Practice Patterns and Complications of Benign Hysterectomy
Following the FDA Statement Warning Against the Use
of Power Morcellation
Francesco Multinu, MD; Jvan Casarin, MD; Kristine T. Hanson, MPH; Stefano Angioni, MD; Andrea Mariani, MD; Elizabeth B. Habermann, PhD, MPH; Shannon K. Laughlin-Tommaso, MD
IMPORTANCEIn November 2014, the US Food and Drug Administration (FDA) issued a black box warning against the use of power morcellation for excision of uterine fibroids to decrease the risk of disseminating malignant cells and worsening survival outcomes of patients with unexpected malignant neoplasms. After the FDA statement was issued, studies showed decreased rates of minimally invasive surgery and increased rates of open abdominal hysterectomy. However, there are limited and controversial data on the association of these changed rates with 30-day hysterectomy complications.
OBJECTIVETo assess changes in the rates of 30-day major and minor complications of hysterectomy for benign gynecologic indications following the FDA-issued statement. DESIGN, SETTING, AND PARTICIPANTSThis retrospective cohort study used the American College of Surgeons National Surgical Quality Improvement Program database and included 603 hospitals participating between January 1, 2013, and December 31, 2015. Thirty-day posthysterectomy complications were compared before and after the FDA-issued warning. Women who underwent hysterectomy for benign gynecologic indications (n = 75 487), including hysterectomies with indication of uterine fibroids (n = 25 571), were included. Complication rates and procedure distributions between the periods were compared with χ2 tests and multivariable logistic regression controlling for patient and operative factors. MAIN OUTCOMES AND MEASURES Major and minor 30-day complication rates before (from 2013 through the first quarter of 2014) and after (from the fourth quarter of 2014 through 2015) the FDA-issued warning.
RESULTS Of 75 487 women (mean [SD] age, 47.8 [10.7] years) who underwent hysterectomy for benign gynecologic indications, 32 186 (42.6%) were treated before and 43 301 (57.4%) after the FDA-issued warning. Non-Hispanic white women comprised most (59.4%) of the total population, followed by African American women (15.1%). Overall, major and minor complications remained stable before and after the FDA-issued warning. By contrast, among a subset of 25 571 women (33.9%) who underwent hysterectomy for uterine fibroids, major complications significantly increased after the FDA-issued warning from 1.9% to 2.4% (adjusted odds ratio [OR], 1.23; 95% CI, 1.04-1.47; P = .02), and minor complications significantly increased from 2.7% to 3.3% (adjusted OR, 1.21; 95% CI, 1.04-1.40; P = .01). In this subgroup, the rate of open abdominal surgery increased from 37.2% to 43.0%, and the rate of minimally invasive surgery (total laparoscopic hysterectomy, laparoscopic
supracervical hysterectomy, and laparoscopic-assisted vaginal hysterectomy) decreased from 56.1% to 49.7% (P < .001).
CONCLUSIONS AND RELEVANCEMajor and minor 30-day complication rates among women undergoing hysterectomy for uterine fibroids increased following the FDA-issued statement. This increased risk corresponding with a decreased use of minimally invasive surgery should be balanced against the potential harms of morcellation during a shared decision-making process between clinician and patient. Regulatory bodies and medical societies should consider these findings when issuing relevant communications.
JAMA Surg. 2018;153(6):e180141. doi:10.1001/jamasurg.2018.0141 Published online April 11, 2018.
Supplemental content
Author Affiliations: Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota (Multinu, Casarin, Mariani, Laughlin-Tommaso); Division of Gynecology and Obstetrics, Department of Surgical Sciences, University of Cagliari, Cagliari, Italy (Multinu, Angioni); Department of Surgery, Mayo Clinic, Rochester, Minnesota (Hanson, Mariani, Laughlin-Tommaso); Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota (Habermann). Corresponding Author: Shannon K. Laughlin-Tommaso, MD, Department of Obstetrics and Gynecology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (laughlintommaso.shannon @mayo.edu).
H
ysterectomy is the most commonly performed gyne-cologic procedure, with more than 600 000 per-formed annually in the United States.1,2Uterine fibroids represent the most common indication, accounting for approximately 40% of all hysterectomies performed.3 By contrast, uterine leiomyosarcoma is a rare and aggressive cancer, occurring in 0.4 to 0.64 cases per 100 000 women,4,5 that can present as a myometrial mass resembling a benign uterine fibroid. Presumed benign fibroids can be treated by medical and surgical approaches.
When an operation is required, most women prefer mini-mally invasive surgery (MIS) that is less invasive, has a short re-covery time,6
and has lower associated complications compared with those following open abdominal surgical procedures.7 Minimally invasive surgical procedures, however, may require the morcellation of the uterus inside the peritoneal cavity to remove the uterus through a smaller incision or through the vagina. The process of morcellation carries the risk of dissemi-nating benign or malignant disease.8In the latter case, dissemi-nation of malignant tissue would increase the risk of recurrence and shorten survival.9,10As a consequence, in April 2014, the US Food and Drug Administration (FDA) issued a safety com-munication statement “discouraging” the use of laparoscopic power morcellation for patients with uterine fibroids.11 Subse-quently, in November 2014, the FDA “warned against” the use of uterine power morcellation,12
issuing “contraindications” for its use for “peri- and post-menopausal” women and for patients with “suspected or known malignancy.”
