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Review of JAMA Article: Association of Hysteroscopic Vs Laparoscopic Sterilization With Procedural, Gynecological, and Medical Outcomes

(Publication Date: 01/23/18)

Introduction: This recently published French article regarding the comparative results of safety, efficacy and outcome of ESSURE Permanent Sterilization vs Laparoscopic Bilateral Tubal Sterilization was internationally well received. Yet, despite the large study group size and author described “exhaustive information” which “can be considered accurate,” a number limitations of the study appear to contradict the validity and conclusions of the authors.

In fact, procedures in the data appear to violate standards of care regarding the use of the ESSURE device, as well as, proper and ethical surgical management of complications of both ESSURE and laparoscopic sterilization.

Further, an in depth review extending beyond the individual disorders listed in the administrative data should have been considered in the evaluation of risks to include preoperative surgical informed consent and intraoperative pain management in fully conscious patients undergoing ESSURE placement.

Confirmation of violations of specific Bayer recommended ESSURE protocols by French physicians would be critical of unacceptable standards of care and would in fact be paramount to medical battery and violations of the basic human rights. https://academic.oup.com/painmedicine/article/17/10/1785/2270355

https://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-8-8

Bayer Promotion Points Regarding ESSURE

· Approved by FDA in 2002. Over 750,000 units sold worldwide

· Permanent birth control procedure

· Minimally invasive procedure (Previously promoted as NON-SURGICAL)

· No General Anesthesia Required

· Non-hormonal

· Return to Normal Activity within 1 to 2 days

· Short Placement Time (Total procedure time average 36 minutes)

· Highly effective (99.3% effective at preventing pregnancy)

· The safety and effectiveness of ESSURE has not been established in women under the age of 21 or over the age of 45

Bayer Contraindications for the placement of ESSURE

· Patient only has single fallopian tube

· Patient has a known abnormal uterine cavity that makes visualization of the tubal ostia impossible and/or abnormal tubal anatomy

· One or both fallopian tubes closed or obstructed

· Patient has undergone a bilateral tubal ligation (“tubes tied”)

· Patient has delivered or terminated a pregnancy less than 6 weeks prior to the ESSURE procedure

Essure Information for Use

http://labeling.bayerhealthcare.com/html/products/pi/essure_ifu.pdf

Essure Clinical Resource, Physican Clinical Manual

http://www.hcp.essure-us.com/assets/pdf/PP-250-US-1583%20Essure%20Clinical%20Resource%20Guide%20Phys%20Manual%20(Digital%20pdf).pdf

Analysis of Clinical Data

Bayer Premarket Studies

“Two clinical trials (Phase II and Pivotal trials) have demonstrated the efficacy and safety of Essure® permanent birth control.”

These studies are considered to be the benchmark of safety and efficacy by Bayer.

Phase II with modified HSG

• Prospective, multi-center, single-arm, non-randomized, international study

Pivotal with modified HSG

• Prospective, multi-center, single-arm, non-randomized, international study which used the U.S. Collaborative Review of Sterilization (CREST study) as a qualitative benchmark.

In both studies, an Essure Confirmation Test with modified HSG was performed 3 months post-insert placement to evaluate insert location and fallopian tube occlusion. If bilateral fallopian tubes were occluded and bilateral inserts were in satisfactory location, then the patient was instructed to discontinue use of alternative contraception and rely on the Essure inserts for prevention of pregnancy.

Patient Characteristics and Demographics

· Phase II and Pivotal trials consisted of 664 women in whom bilateral insert placement was achieved after one or more attempts

· All study participants were between 21 and 45 years of age

· All women had at least 1 live birth

· Average age of women was 33

· 14%: 21-27

· 40%: 28-33

· 46%: 34-45

Results of Combined Phase II and Pivotal Studies

· 1.76% incidence of perforation

· 2.2% incidence of expulsion

· 0.59% incidence of unsatisfactory insert location

· 3.5% initial tubal patency 3 months post insertion, 0% tubal patency 6 months post insertion

· 0% pregnancy rate up to 5 years post insertion

· Note: This perfect sterilization rate has NEVER been documented in any study except in these premarket studies.


