother-fetus interface, appears to facilitate such convergence, re-directing “stress” signals to the fetus. Characterizing converging pathways activated by different adverse environmental conditions is fundamental to assess the emergence of risk signatures of major psychiatric disorders, which might enable preventive measures in risk populations, and open up new diagnostics, and potentially therapeutic approaches for disease prevention and health promotion already during pregnancy.
Exposure to childhood maltreatment and systemic inflammation across pregnancy: The moderating role of depressive symptomatology
2022, Brain, Behavior, and Immunity
Childhood maltreatment (CM) has long-term consequences for dysregulation of the immune system which is particularly pronounced when mental and physical health sequelae have manifested. Higher proinflammatory state has been shown in non-pregnant state in association with CM as well as with depression, one of the most frequent and pernicious psychiatric sequelae of CM. During pregnancy, however, this association is less clear. Given the important role of maternal inflammatory state during pregnancy for fetal, pregnancy, and birth outcomes, we sought to examine the association between CM and proinflammatory state during pregnancy considering the moderating role of maternal depressive symptoms characterized serially across pregnancy.
A prospective, longitudinal study of 180 healthy pregnant women was conducted with serial assessments in early (12.98 ± 1.71 weeks gestation), mid (20.53 ± 1.38 weeks gestation) and late (30.42 ± 1.4 weeks gestation) pregnancy. Maternal history of CM was assessed with the Childhood Trauma Questionnaire (CTQ) and the total score was used as an indicator of CM experience. Maternal depressive symptoms were assessed at each pregnancy visit with the Center for Epidemiologic Studies Depression Scale (CES-D). Serum concentrations of tumor necrosis factor (TNF)-α and interleukin (IL)-6 were obtained at each pregnancy visit and combined to a composite maternal proinflammatory score. Linear mixed effects models were employed to assess the association between CTQ score, CES-D score, and proinflammatory score during pregnancy, adjusting for potential confounders.
Gestational age was associated with the proinflammatory score (B = 0.02; SE = 0.00; p < .001), indicating an increase in inflammation across gestation. Neither CTQ score nor depressive symptoms were independently associated with the proinflammatory score (ps > 0.28). However, the interaction between CTQ score and depressive symptoms was associated with the proinflammatory score (B = 0.03, SE = 0.01, p < .05), indicating higher inflammation across pregnancy with increasing levels of depressive symptoms during pregnancy in women with higher CTQ scores. Exploratory analyses suggested that this interaction was mainly driven by CTQ subscale scores assessing experiences of abuse rather than neglect.
These findings suggest a moderating role of maternal depressive symptoms during pregnancy on the association of early life stress with inflammation and thus highlight the importance of the timely assessment of both CM exposure and depressive symptoms which might allow for the development of targeted and individualized interventions to impact inflammation during pregnancy and to ameliorate the detrimental long-term effects of CM. The current findings add to a better understanding of the prenatal biological pathways that may underlie intergenerational transmission of maternal CM.

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^☆: This study was funded by the Stanley Foundation with additional support provided by NIMH.

¹: Address reprint requests to Stephen L. Buka, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115. E-mail: [email protected]. 617-432-3870.

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Regular ArticleMaternal Cytokine Levels during Pregnancy and Adult Psychosis☆

Abstract

Soc. Sci. Med.

J. Reprod. Immunol.

J. Immunol. Methods

Schizophr. Res.

Schizophr. Res.

Schizophr. Res.

Schizophr. Res.

Lancet

Am. J. Obstet. Gynecol.

Amniotic fluid concentrations of interleukin-1beta, interleukin-6 and TNF-alpha in chorioamnionitis before 32 weeks of gestation: Histological associations and neonatal outcome

Br. J. Obstet. Gynaecol.

Association between G308A tumor necrosis factor alpha gene polymorphism and schizophrenia

Mol. Psychiatr.

Maternal exposure to respiratory infections and adult schizophrenia spectrum disorders: A prospective birth cohort study

Schizophr. Bull.

Defining learning disabilities: The role of longitudinal studies

Thalamus

Pregnancy/delivery complications and psychiatric diagnosis: A prospective study

Arch. Gen. Psychiatr.

Maternal infections and subsequent psychosis among offspring

Arch. Gen. Psychiatr.

Quantitative models of the genetic transmission of schizophrenia

Psychol. Bull.

Structured Clinical Interview for DSM-IV Axis I Disorders—Patient Edition (SCID–I/P), Version 2

Schizophrenia genesis: The origin of madness

Maternal serum tumor necrosis factor-alpha in patients with preterm labor

J. Reprod. Med.

Regular Article
Maternal Cytokine Levels during Pregnancy and Adult Psychosis☆