There is a growing global awareness of the psychological consequences of long COVID, supported by emerging empirical evidence. However, the emergence and long-term trajectories of psychological symptoms following the infection are still unclear.To examine when psychological symptoms first emerge following the infection with SARS-CoV-2, and the long-term trajectories of psychological symptoms comparing long and short COVID groups.We analysed longitudinal data from the UCL COVID-19 Social Study (March 2020-November 2021). We included data from adults living in England who reported contracting SARS-CoV-2 by November 2021 . Of these, 15.9% reported having had long COVID (N=495). They were matched to participants who had short COVID using propensity score matching on a variety of demographic, socioeconomic and health covariates  and data were further analysed using growth curve modelling.Depressive and anxiety symptoms increased immediately following the onset of infection in both long and short COVID groups. But the long COVID group had substantially greater initial increases in depressive symptoms and heightened levels over 22 months follow-up. Initial increases in anxiety were not significantly different between groups, but only the short COVID group experienced an improvement in anxiety over follow-up, leading to widening differences between groups.The findings support work on the psychobiological pathways involved in the development of psychological symptoms relating to long COVID. The results highlight the need for monitoring of mental health and provision of adequate support to be interwoven with diagnosis and treatment of the physical consequences of long COVID. However, increased social isolation due to long COVID symptoms and anxiety related to persistent symptoms could mean that psychological symptoms in fact emerge and increase during and beyond the acute state of infection amongst long COVID patients.16First, when do psychological symptoms of anxiety and depression first emerge in long COVID patients? Mechanistically, the ability of coronaviruses (including SARS-CoV-2) to directly infect the central nervous system (CNS) and cause neuroinflammation and consequential psychiatric symptoms is well reported.17 as has a relationship between neuro-immune inflammation and long COVID.18 As such, it is possible that initial psychological experiences around the onset of infection could predict an individual’s risk of developing long COVID. But, reciprocally, heightened stress, anxiety and low mood at the onset of illness could itself adversely affect an individual’s recovery from SARS-CoV-2 through increasing or prolonging disruption of neuro-endocrine and neuro-inflammatory processes.19 This has been demonstrated both through studies showing bidirectional associations between psychological symptoms and neuro-endo-immune processes as well as genetic studies highlighting pleiotropy between depression and inflammatory processes, suggesting a shared genetic vulnerability that could help explain the relationship between a history of mood disorders and long COVID noted in prior studies.14Second, does the level of psychological symptoms during the acute stage of SARS-CoV-2 infection differ amongst people who will go on to have short COVID vs long COVID? A relationship between the severity of immune-inflammatory dysregulation in patients with SARS-CoV-2 infection and depressive symptoms 3 months later has been reported,20 However, it is also plausible that the reverse is true: the process of dealing with debilitating ongoing symptoms could exacerbate psychological distress.Third, what are the longer-term trajectories of psychological symptoms amongst people with long COVID beyond the acute stage of infection? To date, much research on this topic has been limited by relatively short-term follow-up  and involved limited waves of data collection during that follow-up. Finer-grained data showing trajectories of psychological symptoms over time are still lacking. It is possible that following the acute stage of infection, some of the initial symptoms of psychological distress decline, as can happen for patients with short COVID.Therefore, this study aimed to explore the mental health trajectories of people experiencing long COVID, compared to those with short COVID using data from the UCL COVID-19 Social Study. To ensure that any potential differences were not due to imbalances between long and short COVID patients in socio-demographic factors, histories of mental and physical health prior to infection, or symptoms of COVID-19 during acute infection, we used propensity score matching (PSM) to construct two balanced groups of long vs short COVID patients. Further, to differentiate experiences post-COVID from usual mental health experiences during the pandemic, we used growth curve models accounting for lockdowns, other social restrictions, and time of the year, tracking individuals in the 10 months prior to their infection with SARS-CoV-2 and for 22 months of follow-up. This study therefore presents one of the largest and longest studies to date of the psychological experiences of patients with long COVID.https://osf.io/jm8ra/.Data were derived from the University College London (UCL) COVID-19 Social Study (CSS); a large panel study of the psychological and social experiences of over 75,000 adults (aged 18+) in the UK during the COVID-19 pandemic. The study commenced on 21 March 2020 and involved weekly and then monthly (August 2020 to November 2021) online data collection during the pandemic. Participants were recruited via convenience sampling and targeted recruitment of underrepresented/vulnerable groups. The study was approved by the UCL Research Ethics Committee [12467/005] and all participants gave written informed consent. Detailed information on the study is available online at st March 2020 when the study was launched . Of these, 4,938 participants (22%) reported having had COVID-19 by November 2021. We excluded participants (i) with missing data on COVID-19 specific measures (1%), (ii) who reported infection with SARS-CoV-2 before 21ched see , and (ii21 So we considered both positive tests and suspected cases (category 1 to 4) as having had COVID-19. The information on date of contract was also collected: ‘If you have had COVID-19, when did you first contract it?’ Moreover, participants were asked if they considered themselves to have or have had long COVID, with responses: (1) yes, a medical professional has formally diagnosed me with long COVID; (2) yes, I have not been formally diagnosed but consider myself to have Long COVID; (3) no, I do not consider myself to have Long COVID; (4) I am unsure. This was recoded into a binary variable (yes/no) with unsure being treated as not having COVID.In November 2021, the CSS included a special module on COVID-19 experience. Participants were asked ‘overall, do you believe you have ever had COVID-19?’ The response options included: (1) yes, confirmed by a positive COVID-19 test; (2) yes, confirmed by a positive antibody test; (3) yes, suspected by a doctor but not tested; (4) yes, my own suspicions; (5) No, not that I know of. Due to challenges in diagnosis of COVID-19, , definitions of long COVID do not require having had a positive test result, but rather the presence of symptoms that were initially suggestive of COVID-19.22 a standardised instrument for screening for depression in primary care. The questionnaire includes 9 items with 4-point responses with total scores ranging 0-27. Scores of 0-4 suggest minimal depression, 5-9 mild depression, 10-14 moderate depression, 15-19 moderately severe depression, and 20-27 severe depression.22 We used the total score as a continuous measure.Depressive symptoms were measured using the Patient Health Questionnaire (PHQ-9),23 a well-validated tool used to screen for generalized anxiety disorder in clinical practice and research. The GAD-7 comprises 7 items with 4-point responses with total scores ranging 0-21. Scores of 0-4 are thought to represent minimal anxiety, 5-9 are thought to represent mild anxiety, 10-14 moderate anxiety, and 15 and above severe.23 Again, the total score was used as a continuous measure.Anxiety symptoms were measured using the Generalized Anxiety Disorder assessment (GAD-7),To examine mental health growth trajectories, a key variable is time. The time variable was constructed as month since people contracted SARS-CoV-2 (time 0), which took negative values for the period before infection (-21 to 21). It was calculated based on the self-reported contraction date and system-generated survey date (see (via propensity score matching), a range of factors were taken into account in our analyses. These included gender (women vs men), ethnicity (white vs ethnic minorities), age groups , education , income , employment status , area of living , living situation , number of close friends (0 to 10+) and usual social contacts , self-reported diagnosis of any long-term physical health condition or any disability (yes vs no), and self-reported diagnosis of any long-term mental health condition (yes vs no). All above measures were taken from the study baseline when participants joined the study for the first time. Moreover, we included baseline depressive (PHQ-9) and anxiety (GAD-7) symptoms when participants joined the study. Finally, we included a few COVID-19 specific measures, including month when participants had COVID-19 and whether confirmed by a test (COVID-19/antibody test vs doctor’s/own suspicion). In addition, we considered self-reported severity of symptoms in the first one to two weeks (severe symptoms vs minor/asymptomatic).To construct comparable groups being exposed to or having long COVID based onthe observed covariates, which is used to pair participants with short COVID and long COVID. The two matched groups should have identical or similar distribution of covariates that are used to estimate the propensity score. We used one-to-one nearest neighbour matching within a calliper (a quarter of one standard deviation of the sample estimated propensity scores) without replacement. PSM was implemented using Stata psmatch2 command.We employed propensity score matching (PSM) to construct two comparable groups: short COVID versus long COVID. The propensity score is the probability of It allowed us to estimate the inter-individual heterogeneity in intraindividual changes over time. The model included a quadratic time term to allow for non-linear trajectories (see the Supplement for mathematic equations).To compare mental health growth trajectories between the two matched groups, data were analysed using growth curve models.  As sensitivity analyses, (i) we reran the analyses using alternative matching methods, namely one-to-many nearest neighbour matching and kernel matching; (ii) we excluded anyone who said they were ‘unsure’ if they had long COVID; and (iii) we explored further people’s understanding of the term ‘long COVID’. If individuals reported believing they had long COVID but subsequently indicated that their symptoms had got better after 2 weeks, they were excluded, as were individuals who reported not having long COVID but who said they had symptoms lasting more than 4 weeks. The main analysis based on one-to-one matching were unweighted; whereas growth curve models based on one-to-many or kernel matching were weighted using weights of matched controls generated by psmatch2. Analyses were carried out using Stata version 17.Of the 3,115 participants considered for matching, 495 (15.9%) reported having had long COVID- 19. After matching, 481 participants were successfully matched with a control. There was a considerable reduction of individual covariates imbalance after matching  and S5. 