Background
The fallopian tube may often be the site of origin for the most common and lethal form of ovarian cancer, high-grade serous ovarian cancer. As a result, many colleges of obstetrics and gynecology, which include the American College of Obstetricians and Gynecologists, are recommending surgical removal of the fallopian tube (bilateral salpingectomy) at the time of other gynecologic surgeries (particularly hysterectomy and tubal sterilization) in women at general population risk for ovarian cancer, collectively referred to as opportunistic salpingectomy. Previous research has illustrated no increased risk of complications after opportunistic salpingectomy. However, most studies that have examined potential hormonal consequences of opportunistic salpingectomy have had limited follow-up time and have focused on surrogate hormonal markers.
Objective
We examine whether there are differences in physician visits for menopause and filling a prescription for hormone replacement therapy among women who undergo opportunistic salpingectomy in the population of British Columbia, Canada.
Study Design
We identified all women who were ≤50 years old in British Columbia who underwent opportunistic salpingectomy from 2008–2014. We compared women who underwent opportunistic salpingectomy at hysterectomy with women who underwent hysterectomy alone and women who underwent opportunistic salpingectomy for sterilization with women who underwent tubal ligation. We used Cox Proportional hazards models to model time to physician visits for menopause and for filling a prescription for hormone replacement therapy. We calculated adjusted hazards ratios for these outcomes and adjusted for other gynecologic conditions, surgical approach, and patient age. We performed an age-stratified analysis (<40, 40–44, 45–49 years) and conducted a sensitivity analysis that included only women with ≥5 years of follow up.
Results
We included 41,413 women in the study. There were 6861 women who underwent hysterectomy alone, 6500 who underwent hysterectomy with opportunistic salpingectomy, 4479 who underwent hysterectomy with bilateral salpingo-oophorectomy, 18,621 who underwent tubal ligation, and 4952 who underwent opportunistic salpingectomy for sterilization. In women who underwent opportunistic salpingectomy, there was no difference in time to the first physician visit related to menopause for both women who underwent hysterectomy with opportunistic salpingectomy (adjusted hazard ratio, 0.98; 95% confidence interval, 0.88–1.09) and women who underwent opportunistic salpingectomy for sterilization (adjusted hazard ratio, 0.92; 95% confidence interval, 0.77–1.10). There was also no difference in time to filling a prescription for hormone replacement therapy for women who underwent hysterectomy with opportunistic salpingectomy or opportunistic salpingectomy for sterilization (adjusted hazard ratio, 0.82; 95% confidence interval, 0.72–0.92; and adjusted hazard ratio, 1.00; 95% confidence interval, 0.89–1.12; respectively). In contrast, we report significantly increase hazards for time to physician visit for menopause (adjusted hazard ratio, 1.95; 95% confidence interval, 1.78, 2.13) and filling a prescription for hormone replacement therapy (adjusted hazard ratio, 3.80; 95% confidence interval, 3.45, 4.18) among women who underwent hysterectomy with bilateral salpingo-oophorectomy. There were no increased hazards for physician visits for menopause or initiation of hormone replacement therapy among women who underwent opportunistic salpingectomy in any of the age-stratified analyses, nor among women with at least 5 years of follow up.
Conclusion
Our results reveal no indication of an earlier age of onset of menopause among the population of women who underwent hysterectomy with opportunistic salpingectomy and opportunistic salpingectomy for sterilization as measured by physician visits for menopause and initiation of hormone replacement therapy. Our findings are reassuring, given that earlier age at menopause is associated with increased mortality rates, particularly from cardiovascular disease.
Ovarian cancer remains an important cause of death in the developed world, accounting for more deaths than any other cancer of the female reproductive tract. Currently, there remains no effective screening methods because no mortality benefit has been demonstrated, even with strict adherence to screening protocols, and no recent advances in treatment have significantly improved overall survival. We now recognize that epithelial ovarian cancer encompasses 5 distinct diseases that differ in histologic appearance, clinical presentation, response to therapy, likelihood of recurrence, molecular aberrations, and, most important for prevention purposes, site of origin. , There has been a growing body of evidence pointing to the fallopian tube as the origin of the most common form of ovarian cancer, high-grade serous carcinoma.
Why was this study conducted?
