Psychiatric Disorders In Offspring Research Articles

Maternal experienced bereavement and offspring mental health in early adulthood: the role of modifiable parental factors.

It is estimated that 78% of children experience the death of a close friend or family member by 16 years of age, yet longitudinal research examining the mental health outcomes of wider experiences of bereavement is scarce. We conducted a longitudinal investigation of the association between maternal experienced bereavement before the age of 11 years and offspring depressive and anxiety disorders at age 18 and examined moderation of this association by modifiable parental factors. We analysed data from the Avon Longitudinal Study of Parents and Children, a UK-based birth cohort, including 9,088 child participants with data available on bereavement. Bereavement was measured via maternal report at eight timepoints until children were 11 years. Offspring depressive and anxiety-related disorders were self-reported at 18 years old using the Clinical Interview Schedule-Revised (CIS-R). The potential moderating roles of maternal anxiety, maternal depression, parental monitoring, positive parenting and negative parenting practices were examined. Maternal experienced bereavement was not associated with depression or anxiety-related disorders in early adulthood among offspring. In addition, no support was found for negative parenting practices, parental monitoring or maternal anxiety and depression as moderators of the relationship between maternal experienced bereavement and offspring mental health problems at 18 years old. Findings in relation to the moderating role of positive parenting practices were inconsistent. Findings suggest that a large number of children are exposed to maternal experienced bereavement. We found no evidence that maternal experienced bereavement during childhood increases the risk for offspring psychiatric disorders in early adulthood. Several methodological considerations prudent to bereavement research are discussed.

The PPARα agonist fenofibrate reduces the cytokine imbalance in a maternal immune activation model of schizophrenia

Maternal infections during pregnancy may increase the risk of psychiatric disorders in offspring. We recently demonstrated that activation of peroxisome proliferator-activate receptor-α (PPARα), with the clinically available agonist fenofibrate (FEN), attenuates the neurodevelopmental disturbances induced by maternal immune activation (MIA) in rat offspring. We hypothesized that fenofibrate might reduce MIA-induced cytokine imbalance using a MIA model based on the viral mimetic polyriboinosinic-polyribocytidilic acid [poly (I:C)]. By using the Bio-Plex Multiplex-Immunoassay-System, we measured cytokine/chemokine/growth factor levels in maternal serum and in the fetal brain of rats treated with fenofibrate, at 6 and 24 h after poly (I:C). We found that MIA induced time-dependent changes in the levels of several cytokines/chemokines/colony-stimulating factors (CSFs). Specifically, the maternal serum of the poly (I:C)/control (CTRL) group showed increased levels of (i) proinflammatory chemokine macrophage inflammatory protein 1-alpha (MIP-1α), (ii) tumor necrosis factor-alpha (TNF-α), the monocyte chemoattractant protein-1 (MCP-1), the macrophage (M-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Conversely, in the fetal brain of the poly (I:C)/CTRL group, interleukin 12p70 and MIP-1α levels were lower than in vehicle (veh)/CTRL group. Notably, MIP-1α, TNF-α, keratinocyte derived chemokine (GRO/KC), GM-CSF, and M-CSF levels were lower in the poly (I:C)/FEN than in poly (I:C)/CTRL rats, suggesting the protective role of the PPARα agonist. PPARα might represent a therapeutic target to attenuate MIA-induced inflammation.

Maternal Perinatal Stress Trajectories and Negative Affect and Amygdala Development in Offspring.

Maternal psychological stress during pregnancy is a common risk factor for psychiatric disorders in offspring, but little is known about how heterogeneity of stress trajectories during pregnancy affect brain systems and behavioral phenotypes in infancy. This study was designed to address this gap in knowledge. Maternal anxiety, stress, and depression were assessed at multiple time points during pregnancy in two independent low-risk mother-infant cohorts (N=115 and N=2,156). Trajectories in maternal stress levels in relation to infant negative affect were examined in both cohorts. Neonatal amygdala resting-state functional connectivity MRI was examined in a subset of one cohort (N=60) to explore the potential relationship between maternal stress trajectories and brain systems in infants relevant to negative affect. Four distinct trajectory clusters, characterized by changing patterns of stress over time, and two magnitude clusters, characterized by severity of stress, were identified in the original mother-infant cohort (N=115). The magnitude clusters were not associated with infant outcomes. The trajectory characterized by increasing stress in late pregnancy was associated with blunted development of infant negative affect. This relationship was replicated in the second, larger cohort (N=2,156). In addition, the trajectories that included increasing or peak maternal stress in late pregnancy were related to stronger neonatal amygdala functional connectivity to the anterior insula and the ventromedial prefrontal cortex in the exploratory analysis. The trajectory of maternal stress appears to be important for offspring brain and behavioral development. Understanding heterogeneity in trajectories of maternal stress and their influence on infant brain and behavioral development is critical to developing targeted interventions.