24, it is more than likely that there was an overrepresentation of women in the sample. However, weights were not applied due to a lack of credible information on the demographic characteristics of people who had long COVID in England. Among those with long COVID (N=481), 23.3% of them were formally diagnosed by a medical professional and 76.7% self-diagnosed  or suspected that they had SARS-CoV-2. We were unable to ascertain whether the reported increases in anxiety and depression found here were primarily driven by biological processes or psychological processes (i.e. fear of the virus) as we lacked data on psychological experiences in people with SARS-CoV-2 who were asymptomatic and did not know they had the virus.This study supports work on the mechanisms at play in the development of long COVID. First, symptoms of depression and anxiety emerge quickly following the onset of SARS-CoV-2 infection, with the peak in both symptoms occurring at the first measurement timepoint post-infection (i.e. within 1 week of reported infection). This points to immediate psychobiological pathways being implicated in the aetiology of COVID-related mental distress both in long and short COVID. Existing literature proposes that inflammatory mechanisms could be at play,18 Notably, there was not a significant difference in initial increases in anxiety levels between the two groups, which would support theories that the increase in depressive symptoms amongst long COVID patients is biologically driven by the virus rather than a manifestation of a greater predisposition to emotional distress during illness.Second, even when long and short COVID patients were matched on physical and psychiatric comorbidities prior to COVID and levels of SARS-CoV-2 symptom severity and even though they displayed similar trajectories of anxiety and depressive symptoms in the 10 months prior to infection, those in the long COVID group experienced greater increases in depressive symptoms immediately following the onset of SARS-CoV-2 infection. This complements previous work suggesting that the ability of SARS-CoV-2 to raise levels of systemic and neuro-inflammation may be greater in patients with long COVID and also suggests that whether an individual is likely to experience long COVID is decided early on in their experience of the virus.25 But it may not simply be a case of initial anxiety symptoms experienced during acute infection  persisting, but also a consequence of new psychological challenges relating to the realisation that one’s initial infection is becoming long COVID and the associated psychological, social and behavioural consequences of ongoing illness .16 Notably, whilst there was a slight increase in depressive symptoms in both groups towards the end of the followup, the confidence intervals widened across the follow-up period as numbers of people who had contracted SARS-CoV-2 early enough in the pandemic to be followed-up 22 months later decreased. So this increase is likely a feature of the sample rather than a common pattern amongst both groups over time.However, despite the larger initial increase in depressive symptoms in long COVID patients, both long COVID and short COVID groups experienced parallel decreases in symptoms over time . This could suggest a process of psychological recovery, even potentially whilst experiencing ongoing physiological symptoms. However, we did not ask participants about how their symptoms and functioning at follow-up compared to when their virus started. So some of this improvement in depressive symptoms amongst long COVID patients could be illustrative of an improvement in long COVID itself , whilst for patients who continued to experience physiological symptoms, this psychological recovery may not have been felt. Further, despite some improvement, levels of depressive symptoms remained higher in the long COVID group across the entire 22-month followup than in the 10 months prior to infection, whereas the short COVID group returned to baseline or below baseline levels within 4 months. So any apparent recovery was not complete. Relatedly, levels of anxiety did not improve over time in long COVID patients over the follow-up, with an increasing discrepancy compared to short COVID patients. The evident persistence of mental distress in long COVID patients mirrors findings from previous studies of patients experiencing other coronaviruses. For example, patients who developed SARS-CoV (“SARS”) in 2003-2004 reported persistent stress one year later without signs of decrease, even if physical symptoms had improved.16 Given the well-established interconnection between psychological and inflammatory processes, these additional treatment-related stressors could contribute to the prolonging of long COVID symptoms. So it is important that patients feel listened to, validated, and supported in their diagnosis and treatment.16 There has been a call for long COVID public health response to include personalised treatment and rehabilitation and multidisciplinary care.26 Our findings support this call, and further suggest that (i) clinicians should be aware of the possibility for depression, anxiety and other psychiatric symptoms in patients with long COVID and recognise that such symptoms may not just be a consequence of ongoing physical symptoms but may have been primary outcomes from the initial SARS-CoV-2 infection; (ii) neuropsychological evaluations for patients who are experiencing long COVID could be valuable to determine whether specialised mental health support is also required, and such evaluations should not assume a resolution of psychological symptoms in the absence of treatment; and (iii) psychological support should be provided as part of multidisciplinary care and, given the early onset of psychological symptoms, early provision of such for patients suspected of having long COVID should be recommended.6 In some countries such as the UK, it has been recommended that mental health problems alongside or as a result of long COVID can be managed by following existing relevant guidelines.3 However, we recommend that any mental health support needs to be provided alongside (rather than as a substitute for) broader medical investigation and support for long COVID, given diagnosis of psychiatric symptoms without adequate attention to other symptoms has been found to be detrimental to mental health in patients with long COVID.27 Finally, informal mental health support for patients experiencing long COVID such as peer support groups and community social and cultural activities via schemes such as social prescribing should be encouraged as evidence is already suggesting that the broader support and validation of experiences from others can assist in recovery.16Our findings highlight that for patients with long COVID, psychological symptoms could persist for as long as 2 years post-infection, with clear consequences the treatment of long COVID patients. Barriers to diagnosis with long COVID and subsequent challenges navigating and accessing treatments can in itself exacerbate long COVID symptoms.A main strength of this study lies in repeated monthly follow-ups of the same participant over 22 months since March 2020, allowing the longest and most detailed follow-up to date on psychological experiences of long COVID patients. By using propensity score matching, we were able to reduce the observed differences between long and short COVID groups to render them comparable. We achieved a good quality match, which resulted in equivalent mental health scores in the months prior to infection, improving the comparability of post-infection mental health changes between people with short and long COVID. However, we cannot rule out the possibility of potential biases due to unobserved covariates that are associated with the risk of having long COVID-19 (despite the wide range of covariates included in our models). Moreover, whilst our sample showed good heterogeneity in initial severity of SARS-CoV-2 symptoms and subsequent long COVID experiences, our sample may not be representative of the population who had (long) COVID, especially as those with more severe ongoing long COVID symptoms may have been more likely to drop out of the study. We followed current best practice in epidemiological research in how we defined long COVID. But some of our patients lacked formal diagnoses, so it is possible that some participants’ symptoms were caused by alternative illnesses. Additionally, our sample was relatively heterogeneous in terms of long COVID experiences, with a range of different patterns of symptoms reported, from persistent acute symptoms for months, to relapsing-remitting symptoms, to low-level persistent symptoms. Whilst this heterogeneity is typical in the diagnosis category of “long COVID”, future research could consider whether there are differential psychological experiences depending on pattern of long COVID symptoms. Finally, our sample relied on participants’ self-report of the date they contracted SARS-CoV-2. This could have been affected by recall bias. So whilst we found an increase in psychological symptoms immediately following reported onset of infection, this increase may have lagged by a few days. Nonetheless, this relatively short lag time does not undermine the conclusions or proposed mechanisms.Overall, this study presents the longest and most detailed data on psychological experiences of long COVID patients to date, answering crucial questions. Psychological symptoms of anxiety and depression emerge quickly following onset of SARS-CoV-2 in long COVID patients, with levels of depression rising significantly above levels in patients who go on to experience short COVID. Over the following two years, whilst there is some decrease in depressive symptoms, they remain above pre-infection levels, whilst anxiety levels show little signs of improvement. This presents a contrast to short COVID patients where levels return to below-infection levels within 4 months of infection. The findings shed light on the psychobiological pathways involved in the development of psychological symptoms relating to long COVID as well as suggesting that initial psychological experiences during SARS-CoV-2 infection could be explored further as potential predictors of subsequent risk of developing long COVID. The results also show that we cannot assume a gradual organic recovery from the psychological effects of long COVID, highlighting the need for monitoring of mental health and provision of adequate support to be interwoven with diagnosis and treatment of the physical consequences of long COVID.Supplementary Material


