Prenatal stress, anxiety and depression alter transcripts, proteins and pathways associated with immune responses at the maternal-fetal interface†.

During pregnancy, the immune system is modified to allow developmental tolerance of the semi-allogeneic fetus and placenta to term. Pregnant women suffering from stress, anxiety, and depression show dysfunctions of their immune system that may be responsible for fetal and/or newborn disorders, provided that placental gene regulation is compromised. The present study explored the effects of maternal chronic self-perceived stress, anxiety, and depression during pregnancy on the expression of immune-related genes and pathways in term placenta. Pregnancies were clinically monitored with the Beck Anxiety Inventory (BAI) and Edinburgh Postnatal Depression Scale (EPDS). A cutoff threshold for BAI/EPDS of 10 divided patients into two groups: Index group (>10, n = 11) and a Control group (<10, n = 11), whose placentae were sampled at delivery. The placental samples were subjected to RNA-Sequencing, demonstrating that stress, anxiety, and depression during pregnancy induced a major downregulation of placental transcripts related to immune processes such as T-cell regulation, interleukin and cytokine signaling, or innate immune responses. Expression differences of main immune-related genes, such as CD46, CD15, CD8α & ß ILR7α, and CCR4 among others, were found in the Index group (P < 0.05). Moreover, the key immune-like pathway involved in humoral and cellular immunity named "Primary immunodeficiency" was significantly downregulated in the Index group compared with Controls. Our results show that mechanisms ruling immune system functions are compromised at the maternal-fetal interface following self-perceived depressive symptoms and anxiety during pregnancy. These findings may help unveil mechanisms ruling the impact of maternal psychiatric symptoms and lead to new prevention/intervention strategies in complicated pregnancies.

When pregnancy and pandemic coincide: changes in stress and anxiety over the course of pregnancy.

BACKGROUND: Pregnant women experienced high levels of perceived stress and anxiety at the onset of the COVID-19 pandemic. However, the course of stress and anxiety in individual pregnant women during the pandemic is unknown. METHODS: Participants were 1,087 women ≤20 weeks pregnant in April-May 2020 (T1) at recruitment into the Stony Brook COVID-19 Pregnancy Experiences (SB-COPE) Study, with additional assessments in July-August 2020 (T2) and October 2020 (T3). Growth mixture models conditioned on covariates were used to identify patterns of change over time in pandemic-related stress (originating from feeling unprepared for birth and fearing perinatal infection), pregnancy-specific stress, and anxiety symptoms. RESULTS: A uniform pattern of change (i.e. one-class solution) in stress perceptions was observed over time. Participants showed the same functional form of decreases in all three types of stress perceptions over the course of their pregnancy and as the pandemic persisted. Initial level of stress did not predict change over time. Anxiety symptoms had a two-class solution in which 25% of participants had high and convex patterns of anxiety, and 75% had low levels with concave patterns. DISCUSSION: Stress perceptions and anxiety patterns of change over the course of pregnancy during the COVID-19 pandemic were different. Therefore, to evaluate the well-being of pregnant women during a global health crisis, it is important to assess both stress perceptions and emotional stress responses (i.e. anxiety). Screening for anxiety symptoms in early pregnancy would be valuable as symptoms may not spontaneously decrease even when stressful conditions improve.

Association of maternal prenatal psychological stressors and distress with maternal and early infant faecal bacterial profile.

