Pandemic babies: A systematic review of the association between maternal pandemic-related stress during pregnancy and infant development.

The COVID-19 pandemic, with its far-reaching influence on daily life, constituted a highly stressful experience for many people worldwide, jeopardizing individuals' mental health, particularly in vulnerable populations such as pregnant women. While a growing body of evidence links prenatal maternal stress to biological and developmental alterations in offspring, the specific impact of prenatal exposure to maternal pandemic-related stress (PRS) on infant development remains unclear. A comprehensive literature search was performed in October 2023 according to the PRISMA guidelines, which yielded a total of 28 records. The selected papers investigated a vast range of developmental and biological outcomes in the offspring with large methodological variations. The reviewed studies showed mixed results. Either direct associations between maternal PRS during pregnancy and infant temperament and socio-emotional development, or indirect links, mediated by maternal mental health, emerged in most studies. Furthermore, maternal PRS was associated with epigenetic and brain alterations in the offspring, although studies were limited in number. Collectively, the reviewed findings contribute to a deeper understanding of the role of early adverse exposures on infant development.

Prenatal exposure to environmental air pollution and psychosocial stress jointly contribute to the epigenetic regulation of the serotonin transporter gene in newborns.

Antenatal exposures to maternal stress and to particulate matter with an aerodynamic diameter of less than 2.5 µm (PM2.5) have been independently associated with developmental outcomes in early infancy and beyond. Knowledge about their joint impact, biological mechanisms of their effects and timing-effects, is still limited. Both PM2.5 and maternal stress exposure during pregnancy might result in altered patterns of DNA methylation in specific stress-related genes, such as the serotonin transporter gene (SLC6A4 DNAm), that might, in turn, influence infant development across several domains, including bio-behavioral, cognitive and socio-emotional domains. Here, we investigated the independent and interactive influence of variations in antenatal exposures to maternal pandemic-related stress (PRS) and PM2.5 on SLC6A4 DNAm levels in newborns. Mother-infant dyads (N = 307) were enrolled at delivery during the COVID-19 pandemic. Infants' methylation status was assessed in 13 CpG sites within the SLC6A4 gene's region (chr17:28562750-28562958) in buccal cells at birth and women retrospectively report on PRS. PM2.5 exposure throughout the entire gestation and at each gestational trimester was estimated using a spatiotemporal model based on residential address. Among several potentially confounding socio-demographic and health-related factors, infant's sex was significantly associated with infants' SLC6A4 DNAm levels, thus hierarchical regression models were adjusted for infant's sex. Higher levels of SLC6A4 DNAm at 6 CpG sites were found in newborns born to mothers reporting higher levels of antenatal PRS and greater PM2.5 exposure across gestation, while adjusting for infant's sex. These effects were especially evident when exposure to elevated PM2.5 occurred during the second trimester of pregnancy. Several important brain processes (e.g., synaptogenesis and myelination) occur during mid-pregnancy, potentially making the second trimester a sensitive time window for the effects of stress-related exposures. Understanding the interplay between environmental and individual-level stressors has important implications for the improvement of mother-infant health during and after the pandemic.

Maternal pandemic-related stress during pregnancy associates with infants' socio-cognitive development at 12 months: A longitudinal multi-centric study.

BACKGROUND: Prenatal maternal stress is a key risk factor for infants' development. Previous research has highlighted consequences for infants' socio-emotional and cognitive outcomes, but less is known for what regards socio-cognitive development. In this study, we report on the effects of maternal prenatal stress related to the COVID-19 pandemic on 12-month-old infants' behavioral markers of socio-cognitive development. METHODS: Ninety infants and their mothers provided complete longitudinal data from birth to 12 months. At birth, mothers reported on pandemic-related stress during pregnancy. At infants' 12-month-age, a remote mother-infant interaction was videotaped: after an initial 2-min face-to-face episode, the experimenter remotely played a series of four auditory stimuli (2 human and 2 non-human sounds). The auditory stimuli sequence was counterbalanced among participants and each sound was repeated three times every 10 seconds (Exposure, 30 seconds) while mothers were instructed not to interact with their infants and to display a neutral still-face expression. Infants' orienting, communication, and pointing toward the auditory source was coded micro-analytically and a socio-cognitive score (SCS) was obtained by means of a principal component analysis. RESULTS: Infants equally oriented to human and non-human auditory stimuli. All infants oriented toward the sound during the Exposure episode, 80% exhibited any communication directed to the auditory source, and 48% showed at least one pointing toward the sound. Mothers who reported greater prenatal pandemic-related stress had infants with higher probability of showing no communication, t = 2.14 (p = .035), or pointing, t = 1.93 (p = .057). A significant and negative linear association was found between maternal prenatal pandemic-related stress and infants' SCS at 12 months, R2 = .07 (p = .010), while adjusting for potential confounders. CONCLUSIONS: This study suggests that prenatal maternal stress during the COVID-19 pandemic might have increased the risk of an altered socio-cognitive development in infants as assessed through an observational paradigm at 12 months. Special preventive attention should be devoted to infants born during the pandemic.

