Célia Kowal

PharmaD Hugo Peyre

PhD Ali Amad

PhD Antoine Pelissolo

PhD Marion Leboyer

PhD Franck Schürhoff

PhD Baptiste Pignon
email: baptistepignon@yahoo.fr

Psychotic, mood and anxiety disorders and venous thromboembolism: a systematic review and meta-analysis

Keywords: Venous thromboembolism disease, Deep venous thrombosis, Pulmonary embolism, Psychotic disorders, Bipolar disorders, Depression

Objective

Several studies have shown that psychiatric disorders can be associated with venous thromboembolism (VTE) risk, i.e. pulmonary embolism (PE) and/or deep vein thrombosis (DVT). In this study, we provide a systematic review and meta-analyses of the studies addressing this issue.

Methods

All studies addressing the risk of VTE phenomena (whole VTE, PE, DVT, fatal VTE) in subjects with psychotic, mood and anxiety disorders published between 1998 and 2019 were reviewed and included in the meta-analyses. Main characteristics of the studies and data concerning VTE risk were extracted. The methodological qualities of the studies were also analysed.

A random-effects meta-analysis model was used. A meta-analysis was conducted separately for each disorder, as well as separately for unadjusted and adjusted studies. Metaanalyses were repeated considering only good-quality studies. Heterogeneity was assessed.

Results

Sixteen studies were reviewed and 15 included in the meta-analyses. Psychotic and bipolar disorders were significantly associated with VTE risk (VTE, DVT, PE, fatal VTE for psychotic disorder, ORs between 1.29 and 2.20; VTE, DVT and PE for bipolar disorder, ORs between 1.22 and 2.14). Depression and anxiety disorders were associated with VTE risk only in adjusted analyses (DVT and PE for depression, ORs = 1.29; VTE and PE for anxiety disorders, ORs between 1.14 and 1.49).

Conclusions

The risk of VTE among subjects with psychiatric disorders may be explained by hypercoagulability and stasis, with both being related to, and independent of, treatment sideeffects. VTE risk should be taken into consideration in the treatment of people with psychiatric disorders.

INTRODUCTION

Psychiatric disorders are associated with premature mortality. A recent cohort study in Denmark shows that the mortality rate ratio (MRR) of people with psychiatric disorders was 2.53 (95 % CI [2.52-2.54]), with variations according to the particular disorder (e.g., schizophrenia: MRR = 2.57, or mood disorders: MRR = 1.92) [START_REF] Plana-Ripoll | A comprehensive analysis of mortality-related health metrics associated with mental disorders: a nationwide, register-based cohort study[END_REF]. Considering all psychiatric disorders, the causes of this excessive mortality can be external (i.e., suicide, accidents or homicide) or natural, including circulatory (i.e., cardiovascular or cerebrovascular: MRR = 2.45, 95 % CI [2. 43-2.47]) and diabetes (MRR = 2.61, 95 % CI [2. 53-2.69]). A longitudinal study of subjects with psychotic or bipolar disorders in London found standardized mortality ratios (SMR) of 2.65 (95 % CI [2.45-2.86]) for circulatory system causes, 3.38 (95 % CI [3.04-3.74]) for respiratory system causes, and 1.45 (95 % CI [1.32-1.60]) for cancers deaths [START_REF] Das-Munshi | Ethnicity and excess mortality in severe mental illness: a cohort study[END_REF].

Venous thromboembolism (VTE), i.e. pulmonary embolism (PE) and/or deep vein thrombosis (DVT), are the third most common cardiovascular disorders, after coronary artery disease and heart failure, with an overall annual incidence of between 100 and 200 per 100,000 inhabitants [START_REF] Cohen | VTE Impact Assessment Group in Europe (VITAE). Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality[END_REF][START_REF] Delluc | Current incidence of venous thromboembolism and comparison with 1998: a community-based study in Western France[END_REF]. VTE is associated with high mortality rates. In a Canadian longitudinal study based on general populations registers, the 30-day and 1-year fatality was 2.0 % and 9.2 %, and was higher when PE alone was considered [START_REF] Alotaibi | Secular Trends in Incidence and Mortality of Acute Venous Thromboembolism: The AB-VTE Population-Based Study[END_REF].

Several studies and meta-analysis have shown that some psychotropic medications were associated with VTE phenomena, particularly concerning first-and second-generation antipsychotics (FGA: Odds-ratio (OR) = 1.74, 95 % CI [1. 28-2.37], SGA: OR = 2.07, 95 % CI [1.74-2.52]) [START_REF] Barbui | Antipsychotic drug exposure and risk of venous thromboembolism: a systematic review and meta-analysis of observational studies[END_REF], or antidepressants drugs (Relative-risk (RR) = 1.27, 95 % CI [1.06-1.51]) [START_REF] Kunutsor | Depression, antidepressant use, and risk of venous thromboembolism: systematic review and meta-analysis of published observational evidence[END_REF].

Other factors, such as low-grade inflammation, sedentary lifestyle, tobacco and substance use comorbidities, or metabolic syndrome are also associated with VTE phenomena [START_REF] Healy | Mortality in schizophrenia and related psychoses: data from two cohorts, 1875-1924 and 1994-2010[END_REF][START_REF] Leboyer | Can bipolar disorder be viewed as a multi-system inflammatory disease?[END_REF][START_REF] Saghazadeh | Inflammation as a cause of venous thromboembolism[END_REF][START_REF] Song | Metabolic Syndrome and Deep Vein Thrombosis After Total Knee and Hip Arthroplasty[END_REF][START_REF] Bonaldi | Hospitalizations for cardiovascular diseases attributable to tobacco smoking in France in 2015[END_REF][START_REF] Fond | Chronic low-grade peripheral inflammation is associated with ultra resistant schizophrenia. Results from the FACE-SZ cohort[END_REF]. These various factors are frequently and differentially associated with different psychiatric disorders.

Consequently, it would be interesting to gather and synthesize the different studies pertaining to the risk of VTE among patients with psychiatric disorders, independently of the risk factors.

Aims of the study

In the present systematic review and meta-analysis, our aim was to determine the risk of whole venous thromboembolism, pulmonary embolism, deep vein thrombosis, and fatal venous thromboembolism associated with different psychiatric disorders.

METHODS

We developed and followed a standard meta-analysis protocol previously registered (prospero registration number CRD42020136915, see Supplementary material).

Inclusion and exclusion criteria

The inclusion criteria of the different studies in this systematic review were:

-original studies; -clinical prospective or retrospective studies; -studies analysing the risk of VTE, PE, DVT, and/or fatal VTE among subjects/patients with psychiatric disorders in comparison to subjects/patients without psychiatric disorders (i.e., that published numbers of patients with and without VTE phenomena and with or without psychiatric disorders); -targeted psychiatric disorders were: psychotic disorders, bipolar disorders, depression, anxiety disorders and catatonia.

In addition to these criteria, and in order to be meta-analysed, the different psychiatric disorders need to be studied by at least two studies. Consequently, a psychiatric disorder with only one study would be added in the systematic review but not included in the meta-analysis.

The exclusion criteria were:

-no control population; -clinical psychiatric population (i.e. patients hospitalized in psychiatry settings, or subjects with psychiatric disorders) as control population; -in vitro studies; -no statistical comparison of VTE rates; -case reports or case series; -studies in populations of patients with a history of VTE disease (DVT and/or PE); -no details on the different types of psychiatric disorders (psychiatric disorders treated as a whole, without precision), and/or no data on psychiatric disorders.

