DIRECTORATE-GENERAL FOR RESEARCH WORKING PAPER

DIRECTORATE-GENERAL FOR RESEARCH WORKING PAPER UPDATE REPORT "HEALTH RISKS POSED BY SILICONE IMPLANTS IN GENERAL, WITH A SPECIAL ATTENTION TO BREAST IMPLANTS" Scientific and Technological Options Assessment Series STOA 116 EN

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WORKING PAPER UPDATE REPORT "HEALTH RISKS POSED BY SILICONE IMPLANTS IN GENERAL, WITH A SPECIAL ATTENTION TO BREAST IMPLANTS" Scientific and Technological Options Assessment Series STOA 116 EN 06-2003

This study was requested by the European Parliament's Committee on Petitions within the STOA Workplan 2002. This paper is published in English only. Authors : Dr. L. Gorgojo, Dr. J. González-Enríquez, Ms. W. Wisbaum and Dr. J. Martín-Moreno Madrid (E) Responsible Official : Graham Chambers Division for Industry, Research, Energy, Environment and STOA Tel: (352) 4300 22511 Fax: (352) 4300 27718 E-mail: DG4-STOA@europarl.eu.int Manuscript completed in June 2003 Information on DG4 publications can be accessed through : www.europarl.ep.ec./studies Luxembourg, European Parliament, 2003 The opinions expressed in this document are the sole responsibility of the author and do not necessarily represent the official position of the European Parliament. Reproduction and translation for non-commercial purposes are authorized, provided the source is acknowledged and the publisher is given prior notice and sent a copy. 4

TABLE OF CONTENTS Executive Summary... 7 I. Methods... 13 1. SCIENTIFIC EVIDENCE: COMPREHENSIVE LITERATURE REVIEW... 13 2. VIEWS FROM DIFFERENT INTEREST GROUPS: QUESTIONNAIRES... 15 3. ADDITIONAL MATERIALS... 16 II. Results... 17 1. SCIENTIFIC EVIDENCE... 17 2. SUMMARY OF VIEWS FROM DIFFERENT INTEREST GROUPS... 31 III. Discussion... 43 Bibliography... 47 ANNEX 1: Questionnaires and letters sent... 59 ANNEX 2: Other relevant information received through the interest groups... 71

Acknowledgements We would like to express special gratitude to the STOA/European Parliament for giving us the opportunity to carry out this update. We would also like to thank the National Library of Health Sciences of Spain ( Instituto de Salud Carlos III ), and the library of the Medical College of Madrid ( Ilustre Colegio Oficial de Medicos de Madrid ) for their help in our literature review, as well as the following people on behalf of self-help groups, surgeons and manufacturers for responding to our questionnaire and for providing us with other useful information: on behalf of self-help groups: Cosima Meyer (SSF Schweiz, Switzerland/Germany); Marlou Boots (SVS, the Netherlands); Rosalind Urion (AASG, UK); Sigrun Sigurdardottir, Iceland; on behalf of surgeons, Marita Eisenmann-Klein (IPRAS); on behalf of manufacturers: Adri Hoogwerf and Belinda Jackson (Mentor); Barry Hatt (McGhan); Dario Pirovano and X (Eucomed). Finally, we are most appreciative to the following people for their additional input: Mary Lewis (IBIR); Dr Sarah Myhill; Morris Topas (EQUAM); Dr J-P.A. Nicolai (Afd. Plastische Chirugie). We apologize for anyone we inadvertently left off this list. All of these people have contributed to this study update: thank you! It should be noted that only the study team, however, is responsible for any weaknesses, limitations or problems with this report. 6

Executive Summary In Europe, in 1998, two petitions were tabled by self-help groups of women claiming to have suffered adverse effects from silicone breast implants (SBIs) and calling for their immediate ban. The European Parliament (EP) reacted by asking for formal replies and evidence to be submitted to the Petitions Committee, and requested counsel from the Committee on Women's Rights, the Committee on Environment, Public Health and Consumer Policy and the Committee on Research. As part of the information-gathering exercise, the EP, through its Scientific and Technological Options Assessment Unit (STOA), contracted an independent group to carry out a comprehensive assessment on SBIs. This study was not only to look at the scientific findings on breast implants, but also to take into account the concerns and voices of different interest groups with the aim of providing various policy options and their pros and cons to the Parliament. This study 1 carried out a systematic scientific assessment of the evidence to date, which consisted of a bibliography of 1303 articles (with the 40 most scientifically sound references cited in our report), as well as an analysis of the views of different interest groups (both positive and negative) around the issue, including patients (30), self-help groups (8 groups plus 8 individual experiences), reconstructive surgeons (9), manufacturers (6), countries (12), experts in the field (4) and scientific societies (10). The study was completed in May 2000, and, after all relevant information was gathered from the various committees, a resolution was passed by the EP (approved on 13 June 2001) and subsequently, a Commission Communication (published on 15 November 2001), which proposed tighter controls on the safety of breast implants; new provisions on information and labelling; the content of informed patient consent, national registries and clinical evaluation; reinforced mechanisms to check that these rules are observed; and a reconsideration of European standards for essential safety requirements and conformity assessment schemes of directive 93/42/EEC on medical devices in relation to breast implants. In February 2003, a Commission Directive was completed, upgrading the classification of breast implants to Class III products, subjecting them to the most stringent quality requirements applicable to any medical devices. The Commission Directive reinforces quality and safety control before breast implants can be offered on the European market. Also in February 2003, the Commission published a summary of information from Member States on progress with regard to adequate patient information, informed consent, advertising for breast implants and national registers of women with breast implants. These findings can be found in the Commission Staff Working Paper on National Measures adopted by Member states in Relation to Breast Implants, 14-2-03, SEC(2003) 175. The report is based on information received by the Commission from a questionnaire that was sent out to national authorities. Paraphrasing its conclusion, the report can be briefly summarized as follows: Member States have national policies in place or are implementing 1 Martín-Moreno, J.M., Gorgojo, L., González-Enríquez, J., Wisbaum, W., "Health risks posed by silicone implants in general, with special attention to breast implants". PE 168.396/Fin.St/rew. 2000; http:/www.europarl.eu.int/stoa/publi/pdf/99-20-02_en.pdf 7

national policies in relation to breast implantation. Several Member States use the Commission s Communication to update or to reconsider policy measures. Different mechanisms are being used to implement national policy: in some countries, this matter is covered by legislation of a general nature and in other countries, measures have been adopted specifically relating to breast implants. Some instruments are mandatory, while others are in forms of self-regulation, voluntary standards or ethical codes. Regarding registers for breast implants, positions are quite different by country, and this is also the case as regards advertising for silicone breast implants. The report ends by stating: The matters covered by this working document are of national competence, and possibilities to adopt measures at Community level are extremely limited. However, the Communication and the elaboration of this working document have already produced a significant effect and will continue to provide useful elements for interest groups and authorities at national level. They will promote best practice and may inspire further actions. Furthermore, where the need for co-ordination of national registers would arise, or where Member States are interested in European networking or coordination of national databases and the availability of collated data at a European level, the Commission, through the Joint Research Centre, can certainly provide scientific and technological assistance. Now, three years after the submission of the May 2000 study and in light of the Commission Communication of 2001 and the Commission Directive of 2003, there is interest in a small update of our study to learn whether there is new evidence or information on silicone breast implants and their potential implications. This update does not serve as a stand-alone study, but should be considered alongside, and as an addendum to, the main study, Health risks posed by silicone implants in general, with a special attention to breast implants, from May 2000. Finally, we would like to stress two points as important background information. First of all, we would like to highlight the importance of including an analysis of the views of different interest groups in our study along with a comprehensive analysis of the scientific literature. The human angle deserves focus and needs to be taken into account along with scientific evaluation. In carrying out our May 2000 study, we realized that, in a healthcare technology such as silicone breast implants, patient satisfaction, and the way in which the technology suits the patient, is extremely important. Even if the majority of users are satisfied with a procedure or technology, a great deal of information can be learned from those who are not. Here, a considerable body of users had similar views and concerns, and an analysis of these positions uncovered important deficiencies in the surgical procedure itself and in information given to the patient about the implant and its aftermath. By listening to and incorporating the positions of these women - the majority of whom felt that they had had no voice before in the discussion or debate - real areas of improvement were identified which would not necessarily have been detected from just assessing scientific research alone. Secondly, it should be noted that a great deal of progress regarding the better understanding, application and quality of silicone breast implants has been made since 1998 thanks to the European Parliament. Prior to October 1999, when the EP 8

commissioned our May 2000 study, little focus had been placed on silicone breast implants in Europe. Since this time, a great deal of attention has been given to silicone breast implants and many positive changes have taken place. This effort is thanks to the initiative taken by self-help groups to draw attention to this issue, to the responsiveness of the Parliament, and also STOA and different committees, and, most importantly, to the Parliament s receptivity to the information it received, which influenced the EP resolution and the Commission Communication on the issue. We believe that the process undertaken - starting from community concern, taken up by and seriously acted upon by the Parliament, and leading to positive, concrete changes in this important medical procedure - is a useful approach for other similar issues. Objective and Content of Study Update With this backdrop, the objective of this study update is to determine whether there is new additional evidence or information that changes the policy options presented to the European Parliament on silicone breast implants. In May 2000, after weighing the existing evidence, we presented to the Parliament that the most balanced policy option appeared to be option 3, which proposed no complete ban on SBIs, but the adoption and implementation of critical specific measures to increase and improve information for patients, tracking and surveillance, quality control and assurance and key research. The findings from the May 2000 report are largely reflected in the November 2001 Commission Communication. This study update includes: - A systematic review of the scientific literature and evidence on health risks posed by silicone breast implants from the end of the study to the present; - Opinions of several of the main interested parties: o The opinion of the petitioners/representatives of self-help groups on the current status of the issue; o The view of legitimate representatives of the scientific community (i.e., IPRAS) on the subject; o The view of the two main manufacturers (McGhan and Mentor, as well as the umbrella group, Eucomed) on the subject. It is important to point out the we have not included institutional opinions from Member States in our report, as it was believed that this falls under the direct jurisdiction of the Commission (and this area is largely covered in the Commission Staff Working Paper on National Measures adopted by Member states in Relation to Breast Implants, 14-2-03, SEC(2003) 175, as described above). This update to our May 2000 study has led to the following conclusions. 9

First of all, as for the systematic review of the scientific evidence, the new literature has basically confirmed our original findings: there does not appear to be clear evidence of increased mortality or specific major diseases from silicone breast implants, but there is still a need for further research, particularly regarding some findings that indicate an apparent increased risk for brain and respiratory cancer, as well as suicide. Some confounding factors should be appropriately controlled in the new studies in order to assess the reliability of these preliminary findings. In addition, further research needs to be undertaken on the evidence of a specific syndrome or syndromes in women. Although there is no robust, convincing support for this, it cannot be completely ruled out at this point. In addition, it should be emphasized that there are always limitations and potential sources of error in scientific research and these need to be cited, particularly because in the case of silicone breast implants, there are additional complications. These exist due to the different stages and varieties of implants that have existed; the fact that there has been little tracking or surveillance of breast implants; and because of the inherent methodological limitations (studies focusing on a few well-defined connective tissue diseases or cancer and not a comprehensive evaluation; small sample sizes; and different kinds of implants, present for varying periods of time). This means that, in sum, the need for further research is warranted, due to the limitations of the research to date. Second, and what is exceedingly clear, and even more so through this update study, is that local effects are a large and serious health concern with silicone breast implants, and they should not be taken lightly. It is very apparent from the new research that surgical, local and perioperative complications are so frequent that they are still the main safety issue with silicone breast implants. Reoperations, ruptures, deflations, contractures, infections, hematomas, and pain are very common and are the main cause of women s complaints. Breast implants have a limited lifetime, and the odds of having at least one replacement implant are high. There is not currently enough information on the long-term effects of the third generation implants, making it difficult to predict the frequency of rupture, reoperations and contractures for these implants. Thus, the precise incidence of local and perioperative complications should still be considered a research priority and an essential element of adequate informed consent for women undergoing breast implantation. Local effects are particularly important, given that breast augmentation is not a life-saving or life-sustaining procedure. In order to justify an essentially elective cosmetic procedure, the risks to the patient must be clearly understood and outweighed by the benefits. Third, and regarding the qualitative assessment of perceptions among interested parties, a very relevant conclusion from our study update is that these research results, as well as views on the status of the issue received from self-help groups, surgeons and manufacturers, have confirmed the importance and value of the Commission Communication (15 November 2001), which proposes tighter controls on the safety of breast implants, reinforced mechanisms to check that these rules are observed, and an upgrade in European standards for breast implants. Overall, the three main interest groups believe that the Commission Communication has had, and will have, positive outcomes. Although self-help groups do not believe that the Communication has gone far enough citing such concerns as the lack of attention being 10

paid to the victims, ongoing dangerous advertising of breast implants, and the lack of uniformity around informed consent they do believe that it is a step in the right direction. Manufacturers believe overall that the Communication serves to provide better protection for women on a more consistent basis, even though the two main manufacturers believe that they already abided by top quality standards and Eucomed feels that the new classification of SBIs as Class III products is more an administrative burden than a way to prevent accidents. Finally, IPRAS, on behalf of surgeons, is very satisfied with the EC Communication, although it believes that instead of national registries, countries should use the International Breast Implant Registry (under the umbrella of IPRAS). It needs to be emphasized that there are--and probably always will be--very strong, often opposing interests at stake on either side of this issue, and that it would be extremely difficult to satisfy all parties. Moreover, a global picture can only be obtained if we take into account not only the risks, but also the potential advantages of SBI within the context of its demand after weighing risks and benefits (mainly psychological, self-esteem, or subjective satisfaction). However, it is apparent that the Commission Communication is viewed positively and is having important policy implications in helping lead to the better understanding, application and quality of silicone breast implants. It will be very important to follow and monitor progress to ensure that, indeed, quality standards and safety requirements are being met; national policy measures are being implemented; appropriate research is being supported, conducted, and disseminated; and patients are receiving complete, unbiased, and correct information in order to make informed decisions. This will be an ongoing challenge for the future--but one that this update has shown--is well on its way to being tackled. 11