Sex-dimorphic pathways in the associations between maternal trait anxiety, infant BDNF methylation, and negative emotionality.

Maternal antenatal anxiety is an emerging risk factor for child emotional development. Both sex and epigenetic mechanisms, such as DNA methylation, may contribute to the embedding of maternal distress into emotional outcomes. Here, we investigated sex-dependent patterns in the association between antenatal maternal trait anxiety, methylation of the brain-derived neurotrophic factor gene (BDNF DNAm), and infant negative emotionality (NE). Mother-infant dyads (N = 276) were recruited at delivery. Maternal trait anxiety, as a marker of antenatal chronic stress exposure, was assessed soon after delivery using the Stait-Trait Anxiety Inventory (STAI-Y). Infants' BDNF DNAm at birth was assessed in 11 CpG sites in buccal cells whereas infants' NE was assessed at 3 (N = 225) and 6 months (N = 189) using the Infant Behavior Questionnaire-Revised (IBQ-R). Hierarchical linear analyses showed that higher maternal antenatal anxiety was associated with greater 6-month-olds' NE. Furthermore, maternal antenatal anxiety predicted greater infants' BDNF DNAm in five CpG sites in males but not in females. Higher methylation at these sites was associated with greater 3-to-6-month NE increase, independently of infants' sex. Maternal antenatal anxiety emerged as a risk factor for infant's NE. BDNF DNAm might mediate this effect in males. These results may inform the development of strategies to promote mothers and infants' emotional well-being.

Maternal mood moderates the trajectory of emotional and behavioural problems from pre- to during the COVID-19 lockdown in preschool children.

The COVID-19 outbreak and subsequent lockdown have dramatically impacted families' life, raising serious concerns about children's emotional wellbeing. However, few studies have investigated whether the impact of the COVID-19 lockdown on psychological adjustment in youngest can be moderated by maternal mood and, to our knowledge, none of them has adopted a longitudinal design. The main aim of the current study was to explore if the intensity and directionality of maternal mood symptoms moderated the trajectory of emotional and behavioural problems in Italian pre-schoolers from pre- to during the lockdown adopting a longitudinal design. To assess maternal anxiety and depression symptoms, the EPDS and the STAI-Y were filled in by 94 and 88 women before the lockdown, when their children were 1 (Wave P1) and 3 years old (Wave P2), respectively, and by 74 women during the lockdown, when their children were 4 years old (Wave L). Mothers also filled in the CBCL/1 ½-5 to assess their children's emotional and behavioural problems at each assessment wave. As a whole, children's emotional and behavioural problems significantly increased from pre- to during the lockdown. Furthermore, maternal mood moderated this trajectory. In particular, greater maternal mood symptoms were significantly associated with a greater increase in emotional reactive, anxious-depressed, withdrawn and aggressive symptoms during the lockdown. These results contribute to shed light on the role played by maternal emotional wellbeing in buffering the impact of the COVID-19 lockdown on children's behavioural development. Albeit preliminary, the current findings highlight the need to provide timely psychological interventions to distressed mothers to help their children to better cope with the effects of the pandemic.

Determinants of emotional distress in neonatal healthcare professionals: An exploratory analysis.

