key: cord-0728527-31mjbk4d authors: Matar, Reem; Alrahmani, Layan; Monzer, Nasser; Debiane, Labib G; Berbari, Elie; Fares, Jawad; Fitzpatrick, Fidelma; Murad, Mohammad H title: Clinical Presentation and Outcomes of Pregnant Women with COVID-19: A Systematic Review and Meta-Analysis date: 2020-06-23 journal: Clin Infect Dis DOI: 10.1093/cid/ciaa828 sha: 06efb89b9ef0d29fd2a4b8cb0cc0dd8c3a332501 doc_id: 728527 cord_uid: 31mjbk4d INTRODUCTION: Descriptions of coronavirus disease-2019 (COVID-19) have focused on the non-pregnant adult population. This study aims to describe the clinical characteristics and perinatal outcomes of COVID-19 in pregnancy. METHODS: We searched databases from December 2019 to April 30(th), 2020. Eligible studies reported clinical characteristics, radiological findings and/or laboratory testing of pregnant women during infection. Data were pooled across studies using random-effects model. RESULTS: Twenty-four studies (136 women) were included. Most common symptoms were fever (62.9%) and cough (36.8%). Laboratory findings included elevated C-Reactive Protein (57%) and lymphocytopenia (50%). Ground-glass opacity was the most common radiological finding (81.7%). Preterm birth rate was 37.7% and cesarean delivery rate was 76%. There was one maternal death. There were two fetal COVID-19 cases. CONCLUSION: The clinical picture in pregnant women with COVID-19 did not differ from the non-pregnant population, however, the rate of preterm birth and cesarean delivery are considerably higher than international averages. A c c e p t e d M a n u s c r i p t Table 4 describes the laboratory and radiologic findings on admission. The mean lymphocytes count was 1.233*10 9 /L (95% CI: 0.991, 1.475, I 2 =76.09%). The pooled mean leukocyte count was 10.438*10 9 Of 136 chest CT scans performed at the time of admission, 98% revealed abnormal results. The most common pattern seen on chest CT scan was ground-glass opacity (GGO) and was present in 81.7% of patients (95% CI: 0.701, 0.895, I 2 =0%). Of the 82 patients who presented with GGO, 52 patients presented with bilateral GGO and 10 patients presented with unilateral GGO. There was no specific data regarding the classification of the location of the GGO in the 20 remaining patients. The second most common pattern on chest CT was infiltrated shadows seen in 42.5% (95% CI: 0.126, 0.791, I 2 =29.55%) (Figure 3 ). Most patients were delivered via a cesarean delivery with a rate of 76.3% (95% CI: 0.658, 0.842, I 2 =10.24%). Fifty-nine patients received antibiotic therapy (87.7%; 95% CI: 0.755, 0.943, I 2 =0%) and 45 patients received antiviral therapy (67.5%; 95% CI: 0.484, 0.821, I 2 =33.44%). Details of antiviral therapy are provided in Table 5 . Oxygen therapy, either through nasal cannula or face mask, was administered in 36 patients (73.1%; 95% CI: 0.391, 0.920, I 2 =57.64%) ( Table 5) . Fifteen patients received corticosteroids (50.5%; 95% CI: 0.285, 0.723, I 2 =30.81%). Of which, five patients received betamethasone. Specific indication for use of corticosteroid administration included: fetal lung maturation, acute flare of autoimmune disease, prophylaxis for pneumonia, A c c e p t e d M a n u s c r i p t pneumonia, and to relieve inflammation. Two patients required intubation and mechanical ventilation due to multiorgan failure. One woman died due to multi-organ failure and acute respiratory distress syndrome (ARDS) (mortality 11.1%; 95% CI: 0.063, 0.187, I 2 =0%). As shown in Table 5 , premature rupture of membrane, fetal distress, and stillbirth were the most common complications during pregnancy. All neonates were all delivered in a negative pressure isolation room, and all studies reported separation and lack of contact between the mothers and the neonates. (Figure 4) . Two newborns tested positive for COVID-19 (11.5% [95% CI: 0.067, 0.192, I 2 =0]). Both neonates were delivered via cesarean delivery. The amniotic fluid, placenta fluid, umbilical cord, and gastric juice were all tested for COVID-19 and tested negative in all the studies. The Apgar score at 1 min was 8.811 (95% CI: 8.382, 9.240; I 2 =88.87%) and at 5 min was 9.516 (95% CI: 9.136, 9.895; I 2 =82.91%). In addition, no severe neonatal asphyxia occurred in any of the neonates across the studies. Three fetal deaths were reported; their respective gestational ages were 34 weeks, 31 weeks, and 30 weeks. Neonatal intensive care unit (NICU) admission occurred in 63.7% (95% CI: 0.378, 0.835, I 2 =29.38%) of patients. The