Maternal inflammation during pregnancy and offspring psychiatric symptoms in childhood: Timing and sex matter

https://doi.org/10.1016/j.jpsychires.2019.01.009Get rights and content

Abstract

Objective

Maternal infection during pregnancy has been associated with increased risk of offspring psychopathology, including depression. As most infections do not cross the placenta, maternal immune responses to infection have been considered as potentially contributing to this relationship. This study examined whether gestational timing of maternal inflammation during pregnancy is associated with offspring internalizing and/or externalizing symptoms during childhood and, further, whether fetal sex moderated this relationship.

Method

Participants were 737 pregnant women and their offspring who were continuously followed through late childhood. Archived first and second trimester sera were analyzed for markers of inflammation [interleukin 8 (IL-8), IL-6, IL-1 receptor antagonist (IL-1ra), and soluble tumor necrosis factor receptor-II (sTNF-RII)]. When offspring were aged 9–11, mothers completed a questionnaire assessing psychological symptoms.

Results

Multivariate regression analyses indicated that elevated IL-8 in the first trimester was associated with significantly higher levels of externalizing symptoms in offspring. Higher IL-1ra in the second trimester was associated with higher offspring internalizing symptoms. Further, second trimester IL-1ra was associated with increased internalizing symptoms in females only.

Conclusion

These findings demonstrate that elevated maternal inflammation during pregnancy is associated with the emergence of separate psychological phenotypes and that timing of exposure and fetal sex matter for offspring outcomes. Given that internalizing and externalizing symptoms in childhood increase risk for a variety of mental disorders later in development, these findings potentially have major implications for early intervention and prevention work.

Introduction

Childhood internalizing (e.g., withdrawal, sorrow, and worry) and/or externalizing symptoms (e.g. aggression, impulsivity) increase risk for later psychiatric disorders (e.g., depression, substance use disorders, and schizophrenia) (Cicchetti and Toth, 1991). Antenatal maternal factors (e.g., malnutrition, distress, toxin exposure) are associated with the emergence of childhood internalizing and externalizing symptoms (MacKinnon et al., 2018) as well as later psychiatric conditions, such as schizophrenia and depression (Allen et al., 1998). While there is growing evidence that one antenatal maternal factor, maternal inflammation during pregnancy (MIP), is associated with subsequent psychiatric conditions in offspring (e.g. schizophrenia, bipolar disorder, autism), less is known about the role of MIP in the emergence of childhood internalizing and externalizing phenotypes (Depino, 2018). Since internalizing and externalizing symptoms in childhood increase risk for a variety of mental disorders later in development, understanding the role of maternal inflammation in the emergence of internalizing and externalizing symptoms is important for early identification and prevention.

There is compelling evidence linking maternal exposure to infection during pregnancy with adverse psychiatric outcomes in their offspring (Brown and Derkits, 2009; Machón et al., 1997; Murphy et al., 2017). It is likely that the maternal inflammatory response following exposure to infection is the mechanism by which risk is conferred to the offspring, since some inflammatory cytokines can cross the placenta (Shi et al., 2005) while the majority of viral/bacterial pathogens cannot (Fineberg and Ellman, 2013). In support of this hypothesis, multiple studies using direct assessment of inflammatory activation have linked maternal inflammation with greater likelihood of offspring psychiatric diagnoses of schizophrenia (Brown et al., 2004; Fineberg and Ellman, 2013), autism (Brown et al., 2014), bipolar disorder (Canetta et al., 2014), and major depressive disorder (Gilman et al., 2016). Although internalizing and externalizing symptoms in children as well as elevated maternal inflammation are both predictors of serious psychiatric disorders, it remains unclear whether increased levels of MIP are predictive of internalizing and externalizing symptoms in children. Only one human study has investigated the role of MIP in childhood behavior, which found that elevated interleukin-6 (IL-6) during pregnancy predicted worse impulse control in two year old offspring via differential amygdala development (Graham et al., 2018). Thus, there is strong reason to believe that MIP is associated with internalizing and externalizing behaviors in offspring.

