- Email: [email protected]
Operative Outcomes of Opportunistic Bilateral Salpingectomy at the Time of Benign Hysterectomy in Low-Risk Premenopausal Women: A Systematic Review
Accepted Manuscript Operative Outcomes of Opportunistic Bilateral Salpingectomy at the Time of Benign Hysterectomy in Low-Risk Premenopausal Women: A Systematic Review Rosanne M. Kho, MD, Mary Ellen Wechter, MD, MPH PII:
S1553-4650(16)31212-2
DOI:
10.1016/j.jmig.2016.12.004
Reference:
JMIG 3008
To appear in:
The Journal of Minimally Invasive Gynecology
Received Date: 5 December 2016 Accepted Date: 7 December 2016
Please cite this article as: Kho RM, Wechter ME, Operative Outcomes of Opportunistic Bilateral Salpingectomy at the Time of Benign Hysterectomy in Low-Risk Premenopausal Women: A Systematic Review, The Journal of Minimally Invasive Gynecology (2017), doi: 10.1016/j.jmig.2016.12.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Operative Outcomes of Opportunistic Bilateral Salpingectomy at the Time of Benign Hysterectomy in Low-Risk Premenopausal Women: A Systematic Review
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Rosanne M. Kho, MD1, Mary Ellen Wechter, MD, MPH2
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1 Department of Obstetrics and Gynecology, Cleveland Clinic, Cleveland, OH
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2 North Florida OBGYN, Jacksonville, FL
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For submission as a systematic review to the Journal of Minimally Invasive Gynecologic Surgery Corresponding author:
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Rosanne M. Kho, MD
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Division of Benign Gynecologic Surgery, Department of Obstetrics and Gynecology, Women's Health Institute
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Cleveland, OH
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Office (216 444-6337) Fax: (216 636-5129)
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Email: [email protected]
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Potential benefits outweigh procedure risk for opportunistic bilateral salpingectomy at time of benign hysterectomy
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PRECIS
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Potential risk-reduction benefits outweigh procedure risk from opportunistic bilateral salpingectomy at benign hysterectomy
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ACCEPTED MANUSCRIPT Kho 3 Abstract
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Opportunistic salpingectomy (OBS) is gaining momentum as a potential strategy for preventing epithelial
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ovarian cancer (EOC). OBS has been associated with a 40-65% decrease in the incidence of EOC when
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performed at the time of benign hysterectomy in patients at population-level risk for EOC. Current data
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suggests minimal disadvantage or “cost” to the patient and system from this practice in terms of
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estimated blood loss (EBL), operative time, length of hospital stay, ovarian reserve depletion, and
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complications attributable to OBS. These “costs” merit additional scrutiny in comparison to potential
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benefits before OBS could be adopted or recommended universally as a preventative strategy. This
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systematic review identifies 10 comparative studies (8 cohorts and 2 randomized controlled studies)
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ranging from 19 patients to 425,180 that cumulatively demonstrate a small to no increase in operative
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time and no additional EBL, hospital stay, or complications attributable to OBS at the time of benign
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hysterectomy. We anticipate that more widespread adoption of OBS will necessarily incorporate more
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difficult salpingectomies, thus potentially increasing the time, EBL, and complications associated with
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this practice in large studies. This consideration should be weighed into discussions of whether
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salpingectomy at the time of hysterectomy would ever be considered mandatory (or failure to perform
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OBS be considered negligent) and may have to be considered for fair reimbursement for any additional
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time and risk of this surgical step. Given the available evidence of benefit, further randomized controlled
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trials for salpingectomy versus no salpingectomy at the time of hysterectomy are unlikely to be feasible
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and may be unethical. Going forward, additional large prospective cohorts with historical controls will
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be valuable in assessing the additional “costs” of universal OBS at the time of benign hysterectomy.
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Introduction Opportunistic bilateral salpingectomy (OBS) (also called prophylactic salpingectomy and riskreducing salpingectomy) in patients at population-level lifetime risk (1.3-1.4%) 1, 2 for ovarian cancer is
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gaining increasingly strong epidemiological support for an inverse association with risk of epithelial
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ovarian cancers (EOC). The possibility of a widely accessible and effective prevention strategy for ovarian
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cancer is highly relevant to general gynecologic practice. Mortality from ovarian cancer is greater than
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for any other gynecologic malignancy3 with a 5-year survival of 46.2%,2 and 67% of affected women
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eventually dying of their disease.4 This high mortality incidence is mostly due to epithelial ovarian
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cancers (particularly high grade serous carcinomas and encompassing high grade carcinomas of the
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tubes, ovaries, and peritoneum), presenting at late and advanced stages (at least 65% presenting at
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stage III or IV).4 Early detection efforts have thus far proved unsuccessful. Screening programs are of
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insufficient sensitivity and specificity to justify the potential harm from unnecessary surgery and
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premenopausal oophorectomy.5, 6 Risk prediction is imprecise, and risk factors for ovarian cancers are
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not well defined for the general population, with the exception of known familial cancer syndromes
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such as Lynch syndrome and mutations in the BRCA 1 and 2 genes. While the role of hormone therapy
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in the development of EOC, if any, remains unclear,7, 8 nulliparity,9, 10 endometriosis,11-13 infertility,14 and
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PCOS15 have been identified as associated with increased risk. Unfortunately, even if a predictive model
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were validated from these factors, without effective screening, knowledge of risk factors is still of
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limited benefit toward early detection.
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Prevention of epithelial ovarian cancer (EOC) is likely a more attainable target than early
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detection. There is good epidemiologic evidence that oral contraceptive pills (OCPs) remain a protective
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agent against ovarian cancer. Ever use of OCPs is associated with 27% reduction in risk as compared to
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never use; there is a 20% reduction in ovarian cancer risk for every 5 years of use 16, 17, and a greater
ACCEPTED MANUSCRIPT Kho 5 than 50% decrease in EOC incidence if oral contraceptive pills are used for 10 or more years.16 Bilateral
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salpingo-oophorectomy (BSO) at the time of hysterectomy reduces the risk of future ovarian cancer by
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at least 96% in the general population (HR 0.04, 95% C.I. 0.01-0.09) as compared to no BSO at time of
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hysterectomy. This was demonstrated in 29,380 nurses in the Nurses’ Health Study, approximately 50%
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of whom had BSO at the time of benign hysterectomy. 18 Risk-reducing salpingo-oophorectomy (RRSO)
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also reduces the incidence of ovarian and tubal cancer in patients with BRCA mutations (HR 0.21 (95%
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C.I. 0.12-0.39).19 RRSO is, at this time, advocated for women with a known BRCA mutation or Lynch
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syndrome (or other known increased risk by genetics testing) between age 35-40 and with completed
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childbearing or 10 years before the first degree relative’s age of diagnosis.20, 21 RRSO might be an
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effective strategy for specific other high-risk women as well, but widespread application of RRSO for
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prevention of ovarian cancer in the low-risk population is unlikely to be an acceptable solution due to
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the negative impact of premenopausal BSO on quality of life,22 sexual and vasomotor symptoms,23 and
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fatal and non-fatal coronary heart disease18, 24 as well as an increase in risk of total mortality.18
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OBS began to draw attention as a potentially preferable risk-reduction target in the last decade.
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18, 25
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that a history of bilateral tubal ligation (BTL) was associated with a reduction in epithelial ovarian cancer
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incidence of 18 to 67% 26-33 Hysterectomy has also been associated with a protective effect on EOC (RR
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0.78 95% C.I 0.60-0.96) 34 (and RR 0.67, 95% C.I. 0.45-1.00) for lifetime risk EOC as compared to no
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hysterectomy. 32 2) Pathologists identified that 10-15% of patients with BRCA mutations undergoing
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RRSO had serous tubal intraepithelial carcinoma (STIC) or occult invasive serous carcinoma of the
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tubes35 at the time of surgery. In addition, 50-60% of women with non-BRCA associated ovarian cancers
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had the same STIC or tubal cancers at the time of diagnosis.35, 36 These findings and additional mounting
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data implicate the fallopian tubes (specifically, the fimbriated end) 37 as the site of origin for most high-
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Initial interest was based on two important observations: 1) Multiple quality studies demonstrated
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grade serous peritoneal carcinomas (ovary/tube/peritoneum).36, 38-40 Accordingly, OBS is increasingly viewed as a preventative strategy for ovarian and tubal cancers. For an opportunistic procedure such as OBS, adoption must be supported by careful evaluation
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of the anticipated benefits against potential short-term (surgical outcomes) and long-term (ovarian
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function) consequences. In this review, we seek to answer the question: What are the additional “costs”
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in terms of operative time, estimated blood loss (EBL), complications, hospital readmission and/or
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emergency department visits attributable to OBS at the time of benign hysterectomy (abdominal,
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laparoscopic, robotic-assistance or vaginal route) in women at population-level risk of ovarian cancer?
