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Background: Changes in NR3C1 and IGF2/H19 methylation patterns have been associated with behavioural and psychiatric outcomes. Maternal mental state has been associated with offspring NR3C1 promotor and IGF2/H19 imprinting control region (ICR) methylation patterns. However, there is a lack of prospective studies with long-term follow-up., Methods: 52 mother-offspring pairs were studied from 12 to 22 weeks of pregnancy and offspring was followed-up until 28-29 years-of-age. During pregnancy, mothers filled in a Life Event Scale and a Daily Hassles Scale measuring perceived stress; i.e., appraisal or subjectively experienced severity of impact of important life events and of daily hassles in several life domains during pregnancy, respectively. Green space was quantified around the residence, using high-resolution (1 m 2 ) map data. Saliva and blood samples were obtained from the adult offspring. Absolute DNA methylation levels were determined in blood and saliva on four NR3C1 amplicons, and one IGF2/H19 ICR amplicon using a bisulfite PCR and sequencing method. Linear mixed effect models were used to test the associations between perceived stress and green spaces during pregnancy, and adult offspring methylation patterns., Results: We found associations between maternal perceived stress during pregnancy and methylation patterns on two out of the four NR3C1 amplicons, measured in blood, from offspring in adulthood, but not with IGF2/H19 methylation. For an interquartile-range (IQR) increase in maternal perceived life event or daily hassles stress scores, absolute methylation levels on several NR3C1 CpG sites were significantly changed (-1.62 % to +5.89 %, p<0.05). Maternal perceived stress scores were not associated with IGF2/H19 methylation, neither in blood nor in saliva. Maternal exposure to green spaces surrounding the residence during the pregnancy was associated with IGF2/H19 ICR methylation (-0.80 % to -1.04 %, p<0.05) in saliva, but not with NR3C1 promotor methylation., Conclusion: We observed significant long-term effects of maternal perceived stress during pregnancy on the methylation patterns of the NR3C1 promotor in offspring well into adulthood. This may imply that maternal psychological distress during pregnancy may influence the regulation of the HPA-axis well into adulthood. Additionally, maternal proximity to green spaces was associated with IGF2/H19 ICR methylation patterns, which is a novel finding., Competing Interests: Declaration of Competing Interest None of the findings described in this manuscript were influenced by any financial source or sponsor. None of the authors have potential conflicts of interests to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose of Review: Perinatal mental health research provides an important perspective on neurobehavioral development. Here, we aim to review the association of maternal perinatal health with offspring neurodevelopment, providing an update on (self-)regulation problems, hypothesized mechanistic pathways, progress and challenges, and implications for mental health., Recent Findings: (1) Meta-analyses confirm that maternal perinatal mental distress is associated with (self-)regulation problems which constitute cognitive, behavioral, and affective social-emotional problems, while exposure to positive parental mental health has a positive impact. However, effect sizes are small. (2) Hypothesized mechanistic pathways underlying this association are complex. Interactive and compensatory mechanisms across developmental time are neglected topics. (3) Progress has been made in multiexposure studies. However, challenges remain and these are shared by clinical, translational and public health sciences. (4) From a mental healthcare perspective, a multidisciplinary and system level approach employing developmentally-sensitive measures and timely treatment of (self-)regulation and coregulation problems in a dyadic caregiver-child and family level approach seems needed. The existing evidence-base is sparse., Summary: During the perinatal period, addressing vulnerable contexts and building resilient systems may promote neurobehavioral development. A pluralistic approach to research, taking a multidisciplinary approach to theoretical models and empirical investigation needs to be fostered., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The connectome, constituting a unique fingerprint of a person's brain, may be influenced by its prenatal environment, potentially affecting later-life resilience and mental health., Methods: We conducted a prospective resting-state functional Magnetic Resonance Imaging study in 28-year-old offspring (N = 49) of mothers whose anxiety was monitored during pregnancy. Two offspring anxiety subgroups were defined: "High anxiety" (n = 13) group versus "low-to-medium anxiety" (n = 36) group, based on maternal self-reported state anxiety at 12-22 weeks of gestation. To predict resting-state functional connectivity of 32 by 32 ROIs, maternal state anxiety during pregnancy was included as a predictor in general linear models for both ROI-to-ROI and graph theoretical metrics. Sex, birth weight and postnatal anxiety were included as covariates., Results: Higher maternal anxiety was associated with weaker functional connectivity of medial prefrontal cortex with left inferior frontal gyrus (t = 3.45, p FDR < 0.05). Moreover, network-based statistics (NBS) confirmed our finding and revealed an additional association of weaker connectivity between left lateral prefontal cortex with left somatosensory motor gyrus in the offspring. While our results showed a general pattern of lower functional connectivity in adults prenatally exposed to maternal anxiety, we did not observe significant differences in global brain networks between groups., Conclusions: Weaker (medial) prefrontal cortex functional connectivity in the high anxiety adult offspring group suggests a long-term negative impact of prenatal exposure to high maternal anxiety, extending into adulthood. To prevent mental health problems at population level, universal primary prevention strategies should aim at lowering maternal anxiety during pregnancy., (© 2023. The Author(s).)

