key: cord-1003579-2ef6goqf authors: Aabakke, Anna J. M.; Krebs, Lone; Petersen, Tanja G.; Kjeldsen, Frank S.; Corn, Giulia; Wøjdemann, Karen; Ibsen, Mette H.; Jonsdottir, F.; Rønneberg, Elisabeth; Andersen, Charlotte S.; Sundtoft, Iben; Clausen, Tine; Milbak, Julie; Burmester, Lars; Lindved, Birgitte; Thorsen‐Meyer, Annette; Khalil, Mohammed R.; Henriksen, Birgitte; Jønsson, Lisbeth; Andersen, Lise L. T.; Karlsen, Kamilla K.; Pedersen, Monica L.; Klemmensen, Åse; Vestgaard, Marianne; Thisted, Dorthe; Tatla, Manrinder K.; Andersen, Line S.; Brülle, Anne‐Line; Gulbech, Arense; Andersson, Charlotte B.; Farlie, Richard; Hansen, Lea; Hvidman, Lone; Sørensen, Anne N.; Rathcke, Sidsel L.; Rubin, Katrine H.; Petersen, Lone K.; Jørgensen, Jan S.; Stokholm, Lonny; Bliddal, Mette title: SARS‐CoV‐2 infection in pregnancy in Denmark—characteristics and outcomes after confirmed infection in pregnancy: A nationwide, prospective, population‐based cohort study date: 2021-08-31 journal: Acta Obstet Gynecol Scand DOI: 10.1111/aogs.14252 sha: 36d82c7970bfac343c65c2c30cb28296b08abe4c doc_id: 1003579 cord_uid: 2ef6goqf INTRODUCTION: Assessing the risk factors for and consequences of infection with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) during pregnancy is essential to guide clinical care. Previous studies on SARS‐CoV‐2 infection in pregnancy have been among hospitalized patients, which may have exaggerated risk estimates of severe outcomes because all cases of SARS‐CoV‐2 infection in the pregnant population were not included. The objectives of this study were to identify risk factors for and outcomes after SARS‐CoV‐2 infection in pregnancy independent of severity of infection in a universally tested population, and to identify risk factors for and outcomes after severe infection requiring hospital admission. MATERIAL AND METHODS: This was a prospective population‐based cohort study in Denmark using data from the Danish National Patient Register and Danish Microbiology Database and prospectively registered data from medical records. We included all pregnancies between March 1 and October 31, 2020 and compared women with a positive SARS‐CoV‐2 test during pregnancy to non‐infected pregnant women. Cases of SARS‐CoV‐2 infection in pregnancy were both identified prospectively and through register linkage to ensure that all cases were identified and that cases were pregnant during infection. Main outcome measures were pregnancy, delivery, maternal, and neonatal outcomes. Severe infection was defined as hospital admission due to coronavirus disease 2019 (COVID‐19) symptoms. RESULTS: Among 82 682 pregnancies, 418 women had SARS‐CoV‐2 infection during pregnancy, corresponding to an incidence of 5.1 per 1000 pregnancies, 23 (5.5%) of which required hospital admission due to COVID‐19. Risk factors for infection were asthma (odds ratio [OR] 2.19, 95% CI 1.41–3.41) and being foreign born (OR 2.12, 95% CI 1.70–2.64). Risk factors for hospital admission due to COVID‐19 included obesity (OR 2.74, 95% CI 1.00–7.51), smoking (OR 4.69, 95% CI 1.58–13.90), infection after gestational age (GA) 22 weeks (GA 22–27 weeks: OR 3.77, 95% CI 1.16–12.29; GA 28–36 weeks: OR 4.76, 95% CI 1.60–14.12), and having asthma (OR 4.53, 95% CI 1.39–14.79). We found no difference in any obstetrical or neonatal outcomes. CONCLUSIONS: Only 1 in 20 women with SARS‐CoV‐2 infection during pregnancy required admission to hospital due to COVID‐19. Risk factors for admission comprised obesity, smoking, asthma, and infection after GA 22 weeks. Severe adverse outcomes of SARS‐CoV‐2 infection in pregnancy were rare. The World Health Organization declared a global pandemic of coronavirus disease 2019 in March 2020. 1 COVID-19 is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Assessing the risk factors for and consequences of infection with SARS-CoV-2 during pregnancy is essential to guide clinical guidelines and care. Previous studies have identified risk factors for infection to include obesity, age, ethnicity, and pre-existing morbidities, and SARS-CoV-2 infection in pregnancy has been associated with an increased risk of admission to an intensive care unit (ICU), preterm delivery, and admission of the neonate to a neonatal intensive care unit (NICU). [2] [3] [4] [5] [6] Most previous population-based studies on SARS-CoV-2 infection in pregnancy have been among hospitalized patients, which may exaggerate the risk estimates of severe outcomes because not all cases of SARS-CoV-2 infection in the pregnant population were included. 3, 7 Only one study from the Netherlands included all cases independent of severity and hospital admission. 4 However, in that study, cases were identified prospectively in obstetric clinics, with the risk of selection bias. Additionally, the outcomes are in most studies compared with outcomes of historic cohorts of non-infected women, with the risk that the consequences of the pandemic will be attributed solely to SARS-CoV-2. 3, 4, 8 Lastly, testing strategies influence the estimated prevalence of SARS-CoV-2 infection, and potentially also the estimated severity of outcomes, if mild and asymptomatic cases are also detected. 