Following the issue of the FDA warning, many institu-tions discouraged the use of any morcellation and banned the use of the power morcellator; there was a subsequent de-crease in the use of power morcellation during surgical pro-cedures among women who underwent a minimally invasive hysterectomy from 13.7% in early 2013 to 2.8% in early 2015.13 Moreover, the results of 2 surveys of gynecologists evaluat-ing the influence of the FDA warnevaluat-ing on management strate-gies in hysterectomy and myomectomy showed that a large proportion of respondents shifted from the use of MIS to the use of a larger incision or open abdominal procedures, raising concerns about an increase of surgical complications.14,15
Fur-thermore, the FDA decision was criticized for overestimating the risk associated with using power morcellation compared with the risk associated with preventing its use in a large group of women who could receive benefits from morcellation.16 However, evaluating the contribution of the FDA statement to complications of hysterectomy to date has provided contro-versial results.13,17-19
Most importantly from a patient perspective, a survey dis-tributed to more than 300 women in gynecologic waiting rooms regarding the consequence of limiting access to MIS and lim-iting women’s choices indicated that at the 1 in 350 risk of a malignant tumor reported by the FDA, the majority of women would still choose an MIS approach.20
The present study used the American College of Sur-geons National Surgical Quality Improvement Program (ACS NSQIP) database to overcome the limitations of previous stud-ies because data on complications up to 30 days after the in-dex surgery are collected. We evaluated 30-day major and
minor complications associated with hysterectomy before and after the FDA issued the warning statement about the use of power morcellators.
Methods
Database
Details about sampling methods, data abstraction proce-dures, variables, and outcomes collected by the ACS NSQIP database are described elsewhere.21In brief, the ACS NSQIP database is a prospective, validated, multicenter, clinical data registry designed to facilitate, measure, and enhance the qual-ity of surgical care by providing hospitals with detailed re-ports of their risk-adjusted outcomes. The Mayo Clinic insti-tutional review board deemed this study exempt from requiring approval because the data were deidentified.
Data on more than 150 variables, including demographic characteristics, preoperative risk factors, laboratory test re-sults, operative details, and postoperative outcomes up to 30 days after the index operation are collected from 603 partici-pating academic and nonacademic hospitals. Data collection is performed directly from the medical record by trained data abstractors at each participating hospital, with regular onsite audits aimed to ensure data reliability.
Study Population
The analysis was restricted to patients who underwent hysterectomy for a benign gynecologic indication. Current
Procedural Terminology codes were used to identify patients
who underwent hysterectomy. Indications for hysterectomy were identified using the International Classification of
Diseases, Ninth and Tenth Revision diagnosis codes. We
excluded patients with associated procedures indicating the presence of malignant neoplasms or those who underwent hysterectomy with an indication of malignant neoplasm or uncertain behavioral diseases, as well as patients who under-went a pregnancy-related hysterectomy or an emergent hys-terectomy, in which emergent was identified as patients with
Key Points
QuestionDid 30-day complication rates change among women undergoing hysterectomy for benign gynecologic indications following the US Food and Drug Administration warning against power morcellation?
FindingsIn a cohort of 75 487 patients who underwent hysterectomy for benign gynecologic indications, statistically and clinically significant increases in major and minor complications were observed following the warning in a subset of 25 571 women with uterine fibroids.
MeaningThat potential harms were associated with decreased rates of minimally invasive surgery following reduced morcellation use should be considered by clinicians and patients during shared decision making and by regulatory bodies and medical societies issuing communications on minimally invasive hysterectomy and morcellation among women with uterine fibroids.
American Society of Anesthesiologists class 5; ventilator de-pendence; preoperative systemic inflammatory response syndrome, sepsis, or septic shock; preoperative open wound; preoperative acute renal failure; more than 4 transfusions with packed red blood cells 72 hours prior to surgery; or preopera-tive dialysis. An MIS was defined as total laparoscopic hyster-ectomy, laparoscopic supracervical hysterhyster-ectomy, or laparo-scopic-assisted vaginal hysterectomy. Details of study cohort selection are reported in eTables 1 to 5 in theSupplement.
Study Outcomes
Primary outcomes were 30-day major and minor complica-tions. For evaluating the 30-day outcomes before and after the FDA statement, complications following hysterectomies per-formed from the first quarter of 2013 through the first quar-ter of 2014 (defined as pre-FDA) were compared with those from the fourth quarter of 2014 through the fourth quarter of 2015 (defined as post-FDA). Hysterectomies performed dur-ing the period of transition between the 2 FDA statements (the second through the third quarters of 2014) were excluded. Major complications were defined as unplanned intubation, wound disruption, ventilator use of more than 48 hours, sep-sis, septic shock or systemic inflammatory response syn-drome, pneumonia, deep incisional surgical site infection, acute renal failure, organ space surgical site infection, pro-gressive renal insufficiency, pulmonary embolism, myocar-dial infarction, cardiac arrest requiring cardiopulmonary resuscitation, stroke or cerebrovascular accident with neuro-logical deficit, deep vein thrombosis, or thrombophlebitis. Minor complications were defined as any urinary tract infec-tion or superficial surgical site infecinfec-tion. Routes of hysterec-tomy for benign gynecologic indications were compared be-tween pre- and post-FDA periods.