fetal death rate was 11.7% (95% CI: 0.068, 0.192; I 2 = 0%) ( Figure 5) . Two neonatal deaths were due to multiple organ failure and disseminated intravascular coagulation (DIC). The third neonatal death was occurred immediately after delivery. The neonate was cyanotic and had an Apgar score of 0 at 1 and 5 minutes, respectively. A c c e p t e d M a n u s c r i p t SARS-CoV-2 virus is a highly infective virus causing the greatest pandemic of the century. As we are now in the midst of it hoping to figure out treatments and novel ways to manage the deadly disease. In this contemporary meta-analysis, we have concluded the following: (1) pregnant patients with COVID-19 most commonly present with fever, dry cough, and sore throat; (2) the most common radiological finding in this group of patients was the presence of ground-glass opacities on CT; and (3) the perinatal risk is great, as the risk of prematurity and cesarean delivery are high. To our knowledge, this is the largest meta-analysis of its kind to describe the effects of COVID-19 on pregnancy. We believe that this study provides insight for developing the backbone for counseling and management of pregnant patients at risk for acquiring the disease. The immune suppressed state of pregnancy confers high risk for the development of severe complications of infectious diseases, such as influenza and severe respiratory syndrome (SARS) [37] . During the SARS pandemic of 2003, 40% of affected pregnant women required mechanical ventilation and case-fatality rate of 30%, compared to 13% and 11%, respectively, of non-pregnant cohort [38] . Interestingly, our study did not demonstrate significantly worsened outcomes in COVID-19 affected pregnant patients when compared to non-pregnant patients reported in the literature. Our population has similar clinical presentations, laboratory abnormalities and radiological findings when compared to infected non-pregnant cohorts in the current literature [39] . Additionally, the maternal complication rate seems to be comparable to non-pregnant adults [39] . One theory is that the immunologic adaptations of pregnancy that help mothers from rejecting the fetus, a foreign entity containing paternal antigens, may also aid in mounting a less robust immune response to the virus, consequently leading to less destructive effects on the body [40] . Another is that pregnancy-related organ adaptive changes may result in protection against the virus and its effects [40] . Within our subset of 136 SARS-CoV-2 infected pregnant women, a single case of maternal death secondary to ARDS and multi-organ failure was reported, resulting in a considerably lower mortality rate in comparison to previous pandemics. Moreover, with two patients requiring intubation and mechanical ventilation, morbidity appeared to be lower than anticipated. Although a proportion of women had co-morbidities present, some of which were obstetrical in etiology, they still did not experience life-threatening manifestations of COVID-19. A recently published case series described two cases of COVID-19-related cardiomyopathy in pregnant women [41] . However, both of these patients possessed multiple risk factors for cardiac disease, and it remained unclear as to A c c e p t e d M a n u s c r i p t whether cardiomyopathy occurred as a direct complication of COVID-19, or secondary to multi-organ dysfunction. Another interesting observation was the high rate of preterm birth in this group of patients, much higher than the general pregnant population (12% in the United States and lower in other developed countries). A direct causal link between infection and premature labor has been well established in the literature [42] , and it is estimated that at least 40% of premature births are associated with intrauterine infection or inflammation [43] . Additionally, the high rate of cesarean delivery should not go unnoticed either. Three-quarters of infected patients underwent a cesarean delivery, over double that of the general pregnant population. Cesarean delivery, while a commonly procedure worldwide, is still a major surgery with significantly higher morbidity than a vaginal delivery, both in short-term, such as infections and bleeding, and in long-term, such as the risk of development of placenta accrete spectrum disorder in future pregnancy. It is difficult to make conclusions on the risk of having a pregnancy affected by COVID-19 and pregnancy that is not, namely due to the heterogeneity of the