The risk of miscarriage after COVID-19 vaccination before and during pregnancy.

PURPOSE: Pregnant women are at higher risk of severe illness and adverse pregnancy outcomes due to a SARS-CoV-2 infection, which can be prevented by vaccination. Observational studies are needed to ascertain the safety of COVID-19 vaccination during pregnancy. We aimed to determine whether COVID-19 vaccination before and during pregnancy is associated with the risk of miscarriage. METHODS: In this cohort study, we included 4640 pregnant women (mean age: 32.8 ± 3.7 years) from the Dutch Pregnancy Drug Register between February 2021 and August 2022. Information on COVID-19 vaccinations, miscarriage, and confounders was self-reported, using web-based questionnaires. The hazard ratio (HR) of miscarriage (in gestational weeks 6-20) after a COVID-19 vaccination, was estimated using the survival analyses. A COVID-19 vaccination during pregnancy (≥1 COVID-19 vaccination between week 2 and 20 of pregnancy) was included as a time-dependent exposure and vaccination prior to pregnancy was included as a binary exposure. RESULTS: A total of 3202 pregnant women (69%) received ≥1 COVID-19 vaccine in gestational week 2-20. We observed no association of vaccination during pregnancy with the risk of miscarriage (adjusted HR = 1.29, 95% CI = 0.93-1.74). Vaccination prior to pregnancy, however, was associated with a decreased risk of miscarriage (adjusted HR = 0.69, 95% CI = 0.48-0.99). CONCLUSIONS: We demonstrated that COVID-19 vaccination during pregnancy is not associated with an increased risk of miscarriage in gestational weeks 6-20. This study adds to the growing body of evidence demonstrating the safety of COVID-19 vaccination during pregnancy.

Maternal first trimester COVID-19 vaccination and risk of major non-genetic congenital anomalies.

BACKGROUND: Information regarding the risk of early pregnancy COVID-19 vaccination on the development of major congenital anomalies in the offspring is still limited. Here, we study the association between any COVID-19 vaccination during the 1st trimester and at least one major non-genetic congenital anomaly in the offspring. METHODS: We used data from the Dutch Pregnancy Drug Register, an ongoing cohort study. We selected participants with a pregnancy that ended after at least 20 weeks gestation. Pregnant participants self-reported their COVID-19 vaccination status and the presence of congenital anomalies in the offspring. We used logistic regression analyses to study the association between 1st trimester COVID-19 vaccination (gestational week 2 + 0 to 12 + 6) and the risk of at least one major non-genetic congenital anomaly in the offspring. Clustering of anomalies on the ICD10 level by 1st trimester COVID-19 vaccination status was explored using Fisher exact tests. RESULTS: We included 3721 participants of whom 795 (21.4%) were COVID-19 vaccinated during the 1st trimester. The percentage of participants who gave birth to a child with at least one major non-genetic congenital anomaly was comparable between participants who were 1st trimester vaccinated (1.1%) and participants who were not (1.2%) (adjusted odd ratio 0.78 [95% confidence interval 0.35-1.71]). We found no clustering of major non-genetic congenital anomalies by 1st trimester COVID-19 vaccination status (p > .05). CONCLUSIONS: There were no indications of an increased risk of major non-genetic congenital anomalies in the offspring after maternal 1st trimester COVID-19 vaccination. Our findings suggest COVID-19 vaccines are safe during early pregnancy.

Psychosocial health modifies associations between HPA-axis function and brain structure in older age.

