Mothers' symptoms of anxiety and depression and the development of child temperament: A genetically informative, longitudinal investigation.

Background: Child temperament traits and mothers' emotional symptoms relating to anxiety and depression may drive changes in one another, leading to their 'co-development' across time. Alternatively, links between mother and child traits may be attributable to shared genetic propensities. We explored longitudinal associations between mothers' emotional symptoms and child temperament traits and adjusted for genetic effects shared across generations. Methods: This study is based on the Norwegian Mother, Father and Child Cohort Study (MoBa). Mothers (n = 34,060) reported on their symptoms of anxiety and depression, and temperament among offspring (n = 42,526), at child ages 1.5, 3 and 5 years. Structural equation models parameterised developmental change in traits, and an extended family design adjusted for genetic effects. Results: We found individual differences in stable trait scores and rate of change for all study variables. Longitudinal stability in mothers' emotional symptoms was associated with longitudinal stability in offspring emotionality (r = 0.143), shyness (r = 0.031), and sociability (r = -0.015). Longitudinal change in mothers' symptoms showed very small or negligible correlations with longitudinal change in child temperament. Both genetic and environmental influences explained the stable longitudinal association between mothers' symptoms and child emotionality. Conclusions: The studied associations between mother and child traits across time appeared to be due to stable, trait-like factors, involving genetic and environmental influence, rather than their co-development. Findings contribute knowledge on how emotional symptoms develop in families across time, and the methods with which we can explore such development.

Expert consensus on neurodevelopmental outcomes in pregnancy pharmacovigilance studies.

Background: Exposure in utero to certain medications can disrupt processes of fetal development, including brain development, leading to a continuum of neurodevelopmental difficulties. Recognizing the deficiency of neurodevelopmental investigations within pregnancy pharmacovigilance, an international Neurodevelopmental Expert Working Group was convened to achieve consensus regarding the core neurodevelopmental outcomes, optimization of methodological approaches and barriers to conducting pregnancy pharmacovigilance studies with neurodevelopmental outcomes. Methods: A modified Delphi study was undertaken based on stakeholder and expert input. Stakeholders (patient, pharmaceutical, academic and regulatory) were invited to define topics, pertaining to neurodevelopmental investigations in medication-exposed pregnancies. Experts were identified for their experience regarding neurodevelopmental outcomes following medicinal, substances of misuse or environmental exposures in utero. Two questionnaire rounds and a virtual discussion meeting were used to explore expert opinion on the topics identified by the stakeholders. Results: Twenty-five experts, from 13 countries and professionally diverse backgrounds took part in the development of 11 recommendations. The recommendations focus on the importance of neurodevelopment as a core feature of pregnancy pharmacovigilance, the timing of study initiation and a core set of distinct but interrelated neurodevelopmental skills or diagnoses which require investigation. Studies should start in infancy with an extended period of investigation into adolescence, with more frequent sampling during rapid periods of development. Additionally, recommendations are made regarding optimal approach to neurodevelopmental outcome measurement, comparator groups, exposure factors, a core set of confounding and mediating variables, attrition, reporting of results and the required improvements in funding for potential later emerging effects. Different study designs will be required depending on the specific neurodevelopmental outcome type under investigation and whether the medicine in question is newly approved or already in widespread use. Conclusion: An improved focus on neurodevelopmental outcomes is required within pregnancy pharmacovigilance. These expert recommendations should be met across a complementary set of studies which converge to form a comprehensive set of evidence regarding neurodevelopmental outcomes in pregnancy pharmacovigilance.

Attention-deficit/hyperactivity disorder in children following prenatal exposure to antidepressants: results from the Norwegian mother, father and child cohort study.