studies included in this meta-analysis. Although in the reported cases, most neonates fared well with the exception of 3, the most worrying aspect of our finding is the high rate of preterm birth. Prematurity in and of itself is the most common cause of morbidity and mortality in neonates worldwide, both short-term and long-term. Since the immunological immaturity of neonates renders them susceptible to infections, vertical transmission is a particularly concerning complication of viral infections that occur during pregnancy [44] . In all cases, the amniotic fluid, placenta and umbilical cord samples all tested negative for SARS-CoV-2, while 2 neonates had RT-PCR-confirmed SARS-CoV-2 infection. Based on these findings, it is impossible to conclude that these neonates acquired the infection during fetal life. Three neonatal deaths with gestational ages of 34 weeks, 31 weeks, and 30 weeks were reported in our analysis. Two fetal deaths occurred due to multiple organ failure and DIC, and the third was a perinatal death occurring within 24 hours of birth. This is an alarming finding as neonates born at this gestational age typically have low death rates; however, due to insufficient information in the respective reports, we could not conclusively contribute these deaths to COVID-19-related . In our study, both fetal COVID-19 confirmed cases were delivered via cesarean delivery. However, due to the small sample size for patients who delivery vaginally (n=18), it is difficult to make any conclusions in that regard. Further studies should attempt to delineate these two groups for clarification. This is an important issue that obstetricians should take into account when considering course of treatment for any patient with a confirmed viral infection. Recently published reviews on this topic have reported similar findings [48,49,50]. However, unlike our paper, no categorization was made regarding the specific CT findings. The strengths of our study are, firstly, this is the largest of its kind to date to explore pregnancy and perinatal outcomes of SARS-CoV-2 infections; secondly, patients and their neonates were included had confirmed positive or negative RT-PCR SARS-CoV-2, preventing any uncertainty regarding the group of patients who had a clinical presentation but were not representative of the entire cohort; thirdly, to our knowledge, this is the first meta-analysis to look at the pooled effect of COVID-19 across all eligible studies; and lastly, our study reports medication use for treatment of COVID-19 which includes antiviral therapy and corticosteroid use in more depth than existing studies. Our systematic review and meta-analysis have some limitations. The main limitation is primarily the lack of high-quality data in the included studies. Due to the urgent timeline for data extraction and the complications requiring preterm labor, some cases had incomplete documentation of the epidemiological history, laboratory testing, and outcomes. In addition, our meta-analysis had a limited number of studies, most of which were either case series or case reports. This makes it difficult to draw any conclusions regarding clinical presentation and outcomes of patients. Additionally, patients who were asymptomatic or had mild cases and who did not require hospitalization were not accounted for due to publication bias. Lastly, due to the nature of the virus and the urgent need for more studies our meta-analysis might have missed studies that were recently published in the literature, particularly in languages other than English. As this global pandemic continues to spread, there will be a need for additional information on the effects In summary, our meta-analysis demonstrates that pregnant women with COVID-19 have similar clinical characteristics and outcomes as the non-pregnant population and there appears to be little evidence of vertical transmission. However, when compared to the general pregnant population, infected women are at significantly higher risk for cesarean delivery and preterm birth. We urge obstetricians to continue reporting their data, especially that of asymptomatic patients or those with mild disease, so are better able to understand this novel virus and hopefully improve outcomes. https://www.acog.org/-/media/project/acog/acogorg/files/pdfs/clinical-guidance/practice-advisory/covid-19-algorithm.pdf?la=en&hash=2D9E7F62C97F8231561616FFDCA3B1A6. Accessed 24 April 2020. 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