2 The testing strategy in Denmark rapidly evolved during the pandemic from testing the most ill in March 2020 to testing individuals with mild symptoms from April and testing close contacts from May. Universal testing of all pregnant women admitted to hospital including for delivery was implemented nationwide in early May 2020. The objectives of this study were to identify risk factors for SARS-CoV-2 infection in pregnancy in a universally tested population and risk factors for severe infection requiring hospital admission, and to investigate the consequences of infection and severe infection on pregnancy, delivery, and neonatal outcomes when comparing with all non-infected pregnancies during the same time period. This was a nationwide prospective population-based study investigating the association between SARS-CoV-2 infection in pregnancy and clinical characteristics and maternal, delivery, and neonatal outcomes. The study used prospectively registered data from medical records registered in the Danish COVID-19 in pregnancy database (DCOD) and register data obtained from the following national registers: the Danish National Patient Register (DNPR), 9 the Danish Microbiology Database (MiBa), 10 and the Civil Registration System. 11, 12 The overall study population was identified in DNPR and comprised all women registered with a pregnancy or birth-related International Classification of Diseases 10th revision diagnosis or procedure between March 1 and October 31, 2020 as specified in the Supporting Information Table S1 . SARS-CoV-2-positive cases within the study population were identified by linkage to MiBa. In Denmark, all positive polymerase chain reaction (PCR) tests are registered in MiBa, but antigen and antibody tests were not during the study period. Pregnant women identified in the registers were followed up until December 11, 2020 considering all outcomes. In the DCOD, women with a positive SARS-CoV-2 test during pregnancy between March 1 and October 31, 2020 were registered prospectively. Eligible SARS-CoV-2 tests included (a) PCR tests (of pharyngeal swab or tracheal secretion), (b) antigen tests (of nasal swab), or (c) detection of antibodies (IgG or total antibodies in serum) combined with a history of COVID-19 symptoms during pregnancy. The antibody assays used in Denmark have a high specificity and the risk of false positives is low; 13 a positive test was therefore considered inclusive. All obstetric units in Denmark reported to the DCOD based on data from prospectively collected medical records. DCOD was based in EasyTrial (easytrial.net, Denmark). To secure data completeness, cases were validated every second month by register linkage, with data obtained from the DNPR, Danish National Health Service Register, 14 and MiBa. The validation data set included only personal identification number, date of positive SARS-CoV-2 PCR test, date of hospital contact, and name of the hospital. Non-reported cases identified by validation who were pregnant at the time of a positive SARS-CoV-2 PCR test were entered into the DCOD retrospectively. Women included in the DCOD were followed up until data extraction on February 8, 2021. The register data on the overall study population were pseudoanonymized, making it impossible to validate the SARS-CoV-2-positive cases from the registers against the DCOD cases on an individual level. We therefore present data for SARS-CoV-2-positive women from the DCOD alongside cases identified in the registers to illustrate the degree of comparability. SARS-CoV-2 cases in the DCOD and those registered in the national registers were each compared with the non-infected population. The validity of maternal and neonatal characteristics, surgical procedures, and main diagnoses in the Danish registers is considered high, 15 and we therefore evaluated that a comparison between the DCOD data and the register data was relevant. The estimated date of delivery was registered in the DCOD and based on the first-trimester ultrasound examination offered to all pregnant women between gestational age (GA) 11 and 14 completed weeks. In case of first-trimester abortion, the estimated date of delivery was calculated based on the GA at abortion. In the DCOD, date of the first day of the last menstrual period (LMP) was defined as estimated date of delivery minus 280 days. In the register data, the LMP was calculated based on the registered GA at delivery or abortion. If still pregnant, we calculated the LMP based on GA at ultrasound examination, and if missing, the recommended GA for the registered ultrasound examinations. For abortions with a missing registration of GA, GA was imputed based on the mean GA within the categories miscarriage or induced abortion. Characteristics included maternal age at LMP, pre-pregnancy body mass index (BMI) based on the height and pre-pregnancy weight registered at first contact in pregnancy, smoking defined as any smoking during pregnancy, parity, multiple pregnancy, preeclampsia, gestational diabetes, and diabetes. The register data set also included pre-existing asthma and hypertension diagnosed