129. Psychiatric Disorders in Offspring to Mothers With IBD - A Finnish Cohort Study

129. Psychiatric Disorders in Offspring to Mothers With IBD - A Finnish Cohort Study

Maternal immune activation increases excitability via downregulation of A-type potassium channels and reduces dendritic complexity of hippocampal neurons of the offspring

The epidemiological association between bacterial or viral maternal infections during pregnancy and increased risk for developing psychiatric disorders in offspring is well documented. Numerous rodent and non-human primate studies of viral- or, to a lesser extent, bacterial-induced maternal immune activation (MIA) have documented a series of neurological alterations that may contribute to understanding the pathophysiology of schizophrenia and autism spectrum disorders. Long-term neuronal and behavioral alterations are now ascribed to the effect of maternal proinflammatory cytokines rather than the infection itself. However, detailed electrophysiological alterations in brain areas relevant to psychiatric disorders, such as the dorsal hippocampus, are lacking in response to bacterial-induced MIA. This study determined if electrophysiological and morphological alterations converge in CA1 pyramidal cells (CA1 PC) from the dorsal hippocampus in bacterial-induced MIA offspring. A series of changes in the functional expression of K+ and Na+ ion channels altered the passive and active membrane properties and triggered hyperexcitability of CA1 PC. Contributing to the hyperexcitability, the somatic A-type potassium current (IA) was decreased in MIA CA1 PC. Likewise, the spontaneous glutamatergic and GABAergic inputs were dysregulated and biased toward increased excitation, thereby reshaping the excitation–inhibition balance. Consistent with these findings, the dendritic branching complexity of MIA CA1 PC was reduced. Together, these morphophysiological alterations modify CA1 PC computational capabilities and contribute to explaining cellular alterations that may underlie the cognitive symptoms of MIA-associated psychiatric disorders.

Antipsychotic continuation in pregnancy not linked to risk of psychiatric disorders in offspring

A population‐based cohort study has found no significantly increased risk of psychiatric disorders in the offspring of women who continued antipsychotic use during pregnancy when compared with women who discontinued use. The study found similar outcomes for children whose fathers used antipsychotics.

Parental smoking and young adult offspring psychosis, depression and anxiety disorders and substance use disorder

BackgroundTo study the associations between maternal smoking during pregnancy and paternal smoking before pregnancy and adult offspring psychiatric disorders.MethodsProspective general population cohort study in Northern Finland, with people from the Northern Finland Birth Cohort 1986: 7259 subjects (77% of the original sample). Data on parental smoking were collected from parents during pregnancy using questionnaires. Outcomes were offspring’s register-based diagnoses: any psychiatric disorder, any non-organic psychosis, mood disorder, anxiety disorder and substance use disorder (SUD) until the age of 29–30 years. Maternal smoking during pregnancy and paternal smoking before pregnancy were pooled to three-class variables: (i) none; (ii) 1–9 and (iii) ≥10 cigarettes/day. Information regarding both parents’ alcohol use during pregnancy and at offspring age 15–16 years, maternal education level, family structure, parental psychiatric diagnoses and offspring gender, smoking, intoxication frequency and illicit substance use at the age of 15–16 years were investigated as covariates.ResultsIn the multivariable analyses, maternal smoking during pregnancy did not associate with the studied outcomes after adjusting for offspring smoking and other substance use at offspring age 15–16 years and parental psychiatric disorders. However, paternal smoking ≥10 cigarettes/day before pregnancy [hazard ratio (HR) = 5.5, 95% confidence interval (CI) 2.7–11.2, P < 0.001] and paternal psychiatric disorders (HR = 1.7, 95% CI 1.1–2.8, P = 0.028) associated with offspring SUD after adjustments.ConclusionsInformation across the offspring life course is essential in exploring the association between parental smoking and offspring psychiatric disorders. Paternal smoking before pregnancy and paternal psychiatric disorders may act as modifiers in elevating the risk of substance-use-related problems among offspring.