OBJECTIVE: Findings from animal studies indicate that the early gut bacteriome is a potential mechanism linking maternal prenatal stress with health trajectories in offspring. However, clinical studies are scarce and the associations of maternal psychological profiles with the early infant faecal bacteriome are unknown. This study aimed to investigate the associations of prenatal stressors and distress with early infant faecal bacterial profiles in a South African birth cohort study. METHODS: Associations between prenatal symptoms of depression, distress, intimate partner violence (IPV) and posttraumatic stress disorder (PTSD) and faecal bacterial profiles were evaluated in meconium and subsequent stool specimens from 84 mothers and 101 infants at birth, and longitudinally from a subset of 69 and 36 infants at 4-12 and 20-28 weeks of age, respectively, in a South African birth cohort study. RESULTS: Infants born to mothers that were exposed to high levels of IPV had significantly higher proportions of Citrobacter and three unclassified genera, all of which belonging to the family Enterobacteriaceae detected at birth. Proportions of these Enterobacteriaceae remained significantly increased over time (birth to 20-28 weeks of life) in infants born to mothers with high levels of IPV exposure compared to infants from mothers with no/low IPV exposure. Infants born to mothers exposed to IPV also had higher proportions of the genus Weissella at 4-12 weeks compared to infants from mothers with no/low IPV exposure. Faecal specimens from mothers exposed to IPV had higher proportions of the family Lactobacillaceae and lower proportions of Peptostreptococcaceae at birth. Maternal psychological distress was associated with decreased proportions of the family Veillonellaceae in infants at 20-28 weeks and a slower decline in Gammaproteobacteria over time. No changes in beta diversity were apparent for maternal or infant faecal bacterial profiles in relation to any of the prenatal measures for psychological adversities. CONCLUSION: Maternal lifetime IPV and antenatal psychological distress are associated with altered bacterial profiles in infant and maternal faecal bacteria. These findings may provide insights in the involvement of the gut bacteria linking maternal psychological adversity and the maturing infant brain.

Sex-specific regulation of stress-induced fetal glucocorticoid surge by the mouse placenta.

Antenatal stress increases the prevalence of diseases in later life, which shows a strong sex-specific effect. However, the underlying mechanisms remain unknown. Maternal glucocorticoids can be elevated by stress and are potential candidates to mediate the effects of stress on the offspring sex-specifically. A comprehensive evaluation of dynamic maternal and placental mechanisms modulating fetal glucocorticoid exposure upon maternal stress was long overdue. Here, we addressed this gap in knowledge by investigating sex-specific responses to midgestational stress in mice. We observed increased levels of maternal corticosterone, the main glucocorticoid in rodents, along with higher corticosteroid-binding globulin levels at midgestation in C57Bl/6 dams exposed to sound stress. This resulted in elevated corticosterone in female fetuses, whereas male offspring were unaffected. We identified that increased placental expression of the glucocorticoid-inactivating enzyme 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2; Hsd11b2 gene) and ATP-binding cassette transporters, which mediate glucocorticoid efflux toward maternal circulation, protect male offspring from maternal glucocorticoid surges. We generated mice with an Hsd11b2 placental-specific disruption (Hsd11b2PKO) and observed moderately elevated corticosterone levels in offspring, along with increased body weight. Subsequently, we assessed downstream glucocorticoid receptors and observed a sex-specific differential modulation of placental Tsc22d3 expression, which encodes the glucocorticoid-induced leucine zipper protein in response to stress. Taken together, our observations highlight the existence of unique and well-orchestrated mechanisms that control glucocorticoid transfer, exposure, and metabolism in the mouse placenta, pinpointing toward the existence of sex-specific fetal glucocorticoid exposure windows during gestation in mice.

Adverse family life events during pregnancy and ADHD symptoms in five-year-old offspring.

BACKGROUND: Prenatal exposure to maternal adverse life events has been associated with offspring ADHD, but the role of familial confounding is unclear. We aimed to clarify if adverse life events during pregnancy are related to ADHD symptoms in offspring, taking shared familial factors into account. METHOD: Data were collected on 34,751 children (including 6,427 siblings) participating in the population-based Norwegian Mother and Child Cohort Study. During pregnancy, mothers reported whether they had experienced specific life events. We assessed ADHD symptoms in five-year-old children with the Conners' Parent Rating Scale-Revised: short form. We modeled the associations between life events and mean ADHD scores with ordinary linear regression in the full cohort, and with fixed-effect linear regression in sibling comparisons to adjust for familial confounding. RESULTS: Children exposed to adverse life events had higher ADHD scores at age 5, with the strongest effect observed for financial problems (mean differences 0.10 [95% CI: 0.09, 0.11] in adjusted model), and the weakest for having lost someone close (0.02 [95% CI 0.01, 0.04] in adjusted model). Comparing exposure-discordant siblings resulted in attenuated estimates that were no longer statistically significant (e.g. mean difference for financial problems -0.03 [95% CI -0.07, 0.02]). ADHD scores increased if the mother had experienced the event as painful or difficult, and with the number of events, whereas sibling-comparison analyses resulted in estimates attenuated toward the null. CONCLUSIONS: These results suggest that the association between adverse life events during pregnancy and offspring ADHD symptoms is largely explained by familial factors.