BACKGROUND: Dysregulation of the negative feedback loop of the hypothalamic-pituitary-adrenal (HPA) axis may have damaging effects on the brain, potentially under influence of psychosocial health factors. We studied associations between functioning of the negative feedback loop of HPA-axis, measured with a very low-dose dexamethasone suppression test (DST), and brain structure in middle-aged and older adults, and whether these associations were modified by psychosocial health. METHODS: From 2006 to 2008, 1259 participants (mean age 57.6 ± 6.4, 59.6 % female) of the population-based Rotterdam Study completed a very low-dose DST (0.25 mg) and underwent magnetic resonance imaging (MRI) of the brain. Self-reported psychosocial health (depressive symptoms, loneliness, marital status, perceived social support) were assessed in the same time period. Multivariable linear and logistic regression were used to study cross-sectional associations between cortisol response and brain volumetrics, cerebral small vessel disease markers and white matter structural integrity. To assess the effect of psychosocial health on these associations, analyses were further stratified for psychosocial health markers. RESULTS: Cortisol response was not associated with markers of global brain structure in the overall study sample. However, in participants with clinically relevant depressive symptoms, a diminished cortisol response was associated with smaller white matter volume (mean difference: - 1.00 mL, 95 %CI = - 1.89;- 0.10) and smaller white matter hyperintensity volume (mean difference: - 0.03 mL (log), 95 %CI = - 0.05;0.00). In participants with low/moderate perceived social support compared to those with high social support, a diminished cortisol response was associated with larger gray matter volume (mean difference: 0.70 mL, 95 %CI = 0.01;1.39) and higher fractional anisotropy (standardized mean difference 0.03, 95 %CI = 0.00;0.06). CONCLUSION: Diminished function of the HPA-axis is differently associated with brain structure in community-dwelling middle-aged and older adults with clinically relevant depressive symptoms or suboptimal social support, but not in adults without depressive symptoms or with optimal social support.

The bidirectional association of 24-h activity rhythms and sleep with depressive symptoms in middle-aged and elderly persons.

BACKGROUND: In older populations disturbed 24-h activity rhythms, poor sleep, and depressive symptoms are often lingering and co-morbid, making treatment difficult. To improve insights into these commonly co-occurring problems, we assessed the bidirectional association of sleep and 24-h activity rhythms with depressive symptoms in middle-aged and elderly persons. METHODS: In 1734 participants (mean age: 62.3 ± 9.3 years, 55% women) from the prospective Rotterdam Study, 24-h activity rhythms and sleep were estimated with actigraphy (mean duration: 146 ± 19.6 h), sleep quality with the Pittsburgh Sleep Quality Index, and depressive symptoms with the Center for Epidemiological Studies Depression scale. Repeated measures were available for 947 participants (54%) over a median follow-up of 6 years (interquartile range = 5.6-6.3). Linear-mixed models were used to assess temporal associations of 24-h activity rhythms and sleep with depressive symptoms in both directions. RESULTS: High 24-h activity rhythm fragmentation (IV) (B = 1.002, 95% confidence interval (CI) = 0.641-1.363), long time in bed (TIB) (B = 0.111, 95% CI = 0.053-0.169), low sleep efficiency (SE) (B = -0.015, 95% CI = -0.020 to -0.009), long sleep onset latency (SOL) (B = 0.009, 95% CI = 0.006-0.012), and low self-rated sleep quality (B = 0.112, 95% CI = 0.0992-0.124) at baseline were associated with increasing depressive symptoms over time. Conversely, more depressive symptoms at baseline were associated with an increasing 24-h activity rhythm fragmentation (B = 0.002, 95% CI = 0.001-0.003) and TIB (B = 0.009, 95% CI = 0.004-0.015), and a decreasing SE (B = -0.140, 95% CI = -0.196 to -0.084), SOL (B = 0.013, 95% CI = 0.008-0.018), and self-rated sleep quality (B = 0.193, 95% CI = 0.171-0.215) over time. CONCLUSION: This study demonstrates a bidirectional association of 24-h activity rhythms, actigraphy-estimated sleep, and self-rated sleep quality with depressive symptoms over a time frame of multiple years in middle-aged and elderly persons.

The Cross-Sectional Association Between Tinnitus and Actigraphy-Estimated Sleep in a Population-Based Cohort of Middle-Aged and Elderly Persons.

