The bidirectional association between premenstrual disorders and perinatal depression: A nationwide register-based study from Sweden.

BACKGROUND: Premenstrual disorders (PMDs) and perinatal depression (PND) share symptomology and the timing of symptoms of both conditions coincide with natural hormonal fluctuations, which may indicate a shared etiology. Yet, there is a notable absence of prospective data on the potential bidirectional association between these conditions, which is crucial for guiding clinical management. Using the Swedish nationwide registers with prospectively collected data, we aimed to investigate the bidirectional association between PMDs and PND. METHODS AND FINDINGS: With 1,803,309 singleton pregnancies of 1,041,419 women recorded in the Swedish Medical Birth Register during 2001 to 2018, we conducted a nested case-control study to examine the risk of PND following PMDs, which is equivalent to a cohort study, and transitioned that design into a matched cohort study with onward follow-up to simulate a prospective study design and examine the risk of PMDs after PND (within the same study population). Incident PND and PMDs were identified through clinical diagnoses or prescribed medications. We randomly selected 10 pregnant women without PND, individually matched to each PND case on maternal age and calendar year using incidence density sampling (N: 84,949: 849,482). We (1) calculated odds ratio (OR) and 95% confidence intervals (CIs) of PMDs using conditional logistic regression in the nested case-control study. Demographic factors (country of birth, educational level, region of residency, and cohabitation status) were adjusted for. We (2) calculated the hazard ratio (HR) and 95% CIs of PMDs subsequent to PND using stratified Cox regression in the matched cohort study. Smoking, BMI, parity, and history of psychiatric disorders were further controlled for, in addition to demographic factors. Pregnancies from full sisters of PND cases were identified for sibling comparison, which contrasts the risk within each set of full sisters discordant on PND. In the nested case-control study, we identified 2,488 PMDs (2.9%) before pregnancy among women with PND and 5,199 (0.6%) among controls. PMDs were associated with a higher risk of subsequent PND (OR 4.76, 95% CI [4.52,5.01]; p < 0.001). In the matched cohort with a mean follow-up of 7.40 years, we identified 4,227 newly diagnosed PMDs among women with PND (incidence rate (IR) 7.6/1,000 person-years) and 21,326 among controls (IR 3.8). Compared to their matched controls, women with PND were at higher risk of subsequent PMDs (HR 1.81, 95% CI [1.74,1.88]; p < 0.001). The bidirectional association was noted for both prenatal and postnatal depression and was stronger among women without history of psychiatric disorders (p for interaction < 0.001). Sibling comparison showed somewhat attenuated, yet statistically significant, bidirectional associations. The main limitation of this study was that our findings, based on clinical diagnoses recorded in registers, may not generalize well to women with mild PMDs or PND. CONCLUSIONS: In this study, we observed a bidirectional association between PMDs and PND. These findings suggest that a history of PMDs can inform PND susceptibility and vice versa and lend support to the shared etiology between both disorders.

Quantifying the Relative Importance of Genetics and Environment on the Comorbidity between Mental- and Cardiometabolic Disorders: A Comprehensive Analysis of National Register Data from 17 million Scandinavians.

Mental disorders (MDs) are leading causes of disability and premature death worldwide, partly due to high comorbidity with cardiometabolic disorders (CMDs). Reasons for this comorbidity are still poorly understood. We leverage nation-wide health records and complete genealogies of Denmark and Sweden (n=17 million) to reveal the genetic and environmental contributions underlying the observed comorbidity between six MDs and 14 CMDs. Genetic factors contributed about 50% to the comorbidity of schizophrenia, affective disorders, and autism spectrum disorder with CMDs, whereas the comorbidity of attention-deficit/hyperactivity disorder and anorexia with CMDs was mainly or fully driven by environmental factors. These findings provide causal insight to guide clinical and scientific initiatives directed at achieving mechanistic understanding as well as preventing and alleviating the consequences of these disorders.

Childhood maltreatment and risk of endocrine diseases: an exploration of mediating pathways using sequential mediation analysis.