Search strategy and study selection

The PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines were applied for systematic reviews and meta-analyses. The search covered two databases: MEDLINE and EMBASE. Only English language articles published between June 1, 1998 and December 31, 2019 were included. The search terms were designed to provide maximum sensitivity in the detection of studies (see Supplementary material for the details of the search strategy). Duplicates were removed.

All articles found in the databases searched were reviewed. This was first based on title and abstract screening, and secondly on full-texts. Two researchers (CK and BP) independently carried out the selection of the studies and the extraction of data. Discrepancies were subsequently addressed and discussed with a third researcher (HP).

Systematic review

The considered outcomes were: main characteristics of the studies (including prospective vs. retrospective, source of the data, duration of follow-up), number of patients with and without each considered psychiatric disorder in groups with and without VTE phenomena (whole VTE, DVT, PE, and/or fatal VTE), main characteristics of case and controls (age, sex and available clinical characteristics), adjustment factors, and statistic rates (hazard-ratio (HR), OR, RR, and 95 % CI), and p-values.

The methodological quality of studies was conducted with the Newcastle-Ottawa Scale (NOS). This scale has been developed to assess the quality of nonrandomised studies with its design, content and ease of use directed to the incorporation of the quality assessments in the interpretation of meta-analytic results. Studies were judged on three broad dimensions: the selection of the study groups, the comparability of the groups and the ascertainment of either the exposure or outcome of interest for case-control or cohort studies respectively. To separate studies according to their quality, values were attributed to each grade of the notation (a = 1, b = 2, c = 3, and d = 4). Based on the mean score in the different studied characteristics in NOS, studies were median-spited and separated in two samples (i.e., low and good quality studies).

Meta-analyses

We used a random-effects meta-analysis model, which assumes that the observed estimates of VTE, DVT, PE and fatal VTE can vary across studies because of real differences in each study as well as sampling variability. Analyses were conducted separately for the different psychiatric disorders. To examine the putative role of confounding factors, unadjusted and adjusted estimates were meta-analysed separately for each outcome (i.e. VTE, DVT, PE and fatal VTE) and each psychiatric disorder. We expected differences in the confounding variables taken into account in the adjusted model of the different studies. The robustness of the meta-analyses was determined by including only studies of good quality based on the NOS. Heterogeneity was assessed using the I 2 statistic, which represents the percentage of variation across studies due to heterogeneity, and ranges from 0 to 100 %; higher values indicate greater heterogeneity across studies [START_REF] Higgins | Measuring inconsistency in meta-analyses[END_REF]. Publication bias was assessed using funnel plots. Statistical analyses were performed using the R package "meta" for unadjusted ORs, and the R package "metaphor" (ORs were log-transformed following Chen and Peace (15) methods) for ORs that were adjusted on confounding variables.

RESULTS

Studies selection

The search revealed 6,211 potential studies. After duplicates were removed, and titles and abstracts screened, 398 records were selected. These 398 full-texts were then reviewed to assess eligibility according to inclusion and exclusion criteria. Of these 398 records, 381 were excluded, leaving 17 studies in the qualitative analysis. As adjustment disorder and post-traumatic stress disorder (PTSD) were each analysed in only one article [START_REF] Gradus | Associations between stress disorders and cardiovascular disease events in the Danish population[END_REF], they were not studied in the metaanalysis. No selected article assessed catatonia. As the study of Enga et al. [START_REF] Enga | Emotional states and future risk of venous thromboembolism: the Tromsø Study[END_REF] studied selfreported depression and loneliness without medical assessment, it was not included in the metaanalysis. Thus, 15 articles were included in the meta-analysis. See details in PRISMA diagram (Figure 1).

-FIGURE 1 -

Systematic review

Of the 17 studies included in the qualitative analysis, 15 studies concerned VTE [START_REF] Gradus | Associations between stress disorders and cardiovascular disease events in the Danish population[END_REF][START_REF] Enga | Emotional states and future risk of venous thromboembolism: the Tromsø Study[END_REF][START_REF] Strudsholm | Increased risk for pulmonary embolism in patients with bipolar disorder[END_REF][START_REF] Daumit | Adverse events during medical and surgical hospitalizations for persons with schizophrenia[END_REF][START_REF] Khaykin | National estimates of adverse events during nonpsychiatric hospitalizations for persons with schizophrenia[END_REF][START_REF] Parker | Antipsychotic drugs and risk of venous thromboembolism: nested case-control study[END_REF][START_REF] Menendez | Do Psychiatric Comorbidities Influence Inpatient Death, Adverse Events, and Discharge After Lower Extremity Fractures?[END_REF][START_REF] Menendez | Psychiatric disorders and major spine surgery: epidemiology and perioperative outcomes[END_REF][START_REF] Stundner | Demographics and perioperative outcome in patients with depression and anxiety undergoing total joint arthroplasty: a population-based study[END_REF][START_REF] Browne | Depression is associated with early postoperative outcomes following total joint arthroplasty: a nationwide database study[END_REF][START_REF] Buller | The influence of psychiatric comorbidity on perioperative outcomes following primary total hip and knee arthroplasty; a 17year analysis of the National Hospital Discharge Survey database[END_REF][START_REF] Hsu | A population-based cohort study on deep vein thrombosis and pulmonary embolism among schizophrenia patients[END_REF][START_REF] Lee | Depression and risk of venous thromboembolism: a population-based retrospective cohort study[END_REF][START_REF] Klement | Should We Think Twice About Psychiatric Disease in Total Hip Arthroplasty?[END_REF][START_REF] Drinane | Depression is associated with worse outcomes among women undergoing breast reconstruction following mastectomy[END_REF], and 2 concerned fatal VTE [START_REF] Søgaard | Atrial fibrillation in patients with severe mental disorders and the risk of stroke, fatal thromboembolic events and bleeding: a nationwide cohort study[END_REF][START_REF] Sundbøll | Impact of pre-admission depression on mortality following myocardial infarction[END_REF]. Sixteen were (prospective or retrospective) cohort studies, and one was a nested case-control study. The psychiatric disorders considered were depression (N = 12), schizophrenia (N = 10), anxiety disorders (N = 5), bipolar disorders (N = 4), and adjustment disorder and PTSD (N = 1). All of the studies used registers as source of data, except one that used interview to assess depression. Seven selected studies concerned post-operative risk of VTE. Six studies concerned only inpatients, whilst 10 studies involved inpatients and outpatients.

The details of the articles included in the systematic review are available in Table 1.