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I. Methods 1. Scientific evidence: comprehensive literature review A systematic and structured literature review has been carried out, taking into account not only sources that are catalogued, but also those that are not, the so-called grey literature. In order to do this, contact has been made with different relevant institutions that have facilitated the corresponding material to us. In addition, an active search has been underway to detect possible ongoing studies on silicone breast implants. Specific information resources on effectiveness and evidence-based medicine: Centre for Review and Dissemination, York University, UK. Database of Abstracts of Review on Effectiveness, DARE Cochrane Library Health Technology Assessment (HTA) Database International Network of Agencies for Health Technology Assessment (INAHTA) Health Services/Technology Assessment Text (HSTAT), National Library of Medicine of the USA. Health Service Research Projects in Progress, USA. National Health Technology Assessment Programme, UK. Additional sources from Europe and the United States of America: National Institutes of Health Food and Drug Administration (Center for Devices and Radiological Health) Institute of Medicine, National Academy of Sciences American Council of Science and Health National Cancer Institute National Information Center on Health Services Research and Health Care Technology Office of Research on Women Health (National Institute of Health) The International Agency for Research on Cancer (IARC) Agencies for Health Technology Assessment McGhan Medical Corporation Mentor Corporation EUCOMED Physician and nursing groups Consumer groups Posters, communications and abstracts submitted to Scientific Meetings General search resources in INTERNET 13

GOOGLE (http://www.google.com/) ALTAVISTA (http://www.altavista.digital.com/) GLOBAL NET (http://www.dirglobal.net/) YAHOO (http://www.yahoo.com/) 1.A. Key words and operators used for searches Work began through a manual search of bibliographic sources (including grey literature ), and the specification of all possible key words that could fall under the rubric of our study, to be used in available bibliographic databases or repertoires (MEDLINE, EMBASE). Depending on the database used, different standardized key-words (descriptors), and different logical operators were defined, with the objective of finding complementary, supplementary or overlapping key-words. For bibliographic searches in international databases, the following descriptors were used: 1.A.1. For the study of systemic effects: (SILICONE IMPLANTS or SILICONE BREAST IMPLANTS) and [(CANCER) or (MAMMOGRAPHY and BREAST CANCER) or (NEUROLOGICAL DISEASE) or (WELL-DEFINED CONNECTIVE TISSUE DISEASES) or (RELATED TO AUTOIMMUNE DISORDERS) or (ATYPICAL CONNECTIVE TISSUE) or (NOVEL SYSTEMIC DISEASE)] 1.A.2. For the study of vertical effects (mother to child): (SILICONE BREAST IMPLANTS) and [(INFANTS) or (BREAST FEEDING) or (MOTHER TO CHILD)] 1.A.3. For the study of local effects: (SILICONE BREAST IMPLANTS) and [(REOPERATION) or (REPLACEMENT) or (RUPTURE) or (DEFLATION) or (CAPSULAR CONTRACTURE) or (HEMATOMA) or ( INFECTON) or (PAIN)] 1.B. The grey literature is usually not included in scientific or bibliographic repertoires and not usually indexed. However, we have carried out manual searches through our National Library of Health Sciences (Instituto de Salud Carlos III). Moreover, some documents have been identified in specific institutional web paths or searched by internet (through GOOGLE, ALTAVISTA, GLOBAL NET or YAHOO). 1.C. Contact with Libraries: The search for articles and published sources was carried out through the National Library of Health Sciences through their interlibrary loan service. 14

This enabled us to receive information and documentation from different public and private institutions, both nationally and internationally (see above). 1.D. Analysis of scientific evidence and critical review of studies. To analyze the scientific evidence, we critically appraised the quality of the studies retrieved in the literature search using methodological guides provided by the Evidence Based Medicine Working Group 2, 3. We ranked the evidence of the studies using a model adopted by U.S. Preventive Services Task Force 4. Following this model, the Quality of Evidence ranking system we used is as follows: I: Evidence obtained from at least one properly randomized controlled trial. II-1: Evidence obtained from well-designed controlled trials without randomization. II-2: Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one centre or research group. II-3: Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence. III: Opinions of respected authorities, based on clinical experience descriptive studies and case reports or reports of expert committees. Using this recognized quality control system, in our study update we describe the main outcomes of selected relevant studies on an individual basis and discuss general limitations and problems detected. We assess internal and external validity (generalizability), coherence and consistency of the studies. We then integrate the evidence provided by the most scientifically sound studies and make general conclusions based on the body of evidence concerning different health risks posed by breast implants. Annex 1 contains the complete bibliography for this study. 2. Views from different interest groups: questionnaires 2 Evidence-Based Medicine Working Group. A new approach to teaching the practice of medicine. JAMA 1992;268:2420-5 3 Levine M, Walter S, Hui Lee et al. User's guides to the medical literature, IV: How to Use An Article About Harm. JAMA 1994;271:1615-9. 4 US Preventive Task Force. Guide to clinical preventive services: report of the U.S. Washington, DC: Office of Disease Prevention and Health Promotion, US Government Printing Office, 1996. 15

In our May 2000 study, we incorporated an analysis of the views of different interest groups around the issue. With this aim, and attempting to reflect all views, both positive and negative, we interviewed patients and received information from self-help groups, women s groups, specialist surgeons, manufacturers, scientific societies and Member States, all of which we incorporated into our study. For this update, we decided to select representatives from three main interest groups: - self-help groups (represented by SSF Schweiz) - surgeons (represented by IPRAS) - and the two main manufacturers of silicone breast implants (Mentor and McGhan), as well as the umbrella group Eucomed We sent these three interest groups 5 a questionnaire that consisted of a brief set of targeted questions in order to learn whether they were aware of the Commission Communication, whether they thought it produced any change, and their general perception of the action lines in the Communication. Together with the questionnaire, we sent these groups a letter explaining the purpose of the study update, as well as the kinds of information requested in the questionnaire. These groups, in turn, were free to provide us with other relevant information and/or to distribute the questionnaire to additional parties. All materials were sent via email. All parties responded to our questionnaire, after which we sent out thank you notes. The questionnaires and accompanying letter can be found in Annex 2. 3. Additional materials In Annex 3, we attach other relevant information received through the interest groups. This includes: - Additional information about the International Implant Registry (IBIR), received through IPRAS; - Answers to the questionnaire sent to self-help groups, completed by a doctor who has seen self-help group patients, Dr. Sarah Myhill. 5 It should be explicitly noted that we did not include Member States in our study update, as this is viewed as falling under the responsibility of the Commission; countries progress has been tracked by the European Commission in the Commission Staff working Paper on National Measures adopted by Member States in Relation to Breast Implants, 14-2-2003, SEC(2003) 175. 16

II. Results 1. Scientific evidence 1.A. Systemic effects During the years of review of this update (2000-2003), different studies have been published with large sample sizes on the long-term effects of silicone breast implants. These studies slightly modify the conclusions from our main report regarding the systemic effects of silicone breast implants, but confirm our main findings and suggested policy options. Each of the new reviewed studies will be commented on below. General mortality and specific causes of death A high visibility study on the risks of cancer following breast implants has been conducted by Dr. Louise Brinton, Chief of the Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics of the National Cancer Institute (NCI). The study of American women by Brinton et al (2001) 6 was designed as a retrospective cohort study and included 13,488 women from 18 plastic surgery practices in United States who had cosmetic bilateral augmentation mammoplasties prior to 1989. These women were compared with 3,936 women of similar age who had undergone another type of plastic surgery (like abdominoplasty or liposuction, blepharoplasty, rhinoplasty, etc). The authors had previously shown that other plastic surgery patients may be a more appropriate comparison group for studies of the health effects of breast implants than women in the general population because of certain similarities between the two groups of patients. Average follow up of the study was 13 years, and all causes of mortality in women were compared. This study did not include patients who received implants following a diagnosis of breast cancer. The authors found lower overall mortality and lower cancer mortality of women with implants as compared to the general population (using standardized rates)and a non-statistically significant excess risk compared to women with another type of plastic surgery. The scientists also looked to see if there were mortality differences among the implant patients related to the calendar year of the implant, the woman's age at the time of surgery, or the type of implant. One marginal, non-statistically significant finding was a discrete excess of suicide between women with implants compared with general population (Standard Mortality Rate or SMR= 1.54, 95% CI= 1.0-2.4). The higher suicide rates of the implant patients correlate with characteristics described among implant patients in previous reports, such as marital difficulties, depression, emotional disorders, and low selfesteem 7. Taking this into account, very recently, Koot et al (2003) 8, re-analyzed their prospective cohort of 7,585 Swedish women with cosmetic breast implants in the period 1963-93, and 6 Brinton LA, Lubin JH, Burich MC, Colton T, Hoover RN. Mortality among augmentation mammoplasty patients. Epidemiology 2001;12:321-6. 7 Brinton LA, Brown SL, Colton T, Burich MC, Lubin JH. Characteristics of a Population of Women with Breast Implants Compared with Women Seeking Other Types of Plastic Surgery. Plastic and Reconstructive Surgery 2000;105:919-27. 8 Koot VCM, Peeters PHM, Granath F, Grobbee DE, Nyren O. Total and cause specific mortality amongt Swedish women with cosmetic breast implants: prospective study. BMJ 2003;326:527-8. 17

after cleaning up their database, the final study cohort consisted of 3,521 women. This study considered all causes of death and detected excess mortality (SMR= 1.5; 95%CI=1.2-1.8), mainly due to suicide (Relative Risk or RR= 2.9; 95%CI: 1.6-4.8), and some malignant disease (principally lung cancer). In some earlier studies, (Fryzek et al 2000; Hasan 2000) 9, 10 documented link between mental or psychological / psychiatric disorders and a desire for cosmetic surgery. Cancer The study mentioned above by Brinton et al (2001) 11 compared mortality rates observed in women with cosmetic breast implants to mortality rates in the general population. These authors found that nearly every cause of death--including all cancers; circulatory and digestive system diseases; endocrine, nutritional, metabolic and immune diseases; and cirrhosis of the liver--was decreased among implant patients (SMR= 0.69; 95%CI=0.6-0.8). The lower mortality rates of the implant population support previous findings that people who undergo elective surgery are generally healthier than their peers in the general population. Focusing on the previous main concern about the cancer effects of breast implants, in this study it was also found that the reduced overall cancer mortality observed was mainly due to a lower mortality risk from breast cancer when compared with a comparable group of women from the general population (SMR= 0.55; 95%CI=0.4-0.8). It should be noted that this research team 12 previously found that breast implants did not alter the risk of subsequent breast cancer (Relative Risk, RR= 0.8; 95%CI= 0.6-1.1). Another large cohort study was carried out among 2,171 Finnish women with cosmetic breast implants from 1970 to 1999 13. The authors state that the study provides additional evidence that silicone breast implants do not cause breast cancer and are unlikely to cause other cancers, although the findings were based on small numbers and should be interpreted cautiously. The measure of risk was taken as the ratio for observed to expected cancers, that is, the standardized incidence ratio (SIR) and its 95% confidence interval (CI). Among the women with cosmetic breast implants, there was no evidence for an increase in breast cancer risk (SIR= 0.5; 95% CI= 0.2-1.0), even among those followed for more than 10 years. Overall cancer SIR (all cancers combined) was 0.9 (95% CI = 0.2-1.0). 9 Fryzek J, Weiderpass E, Signorello LB et al. Characteristics of women with cosmetic breast augmentation surgery compared with breast reduction surgery patients and women in the general population of Sweden. Ann Plast Surg 2000;45:349-56. 10 Hasan JS. Psychological issues in cosmetic surgery: a functional overview. Ann Plast Surg 2000;44:89-96. 11 Op.cit, footnote 6. 12 Brinton LA, Burich MC, Colton T, Brown SL, Hoover RN. Cancer Risk at Sites Other than Breast Following Augmentation Mammoplasty. Annals of Epidemiology 2001;11:248-256. 13 Pukkala E, Boice JD, Jr., Hovi SL et al. Incidence of breast and other cancers among Finnish women with cosmetic breast implants, 1970-1999. J Long Term Eff Med Implants 2002;12:271-9. 18