The prevalence of symptoms of depression and anxiety, and the level of life stress and worry in New Zealand Maori and non-Maori women in late pregnancy.

OBJECTIVE: To describe the prevalence of symptoms of depression and anxiety, and the level of life stress and worry in late pregnancy for Maori and non-Maori women. METHODS: In late pregnancy, women completed a questionnaire recording their prior history of mood disorders; self-reported current depressive symptoms (⩾13 on the Edinburgh Postnatal Depression Scale), current anxiety symptoms (⩾6 on the anxiety items from the Edinburgh Postnatal Depression Scale), significant life stress (⩾2 items on life stress scale) and dysfunctional worry (>12 on the Brief Measure of Worry Scale). RESULTS: Data were obtained from 406 Maori women (mean age = 27.6 years, standard deviation=6.3 years) and 738 non-Maori women (mean age = 31.6 years, standard deviation=5.3 years). Depressive symptoms (22% vs 15%), anxiety symptoms (25% vs 20%), significant life stress (55% vs 30%) and a period of poor mood during the current pregnancy (18% vs 14%) were more prevalent for Maori than non-Maori women. Less than 50% of women who had experienced ⩾2 weeks of poor mood during the current pregnancy had sought help. Being young was an independent risk factor for depressive symptoms, significant life stress and dysfunctional worry. A prior history of depression was also consistently associated with a greater risk of negative affect in pregnancy. CONCLUSION: Antenatal mental health requires at least as much attention and resourcing as mental health in the postpartum period. Services need to specifically target Maori women, young women and women with a prior history of depression.

Path model of antenatal stress and depressive symptoms among Chinese primipara in late pregnancy.

BACKGROUND: Antenatal maternal mental health problems have numerous consequences for the well-being of both mother and child. This study aimed to test and construct a pertinent model of antenatal depressive symptoms within the conceptual framework of a stress process model. METHODS: This study utilized a cross-sectional study design. INCLUSION CRITERIA: participants were adult women (18 years or older) having a healthy pregnancy, in their third trimester (the mean weeks gestation was 34.71). DATA COLLECTION: depressive and anxiety symptoms were measured by Zung's Self-rating Depressive and Anxiety Scale, stress was measured by Pregnancy-related Pressure Scale, social support and coping strategies were measured by Social Support Rating Scale and Simplified Coping Style Questionnaire, respectively. ANALYSIS: path analysis was applied to examine the hypothesized causal paths between study variables. RESULTS: A total of 292 subjects were enrolled. The final testing model showed good fit, with normed χ (2) = 32.317, p = 0.061, CFI = 0.961, TLI = 0.917, IFI = 0.964, NFI = 0.900, RMSEA = 0.042. This path model supported the proposed model within the theoretical framework of the stress process model. Pregnancy-related stress, financial strain and active coping have both direct and indirect effects on depressive symptoms. Psychological preparedness for delivery, social support and anxiety levels have direct effects on antenatal depressive symptoms. Good preparedness for delivery could reduce depressive symptoms, while higher levels of anxiety could significantly increase depressive symptoms. Additionally, there were indirect effects of miscarriage history, irregular menstruation, partner relationship and passive coping with depressive symptoms. CONCLUSION: The empirical support from this study has enriched theories on the determinants of depressive symptoms among Chinese primipara, and could facilitate the formulation of appropriate interventions for reducing antenatal depressive symptoms, and enhancing the mental health of pregnant women.

Maternal Stress and Depressive Symptoms and Infant Development at Six Months: the Mothers and Children's Environmental Health (MOCEH) Prospective Study.