OBJECTIVE: To determine the association between child attention-deficit/hyperactivity disorder (ADHD) and prenatal exposure to selective serotonin (SSRI) and serotonin-norepinephrine (SNRI) reuptake inhibitor antidepressants, by timing and duration, with quantification of bias due to exposure misclassification. DESIGN: Norwegian Mother, Father and Child Cohort Study and national health registries. SETTING: Nationwide, Norway. POPULATION: A total of 6395 children born to women who reported depression/anxiety in pregnancy and were either medicated with SSRI/SNRI in pregnancy (n = 818) or non-medicated (n = 5228), or did not report depression/anxiety but used antidepressants 6 months before pregnancy (discontinuers, n = 349). MAIN OUTCOME MEASURE: Diagnosis of ADHD or filled prescription for ADHD medication in children, and mother-reported symptoms of ADHD by child age 5 years. RESULTS: When the hazard was averaged over the duration of the study follow up, there was no difference in ADHD risk between ever in utero SSRI/SNRI-exposed children and comparators (weighted hazard ratio [wHR] 1.07, 95% CI 0.76-1.51 versus non-medicated; wHR 1.53, 95% CI 0.77-3.07 versus discontinuers). Underestimation of effects due to exposure misclassification was modest. In early childhood, the risk for ADHD was lower with prenatal SSRI/SNRI exposure compared with no exposure, and so were ADHD symptoms (weighted ß -0.23, 95% CI -0.39 to -0.08); this risk became elevated at child age 7-9 years (wHR 1.93, 95% CI 1.22-3.05). Maternal depression/anxiety before pregnancy was independently associated with child ADHD. CONCLUSION: Prenatal SSRI/SNRI exposure is unlikely to considerably increase the risk of child ADHD beyond that posed by maternal depression/anxiety. The elevated risk at child age 7-9 years needs to be elucidated. TWEETABLE ABSTRACT: Women with depression who use antidepressants in pregnancy do not have greater risk of having children with ADHD. Findings in school-age children needs follow up.

Diagnostic tests and treatment procedures performed prior to cardiovascular death in individuals with severe mental illness.

OBJECTIVE: To examine whether severe mental illnesses (i.e., schizophrenia or bipolar disorder) affected diagnostic testing and treatment for cardiovascular diseases in primary and specialized health care. METHODS: We performed a nationwide study of 72 385 individuals who died from cardiovascular disease, of whom 1487 had been diagnosed with severe mental illnesses. Log-binomial regression analysis was applied to study the impact of severe mental illnesses on the uptake of diagnostic tests (e.g., 24-h blood pressure, glucose/HbA1c measurements, electrocardiography, echocardiography, coronary angiography, and ultrasound of peripheral vessels) and invasive cardiovascular treatments (i.e., revascularization, arrhythmia treatment, and vascular surgery). RESULTS: Patients with and without severe mental illnesses had similar prevalences of cardiovascular diagnostic tests performed in primary care, but patients with schizophrenia had lower prevalences of specialized cardiovascular examinations (prevalence ratio (PR) 0.78; 95% CI 0.73-0.85). Subjects with severe mental illnesses had lower prevalences of invasive cardiovascular treatments (schizophrenia, PR 0.58; 95% CI 0.49-0.70, bipolar disorder, PR 0.78; 95% CI 0.66-0.92). The prevalence of invasive cardiovascular treatments was similar in patients with and without severe mental illnesses when cardiovascular disease was diagnosed before death. CONCLUSION: Better access to specialized cardiovascular examinations is important to ensure equal cardiovascular treatments among individuals with severe mental illnesses.

Undiagnosed cardiovascular disease prior to cardiovascular death in individuals with severe mental illness.

OBJECTIVE: To examine whether individuals with schizophrenia (SCZ) or bipolar disorder (BD) had equal likelihood of not being diagnosed with cardiovascular disease (CVD) prior to cardiovascular death, compared to individuals without SCZ or BD. METHODS: Multivariate logistic regression analysis including nationwide data of 72 451 cardiovascular deaths in the years 2011-2016. Of these, 814 had a SCZ diagnosis and 673 a BD diagnosis in primary or specialist health care. RESULTS: Individuals with SCZ were 66% more likely (OR: 1.66; 95% CI: 1.39-1.98), women with BD were 38% more likely (adjusted OR: 1.38; 95% CI: 1.04-1.82), and men with BD were equally likely (OR: 0.88, 95% CI: 0.63-1.24) not to be diagnosed with CVD prior to cardiovascular death, compared to individuals without SMI. Almost all (98%) individuals with SMI and undiagnosed CVD had visited primary or specialized somatic health care prior to death, compared to 88% among the other individuals who died of CVD. CONCLUSION: Individuals with SCZ and women with BD are more likely to die due to undiagnosed CVD, despite increased risk of CVD and many contacts with primary and specialized somatic care. Strengthened efforts to prevent, recognize, and treat CVD in individuals with SMI from young age are needed.

