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      Coronavirus Disease 2019 in Pregnancy: A Clinical Management Protocol and Considerations for Practice

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          Abstract

          The coronavirus disease 2019 (COVID-19) pandemic has represented a major impact to health systems and societies worldwide. The generation of knowledge about the disease has occurred almost as fast as its global expansion. The mother and fetus do not seem to be at particularly high risk. Nevertheless, obstetrics and maternal-fetal medicine practice have suffered profound changes to adapt to the pandemic. In addition, there are aspects specific to COVID-19 and gestation that should be known by specialists in order to correctly diagnose the disease, classify the severity, distinguish specific signs of COVID-19 from those of obstetric complications, and take the most appropriate management decisions. In this review we present in a highly concise manner an evidence-based protocol for the management of COVID-19 in pregnancy. We briefly contemplate all relevant aspects that we believe a specialist in obstetrics and maternal medicine should know, ranging from basic concepts about the disease and protection measures in the obstetric setting to more specific aspects related to maternal-fetal management and childbirth.

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          ISUOG Interim Guidance on 2019 novel coronavirus infection during pregnancy and puerperium: information for healthcare professionals

           L. Poon,  H. Yang,  J C S Lee (2020)
          In response to the World Health Organization (WHO) statements and international concerns regarding the novel coronavirus infection (COVID‐19) outbreak, the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) is issuing the following guidance for management during pregnancy and puerperium. With the current uncertainty regarding many aspects of the clinical course of COVID‐19 infection in pregnancy, potentially valuable information is likely to be obtained by obstetricians and ultrasound practitioners that may help in counseling pregnant women and further improve our understanding of the pathophysiology of COVID‐19 infection in pregnancy. This statement is not intended to replace previously published interim guidance on evaluation and management of COVID‐19‐exposed pregnant women. It should, therefore, be considered in conjunction with other relevant advice from organizations such as: WHO: https://www.who.int/emergencies/diseases/novel-coronavirus-2019 Centers for Disease Control and Prevention (CDC): https://www.cdc.gov/coronavirus/2019-ncov/specific-groups/pregnancy-faq.html Pan American Health Organization (PAHO): http://www.paho.org European Centre for Disease Prevention and Control (ECDC): https://www.ecdc.europa.eu Public Health England: https://www.gov.uk/guidance/coronavirus-covid-19-information-for-the-public National Health Commission of the People's Republic of China: http://www.nhc.gov.cn Perinatal Medicine Branch of Chinese Medical Association: https://mp.weixin.qq.com/s/11hbxlPh317es1XtfWG2qg Indicazioni ad interim della Societa Italiana di Neonatologia (SIN): https://www.policlinico.mi.it/uploads/fom/attachments/pagine/pagine_m/79/files/allegati/539/allattamento_e_infezione_da_sars-cov-2_indicazioni_ad_interim_della_societ___italiana_di_neonatologia_sin__2_.pdf Santé Publique France https://www.santepubliquefrance.fr/ Sociedad Española de Ginecología y Obstetricia S.E.G.O.: https://mcusercontent.com/fbf1db3cf76a76d43c634a0e7/files/1abd1fa8-1a6f-409d-b622-c50e2b29eca9/RECOMENDACIONES_PARA_LA_PREVENCIO_N_DE_LA_INFECCIO_N_Y_EL_CONTROL_DE_LA_ENFERMEDAD_POR_CORONAVIRUS_2019_COVID_19_EN_LA_PACIENTE_OBSTE_TRICA.pdf Royal College of Obstetricians and Gynaecologists (RCOG): https://www.rcog.org.uk/globalassets/documents/guidelines/coronavirus-covid-19-infection-in-pregnancy-v3-20-03-18.pdf BACKGROUND The novel coronavirus infection (COVID‐19), also termed SARS‐CoV‐2, is a global public health emergency. Since the first case of COVID‐19 pneumonia was reported in Wuhan, Hubei Province, China, in December 2019, the infection has spread rapidly to the rest of China and beyond1, 2, 3. Coronaviruses are enveloped, non‐segmented, positive‐sense ribonucleic acid (RNA) viruses belonging to the family Coronaviridae, order Nidovirales4. The epidemics of the two β‐coronaviruses, severe acute respiratory syndrome coronavirus (SARS‐CoV) and Middle East respiratory syndrome coronavirus (MERS‐CoV), have caused more than 10 000 cumulative cases in the past two decades, with mortality rates of 10% for SARS‐CoV and 37% for MERS‐CoV5, 6, 7, 8, 9. COVID‐19 belongs to the same β‐coronavirus subgroup and it has genome similarity of about 80% and 50% with SARS‐CoV and MERS‐CoV, respectively10. COVID‐19 is spread by respiratory droplets and direct contact (when bodily fluids touch another person's eyes, nose or mouth, or an open cut, wound or abrasion). The Report of the World Health Organization (WHO)‐China Joint Mission on Coronavirus Disease 2019 (COVID‐19)11 estimated a high R 0 (reproduction number) of 