In the Brinton et al study 14 the exceptions to the overall lower rates were deaths from brain cancer. Breast implant patients were two times more likely to die from brain cancer (RR=2.25; 95%CI=0.5-9.9) compared to a cohort of other plastic surgery patients. Nevertheless, these results were not statistically significant (i.e.: given the limited numbers of deaths from this cause, these results could be attributed simply to chance findings). Brain cancer has not been previously documented as a site at risk among implant patients. As for other tumour sites, the researchers also found no increased risk of respiratory tract cancer among implant patients when compared with women from the general population (RR= 0.94; 95% CI=0.7-1.3), but a statistically significant increased risk when compared with the cohort of other plastic surgery patients (RR= 3.03; 95% CI=1.4-6.5). The same authors state that implant patients, however, did not have higher mortality rates from diseases that have been tentatively linked to silicone exposure (such as sarcoma and multiple myeloma, and other diseases such as scleroderma, Sjögrens disease and lupus erythematosus). The Swedish study also found an increased risk for lung cancer, one kind of respiratory tract cancer (SMR=3.0; 95% CI= 1.3-5.9). Neurological diseases A study carried out by Winther et al (2001) 15 in Denmark examined the occurrence of neurological disorders in a cohort of women who had undergone cosmetic breast implant surgery during the period 1973-95, and in a comparison cohort of women who had other types of cosmetic surgery during the same period of study. This study included 1,653 women who had received cosmetic breast implants and 1,736 women as a comparison group. The results of this study indicate that there is no causal association between silicone breast implants and neurological diseases (OR= 0.8; 95% CI= 0.3-1.7). The present study also expands on previous research 16 by extending the follow-up period for the public hospital implant and comparison cohorts and incorporating outpatient data. Although this study had limited statistical power to detect a potentially moderate excess risk for any specific neurological disease (due to limited sample size), the study was powerful enough to exclude excess relative risks that were about two times or greater for all neurological diseases combined in both the implant and comparison cohort. It is also worth mentioning again the study by Brinton et al (2001) 17 in this section under neurological disease, as breast implant patients were found to present an excess risk of dying from brain cancer compared to the general population. But this excess risk is not statistically significant compared to a more comparable group of women with other kinds of plastic surgery (see above under Cancer). 14 Op.cit., footnote 6. 15 Winther JF, Friis S, Bach FW et al. Neurological disease among women with silicone breast implants in Denmark. Acta Neurol Scand 2001;103:93-6. 16 Winther JF, Bach FW, Friis S et al. Neurological disease among women with breast implants. Neurology 1998;50:951-5. 17 Op.cit., footnote 6. 19

Connective tissue diseases and syndromes Regarding connective tissue diseases, a few studies have followed the robust metaanalysis by Janowsky et al (2000) 18 already discussed in our main report, which found no evidence of an association between breast implants in general, or silicone breast implants specifically, and any of the individual connective- tissue diseases, all definitive connective-tissue diseases combined, or other autoimmune or rheumatic conditions. A National Science Panel was asked by a US District Court Order to review existing studies on the association of silicone breast implants and accepted systemic classic connective tissue diseases, atypical connective tissue diseases and certain signs and symptoms. Tugwell recently summarized the scientific evidence in addition to the Janowsky review, including another 18 classic/accepted diseases and reporting numerous signs and symptoms. Twenty-four studies meeting inclusion criteria were identified. No association was evident between breast implants and any established or atypical connective tissue disorders. (Tugwell et al, 2001) 19. This was also referred to in more detail in our previous report. Supported by the FDA s Office of Women s Health and the National Institutes of Health (USA), Brown, S.L., et al, 2001 20 studied women with silicone gel breast implants who responded to a questionnaire (on health status, satisfaction with implants, symptoms of connective tissue disease and physician diagnosed disease) and then had Magnetic Resonance Imaging (MRI) of their breasts. Women with breast implant rupture diagnosed by MRI were no more likely to report a diagnosis of selected connective tissue diseases than those with intact implants. Women with extracapsular silicone were more likely to report having fibromyalgia 21 or other connective tissue diseases. The odds ratios were 2.8 (95% CI 1.2-6.3) for fibromyalgia, and 2.6 (95% CI 0.8-8.5) for other connective tissue diseases, after adjusting for implant age, implant location, implant manufacture, implant type, self-perceived health, self-perceived rupture status and site of surgery. This study does not show a cause-effect relationship. Women who developed fibromyalgia before they had a breast implant could not be distinguished from women who developed fibromyalgia after breast implant surgery (cross-sectional study). The self-reported diagnosis was not confirmed by medical examination. The same authors in a later study 22 reviewed the existing literature on fibromyalgia and highlighted the need for further 18 Janowsky EC, Kupper LL, Hulka BS. Meta-analyses of the relation between silicone breast implants and the risk of connective-tissue diseases. N Engl J Med 2000;342:781-90. 19 Tugwell P, Wells G, Peterson J et al. Do silicone breast implants cause rheumatologic disorders? A systematic review for a court-appointed national science panel. Arthritis Rheum 2001;44:2477-84. 20 Brown, SL, Pennello, G., Berg, W.A., Soo, M.S., Middleton, M.S. Silicon gel breast implant rupture, extracapsular silicone, and health status in a population of women. J Rheumatol 2001; 28:996-1003. 21 Fibromyalgia (also called fibrositis or fibromyositis) is a syndrome of unknown causes that results in chronic, sometimes debilitating muscle, pain and fatigue. The American College of Rheumatologists (ACR) defined fibromyalgia in 1990 as the presence of 1) body or joint pain above and below the waist, and on the right and left side of the body, 2) axial pain (most often neck or low back pain), and 3) 11 out of 18 possible tender points. Patients most often have associated fatigue, sleep disorders, irritable bowel syndrome, migraine headaches, immune system or endocrine system disorders. 22 Brown SL, Duggirala HJ, Pennello G. An association of silicone-gel breast implant rupture and fibromyalgia. Curr Rheumatol Rep 2002;4:293-8. 20

studies to resolve this issue and test the hypothesis of association. It should be pointed out that case series describing fibromyalgia in patients with implants have been published and are available for review, but these studies have small sample sizes, are not controlled (case series without controls), have no information on extracapsular silicone, or include patients from non-representative or non generalizable populations. A retrospective cohort of breast implants used for reconstruction following mastectomy (mainly saline filled) could be analyzed using the claims files of the Health Care Financing Administration of the Medicare insures in the period 1991-1996 (Greenland et al, 2000) 23. Surgical procedures and 52 diseases and symptoms related to connective tissue diseases and symptoms could be compared between the breast implant cohort and a comparison cohort of mastectomy and breast reconstruction patients without implants. With caution due to the very small numbers of observations, misclassification, problems of validity and completeness of claims files, and limited control of confusion variables, it was observed that the breast implant cohort exhibited an excess risk of undifferentiated connective tissue diseases, such as myalgia and myositis, and systemic lupus erythematosus. Englert, H., et al (2001) 24 in a population-based retrospective cohort study compare the prevalence and incidence of autoimmune and connective tissue disorders in female Sydney residents stratified by augmentation mammoplasty status. There were no differences found between cohorts. Holmich, L.R. et al (2003) 25, conducted an analysis of adverse health outcomes according to breast implant rupture status in 238 Danish women with cosmetic silicone breast implants (92 had implant rupture and 146 had intact implants as determined by MRI). There were no differences in the occurrence of self-reported diseases or symptoms related to connective tissue disease or other rheumatic conditions, or in the presence of autoantibodies between groups. However, capsular contracture was reported six times more frequently by women with extracapsular ruptures than by women with intact implants. 1. B. Vertical effects (mother to child): Risks to infants The American Academy of Pediatrics (2001) 26 has updated its statement on the transfer of certain drugs and other chemicals into human milk. This update also addresses a silicone issue on which there are not new data. On silicone implants, the statement concludes, it is unlikely that elemental silicon causes difficulty, because silicon is present in higher concentrations in cow milk and formula than in milk of humans with implants The Committee on Drugs does not feel that the evidence currently justifies classifying silicone implants as a contraindication to breastfeeding. 23 Greenland S, Finkle WD. A retrospective cohort study of implanted medical devices and selected chronic diseases in Medicare claims data. Ann Epidemiol 2000;10:205-13. 24 Englert H, Joyner E, McGill N et al. Women's health after plastic surgery. Intern Med J 2001;31:77-89. 25 Holmich LR, Kjoller K, Fryzek JP et al. Self-reported diseases and symptoms by rupture status among unselected Danish women with cosmetic silicone breast implants. Plast Reconstr Surg 2003;111:723-32. 26 AMERICAN ACADEMY OF PEDIATRICS (Committee on Drugs). Transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776-89. 21

Kjoller et al (2002) 27 in a study to assess whether maternal breast implants are related to adverse health outcomes in offspring, conducted a retrospective cohort study of esophageal disorders, rheumatic disease, and congenital malformations among 2,854 children born to women with breast implants and among 5,805 children born to a comparison group of women who underwent breast reduction or other plastic surgery. Rates were calculated using both hospitalization and outpatient data. Significantly higher rates of esophageal disorders were observed (O) than were expected (E) for children born before (O/E, 2.0; 95% CI, 1.3-2.8) but not after (O/E, 1.3; 95% CI, 0.5-2.9) maternal breast implant surgery. Risk of rheumatic disease was similar among children born before (O/E, 1.4; 95% CI, 0.7-2.6) and after (O/E, 1.4; 95% CI, 0.2-5.0) maternal breast implant surgery. A marginally significant excess of congenital malformations of the digestive organs was observed among children born after maternal implant surgery (O/E, 1.8; 95% CI, 1.0-3.1), with a similar finding among children born to women in the comparison group (O/E, 1.9; 95% CI, 1.4-2.4). The risk of overall malformations among children born after maternal breast implant surgery was not significantly higher than in the general population. The elevated risks of adverse health outcomes appear to be unrelated to breast implants per se, because similar findings were observed among children born both before and after the mother's implant surgery, as well as among children born to mothers in the comparison cohort. 1.C. Local effects Results from new studies and longer follow-up observation periods reinforce the relevance of local complications, including perioperative complications from the surgical procedure itself, which we again stress as the largest potential health risk from silicone breast implants. Perioperative complications The FDA surveillance system for monitoring adverse events related to breast implants between 1977 and 1997 shows 2 cases of death by toxic shock syndrome after mammoplasty. The most common organism reported was Staphylococcus sp. More than half of the reports of implant manufacturers (56%) asserted only that there was an infection and that breast implants were explanted as a result (Brown et al, 2001) 28. In a study conducted by Kjoller et al (2002) 29, information on short and long term complications was obtained in a total of 754 Danish women (1572 implants). Overall, 77.8% of implantations were followed by no complications, 17.8% were followed by one complication, 3,6% were followed by two complications and 0.8% were followed by three or more complications. In 94.6% of implantations, no additional hospitalization was recorded as a result of complications. Forty-seven of 57 explantations/reimplantations were related to postoperative complications after the initial implants. General surgical complications such as hematoma and infection were rare, occurring in 2.3% and 2% of 27 Kjoller, K., Friis, S., Signorello, L.B. et al. Health outcomes in offspring of Danish mothers with cosmetic breast implants. Ann Plast Surg 2002;48:238-45 28 Brown, S.L., Hefflin, B., Woo, E.K., Parmentier, C.M. Infections related to breast implants reported to the Food and Drug Administration, 1977-1997. J Long Term Eff Med Implants 2001;11:1-12. 29 Kjoller, K., Holmich, L.R., Jacobsen, P.H. et al. Epidemiological investigation of local complications after cosmetic breast implant surgery in Denmark. Ann Plast Surg 2002;48:229-37. 22

implantations, respectively. Capsular contracture remains the most common complication, occurring in 11.4% of implantations. Reoperation or replacement Brown et al (2002) 30 examined the prevalence of additional surgery in which silicone gel breast implants were either removed or replaced in a cohort of women from Birmingham (Alabama). Thirty three per cent of 907 women reported surgery (removal or replacement). The most common reason for surgery (34%) was for problems with the implant that affected the breast (suspected implant rupture, pain, contracture, displaced implant, seroma, hematoma, infection, other). The second most common reason for surgery was due to concern over the safety of silicone (30%). The average time before surgery was 11.5 years after their first breast implants were implanted. Of those reporting surgery, 56% reported knowing that an implant was ruptured or leaking. The rupture rate of the 303 women reporting surgery was 42% according to surgical reports and 51.5% according to self-reports. The review of the safety and efficacy of saline-filled breast implants undertaken by Cunningham et al (2000) 31, part of U.S. pre-market approval review process, was based on physician-reported and patient-reported data on 450 patients with saline filled breast implants placed between 1980 and 1986, mainly for breast augmentation. Mean patient follow-up was 13 years. Excluding a cohort from a centre using Surgitek saline implants (with a high deflation rate), actuarial survival of the implants was 98.4%-99.8% at 5 years and 96.9%-98.9% at 10 years.) The overall complication rate was 20.2%. Reoperation for capsular contracture or implant deflation was necessary in 23.1%. Deflation occurred in 8.3 %. Overall, 93% of patients were satisfied or very satisfied with their implants. In France, where silicone gel implants were taken off the market, Soubirac et al (2002) 32, analyse the deflation rate, the main side effect of saline or hydrogel filled implants, in 650 patients operated on between 1993 and 2000 (1,117 implants). The rate of deflation was up to 15% with a follow up of 5 years (median value). The authors determined that the rate of deflation of breast implants for reconstruction is higher than that for aesthetic reasons, and also that the rate of deflation of pre-filled hydrogel is higher than that of pre-filled saline implants. McGhan s primary study involved 901 women who received saline filled implants for augmentation. After three years, 689 patients (76%) were still in the study. Some of the three-year cumulative risk rates were 21% for additional surgery, 16% for breast pain, 11% for wrinkling, 10% for asymmetry, 9% for capsular contracture, 8% for implant removal and 5% for leakage/deflation. 30 Brown, S.L., Pennello, G., Replacement surgery and silicone gel breast implant rupture: self-report by women after mammoplasty. J Womens Health Gend Based Med 2002;11:255-64. 31 Cunningham, B.L., Lokeh, A., Gutowski, K.A. Saline-filled breast implant safety and efficacy: a multicenter retrospective review. Plast Reconstr Surg 2000;105:2143-9. 32 Soubirac, L., Jougla, E., Hezard, L., Grolleau, J.L., Chavoin, J.P. [Deflation of breast implants, pre-filled with saline or hydrogel. Results and analysis of 650 treated patients]. Ann Chir Plast Esthet 2002;47:273-9. 23