BACKGROUND: Adverse childhood experiences (ACEs), including childhood maltreatment, have been linked with increased risk of diabetes and obesity during adulthood. A comprehensive assessment on the associations between childhood maltreatment and all major endocrine diseases, as well as the relative importance of different proposed mechanistic pathways on these associations, is currently lacking. METHODS: Based on the UK Biobank, we constructed a cohort including 151,659 participants with self-reported data on childhood maltreatment who were 30 years of age or older on/after January 1, 1985. All participants were followed from the index date (i.e., January 1, 1985, or their 30th birthday, whichever came later) until the first diagnosis of any or specific (12 individual diagnoses and 9 subtypes) endocrine diseases, death, or the end of follow-up (December 31, 2019), whichever occurred first. We used Cox models to examine the association of childhood maltreatment, treated as continuous (i.e., the cumulative number of experienced childhood maltreatment), ordinal (i.e., 0, 1 and ≥ 2), or binary (< 2 and ≥ 2) variable, with any and specific endocrine diseases, adjusted for multiple covariates. We further examined the risk of having multiple endocrine diseases using Linear or Logistic Regression models. Then, sequential mediation analyses were performed to assess the contribution of four possible mechanisms (i.e., suboptimal socioeconomic status (SES), psychological adversities, unfavorable lifestyle, and biological alterations) on the observed associations. RESULTS: During an average follow-up of 30.8 years, 20,885 participants received a diagnosis of endocrine diseases. We observed an association between the cumulative number of experienced childhood maltreatment and increased risk of being diagnosed with any endocrine disease (adjusted hazard ratio (HR) = 1.10, 95% confidence interval 1.09-1.12). The HR was 1.26 (1.22-1.30) when comparing individuals ≥ 2 with those with < 2 experienced childhood maltreatment. We further noted the most pronounced associations for type 2 diabetes (1.40 (1.33-1.48)) and hypothalamic-pituitary-adrenal (HPA)-axis-related endocrine diseases (1.38 (1.17-1.62)), and the association was stronger for having multiple endocrine diseases, compared to having one (odds ratio (95% CI) = 1.24 (1.19-1.30), 1.35 (1.27-1.44), and 1.52 (1.52-1.53) for 1, 2, and ≥ 3, respectively). Sequential mediation analyses showed that the association between childhood maltreatment and endocrine diseases was consistently and most distinctly mediated by psychological adversities (15.38 ~ 44.97%), while unfavorable lifestyle (10.86 ~ 25.32%) was additionally noted for type 2 diabetes whereas suboptimal SES (14.42 ~ 39.33%) for HPA-axis-related endocrine diseases. CONCLUSIONS: Our study demonstrates that adverse psychological sequel of childhood maltreatment constitutes the main pathway to multiple endocrine diseases, particularly type 2 diabetes and HPA-axis-related endocrine diseases. Therefore, increased access to evidence-based mental health services may also be pivotal in reducing the risk of endocrine diseases among childhood maltreatment-exposed individuals.

Disease clusters subsequent to anxiety and stress-related disorders and their genetic determinants.

Anxiety/stress-related disorders have been associated with multiple diseases, whereas a comprehensive assessment of the structure and interplay of subsequent associated diseases and their genetic underpinnings is lacking. Here, we first identify 136, out of 454 tested, medical conditions associated with incident anxiety/stress-related disorders attended in specialized care using a population-based cohort from the nationwide Swedish Patient Register, comprising 70,026 patients with anxiety/stress-related disorders and 1:10 birth year- and sex-matched unaffected individuals. By combining findings from the comorbidity network and disease trajectory analyses, we identify five robust disease clusters to be associated with a prior diagnosis of anxiety/stress-related disorders, featured by predominance of psychiatric disorders, eye diseases, ear diseases, cardiovascular diseases, and skin and genitourinary diseases. These five clusters and their featured diseases are largely validated in the UK Biobank. GWAS analyses based on the UK Biobank identify 3, 33, 40, 4, and 16 significantly independent single nucleotide polymorphisms for the link to the five disease clusters, respectively, which are mapped to several distinct risk genes and biological pathways. These findings motivate further mechanistic explorations and aid early risk assessment for cluster-based disease prevention among patients with newly diagnosed anxiety/stress-related disorders in specialized care.

Incidence Trajectories of Psychiatric Disorders After Assault, Injury, and Bereavement.

