Perinatal Stress Research Articles

Cord Blood Adductomics Reveals Oxidative Stress Exposure Pathways of Bronchopulmonary Dysplasia.

Fetal and neonatal exposures to perinatal oxidative stress (OS) are key mediators of bronchopulmonary dysplasia (BPD). To characterize these exposures, adductomics is an exposure science approach that captures electrophilic addition products (adducts) in blood protein. Adducts are bound to the nucleophilic cysteine loci of human serum albumin (HSA), which has a prolonged half-life. We conducted targeted and untargeted adductomics to test the hypothesis that adducts of OS vary with BPD. We studied 205 preterm infants (≤28 weeks) and 51 full-term infants from an ongoing birth cohort. Infant plasma was collected at birth (cord blood), 1-week, 1-month, and 36-weeks postmenstrual age. HSA was isolated from plasma, trypsin digested, and analyzed using high-performance liquid chromatography-mass spectrometry to quantify previously annotated (known) and unknown adducts. We identified 105 adducts in cord and postnatal blood. A total of 51 known adducts (small thiols, direct oxidation products, and reactive aldehydes) were increased with BPD. Postnatally, serial concentrations of several known OS adducts correlated directly with supplemental oxygen exposure. The application of large-scale adductomics elucidated OS-mediated pathways of BPD. This is the first study to investigate the "neonatal-perinatal exposome" and to identify oxidative stress-related exposure biomarkers that may inform antioxidant strategies to protect the health of future generations of infants.

Incidence of Perinatal Post-Traumatic Stress Disorder in Catalonia: An Observational Study of Protective and Risk Factors.

Pregnancy and childbirth have a great impact on women's lives; traumatic perinatal experiences can adversely affect mental health. The present study analyzes the incidence of perinatal post-traumatic stress disorder (PTSD) in Catalonia in 2021 from data obtained from the Registry of Morbidity and Use of Health Resources of Catalonia (MUSSCAT). The incidence of perinatal PTSD (1.87%) was lower than in comparable studies, suggesting underdiagnosis. Poisson regression adjusting for age, income, gestational weeks at delivery, type of delivery, and parity highlighted the influence of sociodemographics, and characteristics of the pregnancy and delivery on the risk of developing perinatal PTSD. These findings underline the need for further research on the risk factors identified and for the early detection and effective management of PTSD in the perinatal setting.

Association of Fetal Catecholamines With Neonatal Hypoglycemia

Perinatal stress and fetal growth restriction increase the risk of neonatal hypoglycemia. The underlying pathomechanism is poorly understood. In a sheep model, elevated catecholamine concentrations were found to suppress intrauterine insulin secretion, followed by hyperresponsive insulin secretion once the adrenergic stimulus subsided. To determine whether neonates with risk factors for hypoglycemia have higher catecholamine concentrations in umbilical cord blood (UCB) and/or amniotic fluid (AF) and whether catecholamines are correlated with postnatal glycemia. In a prospective cohort study of 328 neonates at a tertiary perinatal center from September 2020 through May 2022 in which AF and UCB were collected immediately during and after delivery, catecholamines and metanephrines were analyzed using liquid chromatography with tandem mass spectrometry. Participants received postnatal blood glucose (BG) screenings. Risk factor for neonatal hypoglycemia. Comparison of catecholamine and metanephrine concentrations between at-risk neonates and control participants, and correlation of concentrations of catecholamines and metanephrines with the number and severity of postnatal hypoglycemic episodes. In this study of 328 neonates (234 in the risk group: median [IQR] gestational age, 270 [261-277] days; and 94 in the control group: median [IQR] gestational age, 273 [270-278] days), growth-restricted neonates showed increased UCB median (IQR) concentrations of norepinephrine (21.10 [9.15-42.33] vs 10.88 [5.78-18.03] nmol/L; P < .001), metanephrine (0.37 [0.13-1.36] vs 0.12 [0.08-0.28] nmol/L; P < .001), and 3-methoxytyramine (0.149 [0.098-0.208] vs 0.091 [0.063-0.149] nmol/L; P = .001). Neonates with perinatal stress had increased UCB median (IQR) concentrations of norepinephrine (22.55 [8.99-131.66] vs 10.88 [5.78-18.03] nmol/L; P = .001), normetanephrine (1.75 [1.16-4.93] vs 1.25 [0.86-2.56] nmol/L; P = .004), and 3-methoxytyramine (0.120 [0.085-0.228] vs 0.091 [0.063-0.149] nmol/L; P = .008) (P < .0083 was considered statistically significant). Concentrations of UCB norepinephrine, metanephrine, and 3-methoxytyramine were negatively correlated with AF C-peptide concentration (rs = -0.212, P = .005; rs = -0.182, P = .016; and rs = -0.183, P = .016, respectively [P < .017 was considered statistically significant]). Concentrations of UCB norepinephrine, metanephrine, and 3-methoxytyramine were positively correlated with the number of hypoglycemic episodes (BG concentration of 30-45 mg/dL) (rs = 0.146, P = .01; rs = 0.151, P = .009; and rs = 0.180, P = .002, respectively). Concentrations of UCB metanephrine and 3-methoxytyramine were negatively correlated with the lowest measured BG concentration (rs = -0.149, P = .01; and rs = -0.153, P = .008, respectively). Neonates at risk for hypoglycemia displayed increased catecholamine and metanephrine concentrations that were correlated with postnatal hypoglycemic episodes and lower BG levels; these results are consistent with findings in a sheep model that fetal catecholamines are associated with neonatal β-cell physiology and that perinatal stress or growth restriction is associated with subsequent neonatal hyperinsulinemic hypoglycemia. Improving the pathomechanistic understanding of neonatal hypoglycemia may help to guide management of newborns at risk for hypoglycemia.

