Periodic Reporting for period 4 - TransCTNeurodev (Transgenerational transmission of maternal childhood trauma and its sequelae – Altered maternal physiology during pregnancy and implications for newborn neurodevelopment)
Berichtszeitraum: 2022-03-01 bis 2023-12-31
Traumatic events that occur during a woman’s pregnancy likely impact the development of her as-yet-unborn child. But what if traumatic exposures that may have occurred before the woman became pregnant, perhaps even as early as during her own childhood? Could such exposures, when she becomes pregnant, also impact fetal development? The goal of this proposal is to test specific hypotheses about the transgenerational transmission during gestation of the effects of maternal exposure to trauma in her own childhood, with a focus on newborn brain morphology and connectivity as the primary outcome of interest, and on maternal-placental-fetal endocrine-immune stress biology as the proximate pathway of transmission.
The proposed study will help identify environmental factors associated with mental disorders and risk and protective factors for mental illness. In the context of mother-child transmission of the effects of maternal childhood trauma (CT) exposure we address specific knowledge gaps related to a) ascertainment of the earliest period(s) during the offspring’s development of time when such transgenerational transmission may occur; b) elucidation of the primary pathophysiological pathways that may mediate this effect; and c) delineation of the relative importance of the specific trauma-related maternal psychological, biophysical and behavioral states and conditions that may be amenable to interventions.
The project addresses the following specific aims:
Aim 1: To test the hypothesis that maternal exposure to childhood trauma predicts alterations in her newborn’s brain morphology and connectivity. Structural magnetic resonance imaging and resting state functional MRI scans of the newborn brain will be acquired to quantify anatomy as well as structural and functional connectivity of fronto-limbic stress circuits (hippocampus, amygdala, prefrontal cortex).
Aim 2: To test the hypothesis that alterations in maternal-placental-fetal (MPF) endocrine and immune stress biology during pregnancy mediate the effect of maternal exposure to childhood trauma on her newborn’s brain. Serial measures in early, mid and late pregnancy will be used to characterize the endocrine (CRH, cortisol) and immune (CRP, IL-6) milieu at these periods and their gestational trajectories. Causal pathway analyses will determine the extent to which maternal CT-related alterations in MPF stress biology mediate the link between maternal CT and newborn stress circuit morphology and connectivity.
Aim 3: To test the hypothesis that the effects of maternal exposure to childhood trauma on the newborn brain and on MPF stress biology are modulated by maternal co-morbid states [psychiatric conditions (depression, PTSD), current psychological and biophysical states (stress, obesity), and post-pubertal trauma exposure]. The long-term effects of CT exposure may depend on not only the characteristics of the trauma but also on the presence and magnitude of trauma-associated sequelae. Among CT+ women the prevalence of one or more of these sequelae is expected to be between 20-50%. These sequelae may exacerbate the effects of initial trauma exposure and sensitize central and peripheral systems towards hyper-responsivity to subsequent stress exposures. These states and conditions will be characterized across gestation, composite summary risk scores will be created, and the magnitude of their effects on infant brain fronto-limbic anatomy and connectivity and on MPF biology will be quantified. This aim will establish the relative importance of trauma-related states and conditions that are potentially amenable to intervention.
The proposed study will help identify environmental factors associated with mental disorders and risk and protective factors for mental illness. In the context of mother-child transmission of the effects of maternal childhood trauma (CT) exposure we address specific knowledge gaps related to a) ascertainment of the earliest period(s) during the offspring’s development of time when such transgenerational transmission may occur; b) elucidation of the primary pathophysiological pathways that may mediate this effect; and c) delineation of the relative importance of the specific trauma-related maternal psychological, biophysical and behavioral states and conditions that may be amenable to interventions.
The project addresses the following specific aims:
Aim 1: To test the hypothesis that maternal exposure to childhood trauma predicts alterations in her newborn’s brain morphology and connectivity. Structural magnetic resonance imaging and resting state functional MRI scans of the newborn brain will be acquired to quantify anatomy as well as structural and functional connectivity of fronto-limbic stress circuits (hippocampus, amygdala, prefrontal cortex).
Aim 2: To test the hypothesis that alterations in maternal-placental-fetal (MPF) endocrine and immune stress biology during pregnancy mediate the effect of maternal exposure to childhood trauma on her newborn’s brain. Serial measures in early, mid and late pregnancy will be used to characterize the endocrine (CRH, cortisol) and immune (CRP, IL-6) milieu at these periods and their gestational trajectories. Causal pathway analyses will determine the extent to which maternal CT-related alterations in MPF stress biology mediate the link between maternal CT and newborn stress circuit morphology and connectivity.
