Investigating placental pathologies in pregnant women with SARS-CoV-2: Systematic Review and Meta-analysis Protocol
Authors: Oltean Irina , Demellawy Dina El , Sampson Margaret 
Published: November 2020

An investigation into placental pathology in pregnant women with SARS-CoV-2 has not yet been examined extensively; however, this knowledge would be beneficial in understanding the potential for vertical transmission of SARS-CoV-2 during pregnancy, via the placenta. Currently, results are conflicting, with some evidence suggesting rare placental infection. Conversely, compared to controls, one study determined that third trimester placentas were significantly more likely to show one feature of maternal vascular malperfusion (MVM), and intervillous thrombi, fetal vascular malperfusion or fetal vascular thrombosis, and increased perivillous fibrin deposition and intervillositis. In contrast, another study reported no significant differences in individual or group gross or microscopic pathological features. As well, no ACE2 expression has yet been detected in villous stroma, Hofbauer cells, or endothelial cells, and TMPRSS2 expression is only weakly present in villous endothelium. In light of the inconclusive evidence, the burden of placental pathologies potentially related to SARS-CoV-2 in pregnant women and their neonates or infants, remains at the forefront of medical attention, particularly among pathologists, and obstetricians worldwide. This protocol describes the steps of our systematic review, which aims to investigate differences in placental pathologies in pregnant women with SARS-CoV-2 versus pregnant women without the virus. Our study will identify case series, case-control and cohort studies of asymptomatic and symptomatic pregnant women, who test positive for SARS-CoV-2 during any stage of their pregnancy, as validated by laboratory confirmed positive antibody testing or using real-time reverse-transcriptase-polymerase chain reaction (rRT-PCR). Studies examining pregnant women who test positive during the first, second or third trimester, are eligible. Only articles written in English or French will be included. Literature reviews, systematic reviews, editorials, letters to the editor, conference abstracts, and commentaries will be excluded. The following databases will be searched: MEDLINE including Epub Ahead of Print, In-Process &amp; Other Non-Indexed Citations (1946- November 17, 2020) and Embase (1980- November 17, 2020). Two specialized COVID-19 resources will also be searched November 18, 2020; Cochrane Covid-19 study register which indexes according to study design, and the WHO Covid-19 Collection which includes material from numerous sources including preprint servers. Primary outcomes of interest are: retroplacental hematoma, diffuse parenchymal consolidation, maternal vascular malperfusion, fetal vascular malperfusion, and other diseases of the placenta as detailed in this protocol. Observational studies will be assessed using the Ottawa-Newcastle scale. Data will be aggregated or synthesized at the level of individual participants. Tables will be used to summarize the general characteristics of the studies included. Depending on the data and the level of variation between studies, a meta-analysis will be used to synthesize data. Count and dichotomous data will be expressed as odds ratios with 95% confidence intervals, while continuous data will be expressed as a mean or standardized mean difference with 95% confidence intervals. Statistical heterogeneity of the included studies will be assessed using the I-squared test with 95% confidence intervals, and publication bias will be determined using a funnel plot and Egger’s test when possible (&gt;10 included studies). This review will ultimately aid in informing pathologists, obstetricians, and gynecologists when managing and treating pregnant women with SARS-CoV-2. If no evidence of vertical transmission or changes to placenta can be elucidated, then this work can inform future research investigating alternate routes of SARS-CoV-2 transmission.