Perinatal Posttraumatic Stress Disorder Diagnoses Among Commercially Insured People Increased, 2008-20.

Posttraumatic stress disorder (PTSD) is a burdensome disorder, affecting 3-4percent of delivering people in the US, with higher rates seen among Black and Hispanic people. The extent of clinical diagnosis remains unknown. We describe the temporal and racial and ethnic trends in perinatal PTSD diagnoses among commercially insured people with live-birth deliveries during the period 2008-20, using administrative claims from Optum's Clinformatics Data Mart Database. Predicted probabilities from our logistic regression analysis showed a 394percent increase in perinatal PTSD diagnoses, from 37.7 per 10,000 deliveries in 2008 to 186.3 per 10,000 deliveries in 2020. White people had the highest diagnosis rate at all time points (208.0 per 10,000 deliveries in 2020), followed by Black people, people with unknown race, Hispanic people, and Asian people (188.7, 171.9, 146.9, and 79.8 per 10,000 deliveries in 2020, respectively). The significant growth in perinatal PTSD diagnosis rates may reflect increased awareness, diagnosis, or prevalence of the disorder. However, these rates fall well below the estimated prevalence of PTSD in the perinatal population.

Postpartum Oxytocin Treatment via the Mother Reprograms Long-Term Behavioral Disorders Induced by Early Life Stress on the Plasma and Brain Metabolome in the Rat.

The rat model of perinatal stress (PRS), in which exposure of pregnant dams to restraint stress reduces maternal behavior, is characterized by a metabolic profile that is reminiscent of the "metabolic syndrome". We aimed to identify plasma metabolomic signatures linked to long-term programming induced by PRS in aged male rats. This study was conducted in the plasma and frontal cortex. We also investigated the reversal effect of postpartum carbetocin (Cbt) on these signatures, along with its impact on deficits in cognitive, social, and exploratory behavior. We found that PRS induced long-lasting changes in biomarkers of secondary bile acid metabolism in the plasma and glutathione metabolism in the frontal cortex. Cbt treatment demonstrated disease-dependent effects by reversing the metabolite alterations. The metabolomic signatures of PRS were associated with long-term cognitive and emotional alterations alongside endocrinological disturbances. Our findings represent the first evidence of how early life stress may alter the metabolomic profile in aged individuals, thereby increasing vulnerability to CNS disorders. This raises the intriguing prospect that the pharmacological activation of oxytocin receptors soon after delivery through the mother may rectify these alterations.

Transient Neonatal Hypocortisolism in Neonates with Hypoglycemia - Coexistence or Cause?

