key: cord-0760400-1q86owje
authors: Crovetto, Francesca; Crispi, Fàtima; Llurba, Elisa; Pascal, Rosalia; Larroya, Marta; Trilla, Cristina; Camacho, Marta; Medina, Carmen; Dobaño, Carlota; Gomez-Roig, Maria Dolores; Figueras, Francesc; Gratacos, Eduard
title: Impact of SARS-CoV-2 Infection on Pregnancy Outcomes: A Population-Based Study
date: 2021-02-08
journal: Clin Infect Dis
DOI: 10.1093/cid/ciab104
sha: 54e00c022bbc980ae6f49663c28712d9aac4cf18
doc_id: 760400
cord_uid: 1q86owje

BACKGROUND: A population-based study to describe the impact of SARS-CoV-2 infection on pregnancy outcomes. METHODS: Prospective, population-based study including pregnant women consecutively attended at first/second trimester or at delivery at three hospitals in Barcelona, Spain. SARS-CoV-2 antibodies (IgG and IgM/IgA) were measured in all participants and nasopharyngeal RT-PCR was performed at delivery. The primary outcome was a composite of pregnancy complications in SARS-CoV-2 positive versus negative women: miscarriage, preeclampsia, preterm delivery, perinatal death, small-for-gestational age, neonatal admission. Secondary outcomes were components of the primary outcome plus abnormal fetal growth, malformation, intrapartum fetal distress. Outcomes were also compared between positive symptomatic and positive asymptomatic SARS-CoV-2 women. RESULTS: Of 2,225 pregnant women, 317 (14.2%) were positive for SARS-CoV-2 antibodies (n=314, 99.1%) and/or RT-PCR (n=36, 11.4%). Among positive women, 217 (68.5%) were asymptomatic, 93 (29.3%) had mild COVID-19 and 7 (2.2%) pneumonia, of which 3 required intensive care unit admission. In women with and without SARS-CoV-2 infection, the primary outcome occurred in 43 (13.6%) and 268 (14%), respectively [risk difference -0.4%, (95% CI: -4.1% to 4.1)]. As compared with non-infected women, women with symptomatic COVID-19 had increased rates of preterm delivery (7.2% vs. 16.9%, p=0.003) and intrapartum fetal distress (9.1% vs. 19.2%, p=0.004), while asymptomatic women had similar rates to non-infected cases. Among 143 fetuses from infected mothers, none had anti-SARS-CoV-2 IgM/IgA in cord blood. CONCLUSIONS: The overall rate of pregnancy complications in women with SARS-CoV-2 infection was similar to non-infected women. However, symptomatic COVID-19 was associated with modest increases in preterm delivery and intrapartum fetal distress.

The clinical spectrum of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the coronavirus disease in pregnancy and their consequences on perinatal outcomes are yet to be fully determined. Data from population-based prospective studies and case series suggest that the infection in pregnancy is mostly asymptomatic or mild, 1-3 but serious illness may develop in a small proportion of women. [4] [5] [6] [7] There is scarce evidence on the impact of SARS-CoV-2 on perinatal outcomes. The reported rates of premature delivery in case series of symptomatic COVID-19 in pregnancy ranged 6-32%. [5] [6] [7] [8] While it is anticipated that severe COVID-19 will carry poorer pregnancy outcome, 9 the effect of milder or asymptomatic infections has not been documented. Likewise, most information comes from cases of SARS-CoV-2 reported in the third trimester, but it is unknown whether infection in early pregnancy is associated with increased rates of miscarriage or fetal defects.

We here report a population-based prospective cohort study including early and late pregnant women from the catchment areas of three hospitals in Barcelona (Spain). We conducted universal screening for SARS-CoV-2 infection and evaluated its impact on pregnancy outcomes.