The coronavirus disease-2019 (COVID-19) pandemic has rapidly spread across the world. The disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which first appeared in Wuhan, China in December, 2019. Ever increasing data is continuing to emerge about the impact of COVID-19 on cardiovascular tissue and other organ system. Clinical features associated with COVID-19 suggest that endothelial cell dysfunction and microvascular thrombosis are to a large extent contributing to resultant multi-organ complications. This review is aimed at highlighting the critical aspects associated with COVID-19 and its presumed microvascular angiopathic consequences on the cardiovascular system leading to multi-organ dysfunction. Coronaviruses (CoVs) are enveloped, non-segmented, single strand positive sense RNA viruses that are widely distributed among humans and other mammals. This group of viruses belongs to the coronaviridae family of viruses, and are harbored in animals such as civets, dogs, cats, bats, and camels –3. To-daThe coronavirus disease-2019 (COVID-19) is a novel emerging infectious disease that is caused by SARS-CoV-2. COVID-19 was declared a global pandemic by the World Health Organization on March 11, 2020 . In the Like other SARS-CoV, COVID-19 can cause a severe pulmonary viral pneumonia leading to severe hypoxia and subsequent respiratory failure. However, emerging evidence demonstrates that unlike the majority of upper respiratory viral illness, COVID-19 can also lead to cardiovascular and multi-organ complications –13. AlthThe SARS-CoV2 has been reported to bind to angiotensin converting enzyme 2 (ACE2) protein . SpecifiUpon binding onto the cell membrane ACE2 protein, the SARS-CoV2 virus enters the cell via a receptor mediated endocytosis and uses the host cell nuclear machinery to replicate , which pThe ACE2 mRNA is detectable in virtually all mammalian tissue, however, the protein is most remarkably expressed on the cell surface of lung alveolar epithelial cells and intestinal enterocytes . The proMicrovascular angiopathy is a pathological sequelae of a multitude of conditions that results from over-activation of host immune defense mechanisms. Patients impacted by sepsis or septic shock from a bacterial or viral infection, or autoimmune process, may fall victim to hyperimmune responses that can lead to significant host consequences –25. For Borrelia burgdorferi) and Rocky Mountain spotted fever  also can lead to severe cytokine storm, overexpression of CCL2, and resultant microvascular injury. In presence of such infections, patients can often develop microvascular dysfunction and thrombosis, as well as over-activation of the host fibrinolytic system  . The sysSince the emergence of the pandemic, there has been a multitude of clinical series published regarding the clinical manifestations and outcomes of COVID-19 , 31–34. The median incubation period has been reported to be 5 days and individuals who develop symptoms do so within approximately 11.5 days of infection . The medIn addition to the known initial pulmonary consequences of COVID-19, various reports have demonstrated that patients infected with SARS-CoV2 can develop cardiac dysfunction and myocardial injury , 42. TheThe incidence of acute cardiac injury in patients hospitalized with COVID-19 ranges between 7 and 17% , 35, 39.Cardiac arrhythmias have also been reported as common complication in patients afflicted by COVID-19. One study of 121 patients, it was reported that >71% of patients experienced periods of sinus tachycardia, >14% of patients experienced bradycardia, and 1 patient developed new-onset transient atrial fibrillation . Other rSimilarly, heart failure and fulminant myocarditis have been reported in a subset of patients infected with COVID-19. An analysis of 191 patients, reported that heart failure was observed in 23% of patients who were hospitalized due to COVID-19 infection. Patients with heart failure were noted to have an elevated (up to 28%) risk of mortality . SeveralVarious treatment modalities have been employed in the treatment of patients with COVID-19 and cardiac manifestations. Antivirals such as ribavirin, remdesivir, and oseltamivir, and antibiotics such as ceftriaxone, azithromycin, and immunoglobulins to modulate the immune status have also been reported with variable success , 49, 54.Various reports have cited evidence to suggest microvascular dysfunction in the central nervous system of patients with severe COVID-19 infections –60. The The ACE2 receptor is expressed on brain endothelial and smooth muscle cells , 56. TheThe ACE2 receptor is highly expressed in the gastrointestinal epithelium, and in liver cholangiocytes and arterial endothelium. However, it is not as highly expressed in the liver sinusoidal endothelium –69. A laInitial reports from Wuhan, China informed us that AKI occurred in 7% of individuals who are COVID-19 positive . In patiThe ACE2 receptor is known to be expressed in the renal capillary endotheilum, and is thought to lead to localized tissue inflammation due to COVID-19 infections. Electron microscopy of renal capillary endothelium demonstrated COVID-19 viral inclusion structures, and on tissue histology inflammatory cells were visualized to be associated with endothelium—consistent with endothelitis . In a stSeveral mechanisms of COVID-19 induced renal injury have been proposed. One potential mechanism may simply be due to hypo-perfusion from dehydration and diarrhea related to the systemic inflammatory –83. HoweThe care of patients impacted by COVID-19 related AKI remains largely supportive. Depending on the severity of the presentation, patients may be managed with renal replacement therapy (RRT) in the form of intermittent hemodialysis or continuous renal replacement therapy (CRRT), or slow low efficiency dialysis (SLED). In the current absence of data clearly demonstrating superiority of one modality over another, the choice of dialysis modality is mostly informed by the availability of resources and local clinical expertise .Coagulopathy is a common phenomenon that can occur with sepsis and may predict outcomes in patients with severe pulmonary infections and multisystem organ dysfunction . SeveralSome screening serum biomarkers have been proposed to monitor severity and incidence of VTE. In one study an admission D-dimer level >1,500 ng/mL was found to be an independent marker associated with the incidence of VTE . In anotMultiple studies have demonstrated an overall higher index of morbidity and mortality in patients affected by VTE –96. For The treatment of COVID-19 associated microvascular angiopathies and their effects on the cardiovascular system is yet to be defined, but various strategies can potentially be derived from treatments used for management of other microvascular angiopathies. Conditions such as Kawasaki's disease, Henoch-Schonlein purpura, Rheumatoid Arthritis and Buerger's disease, are typically managed by targeting the underlying disorder and palliating symptoms –101. SomOn May 1st, 2020 the US Food and drug administration (FDA) issued an emergency use authorization of Remdesivir for adults and children with suspected or laboratory confirmed severe COVID-19 . RemdesiAnticoagulants have recently emerged as an important treatment modality for patients infected with COVID-19, and in particular patients who are considered higher risk individuals . VariousSteroid therapy has been used for the treatment of severe ARDS due to COVID-19 infection . In a muThe body of evidence demonstrating the role of microvascular angiopathy in COVID-19 is evolving rapidly. It is evident from the current body of knowledge that COVID-19-induced microvascular angiopathy can lead to a wide range of tissue pathology and clinical complications. Understanding the molecular, biochemical and pathophysiological mechanisms underlying this process is paramount to our ongoing management efforts of individuals afflicted by COVID-19. Additional research is necessary to help further our understanding of microvascular angiopathic complications related to COVID-19, help develop novel therapeutics, and provide an effective cure to this new global pandemic.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Reductions in malaria morbidity have been reported following azithromycin mass drug administration (MDA) for trachoma. The recent Macrolides Oraux pour Reduire les Deces avec un Oeil sur la Resistance (MORDOR) trial reported a reduction in child mortality following biannual azithromycin MDA. Here, we investigate the effects of azithromycin MDA on malaria at the MORDOR-Malawi study site. A cluster-randomized double-blind placebo-controlled trial, with 15 clusters per arm, was conducted. House-to-house census was updated biannually, and azithromycin or placebo syrup was distributed to children aged 1–59 months for a total of four biannual distributions. At baseline, 12-month, and 24-month follow-up visits, a random sample of 1,200 children was assessed for malaria with thick and thin blood smears and hemoglobin measurement. In the community-level analysis, there was no difference in the prevalence of parasitemia , gametocytemia , or anemia  between placebo and azithromycin communities. Further interrogation of the data at the individual level, both per-protocol (including only those who received treatment 6 months previously) and by intention-to-treat, did not identify differences in parasitemia between treatment arms. In contrast to several previous reports, this study did not show an effect of azithromycin MDA on malaria parasitemia at the community or individual levels. Azithromycin is a broad spectrum antibiotic with a relatively long half-life which is used in the treatment of pneumonia and diarrhea but also displays antimalarial activity.3 Field trials of the effects of azithromycin MDA on malaria infection and symptoms have previously reported reductions in malariometric indices; and recent results from the Niger MORDOR site indicate an association between azithromycin MDA and lower parasitemia.7 It is feasible that the mortality benefit seen with azithromycin MDA may be due, at least in part, to a decrease in malaria prevalence or severity.The Macrolides Oraux pour Reduire les Deces avec un Oeil sur la Resistance (MORDOR) trial, conducted in Niger, Malawi, and Tanzania, demonstrated a reduction in child mortality following biannual mass drug administration (MDA) with azithromycin.This study reports malaria parasitemia, parasite density, and gametocytemia data from the MORDOR Malawi study site, aiming to improve our understanding of the effects of azithromycin MDA on malaria infection. Samples were collected from children in villages representative of the MORDOR trial and used the same biannual census updates and cluster-randomized trial structure to make the results as representative as possible of the wider study area and to assess community-level effects of any outcomes. The hypothesis for this study was that azithromycin MDA would reduce the community prevalence of malaria compared with placebo.The randomization unit for the MORDOR trial in Malawi was defined as the catchment area of a health surveillance assistant (HSA), approximately 1,000 total population. Communities with a population < 200 or > 2,000 on a pre-baseline census were excluded. Thirty communities were randomly selected from the pool of communities for the MORDOR trial for follow-up as part of this malaria prevalence study. The randomization was stratified to produce six communities in each of the five geographical zones of Mangochi district for geographical generalizability and for logistical reasons regarding fieldwork. Biannual census updates were performed, and communities received study drug in the same treatment rounds as the MORDOR trial.All children aged 1–59 months and weighing ≥ 3.8 kg were eligible for treatment at each of four biannual mass distributions. At the baseline, 12-month, and 24-month follow-up visits, guardians of a randomly selected sample of 40 children per community were asked to provide written informed consent for finger-prick blood samples. The procedures and study were explained by trained local nursing staff who subsequently collected