Diagnostic and genetic overlap of three common mental disorders in structured interviews and health registries.

OBJECTIVE: To investigate whether diagnostic data from structured interviews, primary care and specialist care registries on major depressive disorder (MDD), anxiety disorders (AD) and alcohol use disorder (AUD) identify the same individuals, yield comparable comorbidity estimates and reflect the same genetic influences. METHODS: Registry data from primary and specialist care were available for 11 727 twins and diagnostic interview data for 2271 of these. We used logistic regression analyses and biometric modelling to investigate the overlap between the data sources. RESULTS: Most individuals meeting diagnostic criteria at interview were not registered with a corresponding diagnosis. The rates of registration were higher for MDD (36% in primary care and 15% in specialist care) and AD (21% and 18%) than for AUD (3% and 7%). Comorbidity estimated as odds ratios, but not as polychoric correlations, was higher in the registries than in the interviews. Genetic influences on the disorders were highly correlated across data sources (median r = 0.81), bordering unity for MDD and AD. CONCLUSION: Prevalence and comorbidity estimates differ between registries and population-based assessment. Nevertheless, diagnoses from health registries reflect the same genetic influences as common mental disorders assessed in the general population, indicating generalizability of aetiological factors across data sources.

The interplay between cognitive ability, alcohol consumption, and health characteristics.

BACKGROUND: Higher cognitive ability is associated with favourable health characteristics. The relation between ability and alcohol consumption, and their interplay with other health characteristics, is unclear. We aimed to assess the relationship between cognitive ability and alcohol consumption and to assess whether alcohol consumption relates differently to health characteristics across strata of ability. METHODS: For 63 120 Norwegian males, data on cognitive ability in early adulthood were linked to midlife data on alcohol consumption frequency (times per month, 0-30) and other health characteristics, including cardiovascular risk factors and mental distress. Relations were assessed using linear regression and reported as unstandardised beta coefficients [95% confidence interval (CI)]. RESULTS: The mean ± s.d. frequency of total alcohol consumption in the sample was 4.0 ± 3.8 times per month. In the low, medium, and high group of ability, the frequencies were 3.0 ± 3.3, 3.7 ± 3.5, and 4.7 ± 4.1, respectively. In the full sample, alcohol consumption was associated with physical activity, heart rate, fat mass, smoking, and mental distress. Most notably, each additional day of consumption was associated with a 0.54% (0.44-0.64) and 0.14% (0.09-0.18) increase in the probability of current smoking and mental distress, respectively. In each strata of ability (low, medium, high), estimates were 0.87% (0.57-1.17), 0.48% (0.31-0.66) and 0.49% (0.36-0.62) for current smoking, and 0.44% (0.28-0.60), 0.10% (0.02-0.18), and 0.09% (0.03-0.15) for mental distress, respectively. CONCLUSIONS: Participants with low cognitive ability drink less frequently, but in this group, more frequent alcohol consumption is more strongly associated with adverse health characteristics.

Do DSM-5 Section II personality disorders and Section III personality trait domains reflect the same genetic and environmental risk factors?

BACKGROUND: DSM-5 includes two conceptualizations of personality disorders (PDs). The classification in Section II is identical to the one found in DSM-IV, and includes 10 categorical PDs. The Alternative Model (Section III) includes criteria for dimensional measures of maladaptive personality traits organized into five domains. The degree to which the two conceptualizations reflect the same etiological factors is not known. METHODS: We use data from a large population-based sample of adult twins from the Norwegian Institute of Public Health Twin Panel on interview-based DSM-IV PDs and a short self-report inventory that indexes the five domains of the DSM-5 Alternative Model plus a domain explicitly targeting compulsivity. Schizotypal, Paranoid, Antisocial, Borderline, Avoidant, and Obsessive-compulsive PDs were assessed at the same time as the maladaptive personality traits and 10 years previously. Schizoid, Histrionic, Narcissistic, and Dependent PDs were only assessed at the first interview. Biometric models were used to estimate overlap in genetic and environmental risk factors. RESULTS: When measured concurrently, there was 100% genetic overlap between the maladaptive trait domains and Paranoid, Schizotypal, Antisocial, Borderline, and Avoidant PDs. For OCPD, 43% of the genetic variance was shared with the domains. Genetic correlations between the individual domains and PDs ranged from +0.21 to +0.91. CONCLUSION: The pathological personality trait domains, which are part of the Alternative Model for classification of PDs in DSM-5 Section III, appears to tap, at an aggregate level, the same genetic risk factors as the DSM-5 Section II classification for most of the PDs.