A multicentre prospective population-based cohort study from March 15 to May 31, 2020, in Barcelona, Spain. Eligible women were all pregnant women from the catchment areas of three university hospitals (Hospital Sant Joan de Déu [HSJD] , Hospital Clinic Barcelona [HCB] , and Hospital de Sant Pau [HSP]) during the recruitment periods. Women referred for a diagnosis of SARS-CoV-2 from outside the catchment areas of the participating centers were not eligible for the study. During the 6-week study period, the catchment areas of these hospitals covered approximately 60% of all deliveries attended in public hospitals in the Health region of Barcelona (https://catsalut.gencat.cat/ca/coneix-catsalut/catsalut-territori/barcelona/). For early pregnancy, all women seen in the outpatient setting and who had a blood sampling for first or second trimester Down's syndrome screening (range 10-16 weeks' gestation) from March 15 to May 31 2020 , were asked to participate in the study. In those accepting, a sample of serum remaining from routine blood test was analysed for the study. For late pregnancy, all women attending for delivery from April 15 to May 31, 2020 , were asked to participate and, if accepting, maternal blood and fetal cord blood samples were obtained. Nasopharyngeal swabs for real time polymerase chain reaction (RT-PCR) were obtained in all women attending delivery. M a n u s c r i p t 5 The study was approved by the Review Board at each institution and informed consent was obtained in all women. Women with COVID-19 were diagnosed and managed according to standard protocols and guidelines. 10, 11 A total of 874 women have previously been reported in a study describing the clinical presentation of SARS-CoV-2 in early and late pregnancy, 1 but the rest of patients, as well as the association with perinatal outcomes of the whole study population, have not been reported elsewhere. The study design contemplated recruiting patients just once, so even if due to the timings of recruitment the risk was almost negligible, all women recruited in the early pregnancy cohort were identified to avoid a double recruitment in the delivery cohort.

Pregnancy, delivery and neonatal data were obtained from electronic medical files. For all women hospitalized for COVID-19, medical information, pregnancy, delivery and neonatal data were retrieved from hospital files. COVID-19 symptoms were recorded using the same structured questionnaire for all pregnant women, which included questions about risk factors and about any symptom suggestive of COVID-19 noticed between mid-February 2020 and the time of testing for SARS-CoV-2. This time represented 1.5 to 3 months (average 2.2 months, 10 weeks) depending on the date of recruitment. All women testing positive for SARS-CoV-2 by antibodies or RT-PCR were reinterviewed with the same questionnaire 4-5 weeks after recruitment. Among SARS-CoV-2 infected women, we defined as symptomatic those with at least one of the following symptoms: fever, dry cough, loss of taste or smell, dyspnoea, myalgia, diarrhoea, sore throat and rash on skin or discolouration of fingers/toes.

Maternal samples were drawn from peripheral veins in all participants. In addition, cord blood from the umbilical vein after cord clamp at delivery was obtained. Serum was separated by centrifugation at 1500 g for 10 min at 4ºC, and samples were immediately stored at −80ºC until analysed. SARS-CoV-2 IgG and IgM/IgA antibodies were tested in all maternal samples and in cord blood samples from SARS-CoV-2 positive mothers using COVID-19 VIRCLIA® Monotest, Vircell Microbiologist, Granada, Spain. All indeterminate results were re-tested (VITROS® Immunodiagnostic Products Anti-SARS-CoV2 Total Tests, Ortho Clinical Diagnostics, Rochester, NY, USA) and classified as positive or negative. Likewise, all samples that were positive for IgM+IgA but negative for IgG in women reporting no symptoms suggestive of COVID-19 during the 10 weeks prior to testing were re-tested by a quantitative suspension array assay based on the xMAP Luminex technology 12 M a n u s c r i p t 6 Nasopharyngeal swab samples for SARS-CoV-2 RNA RT-PCR were collected in women attending for delivery. Samples were collected on Micronics tubes with Zymo DNA/RNA Shield Lysis Buffer. RNA was extracted using the Quick-DNA/RNA Viral MagBead kit (Zymo) and the TECAN Dreamprep robot. Five microliters of RNA solution were added to 15 μl of rRT-PCR master mix (Luna Universal Probe One-Step RT-qPCR Kit; New England Biolabs) and used for amplification of SARS-CoV-2 N1 and N2 regions, as well as the human RNase P gene as control, as described in the CDC-006-00019 CDC/DDID/NCIRD/ Division of Viral Diseases protocol released 3/30/2020. A SARS-CoV-2 positive result was considered if the Ct values for N1, N2 and RNase P were below 40. Samples discordant for N1 and N2 were repeated and samples with a Ct ≥ 40 for RNase P were considered as invalid.

SARS-CoV-2 infection was defined either by a positive serological result or positive RT-PCR in nasopharyngeal swab.

The primary end-point for this study was the occurrence of a pregnancy complication, defined by the presence of miscarriage, preeclampsia, preterm delivery, perinatal death, small-for-gestational age or admission to high-dependency neonatal care. This composite outcome was selected from core outcome sets in the context of maternal infections, as defined by stakeholders, including healthcare professionals, researchers, and patients.