thick and thin blood smears if consent was obtained. Illiterate guardians provided a thumb print to acknowledge consent.Azithromycin was administered at a dose of 20 mg/kg. Children old enough to stand received an approximate dose estimated from their height, and younger children were weighed. The placebo bottles and suspension appeared identical to azithromycin. Distribution of drug took place after sample collection was complete and was performed by the HSAs and field-workers conducting house-to-house visits. Guardians were asked to inform the HSA of any adverse events that occurred within 7 days of receiving study drug. Health surveillance assistants subsequently informed the study team.The primary prespecified outcome was prevalence of malaria parasites on thick blood smears in children aged 1–59 months. Prespecified secondary outcomes included parasite density, gametocyte prevalence and density, hemoglobin concentration, and presence of anemia (Hb < 11 g/dL). Primary analyses were by intention-to-treat, and per-protocol analyses were secondary.Sample collection took place during the baseline visit (May–July 2015) and at 12-month and 24-month visits , approximately 6 months after the second and fourth treatment rounds. Sample collection involved selected children receiving a finger stick and thick and thin blood smears collected on a single slide ). Slides were labeled with a random number and barcode and scanned using the data collection app to link to census data. The thin smear was fixed with absolute methanol and the slide stained with 8% Giemsa. Parasite density was assessed from the thick smear by two independent slide readers at MORDOR trial laboratories in Mangochi and Blantyre. Parasite density was estimated as parasites per microliter by assessing up to 100 high-power fields and assuming that 500 high-power fields contain the equivalent of one microliter of blood. If after two reads there was a discrepancy of greater than 20%, a third reading was taken as the final read. Thin slides were used to assess malaria species.Fifteen communities per arm, with 40 children sampled from each community (600 children per arm), provided 90% power to detect a reduction of malaria parasitemia from 20% to half that value at each study phase.Study drug was labeled with six letters by the manufacturer , with three letters corresponding to azithromycin and three to placebo. Communities were randomly assigned to one of the six drug letters by the study statistician using the statistical package R . All field and laboratory staff and participants in Malawi were blinded to the treatment code until after all data collection was complete.The main analysis was by intention-to-treat at the community level, in keeping with the cluster-randomized design of the MORDOR trial. Further analyses by both intention-to-treat and per-protocol at the individual level were used to further explore the data.Community-level prevalence of parasitemia, anemia, and gametocytemia by treatment arm were assessed for the 12-month and 24-month visits using mixed-effects linear regression models including fixed effects for baseline prevalence and study phase and a random effect for community.Individual-level parasitemia, parasite density, hemoglobin, and gametocytemia by treatment arm were assessed for the 12-month and 24-month visits using mixed-effects logistic or linear regression models, as appropriate, including fixed effects for age, baseline prevalence, and study phase and nested random effects for individuals within communities. Individual-level analyses were performed by both intention-to-treat and per-protocol, including only those who received study drug as indicated at the previous phase. Intra-class correlation coefficients (ICCs) were derived from the regression models at the level of the randomization unit.t-test. Association between the presence of parasitemia and the hemoglobin level was assessed at the individual level using Student’s t-test.The hemoglobin levels in individuals between the treatment arms were split by the presence of parasitemia and compared using Student’s Ethical approval for morbidity assessments alongside the MORDOR trial was obtained from the College of Medicine, University of Malawi; the London School of Hygiene and Tropical Medicine; and the UCSF Committee on Human Research. Written consent was obtained from the guardians of participants. There were no incentives for participation.Demographic details of sampled children in the 30 study communities are shown in Plasmodium falciparum, and the remainder were Plasmodium malariae. Analyses included both malaria species. The community-level prevalence of malaria parasitemia, anemia, and gametocytemia was similar between placebo and azithromycin groups at baseline . The prevalence of anemia, defined as Hb < 11 g/dL, was not significantly different between treatment groups at the 12- and 24-month follow-up visits: 1.7% lower in azithromycin-treated communities . The prevalence of gametocytemia also remained similar between treatment groups at the follow-up rounds: 0.7% lower in azithromycin-treated communities .Over 98% of malaria species detected were P = 0.67; ICC = 0.06). Parasite density in parasitemic individuals was similar between treatment groups at the 12- and 24-month follow-up visits: 23 parasites/µL lower in individuals in azithromycin-treated communities after adjusting for age, baseline parasitemia, and follow-up phase . Hemoglobin was also similar between treatment groups at 12- and 24-month follow-up visits: 0.08 g/dL lower in individuals in azithromycin-treated communities after adjusting for age, baseline community prevalence of anemia, and follow-up phase .Individual-level unadjusted data are shown by intention-to-treat in P = 0.17; ICC = 0.06). Parasite density in parasitemic individuals was similar between treatment groups at 12- and 24-month visits after adjusting for age, baseline parasitemia, and follow-up phase: 19 parasites/µL lower in azithromycin-treated individuals . Hemoglobin levels were also similar between treatment groups at the 12- and 24-month follow-up visits after adjusting for age, baseline community prevalence of anemia, and follow-up phase: 0.03 g/dL lower in azithromycin-treated individuals , shown in Supplemental Tables 1 and 2.In the per-protocol analysis, the odds ratio for parasitemia in azithromycin- compared with placebo-treated individuals at 12- and 24-month visits after adjusting for age, baseline parasitemia, and follow-up phase was 0.71  and both age and baseline community parasitemia or hemoglobin. The effect of treatment did not vary with age when an interaction term between the treatment arm and age was included in the models.Supplemental Table 3.Hemoglobin levels were approximately 1 g/dL lower in parasitemic individuals at all study phases and in azithromycin and placebo groups, shown in Several morbidity sub-studies were nested within the MORDOR trial to investigate mechanisms through which azithromycin MDA may reduce mortality. This research was not carried out in the MORDOR mortality study communities to reduce the risk of interventions impacting the primary MORDOR outcome of mortality. Morbidity study communities were randomly selected from the same pool as the main MORDOR trial, designed so that results would be representative of the mortality study. This malaria study, nested within MORDOR, did not identify a reduction in malaria parasitemia, gametocytemia, or hemoglobin in azithromycin-treated compared with placebo-treated communities. Secondary analyses at the individual level, by intention-to-treat and per-protocol, including only those who received study drug at the previous phase, approximately 6 months earlier, also did not identify significant differences in the prevalence of parasitemia or parasite density in parasitemic individuals.7 The mechanism through which a reduction in parasitemia over this time period may occur is unclear. Azithromycin displays delayed activity against the malaria parasite, preventing the progeny of antibiotic-treated parasites from fully maturing, and has a long terminal half-life of approximately 68 hours. These are properties that could feasibly contribute to a period of antimalarial activity of days to weeks but not months.8 The studies showing longer term effects were in Niger and the Gambia, in areas with lower background levels of parasitemia, which may be more amenable to reductions in transmission that could last longer than individual-level prophylaxis and treatment. This study assessed malaria gametocytemia as an effect of azithromycin on the sexual stages of the parasite which could explain the longer term community-level reductions in parasitemia as previously reported. Reductions in gametocytemia were not identified, which is consistent with previous evidence.9Previous published reports of the effect of azithromycin MDA on malaria have suggested a reduction in malaria over 6-month duration.1 The best estimates for the odds ratio for the presence of parasitemia in individuals in azithromycin communities compared with placebo ones were 0.89 by intention-to-treat and 0.71 per-protocol, and it is possible that this study of limited size with follow-up restricted to 6 months post-MDA represents type II error. However, while the main MORDOR trial suggested increased child survival benefit in those younger than 6 months, in this study, age and parasitemia were positively associated , further suggesting that the child survival benefits in MORDOR were not best explained through effects on malaria. Further investigation of the effects of azithromycin MDA on malaria severity and mortality, as well as cause-specific mortality for all the major causes of child mortality, is required to improve our understanding of whether the reported mortality reductions may be due to specific anti-pathogen effects or to other mechanisms, such as the immunomodulatory and anti-inflammatory effects of azithromycin.11In the context of the MORDOR trial showing a reduction in child mortality, this study does not provide evidence for an effect of azithromycin MDA on malaria mortality at the Malawi site.13 Malaria was also the commonest inferred cause of death from verbal autopsy in the MORDOR trial in Malawi.14 Parasitemic children had significantly lower mean hemoglobin levels at all follow-up rounds, consistent with known effects of malaria as a cause of anemia in children.17 This analysis provides some validation of the integrity of the data. In addition, the ICCs were low for all analyses, suggesting considerable heterogeneity in malaria infection and hemoglobin levels by community, consistent with usual epidemiological patterns of malaria and similar to the MORDOR Niger site data.7The prevalence of malaria parasitemia in this study was approximately 30% in children aged 1–59 months. Malawi is hyperendemic for malaria with 95% of the population susceptible to infection, and large-scale surveys before and after this study reported malaria parasitemia prevalence of 33% and 24%, respectively.18 At the community level, this may also reduce the reservoir of infectious individuals at the beginning of the following high-transmission period. In Malawi, where despite some seasonality, malaria prevalence remains high year-round, the optimal time to treat, if indeed there is any benefit from the intervention, is unclear.One limitation of this study is that treatment took place at the beginning and end of each dry season for logistical reasons. Mathematical modeling