Mentor s primary study involved 1264 women who received saline-filled implants for augmentation. After three years, 955 patients (76%) returned for their 3-year visit. Some of the three-year cumulative risk rates were 21% for wrinkling, 13% for re-operation, 10% for loss of nipple sensation, 9% for capsular contracture, 8% for implant removal and 3% for leakeage/deflation. After product approval, Mentor collected some safety data from questionnaires mailed out to the patients of the study every year through a 10 year postimplantation time period. Follow-up rate at three years is more reliable than the five to ten year data due to loss of follow-up. The five-year complication rates are reoperation (20%), implant removal (14%), capsular contracture III/IV (10%), deflation (10%), pain (7%). Contracture Even though certain studies had very limited power, due to small sample size, it could be useful to mention that a review of the long-term effect of contracture in 53 patients participating in a prospective randomized controlled trial of textured versus smooth silicone gel breast implants observed a 65% incidence of capsular contracture at 10 years for smooth implants and 11% incidence for textured implants (Collis and Sharpe, 2000) 33. Lossing et al (2001) 34 studied a mean of five years in 54 patients between 1984 and 1990 with silicone gel implants (with either a thin or a thick shell) for breast reconstruction. The rate of capsular contracture (Baker III-IV) was 11% (thin shell) and 10% (thick shell). Kjoller et al (2002) 35 investigated 1572 implants (754 women) placed from 1977 to 1997 in two plastic surgery clinics in Denmark. The authors obtained information on implants through medical records and self-administered questionnaires. Capsular contracture occurred in 11.4% of implanted breasts (51.6% bilateral). Overall, 66.1% of capsular contracture occurred within the first year and 79% within the first 2 years of implantation. Rupture This is an important issue, but many authors have underlined the problems and limitations of the available studies conducted to date to document the rate of rupture of silicone breast implants. Several sources of bias in study design (non-representative populations, selection, misclassification, confounding) affect studies based on explantation series. Better and standardized definitions of implant rupture must be developed and adopted by multidisciplinary teams of researchers. The frequency of rupture is reported in most studies based on findings at explantation (standard for diagnosis), detection by mammographic technologies and surveys of results in cohorts of patients. From case series reported from surgeons, the detection of rupture depends on patient complaints, routine screening mammographies or physical examinations, none of which is absolutely reliable. The lower rupture rates reported by manufacturers based on returns, complaints, legal proceedings and other sources probably are affected by underreporting and low sensitivity. The use of 33 Collis N, Sharpe DT. Recurrence of subglandular breast implant capsular contracture: anterior versus total capsulectomy. Plast Reconstr Surg 2000;106:792-7. 34 Lossing C, Elander A, Gewalli F, Holmstrom H. The lateral thoracodorsal flap in breast reconstruction: a long-term follow up study. Scand J Plast Reconstr Surg Hand Surg 2001;35:183-92. 35 Op.cit., footnote 28. 24

MRI and other diagnostic tests in non-selected and representative samples of women with implants should give a more accurate estimation of the prevalence of rupture. The lifespan of a mammary implant has been studied by Benadiba et al (2000) 36 in the framework of 949 implants for breast reconstruction after cancer. The global median lifespan of a breast implant is 127 months or 2.6 years. The lifespan of silicone gel-filled implant is superior to that of saline implants due to deflation. Breast implant rupture was reported by Brown et al (2000) 37 in a cohort study of 344 women with breast implants invited to undergo MR imaging in Birmingham, AL. The majority of women in this study (77%) had at least one breast implant that was rated by three radiologists as ruptured or suspected to be ruptured. The median implant age at rupture was estimated to be 10.8 years with 95% confidence interval of 8.4-13.9 years. This study shows that the prevalence of silent or hidden silicone gel breast implant rupture is higher than was previously suspected. In a study involving 271 Danish women with breast implants randomly selected from women who underwent cosmetic breast implantation from 1973 to 1997 at four plasticsurgery clinics in Denmark, the prevalence of rupture was determined by MRI (Holmich et al, 2001) 38. Overall, 26% of implants in 36% of the women were found to be ruptured, and an additional 6% were possibly ruptured. Of the rupture implants, 22% were extracapsular. Age of implant was significantly associated with rupture among second and thirdgeneration implants (12-fold increase for rupture of implants that were between 16 and 20 years of age, compared with implants between 3 and 5 years of age). Extracapsular ruptures were significantly associated with a history of closed capsulotomy. Marotta et al (2002) 39 conducted a large cohort meta-analysis of failure data for silicone gel breast implants and also investigated shell and gel properties from 74 breast implants explanted. For this explant cohort, 42% were found to be ruptured. This updated large cohort failure analysis (9770 implants) shows that shell rupture is related directly to implant duration (26% failure at 3.9 years, 47% at 10.3 years, 69% at 17.8 years). The authors conclude that after early weakening of shells as a result of swelling of the shell elastomer by diffusion of silicone oil from the gel, implant failure can occur in a timedependent manner as a result of continuing implant motion and cyclic stresses that are exacerbated by stress concentration in thin areas, defects and folds in the shells. In Table I, a summary is presented of the results of the soundest scientific evidence on the relation between silicone breast implants and health disorders. In Table II A and B, we present the principal characteristics of the most relevant studies on breast implants and 36 Benadiba, L., Petoin, D.S., Berlie, J., Rouesse, J., Girard, M. [Survivorship of breast implants used in breast reconstruction. 949 implants]. Ann Chir Plast Esthet 2000;45:31-40. 37 Brown, S.L., Middleton, M.S., Berg, W.A., Soo, M.S., Pennello, G., Prevalence of rupture of silicone gel breast implants revealed on MR imaging in a population of women in Birmingham, Alabama. AJR Am J Roentgenol 2000;175:1057-64. 38 Holmich, L.R., Kjoller, K., Vejborg, I. et al. Prevalence of silicone breast implant rupture among Danish women. Plast Reconstr Surg 2001;108:848-58. 39 Marotta, J.S., Goldberg, E.P., Habal, M.B. et al. Silicone gel breast implant failure: evaluation of properties of shells and gels for explanted prostheses and meta-analysis of literature rupture data. Ann Plast Surg 2002;49:227-42. 25

systemic health effects of this bibliographic review (2000-2003). Studies included in this summary review were selected on the basis of their methodological soundness, following international design and scientific criteria (US Preventive Task Force, 1996) 40, in addition to their added contribution/value to the update. 40 Op.cit., footnote 4. 26

TABLE I: Evidence of serious health effects considered in studies in relation to silicone breast implants. (Update 2000-2003). Health effects Grade of evidence Evidence Based on study design Breast cancer II-2 Good evidence No association Other tumours II-2 Fair evidence No association Mammography and breast cancer detection II-3 Neurological diseases II-2 Fair evidence No association Defined connective tissue diseases II-2 Good evidence of interference No studies available on late diagnosis or mortality differences Good evidence No relevant risk increase No association Fibromyalgia III Poor evidence Atypical or novel systemic disease III Poor evidence Novel syndrome difficult to define or identify Risk to infants III Poor evidence No evidence of any risk of harmful effects to breastfed infants Local complications II-3 Good evidence Great variability Primary safety issue Lack of precise quantitative data Total mortality II-2 Good evidence No risk increase 27

Table II.A.: Principal characteristics of most relevant studies on breast implants and systemic health effects of this bibliographic review. Brinton et al, 2001 (ref #) Winther et al, 2001 (ref #) Pukkala et al, 2002 (ref. #) Koot et al, 2003 (ref. #) Study Design Retrospective cohort study Retrospective cohort study Retrospective cohort study Retrospective cohort study. Grade of evidence II-2 II-2 II-2 II-2 Country USA Denmark Finland Sweden Study Population (n) 13,488 breast implanted 1653 breast implanted 2171 breast implanted 3521 breast implanted in and 3936 other plastic during 1973-1975 and during 1970-1999 period 1965-1993 surgery 1736 comparison cohort other cosmetic surgery Type of implant Cosmetic Cosmetic Cosmetic Cosmetic Follow-up (average) 12.9 years 6.9 years 8.3 11.3 years Outcome Incidence and mortality. Neurological diseases Incidence of breast and Breast cancer. Other (Hospital admission other cancers cancers. Other causes of records) death. Total mortality Main Results Lower overall mortality No association between No evidence of increase in compared with general silicone breast implants breast cancer risk or total population. Higher overall and neurological disease cancer risk mortality compared with other plastic surgery patients. Limitations/problems Rates of no response (30%), no localization (20%). Limited numbers of deaths. Validation of all diagnosis and cause of death. Small number of observations Small number of observations. No control for confusion variables Total and cause specific mortality 50% excess mortality than expected (death rates in female Swedish population) Lack of comparability between cohorts. No control of confusion variables. 28

Table II.B.: Principal characteristics of relevant studies on breast implants and systemic health effects of this bibliography revision. Greenland et al, 2000 (ref. # ) Brown et al, 2001 (ref. # ) Hölmich et al, 2003) (ref.# ) Tugwell et al, 2001 (ref # ) Study Design Retrospective cohort study / Cross-sectional study Cross-sectional study Systematic review cross- sectional study Grade of III III III II-2 evidence Country USA USA Denmark Canada Study Person/year Breast implant 344 breast implanted during 238 breast implanted during (revised 24 studies: cohorts, Population (n) cohort: 31,820 1970-1988: ruptured (MRI) 1973-1998: 92 ruptured (MRI) case-control and crosssectional) Person/year Mastectomy: 10; and 23 extracapsular silicone 806,583 extracapsular silicone 73. Type of implant Reconstruction following Cosmetic Cosmetic Any mastectomy (mainly saline filled) Outcome Connective tissue diseases Symptoms of connective tissue Self-reported connective tissue Classic/ accepted connective diseases. Self-reported diseases or symptoms tissue diseases (CTD); physician diagnosed diseases Atypical presentations of CTD; Symptoms and sign Main Results Excess risk of undifferentiated No association was evident connective tissue diseases, between breast implant and myalgia and myositis and connective tissue diseases. systemic lupus erythematosus Women with implant rupture (MRI) no more likely to report connective tissue disease. Women with extracapsular silicone more likely to report fibromyalgia No association between silicone implant rupture and specific diseases or symptoms related to connective tissue disease. Excess of capsular contracture among women with extracapsular rupture 29

Limitations/pro blems Rates of no response (30%), no localization (20%). Limited numbers of deaths. Validation of all diagnosis and cause of death Cross-sectional. Small size. No response. Misclassification. Self-reported diagnosis without verification Small sample size; selfreported disease. Misclassification Systematic review, not a metaanalysis Not quantitative data shown Heterogeneity Misclassification Small number of observations in several studies 30

2. Summary of views from different interest groups As stated, we sent a targeted questionnaire to representatives from self-help groups, surgeons, and Eucomed/the two main manufacturers of silicone breast implants in order to learn whether they were aware of the Commission Communication, whether they thought it produced any change, and their general perception of the action lines in the Communication. Below, we provide the actual, untouched responses received from these interest groups. 2.1. Self-help groups SSF Schweiz was our targeted focal point for self-help groups, and the leader of this group sent our questionnaire to various other groups that subsequently responded directly to us. In all, we received responses from three self-help groups. Question 1 Do you think that the lines of action published in the Commission Communication have produced a change regarding the protection of women undergoing or considering undergoing this kind of surgery? Please elaborate. If you perceive no change, please state. Responses From SSF Schweiz (also representing views of German support group): No, we do not yet note changes regarding the protection of women. There are still surgeons who promise, that these (new) products are absolutely safe. Other surgeons are informing theirs patients about the risks they believe on. The public is not aware about the published actions. In cases women know something about it, they feel encouraged, because they believe that they guarantee a high protection. Women are convinced, that the EU (or their national health department) would have had taken action, if risks about safety would be real. The CE-certification increase their opinion, that breast implants must be harmless. From Dutch Silicone Support group St- SVS NO! Sorry to tell you, but these lines of action have not produced positive changes at all. Still no protection for women! Still the very same commercials with before- and after pictures about breast augmentation within a week. Get them now and pay later, 50 Euro a moth. No warning at all about possible health risks. 31

From ACTION AGAINST SILICONE GEL (Joint answer for questions 1 and 2) This is very hard to assess at this stage. We recently had an increase in calls from people considering the operation, but this may have due to the publication of the Breast Implant information Booklet in the UK in which our contact number was given. In terms of the protection of women cited in your question, we would be offering our view based on the disease-link risks associated with silicone gel implants, so that we would regard this as having a salutary balancing effect on the continuing heavy promotion of these devices. From our feedback, it may be true to say that the Commission Communication may have had a filtering through effect in pushing on the patient Information aspect, making people ask more questions and plastic surgeons more skilful in answering them, buy this is all rather ad hoc, not significant enough to say a definite yes to. Moreover, since nothing has, to date, been put into place regarding a minimum age, and realistic cooling off period, we feel that the most vulnerable people remain at the greatest risk. Question 2 If you have perceived changes, either individually or collectively, since the publication of the Commission Communication, what kinds of changes have you perceived? etc. Responses From SSF Schweiz (also representing views of German support group) We are very concerned about some changes we note. The lack of handling leads some surgeons and clinics to very aggressive advertising campaigns. Especially in German TV, they show (to mostly very young women) how easy this little step with a big effect is. In the meantime, we note, that some plastic surgeons get more and more angry about those colleagues, who ignore all existing problems. (Of course, there are maybe as many opinions as surgeons, on the definition of a problem!) Should the advertising stop be realized, could this be a very important signal towards all involved parties. Without such a ban, a public discussion on safety aspects will not make sense. From Dutch Silicone Support group St- SVS There is more commotion, more pressure and more faire tales from industry and plastic surgeons. They keep on telling silicone breast implants are tested all over and proven safe. It's used everywhere, even in cardiac valves. (A big and dangerous lie!) Still denial all over! The Dutch Ministry of Foreign Investment Agency even subsidised silicone implant manufactory in Holland (Mentor) to double their sales of 80,000 to 120.000 implants a year. From ACTION AGAINST SILICONE GEL Please see response to answer 1 (answered jointly) 32