Main secondary outcomes were all the individual outcomes considered for the composite primary outcome, plus abnormal fetal growth or malformation at second trimester scan for early pregnancy, and intrapartum fetal distress requiring emergency delivery for late pregnancy. All other clinical findings were exploratory outcomes.

Assuming a prevalence of infection of 15% based on the semi-mechanistic Bayesian hierarchical model, 13 if there is truly no difference between the infected and non-infected women in their risk of pregnancy complications (20% in both groups), then 275 infected are required to be 90% sure that the upper limit of a one-sided 95% confidence interval (or equivalently a 90% two-sided confidence interval) will exclude a difference towards a higher risk in the infected group of more than 10%. To compensate for lost to follow-up, a sample size of 300 infected and 2,250 non-infected women were finally aimed. This sample size of 300 infected women would allow for comparisons between early and late infections (1:2) to test (alpha-risk of 5%) a relative risk of 2 for late infection compared to early infection (assumed risk of hospital admission of 3%) with a power of 80%. M a n u s c r i p t 7 Statistical analysis Primary analysis. For the primary outcome (pregnancy complications), the primary analysis was the comparison between SARS-CoV-2 infected and non-infected pregnant women.

Secondary analyses. The primary outcomes were also compared between symptomatic vs. asymptomatic SARS-CoV-2 infected pregnant women and also between early vs. late pregnancy. The secondary and the exploratory outcomes were compared between SARS-CoV-2 infected and noninfected pregnant women, and between SARS-CoV-2 positive symptomatic vs. asymptomatic pregnant women.

The analysis was performed using SPSS v26 (New York, USA) including the use of  2 test, Student ttest, Mann Whitney U test or Fisher exact test as appropriate. All reported p-values are 2 sided. Differences were considered significant when p<0.05. Data is shown as mean (standard deviation, SD), median (interquartile range, IQR) or number (percentages) as appropriate. Figure 1 displays the flowchart diagram of the study population. From the initial 2,502 eligible pregnant women, 277 were excluded due to withdrawn consent, unavailable serum samples or undetermined SARS-CoV-2 laboratory results (Suppl. Table 1) , thus leaving a final study population of 2,225 pregnant women. Baseline characteristics of women positive and negative for SARS-CoV-2 were mostly similar (Table 1) . Among women with SARS-CoV-2, white ethnicity was less frequent (58.7% vs. 65.1%, p=0.027) and past history of asthma was higher (6.9% vs. 4.1%, p=0.023).

We identified a total of 317 (14.2%) women with evidence of SARS-CoV-2 infection, either by positive antibodies (n=314) and/or PCR (n=36), with a similar prevalence in early (15.3%, 141/921) and late (13.5%, 176/1,304) pregnancy. Baseline characteristics of women positive and negative for SARS-CoV-2 were mostly similar, but in SARS-CoV-2 positive women, White ethnicity (58.7% vs. 65.1%, p=0.027) was less affected, whereas history of asthma (6.9% vs. 4.1%, p=0.023) was more prevalent (Table 1) .

In women with and without SARS-CoV-2 infection, the primary outcome (pregnancy complication) occurred in 13.6% (43/317) and 14% (268/1,908), respectively [risk difference -0.4%, (95% CI: -4.1% Table 2 ). Among secondary outcomes, there was a non-significant trend for increased preterm delivery (11.4% vs. 7.2%, p=0.054), and a significant increase in intrapartum fetal distress (14% vs. 9.1%, p=0.036) in SARS-CoV-2 positive vs. negative pregnancies, respectively. Other secondary or exploratory outcomes were similar among groups.

In a secondary analysis comparing women with asymptomatic and symptomatic COVID-19, the rates of the preterm delivery and intrapartum fetal distress were significantly increased in symptomatic women in comparison with non-infected women, while asymptomatic women had rates similar to non-infected pregnant women ( Table 3 ). The proportion of severe small-forgestational age newborns was higher in symptomatic compared to asymptomatic COVID-19 women (9.6% vs. 1%, p=0.006), whereas the proportion of small-for-gestational age was similar (Table 3) .

Cord blood was available for analysis in 143 SARS-CoV-2 positive pregnancies. A total of 61 (42.7%) newborns were seropositive for IgG, but none for IgM or IgA. None of these IgG positive newborns presented any symptoms suspicious of infection during the neonatal period.

