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Maternal and perinatal outcomes related to COVID‐19 and pregnancy: An overview of systematic reviews

Abstract Introduction Evidence about coronavirus disease 2019 (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 the 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, and preprint repositories, among other sources relevant to COVID‐19), mapping them into PICO (population, intervention, control, and outcomes) questions. The search covered the period from the inception date of each database to 13 September 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 overlap 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% and 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 heterogeneous 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.

Preprints, Research Square, and 22 clinical trial registries-not as critical for this overview as the aforementioned sources.
The searches covered from the inception date of each database until 13 September 2020. No study design, publication status or language restriction was applied to the searches.
The strategy used in the electronic searches and its terms are shown in the Supplementary material (Appendix S1).

| Eligibility criteria
We included all SRs (defined operationally as any secondary research that included only clinical primary studies, reporting an explicit search strategy in at least two databases) assessing maternal and perinatal outcomes related to COVID-19 and pregnancy. We included those SRs that were broader in scope but presenting separate and distinguishable data for our population of interest.
We excluded primary studies, clinical practice guidelines, overviews, and other types of study design aimed at synthesizing evidence.
We included studies assessing both maternal and neonatal outcomes, only maternal outcomes, or only neonatal outcomes regarding COVID-19 and pregnancy. We did not include information about other coronavirus infections.

| Study selection
The results of the electronic searches were automatically incorporated into the L·OVE platform, where they were de-duplicated by an algorithm that compared unique identifiers (database ID, DOI, trial registry ID), and citation details (ie, author names, journal, year of publication, volume number, pages, article title, and article abstract).
Using the L·OVE platform, two researchers (LVM and SBB) independently screened the titles and abstracts yielded by the searches, against the inclusion criteria. We obtained the full reports of all the titles that appeared to meet the inclusion criteria or required further analysis to decide about their inclusion.
In each search stage, we recorded the reasons for excluding reviews and outlined the study selection process in a PRISMA flow diagram adapted for the purpose of this project.

| Extraction and management of data
Using standardized forms, two independent reviewers extracted data from each included SR in duplicate (LVM, CCP, CC, NM, LO, and SBB). We did not extract data from primary studies.
We recorded the following characteristics of included SRs: publication date, search sources and strategies, number of included studies, number of included studies relevant to our overview, 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 at <37 weeks of gestation, (5) preterm delivery at <34 weeks of gestation, (6) premature rupture of membranes, and (7) cesarean delivery. 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 at 5 min, and (6) infection status of the newborn (or products of conception) as defined by the authors of the included SRs.  All the primary studies providing information about any of the outcomes of interest were considered as relevant. 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. This systematic review also included non-pregnant adults and children but described separately outcomes in pregnant women.
e For outcomes "preterm delivery" and "birthweight£ 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, case-control, cohort, case report, or case series.

| Overlap assessment
We built a matrix of evidence to visually examine the overlap among the primary studies included in the different SRs. Primary studies were presented in the rows of the matrix and the systematic reviews were given 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.

| Risk of bias assessment
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 primary studies included in the SRs or the quality of reporting of each SR.

| Data synthesis
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 tabulated the characteristics of each included SR and summarized their results by maternal and perinatal outcomes, as defined above. We graphically presented the overlap of primary studies, and the risk of bias assessment.

| RE SULTS
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 Supplementary material, Table S1), which led to the inclusion of 52 SRs. 7,9,11,21-69 Figure 1 provides the PRISMA flow diagram. 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. Figure 3 provides a detailed assessment of the CCA and the Table S2 provides a matrix of evidence with the included SRs in the columns and their respective primary studies in the rows.

| Neonatal outcomes
Stillbirth and neonatal death were assessed in 35

Risk of bias in the review
Teles Abrao (2020) 61 ?
Abbreviations: , high risk; , low risk; , unclear risk. F I G U R E 3 Detailed assessment of corrected covered area. Our overview includes several systematic reviews (SRs), and 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% are 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 between >5% and <10%), yellow boxes represent high overlap (CCA between >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       b n, n/N (%) or (%; 95% CI) from meta-analyses (fixed or random effect), according to the availability of data in the included systematic reviews.
c Some outcomes were estimated from meta-analyses using fixed or random effects.
d Data from consecutive case series are presented, as the author of the review used these data to combine results from primary studies.
e Data from case reports are presented separately for this outcome.
f Inconsistency between tables and text, or within the manuscript for this outcome.
g Weeks were not specified.
h Nineteen women delivered between 32 and 36 weeks, and one before 32 weeks.       is slightly higher than the global report of 11% in non-COVID-19

| DISCUSS ION
pregnancies. 70   Besides, the presence of SARS-CoV-2 has been described in such different tissues as placenta, umbilical cord, and amniotic fluid, and in neonatal swabs, such as rectal and nasopharyngeal. 46  Our overview has some limitations. We did not undertake a pooled analysis of the results for each outcome because of 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 rapidly since WHO declared the outbreak a pandemic. 12 In the case of maternal and perinatal outcomes related to SARS-CoV-2 infection, the 52 included SRs have already searched the research field. The primary data summarized by these SRs derive mainly from case reports and case series, which are the first studies to become available to researchers aiming to provide information on an emerging clinical phenomenon. 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 summa-

CO N FLI C T O F I NTE R E S T
The authors have stated explicitly that there is no conflict of interest in connection with this article.