-TABLE 1 -

Meta-Analysis

Of the 15 studies included in the meta-analysis, 13 studies concerned VTE [START_REF] Strudsholm | Increased risk for pulmonary embolism in patients with bipolar disorder[END_REF][START_REF] Daumit | Adverse events during medical and surgical hospitalizations for persons with schizophrenia[END_REF][START_REF] Khaykin | National estimates of adverse events during nonpsychiatric hospitalizations for persons with schizophrenia[END_REF][START_REF] Parker | Antipsychotic drugs and risk of venous thromboembolism: nested case-control study[END_REF][START_REF] Menendez | Do Psychiatric Comorbidities Influence Inpatient Death, Adverse Events, and Discharge After Lower Extremity Fractures?[END_REF][START_REF] Menendez | Psychiatric disorders and major spine surgery: epidemiology and perioperative outcomes[END_REF][START_REF] Stundner | Demographics and perioperative outcome in patients with depression and anxiety undergoing total joint arthroplasty: a population-based study[END_REF][START_REF] Browne | Depression is associated with early postoperative outcomes following total joint arthroplasty: a nationwide database study[END_REF][START_REF] Buller | The influence of psychiatric comorbidity on perioperative outcomes following primary total hip and knee arthroplasty; a 17year analysis of the National Hospital Discharge Survey database[END_REF][START_REF] Hsu | A population-based cohort study on deep vein thrombosis and pulmonary embolism among schizophrenia patients[END_REF][START_REF] Lee | Depression and risk of venous thromboembolism: a population-based retrospective cohort study[END_REF][START_REF] Klement | Should We Think Twice About Psychiatric Disease in Total Hip Arthroplasty?[END_REF][START_REF] Drinane | Depression is associated with worse outcomes among women undergoing breast reconstruction following mastectomy[END_REF], and 2 fatal VTE [START_REF] Søgaard | Atrial fibrillation in patients with severe mental disorders and the risk of stroke, fatal thromboembolic events and bleeding: a nationwide cohort study[END_REF][START_REF] Sundbøll | Impact of pre-admission depression on mortality following myocardial infarction[END_REF]. Among the 13 studies on non-fatal VTE, 6 assessed whole VTE phenomena without details on DVT and/or PE, 5 assessed DVT and PE, and 2 assessed only PE. The 15 articles included in the meta-analysis have been assessed according to NOS. Overall, 3 studies were considered as representative of the target population. The comparability of the groups and the follow-up (adequacy and period) were judged appropriate in the 15 studies. More details of the different fields assessed by NOS are available in supplementary table (Supplementary Table 1).

Detailed results of the different meta-analyses are shown in Table 2. Funnel plots of unadjusted meta-analyses of associations between VTE and psychiatric disorders are depicted in Figure 2. The meta-analyses of the good quality studies and the forest and funnel plots of adjusted meta-analyses are available in supplementary materials (Supplementary Figure 1 and Table 2). The different adjustment factors used in the adjusted analyses was available in supplementary table (Supplementary Table 3).

-TABLE 2 AND FIGURE 2 -

In unadjusted analyses, VTE was associated with psychotic disorders (OR = 2.20, 95 % CI [1.06-4.59]), in contrast to DVT, PE, and fatal VTE. Heterogeneity was high (above 99 %).

The funnel plot was consistent with this high heterogeneity (Figure 2), but did not indicate any publication bias in favour of a positive association. Considering only adjusted analyses, VTE, DVT, PE, and fatal VTE were all associated with psychotic disorders (ORs between 1.29 and 2.88). In comparison with unadjusted analyses, heterogeneity was reduced (I 2 = 21.3 % for VTE, 79.1 % for DVT, and 47.4 % for PE). Considering only good quality studies, VTE, DVT and PE were associated with psychotic disorders in both unadjusted and adjusted analyses (ORs between 1.82 and 2.78 in unadjusted analyses, ORs between 1.49 and 2.02 in adjusted analyses). There were no good quality studies concerning fatal VTE and psychotic disorders.

In unadjusted analyses, VTE was associated with depression (OR = 1.86, 95 % CI [1.19-2.92]), in contrast to DVT, PE, and fatal VTE. Heterogeneity was high (I 2 above 99 %). As with psychotic disorders, the funnel plot shows this high heterogeneity, without indication of a publication bias. Considering only adjusted analyses, VTE, DVT and PE were associated with depression (ORs between 1.19 and 1.29), in contrast to fatal VTE. In comparison with unadjusted analyses, heterogeneity was reduced (I 2 = 43.6 % for VTE, and 92.1 % for PE, only 1 study for DVT). When only good quality studies were considered, no studies were considered DVT, PE and fatal VTE, whereas VTE was found not to be associated with depression in both unadjusted and adjusted analyses.

In unadjusted analyses, no VTE phenomena were associated with anxiety disorders (OR = 0.64, 95 % CI [0.29-1.42]). Heterogeneity was high (I 2 above 99 %). The number of studies (N = 3) makes the funnel plot difficult to interpret. There were no studies concerning fatal VTE and anxiety disorders. Considering only adjusted analyses, VTE and PE were considered only in one study, and were found associated with anxiety disorders (ORs between 1.14 and 1.49).

Considering only good quality studies, VTE and PE were also considered in only one study in both unadjusted and adjusted analyses (whilst DVT was not studied). VTE was associated with anxiety disorders only in adjusted analyses (OR = 1.14, 95 % CI [1.00-1.29]), while PE was associated in both unadjusted and adjusted analyses (ORs between 1.42 and 1.49).

In unadjusted analyses, all VTE phenomena, except fatal VTE, were associated with bipolar disorders (ORs between 1.48 and 1.59). Heterogeneity was high (above 99 %). As for anxiety disorder, the number of studies (N = 2) makes the funnel plot difficult to interpret.

Considering only adjusted analyses, VTE and DVT were considered only in one study, with only DVT associated with bipolar disorders (OR = 2.14, 95 % CI [1.87-2.45]). PE was associated with bipolar disorders (OR = 2.06, 95 % CI [1.26-3.37]), with high level of heterogeneity (I 2 = 93.3 %). When considering only good quality studies, PE remained associated with bipolar disorders in both unadjusted and adjusted analyses (ORs between 1.22 and 1.29), whilst VTE was not associated with bipolar disorder in unadjusted and adjusted analyses, and DVT was not considered.

DISCUSSION

The systematic review and meta-analysis indicate significant associations between psychiatric disorders and VTE, DVT and PE risk. Among the psychiatric disorders, psychotic disorders were associated with the highest and most consistent ORs (except for the meta-analysis of unadjusted analyses on DVT and PE). Bipolar disorders were also associated with an increased risk of VTE, DVT and PE in the meta-analyses of unadjusted and adjusted studies, with the exception of the meta-analysis of adjusted studies on VTE risk. Meta-analyses of unadjusted analyses of depression and anxiety disorders did not show any significant associations, whereas meta-analyses of adjusted analyses of indicated associations of DVT and PE with depression, as well as VTE and PE for anxiety disorders.

Several mechanisms have been proposed to explain these associations. To develop VTE, pathophysiological studies assume that one or a combination of Virchow's triadhypercoagulability, stasis of blood flow and vein wall injuryare necessary [START_REF] Goldhaber | Pulmonary embolism and deep vein thrombosis[END_REF][START_REF] Jönsson | Venous Thromboembolism During Treatment with Antipsychotics: A Review of Current Evidence[END_REF]. Psychiatric disorders may be particularly associated with hypercoagulability and stasis factors.