Infants born preterm, with low birth weight (LBW), or with perinatal stress are at high risk for neonatal hypoglycemia. Low cortisol levels have also been demonstrated in this group of neonates, which is often transient. We report a series of neonates with transient hypocortisolism who had neonatal hypoglycemia. A descriptive study on clinic-biochemical parameters of a group of five neonates who had persistent neonatal hypoglycemia and had demonstrated low cortisol on critical sample testing. All five neonates had birth weights below normal and four were born preterm. A history of perinatal asphyxia was seen in four cases and neonatal sepsis in two. During critical sample testing (when blood glucose [BG] was <50 mg/dl), hyperinsulinism (Insulin >2 mIU/ml) was seen in three infants whereas insulin was undetectable in two. The median cortisol during critical sample testing was 1.9 mcg/dl (0.88 - 3.7). Critical GH was normal in all, and ACTH ranged from 7.2 pg/ml to 41.3 pg/ml. None of the infants had overt clinical features of panhypopituitarism or primary adrenal insufficiency. USG brain revealed germinal matrix hemorrhage in two infants, which resolved on follow-up. USG adrenals and electrolytes were normal in all. Four of the five babies were started on oral hydrocortisone, to which they responded well with the resolution of hypoglycemia. No adverse events were noted. On follow-up, the median time to recover of serum cortisol to normal was 4 months. The contribution of transient hypocortisolism to hypoglycemia in infants at risk, including preterm, LBW, or those with perinatal stress, in the presence or absence of hyperinsulinism, is not well known. While the non-specific use of glucocorticoids is not advocated, the role of therapeutic glucocorticoids among at-risk neonates with documented hypocortisolism during hypoglycemia should be an area for research. Close follow-up of these neonates for spontaneous recovery of cortisol levels is warranted.

Prioritizing Maternal Mental Health in Addressing Morbidity and Mortality.

The rate of maternal mortality in the United States is 2-fold to 3-fold greater than that in other high-income countries. While many national initiatives have been developed to combat maternal mortality, these efforts often fail to include mental illness. To highlight the underrecognized contribution of mental illness to maternal mortality, which is nearly double that of postpartum hemorrhage. A topic outline was developed to include challenges in measuring perinatal mental conditions and mortality rates; contributions of social determinants of health to mental conditions and mortality; perinatal psychiatric disorder characterization; mechanisms by which maternal mental illness increases mortality, specifically, suicide and addictive disorders; access limitations and care "deserts"; prenatal stress and its impact on reproductive outcomes; increasing clinician expertise through cross-disciplinary education; intervention sites and models; and asserting that mental health is fundamental to maternal health. Publications in the last 3 years were prioritized, particularly those relating to policy. References were selected through consensus. Sources were PubMed, Ovid, direct data published on government websites, and health policy sources such as the Policy Center for Maternal Mental Health. Priority was given to recent sources. Citations from 2022-2023 numbered 26; within the last 5 years, 14; and historical references, 15. Recommendations to address each topic area serve as concluding statements for each section. To mitigate the contributions of mental illness to the maternal mortality risk, a coordinated effort is required across professional and governmental organizations. Concrete programmatic and policy changes are needed to reduce perinatal stress and address trauma, standardize the collection of social determinant of health data among perinatal patients, increase access to reproductive psychiatry curricula among prescribers, reduce perinatal mental health and obstetrical deserts, institute paid parental leave, and support seamless integration of perinatal and behavioral health care. Moreover, instead of focusing on a relatively minor portion of the contributors to health that current medical practice targets, fortifying the social foundation strengthens the prospects for the health of families for our current and future generations.

Anthropometric, biochemical, dietary, morbidity and well-being assessments in women and children in Indonesia, India and Senegal: a UKRI GCRF Action Against Stunting Hub protocol paper

IntroductionChild stunting has a complex aetiology, especially in the first 1000 days of life. Nutrition interventions alone have not produced expected impacts in reducing/preventing child stunting, indicating the importance of...

