key: cord-0988003-roft0kgf authors: Vergara‐Merino, Laura; Meza, Nicolás; Couve‐Pérez, Constanza; Carrasco, Cynthia; Ortiz‐Muñoz, Luis; Madrid, Eva; Bohorquez‐Blanco, Sandra; Pérez‐Bracchiglione, Javier title: Maternal and perinatal outcomes related to COVID‐19 and pregnancy: overview of systematic reviews date: 2021-02-09 journal: Acta Obstet Gynecol Scand DOI: 10.1111/aogs.14118 sha: 38396651c8c7038c5a86f82f03218bd7b43ce33d doc_id: 988003 cord_uid: roft0kgf INTRODUCTION: Evidence about COVID‐19 and pregnancy has rapidly increased since December 2019, making it difficult to make rigorous evidence‐based decisions. The objective of this overview of systematic reviews is to conduct a comprehensive analysis of the current evidence on prognosis of COVID‐19 in pregnant women. MATERIAL AND METHODS: We used Living OVerview of Evidence (L·OVE) platform for COVID‐19, which continually retrieves studies from 46 data sources (including Pubmed/MEDLINE, Embase, other electronic databases, clinical trials registries, preprint repositories, among other sources relevant to COVID‐19), mapping them into PICO questions. The search covered the period from the inception date of each database to September 13, 2020. We included systematic reviews assessing outcomes of pregnant women with COVID‐19 and/or their newborns. Two authors independently screened the titles and abstracts, assessed full‐texts to select the studies that met the inclusion criteria, extracted data, and appraised the risk of bias of each included systematic review. We measured the overlap of primary studies included among the selected systematic reviews by building a matrix of evidence, calculating the corrected covered area, and assessing the level of overlapping for every pair of systematic reviews. RESULTS: Our search yielded 1132 references. 52 systematic reviews met inclusion criteria and were included in this overview. Only one review had a low risk of bias, three had an unclear risk of bias, and 48 had a high risk of bias. Most of the included reviews were highly overlapped among each other. In the included reviews, rates of maternal death varied from 0% to 11.1%, admission to intensive care from 2.1% to 28.5%, preterm deliveries before 37 weeks from 14.3% to 61.2%, and cesarean delivery from 48.3% to 100%. Regarding neonatal outcomes, neonatal death varied from 0% to 11.7% while the estimated infection status of the newborn varied between 0% and 11.5%. CONCLUSIONS: Only one of 52 systematic reviews had a low risk of bias. Results were heterogenous and the overlap of primary studies was frequently very high between pairs of systematic reviews. High quality evidence syntheses of comparative studies are needed to guide future clinical decisions. assessment of evidence quality of the included studies, and the elements of the systematic review question (patients, exposure definition, and assessed outcomes). We also extracted synthesized results from SRs, both narrative and quantitative. The collected data for maternal outcomes were: 1) maternal mortality 2) admission to intensive care units, 3) mechanical ventilation support, 4) preterm delivery <37 weeks, 5) preterm delivery <34 weeks, 6) premature rupture of membranes, and 7) cesarean delivery. While the collected data for neonatal outcomes were: 1) stillbirth, 2) neonatal mortality 3) neonatal admission to special care and/or intensive care unit, 4) mechanical ventilation support, 5) APGAR score below 7, and 6) infection status of the newborn (or products of conception) as defined by the authors of the included SRs. We built a matrix of evidence to visually examine the overlap among the primary studies included in the different SRs. Primary studies are presented in the rows of the matrix and the systematic reviews in the columns. We calculated the corrected covered area (CCA), which is a quantitative measure of overlap of primary studies among systematic reviews 18 . We considered overlap as low if CCA was below 5%, moderate if CCA was between 5% and 10%, high if CCA was between 10% and 15%, and very high if CCA was above 15%. In order to identify which specific pairs of reviews were highly overlapped, we followed the previously described methods 19 to assess the overlap degree of every pair of SRs: we calculated the CCA for each possible pair of SRs included in our matrix of evidence. Two authors independently assessed the risk of bias of each included SR using the tool Risk of Bias in Systematic Review (ROBIS) 20 . We did not assess the quality of the included primary studies in the SRs nor the quality of reporting of each SR. We expressed the results of the included SRs by using the range of the effect measure reported by the different SRs. We did not calculate any pooled estimates. We presented the characteristics of