Psychotic disorders and venous thromboembolism

Regarding psychotic disorders and schizophrenia, antipsychoticsin particular SGAhave been associated with VTE risk in several studies [START_REF] Barbui | Antipsychotic drug exposure and risk of venous thromboembolism: a systematic review and meta-analysis of observational studies[END_REF][START_REF] Zhang | Antipsychotics and venous thromboembolism risk: a meta-analysis[END_REF], although not all [START_REF] Ray | Antipsychotic and Antidepressant Drug Use in the Elderly and the Risk of Venous Thromboembolism[END_REF][START_REF] Ferraris | The Effect of Antipsychotic Treatment on Recurrent Venous Thromboembolic Disease: A Cohort Study[END_REF]. As the side-effects of antipsychotics include sedation, negative symptoms and sedentary behaviour [START_REF] Leucht | Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multipletreatments meta-analysis[END_REF][START_REF] Vancampfort | Sedentary behavior and physical activity levels in people with schizophrenia, bipolar disorder and major depressive disorder: a global systematic review and meta-analysis[END_REF], they can increase the risk of venous stasis. Moreover, sedentary behaviour has been associated with inflammation-induced hypercoagulability [START_REF] Carrizo | Coagulation and inflammation markers during atypical or typical antipsychotic treatment in schizophrenia patients and drug-free first-degree relatives[END_REF][START_REF] Stubbs | Sedentary behaviour is associated with elevated C-reactive protein levels in people with psychosis[END_REF], indicating that the well-known heightened level of inflammation evident in schizophrenia may interact with sedentary behaviours. Additionally, the putative hypercoagulability associated with antipsychotic use has been directly linked to enhanced platelet aggregation and to increased levels of anti-phospholipid antibodies [START_REF] Jönsson | Venous Thromboembolism During Treatment with Antipsychotics: A Review of Current Evidence[END_REF][START_REF] Shen | Higher serum clozapine level is associated with increased antiphospholipid antibodies in schizophrenia patients[END_REF]. However, results across several studies are inconsistent in regard to antipsychotic-induced hypercoagulability, and thereby the antipsychotic-driven VTE risk among patients with psychotic disorders. In a sample of patients with schizophrenia, Halacheva et al. [START_REF] Halacheva | Elevated anticardiolipin antibodies in schizophrenic patients before and during neuroleptic medication[END_REF] did not find any association between antipsychotics and anti-phospholipid antibodies. In a sample of healthy volunteers, a reduced aggregability, and associated decreased hypercoagulability, of blood samples was present after treatment with clozapine or olanzapine [START_REF] Dietrich-Muszalska | The first-and second-generation antipsychotic drugs affect ADP-induced platelet aggregation[END_REF]. In a study comparing the level of blood factors that are associated with coagulation and inflammation in schizophrenia patients treated chronically with antipsychotics and in their drugnaïve first-degree relatives, Carrizo et al. [START_REF] Carrizo | Coagulation and inflammation markers during atypical or typical antipsychotic treatment in schizophrenia patients and drug-free first-degree relatives[END_REF] did not find a homogeneous profile of inflammation and coagulation according to the different groups. However, these authors did find that the observed blood abnormalities were related to an elevated BMI in both patients and relatives. Moreover, Masoput et al. [START_REF] Masopust | Markers of thrombogenesis are activated in unmedicated patients with acute psychosis: a matched case control study[END_REF] studied the levels of activation of the coagulation factors in patients with acute psychotic disorders, who were antipsychotic naïve. Coagulation factors were higher among patients in comparison to controls, suggestive of a medication independent VTE risk in patients with acute psychotic disorders. Thus, the proposed association of antipsychotic use driving hypercoagulability is questionable. Gaertner et al. ( 46) estimated the incidence of VTE phenomena among 12,320 patients in psychiatric institutions. Although they found an incidence rate of VTE around 20 times higher than in the general population, they did not observe any association between psychotropic drugs and VTE risk. Overall, the role of antipsychotic use in the pathoetiology of VTE is questionable, indicating that the association between psychotic disorder and VTE may be explained at least partly by treatment-independent mechanisms. In the present systematic review, we report the results of one large population based nested case-control study [START_REF] Parker | Antipsychotic drugs and risk of venous thromboembolism: nested case-control study[END_REF], which found a significant association between VTE and psychotic disorders after adjusting for antipsychotics use (OR = 1.34, 95 % CI [1.15-1.55]). The authors proposed that the association between psychotic disorders and VTE may be explained by other factors, such as lifestyle habits, high BMI, or tobacco use [START_REF] Carrizo | Coagulation and inflammation markers during atypical or typical antipsychotic treatment in schizophrenia patients and drug-free first-degree relatives[END_REF][START_REF] Masopust | Markers of thrombogenesis are activated in unmedicated patients with acute psychosis: a matched case control study[END_REF][START_REF] Gaertner | Incidence and risk factors of venous thromboembolism: Peculiarities in psychiatric institutions[END_REF]. Negative symptoms may also be involved, as they are associated with sedentary behaviour [START_REF] Kluge | Combining actigraphy, ecological momentary assessment and neuroimaging to study apathy in patients with schizophrenia[END_REF], as well as hyperprolactinemia, metabolic syndrome, and physical restraint [START_REF] Hem | Thrombosis associated with physical restraints[END_REF][START_REF] Wallaschofski | Hyperprolactinemia in Patients on Antipsychotic Drugs Causes ADP-Stimulated Platelet Activation That Might Explain the Increased Risk for Venous Thromboembolism: Pilot Study[END_REF][START_REF] Ageno | Association Between the Metabolic Syndrome, Its Individual Components, and Unprovoked Venous Thromboembolism[END_REF].

Another explanation, that concerns psychotic and non-psychotic disorders, may lie in risk factors and/or comorbidities shared by psychiatric disorders and VTE. For instance, psychotic, mood and anxiety disorders are associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation and related hypercortisolism [START_REF] Tirabassi | Harmful effects of functional hypercortisolism: a working hypothesis[END_REF][START_REF] Heim | The link between childhood trauma and depression: Insights from HPA axis studies in humans[END_REF][START_REF] Cherian | HPA axis in psychotic major depression and schizophrenia spectrum disorders: Cortisol, clinical symptomatology, and cognition[END_REF][START_REF] Murri | The HPA axis in bipolar disorder: Systematic review and meta-analysis[END_REF], and hypercortisolism is associated with hypercoagulability [START_REF] Trementino | Coagulopathy in Cushing's syndrome[END_REF][START_REF] Świątkowska-Stodulska | Disorders of Hemostasis in Overt and Subclinical Hypercortisolism[END_REF]. Likewise, low education and economic level, occupational status, obesity, metabolic syndrome, smoking, or alcohol use disorders have been linked to both VTE and psychiatric disorders [START_REF] Lorant | Socioeconomic inequalities in depression: a meta-analysis[END_REF][START_REF] Hasin | Prevalence, Correlates, Disability, and Comorbidity of DSM-IV Alcohol Abuse and Dependence in the United States: Results From the National Epidemiologic Survey on Alcohol and Related Conditions[END_REF][START_REF] Rosengren | Psychosocial factors and venous thromboembolism: a long-term follow-up study of Swedish men[END_REF][START_REF] Holst | Risk Factors for Venous Thromboembolism[END_REF][START_REF] Zöller | Socioeconomic and occupational risk factors for venous thromboembolism in Sweden: A nationwide epidemiological study[END_REF][START_REF] Godin | Sleep quality, chronotype and metabolic syndrome components in bipolar disorders during the remission period: Results from the FACE-BD cohort[END_REF][START_REF] Mallet | Cigarette smoking and schizophrenia: a specific clinical and therapeutic profile? Results from the FACE-Schizophrenia cohort[END_REF][START_REF] Callaghan | Patterns of tobacco-related mortality among individuals diagnosed with schizophrenia, bipolar disorder, or depression[END_REF]. A correlate of lower socio-economic status is residence within areas of heightened air pollution, which is also a common risk factor for both VTE and psychiatric disorders [START_REF] Khan | Environmental pollution is associated with increased risk of psychiatric disorders in the US and Denmark[END_REF][START_REF] Crous-Bou | Environmental and Genetic Risk Factors Associated with Venous Thromboembolism[END_REF].