Limitations of Phase II and Pivotal Studies

“The premarketing approval of Essure in 2002 was based on two nonrandomized, nonblinded, prospective studies that lacked a comparator group and enrolled a total of 926 women. The FDA review concluded that 97% of women with bilateral Essure placement could rely on the device. This determination of reliability, however, was not based on an intention-to-treat analysis and considered only women who successfully underwent the procedure and had 3-month hysterosalpingograms showing correct Essure placement and bilateral tubal occlusion (data presented to the FDA described a 14% failure rate for the first attempt at bilateral coil placement). Because of these exclusions, the declared reliability rate was based on only 664 (89%) of the 745 women who underwent an implantation attempt and did not account for 181 enrolled women who subsequently chose not to undergo the procedure (for unstated reasons), did not pass screening tests, or were excluded for not meeting other criteria. Among the 745 women who underwent an attempted Essure procedure, only 632 (85%) were followed up at 1 year for effectiveness outcomes and 682 (92%) for safety outcomes. Just 197 (25%) were followed for effectiveness at 2 years, which further limited the evaluation of adverse events and device safety.”

http://www.nejm.org/doi/full/10.1056/NEJMp1510514

JAMA 2018 French Study

Design Settings and Participants

· French nationwide cohort study using the national hospital discharged database linked to the health insurance claims database.

· Only administrative databases were used

· Individual disorders reported and collected into medical device vigilance databases could not be examined.

· Only 75% of the general population medical database could be evaluated

· Women aged 30 to 54 years receiving a first hysteroscopic or laparoscopic sterilization between 2010 and 2014 were included and were followed up through December 2015.

Study Conclusions

· Among women undergoing first sterilization, the use of hysteroscopic sterilization was significantly associated with higher risk of gynecological complications over 1 year and over 3 years than was laparoscopic sterilization.

· Risk of medical complications, such as adverse autoimmune responses, was not significantly increased with hysteroscopic sterilization as compared to laparoscopic sterilization

Patient Characteristics and Demographics

· 110,299 women who underwent a primary tubal sterilization procedure between January 2010 and December 2014 were eligible.

· Inclusion: 105,357 women, including 71,303 who underwent hysteroscopic sterilization (ESSURE) and 34,054 who underwent laparoscopic sterilization.

· 105,318 (99.6%) were followed-up at least 1 year

· 54,232 (51.5%) were followed for at least 3 years

· 51,086 (48.41%) were not followed up to 3 years due to cut off date of analysis up through December 2015.

· Exclusion: 4942 women were excluded for at least 1 exclusion criteria. (Only 2 listed here)

· 322 were excluded due to non-use of medical services for 3 or more years up to the December 2015 cut-off date.

· 2505 were excluded due to obstetric history 3 months prior to sterilization

· Mean age of patients was 41.3%

· 30-39: 28.39%

· 40-41: 22.48%

· 42-44: 29.93%

· >45: 19.21%

Results of French Study

This study involved a large number of variables, post-operative complications and surgical/medical outcomes.

It is not the intent of this author’s evaluation to critique the evaluation and interpretation of each variable; rather, this author would like to open a discussion of comparison of the French study to the United States ESSURE population since a US national database is not available for comparison. It would be beneficial if the authors of the French study were to consider methods which address concerns regarding apparent violations of standard of care and management as specifically stated by Bayer regarding the use of the ESSURE product.

Further, one of the limitations of the study is the fact that only administrative data based on billing and coding were used to compare hysteroscopic and laparoscopic sterilization. However, no data regarding patient opinion and responses during the hysteroscopic procedure, especially in patients undergoing the procedure without anesthesia were analyzed. This information is critically important when considering the fact that US surveys of ESSURE demonstrate that conscious insertion of the ESSURE can be an exceptionally painful procedure when done without anesthesia.

A key point in obtaining Informed Consent is patient advisement of the severity of pain regarding the completion of a conscious surgical procedure. In the case of ESSURE vs laparoscopic sterilization, it is estimated that a significant number of ESSURE devices are placed without anesthesia or with local, oral or IV sedation. Very few laparoscopic sterilization procedures are performed without general anesthesia which maintains a level of appropriate sedation and pain management.

In the US, this advisement has been severally lacking which compromise a standard of care that has allowed for the systemic violations of pain management protocols and systemic unethical and inappropriate behavior to include medical battery on the part of the inserting physician.

Due to the structure of the French study with an inclusion of only administrative data, these violations could not be evaluated in the case of ESSURE placement; however, based on the history of ESSURE insertion in the US, it is highly unlikely that French surgeons acted differently, especially considering the fact that the French study clearly documents violations of standards of care in regards to ESSURE insertion and management of sterilization failures based on guidelines and contraindications delineated in the Bayer ESSURE Clinical Resource Physician Training Manual.


Therefore, a goal of this author’s review of the French study is to challenge the French Republic to ask the questions of (1)whether Informed Consent was properly obtained prior to the original hysteroscopic and laparoscopic sterilization; (2) whether this included questions regarding pain management during the insertion; (3) whether the procedures were discontinued when requested by the patients; (4) whether patients were informed that secondary sterilization using ESSURE is specifically contraindicates; and, (5) whether patients were properly informed of the probability and risks of secondary surgical procedures if sterilization failed with the original attempt.

