Febrile seizure incidence and age at first occurrence are associated with changes in placental normalized gene expression: the ‘3D’ pregnancy cohort study

Abstract

Self‐reported maternal prenatal stress (MPS) has been associated with earlier febrile seizure (FS) age of onset in offspring. Studies are needed to understand how the biological systems associated with exposure to psychological MPS are linked to seizure disorders in children. The present study aimed to investigate whether placental markers of MPS are linked to FS incidence and age at first occurrence. A subsample of children with FS (n = 28) and matched controls (n = 84), were drawn from the longitudinal 3D pregnancy cohort (N = 2366 mother–child dyads). Expression of placental genes associated with glucocorticoids, serotonin and fetal/placental growth were analysed from placental tissues, compared between groups and associated with age at first FS. Overall placental normalized gene expression was statistically different (p < .001). Children with FS showed overexpression of the serotonin transporter (mean difference = 0.61, 95% confidence interval [CI] = 0.9–1.13), connexin 43 (mean difference = 0.69, 95% CI = 0.30–1.09), zonula occludens‐1 (mean difference = 0.84, 95% CI = 0.42–1.26) and underexpression of glucocorticoid receptor β (mean difference = 0.84, 95% CI = −1.49 to 0.19) and serotonin receptor 2B (mean difference = 1.57, 95% CI = −2.35 to 0.78) compared to controls. Increased expression of the serotonin transporter predicted 37.2% in variation of age at first FS. The correlation matrix showed pregnancy‐specific anxiety during the second trimester was moderately associated with age at first FS (r = −0.38) but was not a significant predictor in the regression model. Although our current results do not display a significant effect of self‐reported MPS on FS, the present study is the first to show that placental gene biomarkers usually known to be associated with MPS display different expressions in children with FS. Specifically, our results suggest that placental genes associated with the glucocorticoid, serotonergic and fetal/placental growth systems may be candidate mechanisms leading to increased vulnerability offspring in FS. Because self‐reported MPS was not found as a significant predictor in our statistical models, future studies are needed to investigate the mechanisms causing the observed changes in placental genes and their association with seizure disorders.

Associations between Prepartum and Postpartum Maternal Symptoms of Depression, Anxiety and Stress Related to COVID-19 Pandemic and Childhood Sensory Avoidance: Results from Conception Study

“…An imbalance in the levels of the excitatory neurotransmitter glutamate or the inhibitory neurotransmitter GABA is likely to lead to hyperexcitability in the neocortex neural circuits involved in sensory perception [ 17 , 20 , 52 ]. Prepartum maternal stress has also been associated with alterations in the serotonergic and norepinephrine systems, with neurotransmitters playing a crucial role in brain development [ 53 , 54 , 55 , 56 , 57 ]. Several brain-development processes (cell migration, neuronal division and synaptogenesis) are influenced by serotonin, which acts as a trophic factor [ 58 ].…”

“…For instance, SSRI use during pregnancy was associated with improved infant performance on a language discrimination task, suggesting accelerated perceptual development in the auditory cortex [ 15 ]. Consequently, exposure to maternal prepartum stress could affect the development of certain brain areas involved in cerebral excitability and sensory processing, lowering the neurological threshold [ 17 , 20 , 21 , 26 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ].…”

Serotonin system in the human placenta – the knowns and unknowns

“…Ten serotonin receptor subtypes (HTR1A, HTR1D, HTR1E, HTR1F, HTR2A, HTR2B, HTR3 (subunit HTR3A), HTR4, HTR5A and HTR5B) have been reported to be expressed in the human term placenta ( 68 , 79 – 81 , 86 , 87 , 91 ). HTR2A has been localized in syncytiotrophoblast, cytotrophoblasts and fetal capillary endothelium of human term placentas ( 80 ).…”

“…HTR2A has been localized in syncytiotrophoblast, cytotrophoblasts and fetal capillary endothelium of human term placentas ( 80 ). HTR2B, the most abundant subtype according to single cell transcriptomic analyses, is also expressed in both syncytiotrophoblast and cytotrophoblasts ( 81 , 87 ). In contrast, HTR1D and HTR1F mRNAs were detected only in syncytiotrophoblast, whereas HTR3A and HTR4 mRNAs were found at low levels only in cytotrophoblasts ( 87 ) of human term placentas.…”

“…As for the human placenta, methylation of the placental HTR2A gene has been linked to key behavioral measures of neurodevelopment (quality of movement and attention) in human newborns ( 141 ), and placental expression of the SERT gene has been linked to regulatory behaviors in infants at two weeks of age ( 142 ). Furthermore, placental expression of the SERT and HTR2B genes has been associated with the incidence of febrile seizure in children ( 81 ), while placental expression of the MAOA gene has been identified as a biological mediator of the association between prenatal stress and child temperament at 12 months of age ( 143 ). Further longitudinal studies in human cohorts are needed to better understand the consequences of altered placental serotonin homeostasis in the developmental origins of health and disease.…”