Question 3 Is the self-help group satisfied with this outcome (i.e. with the EP resolution and subsequent EC Communication)? Please elaborate Responses From SSF Schweiz (also representing views of German support group) We are very thankful for the obvious change on the political level. We notice that the understanding on the breast implant issue is getting better with every debate in Brussels. Of course we hope, that the more stringent regulations will finally lead to a new sight of view and the example of communicating with self-help groups at the European Parliament will encourage national politicians to follow. We are confident, that in future women who consider having breast implants, will have more detailed information, than we ever had in the past. The advertising stop will increase the protection of women against a profit orientated beauty industry. A national registry should allow to take more effective action... - as far as such national registries will be installed and a cooperation with the international breast registry will be realized. These results cannot satisfy our self-help groups. We have a responsibility towards the many thousand women, who are the victims of four decades failed implant practice. Their critical situation will not change by the actions taken. From Dutch Silicone Support group St- SVS We are very happy with the EP resolution and EC communication. It's a very important first step to protect our young girls and babies against money-makers and non bona-fide doctors. Every day we hope and pray that our Health-carers will listen to us, the voluntary so called "fieldworkers" and stop this crime against innocent, helpless and mislead women. From ACTION AGAINST SILICONE GEL This is linked with my answer question 3: We understand the problems, but would, of course, have preferred some hard, legally binding precautions as an outcome from EU negotiations. For example, with regard to advertising of breast implants I note the France and Austria do not advertise breast implants; whereas, we, in the UK they have a most aggressive promotion in our media (whatever the MDA might say about purported safeguards). Similarly, we had hoped that the proposal to link Consent more firmly to the required reading of patient information would have become universal, instead of which, it seems to have more or less disappeared so that there is no real uniformity and therefore no firm reassurances on precautions. We would urge far more attention to the existing evidence for and continued research into systematic disease links with (substantial amounts of) silicone gel in the human body. As a group which encounters so much of the casualty aspect of this operation we feel that not sufficient advice and recommendation is 33

given on medical treatment for casualties; or no how those who report symptoms directly should be treated in relation to research. The registry process (so late in the day) appears unwieldy and will only show results in the long term. Question 4 To which lines of action, if any, would you give additional or different emphasis than that given in the Commission Communication? Why? Please elaborate. Responses From SSF Schweiz (also representing views of German support group) We repeat: For many thousand women in Europe, nearly no improvement has been achieved. This is an extremely heavy burden to us! We don't believe, that the breast implant issue has been understood in their full complexity. This will only be possible, if victims are integrated in this process. There has never been a discussion, on how to deal with the victims. We have many thousand women in Europe, who live with the (well known) 2nd generation implants, which can be called time bombs. Most of these women don't even know about the danger. If they would be informed about the risks and how to identify the symptoms, a dramatic development could be stopped or reduced. Every day, medical prescriptions can worsen the situation (mammography and subsequent rupture, wrong therapy, etc.) The consequences can be fatal! From Dutch Silicone Support group St- SVS A help-program for the thousand of sick women, children and even men is badly needed. There is no treatment at all. Because many complains are A-typical, the common medication won t /doesn t work. We all still get the same message: Nothing proven, it s all in your mind. All these hysterical women are only out for money. From ACTION AGAINST SILICONE GEL This is linked with my answer question 3: We understand the problems, but would, of course, have preferred some hard, legally binding precautions as an outcome from EU negotiations. For example, with regard to advertising of breast implants I note the France and Austria do not advertise breast implants; whereas, we, in the UK they have a most aggressive promotion in our media (whatever the MDA might say about purported safeguards). Similarly, we had hoed that the proposal to link Consent more firmly to the required reading of patient information would have become universal, instead of which, it seems to have more or less disappeared so that there is no real uniformity and therefore no firm reassurances on precautions. We would urge far more attention to the existing evidence for and continued research into systematic disease links with (substantial amounts of) silicone gel in the human body. As a group which encounters so much of the 34

casualty aspect of this operation we feel that not sufficient advice and recommendation is given on medical treatment for casualties; or no how those who report symptoms directly should be treated in relation to research. The registry process (so late in the day) appears unwieldy and will only show results in the long term. Question 5 Any other information/views/documents on this issue from the past 2 years that you would like to provide us? Responses From SSF Schweiz (also representing views of German support group) We would like to draw your attention to the following websites: http://www.center4policy.org/implantsm.html Women s Health > Breast Implants Research findings Here you will find all relevant links/references to the new studies. http://www.fda.gov/cdrh/breastimplants/ > Breast Implant Studies From Dutch Silicone Support group St- SVS I ll send this letter by mail too, together with our last 3 magazines, Stille Kracht, that means Silent Power. Of course, it s Dutch written buy it clearly shows the situation in Holland, thanks to the many stories and letters from our ladies. From ACTION AGAINST SILICONE GEL With regard to clinical evidence and research, I would refer your to the submissions I made to Doctor Martin-Moreno s team during the STOA inquiry. We felt that a number of the peer reviewed clinical studies we submitted at the time (eg., Dr Nyren Baylor studies, Michael Erenfeld & Co & Dr Arthur Brawer s work) was not analysed. Their references were not included in the draft Final Report, buy only pushed into the list of the final report as a information which, at least indicates the need for a follow-through, was not acknowledged. We do understand, however, that the report was drawn up from an amalgam of eclectic views and we appreciated the inclusion of a summary of those more controversial groups, such as ours who are more thoroughly concerned with the problems which breast implants engender. This was an improvement on the UK IRG review which although it received a high compliance of reports from casualties, gave nothing of this in its report. We would like to stress, therefore, the need for a stronger push for follow-up research on existing contra-indications from the EU. 2.2. Surgeons (represented by the International Confederation of Plastic, Reconstructive and Aesthetic Surgery (IPRAS) 35

In the views of the Representative of Europe on the Executive Committee of IPRAS and Chairperson of the Quality Assurance Committee IPRAS, the answers to the questionnaire are: Question 1 Are you aware of the Commission Communication from 15-11-2001 on silicone breast implants.? If YES, when did you learn of it, and through what channels? Please elaborate. Response Yes, one year ago through German Health Authorities Question 2 Do you think that the lines of action published in the Commission Communication have produced a change regarding the protection of women undergoing or considering undergoing this kind of surgery? Please elaborate Response Yes, under these conditions another soybean-oil filler disaster could not happen. Question 3 If you have perceived changes (either individually or collectively) since the publication of the Commission Communication, what kinds of changes have you perceived? Please elaborate. If you have perceived no changes, please state this. Response I have no changes perceived yet, since German Health Authorities had to forward the information to the "States" governments (in my case Bavaria) and this has been done but no actions were taken by the Bavarian Government yet. Question 4 Is IPRAS satisfied with this outcome? (ie, with the EP resolution and subsequent EC Communication). Please elaborate. Response Very satisfied, practically all our suggestions and concerns were adequately addressed. Question 5 To which lines of action, if any, would you give additional or different emphasis than that given in the Commission Communication? Why? Please elaborate 36

Response I would suggest that, instead of NATIONAL resgistries, all participants should turn in their data at the International Breast Implant Registry (under the umbrella of IPRAS). Question 6 What, if any, difficulties is IPRAS experiencing in implementing the action lines of the Commission Communication? Response It seems that currently health authorities and experts have difficulties to keep survey of products on the market in Europe. Question 7 Any other documents/information/views on this issue from the past 2 years that you would like to provide us? Response From of the International Breast Implant Registry 2.3. Manufacturers The responses to the questionnaire for manufacturers received by McGhan, Mentor and Eucomed are as follows: Question 1 Are you aware of the Commission Communication from 15-11-2001 on silicone breast implants.? If YES, when did you learn of it, and through what channels? Please elaborate. Responses From McGhan Yes, we became aware of the Commission Communication by tracking the European petition through the European Parliament. A copy of the communication was made available to us through the trade association s participation in the European Commission s Medical Device Expert Group. From Mentor Yes. Mentor is aware of the Commission Communication from 15-11-2001 on silicone breast implants. Mentor learned about this communication from Eucomed on 15-11-2001 and previous communications with Mr. Putzeys and Mr. Brekelmans. 37

From Eucomed Yes, Eucomed closely followed the events at the European Parliament in March 2001, which led to this initiative by the European Commission. Eucomed issued a statement on 23 March in which the European medical technology industry expressed sympathy with the women who have suffered from injury or illness caused by breast implants, and offered help in developing measures to guarantee the highest quality and safety of products on the market and support in efforts to provide the best product information available. Question 2 Do you think that the lines of action published in the Commission Communication have produced a change regarding the protection of women undergoing or considering undergoing this kind of surgery? Please elaborate. Responses From McGhan The availability of information booklets has provided additional protection to women. The Communication has made both industry and surgeons more aware of the necessity to provide information to women and to make sure that the information is balanced and can be understood. From Mentor There was no large change for Mentor to comply with this part of the Commission Communication. Regarding the preclinical and clinical requirements for breast implants, Mentor had already been testing breast implants to comply with EN 12180, ASTM standards as well as Mentor s own high internal quality standards. Mentor did develop patient brochures to satisfy the patient labelling requirement. If all manufacturers comply with these requirements as does Mentor, then there will be adequate "protection" for women undergoing or considering undergoing this kind of surgery. This full compliance will be demonstrated once all breast implant manufacturers are submitting their Design Dossiers to their notified bodies for conformity assessment as Class III medical devices. From Eucomed The Industry welcomes the Communication, in particular the suggested measures to improve information on the breast implant surgery, effects, contraindications and monitoring. These will certainly help women in taking an informed decision. Question 3 If you have perceived changes (either individually or collectively) since the publication of the Commission Communication, what kinds of changes have you perceived? Please elaborate. If you have perceived no changes, please state this 38

Responses From McGhan Individually, McGhan has moved to broaden its reporting of adverse incidents associated with breast implants. Additionally, McGhan has submitted its first Class III product dossier to its Notified Body in anticipation of the published changes. McGhan also perceives a more pragmatic approach from the Commission in dealing with the issue and adopting of the decision to move to Class III by derogation. From Mentor Mentor has perceived no changes since the publication of the Commission Communication. From Eucomed The change for industry was the subsequent upgrading of the classification of breast implants to class III medical devices. Question 4 How does McGhan / Mentor / Eucomed feel about this outcome? (ie, with the EP resolution and subsequent EC Communication). Please elaborate Responses From McGhan In general, the outcome will provide for better protection of women. The development of the manufacturing standards particularly in the pre-clinical and clinical areas will ensure that the information to show compliance will be enhanced. As Class III products, the review of the information will also be more thorough. The changes to the advertising and consent for minors will ensure that the way in which the procedures are made known and available to women will be more responsible. From Mentor Mentor is pleased with the EP resolution and subsequent EC Communication. Mentor has always had high internal quality standards for testing products. This standard brings consistency to the requirements for all breast implant manufacturers. From Eucomed Concerning the new classification of breast implants as class III medical devices, industry generally considers this as an unfortunate precedent; we feel that this decision was the result of political and emotional pressure, rather than sound scientific evidence. Whilst it is unlikely that the design review will have any major impact on the number of accidents involving breast implants, it will undoubtedly increase the administrative burden on industry. Eucomed calls for a sensible, proportionate and rapid regulatory regime. Question 5 To which lines of action, if any, would you give different emphasis than that given in the 39

Commission Communication? Why? Please elaborate. Responses From McGhan We think that the emphasis is appropriate. From Mentor Mentor would not give different emphasis to any other lines of action other than those given in the Commission Communication. Mentor feels that lines of action addressed in the Communication are those which are the most appropriate to breast implants. From Eucomed Improved patient information should be the priority. Question 6 What, if any, difficulties is McGhan / Mentor / Eucomed experiencing in implementing the action lines of the Commission Communication? Responses From McGhan We believe that the implementation of registries will be impossible in some countries without legislative changes. We are also of the view that the provision of information with the consent to the involved parties may be not forthcoming and may limit the value in examining such information at future dates. From Mentor Mentor Medical is not having difficulties implementing any of the action lines of the Commission Communication. From Eucomed It is too soon to tell. However, we are anxious to know how much time the Notified Bodies will need to be able to cope with the new requirements. Question 7 Any other documents/information/views on this issue from the past 2 years that you would like to provide us? Responses From McGhan 40

McGhan view the Commission Communication as a positive move for the improvement of the situation surrounding silicone breast implants. We regard the products as safe and as providing a necessary tool in managing the healthcare of women. The issue has been handled in a sensitive manner which has taken a balanced view of the many considerations involved. From Mentor Mentor is in close communication with Eucomed (by attendance of a Mentor representative in several working groups, as well as through proper communication on issues relating to breast implants by Eucomed). From Eucomed None. In Table III, a summary is presented of the positions of the three main interest groups (selfhelp groups; surgeons; and manufacturers) on silicone breast implants) 41