Comparative Review of Baseline Characteristics of Participants

Table 1 of the French study reviewed the baseline characteristics of participants such as median age, range of age, prior pregnancy, gynecological history and use of medications. A comparison of statistics to the general population of the French Republic in order to support its validity as well as a comparison to the statistics of a similar population of women in the US could be beneficial to evaluate selection bias.

Age Selection

The authors of the French study acknowledge that the mean age of the women in the study was 41.3. Based on data from the Index Mundi, the average age of females in the French Republic is 42.9. The statistical significant of this difference is unknown and beyond the scope of this commentary.

https://www.indexmundi.com/france/age_structure.html

French Study

· 30-39: 28.39%

· 40-41: 22.48%

· 42-44: 29.93%

· >45: 19.21%

United States vs The French Republic Population Indicators

Indicator

United States

French Republic

Crude Birth Rate

12.653 births/thousand

11.677 births/thousand

Crude Death Rate

8.352 deaths/thousand

9.022 deaths/thousand

Life Expectancy (Both Sexes)

79.62 years

82.8 years

Male Life Expectancy

77.34 years

79.9 years

Female Life Expectancy

81.88 years

85.68 years

Total Fertility Rate

1.886 children/woman

1.973 children/woman

Net Reproduction Rate

0.909 surviving daughters/woman

0.955 surviving daughters/woman

Sex Ratio at Birth

1.048 males per female

1.052 males per female

Mean Age at Childbearing

29.514 years

30.337 years

http://worldpopulationreview.com/countries/united-states-population/

http://worldpopulationreview.com/countries/france-population/

Discussion of Age Selection Bias

A comparison of data from the World Population Review demonstrate a similar fertility rate, net reproduction rate, sex ratio at birth and mean age at childbearing between the US and the French Republic.

If we are to accept the premise of the authors of the French study that the stats of the study can be generalized for the entire French population, there appears to be a significant difference in the mean age of the participants in the French study as compared to the US population as well as the age of participants in the Phase II and Pivotal premarket studies conducted by Conceptus and Bayer. The mean age of the French study participants was 41.3 years of age, whereas the mean age for female sterilization in the US is estimated to be 33 years of age. The mean age for the Phase II and Pivotal premarket studies was also 33.

An important benchmark which is not described in the French study is the calculated mean age of women undergoing sterilization in the French population.

Is the mean age of sterilization in the French Republic comparable to the mean age of the participants in the French study?

This determination is very important since it is well known that fecundity decreases as a woman ages and is significantly reduced as a woman approaches 40 years of age.

As the mean age of participants approaches the age of menopause, the incidence of pregnancy is expected to decrease. This is not solely due to the efficacy of the sterilization procedure, but based on age, thus creating a potential significant age selection bias.

“For example, if you are a healthy 30-year-old woman, you have about a 20% chance per month to get pregnant. By age 40, however, your chance is only about 5% per month.”

American Society For Reproductive Medicine. Age and Fertility, A Guide for Patients. http://fwivf.com/new-patient/documents/AgeandFertilityGuide.pdf

https://www.acog.org/Clinical-Guidance-and-Publications/Committee-Opinions/Committee-on-Gynecologic-Practice/Female-Age-Related-Fertility-Decline

Another example, if a hypothetical patient were to undergo the same procedure under the exact same conditions and with the same result at age 20 vs age 40, the patient would be at higher risk of pregnancy with sterilization failure at age 20 as compared to age 40. Therefore, when studying the incidence of pregnancy following sterilization failure, the incidence is expected to be lower in an aging population of women. If a high incidence of pregnancy is found in an older study group, it could be assumed that the incidence would be even higher in younger women with higher fecundity.

This premise is supported by data analysis of one of the largest studies done in the US regarding permanent sterilization. The US Collaborative Review of Sterilization (CREST) study was a multicenter, prospective study sponsored by the CDC to examine the issue of long-term failure of tubal sterilization. “The 10-year cumulative failure rates varied enormously from a low of 0.18% to a high of 5.4%, depending on age at time of sterilization and method of occlusion used.”

10-year Cumulative Probability of Pregnancy Among Women Undergoing Tubal Sterilization. (Cumulative Probability of Pregnancy per 1000 surgeries and 95% Confidence Interval)

Method

Number

18-27 YRS

28-33 YRS

34-44 YRS

18-44 YRS

Bipolar coagulation

2267

54.3 (28.3-80.4)

21.3 (9.6-33.0)

6.3 (0.1-12.5)

24.8 (16.2-33.3)

Unipolar coagulation

1432

3.7 (0.0-11.1)

15.6 (0.0-31.4)

1.8 (0.0-5.3)

7.5 (1.1-13.9)

Silicone rubber-band

3329

33.2 (10.6-55.9)

21.1 (6.4-35.9)

4.5 (0.6-8.4)

17.7 (10.1-25.3)

Spring-clip

1595

52.1 (31.0-73.3)

