NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

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1 NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE INTERVENTIONAL PROCEDURES PROGRAMME Interventional procedure overview of sterilisation by insertion of intrafallopian implants Sterilisation is sometimes chosen as a method of birth control. It is usually permanent. In this procedure, a tube with a small camera (hysteroscope) is passed through the vagina and cervix, and used to place a very small piece of metal, called a microinsert, into both fallopian tubes (the tubes from the ovaries to the womb). The microinserts cause scar tissue to form in the fallopian tubes. This eventually blocks them and prevents eggs travelling from the ovaries from being fertilised. Introduction The National Institute for Health and Care Excellence (NICE) has prepared this interventional procedure (IP) overview to help members of the interventional procedures advisory committee (IPAC) make recommendations about the safety and efficacy of an interventional procedure. It is based on a rapid review of the medical literature and specialist opinion. It should not be regarded as a definitive assessment of the procedure. Date prepared This IP overview was prepared in August Procedure name Hysteroscopic sterilisation by insertion of intrafallopian implants Specialist societies Royal College of Obstetrics and Gynaecology - Faculty of Sexual and Reproductive Healthcare British Society for Gynaecological Endoscopy Page 1 of 53

2 Description Indications and current treatment Sterilisation is a method of contraception that is usually permanent. In women, it is usually achieved by tubal occlusion using either clips or rings. This can be done laparoscopically under general anaesthesia. Other methods such as salpingectomy (complete removal of the fallopian tubes) may be used if tubal occlusion has been unsuccessful. What the procedure involves Hysteroscopic sterilisation by insertion of intrafallopian implants is usually done with the patient under local anaesthesia, intravenous sedation or a combination of both. A hysteroscope is inserted through the vagina and cervix. A flexible microinsert is then passed through the hysteroscope using a guidewire and placed into each fallopian tube. The microinserts induce scar tissue formation, which blocks the fallopian tubes and prevents conception. The procedure is not intended to be reversible. An additional form of contraception should be used until imaging (X ray or ultrasound scanning) has confirmed satisfactory microinsert placement. Hysterosalpingogram (HSG) may be done routinely or in selected women to ensure that the fallopian tubes have been occluded. Literature review Rapid review of literature The medical literature was searched to identify studies and reviews relevant to sterilisation by insertion of intrafallopian implants. The following databases were searched, covering the period from the publication of the previous guidance in 2009 up to the present: MEDLINE, PREMEDLINE, EMBASE, Cochrane Library and other databases. Trial registries and the Internet were also searched. No language restriction was applied to the searches (see appendix C for details of search strategy). Relevant published studies identified during consultation or resolution that are published after this date may also be considered for inclusion. The following selection criteria (table 1) were applied to the abstracts identified by the literature search. Where selection criteria could not be determined from the abstracts the full paper was retrieved. Further relevant papers were identified through the references of included studies. Page 2 of 53

3 Table 1 Inclusion criteria for identification of relevant studies Characteristic Publication type Patient Intervention/test Outcome Language Criteria Clinical studies were included. Emphasis was placed on identifying good quality studies. Abstracts were excluded where no clinical outcomes were reported, or where the paper was a review, editorial, or a laboratory or animal study. Conference abstracts were also excluded because of the difficulty of appraising study methodology, unless they reported specific adverse events that were not available in the published literature. Women seeking sterilisation Hysteroscopic sterilisation by insertion of intrafallopian implants Articles were retrieved if the abstract contained information relevant to the safety and/or efficacy. Non-English-language articles were excluded unless they were thought to add substantively to the English-language evidence base. List of studies included in the IP overview This IP overview is based on 139,678 women from 1 systematic review and meta-analysis, 1 non-controlled, multicentre phase III study, 2 retrospective cohort studies, 4 retrospective reviews of reported cases of pregnancies or adverse events, 2 retrospective case series analyses and 23 case reports. Other studies that were considered to be relevant to the procedure but were not included in the main extraction table (table 2) have been listed in appendix A. Page 3 of 53

4 Table 2 Summary of key efficacy and safety findings on sterilisation by insertion of intrafallopian implants Study 1 Mao J (2015)] 1 Details Study type Country Retrospective cohort study US Recruitment period Study population and number Age Patient selection criteria Technique Follow-up Conflict of interest/source of funding n=52,326 (8,048 versus 44,278 laparoscopic) women having sterilisation Mode years for both groups (54.9% for versus 55.3% laparoscopic) IP 218/3 [IPGXXX] Inclusion criteria: Patients who had interval sterilisation (i.e. not postpartum) in an outpatient setting in New York State Exclusion criteria: Patients who had sterilisation via laparotomy or concurrent with other abdominal procedures; patients who had previously had sterilisation procedures Essure sterilisation 1-year follow-up period for all patients 2-year follow-up period for subgroup of 5,395 versus 37,361 laparoscopic patients 3-year follow-up period for subgroup of 4,088 versus 33,891 laparoscopic patients Nil relevant Analysis Follow-up issues: Main analyses were restricted to 1-year follow-up because of possible relocation of patients over longer periods; 2- and 3-year follow-up analyses suffered from loss to follow-up, however, should not adversely affect 1 group over the other. Study design issues: Data obtained from comprehensive (all payers) hospital episode database in New York State. Unable to detect other safety outcomes that did not need hospital or emergency department treatment. Primary outcomes of interest were pregnancy or reoperation (repeated procedures on fallopian tubes), with other procedures to treat complications of sterilisation not assessed by study. Study population issues: Significant differences in patient age, race, insurance status, year of procedure, major comorbidities, and history of pelvic inflammatory disease, major abdominal surgeries and caesarean section. Adjusted for in model, as well as clustering of procedures by hospital (but not by surgeon). Other issues: The study assumes that all sterilisation used the Essure device; however, this was not part of the patient selection criteria and study period overlapped when the Adiana device was on the market. Page 4 of 53