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We approached this question with a systematic review strategy using PRISMA guidelines.41
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Search strategy
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We searched PubMed/MEDLINE, Scopus, ScienceDirect, Google Scholar, Cochrane Library, and Web of
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Science databases. For the PubMed search and a version of this strategy applicable to other search
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engines, we used MESH headings (Fallopian Tubes/physiopathology, Salpingectomy*/statistics &
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numerical data and Sterilization, Tubal) as well as keyword searches (Salpingectomy or Adnexectomy or
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(tubal ligation) or (tubal removal) combined with both: ((Surgical complication*) or (Surgical outcome*)
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or (Complication*) or (Ovarian response) or (ovarian reserve) or outcome*) and (Opportunistic or
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Prophylactic or preventing or prevention or (risk-reducing) or (risk reducing) or (risk-reduction) or (risk
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reduction)). We identified innumerous additional articles using the “similar article” feature in PubMed
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and applied this feature only to the articles identified as highly relevant. No unpublished studies,
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ACCEPTED MANUSCRIPT Kho 7 meeting abstracts or unpublished studies were included. We examined the reference lists of included
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studies and reviews for additional relevant studies.
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Selection criteria
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Inclusion criteria were: 1) comparative study reporting 2) at least one of the target surgical outcomes
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related to the performance of opportunistic (prophylactic) bilateral salpingectomy performed 3) during
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benign hysterectomy by any route in 4) women at population-level risk for ovarian cancer (not BRCA-
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positive women) who retained their ovaries at the time of surgery. Studies were 5) English language and
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published in 5) all dates to present (no studies were excluded for date). Disagreements between
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authors on study selection were resolved by discussion of full-text characteristics.
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Data extraction
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Two authors independently evaluated titles, abstracts, and full text articles to identify included studies.
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One author abstracted the data into charts and a second author independently confirmed accuracy of
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the data abstraction. Abstracted data included first author, publication year, methods (study design,
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hysterectomy type, and study size), EBL, operative time, complications not limited to readmission,
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length of stay, and study characteristics relevant to study quality designation.
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Quality assessment
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Quality rating of good, fair or poor was provided for each study based on the quality assessment tool
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provided by NIH (https://www.nhlbi.nih.gov/health-pro/guidelines/in-develop/cardiovascular-risk-
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reduction/tools/).42 Criteria for assessment included clear statement of research objective, calculation of
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sample size, use of appropriate outcome measures, adequate follow up period and adjustment for
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confounding variables.
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Statistical analysis
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ACCEPTED MANUSCRIPT Kho 8 Study heterogeneity prevented meaningful meta-analysis due to heterogeneity in nearly all aspects of
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the studies, not limited to the method of obtaining participants (consecutive vs. undefined prospective
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enrollment) and controls (matched versus unmatched and prospective versus historical control group),
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the type of included hysterectomy, the method and duration of follow-up, the measure of blood loss
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(EBL versus transfusion versus change in hemoglobin), and the method of assessing outcomes and
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length of stay. We sought to limit publication bias by searching for unpublished articles on google.com
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and meeting programs. We evaluated conference abstracts identified by the search engines but chose
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not to publish these abstracts as data often changes dramatically between the time of abstract
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preparation and final assessment.
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Results
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Study selection
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Of the references resulting from the search strategy, we identified 1200 non-duplicate titles, reviewed
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309 abstracts and obtained 46 full-text articles for consideration. Of these full-text articles, we excluded
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36 for the following reasons: review only, participants had BRCA mutation, involved tubal ligation not
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salpingectomy, included oophorectomy cases along with salpingectomy, did not specify bilateral
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salpingectomy during hysterectomy, provided no comparison group (case series), not published in
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English, meeting abstract or letter to the editor or commentary only, and study was not yet completed
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(Figure 1).
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Study characteristics
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Ten studies (8 retrospective cohorts and 2 randomized controlled trials (RCT) were eligible for inclusion.
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The main objective for the studies varied and included evaluation of ovarian function after prophylactic
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salpingectomy,43-45 and rate and uptake of salpingectomy after regional and health care delivery system
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ACCEPTED MANUSCRIPT Kho 9 initiatives.46, 47 To evaluate the surgical outcomes after OBS with hysterectomy was a secondary
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objective in 8 studies and was the primary objective in only 2 of the studies.48, 49 Studies ranged in size
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from 1944 to 425,180 patients.50 Patient follow up period was either immediately postoperative to as
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long as 92 months. Blood loss was assessed by either EBL, change in hemoglobin, or need for
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transfusion. Length of stay was reported as mean or median (hours or days). Six studies were
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retrospective cohorts; 2 studies were prospective cohorts with historical controls (one with matched
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controls). Hysterectomy type was laparoscopic only in 2 of the cohort studies and in both RCTs. In one
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cohort, the included hysterectomy routes were laparoscopic or total abdominal hysterectomy only. In 3
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cohorts, all hysterectomy types were included. Laparoscopic supracervical and laparoscopic-assisted
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vaginal hysterectomy accounted for one cohort study each (Table 1 and 2)
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Quality assessment
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For the retrospective comparative studies, only one study was rated poor because of absence of a
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power calculation and lack of advanced analysis of the surgical outcomes (Table 1). Two were rated as
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fair-good because potential confounders were not addressed and 4 were rated good. One of the RCT,
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rated as poor, was underpowered to detect a difference between the groups and a majority of the study
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patients had had a prior tubal ligation (Table 2).
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Surgical Outcomes
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Operative time
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Of the 9 studies that reported operative time, 7 demonstrated no significant difference in the operative
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time required for OBS. One large cohort (n=12,033) demonstrated that 16.3 (SD) minutes of additional
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time was required for hysterectomy, by any route, combined with OBS, versus hysterectomy alone (p<.
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001).46 Another large cohort study (n=7498) demonstrated a 5 minute time savings, specific for
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ACCEPTED MANUSCRIPT Kho 10 laparoscopic hysterectomy and not vaginal or abdominal hysterectomy with OBS (p=.002).47 Differences
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in operative time were not noted for the other studies for OBS performed via abdominal and vaginal
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routes (Table 1).
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Estimated blood loss
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Some measure of blood loss was reported in 9 of 10 studies. In only one of the studies, a difference in
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blood loss was reported, favoring less EBL for the OBS group (median 100cc, range 50-200cc) compared
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to the hysterectomy alone group (median 150cc, range 50-250cc, p<.001).47 In the other 8 studies, there
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was no significant difference in EBL, blood transfusion incidence, or change in hemoglobin (Table 1).
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Length of hospital stay
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Length of stay was reported by 9 of 10 studies. Statistically significant shorter length of stay was
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reported for patients with OBS by 4 cohort studies, ranging from a mean of 0.03 to 0.43 days to median
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of 1 day of time saved.46, 47, 49, 51 No study reported an increase in length of stay associated with OBS at
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the time of hysterectomy (Table 1).
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Complications of OBS
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Reported complications were varied and included intraoperative complications, readmission, emergency
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department visits, surgical re-intervention, infection, and fever. Two studies used the Clavien-Dindo
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grading system.45, 48 None of the 9 of 10 studies reporting complications demonstrated an increase in
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any complications attributable to OBS as compared to hysterectomy alone. Specifically, none of the
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studies reported increase in intra-operative complications, hospital re-admission, and fever. A single
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study (n=284) reported a significantly lower rate of infection in patients with OBS compared to
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hysterectomy alone (2.2% vs. 9.6%, p=.01) but was not well-adjusted for other covariables that could
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provide a plausible explanation for these findings.51
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ACCEPTED MANUSCRIPT Kho 11 Routes of Hysterectomy with OBS
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Four studies provided surgical outcomes of hysterectomy with OBS comparing different routes.46, 47, 49, 50
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In 2 studies, salpingectomy was more likely to be performed in patients undergoing laparoscopic
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hysterectomy (TLH) (61%, 45%) than those undergoing abdominal (TAH) (25%, 42%), vaginal (VH)
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(17%,11%) or robotic-assisted hysterectomy (1.6%).47, 52 In contrast, a separate study from Canada
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showed that OBS was more likely to be performed with TAH (44%) compared to VH (19%), TLH (15%)
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and laparoscopic assisted vaginal hysterectomy (LAVH) (22%).46
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In 2 large studies, operative time for vaginal hysterectomy with OBS was shorter compared to OBS
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performed with the abdominal and laparoscopic approaches (TVH 115 min vs TAH 155 min vs TLH 147
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min; no p value found) 47, (TVH 112 min; p<.001)46 Compared to open approach, vaginal hysterectomy
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with OBS was associated with significantly shorter LOS (0.9 days less, p<.001) and decreased adjusted
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odds for hospital readmission (aOR=0.51, 95%CI 0.37, 0.70, p<.001) in one large cohort.46
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Discussion
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In the current literature, bilateral salpingectomy (BS) has been associated with an approximately 40-
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65% reduction in future ovarian cancer incidence (OR 0.51, 95% C.I. 0.35-0.75%).53 BS compared to no
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hysterectomy and to no BS in 30,000 ovarian cancer cases had a 65% reduction in future ovarian cancer
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incidence (HR 0.35 (95% C.I. 0.17-0.73).27 In a nested case-control study, excisional BS, compared to BTL
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and no BTL, was associated with a 64% decrease in and reduced adjusted risk (aOR 0.36, 95% C.I. 0.13-
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.02) for ovarian and primary peritoneal cancer.54 Indeed, the apparent preventative benefit on ovarian
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cancer risk is dramatic enough, and the apparent consequences of OBS low enough, in comparison to
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RRSO, that the American College of Obstetricians and Gynecologists,25 The Society of Gynecologic
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Oncology,21, 55The Society of Gynecologic Oncologists of Canada,56 and the American Cancer Association
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have made policy statements in the last 6 years encouraging surgeons to offer OBS to patients as an
ACCEPTED MANUSCRIPT Kho 12 opportunistic procedure during benign hysterectomies and as an alternative to bilateral tubal ligation
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for sterilization procedures. Already, this practice is widely adopted: In 2013, some 54% of gynecologists
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in US teaching hospitals reported routine OBS at time of hysterectomy (based on 79% response from
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surveyed physicians).57 Routine OBS has been an institutional standard in some hospitals, 48 health care
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delivery systems (72.7% of benign hysterectomies in Kaiser system are accompanied by bilateral
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salpingectomy), 47 and in some countries. Indeed in Canada, by 2013, 75% of all hysterectomies for
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benign reason without oophorectomy had OBS, and 48% of all sterilizations were OBS.52 Global adoption
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of any opportunistic procedure, however, must be supported by a weighing of the anticipated benefits
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against potential short-term (surgical outcomes) and long-term (ovarian reserve) consequences.