31.3 (15.1-47.5)

18.2 (0.0-36.4)

36.5 (25.3-47.7)

Interval partial salpingectomy

425

9.7 (0.0-28.6)

33.5 (0.0-74.3)

18.7 (0.0-39.6)

20.1 (4.7-35.6)

Postpartum partial salpingectomy

637

11.4 (1.6-21.1)

5.6 (0.0-11.9)

3.8 (0.0-11.4)

7.5 (2.7-12.3)

All methods

10,685

----

----

----

18.5 (15.1-21.8)

Adapted from the Population Council

https://www.medscape.com/viewarticle/719264_12

A comparison of efficacy and outcomes of the French study to the US population becomes even more difficult, since fecundity is closer to optimal with a US mean age of 33 as compared to the French study mean age of 41.3.

If attempting to create a comparable US-French Republic model, a US mean age of 33 would be comparable to the age range of 30-39 in the French study. However, this age range represents only 25.4% of the French study participants rather than a comparable mean if the study were matching the mean age of the US population or Phase II/Pivotal studies undergoing sterilization as compared to the mean age of the French study.

A disproportionately high number of women in the age French study were above age 40 (74.6%). In comparison to both the US and French Republic population of women between the ages of 40-44, this study appears to include a significantly disproportional percentage of advanced reproductive age women.

In the French study, 54.4% of women were in the age range of 40-44. Data from US Center for Disease Control (CDC), National Survey of Family Growth showed that the percentage of women 40-44 years of age in 2011-2015 (a comparable range of 2010-2015 for the French study) found that only 29.8% underwent tubal sterilization.

Percentage of US women 40-44 years of age in 2011-2015 who have ever had a sterilization operation by type of operation:

Operation Type

2011-2015

Tubal sterilization

29.8% (1.76)

Hysterectomy

10.6% (1.15)

Other operations

6.9% (0.92)

Source: Special tabulation by NCHS

https://www.cdc.gov/nchs/nsfg/key_statistics/s.htm#sterilizationfemale

The French study also documented a population group, women aged > 45, which included 14,404 (20.2%), which include a category of participants with a relative contraindication to having the ESSURE procedure based on age. Specifically, Bayer has stated in the ESSURE Clinical Resource Physician Training Manual, “the safety and effectiveness of Essure has not been established in women under 21 or over 45 years old.”

http://www.essure.com/safety

An obvious question of concern: Why were an estimated 14,000 women allowed to undergo the ESSURE procedure when the safety and effectiveness of the ESSURE has not been established in women over the age of 45?

Is this a violation of the Standard of Care?

Were these women advised prior to the insertion of the ESSURE that their procedure was experimental in nature and did the women sign a written Informed Consent in accordance with WHO International Guidelines for Ethical Review of Epidemiologic Studies (1991) and Ethical Guidelines for Biomedical Research of Human Subjects (1993)?

https://www.ufrgs.br/bioetica/cioms2008.pdf

Prior Pregnancy

The French study lists a category of “Prior Pregnancy” which included 20,309 (28.9%) women who underwent ESSURE sterilization and 10,663 (31.3%) who underwent laparoscopic sterilization.

Based on the description of the category, it appears that 71.1% of the ESSURE group and 68.7% of laparoscopic group had never had a pregnancy.

This is again a clear deviation from the benchmark characteristics of the Phase II/Pivotal study participants where all participants had at least 1 child.

In comparison to the US, which have similar number of children/woman and age of first delivery as the French Republic, only 56.7% of women of childbearing age (15-50) had no children. The inclusion of “prior pregnancy” rather than “no children” suggest that the percentage of nulligravida women would be even lower as compared to both the Phase II/Pivotal and US population.

Data from the 2012 and 2016 US Census is available for comparison in a US-French model. When comparing similar age groups as in the French study, the percentage of parity increased from 69.2% (30-34) to 82.9% (45-50). These numbers are inversely comparable to history of gravida participants in the French study if “prior pregnancy” is defined as the number of women having been pregnant at least 1 time.

https://census.gov/data/tables/2016/demo/fertility/women-fertility.html

If correct, these percentages appear to represent a disproportionately high number of nulligravida women as compared to the general population of both the US and the French Republic. As such, a number of questions regarding the generalization of the French study to the general population of the French Republic should be considered, including confounding variables to include low risk of pregnancy due to interpersonal and social factors and decreased fecundity of the French study participants as compared to the general population of the French Republic.

Gynecological History

The French study includes a category named “Congenital malformation of uterusor cervix,” which includes 43 (0.1%) ESSURE sterilization and 24 (0.1%) laparoscopic sterilization participants.

Although there is no contraindications to performing laparoscopic sterilization on a patient with congenital or secondary malformation of the uterus, there is a specific contraindication to placement of the ESSURE in patients with anomalies or deformities of the fallopian tubes.

