The deleterious effects of adversity are likely intergenerational, such that one generation’s adverse experiences can affect the next. Epidemiological studies link maternal adversity to offspring depression and anxiety, possibly via transmission mechanisms that influence offspring fronto-limbic connectivity. However, studies have not thoroughly disassociated postnatal exposure effects nor considered the role of offspring sex. We utilized infant neuroimaging to test the hypothesis that maternal childhood maltreatment (CM) would be associated with increased fronto-limbic connectivity in infancy and tested brain-behavior associations in childhood. Ninety-two dyads participated (32 mothers with CM, 60 without; 52 infant females, 40 infant males). Women reported on their experiences of CM and non-sedated sleeping infants underwent MRIs at 2.44 ± 2.74 weeks. Brain volumes were estimated via structural MRI and white matter structural connectivity (fiber counts) via diffusion MRI with probabilistic tractography. A subset of parents (n = 36) reported on children’s behaviors at age 5.17 ± 1.73 years. Males in the maltreatment group demonstrated greater intra-hemispheric fronto-limbic connectivity (b = 0.96, p= 0.008, [95%CI 0.25, 1.66]), no differences emerged for females. Fronto-limbic connectivity was related to somatic complaints in childhood only for males (r = 0.673, p = 0.006). Our findings suggest that CM could have intergenerational associations to offspring brain development, yet mechanistic studies are needed.

OBJECTIVES/GOALS: Maternal health and exposures during pregnancy play a major role in shaping the neurodevelopment of our offspring—one influence is maternal immune activation (MIA). Here we explore the association of MIA during pregnancy and the developing human connectome through analysis of 46 markers of activation. METHODS/STUDY POPULATION: 74 healthy women with singleton pregnancies underwent blood draws between 34-37 weeks gestation. 46 markers of maternal immune activation, both adaptive (e.g., IgG) and innate (e.g., cytokines and acute phase reactants), were collected. In addition, for preliminary analyses of MIA in relation to the newborn brain, we utilized 30 participants with MRIs between the ages of 0-6 months. RESULTS/ANTICIPATED RESULTS: Principal component analysis (PCA) identified the first 5 PCs explains ~68% of the variance and the first 10 explains ~83% (top PC is 42.1%). Using the top PC each edge in the connectome was correlated with the immune profiles. Several regions trended towards significance–one survived correction and included 359 edges, showing. The highest number of edges was observed in the inferior parietal lobe of the left hemisphere–a region associated with functions from basic attention toa social cognition, suggesting that deviations in fetal exposure to MIA can longitudinally impact offspring behavior in areas essential for human interaction. DISCUSSION/SIGNIFICANCE: This is the first study in understanding how interruptions (i.e., MIA) influence later development. Identification of alterations, and long-term outcomes could lead to the development of mechanism-based healthcare, facilitate timely referral for appropriate interventions and provide family support.

For mother-infant health especially, the pandemic has brought multiple stressors inside a susceptible psychobiological system. We study the longitudinal associations between maternal prenatal and postpartum: (a) COVID-19 stressful events exposure, (b) pandemic psychological stress, and (c) mental health and infants’ negative affect. A sample of 643 Italian pregnant women completed a web-based survey from April 8th to May 4th, 2020 and a follow-up at 6 months after delivery. Maternal assessment covered prenatal and postpartum measures for: COVID-19 stressful events exposure, pandemic psychological stress, mental health symptoms (i.e., depression, anxiety, posttraumatic stress disorder) and postpartum, social support and report of infants’ negative affect. Maternal mental health symptoms during pregnancy, at the peak of pandemic, is longitudinally associated with infant negative affect, with postpartum mental health mediating this association. Also, maternal COVID-19 stressful events exposure in postpartum is associated with negative affect at 6 months mediated by postpartum mental health symptoms. Maternal pandemic psychological stress during pregnancy predicted mental health symptoms in postpartum. The study supports the association between pandemic-related maternal health across pregnancy and postpartum and offspring’s development (i.e., negative affect). It also puts the spotlight on mental health risk in women experiencing lockdown during pregnancy, especially when feeling high psychological stress in pregnancy or when directly exposed to COVID-19 stressful events postpartum.

