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Prenatal and early postnatal exposure to maternal depression may \"program\" childhood behavior via epigenetic processes such as DNA methylation. Methylenetetrahydro-folate reductase (MTHFR) is an important enzyme in the generation of methyl groups for DNA methylation. The common MTHFR C677T variant is associated with depression in men and non-pregnant women, and with global changes in DNA methylation. This study investigated the effect of maternal MTHFR C677T genotype on antenatal maternal mood, and their impact on the gene-specific methylation in pregnant women and their newborn infants. The methylation status of SLC6A4, which encodes the transmembrane serotonin transporter, and BDNF, which encodes brain derived neurotrophic factor, were assessed because of their potential role in behaviour. Depressed mood was assessed by the Edinburgh Postnatal Depression Scale (EPDS) and the Hamilton Rating Scale for Depression (HAM-D) in women (n = 82, all taking folate) during the 2(nd) and 3(rd) trimesters of pregnancy. The methylation status of SLC6A4 and BDNF were assessed in 3rd trimester maternal peripheral leukocytes and in umbilical cord leukocytes collected from their infants at birth. Women with the MTHFR 677TT genotype had greater 2(nd) trimester depressed mood (p<0.05). Increased 2(nd) trimester maternal depressed mood (EPDS scores) was associated with decreased maternal and infant SLC6A4 promoter methylation (p<0.05), but had no effect on BDNF promoter methylation. These findings show that the MTHFR C677T variant is associated with greater depressed mood during pregnancy. We further showed that prenatal exposure to maternal depressed mood affects gene-specific DNA methylation patterns. These findings support the concept that alterations in epigenetic processes may contribute to developmental programming of behaviour by maternal depression.

Depression is one of the most prevalent mental health disorders affecting pregnant individuals, and serotonin reuptake inhibitors (SRIs) are the most prescribed medications to treat depressive symptoms during pregnancy. Both depression and SRI exposure may have developmental impacts, and as randomizing exposures and non-treatment is not feasible in humans, distinguishing the effect of each factor often remains challenging. To date, much of what guides clinical practice stems from reports of pregnant individuals and fetal/infant outcomes, overlooking the significant role of the placenta in maintaining a healthy pregnancy and mother-fetal health. In this study, we explored the effect of depression and SRI antidepressant treatment during pregnancy on the placental proteome. A shotgun proteomics method with liquid chromatography and tandem mass spectrometry (LC-MS/MS) was performed. A cohort of pregnant individuals (n = 82) was recruited in their 2nd trimester, and clinician-rated mood symptoms measured using the Hamilton Depression Rating Scale (HAM-D) were obtained from them during pregnancy to identify three exposure groups: non-depressed; depressed/non-SRI-treated; depressed/SRI-treated. Differential protein expression and over-representation analyses on the placentas of the group with depression/non-SRI compared with placentas from healthy individuals showed an increase in antioxidant enzymes and various senescence-associated secretory phenotypes (SASP) as well as a decrease in histone proteins. Such protein expression patterns are potentially indicative of placental senescence. Our findings reveal that depression not treated with SRIs is associated with the upregulation of proteins involved in platelet activation, degranulation, coagulation cascade, and amyloid fiber formation in the placenta. In contrast, when comparing placentas from the depressed group treated with SRIs to those with depressive symptoms without SRI treatment, we observed a downregulation of proteins related to senescence, amyloid fiber formation, and platelet activation in the SRI-treated group. This study suggests that treatment with SRIs may prevent the placental alterations observed in antenatal depression, such as placental senescence, platelet activation, and amyloid fiber formation, and, ultimately, pregnancy and fetal outcomes. Further studies are needed to confirm these findings.

Language acquisition reflects a complex interplay between biology and early experience. Psychotropic medication exposure has been shown to alter neural plasticity and shift sensitive periods in perceptual development. Notably, serotonin reuptake inhibitors (SRIs) are antidepressant agents increasingly prescribed to manage antenatal mood disorders, and depressed maternal mood per se during pregnancy impacts infant behavior, also raising concerns about long-term consequences following such developmental exposure. We studied whether infants’ language development is altered by prenatal exposure to SRIs and whether such effects differ from exposure to maternal mood disturbances. Infants from non–SRI-treated mothers with little or no depression (control), depressed but non–SRI-treated (depressed-only), and depressed and treated with an SRI (SRI-exposed) were studied at 36 wk gestation (while still in utero) on a consonant and vowel discrimination task and at 6 and 10 mo of age on a nonnative speech and visual language discrimination task. Whereas the control infants responded as expected (success at 6 mo and failure at 10 mo) the SRI-exposed infants failed to discriminate the language differences at either age and the depressed-only infants succeeded at 10 mo instead of 6 mo. Fetuses at 36 wk gestation in the control condition performed as expected, with a response on vowel but not consonant discrimination, whereas the SRI-exposed fetuses showed accelerated perceptual development by discriminating both vowels and consonants. Thus, prenatal depressed maternal mood and SRI exposure were found to shift developmental milestones bidirectionally on infant speech perception tasks.