of the effect of azithromycin MDA on malaria in areas of highly seasonal transmission suggests there may be most benefit from treatment during the low-transmission season when treatment of established infection may produce more sustained benefit because of the lower risk of reinfection.7 Any effect of azithromycin MDA on malaria may be impacted by other malaria interventions, such as seasonal malaria chemoprophylaxis (SMC), which was not taking place at the MORDOR-Malawi site. A recent study indicated no additional child mortality benefit when adding azithromycin MDA to SMC in Mali and Burkina Faso.19Monitoring for infection took place during the baseline, 12-month, and 24-month visits, early in the dry season, and approximately 6 months after the previous treatment round for the latter two visits. This seasonality and timing of sample collection may not provide a complete understanding of the effect of the biannual azithromycin MDA on malaria prevalence, which may vary with time lapsed after administration. Finally, while carefully designed to be representative of the MORDOR trial site in Malawi, the data may not be representative of other countries with different malaria prevalence and healthcare interventions, although some data are available from other MORDOR sites.In conclusion, a cluster-randomized placebo-controlled study of the effects of azithromycin MDA on malaria parasitemia was unable to detect a difference in malaria parasitemia at the community or individual levels, providing no evidence that any child survival benefit was mediated by effects on malaria mortality. Further investigation is required to understand the effect of azithromycin MDA on malaria morbidity and mortality and, indeed, to elucidate the mechanisms by which azithromycin MDA may reduce child mortality.Supplemental materials


Concerns regarding infection with the novel coronavirus SARS-CoV-2 leading to COVID-19 are particularly marked for pregnant women with autoimmune diseases such as multiple sclerosis (MS). There is currently a relative paucity of information to guide advice given to and the clinical management of these individuals. Much of the limited available data around COVID-19 and pregnancy derives from the obstetric literature, and as such, neurologists may not be familiar with the general principles underlying current advice. In this article, we discuss the impact of potential infection on the pregnant woman, the impact on her baby, the impact of the current pandemic on antenatal care, and the interaction between COVID-19, MS and pregnancy. This review provides a framework for neurologists to use to guide the individualised advice given to both pregnant women with MS, and those women with MS who are considering pregnancy. This includes evidence derived from previous novel coronavirus infections, and emerging evidence from the current pandemic. There is increasing evidence that certain co-morbidities, such as hypertension, are associated with increased severity of COVID-192. Recent data originating from Italian cohorts, currently available in preprint form only, has suggested that exposure to anti-B cell therapies such as Ocrelizumab and/or recent steroid exposure may confer increased risk of severe COVID-19. Much of the limited available data around COVID-19 and pregnancy derive from the obstetric literature, and as such, neurologists may not be familiar with the general principles underlying current advice.Concerns regarding infection with the novel coronavirus SARS-CoV-2 leading to COVID-19 are particularly marked for both people with multiple sclerosis (MS) and pregnant women. There is a relative paucity of information to guide the advice given to, and clinical management of, these individuals. Both individuals with MS and pregnant women are identified as ‘vulnerable’, and stringent social distancing is recommended; however, the precise advice given to people with MS varies. Early data from Italy suggest that there may not be a significantly enhanced risk of adverse outcomes in people with MS;3 This is due to direct changes in the immune cell repertoire, as well as physical changes such as elevation of the diaphragm and splaying of the thoracic cage due to the enlarged uterus. These physical changes decrease the functional residual capacity and ability to clear secretions, in the presence of increased oxygen consumption during pregnancy.4Responses to viral infections differ in pregnant women, and pregnant women are in general at increased risk of respiratory infection. Some infections, such as influenza may be more severe.6 Case fatality rates in pregnant women were estimated to be up to 25% in SARS-CoV5 and 27% in MERS-CoV.7 Fortunately, this pattern has not been replicated thus far in SARS-CoV-2/COVID-19.8 In contrast to SARS and MERS, there appears to be a cohort of minimally symptomatic or even asymptomatic individuals who carry COVID-19, some of whom may be pregnant women.10 However, due to the fact that COVID-19 pneumonia can cause rapidly progressive diffuse bilateral interstitial lung disease, there is a potentially high risk of respiratory decompensation and hypoxaemic respiratory failure in symptomatic pregnant women,11 which likely contributes to the emerging increased risk of critical care admission in pregnant women with COVID-19.12Previous novel coronavirus infections  have been associated with increased risk of adverse outcomes including spontaneous miscarriage with infection in the first trimester of pregnancy and preterm birth and intrauterine growth restriction (IUGR) with infection in the third trimester.There are, therefore, a number of key clinical considerations regarding COVID-19 and MS in pregnancy. Broadly speaking, these are (1) the impact of potential infection on the pregnant woman, (2) the impact on her baby, (3) the impact of the current pandemic on antenatal care, and (4) the interaction between COVID-19, MS and pregnancy. In general, women with MS who are also pregnant should be advised to follow appropriate social distancing measures and/or shielding measures depending on their immunosuppressant exposure and additional clinical co-morbidities. It is important that pregnant women are advised to maintain contact with obstetric services as appropriate to their particular circumstances, as there are mounting concerns regarding poor outcomes related to lack of obstetric input. At present, this is a rapidly evolving field, and guidelines are frequently updated. The number of currently pregnant women with MS is relatively small, and so clinical experience with this group is relatively limited, but increasing.Transmission of COVID-19 is mainly via small respiratory droplets  or via surfaces and touching the nose, mouth or eyes. It enters respiratory epithelium cells via the ACE-2 receptor, which is expressed throughout the upper and lower respiratory tract, and has been associated with a variety of clinical presentations related to upper and lower respiratory tract infection.13 These include localised pro-inflammatory environments during implantation, tolerogenic adaptations during foetal growth and development in the first and second trimester, followed by a second pro-inflammatory phase in preparation for parturition in the third trimester.14 The preferential Th2 immune response in the first and second trimesters leaves the mother more vulnerable to viral infections, which are usually contained by the Th1 immune system.15 The impact of critical illness during pregnancy on maternal and/or foetal outcomes is not insignificant, regardless of underlying aetiology. Physiological changes during pregnancy place additional strain on the cardiopulmonary system of the mother, including increased metabolic, and hence oxygen demands, which may be exacerbated by anaemia. In addition, diaphragmatic splinting by the gravid uterus reduces total lung volume and effective oxygen transfer and impacts the ability to clear secretions. Protracted respiratory compromise and maternal hypoxia drive the release of potent vasoconstrictors including endothelin-1 and hypoxia-inducible factor, which can lead to placental hypoperfusion, increasing the risk of foetal growth restriction.16 Mothers with pneumonia are more likely to deliver before 34 weeks of gestation, which may be secondary to prostaglandin production or the host’s inflammatory response to infection.4The innate and adaptive immune systems undergo various fluid adaptations throughout pregnancy that are precisely timed to promote pregnancy success.8 In contrast, while the majority of pregnant women with COVID-19 had radiological evidence of pneumonia (X-ray or computed tomography (CT)), there have not been significantly increased maternal deaths compared to non-pregnant individuals with COVID-19,17 although emerging evidence suggests an increased risk of critical care admission.12Several case series  and syst31It has been speculated that the apparent differences in pregnancy-associated severity and mortality between COVID-19 and SARS/MERS arises from the fact that in SARS and MERS, there is a preferential activation of Th1 immunity, leading to a marked pro-inflammatory cytokine storm (interferon (IFN)-gamma, interleukin (IL)-1beta, IL-6 and IL-12) resulting in severe lung damage. In COVID-19, the inflammatory response appears different, with activation of both Th1 and Th2 immunity and preferential expression of IL-4 and IL-10. Hence, the inflammatory phase in COVID-19 is of lesser severity compared to SARS and MERS, and this response is even lower in pregnant women where there is already a predominant Th2 response.28 and many cases of neonatal respiratory infection were reported as “not due to COVID-19.”28 The rate of preterm births is potentially higher than previously documented in MERS and SARS-CoV , while IUGR rates are comparable .9 A significant proportion of the preterm births reported in case series appear to be performed in order to protect maternal respiratory function. There were few miscarriages, stillbirths or neonatal deaths  in the first or second trimesters mediated by hyperthermic injury to developing foetal neurons.33Preterm birth and IUGR are associated with long-term sequelae in the child, including increased risk of chronic kidney disease, hypertension, cardiac remodelling due to increased peripheral vascular resistance and vascular growth, and reduced insulin sensitivity leading to higher risk of metabolic syndromes.34 MVM has been associated with oligohydramnios, foetal growth restriction, preterm birth and stillbirth in other studies, thus highlighting a potential mechanism of SARS-CoV-2 infection on pregnancy outcomes. There was an additional significant increase in the number of intervillous thrombi in placentas from women with COVID-19, which are likely to reflect the overall hypercoagulable state associated with infection.34 None of the placentas in this study were tested for SARS-CoV-2 viral RNA or protein. The ACE2 receptor is a co-receptor for viral entry into the host cell, which is thought to increase susceptibility to SARS-CoV-2 when upregulated.35 In pregnant women, there is evidence of increased ACE2 mRNA in the kidney, placenta and uterus,36 but further studies regarding the significance of this are needed.Pathological studies of placental tissue from women with proven SARS-CoV2 infection have demonstrated an increased rate of features of maternal vascular malperfusion (MVM), including atherosis and fibrinoid necrosis and mural hypertrophy of membrane arterioles.37 In a pre-print systematic