Background: High levels of mental health problems have been consistently reported among neonatal healthcare professionals. While studies suggest that personality, coping strategies and safety culture might contribute to the psychological wellbeing of healthcare professionals, they have not been systematically investigated in low-risk (i.e., neonatal wards; NWs) and high-risk (i.e., neonatal intensive care units; NICUs) neonatal contexts. The current study investigated potential predictors of professionals' emotional distress and whether they differ according to the work setting (i.e., NICUs vs. NWs). Methods: Healthcare professionals (N = 314) from 7 level-3 (i.e., NICUs) and 6 level-2 (i.e., NWs) neonatal units in Tuscany were included. Emotional distress (i.e., anxiety, depression, psychosomatic, post-traumatic stress symptoms and emotional exhaustion), Behavioral Inhibition System (BIS) and Behavioral Approach System (BAS) sensitivity, coping strategies and safety culture were assessed through well-validated, self-reported questionnaires. Results: Greater BIS/BAS sensitivity, avoidance coping strategies and a sub-dimension of safety culture (i.e., stress recognition) were significantly associated with greater risk of emotional distress, whereas job satisfaction emerged as a protective factor. Three specific profiles of professionals in term of personality, coping and safety culture were identified and further predicted emotional distress. Neonatal wards and NICUs personnel presented different associations between personality, coping and safety culture. Conclusion: These findings highlighted significant modifiable contributors of neonatal mental healthcare professionals' wellbeing. Institutional initiatives that target these factors and, particularly, job satisfaction may promote professionals' emotional wellbeing and thus improve caring processes.

Sex-dependent association between variability in infants' OXTR methylation at birth and negative affectivity at 3 months.

BACKGROUND: Sex-specific differences in DNA methylation of the oxytocin receptor gene (OXTR) have been shown in adults and are related to several mental disorders. Negative affectivity early in life is a trans-diagnostic risk marker of later psychopathology and is partly under genetic control. However, sex-specific variations in OXTR methylation (OXTRm) in infants and their associations with negative affectivity are still unknown. AIMS: Here, we explored sex differences in the association between infant OXTRm at birth and negative affectivity at 3 months of age. METHODS: Infants and their mothers (N = 224) were recruited at delivery. Infants' methylation status was assessed in 13 CpG sites within the OXTR gene intron 1 region (chr3: 8810654-8810919) in buccal cells at birth while 3-month-old infants' negative affectivity was assessed by mothers using a well-validated temperament questionnaire. RESULTS: OXTRm at 12 CpG sites was higher in females than in males. Moreover, higher infants' OXTRm at 6 specific CpG sites was associated with greater negative affectivity in males, but not in females. CONCLUSIONS: These results provide new insights into the role of sex-dependent epigenetic mechanisms linking OXTRm with early infants' emotional development. Understanding the degree to which epigenetic processes relate to early temperamental variations may help inform the etiology of later childhood psychopathological outcomes.

Maternal and infant NR3C1 and SLC6A4 epigenetic signatures of the COVID-19 pandemic lockdown: when timing matters.

Stress exposure during pregnancy is critically linked with maternal mental health and child development. The effects might involve altered patterns of DNA methylation in specific stress-related genes (i.e., glucocorticoid receptor gene, NR3C1, and serotonin transporter gene, SLC6A4) and might be moderated by the gestational timing of stress exposure. In this study, we report on NR3C1 and SLC6A4 methylation status in Italian mothers and infants who were exposed to the COVID-19 pandemic lockdown during different trimesters of pregnancy. From May 2020 to February 2021, 283 mother-infant dyads were enrolled at delivery. Within 24 h from delivery, buccal cells were collected to assess NR3C1 (44 CpG sites) and SLC6A4 (13 CpG sites) methylation status. Principal component (PC) analyses were used to reduce methylation data dimension to one PC per maternal and infant gene methylation. Mother-infant dyads were split into three groups based on the pregnancy trimester (first, second, third), during which they were exposed to the COVID-19 lockdown. Mothers and infants who were exposed to the lockdown during the first trimester of pregnancy had lower NR3C1 and SLC6A4 methylation when compared to counterparts exposed during the second or third trimesters. The effect remained significant after controlling for confounders. Women who were pregnant during the pandemic and their infants might present altered epigenetic biomarkers of stress-related genes. As these epigenetic marks have been previously linked with a heightened risk of maternal psychiatric problems and less-than-optimal child development, mothers and infants should be adequately monitored for psychological health during and after the pandemic.