Epigenetic changes are associated with altered behavior and neuropsychiatric disorders and they modify the trajectory of aging. Maternal anxiety during pregnancy is a common environmental challenge for the fetus, causing changes in DNA methylation. Here, we determined the mediating role of DNA methylation and the moderating role of offspring sex on the association between maternal anxiety and children's behavioral measures. In 83 mother-child dyads, maternal anxiety was assessed in each trimester of pregnancy when the child was four years of age. Children's behavioral measures and children's buccal DNA methylation levels ( NR3C1 , IGF2/H19 ICR , and LINE1 ) were examined. Higher maternal anxiety during the third trimester was associated with more methylation levels of the NR3C1 . Moderating effects of sex on the association between maternal anxiety and methylation were found for IGF2/H19 and LINE1 CpGs. Mediation analysis showed that methylation of NR3C1 could buffer the effects of maternal anxiety on children's behavioral measures, but this effect did not remain significant after controlling for covariates. In conclusion, our data support an association between maternal anxiety during pregnancy and DNA methylation. The results also underscore the importance of sex differences and timing effects. However, DNA methylation as underlying mechanism of the effect of maternal anxiety during pregnancy on offspring's behavioral measures was not supported.

Excessive crying and sleep problems affect up to 30% of infants and often coexist. Although usually benign and self-limiting, persistent crying, and sleep problems exceeding 6 months of age need attention as they may impair the mental health of the infant and its family. The source and the impact of these persistent regulatory problems is often not restricted to the infant, but extends to the parents and the parent-infant relationship. Clinical practice needs interdisciplinary and multi-method interventions focusing beyond regulatory problems of the infant but also on parental self-regulation and parent's co-regulatory responses toward the infant. Treating clinicians may encounter limitations of home-visits, outpatient, and pediatric residential settings when working with families in distress. We describe an infant mental health day-clinic treatment, drawing attention to this viable future direction. It offers a therapeutic climate based on forming a triangle of co-regulation between clinician, parent and infant to first help the parent and the infant settle down. This stress reduction restores parent-infant connectedness and parental learning and reflecting capacity. Clinicians then use established therapeutic modalities to support parental self- and co-regulatory skills which is important for the development of self-regulation in the infant. Experience with this treatment program suggests that a day-clinic setting facilitates interdisciplinary and integrative multi-method intervention, infant and parental stress reduction and integration of parental self- and co-regulatory skills in daily family life, improving overall outcomes. This perspective warrants further investigation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Singh, Danckaerts and Van den Bergh.)

Cognitive and mental health are major determinants of quality of life, allowing integration into society at all ages. Human epidemiological and animal studies indicate that in addition to genetic factors and lifestyle, prenatal environmental influences may program neuropsychiatric disorders in later life. While several human studies have examined the effects of prenatal stress and nutrient restriction on brain function and mental health in later life, potentially mediating effects of prenatal stress and nutrient restriction on offspring neuroanatomy in humans have been studied only in recent years. Based on neuroimaging and anatomical data, we comprehensively review the studies in this emerging field. We relate prenatal environmental influences to neuroanatomical abnormalities in the offspring, measured in utero and throughout life. We also assess the relationship between neuroanatomical abnormalities and cognitive and mental disorders. Timing- and gender-specific effects are considered, if reported. Our review provides evidence for adverse effects of an unfavorable prenatal environment on structural brain development that may contribute to the risk for cognitive, behavioral and mental health problems throughout life., (Copyright © 2020. Published by Elsevier Ltd.)