5 Key efficacy and safety findings Efficacy Number of patients analysed: 52,326 women (8,048 versus 44,278 laparoscopic) having sterilisation Procedural outcomes Median procedure time (range) Use of general anaesthesia Pregnancy Hysteroscopic Laparoscopic P- value 36 minutes (22 to 52) 50.6% (4072/8048) Pregnancy 0.84 (0.63 to 1.12) 52 minutes (35 to 70) 75.8% (33,551/44,278) <0.01 <0.01 Adjusted odds ratio for versus laparoscopic sterilisation* (95% CI) 1 year 2 years 3 years 0.82 (0.63 to 1.08) 0.89 (0.67 to 1.18) *Adjusted for patient age, race, insurance status, year of procedure, major comorbidities, and history of pelvic inflammatory disease, major abdominal surgeries and caesarean section. Model also accounted for hospital clustering. Safety 30-day follow-up Iatrogenic complications Major medical complications 1-year follow-up Ectopic pregnancy Reoperation** (7.47 to 13.81) Adjusted* odds ratio for versus laparoscopic sterilisation (95% CI) 0.35 (0.20 to 0.61) 0.70 (0.28 to 1.78) Adjusted* odds ratio for versus laparoscopic sterilisation (95% CI) 1 year 2 years 3 years 0.34 N/A N/A (0.10 to 1.13) 7.96 (6.00 to 10.57) 5.88 (4.44 to 7.79) Time to event analysis for reoperation within 1 year Time to event analysis indicates the risk [hazard] of having reoperation within 1 year among women who had compared to laparoscopic sterilisation. Adjusted* hazard ratio=10.13 (7.50 to 13.68) *Adjusted for patient age, race, insurance status, year of procedure, major comorbidities, and history of pelvic inflammatory disease, major abdominal surgeries and caesarean section. Model also accounted for hospital clustering. Abbreviations used: CI, confidence interval; N/A, not available. **Defined as any repeated procedures on fallopian tubes identified in follow-up. Page 5 of 53

6 Study 2 Chudnoff (2015) 2 Details Study type Country Recruitment period Study population and number Extended follow-up of non-controlled, multicentre Phase III study 13 sites with majority of patients from the US and Australia n=518 women wanting sterilisation (476 with successful placement) Age and sex Mean age=32 years (range 21 40) Patient selection criteria Technique Follow-up Conflict of interest/source of funding 100% women (507/507) Inclusion criteria: Age 21 40, weight: lb In a monogamous relationship, willing to use temporary contraception for 3 months Had at least 1 live birth and regular menses for 2 months before procedure Minimum of 4-8 coital acts per cycle Exclusion criteria: tubal, ovarian or endometrial pathology prior history of infertility pre-existing chronic pain Essure sterilisation (ESS205 model) 5 years Study and authors funded by manufacturer. Analysis Follow-up issues: Follow-up through annual scheduled outpatient visits. Unclear if any attempt was made to contact those who did not attend these visits; 366 out of 476 women (76.9%) with successful placement (70.7% of intention-totreat population) followed up for full 5 years; 88 women were lost to follow-up and study participation was prematurely terminated for 22 women for a range of reasons, some of which should not have precluded follow-up. These included 9 women who had subsequent hysterectomy, 8 who voluntarily terminated participation, 1 who missed a follow-up visit, 1 who had unsatisfactory device placement, 1 who died from unrelated causes, 1 patient who was in prison, and 1 who choose to have bilateral salpingectomy and in vitro fertilisation. Study design issues: Although changes to menstrual function and pelvic pain were specifically asked for during followup visits, other adverse events relied on self-reporting. Study population issues: Excluded women with any type of chronic pain, which has been shown elsewhere to be a risk factor for pelvic pain. Other issues: Results of phase III study included in previous guidance. Results in text do not always correspond (e.g. number of hysterectomies). Page 6 of 53

7 Key efficacy and safety findings Efficacy Number of patients analysed: 507 women in whom Essure placement was attempted 453 women with tubal occlusion on HSG 366 women who completed 5 years of follow-up Pregnancy Luteal phase pregnancies: n=4 Intentional pregnancy via in vitro fertilisation: n=1 Pregnancies after confirmation of bilateral tubal occlusion on HSG: n=0 for 24,942 woman-months of follow-up Safety Changes in menstrual function Type of change Irregular bleeding Intermenstrual bleeding Heavier bleeding Recurrent (reported in more than 1 follow-up visit) 70/473 (14.8%) 0/380 89/473 (18.8%) 0/386 Persistent (reported in all 5 follow-up visits) 177/472 (37.5%) 2/377 (0.5%) Lighter bleeding 110/472 (23.3%) 0/377 Pelvic pain Type of pelvic pain Recurrent (reported in more than 1 follow-up visit) Dysmenorrhoea 29/473 (6.1%) 0/386 Dyspareunia 18/473 (3.8%) 0/386 Persistent (reported in all 5 follow-up visits) Ovulatory pain 14/473 (3.0%) 2/386 (0.5%) Other 25/472 (5.3%) 0/386 Adverse events (16 months to 5 years of follow-up) 15 adverse events reported, including heavy periods +/- pain, irregular periods +/- pain dyspareunia, spotting when ovulating (no breakdown available). 3 severe adverse events (unclear whether separate to above): o o o 1 participant with lower abdominal pain and very heavy periods who had hysterectomy at 34 months. 1 participant with irregular menstrual bleeding, treated with dilation and curettage 1 participant who had bilateral salpingectomy ahead of in vitro fertilisation Hysterectomies 15 women known to have had hysterectomy Reason Menorrhagia/ abnormal bleeding No data 5 (3.8%) Pelvic pain 3 Dysmenorrhoea 2 Number citing as reason (can be >1) 7 Abbreviations used: HSG, hysterosalpingogram Only 2 hysterectomies assessed as possibly related to Essure implants by study investigators. Page 7 of 53