OBJECTIVES: Tinnitus is a common and burdensome disease, often accompanied by complaints of poor sleep. However, associations of tinnitus with objective estimates of sleep remain unclear, particularly in the general population. We assessed these associations in a population-based cohort of middle-aged and elderly persons. DESIGN: This study included 1456 participants (mean age: 65.0 ± 7.1 years, 52% women) from the population-based Rotterdam Study. Tinnitus was self-reported and in those who reported tinnitus daily, symptom severity was assessed with the Tinnitus Handicap Inventory. We used actigraphy to estimate sleep and 24-hour activity rhythms objectively and sleep diaries to assess self-reported sleep. We estimated the difference in sleep and 24-hour activity rhythms first between those with and those without tinnitus and secondly with tinnitus severity. RESULTS: Tinnitus, reported by 341 (23%) participants, and tinnitus severity, assessed in 194 participants with daily tinnitus, were not associated with actigraphy-estimated sleep or 24-hour activity rhythms, but were associated with a longer self-reported sleep onset latency (adjusted difference tinnitus = 2.36, 95% confidence interval [CI] = 0.95-3.78, adjusted difference tinnitus severity = 0.27, 95% CI = 0.013-0.54). After stratification for hearing loss, tinnitus was associated with longer self-reported sleep onset latency (adjusted difference = 2.26, 95% CI = 0.98-3.53) and less stable 24-hour activity rhythms (adjusted difference = -0.02, 95% CI = -0.04 to -0.00) in those with hearing loss. In those without hearing loss, tinnitus was associated with more stable rhythms (adjusted difference = 0.03, 95% CI = 0.01-0.05). CONCLUSIONS: Having tinnitus is associated with a longer self-reported sleep onset latency, but not with objective estimates of sleep, suggesting that the subjective experience of sleep may be particularly disturbed in those with tinnitus. In addition, hearing loss may modify the association of tinnitus and 24-hour activity rhythms.

Associations of neuroimaging markers with depressive symptoms over time in middle-aged and elderly persons.

BACKGROUND: Cerebrovascular disease is regarded as a potential cause of late-life depression. Yet, evidence for associations of neuroimaging markers of vascular brain disease with depressive symptoms is inconclusive. We examined the associations of neuroimaging markers and depressive symptoms in a large population-based study of middle-aged and elderly persons over time. METHODS: A total of 4943 participants (mean age = 64.6 ± 11.1 years, 55.7% women) from the Rotterdam Study were included. At baseline, total brain volume, gray matter volume, white matter volume, white matter hyperintensities volume, cortical infarcts, lacunar infarcts, microbleeds, white matter fractional anisotropy, and mean diffusivity (MD) were measured with a brain MRI (1.5T). Depressive symptoms were assessed twice with the Center for Epidemiologic Studies Depression scale (median follow-up time: 5.5 years, IQR = 0.9). To assess temporal associations of neuroimaging markers and depressive symptoms, linear mixed models were used. RESULTS: A smaller total brain volume (ß = -0.107, 95% CI -0.192 to -0.022), larger white matter hyperintensities volume (ß = 0.047, 95% CI 0.010-0.084), presence of cortical infarcts (ß = 0.194, 95% CI 0.047-0.341), and higher MD levels (ß = 0.060, 95% CI 0.022-0.098) were cross-sectionally associated with more depressive symptoms. Longitudinal analyses showed that small total brain volume (ß = -0.091, 95% CI -0.167 to -0.015) and presence of cortical infarcts (ß = 0.168, 95% CI 0.022-0.314) were associated with increasing depressive symptoms over time. After stratification on age, effect sizes were more pronounced at older ages. CONCLUSIONS: Neuroimaging markers of white matter microstructural damage were associated with depressive symptoms longitudinally in this study of middle-aged and elderly persons. These associations were more pronounced at older ages, providing evidence for the role of white matter structure in late-life depressive symptomatology.

The network of psychosocial health in middle-aged and older adults during the first COVID-19 lockdown.