The purpose of this study was to examine whether opportunistic salpingectomy, the removal of fallopian tubes at the time of hysterectomy or in lieu of tubal ligation for the purpose of ovarian cancer prevention, is associated with a decreased age of onset of menopause.
Key findings
There are no differences in time to physician visits for menopause or time to the initiation on hormone replacement therapy among women who undergo opportunistic salpingectomy compared with women who undergo hysterectomy alone or tubal ligation.
What does this add to what is known?
This study adds to the existing body of evidence that opportunistic salpingectomy is a safe alternative to hysterectomy alone or tubal ligation, with the potential benefit of ovarian cancer risk reduction.
Many professional associations are recommending that clinicians discuss the removal of the fallopian tubes (bilateral salpingectomy) among women at general population risk of ovarian cancer who have completed childbearing and are undergoing (1) hysterectomy with ovarian preservation and (2) tubal ligation. This procedure is known as opportunistic salpingectomy (OS). Recommendations for OS were made by the Ovarian Cancer Research team in British Columbia in 2010. Since then, the American College of Obstetricians and Gynecologists and the Society of Obstetricians and Gynecologists of Canada have endorsed the recommendation. ,
Previous research has indicated a substantial uptake of OS in both the United States and Canada. The safety research done to date that has examined both major perioperative events , and minor complications has been reassuring. All data indicate that OS poses no additional risk to hysterectomy alone or tubal ligation. Studies that have examined ovarian function after these procedures have often been small and have focused on surrogate hormonal markers. For example, measurement of ovarian sonographic parameters and hormonal assays were reassuring, with no differences seen in women who undergo hysterectomy with OS vs hysterectomy alone. One series has reported up to 5 years of follow-up data with no negative impact on reported ovarian parameters. However, a recent Swedish Registry study found an increased risk of menopausal symptoms 1 year after hysterectomy among women who underwent hysterectomy with bilateral salpingectomy compared with hysterectomy alone (relative risk, 1.33; 95% confidence interval [CI], 1.04–1.69). Given that an earlier age at menopause has been associated with increased mortality rates, it is imperative that we understand whether OS decreases the age of onset of menopause. Herein, we use population-based data in British Columbia, Canada, to examine indicators of menopause, namely physician visits for menopause or the initiation of hormone replacement therapy (HRT) among women who undergo OS and women who undergo comparator surgeries.
Methods
We conducted a population-based retrospective cohort study of all women who were ≤50 years old at the time that they underwent a hysterectomy or tubal sterilization in the Canadian province of British Columbia, Canada, (population 4.6 million) from 2008–2014. We obtained approvals from all relevant data stewards and worked with Population Data British Columbia to access the British Columbia Cancer Registry, vital statistics death data, the Discharge Abstract Database, which contains all hospital stays and day surgeries in the province, thus capturing all women who underwent a relevant surgical procedure. These data were then linked with data on all physician visits, and the British Columbia PharmaNet (a database that contains all prescriptions drugs dispensed in an outpatient setting). Ethics approval was obtained from the University of British Columbia’s Behavioural Research Ethics Board. All inferences, opinions, and conclusions are those of the authors and do not reflect the opinions or policies of the Data Stewards.
Women who underwent any of the relevant surgical procedures were identified with the use of the Canadian Classification of Health Intervention codes. This system separately identifies each procedure that is performed in the same surgery. For example, a woman who undergoes a hysterectomy with a bilateral salpingectomy has a code that indicates the removal of her uterus and a code that indicates the removal of her fallopian tubes. These codes also indicate the surgical approach for each surgery (ie, open, laparoscopic, or vaginal). We excluded women who were <15 years old or >50 years old at the time of the surgery. We excluded women who had a diagnosis of gynecologic cancer and women who had <183 days (approximately 6 months) of follow-up time after their surgery. We grouped women according to their procedures and stratified the data into 5 groups: (1) women who had undergone a hysterectomy with no concomitant oophorectomy or salpingectomy (referred to as hysterectomy alone), (2) women who underwent a hysterectomy and a bilateral salpingectomy (hysterectomy with OS), (3) women who underwent a hysterectomy with a bilateral salpingo-oophorectomy (BSO), (4) women who underwent a tubal ligation, and (5) women who had a bilateral salpingectomy alone with a diagnosis code that indicated the procedure was for sterilization (International Classification of Diseases, 10th revision [ICD-10], CM Z.30.2). We did not include women who underwent hysteroscopic tubal occlusion. We also used diagnostic codes in the hospital stay to examine other gynecologic conditions that were present in each woman, which included endometriosis (ICD-10, CA N80.X), leiomyoma (ICD-10, CA D25.X), benign ovarian or uterine neoplasm (ICD-10, CA D26.X, D27.X, D28.7), abnormal bleeding (ICD-10, CA N92.X, N93.X), pelvic organ prolapse (ICD-10, CA N81.X), pelvic inflammatory disease (ICD-10, CA N73.X, N74.X), and hydrosalpinx (ICD-10, CA N70.X).