8 Study 3 Munro (2014) 3 Details Study type Country Retrospective review of pregnancies after sterilisation Worldwide Recruitment period Study population and number Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding n=748 pregnancies (508 with sufficient data for analysis of contributing factors) Not applicable Inclusion criteria Pregnancies reported to the US Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience database (MAUDE) between 2001 and 2010 Pregnancies reported to manufacturer Pregnancies reported in the medical literature Essure sterilisation Maximum of 10 years All authors have financial conflicts of interest with manufacturer Analysis Follow-up issues: Not possible to estimate number of woman-years for follow-up from these methods. Study design issues: Unclear whether any attempt to deduplicate reports was made, therefore analysis of contributing factors may be biased due to duplication of records. There may be clustering of reports by facility or surgeon, which was not accounted for and may impact the weighting of contributing factors. Study population issues: Study uses total kits distributed worldwide as denominator, with assumption that distribution of kits is equivalent to use in patients. Likely underreporting of pregnancies due to voluntary nature of reporting. Furthermore, only FDA-specific adverse event reporting database was searched, making underreporting from outside the US very likely. Other issues: Data gathered by manufacturer. Assessment panel for radiographic images consisted of nurses employed by manufacturer and doctors paid as consultants by manufacturer. Page 8 of 53

9 Key efficacy and safety findings Efficacy Number of reported pregnancies: 748 (660 from the US versus 88 outside the US) Rate of pregnancies over 10 years calculated as 748/497,305 kits distributed worldwide = 0.15% Pregnancy Pregnancy reports with sufficient data to evaluate contributing factors = 508/748 (67.9%) Contributing factor n (% out of 508) Patient non-compliance* 229 (45.1%) Misinterpreted 3-month HSG 212 (41.7%) Single microinsert placed (various reasons) 35 (6.9%) Luteal phase pregnancy 32 (6.3%) Safety Ectopic pregnancy Likely diagnosis of ectopic pregnancy: n=30/508 (5.9%) Timing of ectopic pregnancies n (% out of 30) After confirmation of tubal occlusion Before confirmation of tubal occlusion 24 (80.0%) 5 (16.7) Luteal phase pregnancy 1 (3.3%) [percentages calculated for overview] Rate of ectopic pregnancies over 10 years calculated as 30/497,305 kits distributed worldwide =0.006% Timing of pregnancies (excluding luteal phase pregnancies): Months after procedure n (% out of 508) <3 16 (3.1%) (38.1) (30.3%) >36 7 (1.3%) Unknown 105 (20.7%) * Failure to use contraception before imaging to confirm tubal occlusion or failure to return for confirmatory imaging. Abbreviations used: HSG hysterosalpingogram Adverse events detected on review of 3-month HSG images Adverse event n (% out of 748) Perforation 95 (12.7%) Unsatisfactory location 45 (6.0%) Expulsion 24 (3.2%) [percentages calculated for overview] Page 9 of 53

10 Study 4 la Chapelle (2016) 4 Details Study type Country Systematic review and meta-analysis Not applicable Recruitment period Up to 2014 Study population and number Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding n=14,126 women in 37 included articles on Essure Not applicable Not applicable Adriana, Ovabloc and Essure included in review, but only data on Essure extracted here. Not applicable One author declared financial conflicts of interest with Essure manufacturer. Analysis Follow-up issues: No articles contained long-term follow-up data to assess cumulative risk of failure and effectiveness (up to 10 years). Study design issues: Substantial statistical heterogeneity on placement success rates meant that results could not be pooled. Low incidence of pregnancies meant that meta-analysis not meaningful. Study population issues: No randomised controlled trials were identified. Observational studies are often underpowered to detect rare complications and with short-term and incomplete follow-up. Nine articles had study populations that overlapped. The quality of evidence for intra-procedural complications is very low. Other issues: Potential conflicts of interest declared in large proportion of studies. Key efficacy and safety findings Efficacy n=14,126 women in 37 included articles on Essure Safety No safety data reviewed. Successful bilateral procedure rates at first attempt: Range 81-98% (31 studies, n=12,961) Confirmed correct placement at 3-month imaging: Range % (24 studies, n=9,112) Cumulative number of pregnancies after satisfactory placement confirmed on 3-month imaging: 8 pregnancies in 7,706 women. In all cases, pregnancy was related to incorrect position of at least 1 device (despite satisfactory placement on imaging). Page 10 of 53