Pain/Stress, Mitochondrial Dysfunction, and Neurodevelopment in Preterm Infants

Introduction: Preterm infants experience tremendous early life pain/stress during their neonatal intensive care unit (NICU) hospitalization, which impacts their neurodevelopmental outcomes. Mitochondrial function/dysfunction may interface between perinatal stress events and neurodevelopment. Nevertheless, the specific proteins or pathways linking mitochondrial functions to pain-induced neurodevelopmental outcomes in infants remain unidentified. Our study aims to investigate the associations among pain/stress, proteins associated with mitochondrial function/dysfunction, and neurobehavioral responses in preterm infants. Methods: We conducted a prospective cohort study, enrolling 33 preterm infants between September 2017 and July 2022 at two affiliated NICUs located in Hartford and Farmington, CT. NICU Network Neurobehavioral Scale (NNNS) datasets were evaluated to explore potential association with neurobehavioral outcomes. The daily pain/stress experienced by infant’s during their NICU stay was documented. At 36–38 weeks post-menstrual age (PMA), neurobehavioral outcomes were evaluated using the NNNS and buccal swabs were collected for further analysis. Mass spectrometry-based proteomics was conducted on epithelial cells obtained from buccal swabs to evaluate protein expression level. Lasso statistical methods were conducted to study the association between protein abundance and infants’ NNNS summary scores. Multiple linear regression and Gene Ontology (GO) enrichment analyses were performed to examine how clinical characteristics and neurodevelopmental outcomes may be associated with protein levels and underlying molecular pathways. Results: During NICU hospitalization, preterm premature rupture of membrane (PPROM) was negatively associated with neurobehavioral outcomes. The protein functions including leptin receptor binding activity, glutathione disulfide oxidoreductase activity and response to oxidative stress, lipid metabolism, and phosphate and proton transmembrane transporter activity were negatively associated with neurobehavioral outcomes; in contrast, cytoskeletal regulation, epithelial barrier, and protection function were found to be associated with the optimal neurodevelopmental outcomes. In addition, mitochondrial function-associated proteins including SPRR2A, PAIP1, S100A3, MT-CO2, PiC, GLRX, PHB2, and BNIPL-2 demonstrated positive association with favorable neurodevelopmental outcomes, while proteins of ABLIM1, UNC45A, keratins, MUC1, and CYB5B showed positive association with adverse neurodevelopmental outcomes. Conclusion: Mitochondrial function-related proteins were observed to be associated with early life pain/stress and neurodevelopmental outcomes in infants. Large-scale studies with longitudinal datasets are warranted. Buccal proteins could be used to predict potential neurobehavioral outcomes.

Selenium suppressed the LPS-induced oxidative stress of bovine endometrial stromal cells through Nrf2 pathway with high cortisol background.

Stress and infection seriously threaten the reproductive performance and health of dairy cows. Various perinatal stresses increase plasma cortisol concentrations in cows, and chronically high cortisol levels may increase the incidence and severity of the uterine diseases. Selenium (Se) enhances antioxidant capacity of cows. The aim of this study was to explore how Se affects the oxidative stress of primary bovine endometrial stromal cells (BESC) with high cortisol background. The levels of reactive oxygen species (ROS) and other biomarkers of oxidative stress were measured using flow cytometry and assay kits. The changes in nuclear NF-E2-related factor 2 (Nrf2) pathway were detected by Western blot, qPCR, and immunofluorescence. The result showed that lipopolysaccharide (LPS) increased (P < 0.01) ROS and malondialdehyde (MDA) content and reduced (P < 0.01) superoxide dismutase (SOD) concentration, provoking BESC oxidative stress. The elevated levels of cortisol resulted in the accumulation (P < 0.05) of ROS and MDA and inhibition (P < 0.05) of SOD in unstimulated BESC but demonstrated an antioxidative effect in LPS-stimulated cells. Pretreatment with Se reduced (P < 0.01) the levels of ROS and MDA, while increasing (P < 0.05) the antioxidant capacities and the relative abundance of gene transcripts and proteins related to the Nrf2 pathway in BESC. This antioxidant effect was more pronounced in the presence of high cortisol level. In conclusion, cortisol alone induced the oxidative damage but provided an antioxidant protection in the presence of LPS. Se alleviated the LPS-induced cellular oxidative stress, which is probably achieved through activating Nrf2 pathway. At high cortisol levels, Se supplement has a more significant protective effect on BESC oxidative stress. This study provided evidence for the protective role of Se in bovine endometrial oxidative damage of stressed animals and suggested the potential regulatory mechanism in vitro.

