Impaired Developmental Outcome Research Articles

Genome-wide neonatal epigenetic changes associated with maternal exposure to the COVID-19 pandemic

BackgroundDuring gestation, stressors to the fetus, including viral exposure or maternal psychological distress, can fundamentally alter the neonatal epigenome, and may be associated with long-term impaired developmental outcomes. The impact of in utero exposure to the COVID-19 pandemic on the newborn epigenome has yet to be described.MethodsThis study aimed to determine whether there are unique epigenetic signatures in newborns who experienced otherwise healthy pregnancies that occurred during the COVID-19 pandemic (Project RESCUE). The pre-pandemic control and pandemic cohorts (Project RESCUE) included in this study are part of a prospective observational and longitudinal cohort study that evaluates the impact of elevated prenatal maternal stress during the COVID-19 pandemic on early childhood neurodevelopment.Using buccal swabs collected at birth, differential DNA methylation analysis was performed using the Infinium MethylationEPIC arrays and linear regression analysis. Pathway analysis and gene ontology enrichment were performed on resultant gene lists.ResultsWidespread differential methylation was found between neonates exposed in utero to the pandemic and pre-pandemic neonates. In contrast, there were no apparent epigenetic differences associated with maternal COVID-19 infection during pregnancy. Differential methylation was observed among genomic sites that underpin important neurological pathways that have been previously reported in the literature to be differentially methylated because of prenatal stress, such as NR3C1.ConclusionsThe present study reveals potential associations between exposure to the COVID-19 pandemic during pregnancy and subsequent changes in the newborn epigenome. While this finding warrants further investigation, it is a point that should be considered in any study assessing newborn DNA methylation studies obtained during this period, even in otherwise healthy pregnancies.

Mother-to-Infant Bonding in Women With a Bipolar Spectrum Disorder.

Purpose: Offspring of mothers with a bipolar disorder are at high-risk for impaired developmental outcomes and psychopathology (e. g., mood, anxiety, sleep disorders) later in life. This increased risk of psychopathology is not only because of genetic vulnerability, but environmental factors may play an important role as well. The often long and debilitating mood episodes of mothers with bipolar disorder might hamper their qualities as a caregiver and may impact the child. We examined early mother-to-infant bonding 1 year postpartum in mothers with bipolar spectrum disorder as compared to mothers of the general population. The association between mother-to-infant bonding and the type of bipolar spectrum diagnosis (bipolar I, bipolar II, bipolar Not Otherwise Specified) as well as relapse within 12 months postpartum was also assessed.Methods: In total, 75 pregnant women with a bipolar spectrum disorder participated in the current study. The participants were included in a longitudinal cohort study of women with bipolar spectrum disorder and were prospectively followed from pregnancy until 1 year postpartum. Mother-to-infant bonding was assessed using the Pre- and Postnatal Bonding Scale. A longitudinal population-based cohort of 1,419 pregnant women served as the control group. Multiple linear regression analyses were used to assess the association between bipolar spectrum disorder and mother-to-infant bonding scores, controlling for several confounders.Results: Women with bipolar spectrum disorder perceived the bonding with their child as less positive compared to the control group. The type of bipolar spectrum disorder was not associated with poorer bonding scores. Relapse during the 1st year after delivery also did not affect bonding scores in women with bipolar spectrum disorder.Conclusions: Our findings could imply that women with bipolar spectrum disorder are more vulnerable to impairments in bonding due to the nature of their psychopathology, regardless of the occurrence of postpartum relapse. Careful follow-up including monitoring of mother-to-infant bonding of pregnant women with a history of bipolar spectrum disorder should be a standard to this vulnerable group of women. In addition, regardless of severity and mood episode relapse, an intervention to improve bonding could be beneficial for all mothers with bipolar spectrum disorder and their newborns.