The authors of the French study documented no statistical difference between the groups in this category (0.1% vs 0.1%); however, there is no information given as to whether any of the 43 ESSURE participants had a contraindicated structural anomaly (such as unicornuate uterus) or tubal anomaly which is considered contraindicated by Bayer.

If ESSURE was placed in any of these 43 patients as either a primary or secondary surgery, was the patient given proper Informed Consent regarding the contraindication and lack of safety and efficacy information?

Concomitant Medications

The French study includes an analgesic drug category which includes NSAIDs as well as narcotic/opiate medications.

Although the percentage of analgesic drug use between the hysteroscopic and laparoscopic groups were 35.3% and 36.3% respectively, the use were significantly higher in One-Year Follow-up (53.90% and 56.08%) and Three-Year Follow-up (46.60% and 51.03%) as compared to pre-sterilization percentages.

A delineation of over-the-counter medication vs prescription narcotic medication was not documented. This is a significant limiting factor considering the fact that it is possible that the rise in percentage of analgesic use could have been associated with a higher consumption of narcotic pain medication suggesting increased pain levels or narcotic pain use for adverse medical conditions.

An additional consideration regarding concomitant medications is the apparent increase in use of analgesic, benzodiazepines and other medications in both groups as compared to pre-sterilization levels. Although a comparison of use between the ESSURE group and laparoscopic sterilization group did not appear to be statistically significant, a review of pre-operative and post-operative use of medications could shed some light on the increased incidence of the most common complaints from women undergoing permanent sterilization to include dysmenorrhea, abnormal uterine bleeding, dyspareunia and Post Tubal Ligation Syndrome (PTLS), all of which are associated with increased use of a variety of medications.

Violations of Standard of Care Based on Bayer Guidelines (ESSURE Clinical Resource Physician Training Manual)


Management of Failed Sterilization in the

Original/Primary Sterilization Procedure

Table 4 of the French study documents that 2955 (4.1%) in the ESSURE group and 56 (0.16%) in the laparoscopic group underwent a second sterilization procedure within the One-Year Follow-up. These numbers increased to 3230 (4.5%) and 97 (0.28%) respectively within the Three-Year Follow-up. Incidence of reoperation (to include second sterilization procedures) comparably increased as well in each group in the One and Three-Year Follow-ups.

The authors concluded that “the use of hysteroscopic sterilization was significantly associated with higher risk of gynecological complications over 1 year and over 3 years.” https://jamanetwork.com/collections/42111/gynecology?fl_ContentType=Article&fl_Categories=Gynecology&q=association%20of%20hysteroscopic%20vs%20laparoscopic%20sterilization

However, no discussion was included regarding the fact that re-operation in patients with ESSURE via an additional hysteroscopic approach is SPECIFICALLY CONTRAINDICATED due to the fact that ESSURE placement should not be attempted in patients with a history of previous tubal damage or previous tubal ligation.

The severity of potential complication is postulated to be highest with a hysteroscopic(original)-hysteroscopic (repeat) sterilization and lowest with laparoscopic(original)-laparoscopic (repeat) sterilization.

Hysteroscopic(original)-laparoscopic (repeat) sterilization also has fundamental and increasing risks of complication associated with the location of laparoscopic tubal ligation/injury and the Grade location of the ESSURE coil.

A known complication of ESSURE placement is perforation, migration or expulsion of the coil (3-4%) even after scarring due in part to the natural degradation and migration forces induced by the localized inflammatory and foreign body implant response to both the metallic and PET fibers.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240188/

The addition of intentional thermal or compression damage to the coil and its surrounding tissue during a second sterilization procedure would be expected to increase the risk of coil perforation, migration and extrusion.

Table 4 shows second sterilization and reoperation procedures in ESSURE vs laparoscopic sterilization of 4.1-9.04% and 0.16 and 5.81%, respectively. This suggests that between 3000-4000 women may have undergone combined sterilization procedures contraindicated by Bayer guidelines. The specific type of combined techniques is not delineated in Table 4, but it is obvious that it includes a significant number of patients.

The authors did not delineate complications associated with fragmentation or retention of ESSURE segments which is a common complication of improper technique during ESSURE coil removal especially in salpingostomy.

Complications regarding perforation, extrusion, migration, and fragmentation and their associated chronic systemic inflammatory foreign body reaction are known to present themselves years after their occurrence, which significantly limits the evaluation of their effects from a 1-3 year study, especially considering the fact that the clinical outcome of 48.41% of the patients in the study out to 3 years were not included due to the fact that the study data collection was terminated in December 2015.