within 5 years of LMP. Supporting information Table S2 presents In the DCOD, admission to hospital with a concurrent SARS-CoV-2 infection was defined as admission and discharge on two different dates and a positive SARS-CoV-2 test within 14 days before or during admission. Severe infection was defined if admission to hospital was due to COVID-19 symptoms. Categorical variables are presented as count with percentage, and continuous variables as median with interquartile range. For DCOD data numbers less than 3 and for register data numbers less than 5 are not reported to avoid identification according to the respective ethical approvals. The categorical DCOD data were analyzed with chi-squared test when compared with the non-infected population, and with logistic regression when comparing severe and non-severe DCOD cases including multivariate analyses adjusting for the predefined risk factors age, BMI, parity, and smoking. Continuous DCOD variables were analyzed using the Wilcoxon signed rank test. We performed a sub-analysis of the DCOD cases The study was approved by the Danish Patient Safety Authority on The overall incidence of SARS-CoV-2 infection during validated pregnancy in the inclusion period was 5.1 (95% CI 4.7-5.5) per 1000 pregnancies, with the monthly incidence ranging from 0.2 per 1000 pregnancies in July to 3.8 per 1000 pregnancies in October (Supporting Information Figure S1 ). Of the SARS-CoV-2 cases in pregnancy, 23 (5.5%) were admitted to hospital because of COVID-19 symptoms. Basic characteristics of women and their pregnancies according to SARS-CoV-2 status and severity of infection are presented in Table 1 The outcomes of the SARS-CoV-2-infected women compared with all non-infected pregnancies are presented in Table 2 . The risk of pneumonia was significantly higher among SARS-CoV-2-infected pregnant women (OR 15.97, 95% CI 6.92-36.86). All cases of pneumonia (n = 6) were among women admitted to hospital because of COVID-19 and none of them smoked in pregnancy. The rate of thromboembolic events and admission to an ICU was low, and we had no cases of maternal death during the study period. The rate of early pregnancy loss did not vary between the groups after adjusting for exposure time. However, the risk of termination of pregnancy was increased after adjustment (hazard ratio 2.39, 95% CI 1.29-4.45) among the SARS-CoV-2-infected women. The median time between SARS-CoV-2 infection and delivery was 88 days (interquartile range 35-138). We found no difference between the groups regarding any of the delivery or infant outcomes. Adjustment did not change the results. There were no neonatal deaths among the children of SARS-CoV-2-infected women. We found no statistically significant differences in outcomes between women requiring hospital admission due to COVID-19 symptoms compared with less severe SARS-CoV-2 cases (Table 3) . There was no difference in risk of cesarean delivery, induction of labor, preterm birth, or NICU admission in relation to GA at infection among the SARS-CoV-2-infected women (data not shown). week) week (14 +0 -29 +0 week) week (23 +4 -32 +0 week) week ( Register SARS- TA B L E 3 Outcomes for women with severe COVID-19 infection requiring admission to hospital compared to less severe SARS-CoV-2 cases in pregnancy in Denmark between March 1 and October 31, 2020 as registered in the Danish COVID-19 in pregnancy database (DCOD) Women requiring admission to hospital due to COVID-19 symptoms Women with SARS-CoV-2 infection had, as expected, a much higher risk of pneumonia, but otherwise we found no increased risk for adverse maternal or neonatal outcomes in infected compared with non-infected pregnant women. Previous studies have found increased risks of admission to an ICU, induction of labor, preterm delivery, and admission to a NICU, 2-6,20,21 which we could not confirm. The lack of association in our study might be related to the fact that we included all cases of SARS-CoV-2 infection in pregnancy independent of severity. The previously shown associations between SARS-CoV-2 and severe outcomes might be related to severity of disease. We found no statistically significant differences in outcomes among cases requiring hospital admission for COVID-19 compared with less severe cases, but relatively high-risk differences for cesearean section, induction of labor, and admission to a NICU of the neonate. The lack of statistical associations is likely due to low numbers. In a Nordic collaborative study, women with severe COVID-19 were at increased risk of induction of labor cesarean delivery, and preterm delivery. 22 We found few cases of early pregnancy complications among the SARS-CoV-2-infected women. However, after adjustment for exposure time, the risk of termination of pregnancy was higher among the SARS-CoV-2-infected women. In Denmark, all women admitted to hospital are tested for SARS-CoV-2, and we assume that the increased rate of terminations is partly related to more frequent testing and consequently a higher detection rate of SARS-CoV-2 among women opting for provoked abortion rather than the SARS-CoV-2 diagnosis itself. This study has several strengths. The major strength is the combination of real-time register-based data considered complete 9 and prospectively collected medical record data, allowing for validation, analysis of disease severity, and multivariate analyses. Furthermore, the comparison population comprised all pregnancies from the same inclusion period as the SARS-CoV-2 cases, thereby adjusting for the possible consequences of community regulations during a pandemic. 