An Undervalued Diagnosis: Post-Traumatic Stress Disorder in the Perinatal Period: A Case Report

BACKGROUND: Perinatal Post-Traumatic Stress Disorder (PTSD) is a disorder that occurs around childbirth, typically after a traumatic birth experience, where women may feel violated due to traumatic childbirth interventions they cannot control. Traumatic birth is defined as an event in which the mother perceives a real or perceived threat to herself or her baby, causing intense fear, helplessness, and horror. This can be considered an obstetric sequel. It is relevant to note that among pregnant women, perinatal PTSD is the third most common psychiatric disorder, with a prevalence ranging from 0.8% to 43% worldwide. Despite its significance, it is little-known, underdiagnosed, and often confused with other conditions such as depression or anxiety. Furthermore, it results in serious family, social, and occupational dysfunctions and is associated with other pathologies. Clinically, women with perinatal PTSD experience symptoms such as re-experiencing the event, detachment from the newborn, nightmares, irritability, and rejection of motherhood. This can lead to consequences for the mother, ranging from a desire not to become pregnant again to severe symptoms such as dissociation, stress, anxiety, and depression. It also affects those close to the mother, such as the partner and family. The aim of this work is to describe perinatal PTSD and emphasize the importance of early identification and appropriate treatment by medical professionals for the benefit of mothers and their children THE CASE: We describe a 35-year-old patient with a history of mixed depressive and anxiety disorder since 2018 experiences perinatal post-traumatic stress disorder. This is related to physical and verbal abuse during her second childbirth, resulting in a traumatic experience. Her childhood was marked by the feeling that her mother favored her younger sister and subjected her to physical and emotional abuse. The first pregnancy was unplanned, and she faced humiliation and abandonment by her partner. Despite the circumstances, the birth was a positive experience. The second pregnancy was planned and desired, but during childbirth in a different clinic from the first, she experienced inadequate care conditions, a lack of privacy, and physical abuse by medical staff. She also received inappropriate comments from the attending gynecologist. During the postpartum period, she shared a room with a cancer patient, complicating her experience. After childbirth, she experienced a hypertensive disorder in the postpartum and chose not to return to the hospital where she gave birth due to her traumatic experiences. Overall, her story reveals a series of challenging experiences related to motherhood that have contributed to her current mental health state. CONCLUSION: Perinatal PTSD is a psychiatric disorder that affects a significant number of pregnant and postpartum women. Its prevalence varies widely, reflecting the need for increased awareness and early detection. Despite its considerable impact on maternal mental health and well-being, perinatal PTSD is often overlooked or confused with other conditions such as depression and anxiety. It's important to raise awareness among medical staff about this disorder and provide a comprehensive and empathetic approach to enhance care for mothers during childbirth and the postpartum period.

Chronic non-discriminatory social defeat stress during the perinatal period induces depressive-like outcomes in female mice

Depression is more prevalent in women than in men. Perinatal stress is one of the main risk factors for depression in women. However, there is no suitable female model for perinatal depression that uses the social defeat stress (SDS) paradigm. The standard chronic SDS protocol, which is the most useful method for developing a depression-like model, is effective only in male mice. Thus, this study aimed to characterize a novel SDS method for producing a perinatal depression-like model mouse.We induced chronic SDS in perinatal female mice, wherein chronic non-discriminatory SDS (ND-SDS) was used to induce substantial stress in female mice. The female mice were placed in aggressive ICR mouse cages with sentinel male mice under ND-SDS conditions. Stressed female mice subjected to ND-SDS during the perinatal period efficiently exhibited stress-susceptible phenotypes, such as a social avoidance phenotype and anhedonic behavior, whereas stressed female mice subjected to SDS did not show depressive-like behaviors. These results indicate that chronic ND-SDS in perinatal females could be used to develop a female perinatal depression-like model that can be used to study women’s health.

Perinatal Stressors and Consequences for Neonates with Critical Congenital Heart Disease.

The prenatal diagnosis of congenital heart disease (CHD) is a traumatic event that can cause expectant parents to experience anxiety, depression, and toxic stress. Prenatal exposure to stress may impact neonatal postoperative outcomes. In addition, expectant parents may have other psychosocial stressors that may compound maternal stress. We investigated the relationship between stress in pregnancies complicated by prenatally diagnosed CHD and their neonatal outcomes. A pilot retrospective cohort study of pregnancies with prenatally diagnosed critical CHD (2019-2021) was performed. The collected data included pregnancy characteristics and neonatal and postoperative outcomes (including the need for exogenous corticosteroid treatment (ECT)). In order to quantify prenatal stressors, a composite prenatal stress score (PSS) was established and utilized. In total, 41 maternal-fetal dyads were evaluated. Thirteen (32%) neonates had single-ventricle anatomy. The need for ECT after CHD surgery was associated with higher pregnant patient PSS (p = 0.01). PSS did not correlate with birthweight, infection, or hypoglycemia in the neonatal period. Prenatal stress is multifactorial; higher PSS is correlates with post-bypass ECT, suggesting that a stressful intrauterine environment may be associated with worse neonatal postoperative outcomes.