Statistical Analysis
Two-tailed χ2
tests and unpaired, 2-tailed t tests were used to compare complication rates, procedure distributions, and pa-tient factors between pre-FDA and post-FDA periods among all women who underwent hysterectomy for benign gynecologic indications as well as in the subset of women with an indica-tion of uterine fibroids. Multivariable logistic regression com-pared odds of complications before the FDA statement (com-bining all hysterectomies performed from the first quarter of 2013 through the first quarter of 2014) and after the FDA state-ment (combining all hysterectomies performed from the fourth quarter of 2014 through the fourth quarter of 2015) after con-trolling for age, race/ethnicity, body mass index (≥30 vs <30; cal-culated as the weight in kilograms divided by the height in me-ters squared), functional status, corticosteroid use for chronic conditions, preoperative platelet count (reference range of 150-450 × 103
/μL vs lower vs higher [to convert to ×109 per li-ter, multiply by 1.0]), preoperative hematocrit (reference range of 34.9%-44.5% vs lower vs higher [to convert to proportion of 1.0, multiply by 0.01]), preoperative serum albumin level (ref-erence range of 3.5-5.0 g/dL vs lower vs higher [to convert to grams per liter, multiply by 10]), hypertension requiring medi-cations, preoperative serum creatinine level (reference range of 0.6-1.1 mg/dL vs lower vs higher [to convert to micromoles per
liter, multiply by 88.4]), diabetes with oral agent or insulin ad-ministration, smoking status within 1 year, American Society of Anesthesiologists class (1-2 vs 3-4 [healthy to mild systemic dis-ease and severe systemic disdis-ease to constant life threat, respec-tively]), and abdominal, extra-abdominal, upper-abdominal, or other associated procedures (yes vs no). Models, including that for all women with benign gynecologic indications, were also controlled for hysterectomy indication. To verify that in-creases in the complication rates observed among women with uterine fibroids differed compared with the increases among women with all other benign indications, we performed a sec-ondary analysis among all women with benign conditions that included the interaction between indication (uterine fibroids vs all other benign indications) and period (pre-FDA vs post-FDA) in a multivariable logistic regression model of major com-plications, controlling for the aforementioned factors. Statisti-cal analysis was performed using SAS, version 9.4 (SAS Institute Inc). All P values were 2-sided and were considered statisti-cally significant at P < .05.
Results
Patient Characteristics
The characteristics of women who underwent hysterectomy for benign indications and for uterine fibroids in the pre- and post-FDA periods are reported in Table 1. In total, 75 487 women underwent hysterectomy for benign indications, of whom 32 186 (42.6%) were treated in the pre-FDA period and 43 301 (57.4%) were treated in the post-FDA period. The most com-mon indications for hysterectomy were uterine fibroids (33.9%), irregular bleeding (24.6%), and pelvic organ pro-lapse or urinary incontinence (15.8%). The mean (SD) age was 47.8 (10.7) years, and the mean (SD) body mass index was 30.4 (7.4). Non-Hispanic white women comprised most (59.4%) of the population, followed by African American women (15.1%). In a subgroup of 25 571 women (33.9%) treated for an in-dication of uterine fibroids, 10 903 (42.6%) underwent hys-terectomy in the pre-FDA period and 14 668 (57.4%) in the post-FDA period. For this entire subgroup, the mean (SD) age was 46.9 (7.2) years, and mean (SD) body mass index was 30.6 (7.2). The proportion of African American women was almost double (27.0%) compared with the entire cohort of women treated for a benign indication (15.1%), whereas the proportion of Non-Hispanic white women was lower (44.9%).