review, 313 neonates who had been tested for SARS-CoV-2 infection following maternal COVID-19 were identified from across the literature. Of these, 24 (8%) were reported to have evidence of SARS-CoV-2 infection, 7% using reverse transcription polymerase chain reaction (RT-PCR) and 3% antibody. When only those tested in the first 48 hours of life using either RT-PCR or IgM were included, 21/261 (8%) met the criteria for potential vertical transmission.28 There is, as yet, no evidence that neonates who are infected suffer COVID-19 pneumonia have poor outcomes but factors such as prematurity, asphyxia and bacterial sepsis contribute more in critically ill cases.38There are increasing reports of COVID-19 infected neonates, raising the possibility of vertical transmission. In a retrospective review of nine mothers with COVID-19 who had a caesarean section in their third trimester, the amniotic fluid, cord blood, neonatal throat swabs and breast milk after first lactation were all negative for the virus, arguing against the notion of vertical transmission.10 Of all swab positive obstetric patients, 87.9% were asymptomatic. Only 10% of these initially asymptomatic patients developed fever prior to postpartum discharge (median length of stay 2 days). Further data from Connecticut reports a prevalence of SARS-CoV of 3.9% (30/770) among women presenting for childbirth in April 2020, of whom 22 (73.3%) were asymptomatic.9Antenatal care is essential to ensure the best pregnancy outcomes. However, regular attendance at hospital or outpatient settings potentially places obstetric patients at additional risk of contracting SARS-CoV-2. The reported prevalence of SARS-COV-2 in asymptomatic obstetric patients screened using nasopharyngeal swab PCR on admission to hospital during the height of the pandemic was 13.7%.39 these women are also at increased risk of adverse pregnancy outcomes, particularly when they have other vulnerabilities such as lower socioeconomic status.40 It is vital to consider the potential impacts of these risks when considering care pathways.Given the dual concerns of high rates of asymptomatically infected women, and the potential impact of lack of antenatal care, ‘virtual’ consultations should be carried out where appropriate. It is important to note that these are not possible or appropriate for all antenatal visits, and may unacceptably compromise care for some women. Where this is the case, for example, where physical examination and/or screening is required, women must be seen in person. Ensuring women are seen in one-stop clinics that cover all obstetric and medical needs in the same visit are needed to reduce potential exposure to the virus. For women with MS, this means coordinating obstetric and MS clinic reviews and blood tests to minimise hospital attendance and travel. Equipment such as ultrasound machines should be decontaminated after each use. Assessments that can be performed at home, such as blood pressure monitoring should be encouraged. There is increasing evidence that pregnant women of Black, Asian and Minority Ethnic backgrounds are at particular risk of requiring critical care for severe COVID-19;41 Recommendations include that appointments should be conducted remotely via telephone or videoconferencing where practical. Non-urgent routine appointments, including growth scans, antenatal community or secondary care appointments, should be delayed in symptomatic women until after the recommended period of self-isolation  if safe to do so. Appointments should not be repeatedly rescheduled or delayed by more than 3 weeks. Women who need to be seen should always be seen without undue delay, and appropriate personal protective equipment (PPE) may be needed to facilitate this. In the rare cases of an obstetric emergency, obstetric management should be dealt as a matter of priority.The Royal College of Obstetricians and Gynaecologists sets out recommendations for managing pregnant women with suspected or confirmed symptomatic COVID-19.41 Furthermore, a case series showed no evidence of COVID-19 in vaginal secretion specimens, suggesting transmission to the newborn through mucosal contact during vaginal delivery is unlikely.42Since there is no clear evidence of vertical transmission of SARS-CoV-2, there are no specific contraindications to vaginal delivery in the context of maternal infection, unless there is maternal deterioration or foetal compromise. Induction of labour should be minimised for indications that are not strictly necessary in order to minimise hospital inpatient stays.43 This recommendation is not universal, however, with some recommending vaginal delivery via induction with eventual instrumental delivery if complicated or prolonged labour, to avoid unnecessary surgical complications in an already sick patient. They recommend emergency caesarean section only if there is septic shock, acute organ failure or foetal distress.44 The use of birthing pools in hospitals is discouraged due to the risk of infection via faeces.45 Caesarean sections should be carried out with consideration for the potential need for respiratory precautions and full PPE based on clinical risk, given the potential need for aerosol-generating procedures intraoperatively.Symptomatic COVID-19 does not warrant early delivery as a routine consideration. However, if mothers have severe COVID-19, requiring or anticipated to require cardiopulmonary support, early delivery should be considered to ensure maternal safety. The threshold for caesarean section may be lowered, especially if there is a delay in the first stage of labour, in order to reduce maternal inpatient stay, reduce maternal physical exertion during delivery and reduce exposure to the virus and the chance of cross-infection.46 The probable beneficial effect of breastfeeding on relapse rate in at least some women with MS is also a consideration in postpartum MS patients.4749The risks of potential transmission of the virus associated with breastfeeding should be balanced against the benefits for the individual mother–baby dyad. In general, women who give birth during the COVID-19 pandemic should be encouraged to breastfeed where they wish to do so, with appropriate precautions in case of asymptomatic infection. Potential benefits of breastfeeding include protection against allergies and subsequent autoimmune diseases, and maternal IgA secreted via breastmilk, which offers protection against respiratory and gastrointestinal infections. Some of these positive effects may also be long-lasting.50 although most prior studies have not detected viral particles.18 Transmission of infection through breast milk is well documented for cytomegalovirus (CMV), human immunodeficiency virus (HIV1) and human T-cell lymphotropic virus type 1 (HTLV-1) infections. It is thought that recurrent exposures to small amounts of virus in human milk over the breastfeeding period contribute to the high rate of transmission.51 In these cases, whether breastfeeding is contraindicated depends on the rate of transmission, potential complications of infection in the infant or neonate and whether the setting is in low or middle-income nations, where the risk of malnutrition and infectious disease may outweigh the risk of acquiring the maternal infection.In the context of clinical infection, SARS-COV-2 viral RNA has been detected in the breastmilk of at least one infected mother,52 Breast milk of SARS-CoV-2 positive women may be expressed as long as a dedicated breast pump is used with careful hand hygiene exercised and facemask used during milk expression. It is postulated that anti-SARS-COV-2 antibodies may be transferred to the infant via breastmilk, in a similar manner to other viral infections, but this has not been confirmed.A significant concern is potential transmission of the virus via droplets from the respiratory tract of the mother during breastfeeding due to close contact. Current CDC guidelines for women with confirmed COVID-19 advise wearing a cloth face covering while breastfeeding and washing hands prior to each feed.53 There is currently insufficient data to confirm or refute any association between COVID-19 infection and increased MS relapse rate either during pregnancy or in the post-partum ‘rebound’ period (or at any other time); however, there is no reason to suspect that there are any differences to other respiratory tract infections in this particular regard.Symptomatic viral infections have previously been associated with both a transient worsening of MS-related neurological symptoms (pseudo-relapses) and clinically defined relapses. While the MS relapse rate falls significantly during normal pregnancy, it does not completely abate, particularly in those women with more active MS who have received more aggressive disease-modifying treatments prior to pregnancy and then paused treatment during pregnancy.54 These DMTs are not directly immunosuppressive and therefore are currently not routinely being stopped in response to the COVID-19 pandemic.55There is currently limited evidence surrounding the risk(s) associated with COVID-19 while on disease-modifying therapy (DMT). In the context of pregnancy, decisions regarding withholding or continuing DMTs should have already been discussed prior to or shortly after conception. Depending on disease-activity prior to conception, pregnant women are likely to either not be on treatment, or to be continuing treatment with a DMT that has been deemed as having a reasonable safety profile in pregnancy: usually interferon-beta, glatiramer acetate or natalizumab.55 the most recent evidence, available in preprint form only, indicates that there may be potentially increased risk of severe COVID-19 in those treated with anti-B cell monoclonal antibodies.Treatment decisions should be individualised according to disease activity and relapse risk, the number of cycles already taken and co-morbidities associated with potential complications following COVID-19 infection, such as smoking, immobility and increased age.55 While relapses are less common during pregnancy, if they do occur, corticosteroid treatment may be considered as per below.Induction, ‘lymphodepleting’ DMTs, which may be used some months prior to pregnancy to induce disease remission prior to trying to conceive, includes ocrelizumab, alemtuzumab, rituximab and cladribine. Caution is currently recommended when initiating these treatments; however, advice is changing as evidence increases;5659 but concerns remain surrounding the promotion of viral rebound, enhancing viral replication and association with adverse effects, such as acute respiratory distress syndrome, particularly in the context of longer steroid courses.61 One randomised controlled trial examining SARS-CoV measured viral load at regular intervals in non-intubated cases and found higher concentrations of viral RNA in week 2–3 of infection in those treated with early corticosteroids (<7 days of illness) compared with placebo.60MS relapses are known to be more common in the post-partum period, and the use of high-dose corticosteroids to treat these may lead to concerns regarding increased susceptibility to infection. The use of high-dose corticosteroids can suppress antibody responses, with potential implications for both the breastfeeding mother and passive immunity in the newborn. There is limited data on the impact of corticosteroids on the severity or disease course of COVID-19; most advice is based on data from the SARS-CoV epidemic in 2002–2004. Studies in humans and mice