11 Studies 5 and 6 Povedano (2012) 5 and Arjona Berral (2014) 6 Details Study type Country Recruitment period Study population and number Age and sex Patient selection criteria Retrospective case series analyses Spain (Povedano) and (Arjona Berral) The 2 studies report on overlapping cohorts of women having Essure sterilisation in 1 university hospital Povedano: n=4,306 women Arjona Berral: n=4,274 women Povedano: Mean age=36 years (19 to 49 years) Arjona Berral: not reported 100% women Inclusion criteria Age years Able to give informed consent Technique Follow-up Conflict of interest/source of funding Exclusion criteria Abnormal uterine bleeding Active pelvic inflammatory disease Uncertainty over desire for permanent sterilisation Essure sterilisation Maximum of 7 years in both studies Povedano: All authors declared financial conflicts of interest with manufacturer Arjona Berral: No conflicts of interest declared despite 6 out of 7 co-authors the same as on Povedano study Analysis Follow-up issues: Povedano: Length of follow-up varies across patient group, with 921 followed up for 3 months to 1 year, 1010 for 1-2 years, 1,360 for 3-4 years, 660 for 5-6 years and 355 for 7-8 years. 134 women lost to follow-up before confirmation of tubal occlusion at 3 months. Arjona Berral: Not reported, but similar follow-up variability can be assumed. Study design issues: Unclear what contact was made by authors after 3-month follow-up appointment for imaging. It appears adverse events may have only been detected by self-reporting or voluntary reporting by GPs or general gynaecologists. Study population issues: Only includes patients who had procedure at 1 tertiary hospital. Other issues: No cases of pelvic pain were reported in Povedano, whereas 7 cases were reported in Arjona Berral. As the same cohort was used in both cases with slightly different follow-up times, this calls into question the completeness of reporting of adverse events in Povedano. Page 11 of 53

12 Key efficacy and safety findings Efficacy (all from Povedano) Number of patients being analysed: 4306 Procedural success rate 4075/4306 successfully placed at first attempt = 96.0% 4242/4306 successful placements in total = 98.5% Tubal occlusion rate at 3 months imaging 4095/4306 (intention-to-treat) confirmed tubal occlusion at 3 months imaging = 95.1% 4095/4242 successful insertions had confirmed tubal occlusion at 3 months imaging = 96.3% Pregnancy 7/4306 patients became pregnant o o 3 patients before 3-month imaging 4 patients after 3-month imaging (presumably with confirmed tubal occlusion) = 4/4108 patients with confirmed tubal occlusion = failure rate of 0.001% Safety (Povedano and Arjona Berral) Perioperative (Povedano) 85/4306 (1.9%) patients experienced vasovagal syncope Perioperative pain: Adverse events Povedano: o None/mild: 3568/4306 = 82.8% o Moderate: 513/4306 = 11.9% o Severe: 155/4306 = 3.5% o Not recorded: 70/4306 = 1.5% Expulsion: 19/4306 = 0.4% Myometrial placement: 3/4306 = 0.06% Abdominal migration: 2/4306 = 0.04 New-onset pelvic inflammatory disease: 2/4306 = 0.04% Nickel allergy: 2/4306 = 0.04% Persistent abdominal pain: 1/4306 = 0.02% Arjona Berral Chronic pelvic pain: 7/4274 = 0.16% o o Onset within 0-1 week in all cases Resolution of symptoms in all cases after removal of devices Page 12 of 53

13 Study 7 Al-Safi (2013) 7 with updated FDA data Details Study type Country Retrospective review of adverse event reporting system (MAUDE) US Recruitment period Al-Safi: Study population and number FDA updated data: Al-Safi: n=457 reports of adverse events FDA updated data: n=9,900 reports of adverse events Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding Not reported Not relevant Essure sterilisation only Maximum of 13 years Al-Safi: 1 author declared previous financial support from device manufacturer Analysis Study design issues: Review of the Manufacturer and User Facility Device Experience (MAUDE) database [records online reports for Food and Drug Administration (FDA)-approved medical devices] for events related to Essure sterilisation. No denominator available. Reporting of adverse events likely to be lower than true incidence and/or influenced by media attention. Study population issues: Unclear the proportion of reports from outside the US. Other issues: Updated data from the FDA shows the skewed nature of reporting in more recent years. The FDA stated: The majority of reports received since 2013 have been voluntary reports, mostly from women who received Essure implants. Page 13 of 53

14 Key efficacy and safety findings Efficacy Al-Safi: 66 pregnancies reported out of 457 adverse events (13.3%), of which: Type of pregnancy n (%) Pregnancy before confirmation of tubal occlusion 4/66 (0.1%) Ectopic pregnancy 29/66 (47.5%) Pregnancy despite HSG-confirmed tubal occlusion 23/66 (37.7%) FDA updated data: 631 pregnancies reported out of 9,900 adverse events (6.4%) Pregnancy outcome n (%) Live birth 150/631 (23.8%) Pregnancy loss, of which: 294/631 (46.6%) Ectopic pregnancy 96/294 (32.7%) Elective termination 43/294 (14.6%) Other 155/294 (52.7%) Not reported 204/631 (32.3%) Safety Al-Safi Classification of 457 adverse events (total includes pregnancies): Pain: n=217 (47.5%) Delivery catheter malfunction: n=121 (26.4%) Perforation: n=90 (19.7%) Abnormal bleeding: n=44 (9.6%) Microinsert malposition: n=33 (7.2%) Allergic reaction: n=20 (4.4%) Positive allergy testing: n=4/20 (20%) Surgical removal of device: n=11/20 (55%) Other: n=24 (5.3%) FDA updated data: Most frequent patient problems reported (most reports listed multiple problems): Pain/abdominal pain: n=6989 Heavier menses/menstrual irregularities: n=3210 Headache: n=2990 Fatigue: n=2159 Weight fluctuations: n=2088 Most frequent device problems reported (multiple device problems could be listed in each report): Patient-device incompatibility (e.g. possible nickel hypersensitivity): n=2016 Migration of the device or device component: n=854 Device operating differently than expected: n=490 Device breakage: n=429 Device difficult to remove: n=280 Device malposition: n=199 Device difficult to insert: n= reports were coded by the submitter as death; 6 of these were incorrectly coded, as there was no indication of death in the report. Of the remaining 26, 6 relate to 4 adult deaths; 18 reports relate to 15 incidences of pregnancy loss; and 2 reports related to 2 incidents of a death of an infant after live birth. Abbreviations used: HSG, hysterosalpingogram Page 14 of 53