Trends in Routes of Hysterectomy
From Pre- to Post-FDA Period
Among 75 487 women who underwent hysterectomy for benign gynecologic indications, open abdominal hysterectomy increased from 24.0% during the pre-FDA period to 26.1% during the post-FDA period (Figure 1). The use of MIS decreased from 57.3% dur-ing the pre-FDA period to 55.4% durdur-ing the post-FDA period, while vaginal hysterectomy decreased from 18.7% to 18.4%, re-spectively. The change in surgical route was significant (P < .001). Among 25 571 women who underwent hysterectomy for uterine fibroids, the change in route of hysterectomy was more prominent (Figure 2). The rate of open abdominal hysterectomy
Table 1. Clinical and Demographic Characteristics of Patients Who Underwent Hysterectomy for Benign Gynecologic Indications and for Uterine Fibroids Characteristic Patients, No. (%) P Value Patients, No. (%) P Value All Hysterectomies for Benign Indication Hysterectomy for Uterine Fibroids
All (N = 75 487) Pre-FDA (n = 32 186) Post-FDA (n = 43 301) All (N = 25 571) Pre-FDA (n = 10 903) Post-FDA (n = 14 668) Procedure type MIS 42 435 (56.2) 18 436 (57.3) 23 999 (55.4) <.001 13 402 (52.4) 6115 (56.1) 7287 (49.7) <.001 Open abdominal hysterectomy 19 045 (25.2) 7732 (24.0) 11 313 (26.1) 10 374 (40.6) 4061 (37.2) 6313 (43.0) Vaginal hysterectomy 14 007 (18.6) 6018 (18.7) 7989 (18.4) 1795 (7.0) 727 (6.7) 1068 (7.3) Diagnosis group Dysmenorrhea and premenstrual syndrome 2654 (3.5) 1139 (3.5) 1515 (3.5) <.001 NA NA NA Dyspareunia 232 (0.3) 91 (0.3) 141 (0.3) NA NA NA Irregular bleeding 18 535 (24.6) 7651 (23.8) 10 884 (25.1) NA NA NA Endometriosis 5244 (6.9) 2230 (6.9) 3014 (7.0) NA NA NA Uterine fibroids 25 571 (33.9) 10 903 (33.9) 14 668 (33.9) 25 571 (100.0) 10 903 (100.0) 14 668 (100.0) Pelvic organ prolapse
or urinary incontinence
11 917 (15.8) 5329 (16.6) 6588 (15.2) NA NA NA
Family history and genetic susceptibility for gynecologic malignant neoplasm
517 (0.7) 205 (0.6) 312 (0.7) NA NA NA
Benign disorders of the ovary and fallopian tube
3034 (4.0) 1334 (4.1) 1700 (3.9) NA NA NA Other 7783 (10.3) 3304 (10.3) 4479 (10.3) NA NA NA Age, mean (SD), y 47.8 (10.7) 48.2 (10.9) 47.5 (10.7) <.001 46.9 (7.2) 47.2 (7.1) 46.7 (7.2) <.001 Race/ethnicity Non-Hispanic white 44 848 (59.4) 19 720 (61.3) 25 128 (58.0) <.001 11 471 (44.9) 5083 (46.6) 6388 (43.6) <.001 Hispanic white 6066 (8.0) 2465 (7.7) 3601 (8.3) 2492 (9.7) 1032 (9.5) 1460 (10.0) African American 11 401 (15.1) 4641 (14.4) 6760 (15.6) 6894 (27.0) 2826 (25.9) 4068 (27.7) Asian, native Hawaiian, or
Pacific Islander
3208 (4.2) 1423 (4.4) 1785 (4.1) 1569 (6.1) 682 (6.3) 887 (6.0)
American Indian or Alaska native 610 (0.8) 283 (0.9) 327 (0.8) 135 (0.5) 64 (0.6) 71 (0.5)
Other or unknown 9354 (12.4) 3654 (11.4) 5700 (13.2) 3010 (11.8) 1216 (11.2) 1794 (12.2) BMI Not available 376 169 207 <.001 133 65 68 .01 <30 41 154 (54.8) 17 928 (56.0) 23 226 (53.9) 13 587 (53.4) 5889 (54.3) 7698 (52.7) ≥30 33 957 (45.2) 14 089 (44.0) 19 868 (46.1) 11 851 (46.6) 4949 (45.7) 6902 (47.3) Functional status Not available 570 373 197 .10 215 142 73 .42 Independent 74 713 (99.7) 31 738 (99.8) 42 975 (99.7) 25 297 (99.8) 10 739 (99.8) 14 558 (99.7)
Partially or totally dependent 204 (0.3) 75 (0.2) 129 (0.3) 59 (0.2) 22 (0.2) 37 (0.3)
Corticosteroid use for chronic condition
No 74 346 (98.5) 31 696 (98.5) 42 650 (98.5)
.83 25 252 (98.8) 10 775 (98.8) 14 477 (98.7) .36
Yes 1141 (1.5) 490 (1.5) 651 (1.5) 319 (1.2) 128 (1.2) 191 (1.3)
Preoperative platelet count
Not available 5478 2339 3139 .63 1495 628 867 .69 <150 × 109/L 1157 (1.7) 509 (1.7) 648 (1.6) 343 (1.4) 140 (1.4) 203 (1.5) 150-450 × 109/L 67 287 (96.1) 28 675 (96.1) 38 612 (96.1) 22 955 (95.3) 9796 (95.3) 13 159 (95.3) >450 × 109/L 1565 (2.2) 663 (2.2) 902 (2.2) 778 (3.2) 339 (3.3) 439 (3.2) Preoperative hematocrit Not available 4249 1791 2458 <.001 1140 467 673 <.001 <34.9% 10 224 (14.4) 4472 (14.7) 5752 (14.1) 5076 (20.8) 2262 (21.7) 2814 (20.1) 34.9%-44.5% 57 441 (80.6) 24 575 (80.9) 32 866 (80.5) 18 348 (75.1) 7805 (74.8) 10 543 (75.3) >44.5% 3573 (5.0) 1348 (4.4) 2225 (5.4) 1007 (4.1) 369 (3.5) 638 (4.6)
Preoperative serum albumin
Not available 50 380 21 809 28 571 .21 16 864 7279 9585 .65 <3.5 g/dL 1321 (5.3) 533 (5.1) 788 (5.3) 460 (5.3) 201 (5.5) 259 (5.1) 3.5-5.0 g/dL 23 680 (94.3) 9792 (94.4) 13 888 (94.3) 8213 (94.3) 3409 (94.1) 4804 (94.5) >5.0 g/dL 106 (0.4) 52 (0.5) 54 (0.4) 34 (0.4) 14 (0.4) 20 (0.4) (continued)
increased from 37.2% during the pre-FDA period to 43.0% dur-ing the post-FDA period, the rate of MIS decreased from 56.1% during the pre-FDA period to 49.7% during the post-FDA period, and the rate of vaginal hysterectomy increased from 6.7% dur-ing the pre-FDA period to 7.3% durdur-ing the post-FDA period (P < .001).