Respiratory Sinus Arrhythmia (RSA) stress response in preschool age varies by serotonin transporter polymorphism (5-HTTLPR): A preliminary report.

The serotonin transporter promoter region polymorphism (5-HTTLPR) has been implicated in stress regulation, with increased stress reactivity often being found in carriers of the low-expressing short (S) allele. Nevertheless, the role of the 5-HTTLPR in influencing parasympathetic stress reactivity, as indexed by Respiratory Sinus Arrhythmia (RSA), is still unknown. This study examined, for the first time, whether the 5-HTTLPR was associated with variations in RSA response to maternal separation in a sample of 69 healthy 5-year-old children. Preschoolers' RSA was measured during an age-adapted version of the Strange Situation Procedure (SSP). The 5-HTTLPR polymorphism was tested as a predictor of RSA dynamic response to the SSP through multilevel models. A significant interaction between 5-HTTLPR and SSP episodes was found. In particular, whereas a significant decrease in RSA levels was observed during the stranger episode in the whole sample, S allele carriers showed a significant decrease in RSA levels from the stranger episode to the first separation episode, followed by an increase for the rest of the procedure. Albeit preliminary, data support the view that the 5-HTTLPR may contribute to individual differences in RSA stress reactivity from preschool age.

Maternal caregiving moderates the impact of antenatal maternal cortisol on infant stress regulation.

BACKGROUND: Emerging evidence suggests that antenatal exposure to maternal stress signals affects the development of the infant stress response systems. Animal studies indicate that maternal sensitive caregiving can reverse some of these effects. However, the generalizability of these findings to humans is unknown. This study investigated the role of maternal caregiving in the association between multiple markers of maternal antenatal stress and infant stress regulation. METHODS: The sample consisted of 94 mother-infant (N = 47 males, mean postnatal weeks = 12; SD = 1.84) dyads. Maternal levels of Interleukin-6, C-Reactive Protein (CRP), diurnal cortisol and alpha amylase, depressive and anxiety symptoms were assessed in late pregnancy (mean gestational age = 34.76; SD = 1.12), whereas postnatal symptomatology, caregiving, and infant cortisol response to the inoculation were evaluated at 3 months. RESULTS: Hierarchical linear models (HLMs) showed a significant interaction between maternal antenatal cortisol, caregiving, and time on infant cortisol reactivity, while controlling for gender, maternal age, and postnatal depression. Specifically, higher levels of maternal antenatal cortisol were associated with greater cortisol response only among infants of less emotionally available mothers. All other markers of antenatal stress were not significantly associated with infant cortisol reactivity either independently or in interaction with maternal caregiving. CONCLUSIONS: Albeit preliminary, results provide the first evidence in humans that maternal sensitive caregiving may eliminate the association between antenatal maternal cortisol and infant cortisol regulation.

Assessing stress variations in children during the strange situation procedure: comparison of three widely used respiratory sinus arrhythmia estimation methods.

Objective.The respiratory sinus arrhythmia (RSA) is a well-known marker of vagal activity that can be exploited to measure stress changes. RSA is usually estimated from heart rate variability (HRV). This study aims to compare the RSA obtained with three widely adopted methods showing their strengths and potential pitfalls.Approach.The three methods are tested on 69 healthy preschoolers undergoing a stressful protocol, the strange situation procedure (SSP). We compare the RSA estimated by the Porges method, the univariate autoregressive (AR) spectral analysis of the HRV signal, and the bivariate AR spectral analysis of HRV and respirogram signals. We examine RSA differences detected across the SSP episodes and correlation between the estimates provided by each method.Main results.The Porges and the bivariate AR approaches both detected significant differences (i.e. stress variations) in the RSA measured across the SSP. However, the latter method showed higher sensitivity to stress changes induced by the procedure, with the mean RSA variation between baseline and first separation from the mother (the most stressful condition) being significantly different among methods: Porges, -17.5%; univariate AR, -18.3%; bivariate AR, -23.7%. Moreover, the performances of the Porges algorithm were found strictly dependent on the applied preprocessing.Significance.Our findings confirm the bivariate AR analysis of the HRV and respiratory signals as a robust stress assessment tool that does not require any population-specific preprocessing of the signals and warn about using RSA estimates that neglect breath information in more natural experiments, such as those involving children, in which respiratory frequency changes are extremely likely.