2–2.5. The latest report from WHO12, on March 3rd, estimated the global mortality rate of COVID‐19 infection to be 3.4%. Huang et al.1 first reported on a cohort of 41 patients with laboratory‐confirmed COVID‐19 pneumonia. They described the epidemiological, clinical, laboratory and radiological characteristics, as well as treatment and clinical outcome of the patients. Subsequent studies with larger sample sizes have shown similar findings13, 14. The most common symptoms reported are fever (43.8% of cases on admission and 88.7% during hospitalization) and cough (67.8%)15. Diarrhea is uncommon (3.8%). On admission, ground‐glass opacity is the most common radiologic finding on computed tomography (CT) of the chest (56.4%). No radiographic or CT abnormality was found in 157 of 877 (17.9%) patients with non‐severe disease and in five of 173 (2.9%) patients with severe disease. Lymphocytopenia was reported to be present in 83.2% of patients on admission15. Pregnancy is a physiological state that predisposes women to respiratory complications of viral infection. Due to the physiological changes in their immune and cardiopulmonary systems, pregnant women are more likely to develop severe illness after infection with respiratory viruses. In 2009, pregnant women accounted for 1% of patients infected with influenza A subtype H1N1 virus, but they accounted for 5% of all H1N1‐related deaths16. In addition, SARS‐CoV and MERS‐CoV are both known to be responsible for severe complications during pregnancy, including the need for endotracheal intubation, admission to an intensive care unit (ICU), renal failure and death9, 17. The case fatality rate of SARS‐CoV infection among pregnant women is up to 25%9. Currently, however, there is no evidence that pregnant women are more susceptible to COVID‐19 infection or that those with COVID‐19 infection are more prone to developing severe pneumonia. Over and above the impact of COVID‐19 infection on a pregnant woman, there are concerns relating to the potential effect on fetal and neonatal outcome; therefore, pregnant women require special attention in relation to prevention, diagnosis and management. Based on the limited information available as yet and our knowledge of other similar viral pulmonary infections, the following expert opinions are offered to guide clinical management. DIAGNOSIS OF INFECTION AND CLINICAL CLASSIFICATION Case definitions are those included in the WHO's interim guidance, ‘Global surveillance for COVID‐19 disease caused by human infection with the 2019 novel coronavirus’18. Suspected case A patient with acute respiratory illness (fever and at least one sign/symptom of respiratory disease (e.g. cough, shortness of breath)) AND with no other etiology that fully explains the clinical presentation AND a history of travel to or residence in a country/area or territory reporting local transmission of COVID‐19 infection during the 14 days prior to symptom onset; OR A patient with any acute respiratory illness AND who has been in contact (see definition of contact below) with a confirmed or probable case of COVID‐19 infection in the 14 days prior to onset of symptoms; OR A patient with severe acute respiratory infection (fever and at least one sign/symptom of respiratory disease (e.g. cough, shortness breath)) AND who requires hospitalization AND who has no other etiology that fully explains the clinical presentation. Probable case A suspected case for which laboratory testing for COVID‐19 is inconclusive. Confirmed case A person with laboratory confirmation of COVID‐19 infection, irrespective of clinical signs and symptoms. It is plausible that a proportion of transmissions occurs from cases with mild symptoms that do not provoke healthcare‐seeking behavior. Under these circumstances, in areas in which local transmission occurs, an increasing number of cases without a defined chain of transmission is observed19 and a lower threshold for suspicion in patients with severe acute respiratory infection may be recommended by health authorities. Any suspected case should be tested for COVID‐19 infection using available molecular tests, such as quantitative reverse transcription polymerase chain reaction (qRT‐PCR). Lower‐respiratory‐tract specimens likely have a higher diagnostic value compared with upper‐respiratory‐tract specimens for detecting COVID‐19 infection. The WHO recommends that, if possible, lower‐respiratory‐tract specimens, such as sputum, endotracheal aspirate or bronchoalveolar lavage, be collected for COVID‐19 testing. If patients do not have signs or symptoms of lower‐respiratory‐tract disease or specimen collection for lower‐respiratory‐tract disease is clinically indicated but collection is not possible, upper‐respiratory‐tract specimens of combined nasopharyngeal and oropharyngeal swabs should be collected. If initial testing is negative in a patient who is strongly suspected of having COVID‐19 infection, the patient should be resampled, with a sampling time interval of at least 1 day and specimens collected from multiple respiratory‐tract sites (nose, sputum, endotracheal aspirate). Additional specimens, such as blood, urine and