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Despite early concern that performance of salpingectomy at the time of hysterectomy could incur greater surgical risks,58, the consensus from the existing literature is that there is no demonstrable
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disadvantage in terms of blood loss, length of hospital stay, hospital readmission or complications from
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performing OBS at the time of hysterectomy for the low-risk patient. There was a statistically significant
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difference in operating room time of 16 minutes in one study which is clinically acceptable given the
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advantages to reducing future adnexal pathologies.46 OBS was feasible with all hysterectomy routes. All
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studies included here described the technique of removal of the fallopian tubes by staying close to the
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junction of the tube and the mesosalpinx because of the great concern to preserve ovarian function.
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What is not well-studied as yet is whether there is any risk imparted by the mesosalpinx for future EOC
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or mucinous tumors.59 One study by Venturella, et al. does suggest that the wide excision of the tube to
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incorporate the entire mesosalpinx does not have negative implications on ovarian function as
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compared to OBS techniques that preserve the majority of the mesosalpinx.60
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In addition to evaluating the surgical outcomes following OBS with hysterectomy, this review also provided an opportunity to assess the surgical consequences of non-OBS at the time of
ACCEPTED MANUSCRIPT Kho 13 hysterectomy. For the immediate perioperative period, one study 51 suggested that the risk of
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postoperative infectious morbidity was actually increased when OBS is not performed at the time of
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hysterectomy (OR 4.9; 95% CI, 1.1-22.9) suggesting that the remaining fallopian tube may act as a nidus
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for subsequent infection. Another study reported a larger number of surgical complications reported
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using the Clavien-Dindo system with the non-OBS group (73 vs 24 cases; p= .79) but we are unable to
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determine if these were due to febrile or infectious reasons.48 In many studies reviewed here, there
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appeared to be a trend (not statistically significant) toward greater length of hospital stay in patients
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who underwent hysterectomy alone. Though the exact cause of greater LOS cannot be determined from
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any of the studies, it has been speculated that infection may contribute. It should be noted that the
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finding of increased postoperative infectious morbidity with non-OBS with hysterectomy was not
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confirmed in a large study utilizing a nationwide inpatient registry where there was no difference in the
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immediate postoperative infection rate in women undergoing hysterectomy with BS (0.4%) and
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hysterectomy alone (0.2%).50 There was also no difference in immediate postoperative fevers (0.8% in
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hysterectomy + OBS vs 0.6% in hysterectomy, alone). This large study, however, which was based on an
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inpatient registry, did not capture possible readmissions from postoperative infections and fevers that
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may occur after discharge. The question, therefore, of the short- and long-term impact of OBS on post-
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operative infection and subsequent LOS warrants further investigation.
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proposed as another benefit to OBS at hysterectomy. In a series with the longest follow up period from
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this review, non-OBS group had a higher surgical re-intervention rate for ovarian cysts, pyosalpinx, and
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hydrosalpinx. 48 There was an approximately twofold increase in risk for developing symptomatic
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benign tubal or ovarian pathologies in the non-OBS group requiring surgical re-intervention. In one
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small study, hydrosalpinx occurred in 35.5% of 82 patients who had a hysterectomy without
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salpingectomy.61 In a cohort of 337 women, women with tubal ligation and subsequent hysterectomy or
ACCEPTED MANUSCRIPT Kho 14 hysterectomy without prior salpingectomy had a higher risk of later adnexectomy compared to women
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with prior tubal ligation only (RR 3.5, 95% C.I. 1.3-9.4).62 In a large Danish cohort, women who had
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retained tubes after prior hysterectomy had an increased risk of subsequent salpingectomy (HR 2.13,
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95% C.I. 1.88-2.42) as did women with history of prior tubal ligation (HR 2.42, 95% C.I. 2.21-2.64).63
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This review addresses a timely and important surgical decision potentially affecting hundreds of thousands of women per year undergoing hysterectomy. The strengths of this review included a
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rigorous study search that was performed to find all relevant publications. Also, ongoing updates of this
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search were performed up to the time of article submission. Publication bias may exist as for all review
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papers. Unpublished works which amounted to meeting abstracts were also evaluated. We did not
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include meeting abstracts, however, given that final numbers may change dramatically from the time of
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abstract completion to full publication in many studies. The excluded three meeting abstracts reported
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similar findings to included studies. One study reported additional operative time for OBS at the time of
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hysterectomy of “slightly prolonged operative time”.64 Another reported no difference in EBL, VAS score,
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menopausal symptoms, complications or admission overnight in 374 patients with laparoscopic
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hysterectomy with versus without OBS.65 The third abstract reported no difference in pain or EBL in 54
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patients having hysterectomy randomized to OBS or no OBS.66 None of the three abstracts reported any
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increase in operative complications.)64-66
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We found no evidence that OBS incurred additional surgical risks at time of benign
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hysterectomy. We suggest this finding be interpreted with caution. The cohorts in this review likely
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included primarily straightforward salpingectomies since salpingectomy is not as yet mandated in most
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institutions. Thus, we presume that a salpingectomy perceived to be difficult or associated with risk may
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have been more likely avoided in past years. In the future, more global performance of OBS, therefore,
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may demonstrate a somewhat higher average operative time, estimated blood loss, and complications if
ACCEPTED MANUSCRIPT Kho 15 more complex salpingectomies are performed and included in the data. This possibility should be
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weighed into discussions of whether salpingectomy at the time of hysterectomy would ever be
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considered mandatory and should also be an important factor in calculating a fair reimbursement for
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predicted additional time and risk to perform this extra surgical step. Existing studies included in this
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review are of varying quality as discussed previously. Given the increasing body of evidence showing
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benefit to OBS, further randomized controlled trials for salpingectomy versus no salpingectomy at the
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time of hysterectomy may not be feasible and ethical. Going forward, additional large prospective
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cohorts with historical controls may, therefore, be more valuable in assessing the attributable “costs” of
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universal OBS at the time of benign hysterectomy.
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Conclusion
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In this review, performance of OBS at the time of benign hysterectomy in a low risk population demonstrated a small if any increase in operative time and no additional EBL, hospital stay, or
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complications attributed to OBS as compared to hysterectomy alone. Given the growing body of
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evidence that OBS may prevent future ovarian cancers and benign adnexal pathology, performance of
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OBS at the time of benign hysterectomy should be strongly considered.
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ACCEPTED MANUSCRIPT Table 2. Randomized controlled trials evaluating surgical outcomes after prophylactic salpingectomies in low-risk premenopausal patients. Study
Type of procedure (N)
EBL (ml)
OR time (min)
Complications
LOS (days)
Major findings
Quality rating
Findley et al 2013
TLH + OBS (15) vs TLH (14)
70 + 50 vs 91 + 121 (p=.54)
116 + 33 vs 115 + 44 (p=.97)
1 intraoperative hemorrhage. None attributable to OBS
Not reported
No increase in surgical risks with salpingectomy; no change in preop to postop AMH after hysterectomy in OBS or no OBS Underpowered to make any conclusions
Poor
TLH + OBS (34) vs TLH (34)
125 (75-200) vs 150 (100-225) (p=.355)
Median (range) 95 (69-110) vs 90 (65-106) (p=.547)
0 vs 2 (5.9%)(ileus, vag bleeding) p=.493
Median in days (range) 3 (2-3) vs 3 (2-3) p=.342
RI PT AMH decline 12.5% (0.8-60.9%)vs 10.8% (6.9-27.4%) did not differ between groups p=.898; no difference in EBL, OR time, LOS, complications
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Song et al. 2016
Underpowered to detect a difference. No sample size calculation. Small sample size. Single institution. 53% have had prior tubal sterilization. No long term follow up. Good
Sample size calculation. multicenter. 3 month follow up.
