Examining the interaction between prenatal stress and polygenic risk for attention-deficit/hyperactivity disorder on brain growth in childhood: Findings from the DREAM BIG consortium.

This study explored the interactions among prenatal stress, child sex, and polygenic risk scores (PGS) for attention-deficit/hyperactivity disorder (ADHD) on structural developmental changes of brain regions implicated in ADHD. We used data from two population-based birth cohorts: Growing Up in Singapore Towards healthy Outcomes (GUSTO) from Singapore (n = 113) and Generation R from Rotterdam, the Netherlands (n = 433). Prenatal stress was assessed using questionnaires. We obtained latent constructs of prenatal adversity and prenatal mood problems using confirmatory factor analyses. The participants were genotyped using genome-wide single nucleotide polymorphism arrays, and ADHD PGSs were computed. Magnetic resonance imaging scans were acquired at 4.5 and 6 years (GUSTO), and at 10 and 14 years (Generation R). We estimated the age-related rate of change for brain outcomes related to ADHD and performed (1) prenatal stress by sex interaction models, (2) prenatal stress by ADHD PGS interaction models, and (3) 3-way interaction models, including prenatal stress, sex, and ADHD PGS. We observed an interaction between prenatal stress and ADHD PGS on mean cortical thickness annual rate of change in Generation R (i.e., in individuals with higher ADHD PGS, higher prenatal stress was associated with a lower rate of cortical thinning, whereas in individuals with lower ADHD PGS, higher prenatal stress was associated with a higher rate of cortical thinning). None of the other tested interactions were statistically significant. Higher prenatal stress may promote a slower brain developmental rate during adolescence in individuals with higher ADHD genetic vulnerability, whereas it may promote a faster brain developmental rate in individuals with lower ADHD genetic vulnerability.

A developmental framework for understanding the influence of sex and gender on health: Pediatric pain as an exemplar.

Sex differences are a robust finding in many areas of adult health, including cardiovascular disease, psychiatric disorders, and chronic pain. However, many sex differences are not consistently observed until after the onset of puberty. This has led to the hypothesis that hormones are primary contributors to sex differences in health outcomes, largely ignoring the relative contributions of early developmental influences, emerging psychosocial factors, gender, and the interaction between these variables. In this paper, we argue that a comprehensive understanding of sex and gender contributions to health outcomes should start as early as conception and take an iterative biopsychosocial-developmental perspective that considers intersecting social positions. We present a conceptual framework, informed by a review of the literature in basic, clinical, and social science that captures how critical developmental stages for both sex and gender can affect children's health and longer-term outcomes. The literature on pediatric chronic pain is used as a worked example of how the framework can be applied to understanding different chronic conditions.

Association of pre-existing maternal cardiovascular diseases with neurodevelopmental disorders in offspring: a cohort study in Sweden and British Columbia, Canada.

BACKGROUND: We aimed to investigate the associations of pre-existing maternal cardiovascular disease (CVD) with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and intellectual disability (ID) in offspring. METHODS: This population-based cohort study included singletons live-born without major malformations in Sweden (n = 2 699 675) and British Columbia (BC), Canada (n = 887 582) during 1990-2019, with follow-up from age 1 year until the outcome, death, emigration or December 2020, whichever came first. The primary exposure was defined as a composite CVD diagnosed prior to conception: cerebrovascular disease, arrhythmia, heart failure, valvular and congenital heart diseases. The incidences of ADHD, ASD and ID, comparing offspring of mothers with versus without CVD, were calculated as adjusted hazard ratios (aHRs). These results were compared with models using paternal CVD as negative control exposure. RESULTS: Compared with offspring of mothers without CVD, offspring of mothers with CVD had 1.15-fold higher aHRs of ADHD [95% confidence interval (CI): 1.10-1.20] and ASD (95% CI 1.07-1.22). No association was found between maternal CVD and ID. Stratification by maternal CVD subtypes showed increased hazards of ADHD for maternal heart failure (HR 1.31, 95% CI 1.02-1.61), cerebrovascular disease (HR 1.20, 95% CI 1.08-1.32), congenital heart disease (HR 1.18, 95% CI 1.08-1.27), arrhythmia (HR 1.13, 95% CI 1.08-1.19) and valvular heart disease (HR 1.12, 95% CI 1.00-1.24). Increased hazards of ASD were observed for maternal cerebrovascular disease (HR 1.25, 95% CI 1.04-1.46), congenital heart disease (HR 1.17, 95% CI 1.01-1.33) and arrythmia (HR 1.12, 95% CI 1.01-1.21). Paternal CVD did not show associations with ADHD, ASD or ID, except for cerebrovascular disease which showed associations with ADHD and ASD. CONCLUSIONS: In this large cohort study, pre-existing maternal CVD was associated with increased risk of ADHD and ASD in offspring.