each included SR in a table and we summarized their results by maternal and perinatal outcomes, This article is protected by copyright. All rights reserved as defined above. We graphically presented the overlap of primary studies, and the risk of bias assessment. Our initial search yielded 1132 references. After the initial screening we assessed the eligibility of 77 full-text articles; we excluded 25 of them (see Supporting Information Table S1 ), which led to 52 included SRs 7 9 11 21-69 . Figure 1 provides the PRISMA flow diagram. The 52 included SRs referenced a total of 205 primary studies, 142 of which were included in two or more SRs. Most of the SRs were published as journal articles 7 March 17, 2020 7 and September 4, 2020 33 . The median number of relevant primary studies included in the SRs was 16 (IQR: 21) . The median number of included pregnant women with COVID-19 was 145.5 (IQR: 296.5). 51 SRs assessed maternal and neonatal outcomes, one SR assessed only maternal outcomes 42 , and none of the included SRs assessed only perinatal outcomes. The most common reported maternal outcomes were cesarean delivery, preterm delivery before 37 weeks, and maternal death; and the most common mentioned perinatal outcomes were neonatal death, infection status of the newborn, and stillbirth. Table 1 provides the main characteristics of the included studies. Overall, 48 SRs had a high risk of bias 7 11 21 22 24-52 54-65 67-69 . One SR had a low risk of bias 23 and three SRs had an unclear risk of bias 9 53 66 . Figure 2 provides the overall assessment, and Table 2 provides the detailed assessments with the ROBIS tool. Regarding the overlap assessment, the overall CCA was 9.93%, with 64.7% of all possible pairs of SRs showing a very high overlap. Table S2 provides a matrix of evidence with the included SRs in the columns and their respective primary studies in the rows. This article is protected by copyright. All rights reserved Maternal death was reported in 32 SRs 7 11 22 23 25-28 33 35 37 40-45 47 48 50 51 53-55 57-60 62 64 67 68 , and varied from 0% to 11.1% among the included reviews. 33 SRs 11 22 23 25-27 30 31 33 35-37 40-44 47 48 50-53 55 58-62 64 66-68 assessed the requirement of admission to intensive care or mechanical ventilation support, with overall rates varying from 2.1% to 28.5% and from 1.6% to 11%, respectively. 42 SRs estimated preterm deliveries for <37 weeks of gestation 7 This overview of SRs summarizes and critically appraises findings regarding the prognosis of pregnant women with COVID-19 and their newborns. We retrieved a total of 52 SRs assessing This article is protected by copyright. All rights reserved maternal and perinatal outcomes in COVID-19. However, only 2% (n=1) of them is at low risk of bias; this SR 23 was qualified at low risk of bias by satisfactorily fulfilling all steps of the ROBIS. There was a moderate overall overlap of primary studies (CCA=9.93%), with 858 pairs of SRs presenting a very high overlap, which elucidates the presence of redundant efforts. Despite this overlap, the included SRs reported very heterogenous results for maternal and perinatal outcomes related to COVID-19 in pregnancy, and considering the confidence intervals reported by the reviews, the heterogeneity among the results is even higher. During this pandemic, health decision-makers urgently required information to produce evidencebased guidelines: this requirement probably explains the high number of retrieved SRs. However, and probably in response to the rush when elaborating the SRs, more than 95% of the SRs included in this overview are at high risk of bias, resulting in useless information for the above- study includes all pregnant women tested positive for SARS-CoV-2 regardless of their severity, it would surely report better outcomes than series of independent cases. Because of this variability in the reported results and the high risk of bias of more than 95% of the reviews, we cannot safely conclude about maternal and perinatal outcomes. Despite the above, Allotey et al's SR 23 is at low risk of bias, so some of its results must be highlighted. The authors report a 17% (95%CI: 13-21%) rate of preterm births among live births, which is slightly higher than the global report of 11% in non-COVID-19 pregnancies 70 . Interestingly, when they analyzed the preterm births in pregnant women with COVID-19, the rate of premature rupture of membranes and spontaneous labor among those women reached only 5% This article is protected by copyright. All rights reserved and 6% respectively 23 , allowing us to hypothesize that the preterm deliveries reported in the other included SRs were mostly iatrogenic. On the other hand, the rate of cesarean section reported by Allotey et al. seems alarming: 65% (95%CI: 57%-73%). This