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N = sample size; EBL = estimated blood loss; OR = operating room; LOS = length of stay; TLH = total laparoscopic hysterectomy; OBS = opportunistic bilateral salpingectomy; preop = preoperative; postop = postoperative; AMH = anti-mullerian hormone; vag = vaginal.
ACCEPTED MANUSCRIPT Table 1. Retrospective comparative studies evaluating surgical outcomes after opportunistic bilateral salpingectomy (OBS) in lowrisk premenopausal women. Study
Type procedure (N)
EBL (ml)
OR time (min)
Complications
LOS (day)
Major Findings
Quality Rating
Ghezzi et al 2009
TLH + OBS(139) vs TLH (145)
100 (10-600) vs 100 (10-1050)
80 (30-245) vs 90 (30-300)
1 (1-6) vs 2 (1-10)
(p = .35)
Preservation of fallopian tube has OR 4.9 (95% CI 1.1 - 22.9) for infectious morbidity. *not well-adjusted for other covariables
Good
(p = .10)
Lower rate of infections in patients who had TLH+OBS compared to TLH alone (2.2% vs 9.6%; p= 0.01; 95% CI, 1.9-13.5%)
45.6 + 28.0 vs 100 +150.8 (p=.267)
106.32 + 46.4 vs 115.3 + 43.41 (p=.233)
“None attributable to OBS”
3.16 + 0.37 vs 3.44 + 0.65 (p=.091)
LASH + OBS (25) vs LASH (25)
EBL not completely measured and disregarded in one case of hemorrhage
0 vs 0
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81.7+14.8 vs 83.3 +18.6 (p=.79)
2.5 + 0.8 vs 2.7 + 0.8 (p=.16)
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∆Hgb (g/dL) 1.1 + 0.9 vs 1.2 + 0.7 (p=.41)
Concomitant OBS did not result in any statistically sig difference in EBL, OR time or LOS. *Only intraop and immediate postop followup. No longterm data
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TLH + OBS (79) vs TLH (79 matched by uterine weight)
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Morelli et al 2013
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Berlit et al. 2013
(p=.002)
Main objective: post op infection. Sample size calc. Used prospective cohort with historical control. One month follow up.
Days to return to normal activity is not different in both groups 15.0 + 4.4 vx 13.9 +4.8 (p =.11) No difference in change in AMH, FSH, Estradiol, Average follicle count, mean ovarian diameter,
Poor
Small sample. No sample size calculation. One surgeon study. No advanced analysis. One case of hemorrhage excluded from EBL analysis. Fair Sample size calculation. Potential confounders not addressed.
ACCEPTED MANUSCRIPT McAlpine et al 2014
Hyst* + OBS (3671) vs Hyst (8362) *Hysterectomy type: abdominal, laparoscopic and vaginal
No difference in blood transfusion rate of 2.5% across both groups. aOR Hyst + OBS compared to Hyst: 0.86 (95% CI, 0.671.10) (p=.54)
Compared to hyst alone, additional operating room time for OBS was 16.3 min (p<.001) Hyst + OBS: 133.6 + 50.1 vs Hyst: 117.3 + 47.7 (p<.001)
Compared to hyst alone, no difference in hospital readmission.
peak systolic velocity
2.34 + 1.9 vs 2.52 + 3.0 (p=.010)
Hyst + OBS: 4.3% (159/3670) vs Hyst:4.5% (379/8362)
LAVH + OBS (127) vs LAVH (413)
NA
142.97 + 63.31 vs 139.72 + 49.31 (p=.55)
Clavien-Dindo system: Total complications: 24 cases vs 73 (p=.79)
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Gr III complications: 4 vs 28 (p=.19)
4.93 +1.51 (SD) vs 5.11 + 1.82 (p=.31)
Follow up survey (54.6% response rate). In a follow up period of 55.21 + 7.92 mos for OBS and 92.32 + 16.96 months for nonOBS (p <.01), 26.91% (60/413) of non-OBS had postop adnexal path requiring med or surg treatment; (28 surg reinterventions) for ov cysts (33), hydrosalpinx (8), pyosalpinx (1), adnexitis(18) vs 10/127 (13.88% of OBS group) had adnexal
Fair
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Vorwergk et al 2014
Good Large sample in each group with few missing data
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aOR Hyst +OBS compared to Hyst: 0.91 (95% CI, 0.751.10 (p=.632)
OBS was more likely to be performed with TAH (44%) compared to VH (19%), TLH (15%) and LAVH (22%). Compared to open approach, vag approach for hyst with OBS was associated with significantly shorter OR time (112 min; p<.001), LOS and decreased risk for hosp readmission (OR=0.51, 95%CI 0.37, 0.70)
No sample size calculation. Patients converted to laparotomy were excluded. 54.6% survey response rate. Long follow up.
ACCEPTED MANUSCRIPT
Hyst (TLH and TAH) + OBS (97) vs Hyst (71)
126.2 + 100.4 vs 143.2 + 83.5
87.1 + 26.2 vs 94.0 + 31.1
(p=.095)
(p=.119)
Intra-op surgical complications: 4/97=4.1% vs 4/71=5.6% (p=.723)
43.7 + 22.4 hours vs 53.9 + 26.5 hours (p=.008)
Postop complications in Hyst +OBS (12/97) 12.4% vs 8/71=11.3% (p=.827)
(p=<.001)
All routes Hyst + OBS (52,280)
No difference in transfusion rate:
NA
NA
No difference in postop
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Hanley et al 2016
TLH (OBS shorter operative time) 147 vs 152 (p=.002) TAH 155 vs 142 (p=.08) TVH 115 vs 150 (p=.56)
TLH (h) 4 vs 4.9 (p<.001) TAH 45 vs 46 (p=.12) TVH 19 vs 24 (p<.001)
OR time and LOS was significantly shorter in OBS group in patients undergoing laparoscopic route.
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100 (50-200) vs 150 (50-250)
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All routes Hyst +OBS (4,154) vs Hyst (3,344)
Fair No sample size calculation 30 day follow up
Readmission/ED Hyst+OBS=(13/97) 13.4% vs (9/71) 12.7% (p=.890)
Garcia et al 2016
OBS does not worsen surgical outcomes
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Minig et al. 2015
pathologies (p=.02) Rate of hysterectomyrelated surgical reintervention in OBS = 4.16%vs 12.56% in non-OBS (p=.04)
No difference in LOS
TLH were more likely to have OBS (60.5) than TAH (24.6%) and TVH (16.5%)
No difference in blood transfusion,
Good
Large sample size. Potential confounders not addressed
Good
vs Hyst (934,712)
ACCEPTED MANUSCRIPT complications Hyst + OBS:
aOR 0.95 (95% C.I. 0.86-1.05) Hyst +OBS 6.0% Hyst 6.2%
aOR 0.97 (95% CI, 0.88-1.07) No difference in infection incidence Hyst +OBS: 0.4% Hyst: 0.4%
Median 2 (range 12) days Hyst: median 2 (range 1-2) days
postop complications, postop infections, fever between women with hyst +OBS and hyst Hyst +OBS performed more often laparoscopically (44.6%) vs abd(42%), vag (11%), rob (1.6%)
No difference in fever incidence Hyst +OBS: 0.8% Hyst: 0.6%
Large sample size: Nationwide Inpatient Sample Exclusion criteria clearly stated
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N = sample size; EBL = estimated blood loss; OR = operating room; LOS = length of stay; TLH = total laparoscopic hysterectomy; OBS = opportunistic bilateral salpingectomy; CI = confidence interval; OR = odds ratio; LASH = laparoscopic supracervical hysterectomy; ∆Hgb = change in hemoglobin; AMH = anti-mullerian hormone; FSH = follicular stimulating hormone; Hyst = hysterectomy; aOR = adjusted odds ratio; TAH = total abdominal hysterectomy; VH = vaginal hysterectomy; LAVH = laparoscopicassisted vaginal hysterectomy; NA = not available; Gr = grade; ov = ovarian; postop = postoperative.