Can we more precisely classify exposure to antenatal depression and anxiety in multivariable prediction models of pregnancy and birth outcomes: a population-based cohort study.

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.

Prenatal serotonin reuptake inhibitor antidepressant exposure, SLC6A4 genetic variations, and cortisol activity in 6-year-old children of depressed mothers: A cohort study.

Prenatal exposure to maternal depression and serotonin reuptake inhibitor (SRI) antidepressants both affect the development of the hypothalamic-pituitary-adrenal (HPA) system, possibly via the neurotransmitter serotonin (5HT). In a community cohort, we investigated the impact of two factors that shape prenatal 5HT signaling (prenatal SRI [pSRI] exposure and child SLC6A4 genotype) on HPA activity at age 6 years. Generalized estimating equation (GEE) models were used to study associations between cortisol reactivity, pSRI exposure, and child SLC6A4 genotype, controlling for maternal depression, child age, and sex (48 pSRI exposed, 74 nonexposed). Salivary cortisol levels were obtained at five time points during a laboratory stress challenge: arrival at the laboratory, following two sequential developmental assessments, and then 20 and 40 min following the onset of a stress-inducing cognitive/social task. Cortisol decreased from arrival across both developmental assessments, and then increased across both time points following the stress challenge in both groups. pSRI-exposed children had lower cortisol levels across all time points. In a separate GEE model, we observed a lower cortisol stress response among children with LG /S alleles compared with children with La/La alleles, and this was particularly evident among children of mothers reporting greater third trimester depressed mood. Our findings suggest that pSRI exposure and a genetic factor associated with modulating 5HT signaling shaped HPA reactivity to a laboratory stress challenge at school age.

The Role of Parenting Stress as a Mediator in the Relationship Between Postpartum Depressive Symptoms and Early Childhood Internalizing Behaviour.

Parenting stress occurs when demands of the parenting role are perceived as overwhelming and has been proposed as a mechanism through which postpartum mood disturbances may impact child psychopathology. In a prospective longitudinal birth cohort of 111 birthing parent-child dyads, this study examined whether the relationship between birthing parents' mood symptoms in infancy (3 months postpartum) and their child's internalizing behaviour in early childhood (3 and 6 years old) is mediated by parenting stress at 6 months postpartum. The relationship between higher postpartum mood symptoms at 3 months and increased internalizing behaviour at 3 years of age was mediated by increased reports of parenting stress at 6 months (b = .12, 95% CI = .02, .25). This association was not evident at 6 years. Parenting stress in early infancy may provide a treatment target to reduce the impact of perinatal depression on early child behavior.

"Making Data the Drug": A Pragmatic Pilot Feasibility Randomized Crossover Trial of Data Visualization as an Intervention for Pediatric Chronic Pain.

Data tracking is a common feature of pain e-health applications, however, viewing visualizations of this data has not been investigated for its potential as an intervention itself. We conducted a pilot feasibility parallel randomized cross-over trial, 1:1 allocation ratio. Participants were youth age 12-18 years recruited from a tertiary-level pediatric chronic pain clinic in Western Canada. Participants completed two weeks of Ecological Momentary Assessment (EMA) data collection, one of which also included access to a data visualization platform to view their results. Order of weeks was randomized, participants were not masked to group assignment. Objectives were to establish feasibility related to recruitment, retention, and participant experience. Of 146 youth approached, 48 were eligible and consented to participation, two actively withdrew prior to the EMA. Most participants reported satisfaction with the process and provided feedback on additional variables of interest. Technical issues with the data collection platform impacted participant experience and data analysis, and only 48% viewed the visualizations. Four youth reported adverse events not related to visualizations. Data visualization offers a promising clinical tool, and patient experience feedback is critical to modifying the platform and addressing technical issues to prepare for deployment in a larger trial.

Conditioning induced placebo-like and nocebo-like effects of thermal discomfort in adults but not in youth.