PURPOSE: Psychosocial health problems, such as social isolation, loneliness, depression and anxiety, have gained attention during the COVID-19 pandemic and are commonly co-occurring. We investigated the network of psychosocial health constructs during the COVID-19 pandemic. METHODS: This study included 4553 participants (mean age: 68.6 ± 11.2 years, 56% women) from the prospective Rotterdam Study, who filled out a questionnaire between April and July 2020, the time of the first COVID-19 wave in the Netherlands. Psychosocial health constructs included were depressive symptoms (Center for Epidemiological Studies Depression scale), anxiety symptoms (Hospital Anxiety and Depression scale), loneliness (University of California, Los Angeles loneliness scale), social connectedness (five items) and pandemic-related worry (five items). We estimated mixed graphical models to assess the network of items of these constructs and whether age and sex affected the network structure. RESULTS: Within the network of psychosocial constructs, a higher depressive symptoms score was particularly associated with items of loneliness and social connectedness, whereas overall anxiety was particularly associated with items of pandemic-related worry. Between people from different sex and age, the network structure significantly altered. CONCLUSION: This study demonstrates that within the same network of psychosocial health constructs, depressive symptom score is particularly associated with loneliness and social connectedness, whereas anxiety symptom score is associated with pandemic-related worry during the first COVID-19 lockdown. Our results support that psychosocial constructs should be considered in conjunction with one another in prevention and treatment efforts in clinical care, and that these efforts need to be tailored to specific demographic groups.

The longitudinal association of sleep and 24-hour activity rhythms with cortisol response to a very low dose of dexamethasone.

OBJECTIVES: Poor sleep is common in the general population, with hyperarousal and stress often suggested as causal factors. Conversely, sleep might also affect the stress response, in which the hypothalamic-pituitary-adrenal (HPA) axis plays a key role. We assessed the longitudinal association of sleep and 24-hour activity rhythms with functioning of the negative feedback loop of the HPA axis, as indicated by the cortisol response to a very low dose of dexamethasone. DESIGN: Longitudinal cohort. SETTING: Population-based. PARTICIPANTS: This study included 410 participants (mean age: 56.1 ± 5.5 years, 59% women) from the Rotterdam Study. For 217 participants, the cortisol response to dexamethasone was assessed again after a median follow-up of 5.7 years (IQR = 5.5-5.8). MEASUREMENTS: Between 2004 and 2007, sleep and 24-hour activity rhythms were estimated with actigraphy (mean duration: 146 ± 19.6 hours) and sleep quality with the Pittsburgh Sleep Quality Index. To assess the negative feedback loop of the HPA axis we measured cortisol before and after the intake of a very low-dose of dexamethasone (0.25 mg). RESULTS: Unstable (B = 1.64, 95% CI = 0.78; 2.50) and fragmented (B = -1.31, 95% CI = -2.17; -0.45) 24-hour activity rhythms, and a poor self-rated sleep quality (B = -0.02, 95% CI = -0.04; 0.00) were associated with an enhanced cortisol response to dexamethasone over time, also in those without clinically relevant depressive symptoms and those not using psychoactive medication. CONCLUSIONS: This study demonstrates a longitudinal association of disturbed 24-hour activity rhythms and poor self-rated sleep quality with an enhanced cortisol response to dexamethasone, in other words stronger suppression of cortisol. STATEMENT OF SIGNIFICANCE: This study shows that disturbed 24-hour activity rhythms and a poor self-rated sleep quality are associated with functioning of the negative feedback loop over a period of years.

Polysomnography-estimated sleep and the negative feedback loop of the hypothalamic-pituitary-adrenal (HPA) axis.

BACKGROUND: Sleep and stress are highly interrelated. To improve our understanding of the role of sleep in functioning of the negative feedback loop of the stress system, we assessed the association between sleep and functioning of the hypothalamic-pituitary-adrenal (HPA) axis in a population-based sample. METHODS: This study included 403 participants (mean age: 62.4 ± 5.0 years, 55% women) of the population-based Rotterdam Study. Between 2012 and 2014, sleep was assessed with polysomnography. Functioning of the negative feedback loop of the HPA axis was estimated by measuring cortisol levels before and after the intake of a very low dose of dexamethasone (0.25 mg) on average 0.9 ± 37.8 days after the polysomnography. We used linear regression analyses adjusted for multiple confounders and performed sensitivity analyses in a sample excluding those with clinically relevant depressive symptoms and using psychoactive medicine, and a sample excluding non-suppressors. RESULTS: Short N2 sleep (adjusted difference = 0.005, 95%CI = 0.002;0.009), long N3 sleep (adjusted difference = -0.007, 95%CI = -0.010;-0.003), and short sleep onset latency (adjusted difference = 0.006, 95%CI = 0.001;0.011) were associated with an enhanced response to dexamethasone, but the association of sleep onset latency did not survive multiple testing correction. Associations remained similar after excluding those with clinically relevant depressive symptoms and those using psychoactive medicine or exclusion of non-suppressors. CONCLUSIONS: This study suggests that more slow wave sleep is particularly associated with a stronger suppression of cortisol within the negative feedback loop of the HPA axis. These findings provide further support that slow wave sleep is important for health.