Regardless of the outcomes, the French study clearly shows that combined techniques in violation of Bayer guidelines did occur. Since this appears to be indisputable, the question that must be considered is the following: Were the patients that underwent combined hysteroscopic-hysteroscopic, hysteroscopic-laparoscopic or laparoscopic-hysteroscopic procedures properly informed and written Informed Consent stating that these techniques were specifically contraindicated by the manufacturer of the ESSURE obtained?

Failure to obtain Informed Consent in these estimated 3000+ women would not only be a violation of standards of care but warrant investigation of malpractice and violations of the WHO International Guidelines for Ethical Review of Epidemiologic Studies (1991) and Ethical Guidelines for Biomedical Research of Human Subjects (1993). If true, such violations of human rights in such a large number of French women may have last occurred since the creation of the Nuremberg Code of medical ethics.

Management of Sterilization in Hospitals at Inclusion

Table 2, Description of Management of Sterilization in Hospitals at Inclusion, includes a category of anesthetic procedure, which describes the use of no anesthesia, local, IV, regional and general anesthesia.

Background on Placement of ESSURE in Conscious Patients in an Office Setting vs General Anesthesia in a Hospital Setting

ESSURE has been heavily marketed by BAYER as an AWAKE or conscious procedure.

The healthcare system in the US provides for significant financial compensation to the physician-provider for procedures that can be done in an Office Setting as compared to a Hospital Setting.

In 2002, the United States Food and Drug Administration (FDA) approved the marketing of the ESSURE as a conscious procedure that could be done in the office.

In the US, between 2002-2015, net compensation to the inserting doctor of the ESSURE was $1500 for a 10-36 minute procedure as compared to $250-350 if the procedure were done in a hospital. Based on factors associated with time, a physician could be paid $100 per minute for the placement of the ESSURE in the office compared to $100 per hour associated with placing the ESSURE in the hospital.

This became an enormous selling point and financial incentive for physicians. However, a significant number of physicians began to place the ESSURE under general anesthesia after patients complained of excruciating pain during conscious insertion paramount to torture.

Although the healthcare system in the French Republic is fundamentally different as compared to the US, BAYER has continued to promote the benefits of awake or conscious placement in an office or hospital setting due to the lower risks of complications as compared to general anesthesia. The convenience of conscious placement in a physician’s office continues to be a significantly promoted marketing point by BAYER.

Due to the nature of laparoscopic surgery, almost all patients in the laparoscopic group of the French study, 99.5% (33,876), received some type of anesthesia (assumed to be general).

However, based on the fact that ESSURE sterilization can be done awake or conscious, 27.8% (19,107), received no anesthesia.

The data does not include a description of the level of pain or pain management during the placement of the ESSURE. However, based on the data provided from the Pivotal study, 29.6% experienced cramping and 12.9% experienced pain.

“Some women report mild to moderate discomfort, pain and cramping during or after the placement procedure.”

Bayer Patient Information Booklet

http://www.essure.com/assets/pdf/Patient-Information-Booklet.pdf

ESSURE CLINICAL RESOURCE Physician Training Manual


Although the French study does not document pain level or pain management during the placement of the ESSURE, the consideration that a significant number of patients experienced unacceptable levels of pain during insertion while conscious is warranted.

Exclusion of Patients with Obstetric History (3 months prior to Study)

Although the authors decided not to include 2505 patients that had recently been pregnant or following delivery less than 3 months from the start of the study, the inclusion of these patients in order to compare standard protocols in the US may have been helpful.

In the US, a significant number of pregnant women (up to 50%) depend on temporary maternity insurance (MEDICAID) which is available up to 8 weeks following delivery.

https://www.kff.org/womens-health-policy/fact-sheet/womens-health-insurance-coverage-fact-sheet/

This represent a small window of opportunity for placement of the ESSURE which is considered both safe and will be paid by MEDICAID. In accordance with BAYER recommendations, ESSURE is offered and placed in eligible women between 6 to 8 weeks following pregnancy or delivery in order to place the ESSURE before the patient loses her MEDICAID insurance.

The promotion of this option is done without consideration of post-operative ESSURE Confirmatory HSG testing which is required at least 3 months following surgery and has been a major obstacle in proper follow-up care. It has been specifically addressed as an ethical violation of care when a doctor fails to consider and properly inform their patient that confirmation testing will not be available to their patient as a covered service.

http://www.essure.com/assets/pdf/Patient-Information-Booklet.pdf

The authors’ decision not to include this category in the French study may or may not have affected outcome but would not be prudent in a US model.

Number of Days in Hospital

An interesting difference in the management of post-operative patients in the French study as compared to the US is the number of days of hospitalization following laparoscopic sterilization.

In the French study, the percentage of hysteroscopic related hospitalization appears to be similar to the US. However, the number of hospital days following laparoscopic sterilization appears to be significantly higher than in the US.