The association between personality disorders with alcohol use and misuse: A population-based twin study.

BACKGROUND: A clearer understanding of the etiological overlap between DSM-IV personality disorders (PDs) and alcohol use (AU) and alcohol use disorder (AUD) is needed. To our knowledge, no study has modeled the association between all 10 DSM-IV PDs and lifetime AU and AUD. The aim of the present study is to identify which PDs are most strongly associated with the phenotypic, genetic, and environmental risks of lifetime AU and AUD, and to determine if these associations are stable across time. METHODS: Participants were Norwegian twins assessed at two waves. At Wave 1, 2801 twins were assessed for all 10 DSM-IV PD criteria, lifetime AU, and DSM-IV AUD criteria. At Wave 2, six of the 10 PDs were again assessed along with AU and AUD among 2393 twins. Univariate and multiple logistic regressions were run. Significant predictors were further analyzed using bivariate twin Cholesky decompositions. RESULTS: Borderline and antisocial PD criteria were the strongest predictors of AU and AUD across the two waves. Despite moderate phenotypic and genetic correlations, genetic variation in these PD criteria explained only 4% and 3% of the risks in AU, and 5% to 10% of the risks in AUD criteria, respectively. At Wave 2, these estimates increased to 8% and 23% for AU, and 17% and 33% for AUD. CONCLUSIONS: Among a large Norwegian twin sample, borderline and antisocial PD criteria were the strongest predictors of the phenotypic and genotypic liability to AU and AUD. This effect remained consistent across time.

Genetic factors contribute more to hip than knee surgery due to osteoarthritis - a population-based twin registry study of joint arthroplasty.

OBJECTIVE: To explore and quantify the relative strengths of the genetic contribution vs the contribution of modifiable environmental factors to severe osteoarthritis (OA) having progressed to total joint arthroplasty. DESIGN: Incident data from the Norwegian Arthroplasty Registry were linked with the Norwegian Twin Registry on the National ID-number in 2014 in a population-based prospective cohort study of same-sex twins born 1915-60 (53.4% females). Education level and height/weight were self-reported and Body Mass Index (BMI) calculated. The total follow-up time was 27 years for hip arthroplasty (1987-2014, 424,914 person-years) and 20 years for knee arthroplasty (1994-2014, 306,207 person-years). We estimated concordances and the genetic contribution to arthroplasty due to OA in separate analyses for the hip and knee joint. RESULTS: The population comprised N = 9058 twin pairs (N = 3803 monozygotic (MZ), N = 5226 dizygotic (DZ)). In total, 73% (95% confidence intervals (CI) = 66-78%) and 45% (95% CI = 30-58%) of the respective variation in hip and knee arthroplasty could be explained by genetic factors. Zygosity (as a proxy for genetic factors) was associated with hip arthroplasty concordance over time when adjusted for sex, age, education and BMI (HR = 2.98, 95% CI = 1.90-4.67 for MZ compared to DZ twins). Knee arthroplasty was to a greater extent dependent on BMI when adjusted for zygosity and the other covariates (HR = 1.15, 95% CI = 1.02-1.29). CONCLUSION: Hip arthroplasty was strongly influenced by genetic factors whereas knee arthroplasty to a greater extent depended on a high BMI. The study may imply there is a greater potential for preventing progression of knee OA to arthroplasty in comparison with hip OA.

The relationship between anxiety disorders and dimensional representations of DSM-IV personality disorders: A co-twin control study.