Our objective is to evaluate the relationships between prenatal maternal stress and depressive symptoms, respectively, and infant neurodevelopment at 6 months, adjusted for heavy metals and oxidative stress. This research is a part of a multi-center birth cohort study in South Korea. Information on stress and depressive symptoms was collected during the first trimester using Psychosocial Well-Being Index Short Form (PWI-SF) and Center for Epidemiological Studies Depression Scale (CES-D). The Korean Bayley Scales of Infant Development-II assessment (BSID-II), which includes the standardized mental development index (MDI) and psychomotor developmental index (PDI), and Korean Ages & Stages Questionnaires (K-ASQ) were applied to infants at six months of age. A higher index score indicates better development. Among 641 babies, 320 were female (50%). Maternal PWI ≥ 29 (vs. PWI ≤ 18) during early pregnancy was associated with a decrease in MDI scores of 5.37 points (P = 0.02) after adjusting for socioeconomic factors. Maternal CES-D ≥ 26 (vs. CES-D ≤ 10) during early pregnancy was associated with a decrease in MDI scores of 8.18 points (P = 0.01). The associations remained significant even after adjustment for lead, cadmium, and MDA levels (P < 0.05). However, no association was found between maternal PWI/CES-D and PDI score. No interaction was observed between stress and lead exposure. We found an inverse association between prenatal maternal stress and depressive symptoms, and MDI scores in 6-month-old infants after adjustment for prenatal lead exposure, which is known to affect cognitive function negatively.

Antenatal maternal intimate partner violence exposure is associated with sex-specific alterations in brain structure among young infants: Evidence from a South African birth cohort.

Maternal psychological distress during pregnancy has been linked to adverse outcomes in children with evidence of sex-specific effects on brain development. Here, we investigated whether in utero exposure to intimate partner violence (IPV), a particularly severe maternal stressor, is associated with brain structure in young infants from a South African birth cohort. Exposure to IPV during pregnancy was measured in 143 mothers at 28-32 weeks' gestation and infants underwent structural and diffusion magnetic resonance imaging (mean age 3 weeks). Subcortical volumetric estimates were compared between IPV-exposed (n = 63; 52% female) and unexposed infants (n = 80; 48% female), with white matter microstructure also examined in a subsample (IPV-exposed, n = 28, 54% female; unexposed infants, n = 42, 40% female). In confound adjusted analyses, maternal IPV exposure was associated with sexually dimorphic effects in brain volumes: IPV exposure predicted a larger caudate nucleus among males but not females, and smaller amygdala among females but not males. Diffusivity alterations within white matter tracts of interest were evident in males, but not females exposed to IPV. Results were robust to the removal of mother-infant pairs with pregnancy complications. Further research is required to understand how these early alterations are linked to the sex-bias in neuropsychiatric outcomes later observed in IPV-exposed children.

The Impact of Stress and Depression on the Outcome of Human Gestation.

Many researchers have reported on the high prevalence of anxiety and depression during pregnancy as well as the influence on delivery outcomes during the past decade. Preterm birth and premature labor, bleeding, higher frequency of cesarean section (CS), low birth weight, preeclampsia, stillbirth, miscarriage, NICU hospitalization, and a low Apgar score are the most commonly referenced outcomes assessed. Clarifying the relationship between exposure and result may help us to understand the risk factors and guide us to future clinical and research practices. The purpose of this narrative review is to search the following databases: PubMed, Research Gate, Scopus, Medline Plus, and present the most recent, comprehensive literature on the effects of stress and anxiety on pregnancy outcomes. Articles published from 01/01/2000 to 26/11/2022 were obtained from the previous databases. Anxiety and depression-related disorders are common nowadays, and they are frequently correlated with poor pregnancy outcomes. These problems are caused by a number of factors, including health social determinants, the individual obstetric situation, access to healthcare facilities, etc. The effects of each of these factors on birth outcomes range from major, such as preterm labor, congenital deformities, and low birth weight, to minor, such as mutations in the fetal epigenome. Both direct and indirect pathways of substantial interactions between depression, anxiety and stress, risk variables, and delivery problems were identified. Women's health practitioners and mental physicians must provide adequate support to these women in order to improve outcomes for both mothers and infants.

Expression of Stress-Mediating Genes is Increased in Term Placentas of Women with Chronic Self-Perceived Anxiety and Depression.