Accumulating research shows that prenatal exposure to maternal stress increases the risk for behavioral and mental health problems later in life. This review systematically analyzes the available human studies to identify harmful stressors, vulnerable periods during pregnancy, specificities in the outcome and biological correlates of the relation between maternal stress and offspring outcome. Effects of maternal stress on offspring neurodevelopment, cognitive development, negative affectivity, difficult temperament and psychiatric disorders are shown in numerous epidemiological and case-control studies. Offspring of both sexes are susceptible to prenatal stress but effects differ. There is not any specific vulnerable period of gestation; prenatal stress effects vary for different gestational ages possibly depending on the developmental stage of specific brain areas and circuits, stress system and immune system. Biological correlates in the prenatally stressed offspring are: aberrations in neurodevelopment, neurocognitive function, cerebral processing, functional and structural brain connectivity involving amygdalae and (pre)frontal cortex, changes in hypothalamo-pituitary-adrenal (HPA)-axis and autonomous nervous system., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: One potentially relevant neurophysiological marker of internalizing problems (anxiety/depressive symptoms) is the late positive potential (LPP), as it is related to processing of emotional stimuli. For the first time, to our knowledge, we investigated the value of the LPP as a neurophysiological marker for internalizing problems and specific anxiety and depressive symptoms, at preschool age., Method: At age 4 years, children (N = 84) passively viewed a series of neutral, pleasant, and unpleasant pictures selected from the International Affective Pictures System. Affective picture processing was measured via the LPP (EEG recorded) and mothers reported on child behavior via the Child Behavior Checklist 1 ½ - 5 (internalizing, DSM-anxiety, DSM-affective/depression subscales). Difference scores between the neutral and affective pictures (i.e., neutral-pleasant and neutral-unpleasant) were computed for posterior, central and anterior brain locations for early (300-700 ms), middle (700-1200 ms) and late (1200-2000 ms) time windows., Results: Greater LPP difference scores for pleasant images in the anterior recording site, in the middle time window, were associated with greater internalizing behaviors. Greater DSM-anxiety symptoms were associated with greater LPP difference scores for unpleasant and pleasant images. After correcting for multiple testing, only the association between greater DSM-affective/depression symptoms and greater LPP difference scores for unpleasant images in the anterior recording site (early time window) remained significant., Discussion: Our study has identified a potential neural marker of preschool internalizing problems. Children with larger LPPs to unpleasant images may be at greater risk of internalizing problems, potentially due to an increased emotional reactivity., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Evidence is building for an association between the level of anxiety experienced by a mother during pregnancy and offspring cognition and structural and functional brain correlates. The current study uses fMRI to examine the association between prenatal exposure to maternal anxiety and brain activity associated with endogenous versus exogenous cognitive control in 20-year-old males. Endogenous cognitive control refers to the ability to generate control over decisions, strategies, conflicting information and so on, from within oneself without external signals, while exogenous control is triggered by external signals. In line with previous results of this long-term follow-up study we found that 20-year-olds of mothers reporting high levels of anxiety during weeks 12-22 of pregnancy exhibited a different pattern of decision making in a Gambling paradigm requiring endogenous cognitive control, compared to adults of mothers reporting low to average levels of anxiety. Moreover, the blood oxygenation level dependent (BOLD) response in a number of prefrontal cortical areas was modulated by the level of antenatal maternal anxiety. In particular, a number of right lateralized clusters including inferior frontal junction, that were modulated in the adults of mothers reporting low to average levels of anxiety during pregnancy by a task manipulation of cognitive control, were not modulated by this manipulation in the adults of mothers reporting high levels of anxiety during pregnancy. These differences in brain functional correlates provide a neurobiological underpinning for the hypothesis of an association between exposure to maternal anxiety in the prenatal life period and a deficit in endogenous cognitive control in early adulthood.