Table III: Synopsis of positions of three interest groups Self-help groups Surgeons Manufacturers Dissatisfied with Communication, although step in the right direction Propose tighter regulations: o Ban advertising o Further research o Attention to victims: - second generation implants, unaware of potential problems (local complications); if these women informed about risks and how to identify symptoms, dramatic development stopped or reduced. o Better information flow - believe that women still do not receive sufficient accurate information in order to make informed decisions. IPRAS very satisfied with Communication. In Germany, changes have not yet been perceived on the ground due to the decentralized system of governance. Suggest that instead of NATIONAL registries, use International Breast Implant Registry (under the umbrella of IPRAS). Regarding difficulties, IPRAS reports that currently health authorities and experts have difficulties keeping track of products on the market in Europe. Already abide to top quality standards, but say outcome means better protection for women, and a standard that brings consistency to the requirements for all breast implant manufacturers. Biggest change: upgrading classification to class III medical devices. Eucomed sees as unfortunate precedent, political pressure rather than scientific evidence and unlikely that design review will have impact on accidents, but will increase administrative burden on industry. Two main manufacturers have developed information booklets/patient brochures as a concrete change from Communication/ believe that full compliance will come with requirements around SBIs change to class III products. Felt that improved information for women should be the biggest priority. When asked about difficulties in implementing the Communication, stated that some countries may have problems starting patient registries without legislative changes. 42

III. Discussion The review of a complex issue such as silicone breast implants is always a challenge. The scientific evidence gathered after a systematic examination of the literature has to be logically taken into account. But there are also views and perspectives that need to be incorporated in order to have a clear picture of the situation. The human dimension and perception is extremely important in this assessment. Therefore, and together with the quantitative perspective assessing relative risks associated with SBI, we have included a qualitative perspective. This has been done by incorporating into the study update the views of interest groups, namely self-help groups, surgeons specialized in this field, and manufacturers. Based on this approach, and following the lines of the section on Results, we interpret and discuss the findings in a systematic way below. Scientific evidence Regarding new scientific evidence, the currently available information shows that there is not solid evidence linking SBI to severe diseases (such as breast cancer or connective tissue diseases). Local effects remain a matter of serious concern, and emphasis has to be still made to ensure and strengthen the best surgical guidelines and operational procedures. Moreover, this should be complemented with the most transparent process of information to patients, including the likelihood of secondary or adverse effects. Trying to summarise the potential health effects associated to SBI, the following issues emerge as particularly important. The updated evidence on overall mortality does not disclose significant differences when women with implants are compared with analogous women without implants. In fact, women with implants have been found to have lower death rates than women in the general population. This is most likely not due to any protective effect of SBI, but to the self selection process (ie, the kinds of candidates who undergo this kind of surgery: this could be called the healthy candidate effect ). On the other hand, the lower rates are due primarily to fewer deaths from cancer and diseases of the circulatory system, the most common causes of death in the general population. Below we discuss some secondary findings from certain studies that point to increased risk of suicide, brain cancer and respiratory cancers in women with SBI. Regarding suicide, the observed increased risk of death from this cause may be affected by random error (very small number of deaths observed) and may reflect selection bias (i.e. greater prevalence of a priori psychological characteristics) rather than a causal association between implant surgery and suicide. In epidemiological terms, we may have selection bias when the groups to be compared are dissimilar from the beginning, with a different likelihood of developing certain diseases regardless of the intervention that is being assessed. When these individual features can be identified and well-characterised from the beginning, they may be taken into account in the analysis, and this is referred to as "confounding factors" which need to be controlled in the interpretation of the risk estimates. However, when this characterisation is not possible, a cautious interpretation of the differences is essential, since there are systematic differences that may arise from factors other than the one mainly being assessed (in this case, SBI). This explanation attempts to explain the importance of potential selection bias. It is necessary to remember that these studies are retrospective, are limited in their control of confusion variables, have a limited numbers of deaths and have difficulties validating all diagnoses and causes of death. 43

Regarding cancer, in general there is not evidence of a higher incidence or mortality in women with implants compared with women in the general population. It is important to note that an initial concern was that breast cancer could be associated with this type of surgery, but there is currently no evidence that associates higher incidence of or increased mortality from breast cancer with breast implants. With respect to brain cancer, the higher rates found in the US study is difficult interpreted There have been suggestions that implants may have an effect on neurological pathways, but the data on this association are not consistent. It is possible that the higher risks observed for both brain and respiratory cancers are not related to exposure to silicone, but are due to either chance findings or to factors common to women who choose to have implants. In a previous analysis of the data published by Brinton et al (2000) 41 in Cancer Causes and Control, the authors found no association between breast implants and subsequent risk of breast cancer. A second report (Brinton, 2001) showed that risks for most other cancers among implant patients were not increased, with the exception of brain and respiratory cancer {Brinton, Burich, et al. 2001 145 /id}. Findings from these recent studies again point to the need for additional methodologically-sound research to shed further light on the issue and on the unanswered questions to date. The observed increase in respiratory tract cancer is difficult to explain. While in the Swedish study, deaths due to this malignancy were explained by a so-called selection bias mainly linked to smoking status (previously shown, Fryzek et al, 2000) 42, in the American study, the authors state: There is not enough information to evaluate whether this increase may be related to silicone exposure or to higher smoking rates among implant patients. The vast majority of women with respiratory cancers were not alive at the time of the study. Therefore, lifestyle information obtained from questionnaires sent to living participants was not available. However, the surviving implant patients do not have higher smoking rates than the other plastic surgery patients. Regarding connective tissue diseases, additional studies found no evidence of an association between breast implants in general, or silicone breast implants specifically, and any of the individual connective-tissue diseases, all connective-tissue diseases combined, atypical connective tissue disorders or other autoimmune or rheumatic conditions. One cross-sectional study found that women with breast implant rupture diagnosed by MRI were no more likely to report a diagnosis of selected connective-tissue diseases than those with intact implants. However, women with extracapsular silicone were more likely to report having fibromyalgia or other connective tissue diseases. Women who developed fibromyalgia before they had a breast implant could not be distinguished from women who developed fibromyalgia after breast implant surgery (cross-sectional study), and causality could not be established. Thus, currently this is simply a research hypothesis. The self-reported diagnosis was not confirmed by medical examination. Case series studies describing fibromyalgia in patients with implants have been published and are available for review, but these studies have small sample sizes, are not controlled (case series without controls), have no information on extracapsular silicone, or include patients from non-representative or non generalizable populations. Regarding local effects, as we stressed in our previous report, the relatively high frequency of these complications is clear. Recent available studies report higher rupture rates, a more 41 Op.cit., footnote 6. 42 Op.cit., footnote 9. 44

precise lifespan of implants and a more frequent need for additional surgery than was considered ten years ago. While local effects are normally not life-threatening, they may result in discomfort, inconvenience, explantation, disfigurement, pain and other morbidities, and when further corrective procedures are necessary, an additional potential risk (e.g., additional surgery, reoperation or replacement). Breast implants have a limited lifetime, which is still not well-established and depends on individual biological variability, differences in women's characteristics (age, co-morbidities, indication for implant), types of implants, surgical techniques, and the skill of surgeons. In any event, the probability of having a reoperation is high and it increases over time. Many authors have underlined the problems and limitations of the available studies conducted to date to document the rate of rupture of silicone breast implants. Several sources of bias in study design (non-representative populations, selection bias, misclassification, confounding) affect studies based on explant series. Better and standardized definitions of implant rupture must be developed and adopted by multidisciplinary teams of researchers. The frequency of rupture is reported in most studies based on findings at explantation (standard for diagnosis), detection by mammographic technologies and surveys of results in cohorts of patients. From case series reported from surgeons, the detection of ruptures depends on patient complaints, routine screening mammographies or physical examinations, none of which are absolutely reliable. The lower rupture rates reported by manufacturers based on returns, complaints, legal proceedings and other sources probably are affected by underreporting and low sensitivity. The use of MRI and other diagnostic tests in representative samples of women with implants should give a more accurate estimation of the prevalence of rupture. Local and perioperative complications are so frequent that must be considered the primary safety issue with silicone breast implants and also with other types of breast implants. Its importance and the relevance for women s health justifies considering research on this topic as a priority, following the Communication from the Commission on Community and National Measures in relation to breast implants. In addition, quantitative data on long-term effects is lacking for new modern implants. Thus, the precise incidence of local and perioperative complications should be considered a research priority and an essential element of adequate informed consent for women undergoing breast implantation. In addition, women need to have complete, unbiased information in order to make appropriate decisions regarding the decision to undergo surgery to obtain silicone breast implants. As a result, surgeons need to provide a clear description of the pros and cons of going through the surgical procedure, and these should be systematically addressed, with an open interchange of questions and answers, as well as a waiting period for appropriate reflection on behalf of the implant candidate. Women need to understand that breast implants are not a panacea for any larger, underlying self-image problems. Views of interest groups Regarding the opinion of self-help groups, we found that they believe that the Commission Communication represents a step in the right direction. However, they feel that the action lines do not go far enough, as women are still being hurt by SBIs and they still do not receive sufficient accurate information in order to make informed decisions. They would like tighter regulations, particularly regarding such areas as advertising, and also would also emphasize the need for further research on the health impact of silicone breast implants. Just as important, they note that there has been no discussion about how to deal with affected women (for example, who have second generation breast implants and who are completely unaware of potential problems, as local complications). They believe that if these women would be 45

informed about the risks and how to identify the symptoms, a dramatic development could be stopped or reduced. In the views of the Representative of Europe on the Executive Committee of IPRAS and Chairperson of the Quality Assurance Committee, IPRAS is satisfied with the EC Communication. In Germany, changes have not yet been perceived on the ground due to the decentralized system of governance. Regarding the question about how IPRAS might have changed emphasis, it was suggested that instead of national registries, all participants should turn in their data to the International Breast Implant Registry (under the umbrella of IPRAS). Finally, regarding difficulties, IPRAS reports that currently health authorities and experts have difficulties keeping track of products on the market in Europe. Eucomed and both main manufacturers of SBIs, McGhan and Mentor, knew of the EU Communication. Manufacturers acknowledged this relatively positive process, but believe that they already abide to top quality standards and that SBIs are safe and necessary products. However, regarding changes due to the EC Communication, Eucomed mentions the biggest change as the upgrading of the classification of breast implants to Class III medical devices. Eucomed states that industry generally considers this as an unfortunate precedent, believing that this decision was the result of political and emotional pressure, rather than sound scientific evidence. Although they believe that it is unlikely that the design review will have any major impact on the number of accidents involving breast implants, Eucomed says that it will undoubtedly increase the administrative burden on industry. Both McGhan and Mentor cite the development of information booklets/patient brochures as a concrete change resulting from the EC Communciation. In addition, the two manufacturers also seem to believe that full compliance will come with requirements around SBIs change to class III products. Eucomed states that improved information for women should be the biggest priority. When asked about difficulties in implementing the EC Communication, McGhan stated that some countries may have problems starting patient registries without legislative changes. In sum, these manufacturers say that the outcome of the EC Communication means better protection for women, and a standard that brings consistency to the requirements for all breast implant manufacturers. 46

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136.- Taylor WG. Syllogism in plastic surgery. Plast Reconstr Surg 2000; 106(1):234-235. 137.- Tugwell P, Wells G, Peterson J, Welch V, Page J, Davison C et al. Do silicone breast implants cause rheumatologic disorders? A systematic review for a court-appointed national science panel. Arthritis Rheum 2001; 44(11):2477-2484. 138.- Ueki A, Isozaki Y, Tomokuni A, Ueki H, Kusaka M, Tanaka S et al. Different distribution of HLA class II alleles in anti-topoisomerase I autoantibody responders between silicosis and systemic sclerosis patients, with a common distinct amino acid sequence in the HLA-DQB1 domain. Immunobiology 2001; 204(4):458-465. 139.- US Preventive Task Force. Guide to clinical preventive services: report of the U.S. 2nd ed. Washington, DC: Office of Disease Prevention and Health Promotion, US Government Printing Office, 1996. 140.- Vandeweyer E, Hertens D, Nogaret JM, Deraemaecker R. Immediate breast reconstruction with saline-filled implants: no interference with the oncologic outcome? Plast Reconstr Surg 2001; 107(6):1409-1412. 141.- Vasey FB, Mills CR, Wells AF. and fibromyalgia. Plast Reconstr Surg 2001; 108(7):2165-2168. 142.- Villafane O, Garcia-Tutor E, Taggart I. Endoscopic transaxillary subglandular breast augmentation using silicone gel textured implants. Aesthetic Plast Surg 2000; 24(3):212-215. 143.- Weber R, Keerl R, Draf W. [Endonasal endoscopic surgery of maxillary sinus mucoceles after Caldwell-Luc operation]. Laryngorhinootologie 2000; 79(9):532-535. 144.- White FA, Kocsis JD. A-fiber sprouting in spinal cord dorsal horn is attenuated by proximal nerve stump encapsulation. Exp Neurol 2002; 177(2):385-395. 145.- Winther JF, Friis S, Bach FW, Mellemkjaer L, Kjoller K, McLaughlin JK et al. Neurological disease among women with silicone breast implants in Denmark. Acta Neurol Scand 2001; 103(2):93-96. 146.- Wolf CJ, Brandon HJ, Young VL, Jerina KL. Effect of surgical insertion on the local shell properties of SILASTIC II silicone gel breast implants. J Biomater Sci Polym Ed 2000; 11(10):1007-1021. 147.- Yang CC. Prosthesis folding as a cause of the saline breast implant partial deflation 12 years after augmentation mammaplasty: a case report. Kaohsiung J Med Sci 2000; 16(9):486-489. 148.- Yii NW, Khoo CT. Salvage of infected expander prostheses in breast reconstruction. Plast Reconstr Surg 2003; 111(3):1087-1092. 150.- Zuckerman D. Commentary: are breast implants safe? Med Gen Med 2001; 3(4):12. 57