demonstrate that corticosteroids appear effective in reducing immunopathological damage, mainly through reducing Th1 immune responses,62 While the RECOVERY trial demonstrated a significant benefit of dexamethasone in those requiring supplemental oxygen,63 Italian data, available in preprint form only at present, suggests that the risk of severe COVID-19 is increased in those who have recently received high-dose steroids in the context of MS relapse. In view of this, for MS patients, corticosteroid-induced lymphopenia and immunosuppression are important considerations, especially when methylprednisolone dosing for MS relapses is frequently high; up to 500 mg to 1 g daily, albeit usually short courses of 3–5 days. The risks of steroid pulsing in post-partum MS relapses, where DMT options are limited, will need to be balanced against current and potential disability.Recently, a systemic review and meta-analysis of 5270 coronavirus-infected patients from 15 articles  found that corticosteroids were likely to be used in patients with critical illness, were associated with a higher mortality rate (relative risk (RR) = 2.11, 95% confidence interval (CI): 1.13–3.94) and longer length of inpatient stay and higher rate of bacterial infection ; however, selection bias and other confounding factors may have played a role.MS registries around have rapidly adapted to collect data on COVID-19 in MS. These include the COViMS US Registry MS ReCOV, MuSC-19 Italian registry, Swedish Registry, MSBase, Spanish MS Covid-19 Registry, French Registry, OPTIMISE-MS, UK MS Register COVID-19 sub-study, German MS Register, The Australian MS Longitudinal Study, ABEM-Brazilian MS Patients Association, Cleveland Clinic Registry and Esclerosis Multiple Argentina (EMA) COVID-19 survey. The Global Data Sharing Initiative and currently collating COVID-19 data from many of these. In addition, the UK Obstetric Surveillance System (UKOSS) launched a registry for all women admitted to UK hospitals with confirmed COVID-19 in pregnancy to assess the outcomes for mother and the infant. Given the relatively small number of pregnant MS women at any one time, it is vital that they are included in all such registry efforts as a subgroup of interest.Current data appear to indicate an increased risk of preterm birth in pregnant women with COVID-19. Pregnant women do not appear to be at greater risk of COVID-19 infection; while the risk of critical care appears increased relative to the general population, there does not appear to be a significantly higher mortality rate. Management of pregnant women with MS comes with additional considerations due to the unique immunological environment during pregnancy and postpartum, immunomodulatory therapy use and implications for disease activity. Integrating care where possible to minimise hospital visits is an important way by which care can be delivered as safely as possible.Current advice is to exercise stringent social distancing in pregnant women who are greater than 28 weeks of gestation, and this advice should be followed for pregnant women with MS. However, the wider implications of isolation and/or shielding must not be overlooked, particularly in those with chronic diseases such as MS – there is increasing concern regarding the long-term impact on mental and physical health. Consideration must be made to how services can respond to the needs of this small, but highly vulnerable, group, and neurologists should be aware of how service design can positively or negatively impact on their patients. Neurologists may be approached by patients who are either pregnant, or considering pregnancy, and an awareness of risks and areas of relative reassurance is needed, in order to enable patients to make the best decisions informed by current evidence.


Background: In Spain, long-term use of benzodiazepine is prevalent in 7% of the population; however, this longer-term use lacks clinical benefits, costs €90million per year and side-effects further add extra cost through adverse health outcomes. This study aims to estimate the cost-effectiveness of primary care services stepped dose reduction of long-term benzodiazepines using either Structured Interview with Follow-up (SIF) or Without Follow-up (SIW), compared to Treatment as Usual (TAU).Design: Cost-effectiveness analysis was conducted alongside randomised control utilizing data from three arm cluster randomized trial.Setting: Primary care.Participants: 75 general practitioners were randomised to one of the three arms .Measurements: Cost and Cost per Quality-Adjusted Life Year (QALY)Results: Compared to usual care, providing SIW per participant costs an additional €117.94 and adding patient follow-up, €218.4. As a result of intervention, participants showed a gain of, on average, for SIW 0.0144 QALY (95% CI -0.0137 to 0.0425) and for SIF 0.0340 QALYs (0.0069 to 0.0612). The Incremental Cost Effectiveness Ratio was €8190.28/QALY (SIW) and €6423.53/QALY (SIF). At the Spanish reimbursement threshold  the chance interventions are cost effective is 79.8% for SIW and 97.7% for SIF.Conclusions: Brief structured interventions to discontinue long-term benzodiazepine use represent value for money, particularly with scheduled follow-up appointments, and would represent a cost-effective investment by the Spanish healthcare to reduce prevalence of long-term use. The prevalence of long-term benzodiazepine use in Europe3 remains high despite policy recommendations to limit their use7.Long-term prescription of benzodiazepines has significant negative outcomes, causing significant costs to healthcare and wider society; however, many physicians continue to prescribe these and patients wishing to withdraw rarely receive advice or support9, whereas in the United Kingdom, Germany or Netherlands (where policies aim to restrict use), prevalence of their use is less than 2%3. Based on the cost of long-term benzodiazepine prescription alone, we estimate the cost in Spain is over €70 million per annum and, if the consequences of associated morbidities were considered, the full economic cost to healthcare is much higher10.In Spain, long-term use is extensive, with more than 7% of the population using them regularly11, and guidelines clearly recommend prescribing on a short-term basis. Given the implications associated with longer-term use, several programs designed to taper off the use of benzodiazepines have been developed, which have been demonstrated to be effective and safe13. However the uptake and use of such interventions is not widespread. A case for the use of such interventions could be supported by robust evidence of cost effectiveness to show that this was an efficient use of finite healthcare resources. To our knowledge there are no full economic evaluations in this area. Economic evidence on benzodiazepine cessation programs report predominantly how costs vary by level of complexity, as studies have tended to report the absolute costs of programs ). Full economic evaluations are therefore required15.Evidence suggests that long-term use has a lack of clinical benefits16. Having established that both programs are clinically effective in reducing long-term use, the question then arises as to whether they are also cost-effective.A clinical trial in primary care has already been reported, which assesses the effectiveness of two interventions to discontinue long-term benzodiazepine use. The two programs evaluated were found to be more effective than usual care in stopping long-term benzodiazepine use in patients without severe co-morbidity18 and associated costs to healthcare; this aims to inform the decision-makers by comparing the Incremental Cost Effectiveness Ratio (ICER) against willingness-to-pay threshold21. The clinical trial assessed the effectiveness of two interventions in primary care using ‘discontinuation of benzodiazepine use’ as the primary outcome. The economic evaluation adopted the perspective of the Spanish Health system and Spanish unit costs were applied to the cost of general practitioner (GP) training, per-protocol cost of GP intervention, costs of follow up visit and the cost associated with benzodiazepine use.To our knowledge, this is the first cost-effectiveness analysis of benzodiazepine cessation programs in Spain. To inform policy, we simultaneously examine generic health gains )et al. (2014)16. Briefly, a three-arm, parallel, multicentre, cluster-randomised trial was carried out in Spain, which aimed to compare the effectiveness of two brief structured, tapering interventions delivered by the GP, to discontinue long-term benzodiazepine use versus a control group that received TAU. The current study presents the economic analysis conducted alongside this randomised controlled trial from a health systems perspective.The clinical trial has been described by VicensThe interventions included a structured educational interview with gradual dose reduction either (i) with follow-up visits (Structured Interview with Follow-up - SIF) or (ii) with written instructions (Structured Interview without Follow-up - SIW) instead of a follow-up visit. The initial interventions’ visit in both groups lasted about 20 minutes; SIF arm patients scheduled 12 minutes follow-up appointments every 2–3 weeks until the end of the dose reduction and each appointment had reinforced education, reassured patients regarding withdrawal symptoms and obtained patient agreement for the next step in dose reduction. The patients in the SIW group received written instructions reinforcing educational information at their first and only contact with their GP, along with a tailored gradual dose-reduction until benzodiazepine cessation.GPs from 21 primary care centres in the three regions of Spain were enrolled and, in total, 75 GPs were randomised to one of the three arms . Patients eligible for the trial were aged 18 to 80 years and had been taking benzodiazepines daily for at least 6 months and did not have a severe mental or physical illness. GPs were randomised once the patients were included, and GPs from the intervention groups were scheduled to a two-hour training session in benzodiazepine withdrawal. GPs of the SIF arm received an additional 30 minutes training in how to proceed in the follow-up visits. Because each GP treated several patients, the GP time cost was spread across patients seen by the GP during this study.Evidence in the literature would suggest that long-term benzodiazepine use may have negative health consequences that would have cost consequences to health service. However, we restrict our consideration of cost to consider whether the health gains within the trial period justify the cost of the cessation programs plus subsequent benzodiazepine use.The costs of the cessation programs include GP training and subsequent patient follow-ups, if any, with the GP for benzodiazepine discontinuation. The cost of the training programs per GP was calculated. The training programs were run in three regions as group GP-delivered workshops and the required resources were considered to calculate the program cost .24. The cost associated with training GPs in SIF and SIW were based on the trainer time , travel and accommodation costs by regions where training was provided, and cost associated with administration to organise and provide the workshops.Patient resource use (both in terms of training time and follow-up visits) were multiplied by the unit cost of a GP visit to obtain total GP cost. The unit cost of GP visit can vary across Spanish regions and are published