Screening for perinatal depression and stress: a prospective cohort study.

There is currently a heightened need for perinatal medical services to timely recognize and accurately meet the psychological needs of pregnant women. Psychological disturbances a mother experiences during pregnancy, such as depression and anxiety, can be later associated with inadequate maternal capacity for antenatal care for herself and the baby, and may lead to subsequent mental health problems later in the mother's life. Routine prenatal assessment could significantly benefit from being proactively enriched with early prevention mental health screening tools to assess, appropriately manage vulnerable populations, and subsequently implement preventive actions. 178 pregnant women, under routine prenatal medical assessment, were measured regarding depressive symptomatology and stress, through the use of two validated psychometric tools (the Edinburgh Postnatal Depression Scale (EPDS) and the Perceived Stress Scale (PSS-14)). Heightened perceived stress and depressive symptomatology levels were associated with younger maternal age, an obstetrical record of more than one births and a history of abortion. Results additionally showed a connection between the requirement for a psychiatric referral-based on the levels of symptomatology recorded through the psychometric assessment and a clinical interview-and currently running the earlier stages (weeks) of pregnancy. Our revised proposed prenatal screening protocol for depression and stress suggests an amplified follow-up assessment including all pregnant women scoring high in both depression and in perceived stress, regardless of previous history of prenatal depression or of suicidality, to detect earlier or less manifest expressions of distress during pregnancy, in vulnerable perinatal populations.

Low-dose diazoxide is safe and effective in infants with transient hyperinsulinism.

Transient hyperinsulinism (THI) is the most common form of recurrent hypoglycaemia in neonates beyond the first week of life. Although self-resolving, treatment can be required. Consensus guidelines recommend the lower end of the diazoxide 5-15 mg/kg/day range in THI to reduce the risk of adverse events. We sought to determine if doses <5 mg/kg/day of diazoxide can be effective in THI. Infants with THI (duration <6 months) were treated with low-dose diazoxide from October 2015 to February 2021. Dosing was based on weight at diazoxide start: 2 mg/kg/day in infants 1000-2000 g (cohort 1), 3 mg/kg/day in those 2000-3500 g (cohort 2)and 5 mg/kg/day in those >3500 g. A total of 73 infants with THI (77% male, 33% preterm, 52% small-for-gestational age) were commenced on diazoxide at a median age of 11 days (range 3-43) for a median duration of 4 months (0.3-6.8), with no difference between cohorts. The mean effective diazoxide dose was 3 mg/kg/day (range 1.5-10); 35% (26/73) required an increase from their starting dose, including 60% (9/15) of cohort 1. There was no association between perinatal stress risk factors or treatment-related characteristics and dose increase. Adverse events occurred in 13 patients (18%); oedema (12%) and hyponatraemia (5%) were the most common. Two infants developed suspected necrotising enterocolitis (NEC); none had pulmonary hypertension. Diazoxide doses <5 mg/kg/day are effective in THI. While the nature of the association between diazoxide and NEC was unclear, other adverse events were mild. We suggest considering starting doses as low as 2-3 mg/kg/day in THI to balance the side effect risk while maintaining euglycaemia.