Trajectories of depression and anxiety during the COVID-19 pandemic in a population-based sample of middle-aged and older adults.

The COVID-19 pandemic and the related governmental restrictions have greatly impacted the lives of people worldwide and have been suggested to negatively impact mental health. We describe the trajectories of depressive and anxiety symptoms during the pandemic and their determinants in a large population-based sample of middle-aged and older adults. From April to June 2020, participants of the Rotterdam Study were asked to complete questionnaires including questions on depressive symptoms (Center of Epidemiological Studies Depression Scale, 10 item version) and anxiety symptoms (Hospital Anxiety and Depression Scale, anxiety subscale). We compared depressive and anxiety symptom scores to those before the pandemic and described its trajectories during the pandemic by demographic variables, chronic disease status and pre-pandemic clinically relevant depressive or anxiety symptoms. In total, 6241 participants responded to the questionnaires (mean age [standard deviation] 70.1 years [11.6]; 58% women). Participants more often reported clinically relevant depressive symptoms during than before the pandemic (19% vs. 12%, P < .001), which was similar for clinically relevant anxiety symptoms (17% vs. 12%, P < .001). During the pandemic, depressive symptoms persisted over time while anxiety symptoms improved. Depressive and anxiety symptoms were more common among women, persons living alone, with chronic diseases and with pre-pandemic clinically relevant symptoms, although the trajectories of these symptoms over time were broadly similar for the subgroups. Together, these results suggest that it is important to be aware of long-term depressive symptoms following the COVID-19 pandemic in the general population.

Design, implementation and initial findings of COVID-19 research in the Rotterdam Study: leveraging existing infrastructure for population-based investigations on an emerging disease.

The Rotterdam Study is an ongoing prospective, population-based cohort study that started in 1989 in the city of Rotterdam, the Netherlands. The study aims to unravel etiology, preclinical course, natural history and potential targets for intervention for chronic diseases in mid-life and late-life. It focuses on cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, otolaryngological, locomotor, and respiratory diseases. In response to the COVID-19 pandemic, a substudy was designed and embedded within the Rotterdam Study. On the 20th of April, 2020, all living non-institutionalized participants of the Rotterdam Study (n = 8732) were invited to participate in this sub-study by filling out a series of questionnaires administered over a period of 8 months. These questionnaires included questions on COVID-19 related symptoms and risk factors, characterization of lifestyle and mental health changes, and determination of health care seeking and health care avoiding behavior during the pandemic. As of May 2021, the questionnaire had been sent out repeatedly for a total of six times with an overall response rate of 76%. This article provides an overview of the rationale, design, and implementation of this sub-study nested within the Rotterdam Study. Finally, initial results on participant characteristics and prevalence of COVID-19 in this community-dwelling population are shown.

Cross-sectional and Longitudinal Associations Between Tinnitus and Mental Health in a Population-Based Sample of Middle-aged and Elderly Persons.