Anxiety, chronical stress, and depression during pregnancy are considered to affect the offspring, presumably through placental dysregulation. We have studied the term placentae of pregnancies clinically monitored with the Beck's Anxiety Inventory (BAI) and Edinburgh Postnatal Depression Scale (EPDS). A cutoff threshold for BAI/EPDS of 10 classed patients into an Index group (>10, n = 23) and a Control group (<10, n = 23). Cortisol concentrations in hair (HCC) were periodically monitored throughout pregnancy and delivery. Expression differences of main glucocorticoid pathway genes, i.e., corticotropin-releasing hormone (CRH), 11ß-hydroxysteroid dehydrogenase (HSD11B2), glucocorticoid receptor (NR3C1), as well as other key stress biomarkers (Arginine Vasopressin, AVP and O-GlcNAc transferase, OGT) were explored in medial placentae using real-time qPCR and Western blotting. Moreover, gene expression changes were considered for their association with HCC, offspring, gender, and birthweight. A significant dysregulation of gene expression for CRH, AVP, and HSD11B2 genes was seen in the Index group, compared to controls, while OGT and NR3C1 expression remained similar between groups. Placental gene expression of the stress-modulating enzyme 11ß-hydroxysteroid dehydrogenase (HSD11B2) was related to both hair cortisol levels (Rho = 0.54; p < 0.01) and the sex of the newborn in pregnancies perceived as stressful (Index, p < 0.05). Gene expression of CRH correlated with both AVP (Rho = 0.79; p < 0.001) and HSD11B2 (Rho = 0.45; p < 0.03), and also between AVP with both HSD11B2 (Rho = 0.6; p < 0.005) and NR3C1 (Rho = 0.56; p < 0.03) in the Control group but not in the Index group; suggesting a possible loss of interaction in the mechanisms of action of these genes under stress circumstances during pregnancy.

Understanding the multidimensional trajectory of psychosocial maternal risk factors causing preterm birth: A systematic review.

OBJECTIVES: Among all known risk factors of preterm birth, psychosocial factors form an intricate collection, which includes a multidimensional spectrum of interrelated mediating mechanisms. The understanding of these interconnected mechanisms is vital for designing targeted interventions to reduce preterm births. The objective of this systematic review was to investigate potential psychosocial maternal factors and their interactions to cause preterm birth. METHODS: PubMed, CINAHL, Scopus, Medline, and Cochrane Database of Systematic Reviews were searched for U.S.-based English language studies published between 1989 and 2019. Titles, abstracts, and full-texts were screened to determine eligibility for inclusion. Data were extracted from eligible studies using a customized data collection form. The National Institutes of Health assessment tool was utilized for quality assessment. RESULTS: Among the 76 full texts that were reviewed, 9 records met the eligibility criteria, and were included in the final review. The included publications addressed psychosocial factors including racial disparity, lifetime racism, neighborhood disadvantage, lack of partner support, childhood maltreatment and life-course variations, including homelessness and marital status. Antenatal stress was identified as a common mechanism through which psychosocial mediators may act to cause preterm birth. CONCLUSIONS: This review highlights the need for controlling potential risk factors of maternal stress by improving prenatal care, providing proper housing, and establishing conducive social environments for pregnant women. The review also suggests the importance of maternal psychological counselling and extensive maternal health monitoring among minority groups during the pregnancy period.

The COVID-19 Pandemic Can Impact Perinatal Mental Health and the Health of the Offspring.

The COVID-19 ongoing pandemic constitutes a major challenge for countries throughout the world due to the rapid spread of SARS-CoV-2 and devastating consequences in health. No one is free from COVID-19 impact. In this regard, pregnant women are not the exception. The COVID-19 outbreak represents a massive source of stressful agents for women and their babies during the perinatal period. The COVID-19 pandemic has been suggested to potentially have short- and long-term detrimental effects on pregnant women and the baby. These adverse consequences range from mental to medical diseases. During the last centuries, several dreadful and fatal incidents have put pregnant women and their babies at higher risk of mortality and health deterioration. For example, it has been informed that women exposed to the 1918 flu pandemic (commonly known as the Spanish flu) while pregnant showed higher rates of premature delivery in the short term. Long-term consequences have also been reported and individuals (both males and females) who were exposed to the 1918 flu pandemic while in utero had a higher risk of developing schizophrenia, diabetes, coronary heart disease or cancer throughout their lifespan.

"This baby came up and then he said, "I give up!": The interplay between unintended pregnancy, sexual partnership dynamics and social support and the impact on women's well-being in KwaZulu-Natal, South Africa.