BACKGROUND: There is substantial comorbidity between personality disorders (PDs) and anxiety disorders (ADs). Sharing of familial risk factors possibly explains the co-occurrence, but direct causal relationships between the disorders may also exist. METHODS: 2801 persons from 1391 twin pairs from the Norwegian Institute of Public Health Twin Panel were assessed for all DSM-IV PDs and ADs. Bivariate Poisson-regression analyses were performed to assess whether PDs predicted ADs at three different levels: All PDs combined, PDs combined within DSM-IV-clusters and each individual PD separately. Next, bivariate co-twin control analyses were executed within monozygotic (MZ) and dizygotic (DZ) twin pairs. A similar analytic strategy was employed in multivariate models including PDs as independent variables. RESULTS: PDs predicted ADs at all levels of analysis in bivariate regression models. Bivariate co-twin control analyses demonstrated an increased risk of ADs in all PDs combined, all PD-clusters and in schizotypal, paranoid, borderline, antisocial, avoidant and dependent PD. In the multivariate regression model, all PD-clusters and schizotypal, borderline, avoidant and obsessive-compulsive PD predicted ADs. Only borderline and avoidant PD predicted ADs in the multivariate co-twin control analysis. LIMITATIONS: Over-adjustment may explain the results from the multivariate analyses. The cross-sectional study design hampers causal inference. CONCLUSIONS: Comorbidity between ADs and PDs can be largely accounted for by shared familial risk factors. However, the results are also consistent with a direct causal relationship partly explaining the co-occurrence. Our results indicate specific environmental factors for comorbidity of ADs and borderline and avoidant PDs that are not shared with other PDs.

A longitudinal, population-based twin study of avoidant and obsessive-compulsive personality disorder traits from early to middle adulthood.

BACKGROUND: The phenotypic stability of avoidant personality disorder (AVPD) and obsessive-compulsive personality disorder (OCPD) has previously been found to be moderate. However, little is known about the longitudinal structure of genetic and environmental factors for these disorders separately and jointly, and to what extent genetic and environmental factors contribute to their stability. METHOD: AVPD and OCPD criteria were assessed using the Structured Interview for DSM-IV Personality in 2793 young adult twins (1385 pairs, 23 singletons) from the Norwegian Institute of Public Health Twin Panel at wave 1 and 2282 (986 pairs, 310 singletons) of these on average 10 years later at wave 2. Longitudinal biometric models were fitted to AVPD and OCPD traits. RESULTS: For twins who participated at both time-points, the number of endorsed sub-threshold criteria for both personality disorders (PDs) decreased 31% from wave 1 to wave 2. Phenotypic correlations between waves were 0.54 and 0.37 for AVPD and OCPD, respectively. The heritability estimates of the stable PD liabilities were 0.67 for AVPD and 0.53 for OCPD. The genetic correlations were 1.00 for AVPD and 0.72 for OCPD, while the unique environmental influences correlated 0.26 and 0.23, respectively. The correlation between the stable AVPD and OCPD liabilities was 0.39 of which 63% was attributable to genetic influences. Shared environmental factors did not significantly contribute to PD variance at either waves 1 or 2. CONCLUSION: Phenotypic stability was moderate for AVPD and OCPD traits, and genetic factors contributed more than unique environmental factors to the stability both within and across phenotypes.

A longitudinal twin study of borderline and antisocial personality disorder traits in early to middle adulthood.

BACKGROUND: Antisocial personality disorder (ASPD) and borderline personality disorder (BPD) share genetic and environmental risk factors. Little is known about the temporal stability of these etiological factors in adulthood. METHOD: DSM-IV criteria for ASPD and BPD were assessed using structured interviews in 2282 Norwegian twins in early adulthood and again approximately 10 years later. Longitudinal biometric models were used to analyze the number of endorsed criteria. RESULTS: The mean criterion count for ASPD and BPD decreased 40% and 28%, respectively, from early to middle adulthood. Rank-order stability was 0.58 for ASPD and 0.45 for BPD. The best-fitting longitudinal twin model included only genetic and individual-specific environmental factors. Genetic effects, both those shared by ASPD and BPD, and those specific to each disorder remained completely stable. The unique environmental effects, however, changed substantially, with a correlation across time of 0.19 for the shared effects, and 0.39 and 0.15, respectively, for those specific to ASPD and BPD. Genetic effects accounted for 71% and 72% of the stability over time for ASPD and BPD, respectively. The genetic and environmental correlations between ASPD and BPD were 0.73, and 0.43, respectively, at both time points. CONCLUSION: ASPD and BPD traits were moderately stable from early to middle adulthood, mostly due to genetic risk factors which did not change over the 10-year assessment period. Environmental risk factors were mostly transient, and appear to be the main source of phenotypic change. Genetic liability factors were, to a large extent, shared by ASPD and BPD.