ACCEPTED MANUSCRIPT
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Additional records identified through other sources (n = 23 )
Records identified through database searching (n = 2250)
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Identification
Figure 1
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Records excluded (n = 263)
Full-text articles assessed for eligibility (n = 46)
Full-text articles excluded, for the following reasons:
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Abstracts screened (n = 309)
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Included
Eligibility
Screening
Titles reviewed after duplicates removed (n = 1200)
review only, participants had BRCA mutation, involved tubal ligation, included oophorectomy cases, did not specify bilateral salpingectomy during hysterectomy, provided no comparison group (case series), non-English, meeting abstract only, study not yet completed
(n = 36) Studies included in quantitative synthesis (meta-analysis) (n = 10)
S1553-4650(16)31212-2
DOI:
10.1016/j.jmig.2016.12.004
Reference:
JMIG 3008
To appear in:
The Journal of Minimally Invasive Gynecology
Received Date: 5 December 2016 Accepted Date: 7 December 2016
Please cite this article as: Kho RM, Wechter ME, Operative Outcomes of Opportunistic Bilateral Salpingectomy at the Time of Benign Hysterectomy in Low-Risk Premenopausal Women: A Systematic Review, The Journal of Minimally Invasive Gynecology (2017), doi: 10.1016/j.jmig.2016.12.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Kho 1 1 2
Operative Outcomes of Opportunistic Bilateral Salpingectomy at the Time of Benign Hysterectomy in Low-Risk Premenopausal Women: A Systematic Review
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Rosanne M. Kho, MD1, Mary Ellen Wechter, MD, MPH2
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1 Department of Obstetrics and Gynecology, Cleveland Clinic, Cleveland, OH
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2 North Florida OBGYN, Jacksonville, FL
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For submission as a systematic review to the Journal of Minimally Invasive Gynecologic Surgery Corresponding author:
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Rosanne M. Kho, MD
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Division of Benign Gynecologic Surgery, Department of Obstetrics and Gynecology, Women's Health Institute
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Cleveland, OH
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Office (216 444-6337) Fax: (216 636-5129)
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Email: [email protected]
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PRECIS
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Potential risk-reduction benefits outweigh procedure risk from opportunistic bilateral salpingectomy at benign hysterectomy
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ACCEPTED MANUSCRIPT Kho 3 Abstract
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Opportunistic salpingectomy (OBS) is gaining momentum as a potential strategy for preventing epithelial
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ovarian cancer (EOC). OBS has been associated with a 40-65% decrease in the incidence of EOC when
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performed at the time of benign hysterectomy in patients at population-level risk for EOC. Current data
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suggests minimal disadvantage or “cost” to the patient and system from this practice in terms of
35
estimated blood loss (EBL), operative time, length of hospital stay, ovarian reserve depletion, and
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complications attributable to OBS. These “costs” merit additional scrutiny in comparison to potential
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benefits before OBS could be adopted or recommended universally as a preventative strategy. This
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systematic review identifies 10 comparative studies (8 cohorts and 2 randomized controlled studies)
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ranging from 19 patients to 425,180 that cumulatively demonstrate a small to no increase in operative
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time and no additional EBL, hospital stay, or complications attributable to OBS at the time of benign
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hysterectomy. We anticipate that more widespread adoption of OBS will necessarily incorporate more
42
difficult salpingectomies, thus potentially increasing the time, EBL, and complications associated with
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this practice in large studies. This consideration should be weighed into discussions of whether
44
salpingectomy at the time of hysterectomy would ever be considered mandatory (or failure to perform
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OBS be considered negligent) and may have to be considered for fair reimbursement for any additional
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time and risk of this surgical step. Given the available evidence of benefit, further randomized controlled
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trials for salpingectomy versus no salpingectomy at the time of hysterectomy are unlikely to be feasible
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and may be unethical. Going forward, additional large prospective cohorts with historical controls will
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be valuable in assessing the additional “costs” of universal OBS at the time of benign hysterectomy.
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Introduction Opportunistic bilateral salpingectomy (OBS) (also called prophylactic salpingectomy and riskreducing salpingectomy) in patients at population-level lifetime risk (1.3-1.4%) 1, 2 for ovarian cancer is
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gaining increasingly strong epidemiological support for an inverse association with risk of epithelial
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ovarian cancers (EOC). The possibility of a widely accessible and effective prevention strategy for ovarian
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cancer is highly relevant to general gynecologic practice. Mortality from ovarian cancer is greater than
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for any other gynecologic malignancy3 with a 5-year survival of 46.2%,2 and 67% of affected women
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eventually dying of their disease.4 This high mortality incidence is mostly due to epithelial ovarian
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cancers (particularly high grade serous carcinomas and encompassing high grade carcinomas of the
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tubes, ovaries, and peritoneum), presenting at late and advanced stages (at least 65% presenting at
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stage III or IV).4 Early detection efforts have thus far proved unsuccessful. Screening programs are of
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insufficient sensitivity and specificity to justify the potential harm from unnecessary surgery and
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premenopausal oophorectomy.5, 6 Risk prediction is imprecise, and risk factors for ovarian cancers are
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not well defined for the general population, with the exception of known familial cancer syndromes
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such as Lynch syndrome and mutations in the BRCA 1 and 2 genes. While the role of hormone therapy
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in the development of EOC, if any, remains unclear,7, 8 nulliparity,9, 10 endometriosis,11-13 infertility,14 and
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PCOS15 have been identified as associated with increased risk. Unfortunately, even if a predictive model
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were validated from these factors, without effective screening, knowledge of risk factors is still of
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limited benefit toward early detection.
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Prevention of epithelial ovarian cancer (EOC) is likely a more attainable target than early
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detection. There is good epidemiologic evidence that oral contraceptive pills (OCPs) remain a protective
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agent against ovarian cancer. Ever use of OCPs is associated with 27% reduction in risk as compared to
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never use; there is a 20% reduction in ovarian cancer risk for every 5 years of use 16, 17, and a greater
ACCEPTED MANUSCRIPT Kho 5 than 50% decrease in EOC incidence if oral contraceptive pills are used for 10 or more years.16 Bilateral
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salpingo-oophorectomy (BSO) at the time of hysterectomy reduces the risk of future ovarian cancer by
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at least 96% in the general population (HR 0.04, 95% C.I. 0.01-0.09) as compared to no BSO at time of
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hysterectomy. This was demonstrated in 29,380 nurses in the Nurses’ Health Study, approximately 50%
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of whom had BSO at the time of benign hysterectomy. 18 Risk-reducing salpingo-oophorectomy (RRSO)
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also reduces the incidence of ovarian and tubal cancer in patients with BRCA mutations (HR 0.21 (95%
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C.I. 0.12-0.39).19 RRSO is, at this time, advocated for women with a known BRCA mutation or Lynch
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syndrome (or other known increased risk by genetics testing) between age 35-40 and with completed
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childbearing or 10 years before the first degree relative’s age of diagnosis.20, 21 RRSO might be an
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effective strategy for specific other high-risk women as well, but widespread application of RRSO for
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prevention of ovarian cancer in the low-risk population is unlikely to be an acceptable solution due to
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the negative impact of premenopausal BSO on quality of life,22 sexual and vasomotor symptoms,23 and
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fatal and non-fatal coronary heart disease18, 24 as well as an increase in risk of total mortality.18
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OBS began to draw attention as a potentially preferable risk-reduction target in the last decade.
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18, 25
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that a history of bilateral tubal ligation (BTL) was associated with a reduction in epithelial ovarian cancer
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incidence of 18 to 67% 26-33 Hysterectomy has also been associated with a protective effect on EOC (RR
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0.78 95% C.I 0.60-0.96) 34 (and RR 0.67, 95% C.I. 0.45-1.00) for lifetime risk EOC as compared to no
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hysterectomy. 32 2) Pathologists identified that 10-15% of patients with BRCA mutations undergoing
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RRSO had serous tubal intraepithelial carcinoma (STIC) or occult invasive serous carcinoma of the
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tubes35 at the time of surgery. In addition, 50-60% of women with non-BRCA associated ovarian cancers
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had the same STIC or tubal cancers at the time of diagnosis.35, 36 These findings and additional mounting
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data implicate the fallopian tubes (specifically, the fimbriated end) 37 as the site of origin for most high-
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grade serous peritoneal carcinomas (ovary/tube/peritoneum).36, 38-40 Accordingly, OBS is increasingly viewed as a preventative strategy for ovarian and tubal cancers. For an opportunistic procedure such as OBS, adoption must be supported by careful evaluation
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of the anticipated benefits against potential short-term (surgical outcomes) and long-term (ovarian
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function) consequences. In this review, we seek to answer the question: What are the additional “costs”
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in terms of operative time, estimated blood loss (EBL), complications, hospital readmission and/or
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emergency department visits attributable to OBS at the time of benign hysterectomy (abdominal,
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laparoscopic, robotic-assistance or vaginal route) in women at population-level risk of ovarian cancer?