Association of Preeclampsia and Perinatal Complications With Offspring Neurodevelopmental and Psychiatric Disorders

Maternal preeclampsia has been reported to increase the risk of autism spectrum disorder, attention-deficit/hyperactivity disorder (ADHD), and intellectual disability in offspring. However, the association between maternal preeclampsia combined with perinatal complications and neurodevelopmental and psychiatric disorders in offspring is less well documented. To examine the association of maternal preeclampsia, separately and together with perinatal complications, with neurodevelopmental and psychiatric disorders in offspring. This population-based cohort study used data from nationwide registries in Finland to assess all singleton live births (N = 1 012 723) between January 1, 1996, and December 31, 2014. Offspring were followed up until December 31, 2018 (when the oldest reached age 22 years). Exclusion criteria were maternal inpatient psychiatric diagnoses and pregestational diabetes. The study and data analysis were conducted from May 1, 2020, to June 1, 2021. Preeclampsia and perinatal complications (delivery earlier than 34 weeks' gestation and/or small for gestational age). The primary outcomes were neurodevelopmental and psychiatric diagnoses and dispensation of psychotropic drugs among offspring until December 31, 2018. Cox proportional hazards regression analyses were performed to assess the associations. Of 1 012 723 singleton live births (51.1% boys; mean [SD] maternal age at birth, 30.0 [5.4] years; specific data on race and ethnicity were not available in the data set), 21 010 children (2.1%) were exposed to preeclampsia alone, 33 625 children (3.3%) were exposed to perinatal complications alone, and 4891 children (0.5%) were exposed to both preeclampsia and perinatal complications. A total of 93 281 children (9.2%) were diagnosed with a neurodevelopmental or psychiatric disorder. Offspring exposed to both preeclampsia and perinatal complications had an increased risk of any neurodevelopmental or psychiatric disorder after adjusting for potential confounding (adjusted hazard ratio [aHR], 2.11; 95% CI, 1.96-2.26) compared with those not exposed to either preeclampsia or perinatal complications; this risk was higher than exposure to either preeclampsia alone (aHR, 1.18; 95% CI, 1.12-1.23) or perinatal complications alone (aHR, 1.77; 95% CI, 1.72-1.82). Sibling pair analyses did not detect any increase in the risk of neurodevelopmental or psychiatric disorders after exposure to preeclampsia alone, but offspring exposed to both preeclampsia and perinatal complications had increased risks of intellectual disabilities (aHR, 3.24; 95% CI, 1.05-10.06), specific developmental disorders (aHR, 3.56; 95% CI, 2.35-5.41), ADHD and conduct disorders (aHR, 2.42; 95% CI, 1.09-5.39), and other behavioral and emotional disorders (aHR, 2.45; 95% CI, 1.17-5.13). The risk estimates for specific developmental disorders (aHR, 2.82; 95% CI, 2.60-3.05) and ADHD and conduct disorders (aHR, 1.88; 95% CI, 1.65-2.14) were higher among offspring exposed to both preeclampsia and perinatal complications compared with those exposed to perinatal complications alone (aHR, 2.26 [95% CI, 2.18-2.33] and 1.60 [95% CI, 1.52-1.68], respectively). In this study, exposure to both maternal preeclampsia and perinatal complications was associated with intellectual disabilities, specific developmental disorders, ADHD and conduct disorders, and other behavioral and emotional disorders in offspring. For specific developmental disorders and ADHD and conduct disorders, the risk estimates were higher among offspring exposed to both preeclampsia and perinatal complications compared with those exposed to perinatal complications only.

The intergenerational transmission of maternal adverse childhood experiences on offspring's psychiatric disorder and the mediating role of maternal depression: Results from a cross sectional study.

Maternal adverse childhood experiences (ACEs) may negatively affect the mental health and development of their offspring. The purpose of this study was to investigate the association of maternal ACE and offspring's psychiatric disorder and the mediating effect of maternal depression. The subjects included 463 mothers (42.78 ± 5.68years) and their offspring aged 6-18years (13.26 ± 3.90years). Mothers reported their ACE before age 18 and completed the Beck Depression Inventory-II and Diagnostic Predictive Scales (DPS), a screening tool for offspring's psychiatric disorder. 35.42% of subjects had at least one ACE, and 11.0% reported three or more ACEs. Higher maternal ACE scores were associated with a significantly higher prevalence of offspring's psychiatric disorders (p < 0.001). Household dysfunction of maternal ACE (OR = 2.263, p < 0.001) is significantly associated with offspring's psychiatric disorder. In the mediation model in which the household dysfunction affects the number of offspring's psychiatric disorders, the partial mediation model through maternal depression was significant. The mother's experience of household dysfunction before the age of 18 has a significant impact on her offspring's psychiatric disorder and supported significant mediation through maternal depression. Further research is needed to determine the mechanisms of intergenerational transmission of ACE and offspring's psychopathology.