in official regional bulletin by each region25 was used to obtain benzodiazepines cost for this price year. Retrospective levels of benzodiazepine use by participants in the randomised control trial was assessed at baseline, 6 month and 12 months; these consumption patterns were reviewed and confirmed by prescription claims in the clinical records.In Spain, benzodiazepine prescribing is regulated and only formulations with a reference price (published authorised by the Spanish Agency of Drugs and Sanitary products (AEMPS)) are available. The nomenclature web application of the AEMPSCosts are presented in Euros (€) for the price year 2013 and for international comparison, equivalent costs are presented in Pound Sterling (GBP) and US Dollar (USD). Since the follow-up period lasted 1 year, no extrapolation over time was executed, discounting was not necessary. Analysis was conducted using Stata 13.As the original trial does not include a measure of individuals’ generic health-state (e.g. EQ-5D), to provide outcomes that have broad policy-relevant application (e.g. QALYs), we evaluated several mapping functions to allow cross walking of a condition-specific measure to obtain a utility score. Specifically, Hospital Anxiety and Depression Scale (HADS) scores were available in the clinical trial, which were used to estimate generic health utility outcomes.HERC Database of Mapping Studies (Version 3.0 - June 2014) was searched26. Within this resource, we identified that Brazieret al (2014)27 systematically reviewed studies with estimation of mapping functions in mentally ill populations. Specifically, the authors critically appraised two studies mapping HADS to generic preference-based measures of health and based on their appraisal, and after comparing post-estimation statistics from each study, we selected to utilise the regression analysis of EQ-5D and HADS28. The mapping algorithm utilises the specific scores from the two subscales for depression (HADS-D) and anxiety (HADS-A) to estimate EQ5D index. The results provide individual utility at each time point, and by applying an area under the curve approach these utility values were used to estimate QALYs29.To identify an up-to-date and appropriate method to map clinical trial outcomes onto equivalent generic health states,Unadjusted Incremental Cost Effectiveness Ratio (ICER) for each intervention group (SIW and SIF) are calculated against TAU using the following formula:30. Conventionally, the results of the bootstrap are presented as a scatter plot on the cost effectiveness plan31; however, to jointly present confidence interval around costs and outcomes a confidence ellipse is generated. This jointly indicates the incremental costs and QALYs on the 50%, 75% and 95% confidence intervals, indicating in the CE plane the probability space within which we are confident the true ICER is found.To estimate the joint distributions of cost and QALYs, non-parametric bootstrapping was conducted on the observed data21.To evaluate cost-effectiveness of our estimates against willingness-to-pay threshold of a health system decision maker, a range of maximum monetary values were used. To present how the probability of interventions being cost effect increases as decision makers willingness-to-pay increases, a cost effectiveness acceptability curve (CEAC) is generatedOur study protocol has been approved by the Primary Care Research Committee and the Mallorca Ethical Committee of Clinical Research (IB 1146/09 PI).At 12 months, data were available from 523/532 (98.3%) patients. The two structured educational interview programs were found to be more effective than usual care in stopping long-term benzodiazepine use over a 12-month period. The relative risks for benzodiazepine discontinuation were 3.01 (95% CI: 2.03 to 4.46) in the SIW and 3.00 (95% CI: 2.04 to 4.40) in the SIF group compared to usual care.To estimate the costs and cost consequences of implementing the cessation program, mean estimates of the use of healthcare resources associated with benzodiazepine use and cessation are calculated see. This ina.Applying unit cost to resource use,Individual HADS scores were used to estimate health-state utility values at each time point.To control for individual-level variation in baseline utility and to estimate incremental QALYs for the intervention groups, ordinary least squares regression was used with baseline utility included as a covariate =0.7983 and P=0.9777, respectively.At the commonly cited Spanish healthcare decision threshold of €45,000/QALY, the probability that SIW and SIF program being cost-effective was estimated to be P and the calculation of total cost is based on intervention training costs, GP time and costs of benzodiazepine prescribed. The base-case does not extrapolate a model to indicate the adverse event or risk associated with long-term benzodiazepine use . Such extrapolation could augment health-related quality of life  and hypothetically alter ICERs. However, as the cost of intervention justifies health gain, the approach adopted is already justified and, in the absence of a comprehensive measure of resource use, model-based augmentation would require assumptions and may simply raise more questions than answers.et al indicate that the relationship between the EQ-5D and HADS differed across the severity scale, where the concordance between the measures was higher at the less severe end of the scale. Secondly, health state utilities are based on the UK tariff. Finally, the use of HADS scores bases the estimate of generic health solely on changes in anxiety and depression and overlooks other potential domains of generic health . In the absence of a preference-weighted measure of generic health (such as EQ5D), this provides an imperfect solution to estimate QALYs.Conversion of HADS score onto associated EQ5D utility was used to provide a means to estimate incremental QALYs. This approach has some limitation. Firstly, BrazierNevertheless, analyses based on the currently available information are supportive of a wider implementation of GP training for benzodiazepine cessation in Spain. There does remain a level of uncertainty in the estimated results, as well as limitations in the costs and outcomes utilised and a healthcare decision-maker may alternatively commission further research. The confidence ellipse provides support that there is value in additional information, as it would suggest that the true ICER is most likely to lie in the top right quadrant of the cost effectiveness plane suggesting any further investment  will likely represent value for money to the Spanish Ministry of Health.http://doi.org/10.5281/zenodo.382384634.Zenodo: Cost-effectiveness of brief structured interventions to discontinue long-term benzodiazepine use: an economic analysis alongside a randomised controlled trial,https://doi.org/10.5281/zenodo.383549432.Zenodo: Supplemental 1: Full list of all benzodiazepine unit costs. Cost-effectiveness of brief structured interventions to discontinue long-term benzodiazepine use: an economic analysis alongside a randomised controlled trial,https://doi.org/10.5281/zenodo.383550633.Zenodo: Supplemental 2: Costs associated with providing training workshops. Cost-effectiveness of brief structured interventions to discontinue long-term benzodiazepine use: an economic analysis alongside a randomised controlled trialCreative Commons Attribution 4.0 International license (CC-BY 4.0).Data are available under the terms of theaAverage Exchange Rate: GBP/EURO (2012-13): 0.8141; GBP/USD (2012-13): 0.6325 [Sources:http://www.hmrc.gov.uk/exrate/exchangerates-1213.pdf]. In this paper, the authors conduct a within-trial economic evaluation of brief interventions to discontinue long-term benzodiazepines use in the primary care setting in Spain. Specifically, they performed an incremental cost-effectiveness analysis of structured interviews with or without follow-up vs. usual care and find that both interventions are cost-effective, with ICERs well under the Spanish reimbursement threshold in both cases. This is a particularly important topic and evidence is scarce regarding cost-effectiveness in this area. Long-term benzodiazepines use is a public health problem in most developing countries and studies are needed to show value for money of discontinuation strategies. This study therefore makes a valuable contribution to the literature. The paper is methodologically sound and follows best practice guidelines in economic evaluation. It is well structured, and the analytical steps and assumptions are transparent. I have however a few comments and suggestions for clarification/possible improvement. The abstract needs improvement in terms of style and content. Key information is lacking, especially the details on participants . Also, check consistency regarding direct (?) costs of long-term benzodiazepines use (figures in the abstract and in the text are not consistent). More generally, the paper would require some editing (e.g. check consistency of tense). One important aspect is the definition of costs of benzodiazepines use, which is limited to direct drug costs in the paper, and more generally the scope of costs included. I would recommend clarifying the following statement  in the “Resource use and associated unit costs” section: “However, we restrict our consideration of cost to consider whether the health gains within the trial period justify the cost of the cessation programs plus subsequent benzodiazepine use”. Also it is not fully clear whether GP cost is simply the unit cost of a GP visit multiplied by number of visits, or if broader costs were taken into account (including patient time costs) – there is conflicting information about this in the text. In addition, was the cost of training limited to trainer time or also included opportunity cost for trainees? Finally, the authors explain that estimating the benefits of benzo discontinuation in terms of avoided costs related to adverse events is challenging. This is true but they can be quite confident that their ICERs are conservative and this could be more emphasised in the text. In terms of outcomes, mapping is used from HADS to QALYs to derive utility scores. Given the limitations of this approach (that are clearly stated), it could be useful to show results in terms of cost per HADS score change (cost-effectiveness) in addition to cost per QALY (cost-utility), and perhaps other expression of value such as cost per successful discontinuation ?Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?PartlyReviewer Expertise:Health economics, economic evaluation, addiction, health services research, empirical policy evaluation, health care financingI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. The paper is the first study to evaluate the cost effectiveness of this drug in this setting. Protocols seem to have been followed accurately from the methods section. The CEA seems accurately deployed. Costings at programme level were done and every effort at comprehensiveness seems to have been taken. ICER calculations controlling for baseline utility seem accurate at 95% CI.The finding that both interventions are in fact cost-effective at 45k/QALY deserves a little more discussion.There are some typos in the manuscript, e.g. discussion, first para, last sentence should read “hospitals’”. Typographical issues I leave to the journal.I recommend indexing. Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Economics.I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.