Importance: Traumatic events have been associated with elevated risks of psychiatric disorders, while the contributions of familial factors to these associations remain less clear. Objective: To determine the contribution of familial factors to long-term incidence trajectories of psychiatric disorders following potentially traumatic events. Design, Setting, and Participants: This cohort study evaluated 3 separate cohorts of individuals residing in Sweden who were free of previous diagnosed psychiatric disorders when first exposed to assault (n = 49 957), injury (n = 555 314), or bereavement (n = 321 263) from January 1987 to December 2013, together with their unexposed full siblings, and 10 age-, sex-, and birthplace-matched unexposed individuals (per exposed individual). Cohorts were created from the Swedish Total Population Register linked to health and population registers. Data were analyzed from March 2022 to April 2023. Exposures: Potentially traumatic events, including various types of assault, injuries, and bereavement (death of a child or of a spouse or partner), were ascertained from the Swedish national registers. Main Outcomes and Measures: Incident psychiatric disorders were ascertained from the Swedish Patient Register. Flexible parametric and Cox models were used to estimate associations of potentially traumatic events with incident psychiatric disorders after multivariable adjustment. Results: The median (IQR) age at exposure to assault, injury, and bereavement was 22 (18-31), 19 (8-40), and 60 (51-68) years, respectively. During a median (IQR) follow-up of 4.9 (2.2-8.2), 9.1 (4.1-15.6), and 8.1 (3.4-14.8) years, the incidence rates of any psychiatric disorder were 38.1, 13.9, and 9.0 per 1000 person-years for the exposed groups of the 3 cohorts, respectively. Elevated risk of any psychiatric disorder was observed during the first year after exposure to any assault (hazard ratio [HR], 4.55; 95% CI, 4.34-4.77), injury (HR, 3.31; 95% CI,3.23-3.38), or bereavement (HR, 2.81; 95% CI, 2.72-2.91) and thereafter (assault HR, 2.50; 95% CI, 2.43-2.56; injury HR, 1.69; 95% CI, 1.68-1.70; bereavement HR, 1.42; 95% CI, 1.40-1.44). Comparable associations were obtained in sibling comparison (first year: assault HR, 3.70; 95% CI, 3.37-4.05; injury HR, 2.98; 95% CI, 2.85-3.12; bereavement HR, 2.72; 95% CI, 2.54-2.91; thereafter: assault HR, 1.93; 95% CI, 1.84-2.02; injury HR, 1.51; 95% CI, 1.48-1.53; bereavement HR, 1.35; 95% CI, 1.31-1.38). The risk elevation varied somewhat by type of traumatic events and psychiatric disorders, with the greatest HR noted for posttraumatic stress disorder after sexual assault (sibling comparison HR, 4.52; 95% CI, 3.56-5.73 during entire follow-up period). Conclusions and Relevance: In this study, the long-term risk elevation of psychiatric disorders after potentially traumatic events was largely independent of familial factors. The risk elevation observed immediately after these events motivates early clinical surveillance and mental health services for these vulnerable populations.

Bidirectional association between autoimmune disease and perinatal depression: a nationwide study with sibling comparison.

Although major depression, characterized by a pro-inflammatory profile, genetically overlap with autoimmune disease (AD) and the perinatal period involve immune system adaptations and AD symptom alterations, the bidirectional link between perinatal depression (PND) and AD is largely unexplored. Hence, the objective of this study was to investigate the bidirectional association between PND and AD. Using nationwide Swedish population and health registers, we conducted a nested case-control study and a matched cohort study. From 1,347,901 pregnancies during 2001-2013, we included 55,299 incident PND, their unaffected full sisters, and 10 unaffected matched women per PND case. We identified 41 subtypes of AD diagnoses recorded in the registers and compared PND with unaffected population-matched women and full sisters, using multivariable regressions. Women with an AD had a 30% higher risk of subsequent PND (95% CI 1.2-1.5) and women exposed to PND had a 30% higher risk of a subsequent AD (95% CI 1.3-1.4). Comparable associations were found when comparing exposed women with their unaffected sisters (nested case-control OR: 1.3, 95% CI 1.2-1.5, matched cohort HR: 1.3, 95% CI 1.1-1.6), and when studying antepartum and postpartum depression. The bidirectional association was more pronounced among women without psychiatric comorbidities (nested case-control OR: 1.5, 95% CI 1.4-1.6, matched cohort HR: 1.4, 95% CI 1.4-1.5) and strongest for multiple sclerosis (nested case-control OR: 2.0, 95% CI 1.6-2.3, matched cohort HR: 1.8, 95% CI 1.0-3.1). These findings demonstrate a bidirectional association between AD and PND independent of psychiatric comorbidities, suggesting possibly shared biological mechanisms. If future translational science confirms the underlying mechanisms, healthcare providers need to be aware of the increased risk of PND among women with ADs and vice versa.

Perinatal depression and risk of mortality: nationwide, register based study in Sweden.