Importance: Tinnitus is a common disorder, but its impact on daily life varies widely in population-based samples. It is unclear whether this interference in daily life is associated with mental health problems that are commonly detected in clinical populations. Objective: To investigate the association of tinnitus and its interference in daily life with symptoms of depression and anxiety and poor sleep quality in a population-based sample of middle-aged and elderly persons in a cross-sectional analysis and during a 4-year follow-up. Design, Setting, and Participants: This cohort study evaluated data from the population-based Rotterdam Study of individuals 40 years or older living in Rotterdam, the Netherlands. Between 2011 and 2016, data on tinnitus were obtained during a home interview at least once for 6128 participants. Participants with information on depressive and anxiety symptoms and self-rated sleep quality, with Mini-Mental State Examination scores indicating unimpaired cognition, and with repeatedly obtained tinnitus and mental health outcome data were included. Data analyses were conducted between September 2019 and April 2020. Main Outcomes and Measures: The presence of tinnitus and its interference with daily life were assessed during a home interview. Depressive symptoms were assessed with the Center for Epidemiologic Studies-Depression, anxiety symptoms with the Hospital Anxiety and Depression Scale, and sleep quality with the Pittsburgh Sleep Quality Index. Linear regression analyses and linear mixed models adjusted for relevant confounders were used to assess the cross-sectional and longitudinal association of tinnitus with mental health. Results: Of 5418 complete-case participants (mean [SD] age, 69.0 [9.8] years; 3131 [57.8%] women), 975 (mean [SD] age, 71.7 [4.5] years; 519 [53.2%] women) had repeated measurements available for follow-up analyses. Compared with participants without tinnitus and participants with nonbothersome tinnitus, participants with tinnitus interfering with daily life reported more depressive (difference, 0.20; 95% CI, 0.11-0.28) and anxiety (difference, 0.15; 95% CI, 0.08-0.22) symptoms and poorer sleep quality (difference, 0.10; 95% CI, 0.03-0.16). Compared with participants without tinnitus, participants with nonbothersome tinnitus also reported more depressive (difference, 0.06; 95% CI, 0.03-0.09) and anxiety (difference, 0.05; 95% CI, 0.02-0.07) symptoms and poorer sleep quality (difference, 0.05; 95% CI, 0.03-0.08). Individuals indicating more interference with daily life reported having more mental health problems. During a mean follow-up of 4.4 years (range, 3.5-5.1 years), participants with tinnitus reported more anxiety symptoms and poorer sleep quality than those without tinnitus. Conclusions and Relevance: Findings of this population-based cohort study indicate that tinnitus was associated with more mental health problems in middle-aged and elderly persons in the general population, in particular when tinnitus interfered with daily life but not solely. Over time, more severe tinnitus was associated with an increase in anxiety symptoms and poor sleep quality. This outcome suggests that mental health problems may be part of the burden of tinnitus, even among individuals who do not report their tinnitus interfering with daily life.

The longitudinal association of actigraphy-estimated sleep with grief in middle-aged and elderly persons.

Most people experience grief after a loss, about 10% develop complicated grief, often accompanied by sleep complaints. Yet, the role of objectively estimated poor sleep remains unclear. Therefore, we assessed the cross-sectional and longitudinal association of actigraphy-estimated sleep with grief. We included 1,776 participants (mean age: 61.8 ± 8.9 years, 55% women) of a prospective population-based cohort. Of 1,471 participants (83%) repeated measures of grief were available (median follow-up 6 years, inter quartile range 5.6-6.3). At baseline, sleep was objectively estimated using actigraphy (mean duration 6.0 ± 0.8days). At baseline and follow-up, participants were asked about significant losses and completed the Dutch Inventory of Complicated Grief (17 items, cut-off ≥22). At baseline 1,521 (86%) participants experienced no grief, 44 (2%) acute grief (<6 months, any grief score), 158 (9%) non-complicated grief (≥6 months, grief score<22), and 53 (3%) complicated grief (≥6 months, grief score≥22). In those indicating any grief (n = 255), low sleep efficiency (B = -0.16, 95%CI = -0.30;-0.02), long sleep onset latency (B = 0.07, 95%CI = 0.01; 0.14), and long wake after sleep onset (B = 0.06, 95%CI = 0.01; 0.10) were cross-sectionally associated with more grief symptoms. Over time, those with a short total sleep time (OR = 0.59, 95%CI = 0.39; 0.91), low sleep efficiency (OR = 0.95, 95%CI = 0.91; 0.99), long sleep onset latency (OR = 1.02, 95%CI = 1.00; 1.04), and long wake after sleep onset (OR = 1.02, 95%CI = 1.00; 1.03) at baseline more often experienced complicated grief than non-complicated grief at follow-up. This study suggests that objectively estimated poor sleep is associated with grief over time. Poor sleep might not only accompany grief, but also be a risk factor for developing complicated grief after a loss.