Antenatal maternal anxiety, maternal sensitivity and toddlers' behavioral problems: An investigation of possible pathways.

BACKGROUND: While evidence exists of an association between maternal antenatal anxiety and offspring's behavioral outcomes, the role played by maternal care in explaining this link has been poorly investigated. AIM: The current study aimed to investigate the mediating/moderating role of maternal sensitivity in the association between maternal antenatal trait anxiety and toddlers' behavioral problems and temperament, taking also into account potential confounders. Analyses were also replicated for maternal antenatal state anxiety and depression. METHODS: Ninety women filled in the State-Trait Anxiety Questionnaire and the Edinburgh Postnatal Depression Scale to assess anxiety/depressive symptoms during the third trimester of pregnancy (34-36 weeks of gestation) and 14 months post-partum. They also filled in the Child Behavior Checklist and the Infant Behavior Questionnaire to evaluate their 14-month-olds' behavioral problems and negative affectivity, respectively. Maternal sensitivity was assessed through the Emotional Availability Scales. RESULTS: Maternal antenatal trait anxiety was associated with internalizing, but not externalizing, problems. Interestingly, maternal sensitivity moderated the association between antenatal trait anxiety and externalizing problems. Conversely, antenatal maternal depression was significantly associated with toddlers' negative affectivity. CONCLUSIONS: Our findings contribute to shed light on the association between maternal antenatal anxiety and child behaviors, as well as on the role played by parenting in moderating this link, with promising implications for targeted interventions.

Prenatal IL-6 levels and activation of the tryptophan to kynurenine pathway are associated with depressive but not anxiety symptoms across the perinatal and the post-partum period in a low-risk sample.

Depression and anxiety symptoms are highly prevalent among women during pregnancy and post-partum. Previous studies suggest that one of the pathophysiological underpinnings could be an enhanced metabolism of tryptophan (Trp) into kynurenine (Kyn) due to increased inflammation. However, the longitudinal changes in the Kyn pathway and the complex interplay with inflammation and stress in women with perinatal depressive or anxiety symptoms are incompletely understood. We examined a cohort of healthy women at 34-36 gestational weeks. One hundred and ten women were assessed for salivary cortisol and 97 participants were also assessed for serum levels of Trp, Kyn and Interleukin 6 (IL-6). Women filled in two screening questionnaires for depressive (Edinburgh Postnatal Depression Scale (EPDS)) and anxiety (State Trait Anxiety Inventory subscale (STAI-S)) symptoms at 34-36 gestational weeks, delivery, 3 and 12 months postpartum. Unexpectedly, lower prenatal Kyn levels were associated with higher depressive symptoms in late pregnancy. Furthermore, prenatal Trp levels and the Kyn/Trp ratio moderate the association between IL-6 levels and depressive symptoms during the perinatal and the post-partum period. We found no interactions between Trp and Kyn biomarkers and cortisol on depressive symptoms. The observed associations were more robustly found for depressive symptoms, whereas weak and non-significant effects were found for the trajectory of anxiety symptoms. Overall, our data support the involvement of the Trp to Kyn pathway and inflammation in the course of depressive but not anxiety symptoms in women from late pregnancy until one-year post-partum, providing new evidence on the mechanisms regulating emotions during pregnancy and after delivery in a low-risk sample.

Neuroendocrine and immune markers of maternal stress during pregnancy and infant cognitive development.

Antenatal exposure to maternal stress is a factor that may impact on offspring cognitive development. While some evidence exists of an association between maternal antenatal depressive or anxiety symptoms and infants' cognitive outcomes, less is known about the role of biological indices of maternal antenatal stress in relation to infant cognitive development. The current study investigated the association between maternal depressive and anxiety symptoms, stress and inflammatory markers during pregnancy and infant's cognitive development in a sample of 104 healthy pregnant women (mean gestational age = 34.76; SD = 1.12) and their 12-week-old infants (mean postnatal weeks = 11.96; SD = 1.85). Maternal depressive and anxiety symptoms were evaluated during pregnancy, alongside measurements of serum Interleukin-6 (IL-6), C-Reactive Protein (CRP), salivary cortisol, and alpha amylase (sAA) concentrations. Infant cognitive development, maternal caregiving and concurrent anxiety or depressive symptoms were assessed 12 weeks after delivery. Hierarchical linear regressions indicated that higher maternal diurnal cortisol and CRP levels were independently associated with lower infant cognitive development scores, while adjusting for infant gender and gestational age, maternal IQ, caregiving, depressive, or anxiety symptoms. Though correlational, findings seem suggestive of a role for variation in maternal biological stress signals during pregnancy in influencing infants' early cognitive development.