Associations of Maternal Diabetes During Pregnancy With Psychiatric Disorders in Offspring During the First 4 Decades of Life in a Population-Based Danish Birth Cohort

Maternal diabetes has been suggested as a risk factor for attention-deficit/hyperactivity disorder and autism in offspring, but evidence on its association with the full spectrum of psychiatric disorders remains lacking. To investigate the associations between maternal diabetes diagnosed before or during pregnancy and 10 types of psychiatric disorders in offspring during the first 4 decades of life. This population-based cohort study used data from several Danish nationwide medical and administrative registries in Denmark on all 2 413 335 live births from 1978 to 2016. Data were analyzed between October 1, 2019, and July 15, 2021. Any maternal diabetes diagnosis during pregnancy (56 206 offspring [2.3%]) and 3 diabetes subtypes (pregestational type 1 diabetes, 22 614 offspring [1.0%]; pregestational type 2 diabetes, 6713 offspring [0.3%]; and gestational diabetes, 26 879 offspring [1.1%]). Outcomes included 10 types of psychiatric disorders: any psychiatric disorder, substance use disorders, schizophrenia, mood disorders, anxiety disorders, eating disorders, personality disorders, intellectual disorders, developmental disorders, and behavioral disorders. Hazard ratios (HRs) and 95% CIs were computed using Cox proportional hazards regression models. Covariates included maternal and paternal history of any psychiatric disorder, offspring sex, calendar period of birth, singleton status, and several maternal characteristics during pregnancy (ie, age, parity, educational level, smoking, cohabitation, residence, and body mass index). Sibship design and competing risk analyses were also conducted. A total of 2 413 335 individuals (1 239 148 male participants [51%]; age range, 1-39 years; median age, 19.0 years [IQR, 5.8-20.8 years]) were included in this study. During the 39-year follow-up time, 151 208 offspring (6.4%) received a diagnosis of a psychiatric disorder. Offspring born to mothers with any diabetes diagnosis during pregnancy were at increased risk of developing any psychiatric disorder (HR, 1.15; 95% CI, 1.10-1.20), schizophrenia (HR, 1.55; 95% CI, 1.15-2.08), anxiety disorders (HR, 1.22; 95% CI, 1.09-1.36), intellectual disabilities (HR, 1.29; 95% CI, 1.11-1.50), developmental disorders (HR, 1.16; 95% CI, 1.03-1.30), and behavioral disorders (HR, 1.17; 95% CI, 1.08-1.27) compared with offspring born to mothers without a diabetes diagnosis during pregnancy. No association was observed for substance use disorders, mood disorders, eating disorders, and personality disorders. This study shows a pattern that suggests that prenatal exposure to maternal diabetes during pregnancy was associated with increased risk of psychiatric disorders overall and most specific psychiatric disorders in offspring in their first 4 decades of life.

Double trouble: Prenatal immune activation in stress sensitive offspring

Viral infections during pregnancy are associated with increased incidence of psychiatric disorders in offspring. The pathological outcomes of viral infection appear to be caused by the deleterious effects of innate immune response-associated factors on development of the fetus, which predispose the offspring to pathological conditions in adulthood. The negative impact of viral infections varies substantially between pregnancies. Here, we explored whether differential stress sensitivity underlies the high heterogeneity of immune reactivity and whether this may influence the pathological consequences of maternal immune activation. Using mouse models of social dominance (Dom) and submissiveness (Sub), which possess innate features of stress resilience and vulnerability, respectively, we identified differential immune reactivity to the synthetic analogue of viral double-stranded RNA, Poly(I:C), in Sub and Dom nulliparous and pregnant females. More specifically, we found that Sub females showed an exacerbated pro- and anti-inflammatory cytokine response to Poly(I:C) as compared with Dom females.Sub offspring born to Sub mothers (stress sensitive offspring) showed enhanced locomotory response to the non-competitive NMDA antagonist, MK-801, which was potentiated by prenatal Poly(I:C) exposure. Our findings suggest that inherited stress sensitivity may lead to functional changes in glutamatergic signaling, which in turn is further exacerbated by prenatal exposure to viral-like infection. The maternal immunome seems to play a crucial role in these observed phenomena.

Parental death by external causes during childhood and risk of psychiatric disorders in bereaved offspring.