15 Study 8 Bahk (2015) 8 Details Study type Country Review of adverse events reported via a mobile reporting app US Recruitment period Study population and number n=13,135 adverse events from 1,349 reporters Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding Average age = 33.9 years 100% women App was promoted to a Facebook patient community set up for women experiencing adverse events after Essure sterilisation. Essure sterilisation only Not relevant 6 co-authors had financial conflicts of interest with the company developing the mobile app. Analysis Study design issues: Mobile reporting app was promoted to a Facebook community ( Essure Problems ) that was formed for women experiencing adverse events after Essure sterilisation, which may influence type or number of adverse events reported. No physician confirmation of likely relationship of adverse event to Essure procedure was sought. Study population issues: The authors assumed that reporters resided in the US, unless a non-us address was given. Page 15 of 53

16 Key efficacy and safety findings Efficacy Unintentional pregnancies were not reported, however, 18 spontaneous abortions were reported as adverse events. Safety 1,349 reporters out of 17,850 Facebook group members in reported disability or permanent damage 13,135 adverse events reported: On average, 10.1 adverse events were reported per submission 1047 adverse events could be defined as a serious event 598 adverse events could be defined as an important medical event 475 adverse events required hospitalisation IP 218/3 [IPGXXX] 327 unique adverse events were reported. Most frequently reported adverse events Most frequently reported important medical events Adverse event n IME N Fatigue 491 Mental impairment 142 Back pain 468 Device dislocation 108 Pelvic pain 459 Salpingectomy 62 Abdominal pain 430 Post-procedural haemorrhage 43 Abdominal distension 418 Uterine perforation 27 Menorrhagia 411 Endometrial ablation 26 Uterine spasm 411 Spontaneous abortion 18 Headache 397 Autoimmune disorder 16 Pain 368 Suicidal ideation 14 Abnormal weight gain 357 Pelvic inflammatory disease 13 Arthralgia 318 Kidney infection 11 Vaginal haemorrhage 316 Systemic lupus erythematosus 7 Migraine 278 Urinary retention 7 Dyspareunia 271 Appendicectomy 5 Alopecia 252 Salpingitis 5 Abbreviations used: IME, important medical event Page 16 of 53

17 Study 9 Conover (2016) 9 Details Study type Country Retrospective cohort study US Recruitment period Study population and number n=71,875 (26,927 versus 44,948 laparoscopic) women having sterilisation Age and sex Patient selection criteria Crude analysis: Mean age 37.8 years () versus 36.6 years (laparoscopic) 100% women Inclusion criteria Enrolees within over 150 large employer-provided insurance plans across the US Age years Coded as having or laparoscopic sterilisation Technique Follow-up Conflict of interest/source of funding Exclusion criteria 6 months continuous insurance enrolment Second sterilisation procedure Childbirth within 6 months of sterilisation (to exclude postpartum sterilisation) Concurrent endometrial ablation History of opioid use History of pelvic pain Essure sterilisation only 1 year Nil relevant. Analysis Follow-up issues: 1 year only, however, sensitivity analysis using available follow-up data up to 5 years where available. Study design issues: Limitations with coding pelvic pain necessitated using an additional variable of 2 opioid prescriptions in year after procedure; however, pelvic pain may have been managed with no or non-opioid analgesia. Study population issues: Only includes women who have employer-provided insurance plans. Page 17 of 53

18 Key efficacy and safety findings Efficacy Safety Number analysed = 71,875 (26,927 versus 44,948 laparoscopic) 656/71,875 (0.91%) women experienced the outcome of opioid-managed pelvic pain 236 (0.88%) in group versus 420 (0.93%) in laparoscopic group Crude cumulative incidence of pelvic pain Time point Hysteroscopic sterilisation Laparoscopic sterilisation 6 months 0.48% (95% CI %) 0.40% (95% CI %) 12 months 0.40% (95% CI %) 1.29% (95% CI %) Hazard ratio of 12-month cumulative incidence of opioid-managed pelvic pain in versus laparoscopic sterilisation: Analysis Hazard ratio Crude analysis 0.97 (95% CI ) Propensity score matched analysis 1.08 (95% CI ) Sensitivity analysis of available data on incidence of pelvic pain up to 5 years after sterilisation gave a hazard ratio of opioid-managed pelvic pain in versus laparoscopic sterilisation of 1.53 (95% CI ). Abbreviations used: CI, confidence interval Page 18 of 53

19 Study 10 Zurawin (2011) 10 Details Study type Country Retrospective review of suspected nickel hypersensitivity Worldwide Recruitment period Reports between 2001 and 2010 Study population and number n=63 reports of suspected nickel hypersensitivity Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding Not reported Review of reports made to manufacturer, Manufacturer and User Facility Device Experience (MAUDE) database, and 650 patients in phase II and pivotal trials Essure sterilisation only Not reported Lead author has financial conflicts of interest with device manufacturer Analysis Study design issues: Likely underreporting of cases of suspected nickel sensitivity due to voluntary nature of reporting. Furthermore, only FDA-specific adverse event reporting database was searched, making underreporting from outside the US likely. Study population issues: Study used total kits distributed worldwide as denominator, with assumption that distribution of kits is equivalent to use in patients. Key efficacy and safety findings Efficacy Safety Out of 63 reports of possible nickel sensitivity, 20 patients had patch testing. Out of these 20 patients, 13 had positive patch tests and 7 had negative patch tests. Out of these 13 patients, symptoms were deemed to be unrelated to nickel sensitivity in 6 patients. These 6 patients along with the 7 patients with negative patch tests are unlikely to have true nickel sensitivity, leaving 50 (63-6-7) reports assessed by the authors to be possible nickel hypersensitivity (numbers calculated for overview). Authors calculate incidence of possible nickel sensitivity as 63 out of 436,937 Essure kits over 2001 to 2010 = 0.014%. This is below the population prevalence of contact nickel allergy in women reported by authors as 18-24%. Abbreviations used: Page 19 of 53