Aim 3: To test the hypothesis that the effects of maternal exposure to childhood trauma on the newborn brain and on MPF stress biology are modulated by maternal co-morbid states [psychiatric conditions (depression, PTSD), current psychological and biophysical states (stress, obesity), and post-pubertal trauma exposure]. The long-term effects of CT exposure may depend on not only the characteristics of the trauma but also on the presence and magnitude of trauma-associated sequelae. Among CT+ women the prevalence of one or more of these sequelae is expected to be between 20-50%. These sequelae may exacerbate the effects of initial trauma exposure and sensitize central and peripheral systems towards hyper-responsivity to subsequent stress exposures. These states and conditions will be characterized across gestation, composite summary risk scores will be created, and the magnitude of their effects on infant brain fronto-limbic anatomy and connectivity and on MPF biology will be quantified. This aim will establish the relative importance of trauma-related states and conditions that are potentially amenable to intervention.
In order to achieve the objectives of the present study, a cohort of mother-fetus/infant dyads has been recruited in early pregnancy and followed up in mid and late pregnancy and within 6 weeks post delivery. Presentations of the project were given at various clinical sites in Berlin (obstetric practices, midwives, prenatal care centers, birth hospitals, and counseling services, such as Profamilia Berlin) to involve them in identifying potential study subjects for enrollment into the study.
Overall, a total of N=473 women were screened for eligibility of whom 265 women were recruited to participate. After completing the Childhood Trauma Interview (CTI) to determine study group membership, 66 women were not eligible to continue further, leaving a total sample size of N=199 women included in the study. 165 participants remained in the study until the end of the study, 34 women dropped out or were lost to follow-up.
Of the 199 women in the study, 108 were included in the CT+ group and 91 in the CT- group. Magnetic resonance imaging (MRI) was performed in 104 neonates born to these mothers.
Serial measures of maternal psychological, behavioral and physiological characteristics have been collected across early, mid and late gestation. The following biological assays have been completed: Saliva samples collected during participants’ everyday life over a four-day period in early and late pregnancy have been analyzed for cortisol concentrations for all participants. From maternal blood and cord blood samples, metabolic and proinflammatory markers have been assessed and analyses addressing the main study objectives are still ongoing with the results emerging supporting the main hypotheses of the grant. For example, women exposed to maltreatment exhibited lower cortisol concentrations in early pregnancy and a stronger increase in cortisol output from early to late pregnancy. Because alterations in gestational stress biology, such as the observed differences in cortisol concentrations, may in turn affect fetal brain development, we investigated the association of maternal cortisol concentrations during pregnancy and white matter microstructure parameters in one month old neonates. We observed lower maturity of selected white matter fiber tracts in newborns whose mothers had higher cortisol concentrations during pregnancy. Additional analyses have been performed with other datasets and support the moderating role of CT-related sequelae, especially depression, in the association between CT and inflammation during pregnancy as well as in the association between CT and white matter development in the offspring. The same analyses are currently being conducted in the current cohort.
Continuously across the duration of the grant, presentations have been given at national and international research meetings. Furthermore, regular presentations at local institutions that support pregnant and postpartum women (e.g. Frühe Hilfen, Babylotsen) have been given to increase awareness of the high prevalence of childhood maltreatment and how this may affect well-being of pregnant women and their children.
Overall, a total of N=473 women were screened for eligibility of whom 265 women were recruited to participate. After completing the Childhood Trauma Interview (CTI) to determine study group membership, 66 women were not eligible to continue further, leaving a total sample size of N=199 women included in the study. 165 participants remained in the study until the end of the study, 34 women dropped out or were lost to follow-up.
Of the 199 women in the study, 108 were included in the CT+ group and 91 in the CT- group. Magnetic resonance imaging (MRI) was performed in 104 neonates born to these mothers.
Serial measures of maternal psychological, behavioral and physiological characteristics have been collected across early, mid and late gestation. The following biological assays have been completed: Saliva samples collected during participants’ everyday life over a four-day period in early and late pregnancy have been analyzed for cortisol concentrations for all participants. From maternal blood and cord blood samples, metabolic and proinflammatory markers have been assessed and analyses addressing the main study objectives are still ongoing with the results emerging supporting the main hypotheses of the grant. For example, women exposed to maltreatment exhibited lower cortisol concentrations in early pregnancy and a stronger increase in cortisol output from early to late pregnancy. Because alterations in gestational stress biology, such as the observed differences in cortisol concentrations, may in turn affect fetal brain development, we investigated the association of maternal cortisol concentrations during pregnancy and white matter microstructure parameters in one month old neonates. We observed lower maturity of selected white matter fiber tracts in newborns whose mothers had higher cortisol concentrations during pregnancy. Additional analyses have been performed with other datasets and support the moderating role of CT-related sequelae, especially depression, in the association between CT and inflammation during pregnancy as well as in the association between CT and white matter development in the offspring. The same analyses are currently being conducted in the current cohort.
Continuously across the duration of the grant, presentations have been given at national and international research meetings. Furthermore, regular presentations at local institutions that support pregnant and postpartum women (e.g. Frühe Hilfen, Babylotsen) have been given to increase awareness of the high prevalence of childhood maltreatment and how this may affect well-being of pregnant women and their children.
We will continue data analyses and will take advantage of similar available datasets to replicate, wherever possible, the observed findings. Dissemination of study findings to clinical partners has been a focus and will remain a major focus with the aim of increasing the health of vulnerable women and their offspring.