To describe trends, patterns, and determinants of prescription drug use during pregnancy and postpartum. This is a retrospective, population-based study of all women who gave birth between January 2002 and 31 December 2011 in British Columbia, Canada. Study population consisted of 225,973 women who had 322,219 pregnancies. We examined administrative datasets containing person-specific information on filled prescriptions, hospitalizations, and medical services. Main outcome measures were filled prescriptions during pregnancy and postpartum. We used logistic regressions to examine associations between prescription drug use and maternal characteristics. Approximately two thirds of women filled a prescription during pregnancy, increasing from 60% in 2002 to 66% in 2011. The proportion of pregnant women using medicines in all three trimesters of pregnancy increased from 20% in 2002 to 27% in 2011. Use of four or more different types of prescription drug during at least one trimester increased from 8.4% in 2002 to 11.7% in 2011. Higher BMI, smoking during pregnancy, age under 25, carrying multiples, and being diagnosed with a chronic condition all significantly increased the odds of prescription drug use during pregnancy. The observed increase in the number of prescriptions and number of different drugs being dispensed suggests a trend in prescribing practices with potentially important implications for mothers, their neonates, and caregivers. Monitoring of prescribing practices and further research into the safety of most commonly prescribed medications is crucial in better understanding risks and benefits to the fetus and the mother.

Background Depression and anxiety are highly prevalent within the perinatal period and have been associated with myriad adverse pregnancy and birth outcomes. In this study, we sought to investigate whether population-based data can be used to build complex, longitudinal mental health histories that improve our ability to predict adverse pregnancy and birth outcomes. Methods Using population-based, administrative datasets, we examined individual-level mental health services use of all birth parents who delivered a live infant in British Columbia, Canada between April 1, 2000, and December 31, 2013, and who were registered with the provincial Medical Services Plan for over 100 days per year from 10-years preconception to 1-year postpartum. We operationalized variables to proxy severity, persistence, and frequency of depression/anxiety from preconception through pregnancy, then constructed predictive regression models for postpartum depression/anxiety and preterm birth. Results Predictive modeling of postpartum depression/anxiety and preterm birth revealed better predictions and stronger performance with inclusion of a more detailed preconception mental health history. Incorporating dichotomous indicators for depression/anxiety across preconception markedly improved predictive power and model fit. Our detailed measures of mental health service use predicted postpartum depression/anxiety much better than preterm birth. Variables characterizing use of outpatient psychiatry care and outpatient visit frequency within the first five years preconception were most useful in predicting postpartum depression/anxiety and preterm birth, respectively. Conclusion We report a feasible method for developing and applying more nuanced definitions of depression/anxiety within population-based data. By accounting for differing profiles of mental health treatment, mental health history, and current mental health, we can better control for severity of underlying conditions and thus better understand more complex associations between antenatal mental health and adverse outcomes.

Selective serotonin reuptake inhibitors (SSRIs) for treatment of prenatal maternal depression have been associated with neonatal neurobehavioral disturbances, though the molecular mechanisms remain poorly understood.  In utero exposure to SSRIs may affect DNA methylation (DNAme) in the human placenta, an epigenetic mark that is established during development and is associated with gene expression. Chorionic villus samples from 64 human placentas were profiled with the Illumina MethylationEPIC BeadChip; clinical assessments of maternal mood and SSRI treatment records were collected at multiple time points during pregnancy. Case distribution was 20 SSRI-exposed cases and 44 SSRI non-exposed cases. Maternal depression was defined using a mean maternal Hamilton Depression score > 8 to indicate symptomatic depressed mood (“maternally-depressed”), and we further classified cases into SSRI-exposed, maternally-depressed (n = 14); SSRI-exposed, not maternally-depressed (n = 6); SSRI non-exposed, maternally-depressed (n = 20); and SSRI non-exposed, not maternally-depressed (n = 24). For replication, Illumina 450K DNAme profiles were obtained from 34 additional cases from an independent cohort (n = 17 SSRI-exposed, n = 17 SSRI non-exposed). No CpGs were differentially methylated at FDR < 0.05 comparing SSRI-exposed to non-exposed placentas, in a model adjusted for mean maternal Hamilton Depression score, or in a model restricted to maternally-depressed cases with and without SSRI exposure. However, at a relaxed threshold of FDR < 0.25, five CpGs were differentially methylated (|Δβ| > 0.03) by SSRI exposure status. Four were covered by the replication cohort measured by the 450K array, but none replicated. No CpGs were differentially methylated (FDR < 0.25) comparing maternally depressed to not depressed cases. In sex-stratified analyses for SSRI-exposed versus non-exposed cases (females n = 31; males n = 33), three additional CpGs in females, but none in males, were differentially methylated at the relaxed FDR < 0.25 cut-off. We did not observe large-scale alterations of DNAme in placentas exposed to maternal SSRI treatment, as compared to placentas with no SSRI exposure. We also found no evidence for altered DNAme in maternal depression-exposed versus depression non-exposed placentas. This novel work in a prospectively-recruited cohort with clinician-ascertained SSRI exposure and mood assessments would benefit from future replication.