Complications Analyzed by Procedure Type
Among 75 487 women who underwent hysterectomy for benign gynecologic indications, 1639 (2.2%) experienced 30-day major complications, and 2752 (3.6%) experienced 30-day minor com-plications (Table 2). The rates of major comcom-plications were sig-nificantly higher in women undergoing open abdominal surgery (3.5%) compared with women undergoing MIS (1.7%) or vaginal hysterectomy (1.7%) (P < .001). The minor complication rates
were higher in women undergoing vaginal hysterectomy (4.5%), followed by women undergoing open abdominal surgery (4.1%) and women undergoing MIS (3.2%) (P < .001).
Similarly, among women who underwent hysterectomy for uterine fibroids, 556 (2.2%) experienced 30-day major compli-cations, and 777 (3.0%) experienced 30-day minor complica-tions (Table 2). The rates of major complicacomplica-tions were signifi-cantly higher in women undergoing open abdominal surgery (2.8%) compared with women undergoing MIS (1.8%) and women undergoing vaginal hysterectomy (1.8%) (P < .001). Minor complication rates were slightly higher in women undergoing open hysterectomy (3.3%) and women undergo-ing vaginal hysterectomy (3.2%) than in women undergoundergo-ing MIS (2.8%), although the difference was not statistically signifi-cant (P = .07).
Table 1. Clinical and Demographic Characteristics of Patients Who Underwent Hysterectomy for Benign Gynecologic Indications and for Uterine Fibroids (continued) Characteristic Patients, No. (%) P Value Patients, No. (%) P Value All Hysterectomies for Benign Indication Hysterectomy for Uterine Fibroids
All (N = 75 487) Pre-FDA (n = 32 186) Post-FDA (n = 43 301) All (N = 25 571) Pre-FDA (n = 10 903) Post-FDA (n = 14 668) Hypertension requiring medication
No 55 811 (73.9) 23 665 (73.5) 32 146 (74.2)
.03 18 934 (74.0) 8077 (74.1) 10 857 (74.0) .91
Yes 19 676 (26.1) 8521 (26.5) 11 155 (25.8) 6637 (26.0) 2826 (25.9) 3811 (26.0)
Preoperative serum creatinine
Not available 25 405 10 740 14 665 .07 8235 3481 4754 .19 <0.6 mg/dL 5324 (10.6) 2352 (11.0) 2972 (10.4) 2037 (11.8) 894 (12.0) 1143 (11.5) 0.6-1.1 mg/dL 43 470 (86.8) 18 560 (86.5) 24 910 (87.0) 14 958 (86.3) 6396 (86.2) 8562 (86.4) >1.1 mg/dL 1288 (2.6) 534 (2.5) 754 (2.6) 341 (2.0) 132 (1.8) 209 (2.1) Diabetes treatment Insulin 1341 (1.8) 561 (1.7) 780 (1.8) .33 398 (1.6) 159 (1.5) 239 (1.6) .47
Noninsulin or oral agent 4088 (5.4) 1702 (5.3) 2386 (5.5) 1233 (4.8) 517 (4.7) 716 (4.9)
None 70 058 (92.8) 29 923 (93.0) 40 135 (92.7) 23 940 (93.6) 10 227 (93.8) 13 713 (93.5) Smoked within 1 y No 62 477 (82.8) 26 537 (82.4) 35 940 (83.0) .047 21 874 (85.5) 9330 (85.6) 12 544 (85.5) .90 Yes 13 010 (17.2) 5649 (17.6) 7361 (17.0) 3697 (14.5) 1573 (14.4) 2124 (14.5) ASA class 1-2, Healthy to mild systemic disease 61 080 (80.9) 26 166 (81.3) 34 914 (80.6) .02 21 349 (83.5) 9181 (84.2) 12 168 (83.0) .008 3-4, Severe systemic disease
to constant life threat
14 407 (19.1) 6020 (18.7) 8387 (19.4) 4222 (16.5) 1722 (15.8) 2500 (17.0) Associated procedure Abdominal surgery No 73 003 (96.7) 31 098 (96.6) 41 905 (96.8) .23 24 888 (97.3) 10 613 (97.3) 14 275 (97.3) .92 Yes 2484 (3.3) 1088 (3.4) 1396 (3.2) 683 (2.7) 290 (2.7) 393 (2.7) Extra-abdominal surgery No 74 713 (99.0) 31 838 (98.9) 42 875 (99.0) .19 25 373 (99.2) 10 809 (99.1) 14 564 (99.3) .17 Yes 774 (1.0) 348 (1.1) 426 (1.0) 198 (0.8) 94 (0.9) 104 (0.7) Upper-abdominal surgery No 75 216 (99.6) 32 065 (99.6) 43 151 (99.7) .50 25 511 (99.8) 10 878 (99.8) 14 633 (99.8) .88 Yes 271 (0.4) 121 (0.4) 150 (0.3) 60 (0.2) 25 (0.2) 35 (0.2) Other No 74 443 (98.6) 31 815 (98.8) 42 628 (98.4) <.001 25 183 (98.5) 10 758 (98.7) 14 425 (98.3) .04 Yes 1044 (1.4) 371 (1.2) 673 (1.6) 388 (1.5) 145 (1.3) 243 (1.7)
Abbreviations: ASA, American Society of Anesthesiologists; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); NA, not applicable; Pre-FDA, data obtained prior to the US Food and Drug Administration (FDA) warning from Q1 2013 through Q1 2014; Post-FDA, data obtained after the FDA-issued warning from Q4 2014 through Q4 2015.