Background: Maternal psychological distress during pregnancy is related to adverse child behavioral and emotional outcomes later in life, such as ADHD and anxiety/depression. The underlying mechanisms for this, however, are still largely unknown. The hypothalamic-pituitary-adrenal (HPA)-axis, with its most important effector hormone cortisol, has been proposed as a mechanism, but results have been inconsistent. The current study investigated the association between maternal psychological distress (i.e. anxiety and depressive symptoms) and maternal cortisol levels during pregnancy using a mixed models approach., Method: During three pregnancy trimesters, mothers (N = 170) collected four salivary samples for two consecutive days. Mothers reported symptoms of anxiety and depression three times during pregnancy (at 13.3 ± 1.1, 20.2 ± 1.5, and 33.8 ± 1.5 weeks of pregnancy, respectively) using the anxiety subscale of the Symptom Checklist (SCL-90), the Spielberger State and Trait Anxiety Inventory (STAI), and the Edinburgh Postnatal Depression Scale (EPDS). Specific fears and worries during pregnancy were measured with the short version of the Pregnancy Related Anxiety Questionnaire (PRAQ-R)., Results: We found a significant effect of SCL-90 anxiety subscale on cortisol levels at awakening (p = .008), indicating that mothers with higher anxiety showed lower cortisol at awakening. Maternal psychological variables explained 10.5% of the variance at the person level in awakening cortisol level, but none in the overall diurnal cortisol model., Conclusion: More research is necessary to unravel the underlying mechanisms of the association between maternal psychological distress and cortisol and the search for mechanisms other than the HPA-axis should be continued and extended., (Copyright © 2018. Published by Elsevier Ltd.)

The prenatal period is increasingly considered as a crucial target for the primary prevention of neurodevelopmental and psychiatric disorders. Understanding their pathophysiological mechanisms remains a great challenge. Our review reveals new insights from prenatal brain development research, involving (epi)genetic research, neuroscience, recent imaging techniques, physical modeling, and computational simulation studies. Studies examining the effect of prenatal exposure to maternal distress on offspring brain development, using brain imaging techniques, reveal effects at birth and up into adulthood. Structural and functional changes are observed in several brain regions including the prefrontal, parietal, and temporal lobes, as well as the cerebellum, hippocampus, and amygdala. Furthermore, alterations are seen in functional connectivity of amygdalar-thalamus networks and in intrinsic brain networks, including default mode and attentional networks. The observed changes underlie offspring behavioral, cognitive, emotional development, and susceptibility to neurodevelopmental and psychiatric disorders. It is concluded that used brain measures have not yet been validated with regard to sensitivity, specificity, accuracy, or robustness in predicting neurodevelopmental and psychiatric disorders. Therefore, more prospective long-term longitudinal follow-up studies starting early in pregnancy should be carried out, in order to examine brain developmental measures as mediators in mediating the link between prenatal stress and offspring behavioral, cognitive, and emotional problems and susceptibility for disorders.

Maternal anxiety during pregnancy can negatively affect fetal neurodevelopment, predisposing the offspring to a higher risk of behavioral and emotional problems later in life. The current study investigates the association between maternal anxiety during pregnancy and child affective picture processing using event-related brain potentials (ERPs). Mothers reported anxiety during the second trimester using the anxiety subscale of the Symptom Checklist (SCL-90). At age 4 years, child affective picture processing (N = 86) was measured by recording ERPs during viewing of neutral, pleasant, and unpleasant pictures selected from the International Affective Pictures System. The late positive potential (LPP)-an ERP component reflecting individual differences in affective processing-was used as child outcome. The expected positive association between maternal anxiety and LPP amplitude for unpleasant pictures was not found. Nevertheless, we found a positive association between maternal anxiety during pregnancy and LPP amplitudes for neutral pictures in the middle and late time window at anterior locations (all p < .05). These associations remained significant after adjusting for maternal postnatal anxiety and gestational age at birth and after FDR correction for multiple comparisons. Our study provides neurophysiological evidence that children prenatally exposed to higher maternal anxiety devote more attentional resources to neutral pictures, but not to unpleasant pictures. Possibly, these children show enhanced vigilance for threat when viewing neutral pictures. Although useful in dangerous environments, this enhanced vigilance may predispose children prenatally exposed to higher maternal anxiety to developing behavioral and/or emotional problems later in life. A video abstract of this article can be viewed at: https://www.youtube.com/watch?v=kEzYi6IS2HA., (© 2017 John Wiley & Sons Ltd.)