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We approached this question with a systematic review strategy using PRISMA guidelines.41
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Search strategy
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We searched PubMed/MEDLINE, Scopus, ScienceDirect, Google Scholar, Cochrane Library, and Web of
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Science databases. For the PubMed search and a version of this strategy applicable to other search
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engines, we used MESH headings (Fallopian Tubes/physiopathology, Salpingectomy*/statistics &
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numerical data and Sterilization, Tubal) as well as keyword searches (Salpingectomy or Adnexectomy or
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(tubal ligation) or (tubal removal) combined with both: ((Surgical complication*) or (Surgical outcome*)
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or (Complication*) or (Ovarian response) or (ovarian reserve) or outcome*) and (Opportunistic or
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Prophylactic or preventing or prevention or (risk-reducing) or (risk reducing) or (risk-reduction) or (risk
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reduction)). We identified innumerous additional articles using the “similar article” feature in PubMed
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and applied this feature only to the articles identified as highly relevant. No unpublished studies,
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ACCEPTED MANUSCRIPT Kho 7 meeting abstracts or unpublished studies were included. We examined the reference lists of included
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studies and reviews for additional relevant studies.
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Selection criteria
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Inclusion criteria were: 1) comparative study reporting 2) at least one of the target surgical outcomes
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related to the performance of opportunistic (prophylactic) bilateral salpingectomy performed 3) during
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benign hysterectomy by any route in 4) women at population-level risk for ovarian cancer (not BRCA-
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positive women) who retained their ovaries at the time of surgery. Studies were 5) English language and
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published in 5) all dates to present (no studies were excluded for date). Disagreements between
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authors on study selection were resolved by discussion of full-text characteristics.
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Data extraction
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Two authors independently evaluated titles, abstracts, and full text articles to identify included studies.
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One author abstracted the data into charts and a second author independently confirmed accuracy of
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the data abstraction. Abstracted data included first author, publication year, methods (study design,
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hysterectomy type, and study size), EBL, operative time, complications not limited to readmission,
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length of stay, and study characteristics relevant to study quality designation.
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Quality assessment
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Quality rating of good, fair or poor was provided for each study based on the quality assessment tool
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provided by NIH (https://www.nhlbi.nih.gov/health-pro/guidelines/in-develop/cardiovascular-risk-
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reduction/tools/).42 Criteria for assessment included clear statement of research objective, calculation of
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sample size, use of appropriate outcome measures, adequate follow up period and adjustment for
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confounding variables.
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Statistical analysis
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ACCEPTED MANUSCRIPT Kho 8 Study heterogeneity prevented meaningful meta-analysis due to heterogeneity in nearly all aspects of
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the studies, not limited to the method of obtaining participants (consecutive vs. undefined prospective
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enrollment) and controls (matched versus unmatched and prospective versus historical control group),
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the type of included hysterectomy, the method and duration of follow-up, the measure of blood loss
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(EBL versus transfusion versus change in hemoglobin), and the method of assessing outcomes and
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length of stay. We sought to limit publication bias by searching for unpublished articles on google.com
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and meeting programs. We evaluated conference abstracts identified by the search engines but chose
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not to publish these abstracts as data often changes dramatically between the time of abstract
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preparation and final assessment.
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Results
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Study selection
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Of the references resulting from the search strategy, we identified 1200 non-duplicate titles, reviewed
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309 abstracts and obtained 46 full-text articles for consideration. Of these full-text articles, we excluded
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36 for the following reasons: review only, participants had BRCA mutation, involved tubal ligation not
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salpingectomy, included oophorectomy cases along with salpingectomy, did not specify bilateral
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salpingectomy during hysterectomy, provided no comparison group (case series), not published in
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English, meeting abstract or letter to the editor or commentary only, and study was not yet completed
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(Figure 1).
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Study characteristics
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Ten studies (8 retrospective cohorts and 2 randomized controlled trials (RCT) were eligible for inclusion.
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The main objective for the studies varied and included evaluation of ovarian function after prophylactic
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salpingectomy,43-45 and rate and uptake of salpingectomy after regional and health care delivery system
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ACCEPTED MANUSCRIPT Kho 9 initiatives.46, 47 To evaluate the surgical outcomes after OBS with hysterectomy was a secondary
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objective in 8 studies and was the primary objective in only 2 of the studies.48, 49 Studies ranged in size
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from 1944 to 425,180 patients.50 Patient follow up period was either immediately postoperative to as
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long as 92 months. Blood loss was assessed by either EBL, change in hemoglobin, or need for
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transfusion. Length of stay was reported as mean or median (hours or days). Six studies were
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retrospective cohorts; 2 studies were prospective cohorts with historical controls (one with matched
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controls). Hysterectomy type was laparoscopic only in 2 of the cohort studies and in both RCTs. In one
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cohort, the included hysterectomy routes were laparoscopic or total abdominal hysterectomy only. In 3
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cohorts, all hysterectomy types were included. Laparoscopic supracervical and laparoscopic-assisted
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vaginal hysterectomy accounted for one cohort study each (Table 1 and 2)
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Quality assessment
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For the retrospective comparative studies, only one study was rated poor because of absence of a
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power calculation and lack of advanced analysis of the surgical outcomes (Table 1). Two were rated as
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fair-good because potential confounders were not addressed and 4 were rated good. One of the RCT,
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rated as poor, was underpowered to detect a difference between the groups and a majority of the study
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patients had had a prior tubal ligation (Table 2).
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Surgical Outcomes
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Operative time
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Of the 9 studies that reported operative time, 7 demonstrated no significant difference in the operative
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time required for OBS. One large cohort (n=12,033) demonstrated that 16.3 (SD) minutes of additional
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time was required for hysterectomy, by any route, combined with OBS, versus hysterectomy alone (p<.
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001).46 Another large cohort study (n=7498) demonstrated a 5 minute time savings, specific for
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ACCEPTED MANUSCRIPT Kho 10 laparoscopic hysterectomy and not vaginal or abdominal hysterectomy with OBS (p=.002).47 Differences
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in operative time were not noted for the other studies for OBS performed via abdominal and vaginal
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routes (Table 1).
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Estimated blood loss
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Some measure of blood loss was reported in 9 of 10 studies. In only one of the studies, a difference in
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blood loss was reported, favoring less EBL for the OBS group (median 100cc, range 50-200cc) compared
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to the hysterectomy alone group (median 150cc, range 50-250cc, p<.001).47 In the other 8 studies, there
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was no significant difference in EBL, blood transfusion incidence, or change in hemoglobin (Table 1).
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Length of hospital stay
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Length of stay was reported by 9 of 10 studies. Statistically significant shorter length of stay was
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reported for patients with OBS by 4 cohort studies, ranging from a mean of 0.03 to 0.43 days to median
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of 1 day of time saved.46, 47, 49, 51 No study reported an increase in length of stay associated with OBS at
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the time of hysterectomy (Table 1).
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Complications of OBS
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Reported complications were varied and included intraoperative complications, readmission, emergency
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department visits, surgical re-intervention, infection, and fever. Two studies used the Clavien-Dindo
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grading system.45, 48 None of the 9 of 10 studies reporting complications demonstrated an increase in
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any complications attributable to OBS as compared to hysterectomy alone. Specifically, none of the
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studies reported increase in intra-operative complications, hospital re-admission, and fever. A single
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study (n=284) reported a significantly lower rate of infection in patients with OBS compared to
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hysterectomy alone (2.2% vs. 9.6%, p=.01) but was not well-adjusted for other covariables that could
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provide a plausible explanation for these findings.51
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ACCEPTED MANUSCRIPT Kho 11 Routes of Hysterectomy with OBS
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Four studies provided surgical outcomes of hysterectomy with OBS comparing different routes.46, 47, 49, 50
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In 2 studies, salpingectomy was more likely to be performed in patients undergoing laparoscopic
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hysterectomy (TLH) (61%, 45%) than those undergoing abdominal (TAH) (25%, 42%), vaginal (VH)
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(17%,11%) or robotic-assisted hysterectomy (1.6%).47, 52 In contrast, a separate study from Canada
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showed that OBS was more likely to be performed with TAH (44%) compared to VH (19%), TLH (15%)
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and laparoscopic assisted vaginal hysterectomy (LAVH) (22%).46
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In 2 large studies, operative time for vaginal hysterectomy with OBS was shorter compared to OBS
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performed with the abdominal and laparoscopic approaches (TVH 115 min vs TAH 155 min vs TLH 147
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min; no p value found) 47, (TVH 112 min; p<.001)46 Compared to open approach, vaginal hysterectomy
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with OBS was associated with significantly shorter LOS (0.9 days less, p<.001) and decreased adjusted
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odds for hospital readmission (aOR=0.51, 95%CI 0.37, 0.70, p<.001) in one large cohort.46
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Discussion
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In the current literature, bilateral salpingectomy (BS) has been associated with an approximately 40-
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65% reduction in future ovarian cancer incidence (OR 0.51, 95% C.I. 0.35-0.75%).53 BS compared to no
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hysterectomy and to no BS in 30,000 ovarian cancer cases had a 65% reduction in future ovarian cancer
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incidence (HR 0.35 (95% C.I. 0.17-0.73).27 In a nested case-control study, excisional BS, compared to BTL
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and no BTL, was associated with a 64% decrease in and reduced adjusted risk (aOR 0.36, 95% C.I. 0.13-
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.02) for ovarian and primary peritoneal cancer.54 Indeed, the apparent preventative benefit on ovarian
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cancer risk is dramatic enough, and the apparent consequences of OBS low enough, in comparison to
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RRSO, that the American College of Obstetricians and Gynecologists,25 The Society of Gynecologic
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Oncology,21, 55The Society of Gynecologic Oncologists of Canada,56 and the American Cancer Association
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have made policy statements in the last 6 years encouraging surgeons to offer OBS to patients as an
ACCEPTED MANUSCRIPT Kho 12 opportunistic procedure during benign hysterectomies and as an alternative to bilateral tubal ligation
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for sterilization procedures. Already, this practice is widely adopted: In 2013, some 54% of gynecologists
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in US teaching hospitals reported routine OBS at time of hysterectomy (based on 79% response from
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surveyed physicians).57 Routine OBS has been an institutional standard in some hospitals, 48 health care
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delivery systems (72.7% of benign hysterectomies in Kaiser system are accompanied by bilateral
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salpingectomy), 47 and in some countries. Indeed in Canada, by 2013, 75% of all hysterectomies for
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benign reason without oophorectomy had OBS, and 48% of all sterilizations were OBS.52 Global adoption
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of any opportunistic procedure, however, must be supported by a weighing of the anticipated benefits
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against potential short-term (surgical outcomes) and long-term (ovarian reserve) consequences.