151.- Zuckerman D. Commentary: are breast implants safe? Plast Surg Nurs 2002; 22(2):66-71. 58

ANNEX 1: Questionnaires and letters sent 59

SENT BY E-MAIL: Meyerbuchrain@bluewin.ch January 24, 2003 Mrs. Cosima Meyer SSF Schweiz Dorfhald 15 CH-6033 Buchrain Fax 0041-440-0614 Dear Mrs. Meyer, First of all, Happy New Year! It is a pleasure for us to be back in touch with you. As you know, in 1999, we were selected by the Scientific and Technological Options Assessment (STOA) of the European Parliament to carry out a technical report on Health risks posed by silicone implants in general, with a special attention to breast implants. As you are aware, our aim was to reflect the various opinions of different interest groups regarding silicone implants, and among these groups, we were very interested in hearing and reflecting the opinions and views of the Self-Help Group for Women damaged by Silicone. We tried to present these positions in an objective, unbiased way in a report presented to the European Parliament (Martin-Moreno JM, Gorgojo L, Gonzalez-Enriquez J, Wisbaum W. Health risk posed by silicone implants in general with special attention to breast implants. Final Study Report. Published on the Web page of the Scientific and Technological Options Assessment (STOA) of the European Parliament; 2000. http://www.europarl.eu.int/dg4/stoa/en/publi/pdf/99-20-02_en.pdf). Now we have been requested by the STOA to re-assess the issue over the past two years by carrying out a brief update. There is interest in learning what has given that there was a Commission Communication issued on 15-11-2001 (please find attached) proposing tighter controls on the safety of breast implants, reinforced mechanisms to check that these rules are observed, and an upgrade in European standards for breast implants. As part of this study, we would be most appreciative of your valuable views on behalf of the Self-Help Group for Women damaged by Silicone regarding any changes you have seen and your input regarding the lines of action found in the Commission Communication. With this aim, we ask that you please complete and return the attached brief questionnaire (preferably by the 20 th of February). We would also be happy to receive any additional information you may have from the past two years that sheds light on our questions. We thank you very much in advance; we are most grateful! With best wishes for the New Year, Lydia Gorgojo (on behalf of team members J Gonzalez-Enriquez, W Wisbaum and Jose M Martin-Moreno) 60

HEALTH RISKS POSED BY SILICONE IMPLANTS IN GENERAL, WITH A SPECIAL ATTENTION TO BREAST IMPLANTS STUDY UPDATE We would very much appreciate incorporating the general views and position of the Self- Help Group for Women damaged by Silicone, and, with this aim, hope you do not mind answering the following 5 questions. Please write your answers and return to us (preferably by email (lgorgojo@isciii.es); if this is not possible, you can return the questionnaire by fax (Attention J Gonzalez-Enriquez: 34-91- 387-7841) or by mail: J Gonzalez-Enriquez, AETS, ISCIII, Sinesio Delgado 4, Pabellon 4, 28029, Madrid SPAIN). Do you think that the lines of action published in the Commission Communication have produced a change regarding the protection of women undergoing or considering undergoing this kind of surgery? Please elaborate. If you perceive no change, please state. If you have perceived changes, either individually or collectively, since the publication of the Commission Communication, what kinds of changes have you perceived? Please elaborate. If you have perceived no changes, please state this. Is the self-help group satisfied with this outcome? (ie, with the EP resolution and subsequent EC Communication). Please elaborate. To which lines of action, if any, would you give additional or different emphasis than that given in the Commission Communication? Why? Please elaborate. Any other information/views/documents on this issue from the past 2 years that you would like to provide us? PLEASE RETURN TO US PREFERABLY BY THE 20 TH OF FEBRUARY. Thank you very much for you time and assistance! 61

The International Confederation of Plastic Reconstructive and Aesthetic Surgery (IPRAS) Europe: Marita Eisenmann-Klein, M.D. (Germany); Fax: (49) 941 782 440 Sirpa Asko-Seljavaara, M.D. (Finland); Fax: (358) 0 471 7570 Riccardo Mazzola, M.D. (Italy); Fax: +39 02 5831 4727 January 24, 2003 Dear Drs Eisenmann-Klein, Asko-Selijavaara and Riccardo Mazzola: As you might remember, in 1999, we were selected by the Scientific and Technological Options Assessment (STOA) of the European Parliament to carry out a technical report on Health risks posed by silicone implants in general, with a special attention to breast implants. Our aim was to reflect the various opinions of different interest groups regarding silicone implants, and among these groups, we were very interested in hearing and reflecting the opinions and views of IPRAS. Along with scientific evidence, we tried to present these positions in an objective, unbiased way in a report presented to the European Parliament (Martin-Moreno JM, Gorgojo L, Gonzalez-Enriquez J, Wisbaum W. Health risk posed by silicone implants in general with special attention to breast implants. Final Study Report. Published on the Web page of the Scientific and Technological Options Assessment (STOA) of the European Parliament; 2000. http://www.europarl.eu.int/dg4/stoa/en/publi/pdf/99-20- 02_en.pdf). We gathered this input from Ulrich Hinderer, MD; Ph.D., who was President of IPRAS in March 2000 when we carried out our study. Now we have been requested by the STOA to re-assess the issue over the past two years by carrying out a brief update. There is interest in learning what has happened given that there was a Commission Communication issued on 15-11-2001 (please find attached) proposing tighter controls on the safety of breast implants, reinforced mechanisms to check that these rules are observed, and an upgrade in European standards for breast implants. As part of this study, we would be most appreciative of surgeons views represented by IPRAS, specifically regarding your knowledge of the Commission Communication, any changes you have experienced as a result, and input regarding the lines of action found in the Communication. With this aim, we ask that you please complete and return the attached brief questionnaire (preferably by the 20 th of February). We would also be happy to receive any additional information you may have from the past two years on this issue. We thank you very much in advance; we are most grateful! With best wishes for the New Year, Lydia Gorgojo (on behalf of team members J Gonzalez-Enriquez, W Wisbaum and Jose M Martin-Moreno) HEALTH RISKS POSED BY SILICONE IMPLANTS IN GENERAL, WITH A SPECIAL ATTENTION TO BREAST IMPLANTS STUDY UPDATE 62

We would very much appreciate incorporating the general views and position of the The International Confederation of Plastic Reconstructive and Aesthetic Surgery (IPRAS) Europe, representing plastic, reconstructive and aesthetic surgeons, and, with this aim, hope you do not mind answering the following 7 questions. Please write your answers and return to us (preferably by email (lgorgojo@isciii.es); if this is not possible, you can return the questionnaire by fax (Attention J Gonzalez-Enriquez: 34-91-387-7841) or by mail: J Gonzalez-Enriquez, AETS, ISCIII, Sinesio Delgado 4, Pabellon 4, 28029, Madrid SPAIN). Are you aware of the Commission Communication from 15-11-2001 on silicone breast implants.? If YES, when did you learn of it, and through what channels? Please elaborate. Do you think that the lines of action published in the Commission Communication have produced a change regarding the protection of women undergoing or considering undergoing this kind of surgery? Please elaborate. If you have perceived changes (either individually or collectively) since the publication of the Commission Communication, what kinds of changes have you perceived? Please elaborate. If you have perceived no changes, please state this. Is IPRAS satisfied with this outcome? (ie, with the EP resolution and subsequent EC Communication). Please elaborate. To which lines of action, if any, would you give additional or different emphasis than that given in the Commission Communication? Why? Please elaborate. What, if any, difficulties is IPRAS experiencing in implementing the action lines of the Commission Communication? Any other documents/information/views on this issue from the past 2 years that you would like to provide us? PLEASE RETURN TO US PREFERABLY BY THE 20 TH OF FEBRUARY. Thank you very much for you time and assistance! 63

SENT BY E-MAIL: eucomed@eucomed.be January 24, 2003 Mr. Dario Pirovano Business Director Area, Regulatory issues EUCOMED Dear Mr. Pirovano: In 1999, we were selected by the Scientific and Technological Options Assessment (STOA) of the European Parliament to carry out a technical report on Health risks posed by silicone implants in general, with a special attention to breast implants. Our aim was to reflect the various opinions of different interest groups regarding silicone implants, and among these groups, we were very interested in hearing and reflecting the opinions and views of Eucomed. Along with scientific evidence, we tried to present these positions in an objective, unbiased way in a report presented to the European Parliament (Martin-Moreno JM, Gorgojo L, Gonzalez-Enriquez J, Wisbaum W. Health risk posed by silicone implants in general with special attention to breast implants. Final Study Report. Published on the Web page of the Scientific and Technological Options Assessment (STOA) of the European Parliament; 2000. http://www.europarl.eu.int/dg4/stoa/en/publi/pdf/99-20-02_en.pdf). In March 2000, when we carried out our study, we gathered information on behalf of Eucomed from Ms Monique Lamon. Now we have been requested by the STOA to re-assess the issue over the past two years by carrying out a brief update. There is interest in learning what has happened given that there was a Commission Communication issued on 15-11-2001 (please find attached) proposing tighter controls on the safety of breast implants, reinforced mechanisms to check that these rules are observed, and an upgrade in European standards for breast implants. As part of this study, we would be most appreciative of the valuable views of manufacturers represented through Eucomed. We are specifically interested in your knowledge of the Commission Communication, any changes you have experienced as a result, and input regarding the lines of action found in the Communication. With this aim, we ask that you please complete and return the attached brief questionnaire (preferably by the 20 th of February). We would also be happy to receive any additional information you may have from the past two years on this issue. We thank you very much in advance; we are most grateful! With best wishes for the New Year, Lydia Gorgojo (on behalf of team members J Gonzalez-Enriquez, W Wisbaum and Jose M Martin-Moreno) 64

HEALTH RISKS POSED BY SILICONE IMPLANTS IN GENERAL, WITH A SPECIAL ATTENTION TO BREAST IMPLANTS STUDY UPDATE We would very much appreciate incorporating the views and position of EUCOMED, and, with this aim, hope you do not mind answering the 7 questions below. Please write your answers and return to us (preferably by email (lgorgojo@isciii.es); if this is not possible, you can return the questionnaire by fax (Attention Jesus Gonzalez-Enriquez: 34-91-387-7841) or by mail: J Gonzalez-Enriquez, AETS, ISCIII, Sinesio Delgado 4, Pabellon 4, 28029, Madrid SPAIN). Are you aware of the Commission Communication from 15-11-2001 on silicone breast implants.? If YES, when did you learn of it, and through what channels? Please elaborate. Do you think that the lines of action published in the Commission Communication have produced a change regarding the protection of women undergoing or considering undergoing this kind of surgery? Please elaborate. If you have perceived changes (either individually or collectively) since the publication of the Commission Communication, what kinds of changes have you perceived? Please elaborate. If you have perceived no changes, please state this. How do manufacturers feel about this outcome? (ie, with the EP resolution and subsequent EC Communication). Please elaborate. To which lines of action, if any, would you give different emphasis than that given in the Commission Communication? Why? Please elaborate. What, if any, difficulties is EUCOMED experiencing in implementing the action lines of the Commission Communication? Any other documents/information/views on this issue from the past 2 years that you would like to provide us? PLEASE RETURN TO US PREFERABLY BY THE 20 TH OF FEBRUARY. Thank you very much for you time and assistance! 65

SENT BY E-MAIL: bhatt@mcghanltd.com January 24, 2003 Mr Barry Hatt Vice President of International Manufacturing McGhan Ltd Kilbride Industrial Estate IRL Arklow, County Wicklow Dear Mr. Hatt: Happy New Year! It is a pleasure to be back in touch. As you know, in 1999, we were selected by the Scientific and Technological Options Assessment (STOA) of the European Parliament to carry out a technical report on Health risks posed by silicone implants in general, with a special attention to breast implants. Our aim was to reflect the various opinions of different interest groups regarding silicone implants, and among these groups, we were very interested in hearing and reflecting the opinions and views of McGhan. Along with scientific evidence, we tried to present these positions in an objective, unbiased way in a report presented to the European Parliament (Martin-Moreno JM, Gorgojo L, Gonzalez-Enriquez J, Wisbaum W. Health risk posed by silicone implants in general with special attention to breast implants. Final Study Report. Published on the Web page of the Scientific and Technological Options Assessment (STOA) of the European Parliament; 2000. http://www.europarl.eu.int/dg4/stoa/en/publi/pdf/99-20- 02_en.pdf). Now we have been requested by the STOA to re-assess the issue over the past two years by carrying out a brief update. There is interest in learning what has happened given that there was a Commission Communication issued on 15-11-2001 (please find attached) proposing tighter controls on the safety of breast implants, reinforced mechanisms to check that these rules are observed, and an upgrade in European standards for breast implants. As part of this study, we would be most appreciative of the valuable views of McGhan. We are specifically interested in your knowledge of the Commission Communication, any changes you have experienced as a result, and input regarding the lines of action found in the Communication. With this aim, we ask that you please complete and return the attached brief questionnaire (preferably by the 20 th of February).We would also be happy to receive any additional information you may have from the past two years on this issue. We thank you very much in advance; we are most grateful! With best wishes for the New Year, Lydia Gorgojo (on behalf of team members J Gonzalez-Enriquez, W Wisbaum and Jose M Martin-Moreno) 66