Mood and anxiety disorders and venous thromboembolism

The association of VTE with mood disorders parallels its association with psychotic disorders. Several studies have found significant associations between various types of antidepressants, including Selective Serotonin Reuptake Inhibitors (SSRIs), tricyclic, and other antidepressants, with VTE [START_REF] Kunutsor | Depression, antidepressant use, and risk of venous thromboembolism: systematic review and meta-analysis of published observational evidence[END_REF][START_REF] Wu | Association between antidepressants and venous thromboembolism in Taiwan[END_REF]. However, other studies have shown no such significant associations [START_REF] Lee | Depression and risk of venous thromboembolism: a population-based retrospective cohort study[END_REF][START_REF] Ray | Antipsychotic and Antidepressant Drug Use in the Elderly and the Risk of Venous Thromboembolism[END_REF][START_REF] Gaertner | Incidence and risk factors of venous thromboembolism: Peculiarities in psychiatric institutions[END_REF][START_REF] Lacut | Association between antipsychotic drugs, antidepressant drugs and venous thromboembolism: results from the EDITH case-control study[END_REF]. Of note, patients with anxiety disorders often use antidepressant and antipsychotic drugs [START_REF] Perna | Long-Term Pharmacological Treatments of Anxiety Disorders: An Updated Systematic Review[END_REF][START_REF] Pignon | The Place of Antipsychotics in the Therapy of Anxiety Disorders and Obsessive-Compulsive Disorders[END_REF]. In an observational prospective study of patients addressed for thrombophilia investigation after a VTE episode, von Känel et al. [START_REF] Von Känel | Depressive symptoms as a novel risk factor for recurrent venous thromboembolism: a longitudinal observational study in patients referred for thrombophilia investigation[END_REF] examined the role of depressive symptoms in VTE recurrence. Antidepressant use was an exclusion criterion. These authors showed that depressive symptoms were predictive of VTE recurrence, showing a "doseeffect" relationship. The results of this study, in line with the data of Enga et al. [START_REF] Enga | Emotional states and future risk of venous thromboembolism: the Tromsø Study[END_REF], support the role of medication-independent depressive symptoms in VTE risk. Again, an increase of sedentary symptoms has been proposed to underpin this association, as well as an increase in hypercoagulability induced by stress and heightened sympathetic nervous system [START_REF] Thrall | A systematic review of the effects of acute psychological stress and physical activity on haemorheology, coagulation, fibrinolysis and platelet reactivity: Implications for the pathogenesis of acute coronary syndromes[END_REF][START_REF] Känel | Acute mental stress and hemostasis: When physiology becomes vascular harm[END_REF]. Such stress-driven pathophysiological changes may also underpin the association of anxiety disorders with hypercoagulability. In the study by Gaertner et al. [START_REF] Gaertner | Incidence and risk factors of venous thromboembolism: Peculiarities in psychiatric institutions[END_REF] on VTE incidence in psychiatric institutions, almost one third of VTE were diagnosed during the first 48h of hospitalization, and 50 % during the first week of hospitalization, highlighting an association of VTE with the high levels of stress, dysphoria and depressive symptoms that are often evident at this time.

Other studies on psychotropic treatments of mood disorders, including benzodiazepines and mood stabilizers, showed little association with VTE risk (with the exception of one study in pregnant women, where VTE displayed a significant associations with benzodiazepine derivates) [START_REF] Jensen | Risk factors for venous thromboembolism during pregnancy[END_REF][START_REF] Ugras | Protein C, protein S and other pro-and anticoagulant activities among epileptic children using sodium valproate[END_REF].

Limitations

Some limitations of this study should be acknowledged. While it concerns an important topic, relative few studies have been included in this systematic review and meta-analysis. Anxiety (N = 5) and bipolar disorders (N = 4) have been poorly studied and some psychiatric disorders, such as PTSD, catatonia, have not been studied. Moreover, as noted in the systematic review, and as confirmed by the high level of heterogeneity, inclusion criteria and clinical settings of the studies were different. Similarly, in the adjusted analyses, the heterogeneity was lower, but still high, which is consistent with different adjustment factors. Meta regressions, which could have helped to clarify the role of treatment in VTE risk could not be utilized. Other limitations arising from unavailable data, include the analysis of different adjustment factors, and psychiatric subgroups, including with and without psychotropic drug use.

Conclusion

Overall, in this systematic review and meta-analysis, the risk of VTE, DVT and PE associated with psychotic, mood, and anxiety disorders was addressed for the first time should have a focus that emphasizes prevention. Prevention measures, based on the use of compression stockings, hydration, behavioral activation, and sometimes prophylactic anticoagulation should be applied, especially in the case of physical restraint [START_REF] Ishida | Prophylactic use of heparin for deep vein thrombosis in restrained psychiatric patients: a chart review[END_REF][START_REF] Du Montcel | Isolement et contention mécanique dans les soins psychiatriques : modalités de prescription, prise en charge et surveillance[END_REF].

FIGURES LEGENDS Figure1

Title

  . The absolute risks of VTE of each studied psychiatric disorders, estimated based on the meta-analysis of unadjusted analyses, were as follow: psychotic disorders: OR = 2.20, 95 % CI [1.06-4.59]; depression: OR = 1.86, 95 % CI [1.19-2.92]; bipolar disorders: OR = 1.49, 95 % CI [1.23-1.80]; and anxiety disorders: OR = 0.64, 95 % CI [0.29-1.42]. Regarding details, psychotic and bipolar disorders were associated with VTE, DVT and PE risk. Depression and anxiety disorders, in adjusted analyses, show associations of DVT and PE for depression, and VTE and PE for anxiety disorders. Such results highlight the need for clinicians to be vigilant in the monitoring of VTE risk across a wide range of psychiatric disorders, which, as with other cardiovascular diseases,

Figure 2 Title:

 2 Abbreviations: DVT = Deep venous thrombosis, PE = Pulmonary embolism, VTE = Venous thromboembolism events

Abbreviations

Conflict of interest: None

This research received no specific grant from any funding agency, commercial or not-forprofit sectors.

Authors' contribution:

-Concept and design of the study: CK, HP and BP -Systematic review: CK, HP and BP -Analysis and interpretation of data: HP and BP -First draft: CK and BP -Critical review: CK, HP, AA, AP, ML, FS.

Supplementary Figure 1 Title: Forest and funnel plots of adjusted meta-analyses of association between psychiatric disorders and venous thromboembolism


domain: sdv sde

text:
Stéphane Tuffier

Erika Upegui

Christina Raghoumandan

Jean François Viel
email: jean-francois.viel@univ-rennes1.fr

Retrospective assessment of pregnancy exposure to particulate matter from desert dust on a Caribbean island: could satellite-based aerosol optical thickness be used as an alternative to ground PM10 concentration?

Keywords: desert dust, aerosol optical thickness, particulate matter ≤ 10 µm, satellite imagery, MAIAC algorithm, epidemiology

Desert dust transported from the Saharan-Sahel region to the Caribbean Sea is responsible for peak exposures of particulate matter (PM). This study explored the potential added value of satellite aerosol optical thickness (AOT) measurements, compared to the PM concentration at ground level, to retrospectively assess exposure during pregnancy. MAIAC MODIS AOT retrievals in blue band (AOT470) were extracted for the French Guadeloupe archipelago. AOT470 values and PM10 concentrations were averaged over pregnancy for 906 women (2005)(2006)(2007)(2008).

Regression modeling was used to examine the AOT470-PM10 relationship during pregnancy, and test the association between dust exposure estimates and preterm birth. Moderate agreement was shown between mean AOT470 retrievals and PM10 ground-based measurements during pregnancy (R²=0.289). The magnitude of the association between desert dust exposure and preterm birth tended to be lower using the satellite method compared to the monitor method.

The latter remains an acceptable trade-off between epidemiological relevance and exposure misclassification, in areas with few monitoring stations and complex topographical/ meteorological conditions, such as tropical islands.

A c c e p t e d M a n u s c r i p t

Introduction

On a global scale, most atmospheric particles are emitted by natural sources, mineral dust being the second most abundant component (after sea-spray derived aerosols). The Sahara and Sahel regions in Northern Africa generate the most dust in terms of emissions [START_REF] Querol | Monitoring the impact of desert dust outbreaks for air quality for health studies[END_REF].