Previous studies have reported increased risks of psychiatric disorders in offspring who have lost a parent, but knowledge is lacking on the risks of several specific disorders and comorbidity. The present study investigated the influence of parental death by external causes during childhood and adolescence on risk of a range of psychiatric disorders and comorbidity. The study cohort comprised 655,477 individuals born 1970-2012 with a link to both parents. Data on deceased parent's cause and date of death between 1970 and 2012 and offspring's psychiatric disorders between 2008 and 2012 were retrieved from four longitudinal Norwegian registers. Data were analyzed with Cox regression. Compared to nonexposed offspring, offspring exposed to parental death by external causes had a significantly increased risk of depressive disorders, reactions to stress, anxiety disorders, substance use disorders, developmental disorders, childhood behavioral and emotional disorders, psychotic disorders, bipolar disorder, personality disorders, and psychiatric comorbidity, but not eating disorders. These increased risks were especially evident following parental suicide and accidental falls and poisoning. No differences were evident depending on gender of the deceased or age at bereavement, and generally no significant interactions with gender of the bereaved offspring were evident. The improved insight into several different psychiatric disorders and psychiatric comorbidity should guide postvention measures aimed at children and adolescents at greatest risk of future sequelae.

A Longitudinal Study of Psychiatric Disorders in Offspring of Parents With Bipolar Disorder From Preschool to Adolescence

To compare the prevalence of psychopathology, particularly bipolar disorder (BD), between preschool offspring of parents with BD and community controls. A total of 116 offspring of BD-I/II parents and 98 controls (53 parents with non-BD psychopathology and 45 healthy parents) were recruited at ages 2 to 5 years and followed on average 9.6 years (on average: 2-5: 1.6 times; after age 5: 4 times) (average ages at intake/last follow-up: 3.8/13.4, retention: 98%). Participants were evaluated with standardized instruments blinded to parental diagnoses. After adjusting for confounders, offspring of BD parents only showed more attention-deficit/hyperactivity disorder (ADHD) during ages 2 to 5 years than the other 2 groups. After age 5, offspring of BD parents did not differ from offspring of parents with non-BD psychopathology, but they had more anxiety, ADHD, and behavior problems than offspring of healthy parents. Only offspring of BD parents developed BD-I/II: 3.4% (n = 4) and BD-not-otherwise-specified (BD-NOS): 11.2% (n = 13), with mean onset ages 11.4 and 7.4, respectively. About 70% of offspring with BD had non-BD disorders before BD. Only ADHD, diagnosed before age 6 years, and early-onset parental BD were significantly associated with BD risk. Most offspring of BD parents did not develop BD, but they were at specific high risk for developing BD, particularly those with preschool ADHD and early-onset parental BD. BD symptoms were scarce during the preschool years and increased throughout the school age, mainly in the form of BD-NOS, a disorder that conveys poor prognosis and high risk to develop BD-I/II. Developing early interventions to delay or, ideally, to prevent its onset are warranted.

Maternal migraine and the risk of psychiatric disorders in offspring: a population-based cohort study

Maternal migraine may contribute to mental heath problems in offspring but empirical evidence has been available only for bipolar disorders. Our objective was to examine the association between maternal migraine and the risk of any and specific psychiatric disorders in offspring. This population-based cohort study used individual-level linked Danish national health registers. Participants were all live-born singletons in Denmark during 1978-2012 (n = 2 069 785). Follow-up began at birth and continued until the onset of a psychiatric disorder, death, emigration or 31 December 2016, whichever came first. Cox proportional hazards model was employed to calculate the hazard ratios (HRs) of psychiatric disorders. Maternal migraine was associated with a 26% increased risk of any psychiatric disorders in offspring [HR, 1.26; 95% confidence interval (CI), 1.22-1.30]. Increased rates of psychiatric disorders were seen in all age groups from childhood to early adulthood. Increased rates were also observed for most of the specific psychiatric disorders, in particular, mood disorders (HR, 1.53; 95% CI, 1.39-1.67), neurotic, stress-related and somatoform disorders (HR, 1.44; 95% CI, 1.37-1.52) and specific personality disorders (HR, 1.47; 95% CI, 1.27-1.70), but not for intellectual disability (HR, 0.84; 95% CI, 0.71-1.00) or eating disorders (HR, 1.10; 95% CI, 0.93-1.29). The highest risk was seen in the offspring of mothers with migraine and comorbid psychiatric disorders (HR, 2.13; 95% CI, 1.99-2.28). Maternal migraine was associated with increased risks of a broad spectrum of psychiatric disorders in offspring. Given the high prevalence of migraine, our findings highlight the importance of better management of maternal migraine at childbearing ages for early prevention of psychiatric disorders in offspring.

Psychiatric disorders in offspring of childhood or adolescent central nervous system tumor survivors: a national cohort study.