OBJECTIVE: To determine whether women with perinatal depression are at an increased risk of death compared with women who did not develop the disorder, and compared with full sisters. DESIGN: Nationwide, register based study. SETTING: Swedish national registers, 1 January 2001 to 31 December 2018. PARTICIPANTS: 86 551 women with a first ever diagnosis of perinatal depression ascertained through specialised care and use of antidepressants, and 865 510 women who did not have perinatal depression were identified and matched based on age and calendar year at delivery. To address familial confounding factors, comparisons were made between 270 586 full sisters (women with perinatal depression (n=24 473) and full sisters who did not have this disorder (n=246 113)), who gave at least one singleton birth during the study period. MAIN OUTCOME MEASURES: Primary outcome was death due to any cause. Secondary outcome was cause specific deaths (ie, unnatural and natural causes). Multivariable Cox regression was used to estimate hazard ratios of mortality comparing women with perinatal depression to unaffected women and sisters, taking into account several confounders. The temporal patterns of perinatal depression and differences between antepartum and postpartum onset of perinatal depression were also studied. RESULTS: 522 deaths (0.82 per 1000 person years) were reported among women with perinatal depression diagnosed at a median age of 31.0 years (interquartile range 27.0 to 35.0) over up to 18 years of follow-up. Compared with women who did not have perinatal depression, women with perinatal depression were associated with an increased risk of death (adjusted hazard ratio 2.11 (95% confidence interval 1.86 to 2.40)); similar associations were reported among women who had and did not have pre-existing psychiatric disorder. Risk of death seemed to be increased for postpartum than for antepartum depression (hazard ratio 2.71 (95% confidence interval 2.26 to 3.26) v 1.62 (1.34 to 1.94)). A similar association was noted for perinatal depression in the sibling comparison (2.12 (1.16 to 3.88)). The association was most pronounced within the first year after perinatal depression but remained up to 18 years after start of follow up. An increased risk was associated with both unnatural and natural causes of death among women with perinatal depression (4.28 (3.44 to 5.32) v (1.38 (1.16 to 1.64)), with the strongest association noted for suicide (6.34 (4.62 to 8.71)), although suicide was rare (0.23 per 1000 person years). CONCLUSIONS: Even when accounting for familial factors, women with clinically diagnosed perinatal depression were associated with an increased risk of death, particularly during the first year after diagnosis and because of suicide. Women who are affected, their families, and health professionals should be aware of these severe health hazards after perinatal depression.

Adverse childhood experiences and psychological functioning among women with schizophrenia or bipolar disorder: population-based study.

BACKGROUND: Adverse childhood experiences (ACEs) are well-known risk factors for schizophrenia and bipolar disorder. AIMS: The aim was to study the associations between specific ACEs and psychological functioning in women with schizophrenia or bipolar disorder. METHOD: Among 29 367 women (mean age 44 years) from the Icelandic Stress-And-Gene-Analysis (SAGA) study, 534 (1.8%, mean age 40) reported having been diagnosed with schizophrenia or bipolar disorder, which were combined to 'severe mental disorders'. Participants reported on 13 types of ACEs, childhood deprivation and psychological functioning (defined as coping ability and current symptoms of depression, anxiety and sleep disturbances). Adjusted Poisson regression calculated prevalence ratios (PRs) between ACEs and severe mental disorders. Linear regression assessed the association between ACEs and psychological functioning among women with a severe mental disorder. RESULTS: Women with a severe mental disorder reported more ACEs (mean 4.57, s.d. = 2.82) than women without (mean 2.51, s.d. = 2.34) in a dose-dependent manner (fully-adjusted PR = 1.23 per ACE, 95% CI 1.20-1.27). After mutual adjustment for other ACEs, emotional abuse, sexual abuse, mental illness of a household member, emotional neglect, bullying and collective violence were associated with severe mental disorders. Among women with severe mental disorders, a higher number of ACEs was associated with increased symptom burden of depression (ß = 2.79, 95% CI = 1.19-4.38) and anxiety (ß = 2.04, 95% CI = 0.99-3.09) including poorer sleep quality (ß = 0.83, 95% CI = 0.07-1.59). Findings were similar for schizophrenia and bipolar disorder separately. CONCLUSION: Women with schizophrenia or bipolar disorder show a strong history of ACEs, which may interfere with their psychological functioning and, therefore, need to be addressed as part of their treatment, for example, with trauma-focused psychotherapy.

Distinct genomic signatures and modifiable risk factors underly the comorbidity between major depressive disorder and cardiovascular disease.

Major depressive disorder (MDD) and cardiovascular disease (CVD) are often comorbid, resulting in excess morbidity and mortality. Using genomic data, this study elucidates biological mechanisms, key risk factors, and causal pathways underlying their comorbidity. We show that CVDs share a large proportion of their genetic risk factors with MDD. Multivariate genome-wide association analysis of the shared genetic liability between MDD and atherosclerotic CVD (ASCVD) revealed seven novel loci and distinct patterns of tissue and brain cell-type enrichments, suggesting a role for the thalamus. Part of the genetic overlap was explained by shared inflammatory, metabolic, and psychosocial/lifestyle risk factors. Finally, we found support for causal effects of genetic liability to MDD on CVD risk, but not from most CVDs to MDD, and demonstrated that the causal effects were partly explained by metabolic and psychosocial/lifestyle factors. The distinct signature of MDD-ASCVD comorbidity aligns with the idea of an immunometabolic sub-type of MDD more strongly associated with CVD than overall MDD. In summary, we identify plausible biological mechanisms underlying MDD-CVD comorbidity, as well as key modifiable risk factors for prevention of CVD in individuals with MDD.

Mental Distress Among Norwegian Adults During the COVID-19 Pandemic: Predictors in Initial Response and Subsequent Trajectories.