stool, may be collected to monitor the presence of virus and the shedding of virus from different body compartments. When qRT‐PCR analysis is negative for two consecutive tests, COVID‐19 infection can be ruled out. A contact is defined as a person involved in any of the following: Providing direct care for COVID‐19 patients without using proper personal protective equipment (PPE) Being in the same close environment as a COVID‐19 patient (including sharing workplace, classroom or household, or attending the same gathering) Traveling in close proximity (within 1–2 meters) to a COVID‐19 patient in any kind of conveyance The WHO has provided guidance on the rational use of PPE for COVID‐19. When conducting aerosol‐generating procedures (e.g. tracheal intubation, non‐invasive ventilation, cardiopulmonary resuscitation, manual ventilation before intubation), healthcare workers are advised to use respirators (e.g. N95, FFP2 or equivalent standard) with their PPE20, 21. CDC additionally considers procedures that are likely to induce coughing (e.g. sputum induction, collection of nasopharyngeal swabs and suctioning) as aerosol‐generating procedures and CDC guidance includes the option of using a powered air‐purifying respirator (PAPR). CHEST RADIOGRAPHY DURING PREGNANCY Chest imaging, especially CT scan, is essential for evaluation of the clinical condition of a pregnant woman with COVID‐19 infection22, 23, 24. Fetal growth restriction (FGR), microcephaly and intellectual disability are the most common adverse effects from high‐dose (> 610 mGy) radiation exposure25, 26, 27. According to data from the American College of Radiology and American College of Obstetricians and Gynecologists, when a pregnant woman undergoes a single chest X‐ray examination, the radiation dose to the fetus is 0.0005–0.01 mGy, which is negligible, while the radiation dose to the fetus is 0.01–0.66 mGy from a single chest CT or CT pulmonary angiogram28, 29, 30. Chest CT scanning has high sensitivity for diagnosis of COVID‐1924. In a pregnant woman with suspected COVID‐19 infection, a chest CT scan may be considered as a primary tool for the detection of COVID‐19 in epidemic areas24. Informed consent should be acquired (shared decision‐making) and a radiation shield be applied over the gravid uterus. TREATMENT DURING PREGNANCY Place of care Suspected, probable and confirmed cases of COVID‐19 infection should be managed initially by designated tertiary hospitals with effective isolation facilities and protection equipment. Suspected/probable cases should be treated in isolation and confirmed cases should be managed in a negative‐pressure isolation room. A confirmed case that is critically ill should be admitted to a negative‐pressure isolation room in an ICU31. Designated hospitals should set up a dedicated negative‐pressure operating room and a neonatal isolation ward. All attending medical staff should don PPE (respirator, goggle, face protective shield, surgical gown and gloves) when providing care for confirmed cases of COVID‐19 infection32. However, in areas with widespread local transmission of the disease, health services may be unable to provide such levels of care to all suspected, probable or confirmed cases. Pregnant women with a mild clinical presentation may not initially require hospital admission and home confinement can be considered, provided that this is possible logistically and that monitoring of the woman's condition can be ensured33. If negative‐pressure isolation rooms are not available, patients should be isolated in single rooms, or grouped together once COVID‐19 infection has been confirmed. For transfer of confirmed cases, the attending medical team should don PPE and keep themselves and their patient a minimum distance of 1–2 meters from any individuals without PPE. Suspected/probable cases General treatment: maintain fluid and electrolyte balance; symptomatic treatment, such as antipyrexic, antidiarrheal medicines. (1) Surveillance: close and vigilant monitoring of vital signs and oxygen saturation level to minimize maternal hypoxia; conduct arterial blood‐gas analysis; repeat chest imaging (when indicated); regular evaluation of complete blood count, renal‐ and liver‐function testing and coagulation testing. (2) Fetal monitoring: undertake cardiotocography (CTG) for fetal heart rate (FHR) monitoring when pregnancy is ≥ 26 or ≥ 28 weeks of gestation (depending on local practice), and ultrasound assessment of fetal growth and amniotic fluid volume with umbilical artery Doppler if necessary. Note that monitoring devices and ultrasound equipment should be disinfected adequately before further use. (3) The pregnancy should be managed according to the clinical and ultrasound findings, regardless of the timing of infection during pregnancy. All visits for obstetric emergencies should be offered in agreement with current local guidelines. All routine follow‐up appointments should be postponed by 14 days or until positive test results (or two consecutive negative test results) are available. Confirmed cases Non‐severe disease. (1) The approach to maintaining fluid and electrolyte balance, symptomatic