Purpose: The purpose of the present study was to examine relations between children's exogenously triggered response inhibition and stuttering., Method: Participants were 18 children who stutter (CWS; mean age = 9;01 years) and 18 children who not stutter (CWNS; mean age = 9;01 years). Participants were matched on age (±3 months) and gender. Response inhibition was assessed by a stop signal task (Verbruggen, Logan, & Stevens, 2008)., Results: Results suggest that CWS, compared to CWNS, perform comparable to CWNS in a task where response control is externally triggered., Conclusions: Our findings seem to indicate that previous questionnaire-based findings (Eggers, De Nil, & Van den Bergh, 2010) of a decreased efficiency of response inhibition cannot be generalized to all types of response inhibition., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: A cancer diagnosis during pregnancy may be considered as an emotional challenge for pregnant women and their partners. We aimed to identify women and partners at risk for high levels of distress based on their coping profile., Methods: Sixty-one pregnant women diagnosed with cancer and their partners filled out the Cognitive Emotion Regulation Questionnaire (CERQ) and the newly constructed Cancer and Pregnancy Questionnaire (CPQ). K-means cluster analysis was performed on the CERQ scales. Scores on the CPQ were compared between the women and their partners and between the CERQ-clusters., Results: Comparison of women and partners on the CPQ did not reveal significant differences on distress about the child's health, the cancer disease, and the pregnancy or on information satisfaction (P = .16, P = .44, P = .50, and P = .47, respectively). However, women were more inclined to maintain the pregnancy than their partners (P = .011). Three clusters were retrieved based on the CERQ scales, characterized by positive coping, internalizing coping, and blaming. Women and partners using internalizing strategies had significantly higher scores on concerns about the child's health (P = .039), the disease and treatment (P < .001), and the pregnancy and delivery (P = .009) compared with positive and blaming strategies. No cluster differences were found for information satisfaction (P = .71) and tendency to maintain the pregnancy (P = .35)., Conclusion: Women and partners using internalizing coping strategies deal with the highest levels of distress and may benefit from additional psychosocial support., (Copyright © 2016 John Wiley & Sons, Ltd.)

Objective: To examine the association between interpregnancy weight change and the risk for adverse maternal and neonatal outcomes., Methods: All live-born singleton births delivered at 21-42 weeks of gestation in women who had their first two consecutive births between 2009 and 2011 in Flanders (the northern part of Belgium) and who were included in the Study Center for Perinatal Epidemiology database (N=7,897) were included. Interpregnancy weight change was calculated as the difference between the prepregnancy body mass index (BMI) of the first pregnancy and the prepregnancy BMI of the second pregnancy. Multivariate logistic regression analysis to predict gestational diabetes mellitus, pregnancy-induced hypertension, cesarean delivery, macrosomia (4,000 g or greater), low birth weight (less than 2,500 g), and congenital malformations were performed., Results: The adjusted odds ratio (OR) for gestational diabetes mellitus was 2.25 (95% confidence interval [CI] 1.33-3.78; P=.002) for interpregnancy weight retention of 2 or more BMI units, and the adjusted OR for pregnancy-induced hypertension was 3.76 (95% CI 2.16-6.57; P<.001) with an increase of 3 or more BMI units between pregnancies, but these associations were only present in underweight and normal-weight women. In overweight and obese women, the adjusted OR was 2.04 (95% CI 1.41-2.95; P<.001) for cesarean delivery for an interpregnancy weight retention of 2 or more BMI units. In underweight and normal-weight women, the risk for macrosomia was halved if women lost more than 1 BMI unit between pregnancies, but at the same time, the risk for low birth weight doubled., Conclusion: We show that weight retention between the first and second pregnancy is associated with an increased risk for perinatal complications, even in underweight and normal-weight women. Stabilizing interpregnancy weight appears an important target for reducing adverse perinatal outcomes in a second pregnancy., Level of Evidence: II.