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Despite early concern that performance of salpingectomy at the time of hysterectomy could incur greater surgical risks,58, the consensus from the existing literature is that there is no demonstrable
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disadvantage in terms of blood loss, length of hospital stay, hospital readmission or complications from
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performing OBS at the time of hysterectomy for the low-risk patient. There was a statistically significant
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difference in operating room time of 16 minutes in one study which is clinically acceptable given the
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advantages to reducing future adnexal pathologies.46 OBS was feasible with all hysterectomy routes. All
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studies included here described the technique of removal of the fallopian tubes by staying close to the
247
junction of the tube and the mesosalpinx because of the great concern to preserve ovarian function.
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What is not well-studied as yet is whether there is any risk imparted by the mesosalpinx for future EOC
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or mucinous tumors.59 One study by Venturella, et al. does suggest that the wide excision of the tube to
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incorporate the entire mesosalpinx does not have negative implications on ovarian function as
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compared to OBS techniques that preserve the majority of the mesosalpinx.60
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In addition to evaluating the surgical outcomes following OBS with hysterectomy, this review also provided an opportunity to assess the surgical consequences of non-OBS at the time of
ACCEPTED MANUSCRIPT Kho 13 hysterectomy. For the immediate perioperative period, one study 51 suggested that the risk of
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postoperative infectious morbidity was actually increased when OBS is not performed at the time of
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hysterectomy (OR 4.9; 95% CI, 1.1-22.9) suggesting that the remaining fallopian tube may act as a nidus
257
for subsequent infection. Another study reported a larger number of surgical complications reported
258
using the Clavien-Dindo system with the non-OBS group (73 vs 24 cases; p= .79) but we are unable to
259
determine if these were due to febrile or infectious reasons.48 In many studies reviewed here, there
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appeared to be a trend (not statistically significant) toward greater length of hospital stay in patients
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who underwent hysterectomy alone. Though the exact cause of greater LOS cannot be determined from
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any of the studies, it has been speculated that infection may contribute. It should be noted that the
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finding of increased postoperative infectious morbidity with non-OBS with hysterectomy was not
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confirmed in a large study utilizing a nationwide inpatient registry where there was no difference in the
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immediate postoperative infection rate in women undergoing hysterectomy with BS (0.4%) and
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hysterectomy alone (0.2%).50 There was also no difference in immediate postoperative fevers (0.8% in
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hysterectomy + OBS vs 0.6% in hysterectomy, alone). This large study, however, which was based on an
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inpatient registry, did not capture possible readmissions from postoperative infections and fevers that
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may occur after discharge. The question, therefore, of the short- and long-term impact of OBS on post-
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operative infection and subsequent LOS warrants further investigation.
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proposed as another benefit to OBS at hysterectomy. In a series with the longest follow up period from
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this review, non-OBS group had a higher surgical re-intervention rate for ovarian cysts, pyosalpinx, and
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hydrosalpinx. 48 There was an approximately twofold increase in risk for developing symptomatic
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benign tubal or ovarian pathologies in the non-OBS group requiring surgical re-intervention. In one
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small study, hydrosalpinx occurred in 35.5% of 82 patients who had a hysterectomy without
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salpingectomy.61 In a cohort of 337 women, women with tubal ligation and subsequent hysterectomy or
ACCEPTED MANUSCRIPT Kho 14 hysterectomy without prior salpingectomy had a higher risk of later adnexectomy compared to women
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with prior tubal ligation only (RR 3.5, 95% C.I. 1.3-9.4).62 In a large Danish cohort, women who had
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retained tubes after prior hysterectomy had an increased risk of subsequent salpingectomy (HR 2.13,
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95% C.I. 1.88-2.42) as did women with history of prior tubal ligation (HR 2.42, 95% C.I. 2.21-2.64).63
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This review addresses a timely and important surgical decision potentially affecting hundreds of thousands of women per year undergoing hysterectomy. The strengths of this review included a
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rigorous study search that was performed to find all relevant publications. Also, ongoing updates of this
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search were performed up to the time of article submission. Publication bias may exist as for all review
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papers. Unpublished works which amounted to meeting abstracts were also evaluated. We did not
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include meeting abstracts, however, given that final numbers may change dramatically from the time of
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abstract completion to full publication in many studies. The excluded three meeting abstracts reported
289
similar findings to included studies. One study reported additional operative time for OBS at the time of
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hysterectomy of “slightly prolonged operative time”.64 Another reported no difference in EBL, VAS score,
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menopausal symptoms, complications or admission overnight in 374 patients with laparoscopic
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hysterectomy with versus without OBS.65 The third abstract reported no difference in pain or EBL in 54
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patients having hysterectomy randomized to OBS or no OBS.66 None of the three abstracts reported any
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increase in operative complications.)64-66
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We found no evidence that OBS incurred additional surgical risks at time of benign
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hysterectomy. We suggest this finding be interpreted with caution. The cohorts in this review likely
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included primarily straightforward salpingectomies since salpingectomy is not as yet mandated in most
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institutions. Thus, we presume that a salpingectomy perceived to be difficult or associated with risk may
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have been more likely avoided in past years. In the future, more global performance of OBS, therefore,
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may demonstrate a somewhat higher average operative time, estimated blood loss, and complications if
ACCEPTED MANUSCRIPT Kho 15 more complex salpingectomies are performed and included in the data. This possibility should be
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weighed into discussions of whether salpingectomy at the time of hysterectomy would ever be
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considered mandatory and should also be an important factor in calculating a fair reimbursement for
304
predicted additional time and risk to perform this extra surgical step. Existing studies included in this
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review are of varying quality as discussed previously. Given the increasing body of evidence showing
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benefit to OBS, further randomized controlled trials for salpingectomy versus no salpingectomy at the
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time of hysterectomy may not be feasible and ethical. Going forward, additional large prospective
308
cohorts with historical controls may, therefore, be more valuable in assessing the attributable “costs” of
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universal OBS at the time of benign hysterectomy.
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Conclusion
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In this review, performance of OBS at the time of benign hysterectomy in a low risk population demonstrated a small if any increase in operative time and no additional EBL, hospital stay, or
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complications attributed to OBS as compared to hysterectomy alone. Given the growing body of
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evidence that OBS may prevent future ovarian cancers and benign adnexal pathology, performance of
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OBS at the time of benign hysterectomy should be strongly considered.
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ACCEPTED MANUSCRIPT Table 2. Randomized controlled trials evaluating surgical outcomes after prophylactic salpingectomies in low-risk premenopausal patients. Study
Type of procedure (N)
EBL (ml)
OR time (min)
Complications
LOS (days)
Major findings
Quality rating
Findley et al 2013
TLH + OBS (15) vs TLH (14)
70 + 50 vs 91 + 121 (p=.54)
116 + 33 vs 115 + 44 (p=.97)
1 intraoperative hemorrhage. None attributable to OBS
Not reported
No increase in surgical risks with salpingectomy; no change in preop to postop AMH after hysterectomy in OBS or no OBS Underpowered to make any conclusions
Poor
TLH + OBS (34) vs TLH (34)
125 (75-200) vs 150 (100-225) (p=.355)
Median (range) 95 (69-110) vs 90 (65-106) (p=.547)
0 vs 2 (5.9%)(ileus, vag bleeding) p=.493
Median in days (range) 3 (2-3) vs 3 (2-3) p=.342
RI PT AMH decline 12.5% (0.8-60.9%)vs 10.8% (6.9-27.4%) did not differ between groups p=.898; no difference in EBL, OR time, LOS, complications
SC
Song et al. 2016
Underpowered to detect a difference. No sample size calculation. Small sample size. Single institution. 53% have had prior tubal sterilization. No long term follow up. Good
Sample size calculation. multicenter. 3 month follow up.