Animal research provides additional evidence that MIP is associated with the development of internalizing and externalizing behaviors in offspring. Animals exposed to MIP are more likely to exhibit behaviors (e.g. decreased exploration, anhedonia, increased threat sensitivity, cognition, and sensitivity to stimulants) that are analogues of internalizing and externalizing symptoms in humans (Meyer et al., 2009; Simanek and Meier, 2015). Moreover, animal studies suggest that the inconsistent results observed in human studies may, in part, be attributable to the differential effect of MIP by fetal sex and the trimester during which inflammation occurs (Meyer, 2014). Animal studies report a generalized pattern of differential timing of MIP (trimester one (T1) vs. trimester two (T2)) impacting different stages of fetal neurodevelopment, leading to animal offspring phenotypes similar to internalizing and externalizing symptoms in humans (Meyer et al., 2006). In rodents, T1 MIP is associated with sensorimotor gating, associative learning difficulties and sensitivity to amphetamine use – animal behaviors similar to an externalizing phenotype in humans (Krueger et al., 2002). This cluster of T1 deficits may be related to alterations in the dopamine system caused by MIP (e.g., prefrontal hypoactivation and subcortical hyperactivation in dopamine receptor D1; Meehan et al., 2017). Conversely, T2 MIP is associated with deficits in social interactions, anhedonic behavior, as well as perseverative behaviors and cognitive inflexibility in rodent offspring (Babri et al., 2014; Zhang et al., 2012), behaviors similar to internalizing behaviors in humans.

There is also good evidence that the effects of MIP may be dependent upon the sex of the fetus (for a review see (Rana et al., 2012)), however this research question is relatively understudied (Boksa, 2010). First, there are robust sex differences in the prevalence of psychological disorders (e.g., schizophrenia, autism, depression). Second, both human and rodent research have shown that negative behavioral and cognitive outcomes (e.g., depressive and anxious behaviors) following prenatal infection/inflammation are dependent on fetal sex (Gilman et al., 2016; Rana et al., 2012; Wang et al., 2010). The precise relationship between fetal sex and neurodevelopmental outcomes is unclear because of a strong bias in animal research towards the experiments that use male animals only (Beery and Zucker, 2011) and because there are multiple additional factors moderating the relationship between MIP and behavioral outcomes (e.g., the dose and character of immune response as well as the timing of administration during gestations). However, given the elevated prevalence of internalizing disorders in females and the heightened risk of conduct disorders in males (Zahn-Waxler et al., 2008), it is probable that MIP confers a similar risk profile.

The present study tested whether the timing of MIP, as measured by levels of inflammatory biomarkers in maternal sera, differentially predicts internalizing and externalizing symptoms in offspring. Data are based on maternal report via questionnaire of the offspring's symptoms at a 9–11 year follow-up obtained from a large-scale, longitudinal study, and immunoassays performed on archived maternal serum obtained during T1 and T2 of pregnancy. This study hypothesized that:

  • (1)

    Elevated T1 MIP predict more severe offspring externalizing symptoms.

  • (2)

    Elevated T2 MIP predict more severe offspring internalizing symptoms.

  • (3)

    An exploratory aim was to test whether the relationship between MIP and internalizing and externalizing symptoms in offspring would differ by sex.

Section snippets

Participants

Institutional Review Board approval was obtained at two large universities in the United States. Participants were drawn from a prospective, longitudinal study of women that gave birth in a socio-economically and racially diverse county in the United States between 1959 and 1966, resulting in 19,044 live births. The prospective, longitudinal study recruited virtually all pregnant women seeking obstetric care within this diverse county of the United States (van den Berg et al., 1988). Live

Results

From the 737 mothers for whom archived sera was assayed for biomarkers of inflammation, 405 had biomarker data at T1 and/or T2, and had complete offspring data on either the internalizing or externalizing scales. No differences were observed between the analytic (n = 405) and excluded (n = 332) mothers on demographic, maternal health, or inflammatory biomarker variables (see supplementary material). A correlation matrix and descriptive statistics (final two rows) are presented in Table 1.

Discussion

This is the first human study to demonstrate that maternal inflammation during pregnancy is associated with subsequent internalizing and externalizing symptoms in offspring aged 9–11 years. Higher levels of T2 IL-1 receptor antagonist (IL-1ra) were associated with more internalizing symptoms in females while higher levels of T1 IL-8 predicted higher levels of subsequent conduct problems among offspring. This is the first study to suggest that the timing of exposure to MIP and fetal sex are

Declarations of interest

None.

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