A longitudinal twin study of cluster A personality disorders.

BACKGROUND: While cluster A personality disorders (PDs) have been shown to be moderately heritable, we know little about the temporal stability of these genetic risk factors. METHOD: Paranoid PD (PPD) and schizotypal PD (STPD) were assessed using the Structured Interview for DSM-IV Personality in 2793 young adult twins from the Norwegian Institute of Public Health Twin Panel at wave 1 and 2282 twins on average 10 years later at wave 2. Using the program Mx, we fitted a longitudinal latent factor model using the number of endorsed criteria for PPD and STPD. RESULTS: The stability over time of the criteria counts for PPD and STPD, estimated as polychoric correlations, were +0.34 and +0.40, respectively. The best-fit longitudinal model included only additive genetic and individual-specific environmental factors with parameter estimates constrained to equality across the two waves. The cross-wave genetic and individual-specific environmental correlations for a latent cluster A factor were estimated to equal +1.00 and +0.13, respectively. The cross-time correlations for genetic and environmental effects specific to the individual PDs were estimated at +1.00 and +0.16-0.20, respectively. We found that 68% and 71% of the temporal stability of PPD and STPD derived, respectively, from the effect of genetic factors. CONCLUSION: Shared genetic risk factors for two of the cluster A PDs are highly stable in adults over a 10-year period while environmental risk factors are relatively transient. Over two-thirds of the long-term stability of the common cluster A PD liability can be attributed to genetic influences.

Exploring causal pathways of child behavior and maternal mental health in families with a child with congenital heart disease: a longitudinal study.

BACKGROUND: A congenital heart defect (CHD) can increase the risk of mental health problems in affected children and their parents. The extent to which risk factors for these problems are shared in families or are specific to the individual family member is unclear. METHOD: Prospective data from the Norwegian Mother and Child Cohort Study (MoBa; n = 93,009) were linked with a nationwide CHD registry, and 408 children with CHD were identified. Mothers' reports on child internalizing problems and their own distress were assessed by questionnaires at child ages 6, 18 and 36 months. A structural model was applied to distinguish between familial (shared) factors and individual-specific factors for mental health problems. RESULTS: CHD was a substantial risk factor for problems in children and their mothers at all time points. CHD contributed on average 31% and 39% to the variance in children's and mothers' problems respectively. Both shared familial and individual-specific factors unique to CHD families contributed to risk for mental health problems. Whereas individual-specific risk factors contributed to the stability of problems in mothers, the effect of these factors lasted only a short time in children. Mutual influences over time were found between the mother's and the child's mental health at 18 and 36 months. CONCLUSIONS: The burden of CHD in a child is shared between family members but is also specific to the individual. This study points to a need for both an individual and a family-based approach to provide psychological support to children with CHD and their parents.

Feeding infants with CHD with breast milk: Norwegian Mother and Child Cohort Study.

OBJECTIVE: To explore the prevalence of breast milk feeding (BMF) of infants with congenital heart defects (CHD) during first 6 months of life, as compared with general population. DESIGN: The study is based on a subsample of the Norwegian Mother and Child Cohort Study conducted by Norwegian Institute of Public Health. A total of 60,600 mothers completed a questionnaire about infant feeding at 6 months postpartum. Infants with moderate/severe CHD (n = 131) were identified using nationwide CHD registry. A group of infants with CHD with comorbidity was also defined (n = 65). BMF was classified as predominant, continued, or no BMF. Month to month feeding status was analysed by means of Cox regression analyses. RESULTS: Between child age 2-6 months, mothers of infants with CHD had a hazard ratio (HR) of 1.69 of weaning their child compared with mothers of controls. Mothers of infants with CHD with comorbidity weaned at an even faster rate (HR 3.54). At age 6 months, 9.9% of infants with CHD were fed with breast milk predominately, 64.1% continued to receive breast milk, and only 26% were fed no breast milk. For infants with CHD with comorbidity, corresponding percentages were 7.7%, 43.1% and 49.2%, respectively. CONCLUSIONS: Although CHD alone and particularly CHD with comorbidity increased risk that mothers wean earlier, a relatively high rate of continued breastfeeding was maintained. Future studies should investigate factors that support continued BMF even in the most severely affected children with CHD.