Indicators of menopause
We examined 2 separate indicators that a woman was having menopausal symptoms. The first was a physician visit for menopausal or postmenopausal disorders (ICD-9th revision, CM 627), which includes visits for menopausal symptoms. Our data included all physician visits for all women in our dataset, regardless of the provider or the indication for the visit. The second indicator was filling a prescription for HRT, which included all formulations of estrogen alone and all formulations of estrogen, including vaginal, topical and transdermal, and progestin (identified with the use of Anatomical Therapeutic Chemical Classification 3 codes G03A, G03C, G03D, and Anatomical Therapeutic Chemical Classification 4 code L02AA).
Statistical analysis
We examined differences between rates of visits to physicians and the initiation of HRT between women who underwent OS or hysterectomy with BSO and women who underwent the comparator surgery (hysterectomy alone is the comparator for all hysterectomies and tubal ligation is the comparator for OS for sterilization) with the use of chi-squared tests for categoric variables and independent sample t -tests for continuous variables. All statistical tests were 2-sided, and a probability value of <.05 was considered to indicate statistical significance. We used Cox Proportional hazards models to model time to physician visits for menopause and for filling a prescription for HRT and controlled for patient age at surgery, other gynecologic conditions (listed earlier), year of surgery, and surgical approach. We censored our data when a woman died and when she moved outside of the province. An age-stratified analysis (<40, 40–44, 45–49 years old) was performed and controlled for the same variables as the non–age-stratified analysis, except for age. We also conducted a sensitivity analysis that included only women with at least 5 complete years of follow up and only women who had reached age 50 by the end of follow up.
Results
There were 51,352 women who had undergone a hysterectomy alone, a hysterectomy with OS, a hysterectomy with BSO, a tubal ligation, or an OS for sterilization from 2008–2014 in British Columbia, Canada. We eliminated women who were ≤15 years old at the time of surgery (number omitted because of small cell size) and women who were ≥50 years old (n=6078). We also excluded women who had <183 days of follow up (n=3041) or women who were coded as having a gynecologic cancer (n=819), which resulted in a final cohort of 41,413 women. In this study population, 6861 women underwent hysterectomy alone; 6500 underwent hysterectomy with OS; 4479 underwent hysterectomy with BSO; 18,621 underwent tubal ligation, and 4952 underwent OS for sterilization.
Table 1 illustrates characteristics of women who underwent each of these procedures in our cohort. Because recommendations for OS were published in September 2010, the mean year of surgery is significantly later among women who underwent OS. Women who underwent hysterectomy with OS were significantly more likely to experience comorbid gynecologic conditions compared with women who underwent hysterectomy alone, except that they were significantly less likely to have a prolapse (7.0% vs 13.3%; P <.001) and that there was no difference in rates of pelvic inflammatory disease. Women who underwent hysterectomy with BSO had even higher rates of the comorbid gynecologic conditions, with the exception of prolapse and abnormal bleeding, which were slightly less common in this group. There were no differences in income quintiles, and women who underwent hysterectomy with BSO were significantly older at surgery (43.4 vs 41.5 years; P <.001). The mean length of follow up was longer in women who underwent hysterectomy alone (4.8 years) compared with women who underwent hysterectomy with OS (2.7 years).