Association Between Mother-Infant Hair Cortisol Levels, Perinatal Stressors, and Adverse Birth Outcomes Among Kenyan Mother-Infant Pairs

Association Between Mother-Infant Hair Cortisol Levels, Perinatal Stressors, and Adverse Birth Outcomes Among Kenyan Mother-Infant Pairs

Impact of preterm birth on the onset of panic disorder in later life – Results from the Gutenberg Prematurity Study (GPS)

BackgroundThe present study aimed to investigate whether prematurity and perinatal stress exert long-term effects on the onset of panic disorder in later life. MethodsFrom 40,189 adults born in Germany between 1969 and 2002, a study cohort (n = 427) stratified by gestational age (GA) (extremely preterm: GA < 29 weeks; very preterm: GA 29–32 weeks; moderately preterm: GA 33–36 weeks; and full-term GA ≥ 37 weeks) was selected (age 28.5 ± 8.7 years). Multivariable logistic regression analyses were conducted to investigate associations between gestational age at birth and panic disorder adjusting for age, gender, socioeconomic status, and perinatal factors. ResultsThe prevalence of panic disorder was roughly equal in moderate to very preterm and full-term birth groups at 1.9%–3.8%. However, this rate significantly increased to 14.3% in the extreme preterm category (GA <2 9: 14.3 %, p = 0.002). In multivariable analyses, female gender and GA were independently associated with panic disorder. Adjusting for age, gender and socioeconomic status, panic disorder was associated with lower GA at birth (OR = 1.12 per week (CI95%: 1.01–1.26, p = 0.037). Whereas adjustment for nutrition status or indicators of perinatal stress had no effect, correction for the length of postnatal ICU-stay eliminated the association between preterm birth and later panic disorder. LimitationsLimitations include the small number of cases and the reliance on questionnaires to assess mental status. ConclusionsPrematurity likely increases the risk of panic disorder later in life, and the subsequent postnatal ICU-stay appears to be of critical importance. However, due to strong collinearity and other associated factors with preterm births, it remains unclear which is the primary determinant.

Clinical Characteristics, Treatment, and Outcomes of Provoked Acute Cerebral Sinovenous Thrombosis in Patients

Background Cerebral sinus venous thrombosis (CSVT) is a rare pediatric condition with an estimated incidence of 0.7 per 100,000 children. However, amongst pediatric venous thromboembolism (VTE), the proportion of CSVT is high, at about 10% of all pediatric VTE. Key risk factors include perinatal stressors in cases of neonatal CSVT and acute infections, especially head and neck infections, in older children. To date, few multinational trials of pediatric VTE treatment have reported findings specifically among CSVT patients. Aims We sought to describe the clinical characteristics, treatment strategies, and outcomes of the patients with provoked acute CSVT enrolled in the Kids-DOTT trial and to compare these features to those of Kids-DOTT participants with non-CSVT VTE. Methods Kids-DOTT was an NIH-sponsored multinational randomized clinical trial (RCT) comparing 6 weeks vs. 3 months of anticoagulation for provoked acute VTE treatment in patients &amp;lt;21 years, with two non-randomized cohort arms run in parallel to the RCT for patients with persistent antiphospholipid antibodies or complete veno-occlusion at 6 weeks post-diagnosis of the index VTE. The primary RCT findings were recently published. In the present analysis, descriptive statistics were used to summarize patient and thrombus characteristics, treatments, and outcomes, and variables were compared between CSVT and non-CSVT VTE groups using Mann-Whitney U test for continuous variables and Chi-squared or Fisher's exact test, as appropriate, for categorical variables. All statistical analyses were performed using R Core Team, 2021. A P-value of &amp;lt;0.05 was considered statistically significant. Results Among 532 patients enrolled in the Kids-DOTT trial, the index VTE was a CSVT in 75 (14%). Age distribution differed significantly ( P=0.002) between CSVT and non-CSVT VTE patients, with the CSVT more likely to occur in neonates and children, compared to non-CSVT VTE more likely to occur in adolescents. CSVT was less likely to be CVC-related compared to non-CSVT VTE. The frequency of any infection (56.9% vs 26%, p&amp;lt;0.001) and specifically infection of the head/neck (35.4% vs 2%; P&amp;lt;0.001) as a provoking factor was significantly higher for CSVT vs. non-CSVT VTE. Non-head and neck infections were less likely to be associated with CSVT compared to non-CSVT VTE. One-third of CSVT patients received 6 weeks, while two-thirds received &amp;gt; 3 months, of anticoagulation (Table 2). No patients developed ISTH-defined symptomatic recurrent VTE or clinically relevant bleeding. Conclusions These multinational trial findings substantiate those of retrospective studies implicating head/neck infection as an important provoking factor for CSVT in young patients. The absence of recurrent VTE or clinically relevant bleeding among CSVT patients managed with anticoagulation in Kids-DOTT serve to augment recent RCT findings of CSVT treatment in children involving direct oral anticoagulants, demonstrating the safety and efficacy of therapeutic anticoagulation for pediatric CSVT.