SI conversion factor: To convert hematocrit to proportion of 1.0, multiply by 0.01; serum albumin to grams per liter, multiply by 10; serum creatinine to micromoles per liter, multiply by 88.4.
Complications Pre- vs Post-FDA Period
Among women who underwent hysterectomy for benign indications, 30-day major and minor complication rates remained relatively stable from the pre-FDA to post-FDA periods (Figure 3). Major complication rates were 2.1% during the pre-FDA period and 2.2% during the post-FDA period (adjusted odds ratio [OR], 1.03; 95% CI, 0.93-1.13; P = .62). Minor complications were 3.6% pre-FDA and 3.7% post-FDA (adjusted OR, 1.00; 95% CI, 0.92-1.08; P = .97).
By contrast, among women who underwent hysterectomy for uterine fibroids, 30-day major and minor complication rates significantly increased after the FDA statement (Figure 3). The major complication rate increased from 1.9% during the pre-FDA period to 2.4% during the post-FDA period (adjusted OR, 1.23; 95% CI, 1.04-1.47; P = .02), and the minor complication rate in-creased from 2.7% during the pre-FDA period to 3.3% during the post-FDA period (adjusted OR, 1.21; 95% CI, 1.04-1.40; P = .01). The full multivariable models for both major and minor compli-cation rates among all women with benign gynecologic
indica-tions and also among women with uterine fibroids are reported in eTables 6 to 9 in theSupplement.
Comparisons of individual complication rates during the pre- and post-FDA periods among patients who underwent hys-terectomy for benign gynecologic indications and for uterine fibroids are reported in eTable 10 in theSupplement. A model among all women with benign gynecologic indications, including a term for the interaction between indication (uter-ine fibroids vs nonuter(uter-ine fibroids) and period (pre-FDA vs post-FDA period), showed that the association of increased com-plications in the period following the FDA statement was different between women with uterine fibroids and women with nonuterine fibroid indications (P = .009).
Discussion
Our study, using a large nationwide data set, showed that ma-jor and minor complication rates among women who underwent Figure 1. Routes of Hysterectomy for Benign Gynecologic Indications (N = 75 487)
From January 1, 2013, to December 31, 2015
0 No. of hysterectomies Q1 Q3 Q4 Q4 70 60 Hysterectomy R o ute, % Quarter, y 50 40 30 20 10 Q2 Q1 Q2 Q3 Q4 Q1 Q2 Q3 MIS Open hysterectomy Vaginal hysterectomy 2013 2014 2015 5899 6259 6162 6519 7347 7615 7455 7498 8620 8630 8978 9575 Pre-FDA Post-FDA
MIS indicates minimally invasive surgery. Shaded region indicates data collected between the US Food and Drug Administration (FDA) statements from March 31, 2014, through September 30, 2014, that were excluded from analyses.
Figure 2. Routes of Hysterectomy for Uterine Fibroids (n = 25 571 [33.9%]) From January 1, 2013, to December 31, 2015
0 Q1 Q3 Q4 Q4 70 60 Hysterectomy R o ute, % Quarter, y 50 40 30 20 10 Q2 Q1 Q2 Q3 Q4 Q1 Q2 Q3 MIS Open hysterectomy Vaginal hysterectomy 2013 2014 2015 Pre-FDA Post-FDA No. of hysterectomies 2008 2254 2050 2088 2503 2780 2567 2581 2985 2947 3033 3122
MIS indicates minimally invasive surgery. Shaded region indicates data collected between the US Food and Drug Administration (FDA) statements from March 31, 2014, through September 30, 2014, that were excluded from analyses.
hysterectomy for uterine fibroids increased following the FDA statement warning against the use of power morcellation. This 20% increase in the odds of major and minor complications could translate into a large number of additional complications among the 200 000 hysterectomies performed annually for uterine fibroids in the United States.1,2
As one might expect, our results showed that open ab-dominal hysterectomy was associated with significantly more major and minor complications than MIS irrespective of the study period. Considering this superiority of MIS in terms of morbidity over open abdominal hysterectomy, the increased number of complications observed after the FDA statement was likely associated with the shift in the route of hysterectomy. Moreover, a decrease in the rate of open abdominal hysterec-tomies and an increase in the rate of MIS observed from 2003 to 20121,22
support our hypothesis that the inverse trend in the route of hysterectomies observed after 2013 was attributable to the FDA statement and not to other reasons.