The clinical features of SARS-CoV-2 infection among study groups are displayed in Supplementary  Table 3 . Among women with infection, 217 (68.5%) women reported no symptoms. The rate of symptomatic cases and hospital admission was higher in late pregnancy as compared with early pregnancy (Suppl. Table 4 ). There were seven (4%) patients with pneumonia in the late pregnancy (Suppl . Table 5 ), of which three required intensive care unit (ICU) admission during the postpartum. Only one of these three patients necessitated prolongation of mechanical ventilation for 48 hours after caesarean section. All women with pneumonia were discharged well. There were no maternal deaths. The rate of ICU admission among COVID-19 symptomatic third trimester women was 4.2% (3/71), for those presenting symptoms during labour 10.7% (3/28) and for those with pneumonia 42.9% (3/7) (Suppl. Table 4 ). Further details are given in the Supplementary Material section (Results).

The data in this population-based study support that, when the full clinical spectrum of the disease is evaluated, the impact of SARS-CoV-2 infection on pregnancy outcomes is small or negligible. The risk of a pregnancy complication as defined in the study was similar in women with and without SARS-CoV-2 exposed in early or late pregnancy. However, symptomatic COVID-19 women had a modest but significant increase in the risk of preterm delivery and intrapartum fetal distress. The information here provides an overall picture of the impact of SARS-CoV-2 infection in pregnancy. We believe the results are reassuring for pregnant women and are useful for healthcare resource planning and clinical management. M a n u s c r i p t 9 Impact on pregnancy outcomes.

This study reports pregnancy follow-up data of SARS-CoV-2 infection in the first or early second trimester. Among 141 positive cases in early pregnancy, there was no evidence of increased rates of miscarriage, fetal defects or abnormal fetal growth at mid-gestation. Previous reports have reported placental infection with SARS-CoV-2 in a case of miscarriage. 14 Anecdotal evidence of placental infection as potential cause of miscarriage has been reported for many viruses. 15 Our study supports that the risk of miscarriage or fetal defects after SARS-CoV-2 infection is, as with other respiratory viruses, very small. 16 In women with SARS-CoV-2 in late pregnancy, the impact of the infection was small or negligible for the majority of patients. However, our data suggest a difference between asymptomatic and symptomatic infections. The study confirms the findings of case series of women with symptomatic COVID-19, reporting increased preterm delivery 5-8 and fetal intrapartum distress. 17 Intrapartum distress could result from maternal poorer oxygenation and inflammatory response, 18 combined with reduced fetal reserve due to placental insufficiency. We observed increased rates of severe small-for-gestational-age newborns in symptomatic COVID-19 women, which is line with recent studies describing placental invasion and thrombotic events by SARS-CoV-2 in placentas analysed after delivery. 19 In this study, COVID-19 was not associated with increased postpartum obstetric complications such as haemorrhage or infection, but the three patients admitted to ICU deteriorated in the immediate postpartum. This observation is in line with previous studies reporting increased rates of maternal deterioration after delivery in women with COVID-19, 6,7 particularly after caesarean section. 20 Current guidelines 21 recommend promoting vaginal delivery in women with clinically active COVID-19. 22 In this study, the overall rate of caesarean section was not increased in COVID-19 women, supporting that intention of vaginal delivery under strict maternal and fetal surveillance is a safe strategy.

We did not find evidence of anti-SARS-CoV-2 IgM or IgA in cord blood in any of the 143 fetuses from infected mothers evaluated. The observed 43% of positive IgG is in line with a previous study in cord blood of 31 fetuses from infected mothers. 23 Intrauterine transmission of SARS-CoV-2 is supported by case reports describing the virus in newborns, amniotic fluid and placental 24 or cord blood IgM. 25, 26 Our results support that vertical transmission of SARS-CoV-2 is very uncommon. 27

This study was conducted in areas with a high incidence of SARS-CoV-2 infection. The 14.2% prevalence of SARS-CoV-2 in pregnant women is in line with other seroprevalence studies conducted in Spain. 12, 28 Prevalence studies in other heavily affected areas, such as New York City in the USA, A c c e p t e d M a n u s c r i p t reported rates of 16-20% 2 at the peak of the pandemics. This study was mainly conducted in April and May 2020, while the peak of the pandemic in Spain occurred at the end of March (https://www.who.int/countries/esp/). This may explain the relatively low rate of positive RT-PCR results in women screened at delivery, in relation with a much larger proportion of positive serologic results reflecting past infections. The study illustrates the value of population-based seroprevalence studies to capture the high proportion of asymptomatic or mild infections not tested for RT-PCR. 29 In this study, the correlation between antibodies and PCR in women with paired testing was high.