17,600 (51.7%) patients were outpatient or stayed 0 days (less than 1 day) in the hospital. 14,163 (41.6%) stayed at least 1 day and 2291 (6.7%) stayed greater than one day.

In comparison, almost all hysteroscopic and laparoscopic sterilization performed in the US are associated with hospital stays of only a few hours or less than 1 day. Hospitalization exceeding 1 day are most often associated with intraoperative complications.

Based on the data provided, it is not possible to determine if the extended stays associated with laparoscopic sterilization were associated with standard hospital protocols or due to adverse complications requiring medically necessary hospitalization. If hospitalization was extended simply based on protocol, this may have affected incidences of DVT, PE and other conditions if restrictions were made on ambulation.

Surgical and Medical Complications After

Hysteroscopic and Laparoscopic Sterilization

Table 3 includes a number of surgical and medical complications.

Due to the nature of laparoscopic surgery which most often includes the risks of general anesthesia as well as potential blunt, sharp and thermal trauma from its invasive nature and instrumentation, it is not unusual to have found higher incidences of complications associated with laparoscopic sterilization as compared to hysteroscopic sterilization (especially when no anesthesia was used).

When solely considering the risks of general anesthesia, laparoscopic sterilization is assumed to have higher risks of complications. However, when performing ESSURE and laparoscopic sterilization under general anesthesia, many of the assumed benefits of ESSURE sterilization are eliminated. According to the CREST study, the odds ratio of complications from general or regional anesthesia is approximately 3 times that of local anesthesia.

https://emedicine.medscape.com/article/266799-overview#a5

Interestingly, a few differences do stand out in the hysteroscopic group, such has higher incidence of acute myocardial infarction or cardiac arrest 11 (0.02%) vs 2 (0.01%) in the laparoscopic group and the fact that there were more patients with acute MI/cardiac arrest than patients with post operative infection (11 vs 8).

Higher incidence of cardiac complications may be related to age or possibly fluid overload which is a common problem related to hysteroscopic procedures. Although the incidence of MI/cardiac arrest, as well as, other serious intraoperative/post-operative complications could not be compared to the general population based on the data provided, risk management protocols could be reviewed in order to improve outcome especially considering the fact that, in general, permanent sterilization is considered an elective surgery.

Number of Visits to Physicians

Although the authors found no significant difference in the number of visits to the doctor following either ESSURE or laparoscopic sterilization, the number of visits did increase from 1-3 years. This increase was not compared to a benchmark baseline incidence prior to sterilization but if statistically higher this would raise questions regarding the incidence of post sterilization symptomology to include foreign body reactions which could be addressed in additional supplemental analysis of the data.

Creation of a Comparable ESSURE to

Laparoscopic Sterilization Postmarket Study

Since ESSURE IS no longer commercially available in the European Union, the task of further and future prospective analysis of safety and efficacy seems to fall on the US since this is the only country still allowing the sale of ESSURE.

Due in large part to the significant increase in complications documented in the MAUDE data regarding the ESSURE, to include hundreds of fetal deaths and thousands of unintended pregnancies, the FDA has ordered a prospective Postmarket Study of the ESSURE comparing it to laparoscopic sterilization.

Although the CREST study is considered a benchmark regarding female sterilization, it was initiated before the ESSURE came to market so direct comparison through a retrospective study is limited using the CREST data. https://www.medscape.com/viewarticle/719264_6

Nevertheless, a prospective study is not only beneficial, it is the opinion of this author that it should have been mandatory before ESSURE should have been given premarket approval (PMA) Class III classification for sale in the US. https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/ImplantsandProsthetics/EssurePermanentBirthControl/ucm452270.htm

However, a comparison of multiple laparoscopic sterilization techniques to ESSURE sterilization may yield inconsistent results to real world scenarios due to a number of confounding variables.

In order to properly evaluate ESSURE sterilization to laparoscopic sterilization, the study should compare these procedures, their risks and outcomes as closely as possible using the same variables and overall intended effects as compared to what the ESSURE is designed to do.

In other words, among the multiple laparoscopic techniques available, only one technique most closely matches the procedure requirement and anatomical occlusion parameters as compared to the ESSURE.

This laparoscopic procedure is a modification of the bipolar coagulation technique previously reviewed in the CREST study. Although this may be a questionable comparison to some, the following description of the procedure based on this author’s 20 years of experience with the procedure may explain the reasoning:

1. The ESSURE sterilization requires the placement of one 4cm metallic/PET coil within the ostium with an optimal final positioning of Grade 2 as confirmed by hysterosalpingraphy (HSG). In Grade 2, the portion of the coil is positioned within the uterine cavity, the tubal ostium, interstitial portion of the fallopian tube, the utero-tubal junction (UTJ) and distal to the UTJ

2. The expected area of inflammatory response leading to permanent scarring approximates the contiguous length of the coil or 4cm

Therefore, the only laparoscopic procedure that most closely matches the position and effect of scarring of the ESSURE leading to expected permanent tubal occlusion is BILATERAL BIPOLAR COAGULATION/FULGURATION OF THE UTJ and the ISTHMUS UP TO 4cm IN ESTIMATED LENGTH OF THERMAL DAMAGE.