20 Studies 11 to 17 Belotte (2011) 11, Grias (2012) 12, Mantel (2013) 13, Braginsky (2015) 14, Ricci (2014) 15, Rezai (2015) 16, Riley (2015) 17 Details Study type Country Case reports of abdominal migration of intrafallopian implants Various Recruitment period 2003 to 2015 Study population and number n=18 Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding Not reported for all cases 100% women Not relevant Essure intrafallopian implants only Not reported One co-author on Riley et al. reported a personal financial conflict of interest. Conflicts of interest were not declared in Grias. Analysis Other issues: Grias (2012) is a conference abstract with limited detail. Page 20 of 53

21 Key efficacy and safety findings Efficacy Safety Individual case reports and review of literature identified 18 cases of abdominal migration of Essure intrafallopian implants Evidence of uterine or tubal perforation: Perforation Number Yes 4 No 10 Not reported 4 Side of migration: Side Number Left 7 Bilateral 3 Right 3 Not reported 5 Symptomatic at time of identification of abdominal migration Symptomatic Number Yes 6 No 7 Not reported 5 Location of migration Location Number Omentum 4 Peritoneum 3 Small bowel 4 Peritoneal cavity 1 Fragment in small bowel mesentery 1 Douglas pouch 1 Fragments near bladder and in omentum 1 Not reported 3 Complications of abdominal migration Type of complication Number (may be >1 per case) Adhesions 4 Bowel obstruction 1 Bowel strangulation 1 Bowel perforation 2 Nil 11 Page 21 of 53

22 Studies 18 to 20 Brown III (2011) 18, Garcia (2013) 19, Nimaroff (2013) 20 Details Study type Country Case reports of unusual adverse events not covered elsewhere Various Recruitment period 2011 to 2013 Study population and number n=4 Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding Not reported for all cases 100% women Not relevant Essure intrafallopian implants only Not reported Not reported in Brown III (2011) or Nimaroff (2013). No conflicts of interest for Garcia (2013). Analysis Other issues: Nimaroff (2013) is a conference abstract with very limited detail. Key efficacy and safety findings Efficacy Safety Brown (2011) describes a case with difficult placement of bilateral Essure devices, with unravelling of both coils due to release failure of the delivery wire. Attempts to remove the devices or cut the trailing coils were unsuccessful, and the patient was left with multiple unravelled coils throughout the uterine cavity. Long-term follow-up of the patient was not described. Garcia (2013) and Nimaroff (2013) describe 3 cases where expulsion of Essure intrafallopian implants after confirmation of bilateral tubal occlusion at 3-month HSG. In the case report by Garcia et al., expulsion of the left device occurred during withdrawal bleeding after termination of contraceptive use after 3-month HSG. The patient subsequently requested laparoscopic sterilisation with bilateral salpingectomy. Pathological examination of the left fallopian tube showed no inflammation or fibrotic reaction. Abbreviations used: HSG, hysterosalpingogram Page 22 of 53

23 Study 21 Solt I (2011) Details Study type Country Recruitment period Study population and number Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding Case report US Not reported n=1 24 year old woman Not relevant Essure intrafallopian implants Not reported None Key safety findings Safety Complicated ruptured Streptococcus pyogenes tubo-ovarian abscess and peritonitis, 3 years after successful tubal occlusion with Essure microinsert devices. The patient was eventually treated by hysterectomy after an exploratory laparoscopy. Examination of the fallopian tubes and the uterus revealed that the Essure microinserts were properly placed in both fallopian tubes. The most likely causative mechanism leading to tubo-ovarian abscess was an ascending infection, although other mechanisms were not ruled out. The patient had Mitochondrial neurogastrointestinal encephalopathy (MNGIE) syndrome, which may have compromised her immune status. The authors conclude that occlusion of fallopian tubes may not be sufficient to prevent the ascent of bacteria leading to pelvic inflammatory disease. Furthermore, the inserts may serve as a nidus for infection. Page 23 of 53

24 Efficacy Procedural outcomes In a systematic review and meta-analysis of 14,126 women (37 studies), bilateral placement of Essure intrafallopian inserts was successful at first attempt in 81 98% of women (31 studies, n=12,961) 4. In the same review, correct device placement at 3-month imaging was confirmed in % of women (24 studies, n=9,112). In a retrospective cohort study comparing 8,048 women having sterilisation and 44,278 women having laparoscopic sterilisation in 1 US state (n=52,536), there was a statistically significant difference in the median procedure times (36 minutes versus 52 minutes, p<0.01). There was a statistically significantly lower use of general anaesthesia for compared with laparoscopic sterilisation (51% versus 76%, p<0.01) 1. Pregnancy In the systematic review of 14,126 women, there were 8 pregnancies in 7,706 women with satisfactory device placement confirmed at 3-month imaging. In all cases, pregnancy was related to incorrect positioning of at least 1 device (despite satisfactory placement on imaging) 4. In the cohort study of 52,326 women in 1 US state, the odds of becoming pregnant within 1 year was not statistically significantly different between and laparoscopic sterilisation (adjusted odds ratio 0.84, 95% confidence interval [CI] 0.63 to 1.12) 1. In a review of unintentional pregnancies reported to the manufacturer and the US Food and Drug Administration s (FDA s) adverse event reporting database, as well as reports in the medical literature, 748 pregnancies were identified. There were sufficient data for analysis of contributing factors for 508 of these, with patient non-compliance contributing to 45%, misinterpreted 3-month imaging to 42%, insertion of a single implant (for various reasons) to 7% and patients already being pregnant before the procedure (luteal phase pregnancy) in 6%. Nearly 2 out of 5 pregnancies occurred 3 to 11 months after the procedure. On review of available 3-month imaging, perforation was detected in 13% of 748 pregnancies, unsatisfactory location of devices in 6% and expulsion in 3% 3. In a 5-year follow-up of 366 women who took part in a non-controlled, multicentre phase III study, no unintentional pregnancies occurred during 24,942 womanmonths of follow-up (excluding 4 luteal phase pregnancies), after confirmation of Page 24 of 53