is higher than the global report published in The Lancet, showing cesarean sections rates of 28.8% in East Asia and Pacific, 32% in North America and 26.9% in Western Europe 71 , and surely discordant than WHO's statement which declares that cesarean section frequencies higher than 15% are not associated with reductions in maternal and newborn mortality rates 72 Besides, the presence of SARS-CoV-2 has been described in such different tissues as placenta, umbilical cord, amniotic fluid, and neonatal swabs, such as rectal and nasopharyngeal 46 . If we consider that transplacental passage of pathogens increases with the advance of gestational age and that positive viremia occurs only in 1% of adult patients with COVID-19, the transplacental passage of SARS-CoV-2 seems to be unlikely 74 . Regarding intra partum vertical transmission, it is important to notice that the available literature has shown no cases of vaginal samples testing positive for SARS-CoV-2 75 76 . Finally, the clinical implementation of a correct classification system and a case definition of SARS-CoV-2 in pregnant women, fetuses and neonates is required to guide good clinical practice and future investigations 77 . Our overview has some limitations. We did not undertake a pooled analysis of the results for each This article is protected by copyright. All rights reserved outcome due to the expected variability of methods and study designs among the primary and secondary studies retrieved. Also, we did not assess the risk of bias of the primary studies included in each SR, which makes it impossible for us to prudently conclude about clinical outcomes reported in the reviews. Our overview has several strengths. We comprehensively appraised the risk of bias of the included SRs and the overlap of the primary studies among SRs. We performed an exhaustive search and selection of studies, we considered all clinically relevant maternal and perinatal outcomes, and we comprehensively described the characteristics and the results of each included SR. The available information regarding COVID-19 has grown vertiginously since the WHO declared the outbreak a pandemic 12 . In the case of maternal and perinatal outcomes related to the SARS-CoV-2 infection, the 52 included SRs already mine the research field. And yet, the primary data summarized by these SRs derives mainly from case reports and case series; whereas these are the first studies which are available to researchers aiming to provide information on an emerging clinical phenomenon, though. More recent SRs have included more representative observational studies 23 , but they are still insufficient to guide clinical recommendations with the required certainty of the evidence. In addition to the lack of major observational studies, most SRs at high risk of bias did not report any concern about the risk of duplicating patients included among the primary studies they summarized, Allotey et al 23 each SR includes primary studies. It is expected that some primary studies are included in two or more SRs, which is known as 'overlap of primary studies'. To assess this overlap, there is a formula known as 'corrected covered area' (CCA) 18 , where values below 5% are considered low overlap; between 5% and 10% are considered moderate; between 10% and 15% are considered high; and above 15% is considered very high. Usually overlap is presented as an overall assessment for the whole body of evidence, but this approach sometimes fails to identify which specific SRs are contributing to double-counting of the same primary studies. In this figure, we present not an overall CCA, but a CCA for each pair of SRs. White boxes represent low overlap (CCA <5%), green boxes represent moderate overlap (CCA >5% and <10%), yellow boxes represent high overlap (CCA >10% and <15%), and red boxes represent very high overlap (CCA >15%). The interpretation of each one of these boxes or 'nodes' involves two SRs: A white node means that there are none or a minimum proportion of primary studies shared by the two SRs assessed, whereas a red node means that there is a considerable amount of primary studies shared by the pair of SRs assessed. Appendix S1: Epistemonikos database search strategy. This number may be different from the number of included studies in the review for several reasons: the review may have a broader scope, a primary study did not assess any of our outcomes of interest, or primary studies were not well referenced in the review and the authors did not answer our emails. † Pregnant women infected with SARS-CoV-2. ‡ This systematic review also included pregnant women infected with SARS-CoV or MERS-CoV. § This systematic review also included non-pregnant adults and children but described separately outcomes in pregnant women. || For