Most African dust particles travel westwards over the Atlantic over long distances and affect areas in the Caribbean and the Americas, generating peak exposures to particulate matter (PM) in these downwind regions. The dust plume extension varies throughout the year depending on the displacement of the Inter-Tropical Convergence Zone [START_REF] Prospero | Atmospheric transport of soil dust from Africa to South America[END_REF], inducing marked seasonality (emissions peaking in spring and summer). Desert dust typically mixes with locally-or regionally-emitted PM, but the median desert dust mass diameter was found to be 3.2 µm in Barbados and 3.5 µm in Puerto Rico [START_REF] Reid | Comparison of size and morphological measurements of coarse mode dust particles from Africa[END_REF].

Accurately assessing desert dust exposure in the Caribbean region is challenging due to sparse ground monitoring networks. Conversely, satellite remote sensing, in terms of aerosol optical thickness (AOT), has provided new methods to monitor PM air quality with fine spatial and temporal resolution, since the launch of the Moderate Resolution Imaging SpectroRadiometer (MODIS) [START_REF] Xiao | Full-coverage high-resolution daily PM2.5 estimation using MAIAC AOD in the Yangtze River Delta of China[END_REF]. AOT is based on the impedance of light transmission by the absorption or scattering of light by aerosols through the vertical column of the atmosphere from the ground to the satellite sensor [START_REF] Duncan | Satellite data of atmospheric pollution for US air quality applications: examples of applications summary of data end-user resources answers to FAQs and common mistakes to avoid[END_REF]. However, satellite data may be compromised by the non-random absence due to cloud cover, high surface reflectance (desert and snow-covered surfaces), and extremely high aerosol loading, which can be misclassified as clouds [START_REF] Lee | Use of satellite-based aerosol optical depth and spatial clustering to predict ambient PM2.5 concentrations[END_REF][START_REF] Di | Assessing PM 2.5 exposures with high spatiotemporal resolution across the continental United States[END_REF]. Thus, AOT data may not be available for a large fraction of days (non-retrieval days).

A c c e p t e d M a n u s c r i p t

A recent algorithm (released in 2018), called "Multi-Angle Implementation of Atmospheric Correction" (MAIAC C6.1), has greatly improved MODIS AOT retrievals with a more accurate detection of cloudy and clear-sky areas, enabling it to produce AOT data for partially cloudy days [START_REF] Lyapustin | MODIS Collection 6 MAIAC Algorithm[END_REF]. It uses time series (up to 16 days) analysis to exploit multiangle viewing effects and image processing to derive the surface bidirectional reflectance function.

MAIAC relies on dynamic land-water-snow classification from daily observations to select the proper processing path. MAIAC AOT retrieval in blue band (AOT470) is a unitless value ranging from 0 (indicating extremely clear weather with maximum visibility) to a maximum of 4.0. The fine spatial resolution (1 km) and high accuracy of MAIAC AOT470 makes it possible to characterize local-scale aerosol heterogeneity.

The derivation of surface PM from satellite AOT is always challenging because of the effect of various factors (such as aerosol composition, relative humidity, the vertical profile of the particle concentration, and the altitude of the aerosol layer) [START_REF] Duncan | Satellite data of atmospheric pollution for US air quality applications: examples of applications summary of data end-user resources answers to FAQs and common mistakes to avoid[END_REF]. The most widely used method is empirical analysis, in which in situ PM measurements are regressed with the corresponding satellite AOT value, adjusting for meteorological data and land-use variables, in the framework of linear mixed effects models. MAIAC AOT retrievals have been used to estimate ground PM distributions and support air pollution epidemiological studies in the USA and Mexico [START_REF] Di | Assessing PM 2.5 exposures with high spatiotemporal resolution across the continental United States[END_REF][START_REF] Hu | Ten-year spatial and temporal trends of PM2.5 concentrations in the southeastern US estimated using high-resolution satellite data[END_REF][START_REF] Just | Using high-resolution satellite aerosol optical depth to estimate daily PM2.5 geographical distribution in Mexico City[END_REF][START_REF] Strickland | Pediatric emergency visits and short-term changes in PM2.5 concentrations in the US state of Georgia[END_REF]. However, the AOT-PM relationship is spatially and temporally inhomogeneous. Thus, continued research is needed for various regions of the world, especially in locations where few surfaced-based PM measurements have been obtained, to date [START_REF] Chen | Empirical relationship between particulate matter and aerosol optical depth over Northern Tien-Shan Central Asia[END_REF].

We recently showed an association between maternal exposure during pregnancy to desert dust and preterm birth in the French Guadeloupe archipelago (an outermost region of the European Union situated in the Caribbean basin) [START_REF] Viel | Impact of Saharan Dust Episodes on Preterm Births in Guadeloupe (French West Indies)[END_REF]. We assessed exposure A c c e p t e d M a n u s c r i p t through PM ≤ 10 µm (PM10) concentrations recorded at the sole (urban) background air quality monitoring station of Guadeloupe, located in Pointe-à-Pitre (central part of the Guadeloupe archipelago), regardless of the location of the woman's residence. However, spatial heterogeneity in terms of exposure can be supposed, as concentrations may be lower on the island's leeward (i.e., western) side, which is partially sheltered from trade winds by the La Soufrière volcano (1,467 m high, located in Basse-Terre, the south-western part of Guadeloupe). This presumed spatial variability of air pollutants related to topography (and also local micro sources) may not be captured by a single background air quality monitoring station, and non-differential misclassification may occur.

To our knowledge, only two other studies have relied on satellite AOT data to estimate average exposure to PM2.5 during pregnancy, but at the lower spatial resolution of a 10 x 10km grid (across Connecticut and Massachusetts -USA), using daily calibration of PM ground measurements from a dense network of monitoring stations [START_REF] Kloog | Using new satellite based exposure methods to study the association between pregnancy PM2.5 exposure premature birth and birth weight in Massachusetts[END_REF][START_REF] Hyder | PM2.5 exposure and birth outcomes: use of satellite-and monitor-based data[END_REF]. The Guadeloupe archipelago poses, however, several unique challenges in terms of airpollution assessment, both topographically and meteorologically. Land use is heterogeneous, and the islands feature a complex topography (abrupt elevation changes and rugged terrain) and a humid subtropical climate (tempered by trade winds), with frequent cloud cover and a long rainy season (from July to November).

This feasibility study explored the potential added value of MAIAC AOT retrievals, compared to the PM concentration at ground level, to retrospectively assess exposure during pregnancy for epidemiological purposes in a tropical island environment.

A c c e p t e d M a n u s c r i p t

Materials and methods

Study domain and population

Guadeloupe, with a population of 450,000 inhabitants, is an archipelago located in the Leeward Islands in the Caribbean. Pregnancies of the 909 women enrolled in the TIMOUN mother-child cohort occurred during the time period from March 30, 2004to July 30, 2007(last delivery on April 28, 2008) [START_REF] Viel | Impact of Saharan Dust Episodes on Preterm Births in Guadeloupe (French West Indies)[END_REF]. Home addresses during pregnancy were geocoded, showing a median distance from the air quality monitoring station of 13.03 km, as the crow flies (Fig. 1).