Objectives: To identify factors associated with change in mental distress at the onset of the COVID-19 pandemic, relative to pre-pandemic levels, and with changes during the following 1.5 years. Methods: The prospective Norwegian Mother, Father and Child Cohort Study collected eight waves of data during the pandemic (March 2020-September 2021) in 105,972 adult participants used for this analyses. A piecewise latent growth model was fitted to identify initial level and longitudinal changes in mental distress. Results: Mental distress peaked at the beginning of the pandemic. Factors associated with initial increases were: medical conditions, living alone, history of psychiatric disorders, lower education, female sex, younger age, and obesity. Being quarantined or infected with SARS-CoV-2 were associated with increasing distress while being vaccinated was associated with reduced mental distress. Conclusion: Having a chronic disease and being quarantined or infected by the SARS-CoV-2 virus were associated with more mental distress during the pandemic. This knowledge is important for planning interventions to support individuals during future pandemics and other societal crises.

Psychobiological stress response to a lung cancer diagnosis: a prospective study of patients in Iceland and Sweden.

BACKGROUND: A diagnostic work-up leading to a lung cancer diagnosis is a severely stressful experience that may impact tumor progression. Yet, prospective data are scarce on psychological and biological components of stress at the time of lung cancer diagnosis. The aim of this study was to assess pre-to-post diagnosis change in psychological distress and urinary excretion of catecholamines in patients with suspected lung cancer. METHODS: Participants were 167 patients within the LUCASS study, recruited at referral for suspected lung cancer to University Hospitals in Iceland and Sweden. Patients completed questionnaires on perceived distress (Hospital Anxiety and Depression Scale, HADS) before and after diagnosis of lung cancer or a non-malignant origin. A subpopulation of 85 patients also provided overnight urine for catecholamine analysis before and at a median of 24 days after diagnosis but before treatment. RESULTS: A lung cancer diagnosis was confirmed in 123 (73.7%) patients, with a mean age of 70.1 years. Patients diagnosed with lung cancer experienced a post-diagnosis increase in psychological distress (p = 0.010), while patients with non-malignant lung pathology showed a reduction in distress (p = 0.070). Both urinary epinephrine (p = 0.001) and norepinephrine (p = 0.032) levels were higher before the diagnosis among patients eventually diagnosed with lung cancer compared to those with non-malignant lung pathology. We observed indications of associations between pre-to-post diagnosis changes in perceived distress and changes in urinary catecholamine levels. CONCLUSION: Receiving a lung cancer diagnosis is associated with an increase in psychological distress, while elevated catecholamine levels are evident already before lung cancer diagnosis.

Overall and Cervical Cancer Survival in Patients With and Without Mental Disorders.

Importance: Individuals with a mental disorder experience substantial health disparity and are less likely to participate in cervical screening and human papillomavirus vaccination. Additionally, this population may benefit less from tertiary cancer prevention. Objective: To compare clinical characteristics and survival patterns between patients with cervical cancer with and without a preexisting diagnosis of a mental disorder at the time of cervical cancer diagnosis. Design, Setting, and Participants: This cohort study obtained data from Swedish population-based (Swedish Cancer Register, Swedish Cause of Death Register, Swedish Total Population Register, Swedish Patient Register, and Swedish Longitudinal Integration Database for Health Insurance and Labor Market Studies) and quality registries (Swedish Quality Register of Gynecologic Cancer and Swedish National Cervical Screening Register) on patients with cervical cancer. Patients who were included in the analysis were identified using the Swedish Cancer Register and were diagnosed with cervical cancer between 1978 and 2018. The Swedish Patient Register was used to identify patients with mental disorders using codes from the International Classification of Diseases, Eighth Revision and Ninth Revision and the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. Because data on clinical characteristics at the time of cancer diagnosis were available for only for part of the study population, 2 patient groups were created: those with cervical cancer diagnosed from 2002 to 2016 and all patients diagnosed with cervical cancer (1978-2018). Data analyses were carried out between March and September 2022. Exposure: Clinical diagnoses of a mental disorder, including substance abuse, psychotic disorders, depression, anxiety, stress-related disorders, attention-deficit/hyperactivity disorder, autism, and intellectual disability, prior to cervical cancer. Main Outcomes and Measures: Death due to any cause or due to cervical cancer as ascertained from the Swedish Cause of Death Register. Results: The sample included 20 177 females (mean [SD] age, 53.4 [17.7] years) diagnosed with cervical cancer from 1978 to 2018. In a subgroup of 6725 females (mean [SD] age, 52.2 [18.0] years) with cervical cancer diagnosed from 2002 to 2016, 893 (13.3%) had a preexisting diagnosis of a mental disorder. Compared with patients with no preexisting mental disorder diagnosis, those with a preexisting mental disorder had a higher risk of death due to any cause (hazard ratio [HR], 1.32; 95% CI, 1.17-1.48) and due to cervical cancer (HR, 1.23; 95% CI, 1.07-1.42). These risks were lower after adjustment for cancer characteristics at the time of cancer diagnosis (death due to any cause: HR, 1.19 [95% CI, 1.06-1.34] and death due to cervical cancer: HR, 1.12 [95% CI, 0.97-1.30]). Risk of death was higher for patients with substance abuse, psychotic disorders, or mental disorders requiring inpatient care. Among patients with cervical cancer diagnosed from 1978 to 2018, the estimated 5-year survival improved continuously during the study period regardless of preexisting diagnosis of a mental disorder status. For example, in 2018, the estimated 5-year overall survival proportion was 0.66 (95% CI, 0.60-0.71) and 0.74 (95% CI, 0.72-0.76) for patients with and without a preexisting diagnosis of a mental disorder, respectively. Conclusions and Relevance: Findings of this cohort study suggest that patients with cervical cancer and a preexisting diagnosis of a mental disorder have worse overall and cervical cancer-specific survival than patients without a preexisting mental disorder diagnosis, which may be partly attributable to cancer and sociodemographic characteristics at diagnosis. Hence, individuals with mental disorders deserve special attention in the tertiary prevention of cervical cancer.