The programming role of maternal antenatal inflammation on infants' early neurodevelopment: A review of human studies: Special Section on "Translational and Neuroscience Studies in Affective Disorders" Section Editor, Maria Nobile MD, PhD.

BACKGROUND: Maternal inflammation during pregnancy is a frequently proposed mechanism underlying the link between maternal antenatal physical (e.g. infections, immune disease, obesity) and/or psychological (e.g. depression, anxiety) conditions and child outcomes. However, the extent to which maternal inflammation is directly associated with offspring's early development and health in humans remains largely unknown. METHODS: In this review, empirical findings on the prospective association between maternal prenatal levels of inflammatory markers and infants' neurodevelopmental outcomes are summarized. Fifteen studies were included with sample sizes ranging from 36 to 6016 mother-infant dyads and average overall quality score 9.53 (range 6-12). RESULTS: Findings concerning the link between maternal antenatal inflammation and, respectively, infants' health and birth outcomes, stress reactivity or cognitive development are mixed. However, it is noteworthy that all higher quality studies (scores >10) reviewed here do find evidence of an association between levels of inflammation, mostly as indexed by Interleukin-6 (IL-6), in healthy women across the whole gestation and offspring's neurodevelopmental outcomes, including structural and functional brain alterations. LIMITATIONS: The correlational nature of the findings and conspicuous methodological heterogeneity across studies make drawing strong conclusions premature. CONCLUSIONS: Findings, albeit preliminary, are consistent with animal studies and speak in favor of a role of maternal antenatal inflammation in shaping fetal development with possible long-term effects.

Emotional Availability in Samples of Mothers at High Risk for Depression and With Substance Use Disorder.

Background: Maternal substance use disorder (SUD) and depression have been extensively associated with dysfunctions in parent-child interactions. However, few studies have compared caregiving behaviors of these mothers. The current study aims to explore maternal emotional availability (EA) in mothers with maternal SUD and depressive symptoms in order to investigate whether these conditions represent a different risk gradient for early parenting. Methods: Mother-infant relationship was investigated in 18 mothers with SUD, 11 mothers at risk for depression, and 39 mothers from general population. The dyads were videotaped during a free-play session and the quality of parent-child interactions was assessed using the EA Scales (EAS) and the Emotional Attachment and EA Clinical Screener (EA2-CS). Results: Mothers with SUD scored lower on sensitivity, non-intrusiveness, and non-hostility with respect to the low-risk sample, whereas mothers at risk for depression scored lower on sensitivity and non-hostility compared to the latter. No significant differences between mothers with SUD and mothers at risk for depression emerged on the EAS, whereas different specific classifications on the EA Clinical Screener were found for the SUD (i.e., Complicated), depression (i.e., Detached), and low-risk (i.e., Emotionally Available) samples. Conclusion: If the current findings are replicated, they might have significant implications for selecting targets of early mother-infant interventions.

Feasibility and efficacy of an attachment-based intervention in a maltreatment sample in residential care: A pilot study.

The effects of the Video-feedback Intervention to promote Positive Parenting and Sensitive Discipline on improving maternal sensitivity and sensitive discipline were investigated using a randomized control design in a pilot sample of mothers at high risk of maltreatment. The study included 12 mothers and their 10- to 36-month-old children placed in parental residential care, due to a guardianship order issued by the Youth Court. Both at pretest and post-test, maternal sensitivity and sensitive discipline were assessed during mother-child interaction via observational measures. Mothers who received the intervention showed a significant reduction in dysfunctional strategies of maternal discipline. Results highlight the usefulness and feasibility of a brief residential care-based intervention in such a risk sample, with promising implications for the prevention of child maltreatment.