This systematic review and meta-analysis was conducted in accordance with the updated 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline [12]. The protocol has been registered in Prospero (number registration: CRD42023397445).
Table of Contents
Search strategy
Four independent reviewers, by couples, searched PubMed, Embase, Web of Science, and Scopus from inception until 01st November 2022. The full search strategy and the search terms used are the following: “(COVID-19 OR Novel Coronavirus–Infected Pneumonia OR 2019 novel coronavirus OR 2019-nCoV OR SARS-CoV-2) AND (Lopinavir OR ritonavir OR Darunavir/cobicistat OR Methylprednisolone OR Prednisone OR Hydrocortisone OR Hydroxychloroquine OR Dexamethasone OR Enoxaparin OR. Low molecular weight heparins OR Remdesivir OR Anakinra OR Baricitinib. OR Sarilumab OR Tocilizumab OR Casirivimab OR Imdevimab OR Regdanvimab. OR bamlanivimab OR etesevimab OR Sotrovimab OR Tixagevimab OR Cilgavimab. OR Nirmatrelvir OR Molnupiravir OR Favipiravir OR Colchicine OR. Chloroquine OR Nafamostat mesylate OR Camostat mesylate OR Infliximab OR. Tofacitinib OR Bebtelovimab OR Ruxolitinib OR Nitazoxanide OR. Plitidepsin OR Zotatifin OR Niclosamide OR nelfinavir OR inhibitors of HIV protease OR Hyperimmune plasma OR Interferon OR ibuprofen OR Celecoxib) AND (("Pregnancy"[Mesh] OR "Pregnant Women"[Mesh] OR pregnanc*))”. Discrepancies in the literature search process were resolved by a third investigator (N.V.). Rayyan, a free-access website, was used for title/abstract screening (www.rayyan.ai/).
Inclusion and exclusion criteria
Studies were included based on the following PICO question:
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➙Participants: pregnant women;
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➙Intervention: pharmacological intervention for the treatment of acute SARS-CoV2 infection;
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➙Comparison: placebo or standard of care;
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➙Outcomes: delivery and maternal health endpoints;
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➙Study design: randomized controlled trials, clinical controlled trials, observational studies.
Published articles were excluded if they (i) were reviews, letters, in vivo or in vitro experiments, commentaries, or conference abstracts; (ii) absence of a control group or active control group (e.g., another medication); (iii) data non meta-analyzable.
Data extraction and risk of bias
Four authors extracted data independently which included name of first author, date of publication, country of origin, population included, type of study, follow-up (standardized in weeks), mean or median age of the women included, gestational age (weeks), number of vaccinated women, name and dosage of the intervention drugs. Disagreements between authors were resolved by one independent reviewer (N.V.).
The Newcastle–Ottawa Scale (NOS) was used to assess the study quality/risk of bias [13]. The NOS assigns a maximum of 9 points based on three quality parameters: selection, comparability, and outcome. The evaluation was made by one investigator (FVS) and checked by another (NV), independently. The risk of bias was consequently categorized as high (< 5/9 points), moderate (6–7), or low (8–9) [14].
Outcomes
Outcomes were the evaluation of maternal, fetal, delivery and neonatal outcomes according to the International Federation of Gynecology and Obstetrics (FIGO) classification. (Safe Motherhood and Newborn Health Committee. FIGO Consensus Guidelines on Intrapartum Fetal Monitoring. Available online: www.jsog.or.jp/international/pdf/CTG.pdf (accessed on 25 September 2022) [15]. The outcomes of our interest were divided in delivery outcomes, i.e., preterm delivery, Cesarean section, admission to neonatal ICU (intensive care unit), stillbirth/perinatal loss, obstructed labor and maternal outcomes, i.e., COVID-19 progression to severe disease (admission to ICU, respiratory failure and need for invasive ventilation, involvement of multiple organ systems), maternal death, miscarriage/fetal loss, amniotic fluid complications, ectopic pregnancy, placental complications, eclampsia or pre-eclampsia, severe bleeding, obstetric fistula, infections.
Statistical analysis
The analyses investigated the cumulative incidence of delivery and maternal outcomes in pregnant women comparing those taking an active medication vs standard care. We calculated the risk ratios (RRs) with their 95% confidence intervals (CIs), Statistical significance was assessed using the random effects model and inverse-variance method [12, 16].
Statistical heterogeneity of outcome measurements between different studies was assessed using the s I2. The classification of data as having low heterogeneity was based on I2 from 30 to 49%, moderate heterogeneity from 50 to 74%, and high heterogeneity from 75% and above [17]. In case of high heterogeneity and having at least 10 studies for an outcome [17], we plan to run a meta-regression analysis to explore potential sources of variability that could affect estimate rates among studies [18].
Publication bias was assessed by visually inspecting funnel plots and using the Egger bias test [19]. In case of statistically significant publication bias, the trim-and-fill analysis was planned [20]. For all analyses, a P-value less than 0.05 was considered statistically significant. All analyses were performed using STATA version 14.0 (StataCorp).