| Variable | Hysterectomy alone (n=6891) | Hysterectomy with opportunistic salpingectomy (n=6500) | P value a | Hysterectomy with bilateral salpingo-opphorectomy (n=4479) | P value a | Tubal ligation (n=18,621) | Opportunistic salpingectomy for sterilization (n=4952) | P value |
|---|---|---|---|---|---|---|---|---|
| Year of surgery, calendar year mean (SD) | 2009.6 (1.6) | 2011.8 (1.5) | <.001 | 2010.5 (1.6) | <.001 | 2010.1 (1.8) | 2012.3 (1.2) | <.001 |
| Age at time of surgery, y b | 41.5±5.7 | 42.0±5.3 | <.001 | 43.4±5.5 | <.001 | 35.3±5.6 | 36.3±5.4 | <.001 |
| Mean length of follow-up, y b | 4.8±1.5 | 2.7±1.5 | <.001 | 3.9±1.8 | <.001 | 4.3±1.8 | 2.2±1.1 | <.001 |
| Age category, y (%) | ||||||||
| <40 | 2419 (35.3) | 2040 (31.4) | 1029 (23.0) | 14634 (78.6) | 3652 (73.7) | |||
| 40–44 | 2244 (32.7) | 2224 (34.2) | 1262 (28.2) | 3287 (17.7) | 1032 (20.8) | |||
| 45–50 | 2198 (32.0) | 2236 (34.4) | <.001 | 2188 (48.9) | <.001 | 701 (3.8) | 270 (5.5) | <.001 |
| Delivered a baby in the same hospital stay, n (%) | 65 (1.0) | 14 (0.2) | <.001 | 13 (0.3) | <.001 | 7790 (41.8) | 1777 (35.9) | <.001 |
| Income quintile, n (%) | ||||||||
| 1 | 1275 (18.8) | 1237 (19.3) | 873 (19.8) | 4194 (22.9) | 1073 (21.9) | |||
| 2 | 1396 (20.6) | 1298 (20.2) | 942 (21.3) | 4275 (23.3) | 1055 (21.5) | |||
| 3 | 1450 (21.4) | 1339 (20.9) | 946 (21.4) | 3840 (20.9) | 1040 (21.2) | |||
| 4 | 1455 (21.4) | 1386 (21.6) | 878 (19.9) | 3386 (18.5) | 971 (19.8) | |||
| 5 | 1209 (17.8) | 1153 (18.0) | .898 | 777 (17.6) | .262 | 2654 (14.5) | 759 (15.5) | .009 |
| Comorbid gynecologic conditions, y (%) | ||||||||
| Endometriosis | 1269 (18.5) | 1378 (21.2) | <.001 | 1639 (36.6) | <.001 | 427 (2.3) | 196 (4.0) | <.001 |
| Uterine leiomyoma | 2590 (37.8) | 2832 (43.6) | <.001 | 1833 (40.9) | .001 | 154 (0.8) | 42 (0.9) | .886 |
| Benign uterine or ovarian neoplasm | 73 (1.1) | 117 (1.8) | <.001 | 429 (9.6) | <.001 | 119 (0.6) | 89 (1.8) | <.001 |
| Prolapse | 912 (13.3) | 450 (7.0) | <.001 | 132 (3.0) | <.001 | 118 (0.6) | 30 (0.6) | .824 |
| Abnormal bleeding | 4210 (61.4) | 4096 (63.0) | .049 | 1806 (40.3) | <.001 | 1251 (6.7) | 498 (10.0) | <.001 |
| Pelvic inflammatory disease | 200 (2.9) | 219 (3.4) | .132 | 487 (10.9) | <.001 | 322 (1.7) | 147 (3.0) | <.001 |
| Hydrosalpinx | 27 (0.4) | 103 (1.6) | <.001 | 179 (4.0) | <.001 | 168 (0.9) | 28 (0.6) | .004 |
| Surgical approach, n (%) | ||||||||
| Abdominal/open | 2976 (43.4) | 3000 (46.2) | .001 | 3104 (69.3) | <.001 | 8036 (43.2) | 1908 (38.5) | <.001 |
| Laparoscopic | 568 (8.3) | 2620 (40.3) | <.001 | 1194 (26.7) | <.001 | 10,493 (56.4) | 3128 (63.1) | <.001 |
| Vaginal | 3259 (47.5) | 1104 (17.0) | <.001 | 364 (8.1) | <.001 | 2039 (11.0) | 691 (14.0) | <.001 |
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