Similar to our study, previous studies have shown that the FDA statement on morcellation resulted in a shift in ap-proach to hysterectomy, with decreased use of MIS and in-creased use of open abdominal surgery.13,17-19However, to our knowledge, the only study that reported an increase in the number of complications after the FDA statement is a retro-spective study by Harris et al18
evaluating postoperative com-plications of hysterectomy for benign indications in Michi-gan. They showed an increase in the rate of nontransfusion major complications from 2.2% to 2.8% and in the rate of 30-day readmissions from 3.4% to 4.2%; however, those study re-sults were limited by a lack of generalizability because they ex-amined only hospitals in the state of Michigan immediately after the FDA statement. By contrast, to date, no other study dealing with this important issue in gynecologic surgery has
observed an increase in the number of complications after the FDA statement. In particular, to our knowledge, the only study evaluating the influence of the FDA statement on complica-tions across the United States was by Wright et al,13and it showed no changes in major postoperative complications. The reasons for the discrepancies between our study results and those of Wright et al13could be their use of an administrative database (that did not differentiate between types of compli-cations and was not designed to evaluate complicompli-cations), their inclusion of patients with malignant neoplasms (which could be confounders), and their examination of only the immedi-ate period after the FDA stimmedi-atement. Moreover, a study re-cently published by Ottarsdottir et al17examining patients with indication of uterine fibroids who underwent hysterectomy from 2013 to 2015 at Brigham and Women’s Hospital showed an increase in the rate of open surgery from 19% to 29% and a decrease in the rate of laparoscopy from 71.3% to 65.3%. How-ever, except for an increase of blood loss in the later years, other perioperative outcomes remained similar. As recognized by those authors, the generalizability of the study was limited by its single-institution design, and the study was underpow-ered to detect a small difference.
The large sample size in the present study allowed for the detection of a significant 0.5% increase in the rate of major complications among women with an indication of uterine fi-broids. Although this increase may appear small, it is larger than the 0.2% risk of unsuspected leiomyosarcoma estimated by the FDA, which was the motivation for the FDA statement and the impetus for using open techniques instead of morcellation. Fur-thermore, given the large number of women who undergo hys-terectomy for uterine fibroids in the United States, a small in-crease in the rate of complications would translate to a large increase in the number of individual women who experience Table 2. Thirty-Day Major and Minor Complication Rates of Hysterectomy for Benign Gynecologic Indications and for Uterine Fibroids by Procedure Type
Complication Patients, No. (%) P Valuea All (N = 75 487 [100%]) MIS (n = 42 435 [56.2%]) Open Abdominal Hysterectomy (n = 19 045 [25.2%]) Vaginal Hysterectomy (n = 14 007 [18.6%]) Hysterectomy for benign gynecologic indication
Major No 73 848 (97.8) 41 697 (98.3) 18 384 (96.5) 13 767 (98.3) <.001 Yes 1639 (2.2) 738 (1.7) 661 (3.5) 240 (1.7) Minor No 72 735 (96.4) 41 097 (96.8) 18 261 (95.9) 13 377 (95.5) <.001 Yes 2752 (3.6) 1338 (3.2) 784 (4.1) 630 (4.5) (N = 25 571 [100%]) (n = 13 402 [52.4%]) (n = 10 374 [40.6%]) (n = 1795 [7.0%]) Hysterectomy for uterine fibroids
Major No 25 015 (97.8) 13 165 (98.2) 10 087 (97.2) 1763 (98.2) <.001 Yes 556 (2.2) 237 (1.8) 287 (2.8) 32 (1.8) Minor No 24 794 (97.0) 13 026 (97.2) 10 031 (96.7) 1737 (96.8) .07 Yes 777 (3.0) 376 (2.8) 343 (3.3) 58 (3.2)
Abbreviation: MIS, minimally invasive surgery.
a major complication. Moreover, a decision-tree analysis in-cluding the risk of death from leiomyosarcoma and the differ-ences in morbidity between laparoscopy and laparotomy es-timated that the overall mortality would increase if laparoscopic cases were converted to laparotomy cases.23
Strengths and Limitations
The strengths of the present study include a large sample size from a prospective multicenter database, including centers from across the United States. Moreover, standardized proto-cols and central auditing ensured reliability of data collection across the participating institutions.