As previously reported, 1,2 SARS-CoV-2 infection during pregnancy was mostly asymptomatic or mild. Notwithstanding this, in a small proportion of pregnant women SARS-CoV-2 can result in serious illness, 7,30 and case series suggest that this risk could be higher in the third trimester. 23 While not the primary goal of this study, we confirmed our previous observations that SARS-CoV-2 could be associated with higher rates of symptomatic disease and severity in third as compared with first trimester pregnant women. 1 It has been suggested that, as described for other respiratory viruses, 31 the risk of COVID-19 severe complications is increased in pregnancy. 7 While the study was not designed to evaluate this question, our data support previous reports suggesting an increased risk in the postpartum, a notion deserving evaluation in large multicentre studies. 31 

Among the strengths of the study, this is the largest population-based study on SARS-CoV-2 in pregnancy which provides information on SARS-CoV-2 in early pregnancy too. We studied a population of pregnant women defined by geographic boundaries, i.e. the catchment areas covered by each maternity, which during the study period represented about 60% of all deliveries attended in public hospitals in Barcelona. Including all pregnant women consecutively attending for routine follow-up or delivery provided the opportunity to report the full spectrum of the infection in comparison with multicenter registries of cases, which by definition are biased towards reporting the most severe end of the clinical spectrum. Additionally, data from pregnancy outcomes were highly reliable since all women were attended within the same hospitals. We established several quality controls for serological testing in addition to a larger breadth and accuracy of antibody response including multiple isotypes (IgG, IgA and IgM) and viral antigens, and could perform also RT-PCR in women at delivery, allowing a comparison with serological results.

Among the weaknesses, for past infections evaluation of symptoms relied on questionnaires. We reduced the risk of inaccuracies by interviewing twice positive women and we found a strong correlation between reported symptoms and serological results. However, we acknowledge that not having repeated the interview in negative women may have resulted in some degree of ascertainment bias. Some first trimester infections may have occurred before pregnancy, but such cases should be very rare considering that women evaluated became pregnant between mid-M a n u s c r i p t January and early March, when SARS-CoV-2 infection cases were negligible in Spain. 13 For early pregnancy infections, we obtained follow-up data until mid-gestation and this information must be completed in future studies. For early pregnancy, RT-PCR was performed in only a few women with symptoms due to the severe restrictions in RT-PCR availability during the first weeks of the pandemics. Therefore, we may have missed asymptomatic infections that were negative for antibodies but positive for RT-PCR at testing, but such cases should be few considering the 85% agreement between positive PCR and serology in women with paired testing. In addition, the serologic assay here used has a reported 89% sensitivity. This study is unpowered to detect rare complications of COVID-19 in pregnancy. International multicentre registries are established as invaluable tools to describe such uncommon complications. For different reasons, RT-PCR in newborns was seldom performed and we could not evaluate these data. This study was conducted in a high-resource setting and consequently these results should not be extrapolated to medium or low-resource settings.

The data of this population-based study in a heavily affected area, support that for the vast majority of pregnancies SARS-CoV-2 infection has small or negligible consequences. For women with symptomatic SARS-CoV-2 in the third trimester, there were modest but significantly increased risks of preterm delivery and intrapartum distress. Likewise, our findings are in line with previous reports suggesting increased risks of severe COVID-19 in symptomatic women during late pregnancy. Vaginal delivery was achieved in most women with clinically active COVID-19 during labour, supporting the safety of such approach. We believe that these findings provide useful information for pregnant women and healthcare providers, while they support current recommendations of strict clinical surveillance of COVID-19 in late pregnancy and delivery, particularly for symptomatic women.

M a n u s c r i p t NOTES Author contributions: FCro, FC and EG conceived and designed the study. EL, FF and MDGR were responsible of the study protocol at each hospital and guaranteed the correct execution of the study. FCro, FC, and EL were the supervisors at each of the three hospitals for day-to-day running of the study including participant recruitment and data collection. RP, ML, CT, MC, CM were responsible of medical file revision and data collection at the three hospitals involved. CD was responsible of laboratory procedures of antibody analysis. FCro did data analysis. FF supervised the data analysis. FCro, FC and EG drafted the first version of manuscript. EG is the principal investigator the project. All authors critically reviewed and approved the final version of the manuscript. Data are n (%) or median (IQR). M a n u s c r i p t Primary outcome was defined as the occurrence of a pregnancy complication (miscarriage, preeclampsia, preterm delivery, perinatal death, small-for-gestational age or admission to high-dependency neonatal care).