BACKGROUND: Unintended pregnancy is associated with poor maternal and child health outcomes. To improve the health and wellbeing of women during the antenatal period, additional research in settings where unintended pregnancies are common is required to better understand the impact of the pregnancy on women's emotional health, relationships, and support structures. OBJECTIVE: To examine the personal, social and economic factors shaping the antenatal experiences of women in a resource-constrained setting with high rates of unintended pregnancy and HIV. RESEARCH DESIGN AND SETTING: Qualitative, semi-structured interviews were conducted with 30 women from an urban informal settlement in KwaZulu-Natal, South Africa, who had given birth within the last six weeks. FINDINGS: Most participants (n = 27, 90%) reported that their pregnancy had not been planned. Unintended pregnancy marked a period of heightened stress and vulnerability for many participants due to increased financial strain, HIV status, and trauma associated with past or current violence. Family members and sexual partners could mitigate financial stress and be sources of emotional and material support during the antenatal period. However, participants frequently experienced increased instability and conflict in sexual partner and family relationships due to the unintended pregnancy, exacerbating women's stress. KEY CONCLUSIONS: A nuanced understanding of the factors shaping women's emotional responses to an unintended pregnancy may aid in identification of women who are most likely to experience high levels of antenatal stress and to prioritize these women for intervention in order to prevent associated poor maternal and child health outcomes.

The Impact of Antenatal Psychological Group Interventions on Psychological Well-Being: A Systematic Review of the Qualitative and Quantitative Evidence.

Depression, anxiety and stress in the perinatal period can have serious, long-term consequences for women, their babies and their families. Over the last two decades, an increasing number of group interventions with a psychological approach have been developed to improve the psychological well-being of pregnant women. This systematic review examines interventions targeting women with elevated symptoms of, or at risk of developing, perinatal mental health problems, with the aim of understanding the successful and unsuccessful features of these interventions. We systematically searched online databases to retrieve qualitative and quantitative studies on psychological antenatal group interventions. A total number of 19 papers describing 15 studies were identified; these included interventions based on cognitive behavioural therapy, interpersonal therapy and mindfulness. Quantitative findings suggested beneficial effects in some studies, particularly for women with high baseline symptoms. However, overall there is insufficient quantitative evidence to make a general recommendation for antenatal group interventions. Qualitative findings suggest that women and their partners experience these interventions positively in terms of psychological wellbeing and providing reassurance of their 'normality'. This review suggests that there are some benefits to attending group interventions, but further research is required to fully understand their successful and unsuccessful features.

Maternal Stress and Depressive Symptoms and Infant Development at Six Months: the Mothers and Children's Environmental Health (MOCEH) Prospective Study

Our objective is to evaluate the relationships between prenatal maternal stress and depressive symptoms, respectively, and infant neurodevelopment at 6 months, adjusted for heavy metals and oxidative stress. This research is a part of a multi-center birth cohort study in South Korea. Information on stress and depressive symptoms was collected during the first trimester using Psychosocial Well-Being Index Short Form (PWI-SF) and Center for Epidemiological Studies Depression Scale (CES-D). The Korean Bayley Scales of Infant Development-II assessment (BSID-II), which includes the standardized mental development index (MDI) and psychomotor developmental index (PDI), and Korean Ages & Stages Questionnaires (K-ASQ) were applied to infants at six months of age. A higher index score indicates better development. Among 641 babies, 320 were female (50%). Maternal PWI ≥ 29 (vs. PWI ≤ 18) during early pregnancy was associated with a decrease in MDI scores of 5.37 points (P = 0.02) after adjusting for socioeconomic factors. Maternal CES-D ≥ 26 (vs. CES-D ≤ 10) during early pregnancy was associated with a decrease in MDI scores of 8.18 points (P = 0.01). The associations remained significant even after adjustment for lead, cadmium, and MDA levels (P < 0.05). However, no association was found between maternal PWI/CES-D and PDI score. No interaction was observed between stress and lead exposure. We found an inverse association between prenatal maternal stress and depressive symptoms, and MDI scores in 6-month-old infants after adjustment for prenatal lead exposure, which is known to affect cognitive function negatively.