Gene expression in cord blood links genetic risk for neurodevelopmental disorders with maternal psychological distress and adverse childhood outcomes

Prenatal exposure to maternal stress and depression has been identified as a risk factor for adverse behavioral and neurodevelopmental outcomes in early childhood. However, the molecular mechanisms through which maternal psychopathology shapes offspring development remain poorly understood. We applied transcriptome-wide screens to 149 umbilical cord blood samples from neonates born to mothers with posttraumatic stress disorder (PTSD; n = 20), depression (n = 31) and PTSD with comorbid depression (n = 13), compared to carefully matched trauma exposed controls (n = 23) and healthy mothers (n = 62). Analyses by maternal diagnoses revealed a clear pattern of gene expression signatures distinguishing neonates born to mothers with a history of psychopathology from those without. Co-expression network analysis identified distinct gene expression perturbations across maternal diagnoses, including two depression-related modules implicated in axon-guidance and mRNA stability, as well as two PTSD-related modules implicated in TNF signaling and cellular response to stress. Notably, these disease-related modules were enriched with brain-expressed genes and genetic risk loci for autism spectrum disorder and schizophrenia, which may imply a causal role for impaired developmental outcomes. These molecular alterations preceded changes in clinical measures at twenty-four months, including reductions in cognitive and socio-emotional outcomes in affected infants. Collectively, these findings indicate that prenatal exposure to maternal psychological distress induces neuronal, immunological and behavioral abnormalities in affected offspring and support the search for early biomarkers of exposures to adverse in utero environments and the classification of children at risk for impaired development.

Relation of Retinopathy of Prematurity to Brain Volumes at Term Equivalent Age and Developmental Outcome at 2 Years of Corrected Age in Very Preterm Infants

Background: Retinopathy of prematurity (ROP) is a major complication of preterm birth and has been associated with later visual and nonvisual impairments. Objectives: To evaluate relationships between any stage of ROP, brain volumes, and developmental outcomes. Methods: This study included 52 very preterm infants (gestational age [mean ± SD]: 26.4 ± 1.9 weeks). Total brain, gray matter, unmyelinated white matter (UWMV), and cerebellar volumes were estimated in 51 out of 52 infants by magnetic resonance imaging at term-equivalent age. Bayley Scales of Infant Development were used to assess developmental outcomes in 49 out of 52 infants at a mean corrected age of 24.6 months. Results: Nineteen out of 52 infants developed any stage of ROP. Infants with ROP had a lower median (IQR) UWMV (173 [156–181] vs. 204 [186–216] mL, p < 0.001) and cerebellar volume (18.3 [16.5–20] vs. 22.3 [20.3–24.7] mL, p < 0.001) than infants without ROP. They also had a lower median (IQR) mental developmental index (72 [56–83] vs. 100 [88–104], p < 0.001) and a lower psychomotor developmental index (80 [60–85] vs. 92 [81–103], p = 0.002). Brain volumes and developmental outcomes did not differ among infants with different stages of ROP. Conclusion: Any stage of ROP in preterm infants was associated with a reduced brain volume and an impaired developmental outcome. These results suggest that common pathways may lead to impaired neural and neurovascular development in the brain and retina and that all stages of ROP may be considered in future studies on ROP and development.

P.4.a.006 - The role of genes encoding the transcription factors c-Fos, c-Jun and Ier5 in posttraumatic stress disorder

Prenatal exposure to maternal stress and depression has been identified as a risk factor for adverse behavioral and neurodevelopmental outcomes in early childhood. However, the molecular mechanisms through which maternal psychopathology shapes offspring development remain poorly understood. We applied transcriptome-wide screens to 149 umbilical cord blood samples from neonates born to mothers with posttraumatic stress disorder (PTSD; n = 20), depression (n = 31) and PTSD with comorbid depression (n = 13), compared to carefully matched trauma exposed controls (n = 23) and healthy mothers (n = 62). Analyses by maternal diagnoses revealed a clear pattern of gene expression signatures distinguishing neonates born to mothers with a history of psychopathology from those without. Co-expression network analysis identified distinct gene expression perturbations across maternal diagnoses, including two depression-related modules implicated in axon-guidance and mRNA stability, as well as two PTSD-related modules implicated in TNF signaling and cellular response to stress. Notably, these disease-related modules were enriched with brain-expressed genes and genetic risk loci for autism spectrum disorder and schizophrenia, which may imply a causal role for impaired developmental outcomes. These molecular alterations preceded changes in clinical measures at twenty-four months, including reductions in cognitive and socio-emotional outcomes in affected infants. Collectively, these findings indicate that prenatal exposure to maternal psychological distress induces neuronal, immunological and behavioral abnormalities in affected offspring and support the search for early biomarkers of exposures to adverse in utero environments and the classification of children at risk for impaired development.