Cannabis products have been used in the management of headaches in adults and may play a role in pediatric chronic pain. Canadian pediatricians report increasing use of cannabis for the management of chronic headaches, despite no well-controlled studies to inform its dosing, safety, and effectiveness. The aim of our clinical trial is to determine the dosing and safety of a Cannabidiol (CBD)-enriched Cannabis Herbal Extract (CHE) for the treatment of chronic headaches in adolescents. Youth, parents, and an expert steering committee co-designed this tolerability study. Twenty adolescents (aged 14 to 17 years), with a chronic migraine diagnosis for more than 6 months that has not responded to other therapies will be enrolled into an open label, dose escalation study across three Canadian sites. Study participants will receive escalating doses of a CBD-enriched CHE (MPL-001 with a THC:CBD of 1:25), starting at 0.2-0.4 mg/kg of CBD per day and escalating monthly up to 0.8-1.0 mg/kg of CBD per day. The primary objective of this study is to determine the safety and tolerability of CBD-enriched CHE in adolescents with chronic migraine. Secondary objectives of this study will inform the development of subsequent randomized controlled trials and include investigating the relationship between the dose escalation and change in the frequency of headache, impact and intensity of pain, changes in sleep, mood, function, and quality of life. Exploratory outcomes include investigating steady-state trough plasma levels of bioactive cannabinoids and investigating how pharmacogenetic profiles affect cannabinoid metabolism among adolescents receiving CBD-enriched CHE. This protocol was co-designed with youth and describes a tolerability clinical trial of CBD-enriched CHE in adolescents with chronic headaches that have not responded to conventional therapies. This study is the first clinical trial on cannabis products in adolescents with chronic headaches and will inform the development of future comparative effectiveness clinical trials. CAN-CHA trial is registered with ClinicalTrials.gov with a number of register NCT05337033.

Background Antenatal depression and anxiety are highly prevalent conditions that have been associated with increased risk for myriad adverse outcomes. Current literature exploring the connection between antenatal mental health and gestational diabetes mellitus (GDM) is limited, presenting conflicting evidence. We sought to evaluate the association between antenatal depression/anxiety (DEP-ANX) and GDM using population-based, administrative data, accounting for aspects of preconception mental health. Methods In this population-based retrospective cohort study, we included all singleton births in British Columbia, Canada from April 1, 2000, to December 31, 2014. We identified instances of DEP-ANX from outpatient and inpatient records that included relevant diagnostic codes and stratified our cohort by preconception DEP-ANX persistence. Logistic regression models were run to estimate odds of GDM given antenatal DEP-ANX. Models were adjusted for the birthing person’s socio-demographics and pregnancy characteristics. Using an expanded cohort, we ran conditional logistic regression models that matched birthing people to themselves (in a subsequent pregnancy) based on discordance of exposure and outcome. Results Out of the 228,144 births included in this study, 43,664 (19.1%) were to birthing people with antenatal health service use for DEP-ANX. There were 4,180 (9.6%) cases of GDM among those antenatal exposure to DEP-ANX compared to 15,102 (8.2%) among those without exposure (SMD 0.049). We observed an unadjusted odds ratio (OR) of 1.19 (95% CI: 1.15 – 1.23) and fully adjusted OR of 1.15 (95% CI: 1.11 – 1.19) overall. Apparent risk for GDM given antenatal DEP-ANX was highest among the no DEP-ANX history stratum, with a fully adjusted OR of 1.24 (95% CI: 1.15 – 1.34). Associations estimated by matched sibling analysis were non-significant (fully adjusted OR 1.19 [95% CI: 0.86 – 1.63]). Conclusions Results from this population-based study suggest an association between antenatal DEP-ANX and GDM that varied based on mental health history. Our analysis could suggest that incident cases of DEP-ANX within pregnancy are more closely associated with GDM compared to recurring or chronic cases.