Premenstrual Disorders, Timing of Menopause, and Severity of Vasomotor Symptoms.

Importance: Although premenstrual disorders (PMDs) end at menopause, it is unclear whether they are associated with the timing and symptom severity of menopause. Objective: To prospectively examine whether women with PMDs have increased risks of early menopause and menopause-related vasomotor symptoms (VMS). Design, Setting, and Participants: This population-based cohort study was nested in the Nurses' Health Study II (data collected from questionnaire sent between June 1991 and June 2017). Analysis of menopause timing included participants who did not have natural or surgical menopause before study entry, while the analysis of VMS was restricted to women who provided information on VMS. Data were analyzed from August 2022 to March 2023. Exposures: PMDs were identified by self-reported diagnosis and confirmed with symptom questionnaires from 1991 to 2005. Participants were age-matched to women without PMD diagnoses and confirmed absence of or minimal premenstrual symptoms. Main Outcomes and Measures: During follow-up through 2017, timing of natural menopause was assessed biennially, and VMS were assessed in 2009, 2013, and 2017. The association of PMDs with early menopause was assessed by Cox proportional hazards models and with VMS by logistic regression models. Results: Of 1220 included women with PMDs, the median (IQR) age was 40.7 (37.3-43.8) years; of 2415 included women without PMDs, the median (IQR) age was 41.7 (38.3-44.8) years. The median (IQR) follow-up in this study was 20.3 (17.8-22-2) years. Early natural menopause (menopause before age 45 years) was reported by 17 women with PMDs (7.1 per 1000 person-years) and 12 women without PMDs (2.7 per 1000 person-years; adjusted hazard ratio, 2.67; 95% CI, 1.27-5.59). In addition, 795 women with PMDs (68.3%) and 1313 women without PMDs (55.3%) reported moderate or severe VMS (adjusted odds ratio, 1.68; 95% CI, 1.32-2.14). There was no observed association between PMDs and mild VMS (adjusted odds ratio, 0.99; 95% CI, 0.76-1.28). Conclusions and Relevance: In this cohort study of US women, PMDs were associated with increased risks of early menopause and moderate or severe VMS. PMDs may be indicative of underlying physiology linked to early menopause and VMS, suggesting a phenotype observable during the reproductive years that may allow clinicians to target women at risk of earlier menopause and subsequent health risks later in the life course.

Association between adverse childhood experiences and perinatal depressive symptoms: a cross-sectional analysis of 16,831 women in Iceland.

Emerging data suggest that certain adverse childhood experiences (ACEs) are associated with perinatal depression (PND). However, few studies have comprehensively assessed the cumulative number and types of ACEs and their association to PND. We conducted a cross-sectional analysis among 16,831 female participants from the Stress-And-Gene-Analysis (SAGA) cohort in Iceland, 2018. ACEs were surveyed with the World Health Organization ACE-International questionnaire, while PND symptoms were assessed using the Edinburgh Postnatal Depression Scale (lifetime version). We, while adjusting for confounding factors, estimated the prevalence ratio (PR) of PND in relation to total number of ACEs using the Poisson quasi-likelihood model and further performed analyses for type-specific ACEs. At a mean age of 44 years (SD ± 11.1), 6,201 (36.8%) participants had experienced probable PND. Total number of ACEs was positively associated with PND (PR 1.11 per ACE, 95% CI: 1.10-1.11), also among women without any psychiatric comorbidities (PR 1.13, 95% CI: 1.11-1.14). PRs increased in a dose-response manner with the number of ACEs (P for trend < 0.001); women that endorsed 5 or more ACEs were twice as likely to have experienced PND (PR 2.24, 95% CI: 2.09-2.41). All ACE types (n = 13) were associated with PND, with most pronounced association for emotional neglect by a guardian (PR 1.53, 95% CI: 1.47-1.59). Our findings suggest a positive association between number of ACEs and PND symptoms. If our results are confirmed with prospective data, healthcare providers need to be alert of the risk of PND among expecting mothers with history of ACEs.

