Systematic reviews of observational studies of Risk of Thrombosis and Bleeding in General and Gynecologic Surgery (ROTBIGGS): introduction and methodology
Authors: Lavikainen Lauri I. , Guyatt Gordon H. , Lee Yung , Couban Rachel J. , Luomaranta Anna L. , Sallinen Ville J. , Kalliala Ilkka E. J. , Karanicolas Paul J. , Cartwright Rufus , Aaltonen Riikka L. , Ahopelto Kaisa , Aro Karoliina M. , Beilmann-Lehtonen Ines , Blanker Marco H. , Cárdenas Jovita L. , Craigie Samantha , Galambosi Päivi J. , Garcia-Perdomo Herney A. , Ge Fang Zhou , Gomaa Huda A. , Huang Linglong , Izett-Kay Matthew L. , Joronen Kirsi M. , Karjalainen Päivi K. , Khamani Nadina , Kilpeläinen Tuomas P. , Kivelä Antti J. , Korhonen Tapio , Lampela Hanna , Mattila Anne K. , Najafabadi Borna Tadayon , Nykänen Taina P. , Nystén Carolina , Oksjoki Sanna M. , Pandanaboyana Sanjay , Pourjamal Negar , Ratnayake Chathura B. B. , Raudasoja Aleksi R. , Singh Tino , Tähtinen Riikka M. , Vernooij Robin W. M. , Wang Yuting , Xiao Yingqi , Yao Liang , Haukka Jari , Tikkinen Kari A. O. 
Published: October 2021

Abstract
Background
Venous thromboembolism (VTE) and bleeding are serious and potentially fatal complications of surgical procedures. Pharmacological thromboprophylaxis decreases the risk of VTE but increases the risk of major post-operative bleeding. The decision to use pharmacologic prophylaxis therefore represents a trade-off that critically depends on the incidence of VTE and bleeding in the absence of prophylaxis. These baseline risks vary widely between procedures, but their magnitude is uncertain. Systematic reviews addressing baseline risks are scarce, needed, and require innovations in methodology. Indeed, systematic summaries of these baseline risk estimates exist neither in general nor gynecologic surgery. We will fill this knowledge gap by performing a series of systematic reviews and meta-analyses of the procedure-specific and patient risk factor stratified risk estimates in general and gynecologic surgeries.

Methods
We will perform comprehensive literature searches for observational studies in general and gynecologic surgery reporting symptomatic VTE or bleeding estimates. Pairs of methodologically trained reviewers will independently assess the studies for eligibility, evaluate the risk of bias by using an instrument developed for this review, and extract data. We will perform meta-analyses and modeling studies to adjust the reported risk estimates for the use of thromboprophylaxis and length of follow up. We will derive the estimates of risk from the median estimates of studies rated at the lowest risk of bias. The primary outcomes are the risk estimates of symptomatic VTE and major bleeding at 4 weeks post-operatively for each procedure stratified by patient risk factors. We will apply the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate evidence certainty.

Discussion
This series of systematic reviews, modeling studies, and meta-analyses will inform clinicians and patients regarding the trade-off between VTE prevention and bleeding in general and gynecologic surgeries. Our work advances the standards in systematic reviews of surgical complications, including assessment of risk of bias, criteria for arriving at the best estimates of risk (including modeling of the timing of events and dealing with suboptimal data reporting), dealing with subgroups at higher and lower risk of bias, and use of the GRADE approach.

Systematic review registration
PROSPERO CRD42021234119