New challenges beyond nutrition: c-section, air pollution and domestic violence.

The DOHaD research field has successfully associated adult non-communicable diseases with inadequate nutrition in early periods of life. More recently, different types of exposure have been linked with impaired developmental outcomes and later health consequences, such as cesarean section at delivery, air pollution and domestic violence during pregnancy. The aim of this work is to bring up this issue looking at the published evidence on these three highly prevalent hazards in Latin American countries.

Docosahexaenoic acid (DHA): From the maternal–foetal dyad to the complementary feeding period

The docosahexaenoic acid (DHA, C22:6n-3) status of infants at birth and maternal DHA intake during pregnancy are interconnected and associated with infants’ developmental performance. High-dosage supplementation of long-chain polyunsaturated fatty acids (LCPUFAs; particularly DHA) in mothers, started at mid-pregnancy, has been associated with long-term positive effects on intelligence quotient scores of neurodevelopment. Poor maternal and infant DHA status could partly contribute to the observed association between certain conditions and impaired developmental outcome. The dietary DHA enrichment of human milk seems to be functionally effective in breastfed infants only when lactating mothers start supplementation during pregnancy. Results from trials in artificially fed infants are dissimilar and could be related in part to uninvestigated covariates such as infant DHA status at birth and the individual genetic background. Nevertheless, DHA supplementation during the complementary feeding period seems to be effective in improving neurofunctional and visual performance.

Inflammation at Birth is Associated With Subnormal Development in Very Preterm Infants

Preterm birth carries a risk for impaired developmental outcome. We have previously described an association between increased levels of proinflammatory cytokines during the first 72 postnatal hours and cerebral damage as detected by ultrasound in a cohort of 74 very preterm infants. Sixty-seven of 71 surviving children with a mean gestational age of 27.1 (2.0) wk were examined at 2 y corrected age with a standardized neurologic examination and with Bayley Scales of Infant Development. We hypothesized that proinflammatory cytokine concentrations at or shortly after birth would be associated with an adverse developmental outcome. Increased concentrations of TNF-alpha in cord blood odds ratio (95% confidence interval) 3.3 (1.1-10.2), p = 0.013 and at 6 h 7.8 (0.9-71.8), p = 0.015 and of IL-6 in cord blood 1.7 (1.0-2.9), p = 0.048 were associated with psychomotor developmental index <85. Increased concentrations of TNF-alpha in cord blood odds ratio (95% confidence interval) 3.6 (1.002-12.8), p = 0.044 and of IL-8 in cord blood 3.5 (1.2-10.6), p = 0.023 were associated with cerebral palsy. Associations of TNF-alpha and IL-8 in cord blood with the respective outcome measures remained significant after adjustment for other clinical variables. Proinflammation at birth is associated with impaired functional outcome at 2 y of corrected age in children with very preterm birth.

Postnatal Administration of Dexamethasone for Weaning off the Ventilator Affects Thyroid Function

Background: Very preterm neonates are at risk of hypothyroxinemia because of prematurity as well as because of neonatal disease. Hypothyroxinemia is associated with impaired developmental outcome. Preterm infants who cannot be weaned from the ventilator can be treated with dexamethasone. Glucocorticoid administration has been found to alter thyroid hormone parameters. Therefore, dexamethasone treatment in these infants might additionally impair their thyroid function, which could have consequences for developmental outcome. Objective: To assess what changes in thyroid function occur in the first hours after initiating dexamethasone treatment in ventilated preterm infants. Methods: Preterm infants, in whom the decision was taken to start dexamethasone treatment, were included. Thyroxine (T₄), 3,5,3′-triiodothyronine (T₃), reverse T₃ (rT₃), thyroid-stimulating hormone (TSH) and cortisol were determined before and 6–9 h after administration of the first dose of a postnatal dexamethasone course. Details of clinical condition were recorded at both time points. Results: Sixteen very preterm infants were included at a median age of 20 days. While clinical condition was stable between start of dexamethasone and 6–9 h thereafter, TSH and T₃ levels decreased significantly. rT₃ levels significantly increased, resulting in a decrease in the T₃/rT₃ ratio. There was no statistically significant effect on the levels of T₄. Conclusion: Postnatal dexamethasone administration negatively affects thyroid functionin the preterm infant with severe chronic lung disease.