25 bilateral tubal occlusion on HSG. However, loss to follow-up and premature exclusion from study participation were high 2. In a review of adverse events reported in a Facebook group established for women with problems after sterilisation with a particular device 8, 18 spontaneous abortions were reported out of 13,135 adverse events from 1,349 reporters. Safety Periprocedural outcomes In a retrospective case series analysis of 4,306 women having Essure sterilisation in 1 hospital 5, periprocedural vasovagal syncope was reported in 2% of women. In the same study 5, 83% of women described their periprocedural pain levels as none or mild, compared to 12% who described moderate pain and 4% severe. In the cohort study of 52,326 women in 1 US state 1, the adjusted odds ratios of iatrogenic complications or major medical complications at 30-day follow-up were 0.35 and 0.70 respectively for compared with laparoscopic sterilisation (95% CI 0.20 to 0.61 and 0.28 to 1.78 respectively). Risk of reoperation In the cohort study of 52,326 women in 1 US state, the adjusted odds ratio of reoperation (defined as any repeated procedure on the fallopian tubes) was for compared with laparoscopic sterilisation within 1 year (95% CI 7.47 to 13.81) 1. The adjusted odds ratios of reoperation at 2 and 3 year follow-up were 7.96 and 5.88 respectively for compared with laparoscopic sterilisation (95% CI 6.00 to and 95% CI 4.44 to 7.79 respectively). Changes in menstrual function Heavier bleeding after the procedure on more than 1 follow-up appointment was reported in 38% of women in a case series of 518 women 2. Less than 1% of women experienced persistent heavier bleeding, defined as reported on all 5 follow-up visits. In contrast, 23% of women experienced lighter bleeding than previously, although none reported this on all follow-up visits. 15% and 19% women experienced recurrent irregular bleeding and intermenstrual bleeding respectively, although this was not persistent in any participant. Because of menorrhagia or abnormal bleeding, 7 women had hysterectomy. In the review of adverse events reported in a Facebook group established for women with problems after sterilisation with a particular device, Page 25 of 53

26 menorrhagia was 1 of the most frequently reported adverse events (411 reports out of 13,135) 8. Pelvic pain In a retrospective cohort study of 71,875 women 9, there was a statistically insignificant increase in the risk of opioid-managed pelvic pain over 12 months of follow-up in women having compared with laparoscopic sterilisation (hazard ratio 1.08, 95% CI 0.90 to 1.31). Recurrent (reported on more than 1 follow-up appointment) dysmenorrhoea was reported in 6% of women, recurrent dyspareunia in 4%, and other types of pelvic pain in 5% and ovulatory pain in 3% in the case series of 518 women 2. Ovulatory pain alone was reported by 2 women (less than 1%) on all 5 follow-up visits. Three women had a hysterectomy because of pelvic pain and 2 because of dysmenorrhoea. Chronic pelvic pain was reported in less than 1% (7/4,274) of women in a case series of 4,274 women. The symptoms resolved after device removal 5. In the review of adverse events reported in a Facebook group established for women with problems after sterilisation with a particular device, pelvic pain was the third most frequent adverse event reported (459 reports out of 13,135) 8. Back pain (468 reports), abdominal pain (430 reports), pain not otherwise specified (368) and dyspareunia (271) were also frequently reported adverse events. Ectopic pregnancy Ectopic pregnancy rates within 1 year were not statistically significantly different between and laparoscopic sterilisation (adjusted odds ratio 0.34, 95% CI 0.10 to 1.13) in the cohort study of 52,326 women 1. In a review of 748 unintentional pregnancies, 30 (6%) were judged likely to be ectopic pregnancies, with 24 (80%) occurring after confirmation of tubal occlusion. Nickel hypersensitivity In a review of nickel sensitivity cases reported to the manufacturer, the FDA s adverse event reporting database and among women in the phase II and pivotal trials, 63 reports were identified with 50 of these assessed to be possible nickel hypersensitivity 10. Abdominal migration of implants Abdominal migration of intrafallopian implants was described in 18 case reports 11 17, in 4 of which there were also adhesions. The majority had no evidence of uterine or tubal perforation and were of the left device. Six cases were symptomatic at time of identification of device migration and 7 cases were Page 26 of 53