HEALTH RISKS POSED BY SILICONE IMPLANTS IN GENERAL, WITH A SPECIAL ATTENTION TO BREAST IMPLANTS STUDY UPDATE We would very much appreciate incorporating the views and position of McGhan, and, with this aim, hope you do not mind answering the 7 questions below. Please write your answers and return to us (preferably by email (lgorgojo@isciii.es); if this is not possible, you can return the questionnaire by fax (Attention J Gonzalez-Enriquez: 34-91-387-7841) or by mail: J Gonzalez-Enriquez, AETS, ISCIII, Sinesio Delgado 4, Pabellon 4, 28029, Madrid SPAIN). Are you aware of the Commission Communication from 15-11-2001 on silicone breast implants.? If YES, when did you learn of it, and through what channels? Please elaborate. Do you think that the lines of action published in the Commission Communication have produced a change regarding the protection of women undergoing or considering undergoing this kind of surgery? Please elaborate. If you have perceived changes (either individually or collectively) since the publication of the Commission Communication, what kinds of changes have you perceived? Please elaborate. If you have perceived no changes, please state this. How does McGhan feel about this outcome? (ie, with the EP resolution and subsequent EC Communication). Please elaborate. To which lines of action, if any, would you give different emphasis than that given in the Commission Communication? Why? Please elaborate. What, if any, difficulties is McGhan experiencing in implementing the action lines of the Commission Communication? Any other documents/information/views on this issue from the past 2 years that you would like to provide us? PLEASE RETURN TO US PREFERABLY BY THE 20 TH OF FEBRUARY. Thank you very much for you time and assistance! 67

SENT BY E-MAIL ahoogw@mentormedical.nl January 24, 2003 Mr. Adri Hoogwerf MENTOR Medical Einsteinweg 5 NL-2333 CC Leiden Tel: 31-71-521-5007 Fax: 31-71-521-7422 Dear Mr. Hoogwerf: Happy New Year. As you might remember, in 1999, we were selected by the Scientific and Technological Options Assessment (STOA) of the European Parliament to carry out a technical report on Health risks posed by silicone implants in general, with a special attention to breast implants. Our aim was to reflect the various opinions of different interest groups regarding silicone implants, and among these groups, we were very interested in hearing and reflecting the opinions and views of Mentor Medical. Along with scientific evidence, we tried to present these positions in an objective, unbiased way in a report presented to the European Parliament (Martin-Moreno JM, Gorgojo L, Gonzalez-Enriquez J, Wisbaum W. Health risk posed by silicone implants in general with special attention to breast implants. Final Study Report. Published on the Web page of the Scientific and Technological Options Assessment (STOA) of the European Parliament; 2000. http://www.europarl.eu.int/dg4/stoa/en/publi/pdf/99-20-02_en.pdf). Now we have been requested by the STOA to re-assess the issue over the past two years by carrying out a brief update. There is interest in learning what has happened given that there was a Commission Communication issued on 15-11-2001 (please find attached) proposing tighter controls on the safety of breast implants, reinforced mechanisms to check that these rules are observed, and an upgrade in European standards for breast implants. As part of this study, we would be most appreciative of the valuable views of Mentor Medical. We are specifically interested in your knowledge of the Commission Communication, any changes you have experienced as a result, and input regarding the lines of action found in the Communication. With this aim, we ask that you please complete and return the attached brief questionnaire (preferably by the 20 th of February). We would also be happy to receive any additional information you may have from the past two years on this issue. We thank you very much in advance; we are most grateful! With best wishes for the New Year, Lydia Gorgojo (on behalf of team members J Gonzalez-Enriquez, W Wisbaum and Jose M Martin-Moreno) 68

HEALTH RISKS POSED BY SILICONE IMPLANTS IN GENERAL, WITH A SPECIAL ATTENTION TO BREAST IMPLANTS STUDY UPDATE We would very much appreciate incorporating the views and position of Mentor Medical, and, with this aim, hope you do not mind answering the 7 questions below. Please write your answers and return to us (preferably by email (lgorgojo@isciii.es); if this is not possible, you can return the questionnaire by fax (Attention J Gonzalez-Enriquez: 34-91-387-7841) or by mail: J Gonzalez-Enriquez, AETS, ISCIII, Sinesio Delgado 4, Pabellon 4, 28029, Madrid SPAIN). Are you aware of the Commission Communication from 15-11-2001 on silicone breast implants.? If YES, when did you learn of it, and through what channels? Please elaborate. Do you think that the lines of action published in the Commission Communication have produced a change regarding the protection of women undergoing or considering undergoing this kind of surgery? Please elaborate. If you have perceived changes (either individually or collectively) since the publication of the Commission Communication, what kinds of changes have you perceived? Please elaborate. If you have perceived no changes, please state this. How does Mentor Medical feel about this outcome? (ie, with the EP resolution and subsequent EC Communication). Please elaborate. To which lines of action, if any, would you give different emphasis than that given in the Commission Communication? Why? Please elaborate. What, if any, difficulties is Mentor Medical experiencing in implementing the action lines of the Commission Communication? Any other documents/information/views on this issue from the past 2 years that you would like to provide us? PLEASE RETURN TO US PREFERABLY BY THE 20 TH OF FEBRUARY. Thank you very much for you time and assistance! 69

70

ANNEX 2: Other relevant information received through the interest groups This includes: PART 1: Additional information about the International Implant Registry (IBIR)., received through IPRAS PART 2: Answers to the questionnaire sent to self-help groups, completed by a doctor, Dr. Sarah Myhill, who has seen self-help group patients, 71

PART 1: Additional information about the International Implant Registry (IBIR), received through IPRAS We include two items here about the International Breast Implant Registry (IBIR). The first is the actual form that was originally established for the American Society of Plastic Surgery and extended to all members of the International Confederation of Plastic, Reconstructive and Aesthetic Surgery (EQUAM included). Currently, there are more than 10,000 patients in the database. (This was brought to our attention by Dr. Marita Eisenmann-Klein, representative of Europe on the Executive Committee of the International Confederation of Plastic, Reconstructive and Aesthetic Surgery (IPRAS) and Chairperson of the Quality Assurance Committee IPRAS). The second item is a questionnaire about the form, along with responses. When we asked Dr Eisenmann-Klein further questions about the IBIR, she referred us to Ms. Mary K. Lewis, Research Manager of the American Society of Plastic Surgeons/ Plastic Surgery Educational Foundation, who answered our questions. Below please find our questions about the International Breast Implant Registry (IBIR), with responses from Ms. Mary Lewis: 1. When was it developed? - IBIR was formally organized in Istanbul, Turkey in May 2002 under the direction of IPRAF. The first exploratory discussions were undertaken in early 2001 as there were several nations investigating development of national registries. The interest in development of registries arose from published issues and concerns from consumers and federal governments regarding either real or perceived health risks of silicone, specifically breast implants, in the human body, as well as local complications and frequency of re-operations. Interest in collaborating on an international registry was the result of many countries looking for and at the same data, and that there was an opportunity to compare findings as the majority of implants used throughout the world come from the same manufacturers. IBIR is currently in a pilot phase with the goal of understanding data collection issues and concerns in various countries. The pilot is utilizing an electronic format. This format includes collection of data on a paper worksheet during the physical assessment process, or as a chart abstraction worksheet, following which the data is entered into a web-based program. This allows for real-time aggregation of international data, while maintaining individual country confidentiality. Once the final program is built, it is proposed that IBIR would report aggregate international data, identify and prioritize an international research agenda regarding breast implants while it would provide country specific reports back to participants in that country. 2. What is the tools intent? - IBIR was formed to facilitate the collection and analysis of data (the Process) generated by patients who have undergone augmentation mammaplasty or breast reconstruction with all types of breast implants. The primary objective of this organization is the collection of relevant data regarding the utilization, design, surgical implantation, complications, long term outcomes and patient satisfaction. Analysis of this data will allow the application of the knowledge gained to the improvement of breast augmentation and reconstructive procedures. 3. How is it currently used in practice? - As IBIR is in a pilot phase, the data currently lacks enough scientific rigor to be of clinical benefit at this time. 72

4. Do you know its current coverage? - There currently are five countries participating in the pilot, Israel, Deutschland, Austria, Australia, Mexico and the USA. Other countries collaborating on this initiative include Denmark, Netherlands, United Kingdom, Spain (Dr. Ulrich Hinderer) and Brazil (I hope I didn't miss anyone) 5. How is the gathered information used? I think I may have answered this question above? If these answers raise additional thoughts or questions, please feel free to contact me again. We look forward to collaborating with you. 73

ver 72002 SHORT REQUIRED FIELDS INTERNATIONAL Red text BREAST IMPLANT REGISTRY (IBIR) PATIENT INFORMATION Last Six (6) Numbers of National ID Zip code - * Date of Birth / / DD/MM/YYYY Gender M F N/A SURGEON INFORMATION Assigned registry number (ARN) Speciality Code Last Four (4) Numbers of National ID Zip code - * SURGICAL FACILITY Zip code - * * Country Telephone Code IMPLANT ID RIGHT LOT or Serial No Nominal VOLUME cc Actual VOLUME cc MANUFACTURER McGhan Mentor Lab Sebbin Polytech/Silimed Pip/Rofil Nagor Arion LPI CVI Other LEFT LOT or Serial No Nominal VOLUME cc Actual VOLUME cc MANUFACTURER McGhan Mentor Lab Sebbin Polytech/Silimed Pip/Rofil Nagor Arion LPI CVI Other TYPE OF IMPLANT (check all that apply) Smooth Textured Double Lumen Adjustable Prosthesis Tissue Expander Other TYPE OF FILLER Saline Silicone Gel Cohesive Gel Hydrogel Polyurethane Other PRIMARY SURGERY SECTION 1:** IMPLANT OPERATION DETAILS DATE OF OPERATION / / DD/MM/YYYY INDICATIONS (choose one) RECONSTRUCTION AFTER: Mastectomy for Malignant Disease Prophylactic Mastectomy Cosmetic Augmentation / / MM/DD/YYYY of Mastectomy Replacement (if replacement, complete section 2) Mastectomy for Benign Disease / Prophylactic (including sub-cutaneous mastectomy) Congenital / Developmental TECHNIQUE Implant Only Implant & Flap Implant w/ Mastopexy POSITION OF IMPLANT Sub-mammary Sub-muscular Subcutaneous Other INCISION Axillary Inframammary Periaerolar Transumbilical Mastectomy scar Ancillary Drainage yes no. Antibiotics yes no. Betadine yes no. Post Op. massage yes no. SECONDARY SURGERY SECTION 2: EXPLANT OPERATION DETAILS (Information required if procedure is replacement or explantation only) DATE OF PRESENT OPERATION: / / DD/MM/YYYY DATE OF LAST IMPLANTATION: / / DD/MM/YYYY EXPLANTED BREAST IMPLANT INFORMATION (if known) RIGHT LOT or Serial No Nominal VOLUME cc Actual VOLUME cc MANUFACTURER McGhan Mentor Lab Sebbin Polytech/Silimed Pip/Rofil Nagor Arion LPI CVI Other TYPE OF IMPLANT (check all that apply) Smooth Textured Double Lumen Adjustable Prosthesis Tissue Expander Other TYPE OF FILLER Saline Silicone Gel Cohesive Gel Hydrogel Polyurethane Other LEFT LOT or Serial No Nominal VOLUME cc Actual VOLUME cc MANUFACTURER McGhan Mentor Lab Sebbin Polytech/Silimed Pip/Rofil Nagor Arion LPI CVI Other TYPE OF IMPLANT (check all that apply) Smooth Textured Double Lumen Adjustable Prosthesis Tissue Expander Other TYPE OF FILLER Saline Silicone Gel Cohesive Gel Hydrogel Polyurethane Other INDICATION FOR EXPLANTATION (check all that apply) ** Rupture Capsular Contracture Stage I II III IV. Infection Implant Shifted Position Change (above or below muscle Malignancy (answer both 1 & 2) 1. Diagnostic Tool Used to Identify Presence of Mass Mammography Ultrasound MRI Physical Exam 2. Stage of disease on diagnosis I II III IV. Hematoma Exposure of implant In relation to general health Patient wish Change ofvolume Change of Implant Shape Patient Request (other than change in implant size) Other Intra-op findings: Intact Ruptured Gel intra capsualr Gel extra capsular Cell bleeding calcification Other **Sections 1&2 should separately apply to Rt. And Lt. breasts 74

PART 2: Answers to the questionnaire sent to self-help groups, completed by a doctor who has seen self-help group patients, Dr. Sarah Myhill 1) Do you think that the lines of action published in the Commission Communication have produced a change regarding the protection of women undergoing or considering undergoing this kind of surgery? Please elaborate. If you perceive no change, please state. Answer: No. Women continue to have breast implants without proper informed consent. 2) If you have perceived changes, either individually or collectively, since the publication of the Commission Communication, what kinds of changes have you perceived? Please elaborate. If you have perceived no changes, please state this. Answer: No. I am not aware that plastic surgeons have changed their attitudes at all. 3) Is the self-help group satisfied with this outcome? (ie, with the EP resolution and subsequent EC Communication). Please elaborate. Answer: No. The self-help groups with which I have been involved are not in the least bit satisfied with outcomes to date. 4) To which lines of action, if any, would you give additional or different emphasis than that given in the Commission Communication? Why? Please elaborate. Answer: There is a clear need for a proper consent from which all women should sign before they receive their implants. I am very happy to word such a consent form should it be required. 5) Any other information/views/documents on this issue from the past 2 years that you would like to provide us? Answer: There is a clear need for a body that will accept information from women who have had long term effects from silicone breast implants, follow up these women and document it so that it can become generally available. 75