Childhood maltreatment (CM) is a known risk factor for adolescent pregnancy. Sleep disturbances and psychological distress, both common negative sequelae of CM, often co-occur during pregnancy, although directionality remains unclear. Furthermore, little is known about how CM affects sleep–distress associations during pregnancy. In pregnant adolescents, we examined: (a) whether there are significant predictive associations from CM to sleep quality and distress and (b) bidirectional influences of distress and sleep quality. Healthy pregnant adolescents (n = 204) were recruited before or during the 2nd trimester. CM was assessed at enrollment; sleep quality and distress were assessed in the 2nd and 3rd trimesters. Hypotheses were tested using path analysis. Findings revealed that CM was associated with worse 2nd trimester sleep quality and distress (β = .19, p < .05 for sleep; β = .30, p < .001 for distress). Higher levels of 2nd trimester distress were associated with lower 3rd trimester sleep quality (β = .19, p < .05). Findings provide novel information about (a) associations from CM to prenatal mood and sleep in pregnant adolescents, and (b) sleep–distress directionality over the course of pregnancy. These results have implications for better understanding the ways in which CM potentially exerts influences later in life, and for targeting interventions to address physical and mental health during pregnancy.

The World Health Organization recently reported that maternal mental health is a major public health concern. As many as one in four women suffer from psychiatric disorders at some point during pregnancy or the first postpartum year. Furthermore, self-injurious thoughts and behaviors (SITBs) represent one of the leading causes of death among women during this time. Thus, efforts to identify women at risk for serious forms of psychopathology and especially for SITBs are of utmost importance. Despite this urgency, current single-diagnostic approaches fail to recognize a significant subset of women who are vulnerable to perinatal stress and distress. The current study was among the first to investigate emotion dysregulation—a multilevel, transdiagnostic risk factor for psychopathology—and its associations with stress, distress, and SITBs in a sample of pregnant women (26–40 weeks gestation) recruited to reflect a range of emotion dysregulation. Both self-reported emotion dysregulation and respiratory sinus arrhythmia, a biomarker of emotion dysregulation, demonstrated expected associations with measures of mental health, including depression, anxiety, borderline personality pathology, and SITBs. In addition, self-reported emotion dysregulation was associated with blunted respiratory sinus arrhythmia responsivity to an ecologically valid infant cry task. Findings add to the literature considering transdiagnostic risk during pregnancy using a multiple-levels-of-analysis approach.

We investigated whether neurobehavioral markers of risk for emotion dysregulation were evident among newborns, as well as whether the identified markers were associated with prenatal exposure to maternal emotion dysregulation. Pregnant women (N = 162) reported on their emotion dysregulation prior to a laboratory assessment. The women were then invited to the laboratory to assess baseline respiratory sinus arrhythmia (RSA) and RSA in response to an infant cry. Newborns were assessed after birth via the NICU Network Neurobehavioral Scale. We identified two newborn neurobehavioral factors—arousal and attention—via exploratory factor analysis. Low arousal was characterized by less irritability, excitability, and motor agitation, while low attention was related to a lower threshold for auditory and visual stimulation, less sustained attention, and poorer visual tracking abilities. Pregnant women who reported higher levels of emotion dysregulation had newborns with low arousal levels and less attention. Larger decreases in maternal RSA in response to cry were also related to lower newborn arousal. We provide the first evidence that a woman's emotion dysregulation while pregnant is associated with risks for dysregulation in her newborn. Implications for intergenerational transmission of emotion dysregulation are discussed.