treatment and surveillance is the same as for suspected/probable cases. (2) Currently there is no proven antiviral treatment for COVID‐19 patients, although antiretroviral drugs are being trialed therapeutically on patients with severe symptoms34, 35. If antiviral treatment is to be considered, this should be done following careful discussion with virologists; pregnant patients should be counseled thoroughly on the potential adverse effects of antiviral treatment for the patient herself as well as on the risk of FGR. (3) Monitoring for bacterial infection (blood culture, mid‐stream or catheterized‐specimen urine microscopy and culture) should be done, with timely use of appropriate antibiotics when there is evidence of secondary bacterial infection. When there is no clear evidence of secondary bacterial infection, empirical or inappropriate use of antibiotics should be avoided. (4) Fetal monitoring: undertake CTG for FHR monitoring when pregnancy is ≥ 26–28 weeks of gestation, and ultrasound assessment of fetal growth and amniotic fluid volume with umbilical artery Doppler if necessary. Severe and critical disease. (1) The degree of severity of COVID‐19 pneumonia is defined by the Infectious Diseases Society of America/American Thoracic Society guidelines for community‐acquired pneumonia (Appendix 1)36. (2) Severe pneumonia is associated with a high maternal and perinatal mortality rate, therefore, aggressive treatment is required, including supporting measures with hydration, oxygen therapy and chest physiotherapy. The case should be managed in a negative‐pressure isolation room in the ICU, preferably with the woman in a left lateral position, with the support of a multidisciplinary team (obstetricians, maternal–fetal‐medicine subspecialists, intensivists, obstetric anesthetists, midwives, virologists, microbiologists, neonatologists, infectious‐disease specialists)37. (3) Antibacterial treatment: appropriate antibiotic treatment in combination with antiviral treatment should be used promptly when there is suspected or confirmed secondary bacterial infection, following discussion with microbiologists. (4) Blood‐pressure monitoring and fluid‐balance management: in patients without septic shock, conservative fluid management measures should be undertaken38; in patients with septic shock, fluid resuscitation and inotropes are required to maintain an average arterial pressure ≥ 60 mmHg (1 mmHg = 0.133 kPa) and a lactate level  38°C lasting 1–4 days in early pregnancy, compared to those without a fever in early pregnancy, the overall risk of fetal malformation was not increased (odds ratio = 0.99 (95% CI, 0.88–1.12))60. Previous studies have reported no evidence of congenital infection with SARS‐CoV61, and currently there are no data on the risk of congenital malformation when COVID‐19 infection is acquired during the first or early second trimester of pregnancy. Nonetheless, a detailed morphology scan at 18–24 weeks of gestation is indicated for pregnant women with suspected, probable or confirmed COVID‐19 infection. GENERAL PRECAUTIONS Currently, there are no effective drugs or vaccines to prevent COVID‐19. Therefore, personal protection should be considered in order to minimize the risk of contracting the virus62. Patients and healthcare providers Maintain good personal hygiene: consciously avoid close contact with others during the COVID‐19 epidemic period, reduce participation in any gathering in which a distance of at least 1 meter between individuals cannot be maintained, pay attention to hand washing and use hand sanitizer (with 70% alcohol concentration63) frequently. Some national health authorities and some hospital systems recommend wearing a three‐ply surgical mask when visiting a hospital or other high‐risk area. Seek medical assistance promptly for timely diagnosis and treatment when experiencing symptoms such as fever and cough. Healthcare providers d Consider providing educational information (brochures, posters) in waiting areas. e Set up triage plans for screening. In units in which triage areas have been set up, staff should have appropriate protective equipment and be strictly compliant with hand hygiene. f All pregnant patients who present to the hospital and for outpatient visits should be assessed and screened for symptoms and risk factors based on travel history, occupation, significant contact and cluster (TOCC) (Appendix 2). g Pregnant patients with known TOCC risk factors and those with mild or asymptomatic COVID‐19 infection should delay antenatal visit and routine ultrasound assessment by 14 days. h Consider reducing the number of visitors to the department. i In units in which routine group‐B streptococcus (GBS) screening is practiced, acquisition of vaginal and/or anal swabs should be delayed by 14 days in pregnant women with TOCC risk factors or should be performed only after a suspected/probable case tests negative or after recovery in a confirmed case. Intrapartum prophylactic antibiotic cover for women with ante‐ or intrapartum risk factors for GBS is an alternative. j On presentation to triage areas, pregnant patients with TOCC risk factors should be