202 Postnatal Administration of Dexamethasone for Weaning off the Ventilator has Short Term Consequences for Thyroid Function

Background: Corticosteroids can alter thyroid hormone metabolism. Preterm born neonates are at risk of low T4 and T3 serum levels, these low levels are associated with impaired developmental outcome. Preterm infants who cannot be weaned from the ventilator are treated with dexamethasone, but adverse effects on developmental outcome are known. Because the harmful effects of both postnatal dexamethasone and low T4 on brain development it is important to know whether dexamethasone in these infants alters thyroid function.

Depression and the Parenting of Young Children: Making the Case for Early Preventive Mental Health Services

Numerous developmental and clinical studies over the past 25 years have documented that parental depression is related to a wide range of impaired developmental outcomes in children. Conversely, the burden of caring for young children may be a risk factor for adult depression. We briefly summarize the negative developmental correlates of parental depression, beginning in the first year of life. We relate these findings to the results of a recent national survey of depressive symptoms and parenting behaviors among parents of children under 3 years old in the United States. We then look at epidemiological data on correlates of adult depression that point to stress associated with the care of children as a potential contributor to rates of depression among women. Finally, we discuss the implications of these data for the organization of mental health services for young families.

THYROXINE SUPPLEMENTATION IN INFANTS &lt;30 WEEKS GESTATIONAL AGE: NEURODEVELOPMENTAL OUTCOME AT 2 YEARS OF AGE. • 1679

Background: Transient hypothyroxinemia is a common phenomenon in preterm infants. An association has been found between low neonatal T4 levels and an increased risk of impaired developmental outcome. Until now however, it is unclear whether T4 administration is required in preterm infants.Methods: We carried out a randomized, placebo-controlled, double-blind trial. 200 infants <30 weeks gestational age were enrolled. Administration of T4/placebo was started 12-24 hours after birth at a daily dose of 8 μg per kg birthweight per day and discontinued 6 weeks later. Neurological examinations were carried out at term, and at the corrected ages of 6, 12, and 24 months of age. Bayley developmental scales were performed at the latter 3 time points. Results: After the NICU-period 85 infants remained in the T4 group and 76 in the Placebo group. The 2 study groups did not differ with respect to birthweight, gestational age, sex, social and racial background, neonatal disease and cerebral hemorrhage and ischaemia. Mental nor psychomotor development differed between the 2 groups. At term age and at 24 months a significant reduction of abnormal neurological outcome was found in the T4 group (p=0.019 and 0.014 resp.). Also, a reduction of adverse outcome (death or an abnormal mental and neuromotor outcome) was found in the T4 group (RR 0.62, 95%-CI: 0.35-0.99). Conclusions: T4 administration to very preterm infants does not alter developmental outcome, but is associated with an improvement of neurological and adverse outcome at 24 months of age.

Effect of cocaine in early gestation on striatal dopamine and neurotrophic activity.

Prenatal exposure to the dopamine (DA) agonist cocaine, even if limited to early gestation, is associated with impaired developmental outcome in the human infant. We investigated the possible role of neurotrophic factors in this process by evaluating 4- to 6-d-old New Zealand White rabbit pups (n = 14) born to cocaine-exposed does (30 mg/kg/d s.c. from days 7 to 15 of a 32-d gestation) and control does (sterile H2O). Cocaine exposure reduced striatal dopamine by 46% (t = 2.31; p < 0.05) and striatal 3,4-dihydroxyphenyl acetic acid by 49% (t = 2.44; p < 0.05). The number of neuron-specific enolase immunoreactive neurons in mesencephalic cultures incubated with striatal extracts from pups exposed to cocaine was reduced by 61% relative to the effect of striatal extracts from control pups (t = 4.84; p < 0.01). The present results suggest that the reduction in striatal dopamine observed may result from a cocaine-induced decrease in striatal trophic activity.