Introduction: Conditioning can be used to modulate the perception of pain, in the form of placebo and nocebo effects. Previous studies show inconsistent results as to whether adolescents show similar, weaker, or non-significant conditioned placebo and nocebo effects compared to effects found in adults. There are suggestions that such differences (if any) may dependent on the cues used in the thermal conditioning paradigms. Therefore, in this current study, we utilized novel, neutral 3D-shaped visual cues to implicitly induce conditioned placebo-like and nocebo-like effects in adolescents and adults. Methods: During the conditioning paradigm, distinct cues (Fribbles) were paired with low and high temperatures in 24 adults and 20 adolescents (mean age = 25.5 years). In the testing phase, these conditioned cues as well as a neutral (unconditioned) cue were presented with moderate temperatures. Results: Thermal discomfort of moderate temperatures was lower when presented with the conditioned low heat cue (placebo-like effect) and higher when thermal stimuli were presented with the high heat cue (nocebo-like effect) compared to the neutral cue. The effects were driven by adults, as neither the placebo-like nor the nocebo-like effect was significant in adolescents. The difference between adolescents and adults was not explained by differences in temperature or discomfort levels, as adults and adolescents had comparable calibrated temperatures and levels of discomfort during heat stimuli. Conclusion: Our findings suggest that thermal perception in adolescents is less influenced by conditioning to an engaging novel visual cue, compared to adults. Our work may have implications for better understanding the scope and limitations of conditioning as a key mechanism of placebo and nocebo effects in youth.

The application of epiphenotyping approaches to DNA methylation array studies of the human placenta.

Background : Genome-wide DNA methylation (DNAme) profiling of the placenta with Illumina Infinium Methylation bead arrays is often used to explore the connections between in utero exposures, placental pathology, and fetal development. However, many technical and biological factors can lead to signals of DNAme variation between samples and between cohorts, and understanding and accounting for these factors is essential to ensure meaningful and replicable data analysis. Recently, "epiphenotyping" approaches have been developed whereby DNAme data can be used to impute information about phenotypic variables such as gestational age, sex, cell composition, and ancestry. These epiphenotypes offer avenues to compare phenotypic data across cohorts, and to understand how phenotypic variables relate to DNAme variability. However, the relationships between placental epiphenotyping variables and other technical and biological variables, and their application to downstream epigenome analyses, have not been well studied. Results : Using DNAme data from 204 placentas across three cohorts, we applied the PlaNET R package to estimate epiphenotypes gestational age, ancestry, and cell composition in these samples. PlaNET ancestry estimates were highly correlated with independent polymorphic ancestry informative markers, and epigenetic gestational age, on average, was estimated within 4 days of reported gestational age, underscoring the accuracy of these tools. Cell composition estimates varied both within and between cohorts, but reassuringly were robust to placental processing time. Interestingly, the ratio of cytotrophoblast to syncytiotrophoblast proportion decreased with increasing gestational age, and differed slightly by both maternal ethnicity (lower in white vs. non-white) and genetic ancestry (lower in higher probability European ancestry). The cohort of origin and cytotrophoblast proportion were the largest drivers of DNAme variation in this dataset, based on their associations with the first principal component. Conclusions : This work confirms that cohort, array (technical) batch, cell type proportion, self-reported ethnicity, genetic ancestry, and biological sex are important variables to consider in any analyses of Illumina DNAme data. Further, we demonstrate that estimating epiphenotype variables from the DNAme data itself, when possible, provides both an independent check of clinically-obtained data and can provide a robust approach to compare variables across different datasets.

Exogenous oxytocin administration during labor and autism spectrum disorder.