BackgroundChildren experience a higher risk of psychiatric problems when their parents are diagnosed with cancer. However, the psychological effect among offspring who are born after parental cancer diagnosed in childhood or adolescence is unknown. We aimed to investigate the risk of psychiatric disorders in children of survivors with childhood or adolescent central nervous system (CNS) tumors.MethodsBy combining several nationwide Swedish registers, we identified all children who had at least one parent previously diagnosed with CNS tumor below the age of 20. Five children without parental CNS tumor were randomly selected for the matching. Cox proportional hazards model was used to calculate hazard ratios (HRs) with 95% confidence interval (CI).ResultsThe incidence rate of psychiatric disorders was 8.46 per 1000 person‐years in children of CNS tumor survivors, whereas the rate was 7.47 in the matched comparisons, yielding an adjusted HR of 1.10 (95% CI = 0.94, 1.28). Boys of survivors had a higher risk of psychiatric disorders (adjusted HR = 1.29, 95% CI = 1.04, 1.59). The risk of the specific types of psychiatric disorders in children of tumor survivors was comparable with that in the matched comparisons, except for mental retardation. Children of survivors experienced 2.36 times higher risk of mental retardation (95% CI = 1.21, 4.58), mainly of mild mental retardation (adjusted HR = 2.99, 95% CI = 1.40, 6.38).ConclusionChildren of survivors with CNS tumor in early life did not experience a significantly increased risk of overall psychiatric disorders, with the exception of an elevated risk of mental retardation that was mainly mild.

Maternal Immune activity during pregnancy and socioeconomic disparities in children’s self-regulation

Maternal immune activity during pregnancy has been associated with risk for psychiatric disorders in offspring, but less is known about its implications for children’s emotional and behavioral development. This study examined whether concentrations of five cytokines assayed from prenatal serum were associated with socioeconomic status (SES) and racial disparities in their offspring’s self-regulation abilities. Participants included 1628 women in the Collaborative Perinatal Project (CPP). Seven behavioral items conceptually related to self-regulation were rated by CPP psychologists when children were 4 years old. Concentrations of interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, and IL-10 were assessed. Covariates included child sex and mother’s age, psychiatric disorders, and medical conditions during pregnancy. There were significant SES differences in child self-regulation, with higher SES children scoring higher on self-regulation (β = 0.18, 95% CI [0.11, 0.25]), but no racial differences. The concentration of IL-8 in maternal serum was associated with higher child self-regulation, β = 0.09, 95% CI [0.02, 0.16]. In mediation analyses, variation in maternal IL-8 contributed to the association between family SES and child self-regulation (β = 0.02, 95% CI [0.003, 0.030]), explaining about one-tenth of the SES disparities. This study suggests pregnancy as an early sensitive period and maternal immune activity as an important context for child development.

Association of polycystic ovary syndrome or anovulatory infertility with offspring psychiatric and mild neurodevelopmental disorders: a Finnish population-based cohort study.