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N = sample size; EBL = estimated blood loss; OR = operating room; LOS = length of stay; TLH = total laparoscopic hysterectomy; OBS = opportunistic bilateral salpingectomy; preop = preoperative; postop = postoperative; AMH = anti-mullerian hormone; vag = vaginal.
ACCEPTED MANUSCRIPT Table 1. Retrospective comparative studies evaluating surgical outcomes after opportunistic bilateral salpingectomy (OBS) in lowrisk premenopausal women. Study
Type procedure (N)
EBL (ml)
OR time (min)
Complications
LOS (day)
Major Findings
Quality Rating
Ghezzi et al 2009
TLH + OBS(139) vs TLH (145)
100 (10-600) vs 100 (10-1050)
80 (30-245) vs 90 (30-300)
1 (1-6) vs 2 (1-10)
(p = .35)
Preservation of fallopian tube has OR 4.9 (95% CI 1.1 - 22.9) for infectious morbidity. *not well-adjusted for other covariables
Good
(p = .10)
Lower rate of infections in patients who had TLH+OBS compared to TLH alone (2.2% vs 9.6%; p= 0.01; 95% CI, 1.9-13.5%)
45.6 + 28.0 vs 100 +150.8 (p=.267)
106.32 + 46.4 vs 115.3 + 43.41 (p=.233)
“None attributable to OBS”
3.16 + 0.37 vs 3.44 + 0.65 (p=.091)
LASH + OBS (25) vs LASH (25)
EBL not completely measured and disregarded in one case of hemorrhage
0 vs 0
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81.7+14.8 vs 83.3 +18.6 (p=.79)
2.5 + 0.8 vs 2.7 + 0.8 (p=.16)
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∆Hgb (g/dL) 1.1 + 0.9 vs 1.2 + 0.7 (p=.41)
Concomitant OBS did not result in any statistically sig difference in EBL, OR time or LOS. *Only intraop and immediate postop followup. No longterm data
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TLH + OBS (79) vs TLH (79 matched by uterine weight)
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Morelli et al 2013
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Berlit et al. 2013
(p=.002)
Main objective: post op infection. Sample size calc. Used prospective cohort with historical control. One month follow up.
Days to return to normal activity is not different in both groups 15.0 + 4.4 vx 13.9 +4.8 (p =.11) No difference in change in AMH, FSH, Estradiol, Average follicle count, mean ovarian diameter,
Poor
Small sample. No sample size calculation. One surgeon study. No advanced analysis. One case of hemorrhage excluded from EBL analysis. Fair Sample size calculation. Potential confounders not addressed.
ACCEPTED MANUSCRIPT McAlpine et al 2014
Hyst* + OBS (3671) vs Hyst (8362) *Hysterectomy type: abdominal, laparoscopic and vaginal
No difference in blood transfusion rate of 2.5% across both groups. aOR Hyst + OBS compared to Hyst: 0.86 (95% CI, 0.671.10) (p=.54)
Compared to hyst alone, additional operating room time for OBS was 16.3 min (p<.001) Hyst + OBS: 133.6 + 50.1 vs Hyst: 117.3 + 47.7 (p<.001)
Compared to hyst alone, no difference in hospital readmission.
peak systolic velocity
2.34 + 1.9 vs 2.52 + 3.0 (p=.010)
Hyst + OBS: 4.3% (159/3670) vs Hyst:4.5% (379/8362)
LAVH + OBS (127) vs LAVH (413)
NA
142.97 + 63.31 vs 139.72 + 49.31 (p=.55)
Clavien-Dindo system: Total complications: 24 cases vs 73 (p=.79)
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Gr III complications: 4 vs 28 (p=.19)
4.93 +1.51 (SD) vs 5.11 + 1.82 (p=.31)
Follow up survey (54.6% response rate). In a follow up period of 55.21 + 7.92 mos for OBS and 92.32 + 16.96 months for nonOBS (p <.01), 26.91% (60/413) of non-OBS had postop adnexal path requiring med or surg treatment; (28 surg reinterventions) for ov cysts (33), hydrosalpinx (8), pyosalpinx (1), adnexitis(18) vs 10/127 (13.88% of OBS group) had adnexal
Fair
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Vorwergk et al 2014
Good Large sample in each group with few missing data
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aOR Hyst +OBS compared to Hyst: 0.91 (95% CI, 0.751.10 (p=.632)
OBS was more likely to be performed with TAH (44%) compared to VH (19%), TLH (15%) and LAVH (22%). Compared to open approach, vag approach for hyst with OBS was associated with significantly shorter OR time (112 min; p<.001), LOS and decreased risk for hosp readmission (OR=0.51, 95%CI 0.37, 0.70)
No sample size calculation. Patients converted to laparotomy were excluded. 54.6% survey response rate. Long follow up.
ACCEPTED MANUSCRIPT
Hyst (TLH and TAH) + OBS (97) vs Hyst (71)
126.2 + 100.4 vs 143.2 + 83.5
87.1 + 26.2 vs 94.0 + 31.1
(p=.095)
(p=.119)
Intra-op surgical complications: 4/97=4.1% vs 4/71=5.6% (p=.723)
43.7 + 22.4 hours vs 53.9 + 26.5 hours (p=.008)
Postop complications in Hyst +OBS (12/97) 12.4% vs 8/71=11.3% (p=.827)
(p=<.001)
All routes Hyst + OBS (52,280)
No difference in transfusion rate:
NA
NA
No difference in postop
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Hanley et al 2016
TLH (OBS shorter operative time) 147 vs 152 (p=.002) TAH 155 vs 142 (p=.08) TVH 115 vs 150 (p=.56)
TLH (h) 4 vs 4.9 (p<.001) TAH 45 vs 46 (p=.12) TVH 19 vs 24 (p<.001)
OR time and LOS was significantly shorter in OBS group in patients undergoing laparoscopic route.
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100 (50-200) vs 150 (50-250)
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All routes Hyst +OBS (4,154) vs Hyst (3,344)
Fair No sample size calculation 30 day follow up
Readmission/ED Hyst+OBS=(13/97) 13.4% vs (9/71) 12.7% (p=.890)
Garcia et al 2016
OBS does not worsen surgical outcomes
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Minig et al. 2015
pathologies (p=.02) Rate of hysterectomyrelated surgical reintervention in OBS = 4.16%vs 12.56% in non-OBS (p=.04)
No difference in LOS
TLH were more likely to have OBS (60.5) than TAH (24.6%) and TVH (16.5%)
No difference in blood transfusion,
Good
Large sample size. Potential confounders not addressed
Good
vs Hyst (934,712)
ACCEPTED MANUSCRIPT complications Hyst + OBS:
aOR 0.95 (95% C.I. 0.86-1.05) Hyst +OBS 6.0% Hyst 6.2%
aOR 0.97 (95% CI, 0.88-1.07) No difference in infection incidence Hyst +OBS: 0.4% Hyst: 0.4%
Median 2 (range 12) days Hyst: median 2 (range 1-2) days
postop complications, postop infections, fever between women with hyst +OBS and hyst Hyst +OBS performed more often laparoscopically (44.6%) vs abd(42%), vag (11%), rob (1.6%)
No difference in fever incidence Hyst +OBS: 0.8% Hyst: 0.6%
Large sample size: Nationwide Inpatient Sample Exclusion criteria clearly stated
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N = sample size; EBL = estimated blood loss; OR = operating room; LOS = length of stay; TLH = total laparoscopic hysterectomy; OBS = opportunistic bilateral salpingectomy; CI = confidence interval; OR = odds ratio; LASH = laparoscopic supracervical hysterectomy; ∆Hgb = change in hemoglobin; AMH = anti-mullerian hormone; FSH = follicular stimulating hormone; Hyst = hysterectomy; aOR = adjusted odds ratio; TAH = total abdominal hysterectomy; VH = vaginal hysterectomy; LAVH = laparoscopicassisted vaginal hysterectomy; NA = not available; Gr = grade; ov = ovarian; postop = postoperative.
ACCEPTED MANUSCRIPT
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Additional records identified through other sources (n = 23 )
Records identified through database searching (n = 2250)
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Identification
Figure 1
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Records excluded (n = 263)
Full-text articles assessed for eligibility (n = 46)
Full-text articles excluded, for the following reasons:
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Abstracts screened (n = 309)
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Included
Eligibility
Screening
Titles reviewed after duplicates removed (n = 1200)
review only, participants had BRCA mutation, involved tubal ligation, included oophorectomy cases, did not specify bilateral salpingectomy during hysterectomy, provided no comparison group (case series), non-English, meeting abstract only, study not yet completed
(n = 36) Studies included in quantitative synthesis (meta-analysis) (n = 10)