BACKGROUND: Oxytocin is a neuropeptide hormone that plays a key role in social behavior, stress regulation, and mental health. Synthetic oxytocin administration is a common obstetrical practice, and importantly, previous research has suggested that intrapartum exposure may increase the risk of neurodevelopmental disorders, such as autism spectrum disorder. OBJECTIVE: This study aimed to examine the association between synthetic oxytocin exposure during labor and autism spectrum disorder diagnosis in the child. STUDY DESIGN: This population-based retrospective cohort study compared 2 cohorts of children: (1) all children born in British Columbia, Canada between April 1, 2000 and December 31, 2014 (n=414,336 births), and (2) all children delivered at Soroka University Medical Center in Be'er-Sheva, Israel between January 1, 2011 and December 31, 2019 (n=82,892 births). Nine different exposure groups were examined. Cox proportional hazards models were used to estimate crude and adjusted hazard ratios of autism spectrum disorder in both cohorts on the basis of induction and/or augmentation exposure status. To further control for confounding by indication, we conducted sensitivity analyses among a cohort of healthy, uncomplicated deliveries and among a group that was induced only for postdates. In addition, we stratified our analyses by infant sex to assess for potential sex differences. RESULTS: In the British Columbia cohort, 170,013 of 414,336 deliveries (41.0%) were not induced or augmented, 107,543 (26.0%) were exposed to oxytocin, and 136,780 (33.0%) were induced or augmented but not exposed to oxytocin. In the Israel cohort, 51,790 of 82,892 deliveries (62.5%) were not induced or augmented, 28,852 (34.8%) were exposed to oxytocin, and 2250 (2.7%) were induced or augmented but not exposed to oxytocin. On adjusting for covariates in the main analysis, significant associations were observed in the Israel cohort, including adjusted hazard ratios of 1.51 (95% confidence interval, 1.20-1.90) for oxytocin-augmented births and 2.18 (95% confidence interval, 1.32-3.57) for those induced by means other than oxytocin and not augmented. However, oxytocin induction was not significantly associated with autism spectrum disorder in the Israel cohort. In the Canadian cohort, there were no statistically significant adjusted hazard ratios. Further, no significant sex differences were observed in the fully adjusted models. CONCLUSION: This study supports that induction of labor through oxytocin administration does not increase the risk of autism spectrum disorder in the child. Our international comparison of 2 countries with differences in clinical practice regarding oxytocin administration for induction and/or augmentation suggests that previous studies reporting a significant association were likely confounded by the underlying indication for the induction.

Gestational stress and perinatal SSRIs differentially impact the maternal and neonatal microbiome-gut-brain axis.

Selective serotonin reuptake inhibitors (SSRIs) are the most popular antidepressant medications used to manage perinatal mood disturbances, yet our understanding of how they affect the microbiome-gut-brain axis of the mother and offspring is limited. The purpose of this study was to determine how peripartum SSRI treatment may prevent the effects of gestational stress on plasticity in the maternal hippocampus, plasticity in the neonatal brain and related changes in gut microbiota. To do this Sprague-Dawley female rats were left untreated or subjected to unpredictable stress during pregnancy. Half of the females were supplemented daily with fluoxetine. On postpartum day 2 brains were collected for measurement of plasticity (neurogenesis and microglia content) in the maternal hippocampus and in the neonatal brain. Glucocorticoid receptor density was also investigated in the maternal hippocampus. Microbiota composition was analyzed in fecal samples of dams during and after pregnancy, and colon tissue samples from offspring on postnatal day 2. Main findings show there are significant changes to the maternal microbiome-gut-brain axis that may be fundamental to mediating plasticity in the maternal hippocampus. In addition, there is significant impact of gestational stress on neonatal gut microbiota and brain microglia density, while the effects of SSRIs are limited. This is the first study to explore the impact of gestational stress and SSRIs on the microbiome-gut-brain axis in the mother and neonate. Findings from this study will help inform pathways to intervention strategies including stress reduction techniques and/or microbiota targeted nutritional approaches directed towards improving maternal gut health and outcomes for mother and neonate.

Family Perspectives on In-Home Multimodal Longitudinal Data Collection for Children Who Function Across the Developmental Spectrum.

OBJECTIVE: Quality child health research requires multimodal, multi-informant, longitudinal tools for data collection to ensure a holistic description of real-world health, function, and well-being. Although advances have been made, the design of these tools has not typically included community input from families with children whose function spans the developmental spectrum. METHODS: We conducted 24 interviews to understand how children, youth, and their families think about in-home longitudinal data collection. We used examples of smartphone-based Ecological Momentary Assessment of everyday experiences, activity monitoring with an accelerometer, and salivary stress biomarker sampling to help elicit responses. The children and youth who were included had a range of conditions and experiences, including complex pain, autism spectrum disorder, cerebral palsy, and severe neurologic impairments. Data were analyzed using reflexive thematic analysis and descriptive statistics of quantifiable results. RESULTS: Families described (1) the importance of flexibility and customization within the data collection process, (2) the opportunity for a reciprocal relationship with the research team; families inform the research priorities and the development of the protocol and also benefit from data being fed back to them, and (3) the possibility that this research approach would increase equity by offering accessible participation opportunities for families who might otherwise not be represented. Most families expressed interest in participating in in-home research opportunities, would find most methods discussed acceptable, and cited 2 weeks of data collection as feasible. CONCLUSION: Families described diverse areas of complexity that necessitate thoughtful adaptations to traditional research designs. There was considerable interest from families in active engagement in this process, particularly if they could benefit from data sharing. This feedback is being incorporated into pilot demonstration projects to iteratively codesign an accessible research platform.