Improving behavioral deficits induced by perinatal ethanol and stress exposure in adolescent male rat progeny via maternal melatonin treatment.

Early-life stressful situations and binge drinking have been thus far acknowledged as two burdensome conditions that potentially give rise to negative outcomes and then synergistically affect brain development. In this context, the hippocampus, with the greatest number of glucocorticoid receptors (GCRs) in the brain, is responsible for regulating negative responses to stress. Prolonged glucocorticoid (GC) exposure can accordingly cause oxidative stress (OS), leading to cognitive and emotional dysfunction. Against this background, melatonin, as a powerful antioxidant and hypothalamus-pituitary-adrenal (HPA) axis regulator, was administered in this study to ameliorate cognitive impairments induced by perinatal ethanol and stress exposure in adolescent male rat progeny. Wistar rat dams were exposed to ethanol (4 g/kg) and melatonin (10 mg/kg) from gestational day (GD) 6 to postnatal day (PND) 14 and then limited nesting material (LNS) from PND0 to PND14 individually or in combination. Maternal behavior was then investigated in mothers. Afterward, the plasma corticosterone (CORT) concentration, the OS marker, the corticotropin-releasing hormone receptor type 1 (CRHR1) expression, and the GCR and brain-derived neurotrophic factor (BDNF) levels were measured in the male pups. Moreover, behavioral tasks, including the elevated plus maze (EPM), the Morris water maze (MWM), the novel object recognition (NORT), and the object-location memory (OLM) tests were completed and assessed. The quantity and quality of maternal care significantly decreased in the mothers with dual exposure to ethanol and stress. The plasma CORT concentration in the progeny also dropped in the Ethanol + LNS group, but the risk-taking behavior elevated significantly. The ethanol and stress exposure further revealed a significant fall in the GCR and CRHR1 expression levels, compared with stress alone. The results of learning and memory tasks also indicated a significant reduction in spatial learning and memory among animals exposed to ethanol and stress. The BDNF mRNA levels correspondingly increased in the Ethanol + LNS group, compared with LNS alone. In the presence of ethanol and stress, the superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities correspondingly declined. On the other hand, the malondialdehyde (MDA) levels augmented in the hippocampus of the animals with ethanol and LNS dual exposure, as compared with the control group. Melatonin treatment (MT) thus improved nursing behaviors in dams, prevented OS, enhanced the CRHR1 and GCR expression, and reduced the BDNF levels to the similar ones in the control group. The animals in the Ethanol + LNS + MT group ultimately showed an ameliorated performance at behavioral tasks, including the memory and risk-taking behavior. It was concluded that MT could prevent stress response and memory impairments arising from dual exposure to ethanol and stress by inhibiting OS.

Pre- and perinatal exposures associated with molar incisor hypomineralization: Birth cohort, Brazil.

To analyze prenatal and perinatal stressors associated with molar incisor hypomineralization (MIH) in adolescents. Prospective cohort study collected prenatal (socioeconomic status, maternal age, number of prenatal visits, smoking, obesity during pregnancy, abortion history, gestational hypertension) and perinatal stressors (type of delivery, gestational age, birth weight, intensive care unit-ICU at birth). The outcome was MIH at 18-19 years follow-up (n = 590). MIH was defined according to the Ghanim criteria - Model I. We performed a sensitivity analysis, including opacities demarcated in index tooth, incisive or molars, Model II. Through structural equation modeling, we analyzed direct and mediating pathways between multiple stressors with outcomes. MIH was observed in 15.25% (n = 90), and opacities demarcated in any index tooth were observed in 22.8% of adolescents (n = 135). In Model I, no stressor explained MIH significantly, although we watched high standardized coefficients (SC) for low birth weight (SC = 0.223, p = 0.147), lower gestational age (SC = 0.351; p = 0.254), and ICU admission (SC = 0.447, p = 0.254). In Model II, advanced maternal age (SC = 0.148; p < 0.05) and not undergoing prenatal care (SC = 0.384, p < 0.03) explained opacities demarcated in incisors or molars. Advanced maternal age and not undergoing prenatal care were associated with MIH lesion-like in incisors or molars.