placed in an isolation room for further assessment. k Medical staff who are caring for suspected, probable or confirmed cases of COVID‐19 patients should be monitored closely for fever or other signs of infection and should not be working if they have any COVID‐19 symptoms. Common symptoms at onset of illness include fever, dry cough, myalgia, fatigue, dyspnea and anorexia. Some national health authorities and hospital systems recommend that medical staff assigned to care for suspected, probable or confirmed cases of COVID‐19 patients should minimize contact with other patients and colleagues, with the aim of reducing the risk of exposure and potential transmission. l Medical staff who have been exposed unexpectedly, while without PPE, to a COVID‐19‐infected pregnant patient, should be quarantined or self‐isolate for 14 days. m Pregnant healthcare professionals should follow risk‐assessment and infection‐control guidelines following exposure to patients with suspected, probable or confirmed COVID‐19. KEY POINTS FOR CONSIDERATION Pregnant women with confirmed COVID‐19 infection should be managed by designated tertiary hospitals, and they should be informed of the risk of adverse pregnancy outcome. Negative‐pressure isolation rooms should be set up for safe labor and delivery and neonatal care. During the COVID‐19 epidemic period, a detailed history regarding recent travel, occupation, significant contact and cluster (i.e. TOCC) and clinical manifestations should be acquired routinely from all pregnant women attending for routine care. Chest imaging, especially CT scan, should be included in the work‐up of pregnant women with suspected, probable or confirmed COVID‐19 infection. Suspected/probable cases should be treated in isolation and confirmed cases should be managed in a negative‐pressure isolation room. A woman with confirmed infection who is critically ill should be admitted to a negative‐pressure isolation room in the ICU. Antenatal examination and delivery of pregnant women infected with COVID‐19 should be carried out in a negative‐pressure isolation room on the labor ward. Human traffic around this room should be limited when it is occupied by an infected patient. All medical staff involved in management of infected women should don PPE as required. Management of COVID‐19‐infected pregnant women should be undertaken by a multidisciplinary team (obstetricians, maternal–fetal‐medicine subspecialists, intensivists, obstetric anesthetists, midwives, virologists, microbiologists, neonatologists, infectious‐disease specialists). Timing and mode of delivery should be individualized, dependent mainly on the clinical status of the patient, gestational age and fetal condition. Both regional anesthesia and general anesthesia can be considered, depending on the clinical condition of the patient and after consultation with the obstetric anesthetist. At present, limited data suggest that there is no evidence of vertical mother‐to‐baby transmission in women who develop COVID‐19 infection in late pregnancy. There is currently insufficient evidence regarding the safety of breastfeeding and the need for mother–baby separation. If the mother is severely or critically ill, separation appears the best option, with attempts to express breastmilk in order to maintain milk production. If the patient is asymptomatic or mildly affected, breastfeeding and colocation (rooming‐in) can be considered by the mother in coordination with healthcare providers. Healthcare professionals engaged in obstetric care and those who perform obstetric ultrasound examinations should be trained and fitted appropriately for respirators and/or PAPR. Following an ultrasound scan of a suspected, probable or confirmed COVID‐19‐infected pregnant patient, surfaces of transducers should be cleaned and disinfected according to manufacturer specifications, taking note of the recommended ‘wet time’ for wiping transducers and other surfaces with disinfection agents. AUTHORS This Interim Guidance was produced by: L. C. Poon, Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong SAR H. Yang, Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing, China J. C. S. Lee, Department of Obstetrics and Gynaecology, KK Women's and Children's Hospital, Singapore J. A. Copel, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA T. Y. Leung, Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong SAR Y. Zhang, Department of Obstetrics and Gynaecology, Zhongnan Hospital of Wuhan University, Wuhan, China D. Chen, Department of Obstetrics and Gynaecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China F. Prefumo, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy CITATION This Interim Guidance should be cited as: Poon LC, Yang H, Lee JCS, Copel JA, Leung TY, Zhang Y, Chen D, Prefumo F. ISUOG Interim Guidance on 2019 novel coronavirus infection during pregnancy and puerperium: information for healthcare professionals. Ultrasound Obstet Gynecol 2020. DOI: 10.1002/uog.22013.
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            Accuracy of Smartphone-Based Pulse Oximetry Compared with Hospital-Grade Pulse Oximetry in Healthy Children