Traditional bipolar coagulation has most commonly involved coagulation of 2 to 3 non-contiguous areas of the fallopian tube beginning 2 to 3 cm from the UTJ. The failure of this technique is commonly due to improper or incomplete thermal damage of the tube which allows for only temporary or incomplete luminal occlusion.

The use of Hulka clips, silicone bands, partial salpingectomy, complete salpingectomy or Fimbriectomy do not allow for contiguous scarring up to 4cm with the tubes remaining in place nor do these techniques routinely cause scarring of tubal ostium, interstitial and UTJ as is seen with the ESSURE.

The safety of thermal injury to the uterus, tubal ostium, interstitial and UTJ portions of the fallopian tubes has been supported by decades of research regarding uterine ablation (with or without ESSURE in place) as well as thermal injury during myomectomy and cornual resection.

Based on the experience of this author, the efficacy of this technique has been exceptionally high, having performed over 1000 procedures without subsequent pregnancy and absence of any evidence of thermal bowel injury.

The study would thus compare ESSURE sterilization performed under general anesthesia to laparoscopic bipolar coagulation/fulguration with expected intentional anatomical damage and occlusion of similar areas.

The study would also avoid confounding variables of foreign body reactions which could exist with the use of Hulka-Clemens spring clip, the Filshie hinged clip, the Falope or Yoon silastic ring/band or permanent suture.

Although I do not endorse any specific study, since the FDA is requiring BAYER to perform a postmarket comparison, the aforementioned consideration is offered in order to avoid selection bias. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2492586/

Conclusions

Although the number of women included in the French study is large and is quoted by the authors to represent 75% of the French Republic population, there appears to be a number of biases in comparison to the general female French population, to include disportionality of age groups, possible effects of decreased fecundity based on age and inclusion of women undergoing ESSURE placement specifically contraindicated by BAYER. For these reasons, among others, generalizations to the remaining 25% of the French population should not be made.

Another consideration regarding the use of the healthcare system by the 25% of the French population not included in the study are the suspected differences in out of pocket expenses paid for services. This is especially important for procedures such as the ESSURE which can be done at lower cost in an office setting. Although reduced costs as a conscious procedure may seem appealing to patients, significant problems and adverse outcomes have been well documented in the United States MAUDE data associated with complaints by patients of exceptionally painful insertion and insertion time exceeding recommended guidelines by BAYER most commonly associated with doctors placing the ESSURE virtually unregulated in their offices. Since much of the data comparing the US to the French Republic are similar, a consideration of similar issues in an office setting should be studied before any generalization can be made. Risks and complications associated with improper placement of the ESSURE and unintended pregnancies could be higher in this population of women and therefore generalization of hospital placement compared to office cannot and should not be made.

MAUDE - https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/ImplantsandProsthetics/EssurePermanentBirthControl/ucm452254.htm

A significant limiting factor with the study is the fact that a high percentage of patients were not followed to the 3 year mark. For most doctors treating patients with complications associated with the ESSURE, the incidence of failed sterilization leading to pregnancy, ESSURE induced abortion, stillborn, preterm delivery, premature rupture of membranes and adverse symptoms to include chronic systemic Type IV hypersensitivity foreign body implant reactions, do not manifest themselves for years after the placement of the ESSURE and tend to increase over time.

A comparable body of evidence of the autoimmune reactions associated with the PET fibers components of the ESSURE can be studied regarding the polyester fibers of the vaginal mesh used in urogynecological and vaginal prolapse cases. An autoimmune response to both the metallic and PET fibers of the ESSURE is a suspected cause of Systemic Nickel Allergy Syndrome (SNAS), Fibromyalgia, Chronic Fatigue Syndrome and Chronic Pain Syndrome. Due to the nature of the insult, the autoimmune response can mimic or worsen the severity of specific autoimmune diseases, such as, Sjogren’s or Ulcerative colitis without meeting the specific criteria to be defined as having these conditions.

SNAS- https://www.medscape.com/viewarticle/753985

Most troubling is that the data collected in the French study suggests that doctors are performing procedures on women which are specifically contraindicated by BAYER. Whether or not these doctors obtained proper Informed Consent regarding their actions for what would be considered experimental techniques cannot be determined by the data, but warrants further investigation to confirm the professional and ethical integrity of the specialty of gynecology in the French Republic.

Sincerely,

Dr. Julio Cesar Novoa, MD

Novoa Medical Services, PA

El Paso, Texas 79902 USA

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