Following recent advances in behavioral and psychiatric epigenetics, researchers are increasingly using epigenetic methods to study prenatal exposure to maternal mood disorder and its effects on fetal and newborn neurobehavior. Despite notable progress, various methodological limitations continue to obscure our understanding of the epigenetic mechanisms underpinning prenatal exposure to maternal mood disorder on newborn neurobehavioral development. Here we detail this problem, discussing limitations of the currently dominant analytical approaches (i.e., candidate epigenetic and epigenome-wide association studies), then present a solution that retains many benefits of existing methods while minimizing their shortcomings: epigenetic pathway analysis. We argue that the application of pathway-based epigenetic approaches that target DNA methylation at transcription factor binding sites could substantially deepen our mechanistic understanding of how prenatal exposures influence newborn neurobehavior.

Psychotropic medication use and psychiatric symptoms during pregnancy each are associated with adverse neurodevelopmental outcomes in offspring. Commonly, studies considering medication effects do not adequately assess symptoms, nor evaluate children when the effects are believed to occur, the fetal period. This study examined maternal serotonin reuptake inhibitor and polypharmacy use in relation to serial assessments of five indices of fetal neurobehavior and Bayley Scales of Infant Development at 12 months in N = 161 socioeconomically advantaged, non-Hispanic White women with a shared risk phenotype, diagnosed major depressive disorder. On average fetuses showed the expected development over gestation. In contrast, infant average Bayley psychomotor and mental development scores were low (M = 84.10 and M = 89.92, range of normal limits 85–114) with rates of delay more than 2–3 times what would be expected based on this measure's normative data. Controlling for prenatal and postnatal depressive symptoms, prenatal medication effects on neurobehavioral development were largely undetected in the fetus and infant. Mental health care directed primarily at symptoms may not address the additional psychosocial needs of women parenting infants. Speculatively, prenatal serotonin reuptake inhibitor exposure may act as a plasticity rather than risk factor, potentially enhancing receptivity to a nonoptimal postnatal environment in some mother–infant dyads.

The consequences of childhood maltreatment are profound and long lasting. Not only does the victim of abuse suffer as a child, but there is mounting evidence that a history of maltreatment places the next generation at risk for significant psychopathology. Research identifies postnatal factors as affecting this intergenerational transmission of trauma. However, emerging evidence suggests that part of this risk may be transmitted before birth, passed on via abuse-related alterations in the in utero environment that are as yet largely unidentified. To date, no study has directly assessed the influence of pregnant women's abuse history on fetal neurobehavioral development, nor considered trauma-associated poor sleep quality as a mediator reflecting established physiological dysregulation. Using data from 262 pregnant adolescents (ages 14–19), a population at elevated risk for childhood maltreatment, the current study examined maternal emotional abuse history and sleep quality in relation to third-trimester fetal resting heart rate variability, an index of parasympathetic nervous system functioning. The results indicate that maternal emotional abuse history is indirectly associated with lower fetal heart rate variability via abuse-related sleep disturbances. These data demonstrate an association between maternal abuse histories and fetal development, showing that at least part of the intergenerational transmission of risk occurs during pregnancy.

Prenatal exposure to maternal stress, anxiety, and depression can have lasting effects on infant development with risk of psychopathology. Although the impact of prenatal maternal distress has been well documented, the potential mechanisms through which maternal psychosocial variables shape development have yet to be fully elucidated. Advances in molecular biology have highlighted the role of epigenetic mechanisms in regulating gene activity, neurobiology, and behavior and the potential role of environmentally induced epigenetic variation in linking early life exposures to long-term biobehavioral outcomes. In this article, we discuss evidence illustrating the association between maternal prenatal distress and both fetal and infant developmental trajectories and the potential role of epigenetic mechanisms in mediating these effects. Postnatal experiences may have a critical moderating influence on prenatal effects, and we review findings illustrating prenatal–postnatal interplay and the developmental and epigenetic consequences of postnatal mother–infant interactions. The in utero environment is regulated by placental function and there is emerging evidence that the placenta is highly susceptible to maternal distress and a target of epigenetic dysregulation. Integrating studies of prenatal exposures, placental function, and postnatal maternal care with the exploration of epigenetic mechanisms may provide novel insights into the pathophysiology induced by maternal distress.