Premenstrual disorders and gender differences in adolescent mental health.

BACKGROUND: Gender differences in mental health emerge in adolescence. The timing coincides with the development of premenstrual disorders (PMDs). Here, we examine the association between PMDs and adolescent mental health in the context of gender differences. METHODS: A cross-sectional analysis comprising 21,239[10,563 (49.7 %) girls] individuals aged 10-19 years from the Santai Youth Mental Health Promotion Cohort in China. Possible PMDs, major depression disorder (MDD), general anxiety disorder (GAD), history of self-injury, and high suicide-risk status were surveyed using standard questionnaires. We used logistic regression to contrast the prevalence of outcomes between girls with and without PMDs, and boys. RESULTS: The prevalence rates of possible MDD and GAD were comparable between girls without PMDs and boys [OR1.03 (0.96-1.11) and 0.99 (0.92-1.07)], whereas a higher burden was observed in girls with PMDs [OR4.76(4.31-5.26) and 3.86(3.50-4.27), respectively]. Moreover, MDD/GAD prevalence among premenarchal girls was comparable to their peer boys. Greater gender differences in self-injury and high suicide-risk status were also found for girls with PMDs [OR 4.70 (4.22-5.24) and 7.49 (6.6-8.5)] than that for girls without PMDs [OR1.45(1.33-1.59) and 1.81 (1.62-2.03)]. LIMITATION: Girls with PMDs may have overreported depressive and/or anxiety symptoms due to the overlap of symptomology. CONCLUSIONS: The greater gender differences in adolescent mental ill-health among girls with PMDs lend support to the hypothesis that PMDs play an important role in the gender disparities in adolescent mental health, particularly in depression and anxiety.

Adverse health consequences of undiagnosed hearing loss at middle age: A prospective cohort study with the UK Biobank.

OBJECTIVES: Hearing impairment is common in the middle-aged population but remains largely undiagnosed and untreated. The knowledge about to what extent and how hearing impairment matters for health is currently lacking. Thus, we aimed to comprehensively examine the adverse health consequences as well as the comorbidity patterns of undiagnosed hearing loss. STUDY DESIGN: Based on the prospective cohort of the UK Biobank, we included 14,620 individuals (median age 61 years) with audiometry-determined (i.e., speech-in-noise test) objective hearing loss and 38,479 individuals with subjective hearing loss (i.e., tested negative but with self-reported hearing problems; median age 58 years) at recruitment (2006-2010), together with 29,240 and 38,479 matched unexposed individuals respectively. MAIN OUTCOME MEASURES: Cox regression was used to determine the associations of both hearing-loss exposures with the risk of 499 medical conditions and 14 cause-specific deaths, adjusting for ethnicity, annual household income, smoking and alcohol intake, exposure to working noise, and BMI. Comorbidity patterns following both exposures were visualized by comorbidity modules (i.e., sets of connected diseases) identified in the comorbidity network analyses. RESULTS: During a median follow-up of 9 years, 28 medical conditions and mortality related to nervous system disease showed significant associations with prior objective hearing loss. Subsequently, the comorbidity network identified four comorbidity modules (i.e., neurodegenerative, respiratory, psychiatric, and cardiometabolic diseases), with the most pronounced association noted for the module related to neurodegenerative diseases (meta-hazard ratio [HR] = 2.00, 95%confidence interval [CI] 1.67-2.39). For subjective hearing loss, we found 57 associated medical conditions, which were partitioned into four modules (i.e., diseases related to the digestive, psychiatric, inflammatory, and cardiometabolic systems), with meta-HRs varying from 1.17 to 1.25. CONCLUSIONS: Undiagnosed hearing loss captured by screening could identify individuals with at greater risk of multiple adverse health consequences, highlighting the importance of screening for speech-in-noise hearing impairment in the middle-aged population, for potential early diagnosis and intervention.

Genetic Associations Between Stress-Related Disorders and Autoimmune Disease.