Ground PM measurements

The assessment of exposure has been fully described elsewhere [START_REF] Viel | Impact of Saharan Dust Episodes on Preterm Births in Guadeloupe (French West Indies)[END_REF]. Briefly, mean daily PM10 concentrations (μg/m 3 ) recorded at the Pointe-à-Pitre monitoring station were provided by Gwad'Air (the official air quality monitoring agency for Guadeloupe) from 2005 to 2008 (no data were available before 2005). PM10 concentrations were measured using the Thermo Scientific Tapered Element Oscillating Microbalance (TEOM) models 1400ab and 1400-FDMS. The TEOM is widely used in air quality programs in Europe and the United States and qualifies as a U.S. Environmental Protection Agency equivalent method (http://www.epa.gov/ttn/amtic/criteria.html). No PM2.5 concentrations were measured and no other air quality monitoring station was operating in the Guadeloupe archipelago during this period. AOT470 retrievals were extracted from each atmospheric properties file. Pixel maps were orthorectified using NASA SeaDAS 7.5.1 software, the Global Earth Topography and Sea Surface Elevation (at 30 arcsecond resolution -GETASSE30) model, the linear polynomial method, and five photo-identified ground control points (extracted from ESRI World Imagery).

MODIS AOT retrievals

Positional accuracy was assessed through the root-mean-square error (RMSE), representing an averaged difference between the rectified imagery and ground truth. RMSE was 0.00812° (901.6 m) in latitude, and 0.00996° (1108.7 m) in longitude, respecting the general rule of an RMSE equivalent to the size of a pixel in the output image. We applied a sliding-window spatial filter, replacing the center value in the 3 x 3 window with the median of the nine pixel values in the window.

As a result, we obtained daily Aqua and Terra AOT470 retrievals for the terrestrial part of the Guadeloupe archipelago (1,054 pixels) for the period from 2005 to 2008. We primarily used the Aqua AOT470 measurements, estimating their missing values from the Terra AOT470 values (if available) using an adjustment factor. This factor was equal to the ratio of the average Aqua AOT470 to Terra AOT470 for the days for which both the Aqua and Terra measurements were available [START_REF] Lee | Use of satellite-based aerosol optical depth and spatial clustering to predict ambient PM2.5 concentrations[END_REF].

Finally, we overlaid a map of the mothers' residence onto the grid cell maps to obtain a median smoothed AOT470 value for each place of residence and each day. To avoid temporal

Statistical analyses

We averaged the AOT470 values and PM10 concentrations over each pregnancy to assess desertdust exposure (for the 234 pregnancies which started in 2004, the means were calculated for their 2005 component). Then, we considered topographical and land-cover contrasts to control for spatial variability of the AOT470 values for exposure. First, we split the Guadeloupe territory into the windward and leeward sides of La Soufrière volcano to investigate the potential effect of trade winds. Second, we distinguished the capital city (Pointe-à-Pitre) and its suburbs (as the city spreads beyond the old municipal boundary lines) from the rest of Guadeloupe because a recent study showed lower correlations between MAIAC AOT retrievals and ground-truth data over bright areas than those over vegetated areas [START_REF] Martins V S, Lyapustin | Validation of high-resolution MAIAC aerosol product over South America[END_REF]. We used linear regression modeling with average AOT470 values during pregnancy as the dependent variable and the geographical contrast (windward vs. leeward) as the independent variable. We introduced time (autumn-winter semester vs. spring-summer semester of each year of the study period, defined a priori as the semester including week 14 of the corresponding pregnancy) and space (geographical contrast) x time (semester) interaction terms in multivariate models, as pregnancies occurred throughout the study period and as desert-dust episodes can vary between years. We created a similar model but with the urbanization contrast as the independent variable. Finally, the association between the average AOT470 value and PM10 concentration during pregnancy was examined by univariate linear regression. As external validation, a multivariate logistic regression model was used to estimate the association between the AOT-based desert dust exposure and preterm birth while adjusting for numerous individual risk factors, as in our previous PM10-based analysis (place of inclusion, maternal age, marital status, years of education, body mass index, parity, prior preterm birth, prior miscarriage, prior induced abortions, lupus, asthma, chronic hypertension, gestational weight gain, gestational hypertension, gestational diabetes, urinary tract infection, sex of the newborn) [START_REF] Viel | Impact of Saharan Dust Episodes on Preterm Births in Guadeloupe (French West Indies)[END_REF]). To compare the impact of this exposure proxy with the PM10-based proxy, we calculated the odds ratios (ORs) per standard deviation (SD) change (0.037).

Statistical analyses were performed using R software (R Foundation for Statistical Computing, Vienna, Austria, 2020).

Results

Descriptive results

During the 1,214-day study period, PM10 concentrations ranged from 9.3 to 157.0 μg/m 3 (median: 21.0 μg/m 3 ), with data missing for 55 days because of routine maintenance or mechanical failure. Of the 1,279,556 expected AOT470 values (1,054 pixels x 1,214 days), only 252,630 were retrieved (19.7%), ranging from 0.002 to 0.964 (median: 0.199).

Plotting of all daily mean values against the day-of-the-year yielded much the same irregular picture for both series (Fig. 2). The month-to-month variation (reflecting more frequent dust outbreaks in the late spring -early summer) was not similar between years.

Averaging the available daily measures over the entire pregnancy showed the mean PM10 concentrations to range from 13.2 to 34.9 μg/m 3 (median: 28.2 μg/m 3 ) and the mean AOT470

Spatial variability

The mean AOT470 values during pregnancy, according to the place of residence of the mothers, are presented in Table 1. We plotted the mean AOT470 retrievals during pregnancy, over Guadeloupe across time to examine both spatial variability and potential space x time interactions (Fig. 3).

Univariate analysis showed higher values on the windward (eastern) side of the island (p < 10 ⁻ 4 ). However, the spatial difference was no longer found when adjusting for time period (p = 0.30), whereas the difference between all semesters was significant (p < 10 -15 ), as well as three space x semester interactions (p < 0.05). Finally, we found no significant difference in the mean AOT470 values when considering urbanization (Table 1).

AOT470-PM10 association during pregnancy

Average AOT470 values showed moderate agreement with average PM10 ground-based measurements (both calculated during pregnancy), with a squared correlation coefficient (R²) of 0.289 (slope 0.006, p < 10 -15 ) (Fig. 4). The offset (equal to 0.005) did not differ significantly from zero (p = 0.50).

Associations between preterm birth and AOT470-based exposure estimates

A c c e p t e d M a n u s c r i p t

13/24

The crude and adjusted associations between AOT470-based exposure estimates and preterm birth were very similar and elevated, but not significantly (OR = 1.19, 95% CI = 0.98 -1.46, p = 0.08, and OR = 1.18, 95% CI = 0.95 -1.47, p = 0.14, in univariate model and multivariate model, respectively).

Discussion

Here, we used recent high-resolution (1 km) AOT MODIS data based on the MAIAC algorithm to assess past exposure (2005)(2006)(2007)(2008) of pregnant women to desert dust and to check its accuracy for epidemiological purposes.

The mean coverage of AOT values in Guadeloupe was poor (19.7%), due to cloud cover and unfavorable surface conditions. This is similar to the fraction (19.8%) reported for another complex terrain (Switzerland) (de Hoog et al. 2018) and slightly lower than results reported for Taiwan (a much broader, more highly populated, and more industrialized island than Guadeloupe but sharing a similar climate), with a mean overall coverage of Terra and Aqua AOT values of 23.0% [START_REF] Jung | Incorporating long-term satellite-based aerosol optical depth localized land use data and meteorological variables to estimate ground-level PM2.5 concentrations in Taiwan from 2005 to 2015[END_REF]. Despite continuous improvements of cloud detection and atmospheric corrections over inlands and coastal water, missing MAIAC AOT values due to cloud cover and bright surfaces is still a major limitation and challenge. The MAIAC algorithm consistently misses a specific type of cloud cover (moderately thin and homogeneous cumulus) over water, generating high AOT values [START_REF] Lyapustin | MODIS Collection 6 MAIAC Algorithm[END_REF], and MAIAC retrievals over bright surfaces are generally poorer than those over vegetated areas [START_REF] Chen | Empirical relationship between particulate matter and aerosol optical depth over Northern Tien-Shan Central Asia[END_REF]. The high concentration of the Guadeloupean population in coastal areas is another challenge. Indeed, because of the inherent uncertainties of gridding on the coastline (and the different land/water processing paths), the area within 2 km of the coastline may contain frequent artifacts in cloud mask (usually over-detection) and AOT (higher values) [START_REF] Lyapustin | MODIS Collection 6 MAIAC Algorithm[END_REF], potentially biasing individual exposure estimates.