27 asymptomatic. The most frequent sites of migration were into the omentum, peritoneum and small bowel. Bowel obstruction and strangulation were seen in 1 case each and bowel perforation in 2 cases. In the review of adverse events reported in a Facebook group established for women with problems after sterilisation with a particular device, there were 108 reports of device dislocation 8. Fatigue In the review of adverse events reported in a Facebook group established for women with problems after sterilisation with a particular device, fatigue was the most frequently reported adverse event (n=491) 8. Late expulsion of devices and device coils in uterine cavity Three case reports in the literature described expulsion of Essure devices after satisfactory placement and bilateral tubal occlusion had been confirmed on imaging 3 months after the procedure 19, 20. One case report describes a case with difficult placement of bilateral Essure devices, with unravelling of both coils due to release failure of the delivery wire. Attempts to remove the devices or cut the trailing coils were unsuccessful, and the patient was left with multiple unravelled coils throughout the uterine cavity 18. Validity and generalisability of the studies A large proportion of authors on identified studies had potential conflicts of interest with the device manufacturer. A Cochrane review of techniques for the interruption of tubal patency for female sterilisation carried out in July 2015 noted that there were no randomised controlled trials comparing sterilisation using intrafallopian implants with other methods 22. The observational studies available were often retrospective and/or underpowered to detect rare outcomes such as pregnancy and adverse events. No prospective study followed up patients for longer than 5 years. Studies of adverse events often had no reliable denominator to determine incidence. No adverse event reporting database outside of the US was examined. Page 27 of 53

28 Lack of good-quality data limits the potential for meta-analysis from the various studies available. Existing assessments of this procedure The FDA is in the process of completing its evaluation of the Essure system. It has ordered Bayer to conduct a postmarket surveillance study and intends to require that a boxed warning and Patient Decision Checklist is added to the product labelling (draft guidance circulated March 2016). Health Canada has completed a safety review of Essure and has recommended increased monitoring of the safety of the Essure system. It will work with the manufacturer to issue a risk communication to help clarify information about the device and associated safety concerns. Health Canada is working with the manufacturer to update the Essure product labelling and to develop a patient information sheet and checklist (summary safety review issued May 2016) 23. The American Association of Gynecologic Laparoscopists (AAGL) has published an advisory statement on Essure sterilisation 24. They state that sterilisation offers women a less invasive alternative with clear advantages over laparoscopic sterilisation; however, women must be fully informed of the risks, benefits, indications and alternatives and be able to maintain their right to choose. Women should be monitored closely after the procedure and evaluated for possible complications. Removal of an Essure device is only indicated if other causes of pelvic pain and menstrual irregularities have been excluded and women must be counselled on the risks of surgical removal. The AAGL supports further research and education in this area, particularly with regard to optimal patient selection, proper surgical placement, monitoring of possible complications and removal techniques. Related NICE guidance Below is a list of NICE guidance related to this procedure. Appendix B gives details of the recommendations made in each piece of guidance listed. Interventional procedures Hysteroscopic sterilisation by tubal cannulation and placement of intrafallopian implant. NICE interventional procedures guidance 315 (2009) Specialist advisers opinions Specialist advice was sought from consultants who have been nominated or ratified by their Specialist Society or Royal College. The advice received is their individual opinion and is not intended to represent the view of the society. The advice provided by specialist advisers, in the form of the completed Page 28 of 53

29 questionnaires, is normally published in full on the NICE website during public consultation, except in circumstances but not limited to, where comments are considered voluminous, or publication would be unlawful or inappropriate. Eight Specialist Advisor Questionnaires for sterilisation by insertion of intrafallopian implant were submitted and can be found on the NICE website. Patient commentators opinions NICE s Public Involvement Programme will send questionnaires to NHS trusts for distribution to patients who had the procedure (or their carers). When NICE has received the completed questionnaires these will be discussed by the committee. Company engagement A structured information request was sent to 3 companies who manufacture a potentially relevant device for use in this procedure. NICE received 2 completed submissions. These were considered by the IP team and any relevant points have been taken into consideration when preparing this overview. Issues for consideration by IPAC Emerging key trials include: A Multi-Center, Multi-National Clinical Study to Evaluate the Safety and Effectiveness of the Essure (Model ESS505) Device to Prevent Pregnancy in Women Who Are Seeking Permanent Contraception (NCT ); US, Canada, Netherlands and Spain; enrolment=612; estimated study completion date=december 2024 Survey on Use and Characteristics of Definitive Contraception With Essure (SUCCES II; NCT ); France; enrolment=2546; estimated study completion date=october 2016 Use of Transvaginal Ultrasound to Confirm Essure Micro-insert Placement in Women: Demonstration of Effectiveness (NCT ); US, Canada, Netherlands and Spain; enrolment=547; estimated study completion date=july 2023 A Study to Evaluate the Effectiveness of Essure Post-NovaSure Radiofrequency Endometrial Ablation Procedure Following a Successful Page 29 of 53

30 Essure Confirmation Test (NCT ); US; enrolment=200; estimated study completion date=february Three other devices for sterilisation by insertion of intrafallopian implants were identified; however, Essure is the only system currently used in clinical practice and therefore the only 1 reviewed here. The other systems are: The Adiana system, which uses radiofrequency energy and deployment of a silicone matrix to achieve tissue ingrowth in the fallopian tubes. It was approved by the FDA in 2009, but was voluntarily withdrawn from the market in The Ovabloc system, which has been used in the US since 1978; however, it was withdrawn in It was recently redesigned as Ovalastic with CE approval in It uses a silicon elastomer plug to achieve tubal occlusion, rather than tissue ingrowth. The Altaseal system, which is a stainless steel implant that achieves immediate tubal occlusion. It is currently being piloted in Ireland. The Essure system has evolved since FDA approval, with the first-generation device ESS205 giving way to the second-generation ESS305 in Because most of the evidence does not specify which device has been used, this can only be assumed from the date of publication. Several reports described efficacy and safety associated with performance of endometrial ablation simultaneously with the placement of Essure intrafallopian implants. However, the company recommends that the Essure procedure should not be performed concomitantly with any endometrial ablation technique because intrauterine synechiae that result from ablation can compromise the interpretation of the HSG confirmation test for tubal occlusion. Therefore, these studies were not reviewed here. Page 30 of 53