Objective: Emerging evidence supports a bidirectional phenotypic association between stress-related disorders and autoimmune disease. However, the biological underpinnings remain unclear. Here, the authors examined whether and how shared genetics contribute to the observed phenotypic associations. Methods: Based on data from 4,123,631 individuals identified from Swedish nationwide registers, familial coaggregation of stress-related disorders (any disorder or posttraumatic stress disorder [PTSD]) and autoimmune disease were initially estimated in seven cohorts with different degrees of kinship. Polygenic risk score (PRS) analyses were then performed with individual-level genotyping data from 376,871 participants in the UK Biobank study. Finally, genetic correlation analyses and enrichment analyses were performed with genome-wide association study (GWAS) summary statistics. Results: Familial coaggregation analyses revealed decreasing odds of concurrence of stress-related disorders and autoimmune disease with descending kinship or genetic relatedness between pairs of relatives; adjusted odds ratios were 1.51 (95% CI=1.09­2.07), 1.28 (95% CI=0.97­1.68), 1.16 (95% CI=1.14­1.18), and 1.01 (95% CI=0.98­1.03) for monozygotic twins, dizygotic twins, full siblings, and half cousins, respectively. Statistically significant positive associations were observed between PRSs of stress-related disorders and autoimmune disease, as well as between PRSs of autoimmune disease and stress-related disorders. GWAS summary statistics revealed a genetic correlation of 0.26 (95% CI=0.14­0.38) between these two phenotypes and identified 10 common genes and five shared functional modules, including one module related to G-protein­coupled receptor pathways. Similar analyses performed for PTSD and specific autoimmune diseases (e.g., autoimmune thyroid disease) largely recapitulated the results of the main analyses. Conclusions: This study demonstrated familial coaggregation, genetic correlation, and common biological pathways between stress-related disorders and autoimmune disease.

Short-term improvement of mental health after a COVID-19 vaccination.

INTRODUCTION: The role of COVID-19 vaccination on the mental health of the general population remains poorly understood. This study aims to assess the short-term change in depressive and anxiety symptoms in relation to COVID-19 vaccination among Swedish adults. METHODS: A prospective study of 7,925 individuals recruited from ongoing cohort studies at the Karolinska Institutet, Stockholm, Sweden, or through social media campaigns, with monthly data collections on self-reported depressive and anxiety symptoms from December 2020 to October 2021 and COVID-19 vaccination from July to October 2021. Prevalence of depressive and anxiety symptoms (defined as a self-reported total score of ≥10 in PHQ-9 and GAD-7, respectively) was calculated one month before, one month after the first dose, and, if applicable, one month after the second dose. For individuals not vaccinated or choosing not to report vaccination status (unvaccinated individuals), we selected three monthly measures of PHQ-9 and GAD-7 with 2-month intervals in-between based on data availability. RESULTS: 5,079 (64.1%) individuals received two doses of COVID-19 vaccine, 1,977 (24.9%) received one dose, 305 (3.9%) were not vaccinated, and 564 (7.1%) chose not to report vaccination status. There was a lower prevalence of depressive and anxiety symptoms among vaccinated, compared to unvaccinated individuals, especially after the second dose. Among individuals receiving two doses of vaccine, the prevalence of depressive and anxiety symptoms was lower after both first (aRR = 0.82, 95%CI 0.76-0.88 for depression; aRR = 0.81, 95%CI 0.73-0.89 for anxiety) and second (aRR = 0.79, 95%CI 0.73-0.85 for depression; aRR = 0.73, 95%CI 0.66-0.81 for anxiety) dose, compared to before vaccination. Similar results were observed among individuals receiving only one dose (aRR = 0.76, 95%CI 0.68-0.84 for depression; aRR = 0.82, 95%CI 0.72-0.94 for anxiety), comparing after first dose to before vaccination. CONCLUSIONS: We observed a short-term improvement in depressive and anxiety symptoms among adults receiving COVID-19 vaccines in the current pandemic. Our findings provide new evidence to support outreach campaigns targeting hesitant groups.

The Association of Physical Activity Behaviors and Patterns With Aging Acceleration: Evidence From the UK Biobank.

Prior evidence suggests that physical activity may reduce the risk of multiple diseases and mortality. However, whether and how physical activity affects the aging process remains largely unexplored. We included 284 479 UK Biobank participants and computed leukocyte telomere length (LTL) deviation (ie, the difference between genetically determined and observed LTL) and biological age acceleration (defined as the discrepancy between the phenotypic age of a person and the average phenotypic age in the cohort of individuals with the same age and sex) as the indexes for aging acceleration. Linear and logistic models were used to estimate the associations of self-reported physical activity items and patterns (identified by principal component analysis), as well as accelerometer-assessed physical activity, with aging acceleration. Analyses of physical activity patterns indicated, a higher level of adherence to activity patterns predominated by strenuous sports, other exercises, walking for pleasure, heavy and light housework, and public transportation use was associated with a lower risk of aging acceleration, whereas a higher level of adherence to patterns predominated by job-related activities was associated with a higher risk of aging acceleration. Analysis among 62 418 participants with accelerometer-measured physical activity corroborated these results. Physical activity, such as strenuous sports and other exercises in leisure time and the use of public transportation, was associated with reduced biological aging. Besides highlighting the importance of engaging in physical activity for healthy aging, our results provide further evidence for the beneficial effect of physical activity on the telomere attrition process.