When feelings hurt: Learning how to talk with families about the role of emotions in physical symptoms.

Emotions are at the core of all human experiences, but talking about emotions is challenging, particularly in the context of medical encounters focused on somatic symptoms. Transparent, normalizing, and validating communication about the mind-body connection opens the door for respectful, open dialogue between the family and members of the care team, acknowledging the lived experience that is brought to the table in understanding the problem and co-creating a solution.

Association between prenatal antibiotic exposure and autism spectrum disorder among term births: A population-based cohort study.

BACKGROUND: Prenatal antibiotic exposure induces changes in the maternal microbiome, which could influence the development of the infant's microbiome-gut-brain axis. OBJECTIVES: We assessed whether prenatal antibiotic exposure is associated with an increased risk of autism spectrum disorder (ASD) in offspring born at term. METHODS: This population-based retrospective cohort study included everyone who delivered a live singleton-term infant in British Columbia, Canada between April 2000 and December 2014. Exposure was defined as filling antibiotic prescriptions during pregnancy. The outcome was an ASD diagnosis from the British Columbia Autism Assessment Network, with a follow-up to December 2016. To examine the association among pregnant individuals treated for the same indication, we studied a sub-cohort diagnosed with urinary tract infections. Cox proportional hazards models were used to estimate unadjusted and adjusted hazard ratios (HR). The analysis was stratified by sex, trimester, cumulative duration of exposure, class of antibiotic, and mode of delivery. We ran a conditional logistic regression of discordant sibling pairs to control for unmeasured environmental and genetic confounding. RESULTS: Of the 569,953 children included in the cohort, 8729 were diagnosed with ASD (1.5%) and 169,922 were exposed to prenatal antibiotics (29.8%). Prenatal antibiotic exposure was associated with an increased risk of ASD (HR 1.10, 95% confidence interval [CI] 1.05, 1.15), particularly for exposure during the first and second trimesters (HR 1.11, 95% CI 1.04, 1.18 and HR 1.09, 95% CI 1.03, 1.16, respectively), and exposure lasting ≥15 days (HR 1.13, 95% CI 1.04, 1.23). No sex differences were observed. The association was attenuated in the sibling analysis (adjusted odds ratio 1.04, 95% CI 0.92, 1.17). CONCLUSIONS: Prenatal antibiotic exposure was associated with a small increase in the risk of ASD in offspring. Given the possibility of residual confounding, these results should not influence clinical decisions regarding antibiotic use during pregnancy.

Placebo effects in children with autism spectrum disorder.

Placebo responses are frequently observed in research studies and clinical contexts, yet there is limited knowledge about the placebo effect among children with neurodevelopmental disorders. Here, we review the placebo effect in autism spectrum disorder (ASD). Placebo responses are widely evident in ASD clinical trials and could partly operate via so-called placebo-by-proxy, whereby caregivers or clinicians indirectly shape patient outcomes. Understanding the role of placebo effects in ASD may help discern genuine treatment effects from contextual factors in clinical trials. The much less studied nocebo effect, or negative placebo, might contribute to the experience of side effects in ASD treatments but empirical data is missing. Better knowledge about placebo and nocebo mechanisms may contribute to the development of more effective research designs, such as three-armed designs that account for natural history, and improved treatments for ASD symptoms. At a clinical level, deeper knowledge about placebo and nocebo effects may optimize the delivery of care for individuals with ASD in the future. WHAT THIS PAPER ADDS: Placebo responses are evident in autism spectrum disorder (ASD) clinical trials. Placebo responses in ASD are likely dependent on a placebo-by-proxy mechanism.

Associations between maternal depressive symptoms and selective serotonin reuptake inhibitor antidepressant treatment on internalising and anxiety behaviours in children: 12-year longitudinal study.