Is maternal polycystic ovary syndrome (PCOS) associated with increased risks for a broad spectrum of psychiatric and mild neurodevelopmental disorders in offspring? Maternal PCOS and/or anovulatory infertility is independently, and jointly with maternal obesity, perinatal problems, cesarean delivery and gestational diabetes, associated with increased risks in offspring for almost all groups of psychiatric and mild neurodevelopmental disorders with onset in childhood or adolescence. Maternal PCOS was previously associated with autism spectrum disorder, attention-deficit/hyperactivity disorders and possibly developmental delay in offspring. Few studies have investigated the association between maternal PCOS and other psychiatric and neurodevelopmental disorders in offspring. This was a population-based cohort study in Finland including all live births between 1996 and 2014 (n = 1 105 997). After excluding births to mothers with symptoms similar to PCOS, a total of 1 097 753 births by 590 939 mothers remained. Children were followed up until 31 December 2018, i.e. up to the age of 22 years. National registries were used to link data of the included births and their mothers. Data from 24 682 (2.2%) children born to mothers with PCOS were compared with 1 073 071 (97.8%) children born to mothers without PCOS. Cox proportional hazards modeling was used to evaluate the hazard ratio (HR) and 95% CI for the risk of neuropsychiatric disorders in relation to maternal PCOS. Stratified analyses were performed to test the independent role of PCOS and the joint effects of PCOS with maternal obesity, perinatal problems, cesarean delivery, gestational diabetes and use of fertility treatment. The analysis was adjusted for maternal age, country of birth, marriage status at birth, smoking, parity, psychiatric disorders, prescription of psychotropic N05/N06 during pregnancy and systemic inflammatory diseases when applicable. A total of 105 409 (9.8%) children were diagnosed with a neurodevelopmental or psychiatric disorder. Firstly, maternal PCOS was associated with any psychiatric diagnosis (HR 1.32; 95% CI 1.27-1.38) in offspring. Particularly, the risk was increased for sleeping disorders (HR 1.46; 95% CI 1.27-1.67), attention-deficit/hyperactivity disorders and conduct disorders (HR 1.42; 95% CI 1.33-1.52), tic disorders (HR 1.42; 95% CI 1.21-1.68), intellectual disabilities (HR 1.41; 95% CI 1.24-1.60), autism spectrum disorder(HR 1.40; 95% CI 1.26-1.57), specific developmental disorders (HR 1.37; 95% CI 1.30-1.43), eating disorders (HR 1.36; 95% CI 1.15-1.61), anxiety disorders (HR 1.33; 95% CI 1.26-1.41), mood disorders (HR 1.27; 95% CI 1.18-1.35) and other behavioral and emotional disorders (ICD-10 F98, HR 1.49; 95% CI 1.39-1.59). In short, there was no significant difference between sexes. The results were robust when restricting the analyses to the first-born children or births to mothers without psychiatric diagnosis or purchase of psychotropic medication. Secondly, stratified analysis according to maternal BMI showed that the risk of any neuropsychiatric disorder was increased in offspring to normal-weight mothers with PCOS (HR 1.20; 95% CI 1.09-1.32), and markedly higher in those to severely obese mothers with PCOS (HR 2.11; 95% CI 1.76-2.53) compared to offspring to normal-weight mothers without PCOS. When excluding perinatal problems, mothers with PCOS were still associated with increased risks of any neuropsychiatric disorders in offspring (HR 1.28; 95% CI 1.22-1.34) compared to mothers without PCOS. However, an additional increase was observed for PCOS in combination with perinatal problems (HR 1.99; 95% CI 1.84-2.16). Likewise, excluding cases with maternal gestational diabetes (HR 1.30; 95% CI 1.25-1.36), cesarean delivery (HR 1.29; 95% CI 1.23-1.35) or fertility treatment (HR 1.31; 95% CI 1.25-1.36) did not eliminate the associations. The register-based prevalence of PCOS was lower than previously reported, suggesting that this study may capture the most severe cases. To combine anovulatory infertility with PCOS diagnosis as PCOS exposure might introduce diagnostic bias. It was not feasible to distinguish between subtypes of PCOS. Furthermore, familial factors might confound the association between maternal PCOS and neuropsychiatric disorders in offspring. Maternal BMI was available for birth cohort 2004-2014 only and there was no information on gestational weight gain. This study provides further evidence that maternal PCOS and/or anovulatory infertility, independently and jointly with maternal obesity, perinatal problems, gestational diabetes and cesarean delivery, implies a broad range of adverse effects on offspring neurodevelopment. These findings may potentially help in counseling and managing pregnancies. This study was supported by the joint research funding of Shandong University and Karolinska Institute (SDU-KI-2019-08 to X.C and C.L.), THL Finnish Institute for Health and Welfare: Drug and pregnancy project [M.G.], the Swedish Research Council [2014-10171 to C.L.], the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institute Stockholm County Council [SLL20170292 to C.L.], the Swedish Brain Foundation [FO2018-0141 and FO2019-0201 to C.L.]. X.C. was supported by the China Scholarship Council during her training in Karolinska Institute. L.K. was supported by the China Scholarship Council for his PhD study in Karolinska Institute. The authors have no competing interests to disclose. N/A.

Associations of Different Types of Maternal Diabetes and Body Mass Index With Offspring Psychiatric Disorders