23 Additionally, we identified the vast majority of SARS-CoV-2 cases in pregnancy because testing was widespread in Denmark during the inclusion period, and the DCOD data were validated against registry data. The study also has limitations. First, the register data set was pseudoanonymized, making individual-level linkage to DCOD impossible. Additionally, the data sources of the DCOD and the national registers are different, and the data might not be directly comparable. Nevertheless, the number of SARS-CoV-19 cases was similar in the two cohorts, and data did not differ significantly between the cohorts, indicating agreement between cases and data sources. Some descriptive variables, including BMI and smoking status, are not reported to the registers before delivery and are not reported for early pregnancy losses, causing higher rates of missing data in the registers. Nevertheless, the rates of missing data were similar in the infected and non-infected groups, reducing the risk of bias caused by the missing numbers. Additionally, complete data were available in the DCOD, which also allowed for national surveillance of the infection to support national guidelines until register data were available. [24] [25] [26] Second, the lack of association in some outcomes for severe cases might be a result of low numbers. Additionally, the threshold of admitting pregnant women to hospital due to COVID-19 symptoms might be lower than for non-pregnant women, thus diluting the risk estimates of severe disease. Third, universal testing of pregnant women was not implemented in Denmark before May 2020, and we might therefore have missed SARS-CoV-2positive cases early in the inclusion period. Furthermore, MiBa only included information on PCR tests, so we might have missed pregnant women diagnosed through antigen or antibody tests, which were possibly milder cases. Inclusion of these plausibly positive but non-identified cases in the comparison population of pregnancies might have affected our estimates. In this prospective population-based cohort study with universal SARS-CoV-2 testing, we found no difference in outcomes related to delivery or the neonate among infected women compared with noninfected women. Nor did severity of infection statistically affect the results, but these results have to be interpreted with caution because of low numbers. The results indicate that the outcomes of SARS-CoV-2 infection in pregnancy might not be as severe as proposed by previous studies. The testing strategy and how cases are included naturally influences the results and should be considered. We found that the incidence of termination of pregnancy among SARS-CoV-2-infected women was increased compared with that in non-infected pregnant women, which might be related to universal screening of women admitted to hospital. Further studies are needed to explore a possible relation between late termination of pregnancy and SARS-CoV-2 infection. Lone K. 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Data quality report 2019 Strengthening the reporting of observational studies in epidemiology (STROBE): explanation and elaboration Birth and infant outcomes following laboratory-confirmed SARS-CoV-2 infection in pregnancy -SET-NET, 16 jurisdictions Maternal and neonatal morbidity and mortality among pregnant women with and without COVID-19 infection: the INTERCOVID Multinational Cohort Study COVID-19 in pregnancycharacteristics and outcomes of pregnant women admitted to hospital because of SARS-CoV-2 infection in the Nordic countries Effects of the COVID-19 pandemic on maternal and perinatal outcomes: a systematic review and meta-analysis Rapport for Perioden 1. Marts -30 Rapport for Perioden 1. Marts -31 Available online at: https://stati c1.squar espace.com/stati c/5467a bcce4 b056d 72594 db79/t/5ecfe 76495 02534 3e22c cb07/15906 83493 294/Bilag +F+-+COVID -19+i+gravi ditet +-+Rappo rt+for+marts -april +2020_ final The authors would like to thank EasyTrial, who provided their clinical trial management software, used for data management in the DCOD study, free of charge for this study because the company offered free access to the software to COVID-19 research projects.The authors also wish to thank Professor Marian Knight, DPhil, National Perinatal Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, UK, for her initiation of the International Network of Obstetric Survey Systems study, in which the DCOD participates, and her contribution to the international case report form, on which the DCOD is based. All authors declare no conflict of interest. Additional Supporting Information may be found online in the Supporting Information section.