            Pulse oximetry, a ubiquitous, noninvasive method to monitor oxygen saturation (SpO2), requires larger, nonportable equipment. Smartphone pulse oximeter applications (apps) provide a portable, cost-effective option, but are untested in children. We hypothesize that smartphone pulse oximetry will not be inferior to standard pulse oximetry measured in healthy children.
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              Neonatal Early-Onset Infection With SARS-CoV-2 in 33 Neonates Born to Mothers With COVID-19 in Wuhan, China

               L ZENG,  S. XIA,  W. YUAN (2020)
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                Author and article information

                Journal
                Fetal Diagn Ther
                Fetal. Diagn. Ther
                FDT
                Fetal Diagnosis and Therapy
                S. Karger AG (Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com )
                1015-3837
                1421-9964
                12 June 2020
                : 47
                : 7
                : 519-528
                Affiliations
                aBarcelona Centre for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Centre for Biomedical Research on Rare Diseases (CIBER-ER), Barcelona, Spain
                bAnaesthesiology Department, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
                cDepartment of Infectious Diseases, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
                Author notes
                *Francesc Figueras, Fetal Medicine Department, Hospital Clínic, University of Barcelona, 1 Sabino de Arana, ES–08028 Barcelona (Spain), ffiguera@ 123456clinic.cat

                M. López and A. Gonce equally contributed as first authors.

                Article
                fdt-0001
                10.1159/000508487
                7362587
                32535599
                Copyright © 2020 by S. Karger AG, Basel

                This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.

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