outcomes "preterm delivery" and "birth weight" it included case-control or cohort study with pregnant women without COVID-19 as a control group. For outcome "vertical transmission" it included cross-sectional studies, casecontrol, cohort, case report, or case series. This article is protected by copyright. All rights reserved This article is protected by copyright. All rights reserved This article is protected by copyright. All rights reserved Eurosurveillance editorial t. Note from the editors: World Health Organization declares novel coronavirus (2019-nCoV) sixth public health emergency of international concern The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health -The latest 2019 novel coronavirus outbreak in Wuhan, China An interactive web-based dashboard to track COVID-19 in real time Emerging infections and pregnancy Acute respiratory failure in pregnancy An Analysis of 38 Pregnant Women with COVID-19, Their Newborn Infants, and Maternal-Fetal Transmission of SARS-CoV-2: Maternal Coronavirus Infections and Pregnancy Outcomes Epub ahead of print Coronavirus in pregnancy and delivery: rapid review Coronavirus disease 2019 (COVID-19) and pregnancy: a systematic review Potential Maternal and Infant Outcomes from Coronavirus 2019-nCoV (SARS-CoV-2) Infecting Pregnant Women: Lessons from SARS, MERS, and Other Human Coronavirus Infections Outcome of Coronavirus spectrum infections (SARS, MERS, COVID 1 -19) during pregnancy: a systematic review and meta-analysis Speed Science: The risks of swiftly spreading coronavirus research Waste in covid-19 research Preferred Reporting Items for Overviews of Reviews (PRIOR): a protocol for development of a reporting guideline for overviews of reviews of healthcare interventions Cochrane Handbook for Systematic Reviews of Interventions Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement Evidence synthesis relevant to COVID-19: a protocol for multiple systematic reviews and overviews of systematic reviews Systematic review finds overlapping reviews were not mentioned in every other overview Graphical representation of overlap degree of primary studies in systematic reviews included in overviews ROBIS: A new tool to assess risk of bias in systematic reviews was developed COVID-19 during pregnancy should we really worry from vertical transmission or rather from fetal hypoxia and placental insufficiency? A systematic review and meta -analysis. Resarch Square COVID-19 (SARS-CoV-2) Infection in Pregnancy: A Systematic Review Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and metaanalysis Clinical characteristics of COVID-19 infection in pregnant women: a systematic review and meta-analysis COVID-19): A Systematic Review of Pregnancy and the Possibility of Vertical Transmission Obstetrics and Neonatal Outcomes in Pregnant Women with COVID-19: A Systematic Review COVID-19 in pregnant women: A systematic review and meta-analysis Pregnancy and Neonatal Outcomes in SARS-CoV-2 Infection: A Systematic Review Clinical characteristics and diagnostic challenges of pediatric COVID-19: A systematic review and meta-analysis Clinical features of neonates born to mothers with coronavirus disease-2019: A systematic review of 105 neonates Epub ahead of print Coronavirus disease 2019 during pregnancy: a systematic review of reported cases Clinical Features and Outcome of SARS-CoV-2 Infection in Neonates: A Systematic Review The effect of coronavirus infection (SARS-CoV-2, MERS-CoV, and SARS-CoV) during pregnancy and the possibility of vertical maternal-fetal transmission: a systematic review and meta-analysis Accepted Article systematic review and meta-analysis. Authorea Clinical manifestations and perinatal outcomes of pregnant women with COVID-19: a systematic review and meta-analysis National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications Global epidemiology of use of and disparities in caesarean sections World Health Organization Human Reproduction Programme Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Antibodies at Delivery in Women, Partners, and Newborns Evidence for and against vertical transmission for severe acute respiratory syndrome coronavirus 2 Coronavirus disease 2019 among pregnant Chinese women: case series data on the safety of vaginal birth and breastfeeding SARS-CoV-2 Is Not Detectable in the Vaginal Fluid of Women With Severe COVID-19 Infection Classification system and case definition for SARS-CoV-2 infection in pregnant women, fetuses, and neonates Chang 2020 3.5% 9 1% 28.6% 26.3% 12.8% 31.6% 9.6% 25.0% 33 The members of the COVID-19 L·OVE Working Group and Epistemonikos Foundation have made it possible to build the systems and compile the information needed by this project. Franco Pesce and Gabriel Rada helped revise the final draft of the manuscript.