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

Seroprevalence and presentation of SARS-CoV-2 in pregnancy

Universal Screening for SARS-CoV-2 in Women Admitted for Delivery

Universal SARS-Cov-2 Screening in Women Admitted for Delivery in a Large Managed Care Organization

Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records

Coronavirus disease 2019 in pregnant women: a report based on 116 cases

Characteristics and outcomes of pregnant women admitted to hospital with confirmed SARS-CoV-2 infection in UK: national population based cohort study

Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis

Clinical Findings and Disease Severity in Hospitalized Pregnant Women With Coronavirus Disease 2019 (COVID-19)

Effects of coronavirus disease 2019 ( COVID -19) on maternal, perinatal and neonatal outcomes: a systematic review

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

Diagnosis and treatment of adults with community-acquired pneumonia

Seroprevalence of antibodies against SARS-CoV-2 among health care workers in a large Spanish reference hospital

Estimating the number of infections and the impact of non-pharmaceutical interventions on COVID-19 in European countries: technical description update

Second-Trimester Miscarriage in a Pregnant Woman with SARS-CoV-2 Infection

Risks associated with viral infections during pregnancy

SARS-CoV-2 in first trimester pregnancy: a cohort study

Emergency cesarean section on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) confirmed patient

Fetal heart rate changes on the cardiotocograph trace secondary to maternal COVID-19 infection

Pregnancy and postpartum outcomes in a universally tested population for SARS-CoV-2 in New York City: A prospective cohort study

Association between Mode of Delivery among Pregnant Women with COVID-19 and Maternal and Neonatal Outcomes in Spain

Covid-19 and pregnancy

Rates of Maternal and Perinatal Mortality and Vertical Transmission in Pregnancies Complicated by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Co-V-2) Infection

−2 TRANSMISSION: viral detection and fetal immune response

Preterm delivery in pregnant woman with critical COVID-19 pneumonia and vertical transmission

Antibodies in Infants Born to Mothers with COVID-19 Pneumonia

Possible Vertical Transmission of SARS-CoV-2 from an Infected Mother to Her Newborn

Neonatal management and outcomes during the COVID-19 pandemic: an observation cohort study

Prevalence of SARS-CoV-2 in Spain (ENE-COVID): a nationwide, population-based seroepidemiological study

Use of serological surveys to generate key insights into the changing global landscape of infectious disease

Clinical course of severe and critical COVID-19 in hospitalized pregnancies: a US cohort study

H1N1 2009 influenza virus infection during pregnancy in the USA

225: 1,908 SARS-CoV-2 negative; 317 SARS-CoV-2 positive) † Including all early pregnancies (n=921: 780 SARS-CoV-2 negative

¶ Data are calculated over 285 consecutive scans completed at the time of data analysis (n=231 SARS-CoV-2 negative, n=54 SARS-CoV-2 positive)

¥ Data calculated over 540 consecutive scans completed at the time of data analysis (n=460 SARS-CoV-2 negative, n=80 SARS-CoV-2 positive)

Including multiple gestation (n=1,338: 1,1160 SARS-CoV-2 negative

** Including 1024 neonates (n=903 SARS-CoV-2 negative, n=121 SARS-CoV-2 positive)

We thank the Biobanks of Fundació Sant Joan de Déu, Clínic-IDIBAPS and Sant Pau for valuable management of samples, and the Centre for Regulation Genomic in Barcelona for the analysis of nasopharyngeal samples. We are indebted to the nursing staff at Hospital Clínic and to the patients for their generous donation, to Fundació Glòria Soler for its support to the COVIDBANK initiative and to the HCB-IDIBAPS Biobank for the biological human samples and data procurement.

Dr. Gratacós reports grants from Stavros Niarchos Foundation, Santander Foundation, and "La Caixa" Foundation, during the conduct of the study. Dr Carmen Muñoz-Almagro reports grants and personal fees from BioMerieux, Roche, and Pfizer; personal fees from Qiagen; grants from Qiastat and Genomica, outside the submitted manuscript. The remaining authors had no conflicts of interest to be declared. 

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