In Guadeloupe, the maximum AOT value was 0.964, in agreement with results from South America, where 98% of AOT values ranged from 0.01 to 1.0 [START_REF] Martins V S, Lyapustin | Validation of high-resolution MAIAC aerosol product over South America[END_REF].

Unfortunately, we could not use aerosol optical measurements from the local AERONET site as "ground trust" in satellite retrieval calibration and aerosol characterization because of numerous missing data during the study period (695 of 1214 days).

Consistent with our epidemiology-oriented approach, also shared by other researchers [START_REF] Kloog | Using new satellite based exposure methods to study the association between pregnancy PM2.5 exposure premature birth and birth weight in Massachusetts[END_REF][START_REF] Hyder | PM2.5 exposure and birth outcomes: use of satellite-and monitor-based data[END_REF], available daily AOT470 estimates were averaged to pregnancy values for the place of residence of each woman (with some uncertainty because of the missing retrievals).We found little evidence of geographical variability for AOT470 retrievals during pregnancy over Guadeloupe when considering a windward/leeward or urbanization contrast. The correlation found in this study (R = 0.537) between average AOT470 retrievals and PM10 ground-based measurements during pregnancy was moderate.

This could be partially due to the fact that satellite-derived AOT is a measure of light attenuation in the column, which is affected by ambient conditions, whereas PM10 is a measure of dry particle mass near the surface. However, the regression line passing through the origin suggests that the same phenomenon is measured by both metrics.

Quantifying the fraction of PM10 concentrations attributed to the African dust outbreak for the days with identified African influence was unfortunately out of reach because particle filters were no longer available for the study period. However, Guadeloupe anthropogenic particle pollution is low (approximately 20 μg/m 3 ), because of the absence of heavy industries and the year-round presence of trade winds. As a result, desert dust natural pollution is the A c c e p t e d M a n u s c r i p t 15/24 main factor affecting PM10 data [START_REF] Euphrasie-Clotilde | The relationship between coastal West African dust level and Caribbean island dust[END_REF]. This is the reason why the local air quality monitoring agency classifies desert dust episodes according to PM10 concentrations: light, 28-38 μg PM10/m 3 ; moderate, 39-54 μg PM10/m 3 ); intense, ≥ 55 μg PM10/m 3 [START_REF] Viel | Impact of Saharan Dust Episodes on Preterm Births in Guadeloupe (French West Indies)[END_REF].

Unfortunately, a number of geo-climatic features distinguish the Guadeloupe archipelago (territory of rather limited size, complex topography, humid sub-tropical weather and maritime surroundings), precluding any comparison with results reported in Connecticut and Massachusetts -USA [START_REF] Kloog | Using new satellite based exposure methods to study the association between pregnancy PM2.5 exposure premature birth and birth weight in Massachusetts[END_REF][START_REF] Hyder | PM2.5 exposure and birth outcomes: use of satellite-and monitor-based data[END_REF]. In Guadeloupe, the magnitude of the association between desert dust exposure and preterm birth tended to be lower using the satellite method compared to the monitor method. Indeed, the crude and adjusted ORs per SD change for the PM10-based proxy were significantly increased (OR = 1.36, 95% CI 1.07, 1.73, p = 0.01, and OR 1.40, 95% CI 1.08, 1.81, p = 0.01, respectively) [START_REF] Viel | Impact of Saharan Dust Episodes on Preterm Births in Guadeloupe (French West Indies)[END_REF]). One explanation could be that when AOT retrieval is successful, the variability of PM concentrations is dominated by its temporal component and concentration levels tend to be spatially smooth [START_REF] Liu | Estimating regional spatial and temporal variability of PM2.5 concentrations using satellite data meteorology and land use information[END_REF]. Because of the high proportion of non-retrieval days (80.3%), the satellite method cannot compete regarding the temporal dimension, attenuating associations towards the null.

Conclusion

Given the above-mentioned limitations, the AOT-based proxy does not appear to be more appropriate than the PM-based proxy to retrospectively assess the exposure of pregnant women to desert dust in the Caribbean. We believe that the conventional estimation of PM10 exposure (assigning ground-level measurements to populations within a specified distance of A c c e p t e d M a n u s c r i p t 16/24 the monitoring station) remains an acceptable trade-off between epidemiological relevance and exposure misclassification, given the specific local conditions of the Guadeloupe, the spatial homogeneity of the AOT470 retrievals, and the short median distance, as the crow flies, between the places of residence and the monitoring station. More generally, estimating historical levels of PM concentrations on a small spatial and temporal scale to support epidemiological studies on the air pollution related health burden is still challenging, at least in areas with few monitoring stations and complex topographical/ meteorological conditions, such as tropical areas.

A c c e p t e d M a n u s c r i p t

  This study relied on MAIAC AOT470 retrievals from both the Aqua and Terra satellites. We used the MCD19A2 Version 6 data product, a MODIS Terra and Aqua combined MAIAC AOT gridded dataset, containing 13 daily atmospheric properties at 1 km pixel resolution, in 1,200 x 1,200-km local tiles. MCD19A2 data were provided by the NASA Center for Climate Simulations for the local tile HH12VV07 for the years 2005 to 2008.

  A c c e p t e d M a n u s c r i p t 10/24 mismatch between the PM10 and AOT470 values, the time period spanned from January 1, 2005 (first PM10 concentration available) to April 28, 2008 (last delivery in the TIMOUN cohort) (1,214 days).

  s c r i p t values to range from 0.042 to 0.283 (median: 0.189). Three women were excluded because of childbirth in early January 2005 and the absence of daily AOT470 estimates during this short period of observation.

Fig. 1

 1 Fig. 1 Geographical features of the Guadeloupe archipelago and places of residence of

Fig. 2 AFig. 3 AFig. 4

 234 Fig. 2 Time series of average daily PM10 concentrations (red line) and average daily AOT470 410

Table 1

 1 Mean AOT470 values during pregnancy and comparisons according to the place of residence of pregnant women(n = 906, mother-child cohort, 2005(n = 906, mother-child cohort, -2008, Guadeloupe) , Guadeloupe)

	Univariate analysis	Multivariate analysis a

a adjusting for time period (semesters) and space (geographical contrast) x time (semesters) interactions

Acknowledgements

The authors are grateful to Yujie Wang and Alexei Lyapustin from the NASA Center for Climate Simulations for providing MCD19A2 data and valuable advice. The authors thank the gynecologists, obstetricians, ultra-sonographers, midwives, pediatricians, and families who participated in the TIMOUN study.

Funding

This work was funded by the French National Research Program for Environmental and Occupational Health of ANSES (EST-2016/1/015).

Availability of data and materials

The dataset used and analyzed during the current study is available from the corresponding author on reasonable request.

Declaration Ethics approval and consent to participate

The TIMOUN study was approved by the Guadeloupean Ethics Committee for studies involving human subjects. Written informed consent was provided by each participant.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Author contributions

S.T. analyzed and interpreted