BACKGROUND: Prenatal selective serotonin reuptake inhibitor (SSRI) antidepressant exposure is associated with increased internalising and anxious behaviours in young children; whether this continues into early adolescence is unknown. Also, it is not well established whether it is the in utero exposure to SSRIs or the underlying maternal mood that contributes more to these associations. AIMS: To examine associations between maternal depressive symptoms, prenatal SSRI antidepressant treatment and internalising and anxiety behaviours from childhood into pre-adolescence. METHOD: From a prospective longitudinal cohort, measures of maternal depressive symptoms and SSRI use and child outcomes (n = 191 births) were obtained from the second trimester to 12 years. Maternal reports of internalising and anxiety behaviours in children were obtained at 3, 6 and 12 years. RESULTS: Multilevel mixed-effects models revealed that maternal depressed mood at the third trimester assessment, not prenatal SSRI exposure, was associated with longitudinal patterns of higher levels of internalising and anxiety behaviours across childhood from 3 to 12 years of age. At each age, hierarchical regressions showed that maternal mood at the third trimester, compared with current maternal depression or prenatal SSRI exposure, explained a greater proportion of the variance in internalising and anxiety behaviours. CONCLUSIONS: Even with prenatal SSRI treatment, maternal depressed mood during the third trimester still had an enduring effect as it was associated with increased levels of internalising and anxiety behaviours across childhood and into early adolescence. Importantly, we found no evidence of a 'main effect' association between prenatal SSRI exposure and internalising and anxiety behaviours in children.

Rethinking diagnosis-based service models for childhood neurodevelopmental disabilities in Canada: a question of equity.

Neurodevelopmental disability in children covers a vast array of congenital and acquired long-term conditions associated with brain or neuromuscular impairments that impact function. While some presentations of neurodevelopmental disability align with diagnostic labels, many do not, leaving children whose conditions don't fit neatly under diagnostic labels struggling to access services or families and professionals feeling pressured to assign a diagnostic label in order to access services. In this paper, we (1) discuss the evidence showing that there is often a mismatch between a child's neurodevelopmental diagnosis, or lack of diagnosis, and function, (2) comment on the inequities exacerbated by diagnosis-based approaches for services, and (3) highlight the potential benefits of using a function and participation-based approach for providing services to children with neurodevelopmental disabilities. We close with three calls to action for function and participation-based approaches that could better support equitable services for children with neurodevelopmental disabilities.

Profiling placental DNA methylation associated with maternal SSRI treatment during pregnancy.

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 (|Δß| > 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.

The PPD-ACT app in Canada: feasibility and a latent class analysis of participants with postpartum depression recruited to a psychiatric genetics study using a mobile application.

BACKGROUND: Postpartum depression (PPD) and postpartum psychosis (PPP) are linked to negative consequences for women and families. Virtual applications present a solution to the challenge of recruiting large samples for genetic PPD/PPP research. This study aimed to evaluate the feasibility of a protocol for enrolling Canadian women with PPD and PPP to a large international psychiatric genetics study using a mobile application (PPD-ACT), and identify clinically distinct subtypes of PPD in the recruited sample. METHODS: From April 2017-June 2019, Canadian women provided phenotypic data through the PPD-ACT app. Requests for a genetic sample were made from those with a current or past PPD episode based on an Edinburgh Postnatal Depression Scale (EPDS) score > 12 with onset in pregnancy or 0-3 months postpartum, and from those self-reporting lifetime PPP. Latent class analysis (LCA) was used to identify clinically distinct PPD subgroups based on participant responses to the EPDS scale. RESULTS: We identified 797 PPD cases, 404 of whom submitted DNA. There were 109 PPP cases, with 66 submitting DNA. PPD cases (86.7% White, mean 4.7 +/- 7.0 years since their episode) came from across Canadian provinces/territories. LCA identified two PPD classes clinically distinct by symptom severity: [1] moderate-severity (mean EPDS = 18.5+/- 2.5; 8.6% with suicidality), and [2] severe (mean EPDS = 24.5+/- 2.1; 52.8% with suicidality). CONCLUSIONS: A mobile application rapidly collected data from individuals with moderate and severe symptoms of PPD, an advantage for genetics where specificity is optimal, as well as from women with a history of PPP, supporting future work using this approach.