The present study has several potential limitations. First, its retrospective design might have introduced bias inherent with
such a data set. Second, although the ACS NSQIP is accurate in capturing 30-day complications, it does not follow-up with pa-tients beyond 30 days; therefore, we were unable to assess long-term complications. Third, owing to the lack of data on the use of power morcellation and on the prevalence of abnormal uter-ine pathology during the pre- and post-FDA periods among women who underwent MIS, we were unable to assess whether the shift in the route of hysterectomy consequent to the FDA statement was associated with a reduction in the prevalence of spreading unexpected malignant neoplasms. However, Wright et al13showed that the prevalence of abnormal uterine pathol-ogy among woman who underwent MIS with electric power morcellation after the post-FDA period did not change com-pared with that in the pre-FDA period. Fourth, the increase in the number of participating hospitals between the pre- and post-FDA periods (435 hospitals in 2013, 517 hospitals in 2014, and 603 hospitals in 2015) and the change in the sampling method that occurred for hysterectomy procedures during the study pe-riod may have affected our results; however, this limitation can-not be overcome with the available data. Finally, although we could speculate that an increase in the number of complica-tions could have resulted in increased costs and delayed re-turn to work, the lack of data on these variables prevented us from addressing these aspects.
Conclusions
The FDA statement warning against the use of power mor-cellation was associated with an increased risk in the num-ber of major and minor complications among women under-going hysterectomy for uterine fibroids. This increased risk corresponded with an abrupt shift in the route of hysterec-tomy; we believe that many hospitals and payers reduced the use of both forms of morcellation (power and hand), which decreased options for MIS. Although caution is required to avoid morcellation of unexpected uterine malig-nant neoplasms, our results should be considered by women and clinicians during the process of shared decision making and by medical societies and regulatory bodies when issuing safety communications. Until new studies discover either preoperative techniques to identify patients with sarcomas or alternative intraoperative technology, such as contained power morcellation to remove a large uterus from the abdominal cavity without disseminating tissue, the decision regarding the surgical approach should be guided by the val-ues and informed preferences of the patient. Further research is warranted focusing on the refinement of these alternative techniques of uterine morcellation and on the identification of women who would benefit from MIS.
ARTICLE INFORMATION
Accepted for Publication: January 14, 2018. Published Online: April 11, 2018.
doi:10.1001/jamasurg.2018.0141 Author Contributions: Drs Multinu and Laughlin-Tommaso had full access to all of the data
in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Multinu, Casarin, Angioni, Mariani, Habermann, Laughlin-Tommaso. Acquisition, analysis, or interpretation of data: Multinu, Hanson, Mariani, Habermann. Drafting of the manuscript: Multinu, Mariani, Laughlin-Tommaso.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Multinu, Hanson, Habermann. Administrative, technical, or material support: Casarin.
Study Supervision: Multinu, Casarin, Mariani, Habermann, Laughlin-Tommaso. Figure 3. Thirty-Day Major and Minor Complication Rates
for Hysterectomy for Benign Gynecologic Indications and for Uterine Fibroids Before and After
the US Food and Drug Administration (FDA) Statement
4.0 3.5 3.0 2.5 1.5 2.0 1.0 0.5 0 Rate of Complications, % All Hysterectomies for Uterine Fibroids (n=25 571; 33.9%) Minor Major
All Hysterectomies for Benign Indication
(n=75 487; 100%) Minor Major 1.21 1.23 1.00 1.03 1.04-1.40 1.04-1.47 0.92-1.08 0.93-1.13 .01 .02 .97 .62 Complication Adjusted OR 95% CI P value Pre-FDA period Post-FDA period
The pre-FDA period indicates data from the first quarter (Q1) of 2013 through Q1 2014, and the post-FDA period indicates data from Q4 2014 through Q4 2015. Odds ratios (ORs) were adjusted for age, race/ethnicity, body mass index (ⱖ30 vs <30; calculated as the weight in kilograms divided by the height in meters squared), functional status, corticosteroid use for chronic conditions, preoperative platelet count (reference range of 150-450 × 103
/μL vs lower vs higher [to convert to ×109per liter, multiply by 1.0]), preoperative hematocrit
(reference range of 34.9%-44.5% vs lower vs higher [to convert to proportion of 1.0, multiply by 0.01]), preoperative serum albumin level (reference range of 3.5-5.0 g/dL vs lower vs higher [to convert to grams per liter, by 10]), hypertension requiring medications, preoperative serum creatinine level (reference range of 0.6-1.1 mg/dL vs lower vs higher [to convert to micromoles per liter, by 88.4]), diabetes with oral agent or insulin administration, smoking status within 1 year, American Society of Anesthesiologists class (1-2 vs 3-4), and abdominal, extra-abdominal, upper-abdominal, or other associated procedures (yes vs no). Models, including that for all women with benign indications, were also controlled for hysterectomy indication.
Conflict of Interest Disclosures: None reported. Funding/Support: This publication was made possible by a Clinical Translation Science Award (UL1 TR000135) to the Mayo Clinic Graduate School of Biomedical Sciences from the National Center for Advancing Translational Sciences, a component of the National Institutes of Health. Dr Casarin is supported by the University of Insubria, Varese, Italy, and by Fondo Miglierina, Provincia di Varese, Italy.
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Disclaimer: The contents are solely the responsibility of the authors and do not necessarily represent the official view of the National Institutes of Health. The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) and the hospitals participating in the ACS NSQIP have not verified and are not responsible for the statistical validity of the data analysis or the derived conclusions.
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