Maternal obesity, pregestational type 1 and 2 diabetes, and gestational diabetes have been reported to increase the risk of autism spectrum disorder and attention-deficit/hyperactivity disorder in the mothers' offspring. However, the associations of maternal diabetes disorders and body mass index jointly with psychiatric disorders among offspring are less well documented, especially for type 2 diabetes. To examine the associations of different types of maternal diabetes, separately and together with maternal obesity, with psychiatric disorders in the mothers' offspring. This population-based cohort study used data from nationwide registries in Finland encompassing all 649 043 live births occurring between 2004 and 2014. The study and data analysis were conducted from January 1, 2019, to July 5, 2019. Maternal prepregnancy body mass index, insulin-treated pregestational diabetes, and pregestational type 2 diabetes and gestational diabetes without insulin treatment. Psychiatric diagnoses and prescription of psychotropic drugs among the mothers' offspring. Cox proportional hazards models were adjusted for birth year, sex, mode of delivery, maternal age, number of fetuses, parity, mother's country of birth, mother's marital status, maternal smoking, maternal psychiatric disorder, and maternal systemic inflammatory disease. The mean (SD) age of mothers was 30.20 (5.37) years; 357 238 of 394 302 mothers (90.6%) were born in Finland. Of the 647 099 births studied, 4000 fetuses (0.62%) were exposed to maternal insulin-treated pregestational diabetes, 3724 (0.57%) were exposed to type 2 diabetes, and 98 242 (15.18%) were exposed to gestational diabetes; 34 892 offspring (5.39%) later received a diagnosis of a mild neurodevelopmental or psychiatric disorder. Non-insulin-treated type 2 diabetes in severely obese mothers, compared with normal-weight mothers without diabetes, was associated with psychiatric disorders in the offspring (hazard ratio, 1.97; 95% CI, 1.64-2.37), although with a lower effect size than that for severely obese mothers with insulin-treated pregestational diabetes (hazard ratio, 2.71; 95% CI, 2.03-3.61). The largest effect sizes were found for mood disorders, attention-deficit/hyperactivity disorder and conduct disorders, and autism. Gestational diabetes in severely obese mothers had a lower overall effect size (hazard ratio, 1.61; 95% CI, 1.50-1.72). Diabetes in normal-weight mothers was not associated with psychopathologic disorders in the offspring. Severe obesity in mothers with diabetes was associated with an increased overall risk for psychiatric disorders in their offspring. The risk was highest for those exposed to insulin-treated pregestational diabetes, followed by non-insulin-treated type 2 diabetes and gestational diabetes. These findings may have implications for managing pregnancies.

Early exposure to antibiotic drugs and risk for psychiatric disorders: a population-based study

Early life exposure to infection, anti-infectives and altered immune activity have been associated with elevated risk of some psychiatric disorders. However, the risk from exposure in fetal life has been proposed to be confounded by familial factors. The hypothesis of this study is that antibiotic drug exposure during the fetal period and the first two postnatal years is associated with risk for later development of psychiatric disorders in children. All births in Finland between 1996 and 2012, 1 million births, were studied for antibiotic drug exposure: mothers during pregnancy and the children the first two postnatal years. The children were followed up for a wide spectrum of psychiatric diagnoses and psychotropic drug treatment until 2014. Cox proportional hazards modeling was used to estimate effects of antibiotic drug exposure on offspring psychiatric disorders. Modestly (10–50%) increased risks were found on later childhood development of sleep disorders, ADHD, conduct disorder, mood and anxiety disorders, and other behavioral and emotional disorders with childhood onset (ICD-10 F98), supported by increased risks also for childhood psychotropic medication. The prenatal exposure effects detected were not explained by explored familial confounding, nor by registered maternal infections. To conclude, this longitudinal nation-wide study shows that early life antibiotic drug exposure is associated with an increased risk for childhood development of psychopathology. Given the high occurrence of early-life antibiotic exposure, these findings are of public health relevance. Whether the associations reflect effects of the antibiotic drug use or of the targeted infections remains to be explored further.

Parental morphine exposure affects repetitive grooming actions and marble burying behavior in the offspring: Potential relevance for obsessive-compulsive like behavior

Family, adoption and twin studies have highlighted the significant role of heritable influences on individual differences in opioid addiction. Meanwhile, obsessive-compulsive disorder (OCD) is a disorder wherein the individual experiences recurring thoughts that cause irrational fears and anxiety. In the present study, adult male and female rats received morphine solution for 21 days and were drug-free for 10 days. Offspring were used in 4 distinct groups; (1) paternal morphine-exposed, (2) maternal morphine-exposed, (3) maternal and paternal morphine-exposed, and (4) drug-naïve subjects. We assessed the grooming behavior and marble burying test as an indicator of obsessive-compulsive behavior. To clarify the mechanisms underlying these changes, the mRNA level of BDNF, the phosphorylation level of CREB and the protein level of D2 dopamine receptor (DR) were evaluated in the nucleus accumbens (NAc). The grooming behavior in male offspring with one or two morphine-abstinent parent(s) increased compared with the offspring of drug naïve rats. In addition, the offspring of morphine-exposed parents buried more marbles when compared with the offspring of drug-naïve parents. Also, the BDNF mRNA was down-regulated in the NAC. However, the levels of phospho-CREB and D2 DR were elevated. Previous studies indicated that exposure to morphine in adulthood enhances the risk of psychiatric disorders in offspring. OCD is one the comorbid disorders with addiction and increases the risk of substance abuse disorder in patients. In this survey, we found that morphine exposure in parents before gestation can encourage obsessive-compulsive behavior in offspring.