Developmental coordination disorder (DCD) is a motor impairment that significantly interferes with activities of daily living. Little is known about the cause of DCD and how it develops, making it difficult to understand why children with DCD struggle in learning motor skills and to determine the best intervention to optimize function. To characterize white matter differences using diffusion tensor imaging in children with and without DCD. This cross-sectional study collected diffusion tensor imaging data at BC Children's Hospital Research Institute in Vancouver, British Columbia, Canada, from September 2014 to January 2017. Using a sample of convenience, children with DCD and children without DCD aged 8 to 12 years underwent magnetic resonance imaging. Data analysis was conducted from January 2017 to January 2020. The main outcome measures were diffusion parameters, including fractional anisotropy and mean, axial, and radial diffusivity, which are thought to provide an indirect measure of white matter microstructure. Tract-based spatial statistics, a voxelwise statistical analysis of diffusion parameters, were conducted using a 2-group comparison design matrix with age and attention as covariates. Thirty children without DCD (mean [SD] age, 9.9 [1.4] years; 21 [70%] boys) and 31 children with DCD (mean [SD] age, 10.1 [1.2] years; 26 [84%] boys) were included in the study. Compared with children without DCD, children with DCD were characterized by significantly lower fractional anisotropy and axial diffusivity in regions of white matter pathways associated with motor and sensorimotor processing, including the corticospinal tract (fractional anisotropy: mean [SD], 0.54 [0.03] vs 0.51 [0.03]; P < .001; axial diffusivity: mean [SD], 0.13 [0.98] vs 0.12 [0.46]; P = .01), posterior thalamic radiation at the retrolenticular part of the internal capsule (axial diffusivity: mean [SD], 0.14 [0.57] vs 0.14 [0.44]; P = .01), and cerebellar pathways (eg, superior cerebellar peduncle, fractional anisotropy: mean [SD], 0.49 [0.05] vs 0.46 [0.03]; P = .03; axial diffusivity: mean [SD], 0.14 [0.66] vs 0.14 [0.63]; P = .009). There were no significant differences in mean diffusivity and radial diffusivity between children with and without DCD. These findings suggest that children with DCD show significant brain differences in motor and sensorimotor white matter pathways compared with children without DCD. The pattern of diffusion parameters in children with DCD suggests that axonal development may be disrupted in this neurodevelopmental disorder.

The hypothalamic-pituitary-adrenal (HPA) axis is impacted by a multitude of pre- and postnatal factors. Developmental programming of HPA axis function by prenatal alcohol exposure (PAE) has been demonstrated in animal models and in human infants, but remains understudied in older children and adolescents. Moreover, early life adversity (ELA), which occurs at higher rates in children with PAE than in non-exposed children, may also play a role in programming the stress response system. In a cohort of children and adolescents with PAE and ELA (PAE + ELA), we evaluated HPA function through assessment of diurnal cortisol activity compared to that in typically developing controls, as well as the associations among specific ELAs, adverse outcomes, protective factors, and diurnal cortisol. Morning and evening saliva samples were taken under basal conditions from 42 children and adolescents (5–18 years) with PAE + ELA and 43 typically developing controls. High rates of ELA were shown among children with PAE, and significantly higher evening cortisol levels and a flatter diurnal slope were observed in children with PAE + ELA, compared to controls. Medication use in the PAE + ELA group was associated with lower morning cortisol levels, which were comparable to controls. Complex associations were found among diurnal cortisol patterns in the PAE + ELA group and a number of ELAs and later adverse outcomes, whereas protective factors were associated with more typical diurnal rhythms. These results complement findings from research on human infants and animal models showing dysregulated HPA function following PAE, lending weight to the suggestion that PAE and ELA may interact to sensitize the developing HPA axis. The presence of protective factors may buffer altered cortisol regulation, underscoring the importance of early assessment and interventions for children with FASD, and in particular, for the many children with FASD who also have ELA. •We observed higher PM cortisol levels and flatter diurnal slope in children with PAE + ELA.•Differences in PM cortisol are particularly evident in lower SES children with PAE + ELA.•Early life adversity is associated with cortisol dysregulation in children with PAE + ELA.•Protective factors are linked with more typical cortisol patterns in children with PAE + ELA.